Mitochondrial uncouplers for the treatment of metabolic diseases and cancer

Abstract

SOLUTION: The present application discloses a unique class of mitochondrial uncoupling compounds, similar to conventional mitochondrial uncoupling compounds, with dramatically improved pharmacokinetic properties, pharmaceutical compositions containing the compounds and / or prodrugs, and methods of using the compounds, prodrugs, and pharmaceutical compositions in the treatment of diseases associated with mitochondrial dysfunction or that would benefit from modulation of mitochondrial activity, including diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), mitochondrial genetic diseases, neurodegenerative diseases, cancer, autoimmune diseases, and infectious diseases.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 374,927, filed September 8, 2022, which is incorporated herein by reference in its entirety. Summary of the Invention

[0002] The present disclosure relates to novel mitochondrial uncoupling compounds that preserve mitochondrial membrane potential, as well as novel mitochondrial uncoupling compounds with unexpectedly improved pharmacokinetic properties. Various embodiments described herein provide benzamide compounds, prodrugs of the compounds, pharmaceutical compositions containing the compounds and / or prodrugs, and methods of using the compounds, prodrugs, and pharmaceutical compositions in the treatment of metabolic disorders, including diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cancer, autoimmune disorders, dyslipidemia, and infectious diseases.

[0003] Some embodiments of the present disclosure provide a compound of formula A,

[0004] [ka] In the formula, R in formula A 1000a but, -CH3, -CH2CH3, -C1 to C6 alkyl, -C3 to C6 cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0005] [ka] -(CH2) r’ NR 5000A R 5000B , -(CH2) r R 6000 and C(O)N(CH2CH2OCH3)2; Substituent R 5000A and R 5000B are each independently selected from the group consisting of —C1-C6 alkyl and —C1-C6 alkyl substituted with one or more groups selected from —C1-C6 alkoxy and —O(CH2)2OCH3, or 5000A and R 5000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl; R 6000 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; r' is an integer selected from the group consisting of 1, 2, and 3; r is an integer selected from the group consisting of 0, 1, 2, and 3; R in Formula I 1000c is selected from the group consisting of chloro, fluoro, iodo, and bromo; R 4000b and R 4000d Each of the 1000 and Z 1000 independently selected from the group consisting of: 4000b Y 1000 If R 4000d is Z 1000 and R 4000b Z 1000 If R 4000d is Y 1000 and Y 1000is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z 1000 is, H, -CH2OCH3, -CH2OCH2CH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2000A R 2000B , -(CH2) s R 3000 , -CH2OCH2Ar 1 , OCH3CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) t’ NR 7000A R 7000B , and -(CH2) t R 8000 is selected from the group consisting of R 2000A and R 2000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups; R 3000 is a 5- to 6-membered heterocyclic ring, Ar 1 is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halo, hydroxyl and alkoxy; R 7000A and R 7000B are each independently selected from C1-C6 alkyl, or R 7000A and R 7000B together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 8000is selected from the group consisting of a 5- to 6-membered heterocycle optionally substituted with methyl; s is an integer selected from the group consisting of 0, 1, 2, and 3; t' is an integer selected from the group consisting of 1, 2, and 3; t is an integer selected from the group consisting of 0, 1, 2, and 3; however, R 5000A and R 5000B However, both are not C1-C6 alkyl, Z 1000 If is H, then R 1000a is directed to a compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, that is not C1-C6 alkyl, —C3-C6 cycloalkyl, CH3, or CH2CH3.

[0006] Some embodiments of the present disclosure are compounds of formula I,

[0007] [ka] During the ceremony, R 1a -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0008] [ka] -(CH2) m’ NR 5A R 5B , (CH2) m R 6 and C(O)N(CH2CH2OCH3)2; R 5A and R 5Beach independently represents -C1-C6 alkyl, and -C1-C6 alkoxy, and -C1-C6 alkyl substituted with one or more groups selected from -O(CH2)2OCH3; or 5A and R 5B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl; R 6 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; m' is an integer selected from the group consisting of 1, 2, and 3; m is an integer selected from the group consisting of 0, 1, 2, and 3; R 1c is selected from the group consisting of chloro, fluoro, iodo, and bromo; R 4b and R 4d are each independently selected from the group consisting of Y and Z, with the proviso that R 4b If Y, then R 4d is Z and R 4b If Z, then R 4d is Y, Y is chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z is -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B, -(CH2) n R 3 , —CH2OCH2Ar, and —OCH3; R 2A and R 2B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups; R 3 is selected from the group consisting of a 5- to 6-membered heterocycle and phenoxy; n is an integer selected from the group consisting of 0, 1, 2, and 3; The present invention relates to compounds, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ar is a 5- to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of -C1-C6 alkyl, halo, hydroxy, and alkoxy.

[0009] Some embodiments of the present disclosure are compounds of formula II,

[0010] [ka] During the ceremony, R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0011] [ka] -(CH2) o’ NR 50A R 50B , -(CH2) o R 60 and C(O)N(CH2CH2OCH3)2; R 50A and R 50Beach independently represents -C1-C6 alkyl, and -C1-C6 alkoxy, and -C1-C6 alkyl substituted with one or more groups selected from -O(CH2)2OCH3; or 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl; R 60 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; o' is an integer selected from the group consisting of 1, 2, and 3; o is an integer selected from the group consisting of 0, 1, 2 and 3; R 10c is selected from the group consisting of chloro, fluoro, iodo, and bromo; R 40b and R 40d One of the groups is H and the other is R 40b and R 40d the other is selected from the group consisting of chloro, fluoro, iodo, bromo, —CF3, —CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, —OCF3, —SO2(C1-C6)alkyl, cyano, and —CO2(C1-C6)alkyl; However, R 50A and R 50B but both are not C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0012] Some embodiments of the present disclosure provide a compound of formula III,

[0013] [ka] During the ceremony, R 100aBut -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0014] [ka] -(CH2) p’ NR 500A R 500B , -(CH2) p R 600 and C(O)N(CH2CH2OCH3)2; R 500A and R 500B Each of the -C1-C6 alkyl, and -C1-C6 alkyl substituted with one or more groups selected from -C1-C6 alkoxy, and -O(CH2)2OCH3, or R 500A and R 500B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl; R 600 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; p' is an integer selected from the group consisting of 1, 2, and 3; p is an integer selected from the group consisting of 0, 1, 2, and 3; R 100c is selected from the group consisting of chloro, fluoro, iodo, and bromo; R 400b and R 400d Each of the 1 and Z 1 independently selected from the group consisting of: 400b Y1 If R 400d is Z 1 and R 400b Z 1 If R 400d is Y 1 and Y 1 But chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z 1 But -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) q’ NR 7A R 7B , and -(CH2) q R 8 is selected from the group consisting of R 7A and R 7B are each independently selected from C1-C6 alkyl, or R 7A and R 7B together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more independently selected C1-C6 alkyl; R 8 is selected from the group consisting of a 5- to 6-membered heterocycle optionally substituted with methyl; q' is an integer selected from the group consisting of 1, 2, and 3; a compound wherein q is an integer selected from the group consisting of 0, 1, 2 and 3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0015] Embodiments herein describe pharmaceutical compositions comprising a compound according to any embodiment described herein, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

[0016] Some embodiments describe methods of treating a mitochondrial-associated condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the mitochondrial-associated condition or disorder has one or more underlying causative factors or symptoms selected from the group consisting of hyperglycemia, abnormal accumulation of lipids in cells, abnormal accumulation of lipids in tissues, abnormal lipid metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis. In some embodiments, the mitochondrial-associated condition or disorder is selected from the group consisting of a metabolic disease, cancer, an autoimmune disease, pulmonary fibrosis, a skin disorder, an infectious disease, and a neurodegenerative disease.

[0017] In some embodiments, the mitochondrial-related condition or disorder is a metabolic disease selected from the group consisting of type 2 diabetes, diseases characterized by insulin resistance or hyperglycemia, obesity or obesity-related complications, and diseases characterized by abnormal lipid accumulation. In some embodiments, the metabolic disease is a complication caused by type 2 diabetes selected from the group consisting of diabetes-induced cardiovascular disease, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart disease, nephropathy, retinopathy, neuropathy, and diabetic heart failure. In some embodiments, the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD), and at least one prognostic stage of the disease is selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and NAFLD-induced hepatocellular carcinoma (HCC). In some embodiments, the metabolic disease or disorder is alcoholic fatty liver disease or one or more complications caused by alcoholic fatty liver disease, and the one or more complications caused by alcoholic fatty liver disease are selected from the group consisting of alcoholic hepatitis, cirrhosis, and combinations thereof. In some embodiments, the metabolic disease or disorder is dyslipidemia or one or more complications caused by dyslipidemia. In some embodiments, the pharmaceutical composition is administered in combination with a second drug indicated for a metabolic disease. In some embodiments, the second drug is an antidiabetic drug selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors. In some embodiments, the second drug is selected from the group consisting of anti-obesity agents, anti-non-alcoholic fatty liver disease agents, anti-non-alcoholic fatty liver disease agents, and anti-dyslipidemia agents.

[0018] In some embodiments, the mitochondrial-related condition or disorder is a primary cancer selected from the group consisting of hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer. In some embodiments, the cancer is a metastatic cancer derived from a primary tumor of another tissue type. In some embodiments, the pharmaceutical composition is administered in combination with a second anti-cancer agent or anti-cancer regimen. In some embodiments, the second anti-cancer agent is a cancer immunotherapy agent. In some embodiments, the cancer immunotherapy agent is selected from the group consisting of antibodies against PD-1 / PD-L1, antibodies against other immune checkpoint proteins, CAR-T cells, and other therapeutic immune cells.

[0019] In some embodiments, the mitochondrial-related condition or disorder is a skin disorder selected from eczema, dyshidrotic eczema, seborrheic eczema, psoriasis, rosacea, dermatitis, and atopic dermatitis.

[0020] In some embodiments, the mitochondrial-related condition or disorder is an infectious disease. In some embodiments, the infectious disease is a bacterial infection. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is selected from a SARS-CoV-2 infection, a coronavirus infection, and an Ebola virus infection.

[0021] Some embodiments describe methods of treating a metabolic disease or disorder characterized by hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues, or a disease or disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues is a symptom, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0022] Some embodiments describe a method of treating cancer or hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0023] Some embodiments describe a method of treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0024] Some embodiments describe a method of treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0025] Some embodiments describe a method of treating or preventing a skin disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0026] Some embodiments describe a method of treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0027] Some embodiments describe a method of treating or preventing a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0028] Some embodiments describe a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0029] Some embodiments herein describe methods wherein the subject is a mammal or a human. In some embodiments, the subject is a human.

[0030] Some embodiments herein describe methods in which the pharmaceutical composition is administered orally, intravenously, subcutaneously, intramuscularly, transdermally, intraperitoneally, or by other pharmacologically acceptable routes.

[0031] Some embodiments describe methods for long-term disease management of a metabolic disease or disorder or for long-term disease management of cancer, comprising administering to a subject in need of such long-term management an effective amount of a compound or pharmaceutical composition described herein.

[0032] Some embodiments describe the use of a compound described herein in the manufacture of a medicament for the treatment of a metabolic disease or disorder. In some embodiments, the metabolic disease or disorder can be selected from diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, hyperglycemia or insulin resistance, or a disease in which abnormal accumulation of lipids in tissues is a symptom, or an associated disorder or complication.

[0033] Some embodiments provide a method for preparing a mitochondrial membrane potential (MMP)-preserving mitochondrial uncoupling agent, comprising: 1. Identifying conventional mitochondrial uncouplers; 2. Designing a compound that covalently attaches at least one secondary or tertiary amino moiety to a conventional mitochondrial uncoupler; 3. preparing a compound of Step 2, wherein the compound is a mitochondrial membrane-retaining uncoupler compound.

[0034] Some embodiments are of the formula: (R A ) u -R Bmitochondrial membrane-retaining uncoupler compounds, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, In the formula, R A and R B are covalently bonded, Each R A is independently a secondary or tertiary amine-containing moiety; u is an integer selected from the group consisting of 1 and 2; R B But R A a conventional mitochondrial uncoupler prior to covalent binding to However, mitochondrial membrane-retaining uncoupler compounds

[0035] [ka] isn't it. [Brief explanation of the drawings]

[0036] [Figure 1] A schematic diagram showing the role of mitochondrial function and dysfunction in various diseases, including obesity, T2D (type 2 diabetes), NASH (non-alcoholic steatohepatitis), viral infections, cancer, cancer immunosuppression (cancer ME, cancer microenvironment), and neurodegenerative diseases is shown. Mitochondrial uncoupling helps eliminate the causative factors of these diseases by reducing metabolic output of metabolites and ROS. [Figure 2A] The oxygen consumption rate (OCR) over time is shown for two representative compounds: Compound 16 (Figure 2A) and Compound 69 (Figure 2B). Oligo stands for oligomycin, Compound A stands for Compound 16, Compound B stands for Compound 69, and Rot / AA stands for rotenone / antimycin. Assays were performed using a Seahorse XF-24 instrument. Compounds were injected into the assay medium in the order shown: 2.5 μM oligomycin, 1.0 μM each of Compound A and Compound B, 2.0 μM rotenone, and 2.0 μM antimycin A. [Figure 2B] The oxygen consumption rate (OCR) over time is shown for two representative compounds: Compound 16 (Figure 2A) and Compound 69 (Figure 2B). Oligo stands for oligomycin, Compound A stands for Compound 16, Compound B stands for Compound 69, and Rot / AA stands for rotenone / antimycin. Assays were performed using a Seahorse XF-24 instrument. Compounds were injected into the assay medium in the order shown: 2.5 μM oligomycin, 1.0 μM each of Compound A and Compound B, 2.0 μM rotenone, and 2.0 μM antimycin A. [Figure 3] This figure shows the molecular mechanism of conventional mitochondrial uncoupling. Dissipation of mitochondrial membrane potential is an inherent characteristic of conventional mitochondrial uncoupling agents. The mitochondrial outer membrane, inner membrane, electron transport complexes I-IV, ATP synthase, chemical uncouplers (U-, UH), and mitochondrial matrix are depicted. Conventional uncouplers are weakly lipophilic weak acids localized in the inner mitochondrial membrane (deprotonated form U- and protonated form UH). U- binds protons (protonation) on the outside of the inner mitochondrial membrane and releases them into the mitochondrial matrix (deprotonation). As a result, mitochondrial uncouplers catalyze proton transfer across the inner membrane without ATP synthesis, resulting in the "futile" oxidation of acetyl-CoA (the end product of lipid oxidation and glucose metabolism). Because MMP is established by a proton gradient across the inner mitochondrial membrane, conventional mitochondrial uncoupling is accompanied by concomitant MMP dissipation. [Figure 4A]The effects of trifluoromethoxycarbonylcyanide phenylhydrazone (FCCP), a representative conventional mitochondrial uncoupler, on oxygen consumption rate and mitochondrial membrane potential are shown in Figure 4A. FCCP simultaneously increases oxygen consumption rate (Figure 4A) and dissipates mitochondrial membrane potential (Figure 4B). Figure 4A shows the cellular oxygen consumption rate (OCR) determined by the Seahorse OCR assay using C2C12 cells. In Figure 4A, diamonds represent DMSO (vehicle-treated control), triangles represent 3.0 μM FCCP, squares represent 6.0 μM FCCP, crosses represent 12.0 μM FCCP, * represents 18.0 μM FCCP, and circles represent 24 μM FCCP. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 4B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining, respectively, in the presence of the indicated concentrations of FCCP. Fluorescence intensity indicates MMP. FCCP had a C10%TMRE / Cmin-OCR ratio of less than 3, where C10%TMRE is the concentration resulting in 10% MMP retention (or 90% MMP loss as measured by TMRE staining), and Cmin-OCR is the minimum concentration resulting in an OCR increase. [Figure 4B]The effects of trifluoromethoxycarbonylcyanide phenylhydrazone (FCCP), a representative conventional mitochondrial uncoupler, on oxygen consumption rate and mitochondrial membrane potential are shown in Figure 4A. FCCP simultaneously increases oxygen consumption rate (Figure 4A) and dissipates mitochondrial membrane potential (Figure 4B). Figure 4A shows the cellular oxygen consumption rate (OCR) determined by the Seahorse OCR assay using C2C12 cells. In Figure 4A, diamonds represent DMSO (vehicle-treated control), triangles represent 3.0 μM FCCP, squares represent 6.0 μM FCCP, crosses represent 12.0 μM FCCP, * represents 18.0 μM FCCP, and circles represent 24 μM FCCP. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 4B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining, respectively, in the presence of the indicated concentrations of FCCP. Fluorescence intensity indicates MMP. FCCP had a C10%TMRE / Cmin-OCR ratio of less than 3, where C10%TMRE is the concentration resulting in 10% MMP retention (or 90% MMP loss as measured by TMRE staining), and Cmin-OCR is the minimum concentration resulting in an OCR increase. [Figure 5A]Figure 5A shows the effects of Compound 25 (#25), a representative MMP-retaining mitochondrial uncoupler, on oxygen consumption rate and mitochondrial membrane potential. Compound 25 effectively uncouples mitochondria (inducing OCR, Figure 5A) without reducing MMP (Figure 5B). Figure 5A shows cellular oxygen consumption rate determined by a Seahorse OCR assay using C2C12 cells. In Figure 5A, diamonds represent vehicle-treated controls, squares represent 1.0 μM Compound 25 (#25), triangles represent 3.0 μM Compound 25, crosses represent 6.0 μM Compound 25, * represents 9.0 μM Compound 25, and circles represent 12.0 μM Compound 25. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 5B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) and DilC1(5), respectively, in the presence of the indicated concentrations of Compound 25 (#25). Fluorescence intensity indicates MMP. Compound 25 represents an MMP-sparing uncoupler that does not cause observable MMP reduction while uncoupling mitochondria (ratio of C10%TMRE / Cmin-OCR greater than 25). [Figure 5B]Figure 5A shows the effects of Compound 25 (#25), a representative MMP-retaining mitochondrial uncoupler, on oxygen consumption rate and mitochondrial membrane potential. Compound 25 effectively uncouples mitochondria (inducing OCR, Figure 5A) without reducing MMP (Figure 5B). Figure 5A shows cellular oxygen consumption rate determined by a Seahorse OCR assay using C2C12 cells. In Figure 5A, diamonds represent vehicle-treated controls, squares represent 1.0 μM Compound 25 (#25), triangles represent 3.0 μM Compound 25, crosses represent 6.0 μM Compound 25, * represents 9.0 μM Compound 25, and circles represent 12.0 μM Compound 25. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 5B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) and DilC1(5), respectively, in the presence of the indicated concentrations of Compound 25 (#25). Fluorescence intensity indicates MMP. Compound 25 represents an MMP-sparing uncoupler that does not cause observable MMP reduction while uncoupling mitochondria (ratio of C10%TMRE / Cmin-OCR greater than 25). [Figure 6A]The effects of compound 64 (#64) on oxygen consumption rate (Figure 6A) and mitochondrial membrane potential (Figure 6B) are shown. Compound 64 increases OCR without dramatically diminishing mitochondrial membrane potential. Figure 6A shows cellular oxygen consumption rates determined by a Seahorse OCR assay using C2C12 cells at the indicated concentrations. Diamonds in Figure 6A represent vehicle-treated controls, squares represent 0.3 μM compound 64 (#64), triangles represent 1.0 μM compound 64, crosses represent 2.0 μM compound 64, * represents 3.0 μM compound 64, and circles represent 4.0 μM compound 64. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 6B shows the mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining, respectively, in the presence of the indicated concentrations of compound 64 (#64). Fluorescence intensity indicates MMP. Compound 64 represents an MMP-preserving uncoupler that does not dramatically reduce MMP while uncoupling mitochondria (the ratio of C10%TMRE / Cmin-OCR is 10-25). [Figure 6B]The effects of compound 64 (#64) on oxygen consumption rate (Figure 6A) and mitochondrial membrane potential (Figure 6B) are shown. Compound 64 increases OCR without dramatically diminishing mitochondrial membrane potential. Figure 6A shows cellular oxygen consumption rates determined by a Seahorse OCR assay using C2C12 cells at the indicated concentrations. Diamonds in Figure 6A represent vehicle-treated controls, squares represent 0.3 μM compound 64 (#64), triangles represent 1.0 μM compound 64, crosses represent 2.0 μM compound 64, * represents 3.0 μM compound 64, and circles represent 4.0 μM compound 64. Oligo is oligomycin 2.5 μM, AA is antimycin A 2 μM, and Rot is rotenone 2 μM. Figure 6B shows the mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining, respectively, in the presence of the indicated concentrations of compound 64 (#64). Fluorescence intensity indicates MMP. Compound 64 represents an MMP-preserving uncoupler that does not dramatically reduce MMP while uncoupling mitochondria (the ratio of C10%TMRE / Cmin-OCR is 10-25). [Figure 7A]Figure 7A shows a schematic of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and the proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B). Figures 7C-7E also show diagrams and examples of methods for converting a conventional uncoupler to an MMP-retaining uncoupler. Figures 7A and 7B show mitochondrial electron transport chain complexes I, II, III, and IV, ATP synthase, and the uncoupler (UH or U-). The conventional uncoupler allows proton transfer across the inner mitochondrial membrane, resulting in the loss of MMP (Figure 7A). The presence of positively charged side chains and the asymmetric distribution of the MMP-retaining uncoupler creates an electrochemical gradient that compensates for the loss of MMP due to proton transfer (Figure 7B). Figures 7C and 7D show a general approach for generating new MMP-retained uncouplers by adding positively charged side chains to a conventional uncoupler (Figure 7C), e.g., by adding tertiary amine (or secondary amine)-containing side chains to yield an MMP-retained uncoupler (Figure 7D), where N is nitrogen and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP-retained uncoupler, showing the conventional uncoupling components in frame. [Figure 7B]Figure 7A shows a schematic of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and the proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B). Figures 7C-7E also show diagrams and examples of methods for converting a conventional uncoupler to an MMP-retaining uncoupler. Figures 7A and 7B show mitochondrial electron transport chain complexes I, II, III, and IV, ATP synthase, and the uncoupler (UH or U-). The conventional uncoupler allows proton transfer across the inner mitochondrial membrane, resulting in the loss of MMP (Figure 7A). The presence of positively charged side chains and the asymmetric distribution of the MMP-retaining uncoupler creates an electrochemical gradient that compensates for the loss of MMP due to proton transfer (Figure 7B). Figures 7C and 7D show a general approach for generating new MMP-retained uncouplers by adding positively charged side chains to a conventional uncoupler (Figure 7C), e.g., by adding tertiary amine (or secondary amine)-containing side chains to yield an MMP-retained uncoupler (Figure 7D), where N is nitrogen and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP-retained uncoupler, showing the conventional uncoupling components in frame. [Figure 7C]Figure 7A shows a schematic of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and the proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B). Figures 7C-7E also show diagrams and examples of methods for converting a conventional uncoupler to an MMP-retaining uncoupler. Figures 7A and 7B show mitochondrial electron transport chain complexes I, II, III, and IV, ATP synthase, and the uncoupler (UH or U-). The conventional uncoupler allows proton transfer across the inner mitochondrial membrane, resulting in the loss of MMP (Figure 7A). The presence of positively charged side chains and the asymmetric distribution of the MMP-retaining uncoupler creates an electrochemical gradient that compensates for the loss of MMP due to proton transfer (Figure 7B). Figures 7C and 7D show a general approach for generating new MMP-retained uncouplers by adding positively charged side chains to a conventional uncoupler (Figure 7C), e.g., by adding tertiary amine (or secondary amine)-containing side chains to yield an MMP-retained uncoupler (Figure 7D), where N is nitrogen and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP-retained uncoupler, showing the conventional uncoupling components in frame. [Figure 7D]Figure 7A shows a schematic of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and the proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B). Figures 7C-7E also show diagrams and examples of methods for converting a conventional uncoupler to an MMP-retaining uncoupler. Figures 7A and 7B show mitochondrial electron transport chain complexes I, II, III, and IV, ATP synthase, and the uncoupler (UH or U-). The conventional uncoupler allows proton transfer across the inner mitochondrial membrane, resulting in the loss of MMP (Figure 7A). The presence of positively charged side chains and the asymmetric distribution of the MMP-retaining uncoupler creates an electrochemical gradient that compensates for the loss of MMP due to proton transfer (Figure 7B). Figures 7C and 7D show a general approach for generating new MMP-retained uncouplers by adding positively charged side chains to a conventional uncoupler (Figure 7C), e.g., by adding tertiary amine (or secondary amine)-containing side chains to yield an MMP-retained uncoupler (Figure 7D), where N is nitrogen and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP-retained uncoupler, showing the conventional uncoupling components in frame. [Figure 7E]Figure 7A shows a schematic of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and the proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B). Figures 7C-7E also show diagrams and examples of methods for converting a conventional uncoupler to an MMP-retaining uncoupler. Figures 7A and 7B show mitochondrial electron transport chain complexes I, II, III, and IV, ATP synthase, and the uncoupler (UH or U-). The conventional uncoupler allows proton transfer across the inner mitochondrial membrane, resulting in the loss of MMP (Figure 7A). The presence of positively charged side chains and the asymmetric distribution of the MMP-retaining uncoupler creates an electrochemical gradient that compensates for the loss of MMP due to proton transfer (Figure 7B). Figures 7C and 7D show a general approach for generating new MMP-retained uncouplers by adding positively charged side chains to a conventional uncoupler (Figure 7C), e.g., by adding tertiary amine (or secondary amine)-containing side chains to yield an MMP-retained uncoupler (Figure 7D), where N is nitrogen and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP-retained uncoupler, showing the conventional uncoupling components in frame. [Figure 8A]Figure 8A shows the acute lethal dose (acute LD50 or LD50) and minimum effective dose (MED) for the conventional uncoupler DNP (US EPA, 2,4-dinitrophenol; https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, Figure 8A) and the MMP-retaining uncouplers, compound 64 (#64, Figure 8B) and compound 25 (#25, Figure 8C). Compounds 64 and 25 exhibit dramatically improved acute toxicity profiles over DNP. Acute toxicity studies were performed in C57B16 mice (male, 6 weeks old, n = 6). Compounds 64 and 25 were prepared as fine suspensions in 0.5% CMC-Na / 1% Tween 80 aqueous solution. Tests were performed under fed conditions by oral gavage of 100–400 μL of compound suspension depending on body weight to the desired dose (mg / kg). Drinking water was provided to mice throughout the test period. Mice behavior was monitored every 15–30 min, and the LD50 was determined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 8B]Figure 8A shows the acute lethal dose (acute LD50 or LD50) and minimum effective dose (MED) for the conventional uncoupler DNP (US EPA, 2,4-dinitrophenol; https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, Figure 8A) and the MMP-retaining uncouplers, compound 64 (#64, Figure 8B) and compound 25 (#25, Figure 8C). Compounds 64 and 25 exhibit dramatically improved acute toxicity profiles over DNP. Acute toxicity studies were performed in C57B16 mice (male, 6 weeks old, n = 6). Compounds 64 and 25 were prepared as fine suspensions in 0.5% CMC-Na / 1% Tween 80 aqueous solution. Tests were performed under fed conditions by oral gavage of 100–400 μL of compound suspension depending on body weight to the desired dose (mg / kg). Drinking water was provided to mice throughout the test period. Mice behavior was monitored every 15–30 min, and the LD50 was determined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 8C]Figure 8A shows the acute lethal dose (acute LD50 or LD50) and minimum effective dose (MED) for the conventional uncoupler DNP (US EPA, 2,4-dinitrophenol; https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, Figure 8A) and the MMP-retaining uncouplers, compound 64 (#64, Figure 8B) and compound 25 (#25, Figure 8C). Compounds 64 and 25 exhibit dramatically improved acute toxicity profiles over DNP. Acute toxicity studies were performed in C57B16 mice (male, 6 weeks old, n = 6). Compounds 64 and 25 were prepared as fine suspensions in 0.5% CMC-Na / 1% Tween 80 aqueous solution. Tests were performed under fed conditions by oral gavage of 100–400 μL of compound suspension depending on body weight to the desired dose (mg / kg). Drinking water was provided to mice throughout the test period. Mice behavior was monitored every 15–30 min, and the LD50 was determined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 9A]The safety profile of compound 64 (#64) compared to DNP is shown. Figure 9A shows the NOAEL (no-observable-adverse-effect-level) / MED of DNP (https: / / www.atsdr.cdc.gov / ToxProfiles / tp64.pdf, US EPA, 2,4-dinitrophenol (https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, and US CDC). Figure 9B shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by oral dose. Figure 9C shows the MED, median NOAEL, and NOAEL / MED of compound 64 relative to DNP calculated by Cmax (maximum blood concentration). Figure 9D shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by AUC (area under the curve). These figures demonstrate that compound 64, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 64, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food consumption, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 9B]The safety profile of compound 64 (#64) compared to DNP is shown. Figure 9A shows the NOAEL (no-observable-adverse-effect-level) / MED of DNP (https: / / www.atsdr.cdc.gov / ToxProfiles / tp64.pdf, US EPA, 2,4-dinitrophenol (https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, and US CDC). Figure 9B shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by oral dose. Figure 9C shows the MED, median NOAEL, and NOAEL / MED of compound 64 relative to DNP calculated by Cmax (maximum blood concentration). Figure 9D shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by AUC (area under the curve). These figures demonstrate that compound 64, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 64, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food consumption, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 9C]The safety profile of compound 64 (#64) compared to DNP is shown. Figure 9A shows the NOAEL (no-observable-adverse-effect-level) / MED of DNP (https: / / www.atsdr.cdc.gov / ToxProfiles / tp64.pdf, US EPA, 2,4-dinitrophenol (https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, and US CDC). Figure 9B shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by oral dose. Figure 9C shows the MED, median NOAEL, and NOAEL / MED of compound 64 relative to DNP calculated by Cmax (maximum blood concentration). Figure 9D shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by AUC (area under the curve). These figures demonstrate that compound 64, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 64, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food consumption, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 9D]The safety profile of compound 64 (#64) compared to DNP is shown. Figure 9A shows the NOAEL (no-observable-adverse-effect-level) / MED of DNP (https: / / www.atsdr.cdc.gov / ToxProfiles / tp64.pdf, US EPA, 2,4-dinitrophenol (https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, and US CDC). Figure 9B shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by oral dose. Figure 9C shows the MED, median NOAEL, and NOAEL / MED of compound 64 relative to DNP calculated by Cmax (maximum blood concentration). Figure 9D shows the MED, median NOAEL, and NOAEL / MED of compound 64 calculated by AUC (area under the curve). These figures demonstrate that compound 64, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 64, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food consumption, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 10A]The safety profile of compound 25 (#25) is shown in Figure 10A. Figure 10A shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by oral dose. Figure 10B shows the MED, median NOAEL, and NOAEL / MED of compound 25 relative to DNP calculated by Cmax (maximum blood concentration). Figure 10C shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by AUC (area under the curve). These figures demonstrate that compound 25, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 25, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food intake, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 10B] The safety profile of compound 25 (#25) is shown in Figure 10A. Figure 10A shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by oral dose. Figure 10B shows the MED, median NOAEL, and NOAEL / MED of compound 25 relative to DNP calculated by Cmax (maximum blood concentration). Figure 10C shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by AUC (area under the curve). These figures demonstrate that compound 25, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 25, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food intake, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 10C]The safety profile of compound 25 (#25) is shown in Figure 10A. Figure 10A shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by oral dose. Figure 10B shows the MED, median NOAEL, and NOAEL / MED of compound 25 relative to DNP calculated by Cmax (maximum blood concentration). Figure 10C shows the MED, median NOAEL, and NOAEL / MED of compound 25 calculated by AUC (area under the curve). These figures demonstrate that compound 25, an MMP-retaining uncoupler, exhibits a significantly improved short-term safety profile compared with the conventional uncoupler DNP. To determine the NOAEL of compound 25, a 10-day toxicity study was conducted in CD-1 mice, in which animals (n = 5) were dosed once daily for 10 consecutive days. Clinical signs, body weight, food intake, rectal temperature, hematology, serum chemistry, plasma exposure, necropsy, and tissue histopathology were examined. The MED was determined in diabetic and steatotic mouse models (Table 9). [Figure 11A] Figure 11 shows the efficacy of Compound 25 (#25) and Compound 64 (#64) in reducing blood glucose and glycated hemoglobin A1C in a db / db diabetic mouse model. Figure 11A shows a graph of blood glucose levels in vehicle-treated mice and Compound 25-treated mice. Figure 11B shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 25-treated mice. Figure 11C shows a graph of blood glucose levels in vehicle-treated mice and Compound 64-treated mice. Figure 11D shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 64-treated mice. BKSdb / db mice were treated with or without 5 mg / kg of Compound 25 or Compound 64 by daily oral gavage for 3 weeks. Blood glucose and glycated hemoglobin A1C levels were measured. Statistical significance (P) was determined by Student's t-test. All error bars are sd, ***p<0.001. n=6 in each group. Vehicle, vehicle-treated control group. [Figure 11B]Figure 11 shows the efficacy of Compound 25 (#25) and Compound 64 (#64) in reducing blood glucose and glycated hemoglobin A1C in a db / db diabetic mouse model. Figure 11A shows a graph of blood glucose levels in vehicle-treated mice and Compound 25-treated mice. Figure 11B shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 25-treated mice. Figure 11C shows a graph of blood glucose levels in vehicle-treated mice and Compound 64-treated mice. Figure 11D shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 64-treated mice. BKSdb / db mice were treated with or without 5 mg / kg of Compound 25 or Compound 64 by daily oral gavage for 3 weeks. Blood glucose and glycated hemoglobin A1C levels were measured. Statistical significance (P) was determined by Student's t-test. All error bars are sd, ***p<0.001. n=6 in each group. Vehicle, vehicle-treated control group. [Figure 11C] Figure 11 shows the efficacy of Compound 25 (#25) and Compound 64 (#64) in reducing blood glucose and glycated hemoglobin A1C in a db / db diabetic mouse model. Figure 11A shows a graph of blood glucose levels in vehicle-treated mice and Compound 25-treated mice. Figure 11B shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 25-treated mice. Figure 11C shows a graph of blood glucose levels in vehicle-treated mice and Compound 64-treated mice. Figure 11D shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 64-treated mice. BKSdb / db mice were treated with or without 5 mg / kg of Compound 25 or Compound 64 by daily oral gavage for 3 weeks. Blood glucose and glycated hemoglobin A1C levels were measured. Statistical significance (P) was determined by Student's t-test. All error bars are sd, ***p<0.001. n=6 in each group. Vehicle, vehicle-treated control group. [Figure 11D]Figure 11 shows the efficacy of Compound 25 (#25) and Compound 64 (#64) in reducing blood glucose and glycated hemoglobin A1C in a db / db diabetic mouse model. Figure 11A shows a graph of blood glucose levels in vehicle-treated mice and Compound 25-treated mice. Figure 11B shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 25-treated mice. Figure 11C shows a graph of blood glucose levels in vehicle-treated mice and Compound 64-treated mice. Figure 11D shows a graph of glycated hemoglobin A1C in vehicle-treated mice and Compound 64-treated mice. BKSdb / db mice were treated with or without 5 mg / kg of Compound 25 or Compound 64 by daily oral gavage for 3 weeks. Blood glucose and glycated hemoglobin A1C levels were measured. Statistical significance (P) was determined by Student's t-test. All error bars are sd, ***p<0.001. n=6 in each group. Vehicle, vehicle-treated control group. [Figure 12A] Figure 12 shows the effects of Compound 25 on body weight (Figure 12A), blood glucose (Figure 12B), liver weight (Figure 12C), and plasma insulin levels (Figure 12D) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p<0.05, ***p<0.001. n=6 in each group. #25: Mice treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. Figures 12A-B, light bars, initial levels; dark bars, levels after 3 weeks of vehicle or drug treatment. [Figure 12B]Figure 12 shows the effects of Compound 25 on body weight (Figure 12A), blood glucose (Figure 12B), liver weight (Figure 12C), and plasma insulin levels (Figure 12D) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p<0.05, ***p<0.001. n=6 in each group. #25: Mice treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. Figures 12A-B, light bars, initial levels; dark bars, levels after 3 weeks of vehicle or drug treatment. [Figure 12C] Figure 12 shows the effects of Compound 25 on body weight (Figure 12A), blood glucose (Figure 12B), liver weight (Figure 12C), and plasma insulin levels (Figure 12D) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p<0.05, ***p<0.001. n=6 in each group. #25: Mice treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. Figures 12A-B, light bars, initial levels; dark bars, levels after 3 weeks of vehicle or drug treatment. [Figure 12D] Figure 12 shows the effects of Compound 25 on body weight (Figure 12A), blood glucose (Figure 12B), liver weight (Figure 12C), and plasma insulin levels (Figure 12D) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p<0.05, ***p<0.001. n=6 in each group. #25: Mice treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. Figures 12A-B, light bars, initial levels; dark bars, levels after 3 weeks of vehicle or drug treatment. [Figure 13A]Figure 13A shows the effect of Compound 64 on blood glucose levels (Figure 13A) and plasma insulin levels (Figure 13B) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars, sd, *p<0.05, ***p<0.001. n=6 in each group. #64: Mice treated with Compound 64 (5 mg / kg / day, daily gavage) for 2 weeks. Vehicle, vehicle-treated control group. Figure 13A, dark bars, initial levels; light bars, levels after 2 weeks of vehicle or drug treatment. [Figure 13B] Figure 13A shows the effect of Compound 64 on blood glucose levels (Figure 13A) and plasma insulin levels (Figure 13B) in an HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by Student's t-test. All error bars, sd, *p<0.05, ***p<0.001. n=6 in each group. #64: Mice treated with Compound 64 (5 mg / kg / day, daily gavage) for 2 weeks. Vehicle, vehicle-treated control group. Figure 13A, dark bars, initial levels; light bars, levels after 2 weeks of vehicle or drug treatment. [Figure 14A] Figure 14 shows the effects of Compound 25 on blood triglyceride (Figure 14A), total cholesterol (Figure 14B), and non-HDL cholesterol levels (Figure 14C) in high-fat diet-induced diabetic / hepatic steatosis mice. Statistical significance (P) was determined by Student's t-test. All error bars are SD, *p<0.05, n=6 in each group. #25: Treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. [Figure 14B] Figure 14 shows the effects of Compound 25 on blood triglyceride (Figure 14A), total cholesterol (Figure 14B), and non-HDL cholesterol levels (Figure 14C) in high-fat diet-induced diabetic / hepatic steatosis mice. Statistical significance (P) was determined by Student's t-test. All error bars are SD, *p<0.05, n=6 in each group. #25: Treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. [Figure 14C]Figure 14 shows the effects of Compound 25 on blood triglyceride (Figure 14A), total cholesterol (Figure 14B), and non-HDL cholesterol levels (Figure 14C) in high-fat diet-induced diabetic / hepatic steatosis mice. Statistical significance (P) was determined by Student's t-test. All error bars are SD, *p<0.05, n=6 in each group. #25: Treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks. Vehicle, vehicle-treated control group. [Figure 15A] The effects of Compound 25 and Compound 64 on hepatic steatosis induced by a high-fat diet are shown. Representative liver histology images using H&E staining of mice are shown below: Figure 15A, Normal: Liver section of healthy C57 / B16 mice without HFD feeding; Figure 15B, HFD, Liver section of HFD-fed mice; Figure 15C, HFD+#25, Liver section of HFD-fed mice after 3 weeks of Compound 25 treatment (daily gavage at 5 mg / kg PO); and Figure 15D, HFD+#64, Liver section of HFD-fed mice after 3 weeks of Compound 64 treatment (daily gavage at 5 mg / kg PO). N=6 in each group. [Figure 15B] The effects of Compound 25 and Compound 64 on hepatic steatosis induced by a high-fat diet are shown. Representative liver histology images using H&E staining of mice are shown below: Figure 15A, Normal: Liver section of healthy C57 / B16 mice without HFD feeding; Figure 15B, HFD, Liver section of HFD-fed mice; Figure 15C, HFD+#25, Liver section of HFD-fed mice after 3 weeks of Compound 25 treatment (daily gavage at 5 mg / kg PO); and Figure 15D, HFD+#64, Liver section of HFD-fed mice after 3 weeks of Compound 64 treatment (daily gavage at 5 mg / kg PO). N=6 in each group. [Figure 15C]The effects of Compound 25 and Compound 64 on hepatic steatosis induced by a high-fat diet are shown. Representative liver histology images using H&E staining of mice are shown below: Figure 15A, Normal: Liver section of healthy C57 / B16 mice without HFD feeding; Figure 15B, HFD, Liver section of HFD-fed mice; Figure 15C, HFD+#25, Liver section of HFD-fed mice after 3 weeks of Compound 25 treatment (daily gavage at 5 mg / kg PO); and Figure 15D, HFD+#64, Liver section of HFD-fed mice after 3 weeks of Compound 64 treatment (daily gavage at 5 mg / kg PO). N=6 in each group. [Figure 15D] The effects of Compound 25 and Compound 64 on hepatic steatosis induced by a high-fat diet are shown. Representative liver histology images using H&E staining of mice are shown below: Figure 15A, Normal: Liver section of healthy C57 / B16 mice without HFD feeding; Figure 15B, HFD, Liver section of HFD-fed mice; Figure 15C, HFD+#25, Liver section of HFD-fed mice after 3 weeks of Compound 25 treatment (daily gavage at 5 mg / kg PO); and Figure 15D, HFD+#64, Liver section of HFD-fed mice after 3 weeks of Compound 64 treatment (daily gavage at 5 mg / kg PO). N=6 in each group. [Figure 16A] Figure 16A shows the inhibitory effect of compound 25 on the differentiation of hepatic stellate cells into myofibroblast-like cells. Figure 16A is a schematic diagram of the experimental procedure (see procedure B5). Figure 16B is a microscopic image showing the cell morphology of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL TGFβ, and TGFβ + 7.5 ng / mL compound 25. TGFβ treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form a "ring"-shaped morphology after TGFβ treatment (TGFβ, center panel). Compound 25 (TGFβ + #25, right panel) prevents TGFβ-induced differentiation of LX-2 cells. [Figure 16B]Figure 16A shows the inhibitory effect of compound 25 on the differentiation of hepatic stellate cells into myofibroblast-like cells. Figure 16A is a schematic diagram of the experimental procedure (see procedure B5). Figure 16B is a microscopic image showing the cell morphology of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL TGFβ, and TGFβ + 7.5 ng / mL compound 25. TGFβ treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form a "ring"-shaped morphology after TGFβ treatment (TGFβ, center panel). Compound 25 (TGFβ + #25, right panel) prevents TGFβ-induced differentiation of LX-2 cells. [Figure 17A] Figure 17A shows the inhibitory effect of Compound 64 on the differentiation of hepatic stellate cells into myofibroblast-like cells. Figure 17A shows microscopic images of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL TGFβ, and TGFβ + 1 ng / mL Compound 64, showing the cell morphology. TGFβ treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form a "ring"-shaped morphology after TGFβ treatment (TGFβ, center panel). Compound 64 (TGFβ + #64, right panel) prevents TGFβ-induced differentiation of LX-2 cells. Figure 17B shows immunoblot analysis showing that Compound 64 blocks activation of the TGFβ signaling pathway, as evidenced by loss of Smad2 / 3 phosphorylation. LX-2 cells were treated with either vehicle (control), TGF-β alone, or TGF-β + the indicated concentrations of Compound 64 for 6 hours. Cells were then harvested and subjected to immunoblot analysis using antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated. [Figure 17B]Figure 17A shows the inhibitory effect of Compound 64 on the differentiation of hepatic stellate cells into myofibroblast-like cells. Figure 17A shows microscopic images of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL TGFβ, and TGFβ + 1 ng / mL Compound 64, showing the cell morphology. TGFβ treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form a "ring"-shaped morphology after TGFβ treatment (TGFβ, center panel). Compound 64 (TGFβ + #64, right panel) prevents TGFβ-induced differentiation of LX-2 cells. Figure 17B shows immunoblot analysis showing that Compound 64 blocks activation of the TGFβ signaling pathway, as evidenced by loss of Smad2 / 3 phosphorylation. LX-2 cells were treated with either vehicle (control), TGF-β alone, or TGF-β + the indicated concentrations of Compound 64 for 6 hours. Cells were then harvested and subjected to immunoblot analysis using antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated. [Figure 18A]Figure 18A shows the efficacy of Compound 25 in reducing liver fibrosis as determined by histology and molecular analysis. Figure 18A shows a microscopic image of liver sections from CCl4-treated mice subjected to H&E staining (upper left panel). Mice treated with CCl4 + Compound 25 (7.5 mg / kg / day) were subjected to H&E staining (lower left panel). CCl4-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, upper right panel), and CCl4 + Compound 25 (7.5 mg / kg / day)-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, lower left panel). Figure 18B shows fibrosis and lipofuscin scoring in mice treated with vehicle (control), CCl4 alone, and CCl4 + Compound 25 (CCl4 + 25). Each slice in the pie chart represents one mouse. The severity of liver fibrosis and the amount of lipofuscin present in each mouse are indicated by different shades of color. Lipofuscin is an intracellular aggregate of indigestible, highly oxidized proteins and lipids. Lipofuscin primarily accumulates in lysosomes in senescent and pathologically affected cells. Figure 18C shows immunoblot analysis of collagen expression (Col1a1) in mice treated with vehicle, CCl4 alone, or CCl4 + Compound 25 (CCl4 + #25). The fibrosis score for each sample is listed between the immunoblot panels as indicated. GAPDH served as an internal control. n = 7, treatment duration 6 weeks. Histological and molecular markers indicate that Compound 25 reduces fibrosis in CCl4-treated animals. [Figure 18B]Figure 18A shows the efficacy of Compound 25 in reducing liver fibrosis as determined by histology and molecular analysis. Figure 18A shows a microscopic image of liver sections from CCl4-treated mice subjected to H&E staining (upper left panel). Mice treated with CCl4 + Compound 25 (7.5 mg / kg / day) were subjected to H&E staining (lower left panel). CCl4-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, upper right panel), and CCl4 + Compound 25 (7.5 mg / kg / day)-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, lower left panel). Figure 18B shows fibrosis and lipofuscin scoring in mice treated with vehicle (control), CCl4 alone, and CCl4 + Compound 25 (CCl4 + 25). Each slice in the pie chart represents one mouse. The severity of liver fibrosis and the amount of lipofuscin present in each mouse are indicated by different shades of color. Lipofuscin is an intracellular aggregate of indigestible, highly oxidized proteins and lipids. Lipofuscin primarily accumulates in lysosomes in senescent and pathologically affected cells. Figure 18C shows immunoblot analysis of collagen expression (Col1a1) in mice treated with vehicle, CCl4 alone, or CCl4 + Compound 25 (CCl4 + #25). The fibrosis score for each sample is listed between the immunoblot panels as indicated. GAPDH served as an internal control. n = 7, treatment duration 6 weeks. Histological and molecular markers indicate that Compound 25 reduces fibrosis in CCl4-treated animals. [Figure 18C]Figure 18A shows the efficacy of Compound 25 in reducing liver fibrosis as determined by histology and molecular analysis. Figure 18A shows a microscopic image of liver sections from CCl4-treated mice subjected to H&E staining (upper left panel). Mice treated with CCl4 + Compound 25 (7.5 mg / kg / day) were subjected to H&E staining (lower left panel). CCl4-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, upper right panel), and CCl4 + Compound 25 (7.5 mg / kg / day)-treated mice were subjected to picrosirius red staining (staining for fibrillar collagen, lower left panel). Figure 18B shows fibrosis and lipofuscin scoring in mice treated with vehicle (control), CCl4 alone, and CCl4 + Compound 25 (CCl4 + 25). Each slice in the pie chart represents one mouse. The severity of liver fibrosis and the amount of lipofuscin present in each mouse are indicated by different shades of color. Lipofuscin is an intracellular aggregate of indigestible, highly oxidized proteins and lipids. Lipofuscin primarily accumulates in lysosomes in senescent and pathologically affected cells. Figure 18C shows immunoblot analysis of collagen expression (Col1a1) in mice treated with vehicle, CCl4 alone, or CCl4 + Compound 25 (CCl4 + #25). The fibrosis score for each sample is listed between the immunoblot panels as indicated. GAPDH served as an internal control. n = 7, treatment duration 6 weeks. Histological and molecular markers indicate that Compound 25 reduces fibrosis in CCl4-treated animals. [Figure 19A]Figure 19A shows immunoblot analysis of human Jurkat cells treated for 6 hours with either vehicle alone (lane 1), TGF-β alone (lane 2), or TGF-β plus Compound 64 (0.5, 1.0, or 2.0 μM compound) (lanes 3–5), as indicated. Figure 19B shows immunoblot analysis of mouse primary T cells (B) treated for 6 hours with either vehicle alone (lane 1), TGF-β alone (lane 2), or TGF-β plus various concentrations of Compound 64 (1.0 or 2.0 μM compound) (lanes 3 and 4), as indicated. Immunoblot analysis was performed using antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated. Loss of Smad2 / 3 phosphorylation indicates the effectiveness of compound 64 in blocking TGF-β activation in T cells. [Figure 19B] Figure 19A shows immunoblot analysis of human Jurkat cells treated for 6 hours with either vehicle alone (lane 1), TGF-β alone (lane 2), or TGF-β plus Compound 64 (0.5, 1.0, or 2.0 μM compound) (lanes 3–5), as indicated. Figure 19B shows immunoblot analysis of mouse primary T cells (B) treated for 6 hours with either vehicle alone (lane 1), TGF-β alone (lane 2), or TGF-β plus various concentrations of Compound 64 (1.0 or 2.0 μM compound) (lanes 3 and 4), as indicated. Immunoblot analysis was performed using antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated. Loss of Smad2 / 3 phosphorylation indicates the effectiveness of compound 64 in blocking TGF-β activation in T cells. [Figure 20A]This shows that compound 64 is effective in combination with PD-1 antibodies in the treatment of metastatic cancer in mice. Figure 20A shows the experimental design (see Example B12). Briefly, C57 / B16 mice (day 0) intrahepatically implanted with MC38 cancer cells were subjected to various treatments starting on day 7: aPD-1 or isotype, mice were treated with either PD-1 antibody or its isotype antibody (control) by intraperitoneal (IP) injection on the indicated days (PD-1 antibodies have a half-life of more than one week in mice); compound #64 or vehicle, mice were treated by daily gavage with either compound #64 or vehicle. Figure 20B is a table showing the results of the experiment described in Figure 20A and Example B12. aPD-1+#64 represents mice treated with PD-1 antibody (IP) and #64 (daily gavage); aPD-1 represents mice treated with PD-1 antibody (IP) and vehicle (gavage); and control represents mice treated with isotype antibody (IP) and vehicle (gavage). n represents the number of mice in each group. Tumor positive represents the number of tumor-bearing mice in each group. Tumor free represents the number of tumor-free mice in each group. % tumor free represents the percentage of tumor-free animals in each group. Fisher's exact 2x2 test is the P value for comparing each experimental group with the control group using statistical analysis by Fisher's exact 2x2 test. P<0.05 indicates a statistically significant difference. [Figure 20B]This shows that compound 64 is effective in combination with PD-1 antibodies in the treatment of metastatic cancer in mice. Figure 20A shows the experimental design (see Example B12). Briefly, C57 / B16 mice (day 0) intrahepatically implanted with MC38 cancer cells were subjected to various treatments starting on day 7: aPD-1 or isotype, mice were treated with either PD-1 antibody or its isotype antibody (control) by intraperitoneal (IP) injection on the indicated days (PD-1 antibodies have a half-life of more than one week in mice); compound #64 or vehicle, mice were treated by daily gavage with either compound #64 or vehicle. Figure 20B is a table showing the results of the experiment described in Figure 20A and Example B12. aPD-1+#64 represents mice treated with PD-1 antibody (IP) and #64 (daily gavage); aPD-1 represents mice treated with PD-1 antibody (IP) and vehicle (gavage); and control represents mice treated with isotype antibody (IP) and vehicle (gavage). n represents the number of mice in each group. Tumor positive represents the number of tumor-bearing mice in each group. Tumor free represents the number of tumor-free mice in each group. % tumor free represents the percentage of tumor-free animals in each group. Fisher's exact 2x2 test is the P value for comparing each experimental group with the control group using statistical analysis by Fisher's exact 2x2 test. P<0.05 indicates a statistically significant difference. [Figure 21]The antiviral activity (EC50), cytotoxicity (TC50), and specificity index (SI) of compounds 64, 25, and 57 against enveloped viruses are shown. Each row represents the results of an experiment using the specified compound on host cells infected or uninfected with the specified virus. EC50 is the compound concentration that reduces virus-induced cytopathic effect (CPE) by 50%. TC50 is the compound concentration that results in 50% cell viability compared to uninfected cells. SI is the ratio between TC50 and EC50. Experiments were performed as follows: Host cells (either Vero 760 or MRC-5) were seeded into 96-well flat-bottom tissue culture plates as indicated and allowed to adhere overnight. After overnight incubation, cells were either infected with virus (either SARS-CoV-2 or alphacoronavirus 229E) or not, and diluted test compounds were added to each well. After 3 or 6 days of incubation at 37°C, 5% CO2, cell viability was determined. The percentage of CPE reduction in virus-infected wells and the percentage of cell viability in uninfected drug control wells were measured to calculate and determine EC50 and TC50 values. SI was calculated accordingly. DETAILED DESCRIPTION OF THE INVENTION

[0037] The following factors make mitochondria an ideal target for treating many important diseases: (1) they are the final site of consumption (oxidation) of lipid or glucose metabolites, (2) they are important for regulating the abundance of metabolic intermediates that are essential biosynthetic components for cell growth and proliferation in cancer cells and viral envelope production and assembly, and (3) they are the primary site of ROS production in neurons and many other cells (Figure 1).

[0038] Mitochondrial uncoupling is a unique method for regulating mitochondrial activity and function. Essentially, mitochondrial uncoupling is the process by which mitochondrial electron transport chain activity is uncoupled from ATP synthesis. Mechanistically, mitochondrial uncoupling is caused by the action of mitochondrial uncouplers, which transport protons across the inner mitochondrial membrane into the mitochondrial matrix independently of ATP synthase (Terada, H. (1990) Environmental Health Perspectives 87, 213-218). The technical definition of a mitochondrial uncoupler is an increase in the oxygen consumption rate (OCR) by cells in the presence of an ATP synthase inhibitor, such as oligomycin. As a result, mitochondrial uncouplers result in futile mitochondrial oxidation and increased electron transport chain flux. Consequently, mitochondrial uncouplers may promote glucose or lipid catabolism in cells, reduce small molecule component output, and decrease electron stall in the electron transport chain, thus reducing electron leakage and mitochondrial ROS production. Through these actions, mitochondrial uncouplers represent an effective strategy for the potential treatment of many important diseases.

[0039] Mitochondrial and Metabolic Diseases. Metabolic diseases are a family of diseases characterized by symptoms of abnormal glucose and / or lipid metabolism, such as obesity, type 2 diabetes, alcoholic fatty liver disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. These diseases are associated with aging-, environmental-, and genetic-related declines in mitochondrial function, such as reduced oxidative capacity. Importantly, these diseases also share common causative factors, namely, in most cases, abnormal accumulation of intracellular lipids in cells of various tissues and insulin resistance. For example, obesity is characterized by excessive fat accumulation in adipose tissue cells. Metabolic syndrome is characterized by insulin resistance in peripheral tissues, usually caused by ectopic fat accumulation in liver, muscle, or adipose tissue cells. Type 2 diabetes is usually characterized by insulin resistance caused by ectopic fat accumulation in liver, muscle, or adipose tissue cells, and hyperglycemia caused by insulin resistance. Alcoholic fatty liver disease is characterized by ectopic lipid accumulation in hepatocytes and liver damage, liver inflammation, and fibrosis. The various stages of nonalcoholic fatty liver disease (or NAFLD), including hepatosteatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and NAFLD-induced hepatocellular carcinoma (HCC), are primarily caused by ectopic lipid accumulation in hepatocytes, leading to liver injury, inflammation, and fibrosis. Various types of dyslipidemia are partially caused by ectopic lipid accumulation in liver, muscle, or heart cells as a result of lipid redistribution from adipose tissue to other tissues.

[0040] Mitochondrial uncouplers, which reduce energy efficiency and promote wasteful lipid oxidation, effectively reduce cellular lipid accumulation. Because ectopic intracellular accumulation of fat in the liver and muscle, and excessive accumulation of fat in adipose tissue are the underlying causes of insulin resistance in various forms of metabolic diseases (Samuel VT, et al., Lancet, 2010, 375:2267-77), applicants have demonstrated in animal models that small molecule (chemical) mitochondrial uncouplers are effective in preventing and treating metabolic diseases (Tao, H., Zhang, Y., Zeng, X., Shulman, GI, and Jin, S., 2014, Nature Medicine, 20, 1263-1269; Perry, RJ, Zhang, D., Zhang, XM, Boyer, JL, and Shulman, GI (2015) Science, 347 (6227), 1253-6) demonstrated that mitochondrial uncouplers (MUNs) can (1) reduce lipid accumulation in various tissues, including adipose tissue, (2) reduce insulin resistance, (3) reduce blood glucose concentrations, and (4) improve glycemic control and slow disease progression. Importantly, using mitochondrial uncouplers to treat metabolic diseases has several attractive features; for example, because they correct the cause of insulin resistance (ectopic lipid accumulation), such an approach may offer a cure for some metabolic diseases.

[0041] Cancer is a family of diseases characterized by uncontrolled growth and proliferation of cells of various tissue types, resulting from a combination of genetic mutations in oncogenes and tumor suppressor genes. It is widely recognized that one prerequisite for tumorigenesis is altered cellular metabolism. To support rapid cell growth and proliferation, cancer cells require not only energy but also building blocks (metabolic intermediates) for the biosynthesis of macromolecules, such as DNA and RNA. Metabolism in cancer cells is altered to support both the need for energy and the need for various metabolic intermediates (building blocks) for macromolecular biosynthesis (Vander Heiden, MG, Cantley, LC, and Thompson, CB (2009) Science, 324 (5930), 1029-33). As a result, most cancers exhibit a unique cellular metabolic pattern known as the Warburg effect or aerobic glycolysis, which prevents the complete oxidation of glucose or lipids and allows the production of glucose metabolites for macromolecular biosynthesis (Vander Heiden, et al., 2009).

[0042] Mitochondrial uncoupling reduces energy efficiency, thereby impairing the energy requirements of cancer cells. Furthermore, mitochondrial uncoupling promotes complete mitochondrial oxidation of glucose and lipids, thereby reducing the production of metabolic intermediates essential for the biosynthesis of macromolecules required for cell proliferation. Furthermore, mitochondrial uncoupling can lead to AMPK activation, a known event for inhibiting cell growth. Indeed, prior literature has shown that mitochondrial uncoupling agents exhibit anticancer activity (U.S. Patent No. 10,227,315). Targeting cancer cells through mitochondrial uncoupling deprives them of energy and biosynthetic metabolic intermediates absolutely essential for cancer cell growth and proliferation, which has proven to be an effective anticancer strategy (Alasadi, A. et al., (2018) Cell Death Dis., 9(2), 215).

[0043] Autoimmune diseases are conditions in which the body's immune system attacks its own healthy organs. Common autoimmune diseases include celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. To activate and maintain autoimmune activity, the body's own self-adherent immune cells require proliferation, which requires metabolic changes similar to the Warburg effect observed in cancer cells to provide sufficient building blocks for biosynthesis (Ganeshan, K., et al. (2014) Annual Review of Immunology, 32, 609-634). Therefore, mitochondrial uncoupling may inhibit the activation and proliferation of auto-attacking immune cells.

[0044] Neurodegenerative diseases, a large group of neurological disorders including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, are characterized by the relative selective death of neuronal subtypes. There is overwhelming evidence of mitochondrial dysfunction as a causative factor in these diseases, with mitochondrial ROS production being one of the most important factors (Elfawy, HA and Das, B. (2019) Life Sci., 218, 165-184).

[0045] Mitochondrial uncouplers can increase mitochondrial electron transport chain flux and reduce electron stall in electron transport chain complexes, thus effectively reducing mitochondrial ROS. Therefore, mitochondrial uncoupling is considered a powerful antioxidant strategy and may have therapeutic potential for treating neurodegenerative diseases.

[0046] Declines in mitochondrial function and capacity are associated with normal aging and correlate with the development of a wide range of age-related diseases. Several proven anti-aging and pro-longevity approaches, such as calorie restriction, are highly correlated with improved mitochondrial function (Sun, N., et al. (2016) Mol. Cell, 61(5), 654-666). Regulation of mitochondrial function through mitochondrial uncoupling has been proposed as an anti-aging strategy (Caldeira da Silva, CC, et al. (2008) Aging Cell, 7(4), 552-60).

[0047] Mitochondria are ancient bacteria that formed a symbiotic relationship with host cells. Bacterial plasma membranes contain electron transport systems and ATP synthases similar to those of mitochondria, and therefore compounds that affect mitochondrial uncoupling are useful inhibitors of bacterial growth and may be effective as antibiotics (U.S. Pat. No. 10,227,315).

[0048] Despite the attractive and beneficial features of mitochondrial uncoupling, there are currently no FDA-approved drugs in human use in the United States that use mitochondrial uncoupling as a mechanism of action to treat the above diseases. There are significant obstacles to the development of mitochondrial uncoupling agents as therapeutic agents. The discovery of novel synthetic mitochondrial uncoupling agents with better druggable characteristics is crucial for developing mitochondrial uncoupling therapies.

[0049] Benzamide mitochondrial uncouplers have been developed for potential therapeutic applications (International Patent Publication No. 2012 / 068274, International Patent Publication No. 2016 / 081599, U.S. Patent No. 10,227,315, and Tao et al., 2014). One major limitation of conventional benzamide compounds is their poor pharmacokinetic properties and low systemic exposure. For example, to overcome the poor pharmacokinetic properties of previously disclosed compounds, such as low systemic exposure and short half-lives, studies in animal models required the compounds to be mixed with food, necessitating high doses of the compounds to achieve efficacy (e.g., 1500 ppm niclosamideethanolamine (NEN) in the diet, equivalent to 150 mg / kg / day (Tao, et al. 2014, and WO 2012 / 068274), or 600-750 ppm Compound 27 in the diet (U.S. Pat. No. 10,227,315), equivalent to 60-75 mg / kg / day). Neither the high doses required nor the need to mix the compound into food are compatible with therapeutic development in humans.

[0050] Another limitation of available mitochondrial uncouplers is safety concerns, as some are known to have narrow therapeutic indices. For example, the most well-known mitochondrial uncoupler, 2,4-dinitrophenol, was previously used in humans but was withdrawn from the market due to its narrow therapeutic window. 2,4-dinitrophenol has a concentration (intracellular) / dosage (in vivo) ratio between toxicity and efficacy of only approximately threefold. Therefore, new properties that enable mitochondrial uncouplers to improve safety margins are considered important for the therapeutic development of mitochondrial uncouplers.

[0051] Various embodiments provide novel benzamide mitochondrial uncouplers that effectively induce mitochondrial uncoupling (increase mitochondrial oxygen consumption in the presence of oligomycin) without significantly reducing mitochondrial membrane potential (see below) over a wide concentration range. These compounds are referred to herein as mitochondrial membrane potential preserving (MMP preserving) compounds (MMP preserving).

[0052] These MMP-retaining compounds exhibit a dramatically improved safety profile compared to the benchmark conventional mitochondrial uncoupler, DNP. These compounds exhibit a broader therapeutic index when used to treat metabolic diseases.

[0053] Various embodiments provide new benzamide mitochondrial uncouplers that exhibit significantly improved pharmacokinetic properties, such as significantly increased systemic exposure (some compounds have a greater than 100-fold increase in AUC over some previously disclosed druggable benzamide mitochondrial uncouplers with the highest reported systemic exposure).

[0054] Various embodiments describe the use of these compounds for the prevention and treatment of bacterial infections, skin disorders, viral infections, metabolic diseases or disorders including, but not limited to, obesity, metabolic syndrome, type 2 diabetes, alcoholic fatty liver disease, non-alcoholic fatty liver disease, dyslipidemia, and primary and metastatic cancers of various tissue origins.

[0055] Various embodiments provide for the use of these compounds for the treatment of disease conditions such as hyperglycemia, insulin resistance, abnormal lipid accumulation, fibrosis, and abnormal TGF-β activation.

[0056] Various embodiments describe the use of these compounds alone or in combination with other agents for the prevention and treatment of diseases.

[0057] compound In one embodiment, the present disclosure provides a compound of formula A:

[0058] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0059] Substituent R of Formula A 1000a teeth, -CH3, -CH2CH3, -C1 to C6 alkyl, -C3 to C6 cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0060] [ka] -(CH2) r’ NR 5000A R 5000B , -(CH2) r R 6000 and C(O)N(CH2CH2OCH3)2. 5000A and R 5000B are each independently selected from the group consisting of —C1-C6 alkyl and —C1-C6 alkyl substituted with one or more groups selected from —C1-C6 alkoxy and —O(CH2)2OCH3, with the proviso that R 5000A and R 5000B However, they cannot both be C1-C6 alkyl. 5000A and R 5000B taken together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. The integer r' is an integer selected from the group consisting of 1, 2, and 3. The substituent R 6000 is selected from the group consisting of 5-6 membered heterocyclyl, pyridinyl, and thiazolyl; and r is an integer selected from the group consisting of 0, 1, 2, and 3.

[0061] Substituent R of Formula I 1000c is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0062] Substituent R of Formula A 4000b and R 4000d Each of Y 1000 and Z 1000 independently selected from the group consisting of: 4000b If Y, then R 4000d is Z and R 4000b If Z, then R 4000d is Y. Substituent Y 1000 is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl. 1000 H, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2O(CH2)2NR 2000A R 2000B , -(CH2) s R 3000 , -CH2OCH2Ar 1 , -OCH3CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) t’ NR 7000A R 7000B , and -(CH2) t R 8000 wherein Z is selected from the group consisting of 1000 If is H, then R 1000a is not C1-C6 alkyl, -C3-C6 cycloalkyl, -CH3 or -CH2CH3. 2000A and R 2000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups. 3000 is a 5- to 6-membered heterocycle, and s is an integer selected from the group consisting of 0, 1, 2, and 3. 1R is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halo, hydroxyl, and alkoxy. 7000A and R 7000B each of which independently C1-C6 alkyl. Alternatively, R 7000A and R 7000B together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, and t' is an integer selected from the group consisting of 1, 2, and 3. 8000 teeth, and t is an integer selected from the group consisting of 0, 1, 2, and 3.

[0063] In some embodiments, R 4000d is H, R described in paragraph

[0078] 4d , and R described in paragraph

[0149] 400d is selected from the group consisting of:

[0064] In some embodiments, the compound of formula A is a compound selected from the group consisting of a compound of formula I, a compound of formula II, and a compound of formula III, as defined herein.

[0065] In some embodiments, the compound of formula A is selected from the group consisting of compounds described in any of paragraphs

[0089] ,

[0120] , and

[0156] .

[0066] In one embodiment, the present disclosure provides a compound of formula I:

[0067] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0068] Substituent R of Formula I 1a teeth, -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0069] [ka] -(CH2) m’ NR 5A R 5B , -(CH2) m R 6 and C(O)N(CH2CH2OCH3)2. 5A and R 5B are each independently selected from the group consisting of -C1-C6 alkyl, -C1-C6 alkoxy, and -C1-C6 alkyl substituted with one or more groups selected from -O(CH2)2OCH3. 5A and R 5B together with the nitrogen to which they are attached form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -forms a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of CF3, C1-C6 alkyl, halo, and acyl. The integer m' is an integer selected from the group consisting of 1, 2, and 3. The substituent R 6 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; and m is an integer selected from the group consisting of 0, 1, 2, and 3.

[0070] Substituent R of Formula I 1c is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0071] Substituent R of Formula I 4b and R 4d are each independently selected from the group consisting of Y and Z, with the proviso that R 4b If Y, then R 4dis Z and R 4b If Z, then R 4d is Y. The substituent Y is chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and The substituent Z is selected from the group consisting of -CO2(C1-C6)alkyl, -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2O(CH2)2NR 2A R 2B , -(CH2) n R 3 , The substituent R is selected from the group consisting of —CH2OCH2Ar and OCH3. 2A and R 2B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups. 3 is selected from the group consisting of 5-6 membered heterocycle and phenoxy, and n is an integer selected from the group consisting of 0, 1, 2, and 3. The substituent Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halo, hydroxy, and alkoxy.

[0072] A further embodiment is a compound according to formula Ia:

[0073] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R of formula Ia 1a and R 4d each of which is as described above for Formula I.

[0074] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -CH2NR 5A R 5B Selected from R 5A and R 5B are each independently selected from methyl, and C1-C6 alkyl substituted with one or more groups selected from methoxy and -O(CH2)2OCH3.

[0075] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -CH2NR 5A R 5B and R 5A and R 5B Each of Independently selected from C1-C6 alkyl substituted with one or more methoxy. In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -CH2NR 5A R 5B and R 5A and R 5B together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, -forms a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl, wherein the heterocyclyl is oxo, cyano, hydroxyl, alkoxy, -Optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is oxo, cyano, hydroxyl, methoxy, It is optionally substituted with one or more substituents independently selected from the group consisting of -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl. In some embodiments, the 4-8-membered heterocyclyl is optionally substituted with one or more methyl substituents. In some embodiments, the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorpholinyl; and azabicyclo[3.2.1]octanyl.

[0076] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -CH2NR 5A R 5B and R 5A and R 5Btaken together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 6-membered heterocyclyl is selected from the group consisting of piperidinyl optionally substituted with one or more C1-C6 alkyl substituents, and morpholinyl optionally substituted with one or more C1-C6 alkyl substituents.

[0077] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -CH2NR 5A R 5B -CHNR 5A R 5B teeth, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0078] [ka] In some embodiments, -CHNR 5A R 5B is -(CH2)N(CH2CH2OCH3)2,

[0079] [ka] is selected from the group consisting of:

[0080] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a is -(CH2) m R 6 and R 6is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and piperidinyl, and m is as defined above. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, —(CH) m R 6 teeth,

[0081] [ka] is selected from the group consisting of:

[0082] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a are -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)2NHCO2CH3,

[0083] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0084] [ka] is selected from the group consisting of:

[0085] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a are -CH3, -CH2CH3 and -CH2NR 5A R 5B and R 5A and R 5Bis as previously described in any embodiment described herein. In some embodiments, R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more methoxy; or 5A and R 5B taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl.

[0086] In some embodiments, R of Formula I or Formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1a are -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2,

[0087] [ka] is selected from the group consisting of:

[0088] In some embodiments, R of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1c is chloro.

[0089] Some embodiments include R 4b is Y and R 4d is Z, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0090] Some embodiments include R 4d is Y and R 4b is Z, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0091] In some embodiments, Y of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is —CF 3 .

[0092] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is —(CH 2 )O(CH 2 )2NR 2A R 2B and R 2A and R 2B is as previously described herein. In some embodiments, R 2A and R 2B taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with a methyl group. In some embodiments, R 2A and R 2B taken together with the nitrogen to which they are attached form a heterocyclyl selected from piperazinyl or 4-methylpiperazinyl.

[0093] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH2) n R 3 and R 3 is as previously described herein. In some embodiments, R 3 is a 5-membered heterocycle. In some embodiments, R 3 is selected from the group consisting of tetrahydrofuranyl and phenoxy. 3 is tetrahydrofuranyl. In some embodiments, R 3 teeth,

[0094] [ka] and phenoxy. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, —(CH) n R 3 teeth,

[0095] [ka] In some embodiments, the compound is selected from the group consisting of -(CH) n R 3 teeth,

[0096] [ka] is.

[0097] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CHOCHAr, where Ar is as previously described herein. In some embodiments, Ar is a 5-6 membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy. In some embodiments, Ar is selected from the group consisting of thiazolyl, phenyl, and phenyl substituted with one or more groups independently selected from methyl, fluoro, chloro, hydroxy, and methoxy. In some embodiments, Ar is phenyl,

[0098] [ka] is selected from the group consisting of:

[0099] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CHO(CH2)2OH, -CHO(CH2)2OCH3, CHO(CH2)2NHCH3, -CHO(CH2)2N(CH3)2, -CHO(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B , -(CH2) n R 3 , -CH2OCH2Ar and OCH3, R 2A R 2B , R3 , n and Ar are as described in any embodiment herein.

[0100] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B , -(CH2) n R 3 , R is selected from the group consisting of —CH2OCH2Ar and OCH3; 2A R 2B , R 3 , n and Ar are as described in any embodiment herein.

[0101] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B , -(CH2) n R 3 , R is selected from the group consisting of —CH2OCH2Ar and OCH3; 2A and R 2B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl and 4-methylpiperazinyl, R 3 is tetrahydrofuranyl, and Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.

[0102] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0103] [ka] and —OCH3.

[0104] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0105] [ka] and —OCH3.

[0106] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0107] [ka] and —OCH3, and Y in formula I is selected from the group consisting of chloro, fluoro, iodo, bromo, —CF3, —CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, —OCF3, —SO2(C1-C6)alkyl, cyano, and —CO2(C1-C6)alkyl.

[0108] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0109] [ka] and —OCH3, and Y is —CF3.

[0110] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0111] [ka] and —OCH3, and Y is selected from the group consisting of chloro, fluoro, iodo, bromo, —CF3, —CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, —OCF3, —SO2(C1-C6)alkyl, cyano, and —CO2(C1-C6)alkyl.

[0112] In some embodiments, Z of Formula I or R of Formula Ia 4d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0113] [ka] and -OCH3, and Y is -CF3.

[0114] Some embodiments are compounds of Formula I, wherein: R 1a -CH3, -CH2CH3 and -CH2NR 5A R 5B is selected from the group consisting of R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more groups selected from methoxy, or 5A and R 5B together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 1c But it's Chloro. R 4b and R 4d are each independently selected from the group consisting of Y and Z, with the proviso that R 4b If Y, then R 4d is Z and R 4b If Z, then R 4d is Y, Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B , -(CH2) n R 3 , -CH2OCH2Ar and OCH3, R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl and 4-methylpiperazinyl, R 3 is tetrahydrofuranyl and Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.

[0115] Some embodiments are compounds of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 1a -CH3, -CH2CH3 and -CH2NR 5A R 5B and R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more groups selected from methoxy, or 5A and R 5B together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 1c But it's Chloro. R 4b and R 4d are each independently selected from the group consisting of Y and Z, with the proviso that R 4b If Y, then R 4d is Z and R 4b If Z, then R 4dis Y, Y is CF3, and Z is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2O(CH2)2NR 2A R 2B , -(CH2) n R 3 , R is selected from the group consisting of —CH2OCH2Ar and —OCH3; 2A and R 2B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl and 4-methylpiperazinyl, R 3 is tetrahydrofuranyl and Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0116] Some embodiments are compounds of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 1a is -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2,

[0117] [ka] is selected from the group consisting of R 1c But it's Chloro. R 4b and R 4d are each independently selected from the group consisting of Y and Z, with the proviso that R 4b If Y, then R 4d is Z and R 4b If Z, then R 4dis Y, Y is CF3, Z is -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0118] [ka] and -OCH3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0119] Some embodiments are compounds of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 1a is -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2,

[0120] [ka] is selected from the group consisting of R 1c But it's Chloro. R 4b is CF3, R 4d But -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0121] [ka] and -OCH3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0122] Some embodiments are compounds of formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1ais -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2,

[0123] [ka] and R 4d is -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0124] [ka] and -OCH3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0125] Some embodiments are compounds of formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1a but, -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2,

[0126] [ka] and R 4d -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0127] [ka] and -OCH3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0128] Some embodiments are compounds selected from the group consisting of:

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131] [Table 1-3]

[0132] [Table 1-4]

[0133] [Table 1-5]

[0134] [Table 1-6]

[0135] [Table 1-7] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0136] Some embodiments include a compound selected from the group consisting of:

[0137] [Table 2-1]

[0138] [Table 2-2] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0139] In one embodiment, the compound is

[0140] [Table 3] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0141] In one embodiment, the present disclosure provides a compound of formula II:

[0142] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0143] Substituent R of Formula I 10a teeth, OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0144] [ka] -(CH2) o’ NR 50A R 50B , -(CH2) o R 60 and C(O)N(CH2CH2OCH3)2. 50A and R 50B are each independently selected from the group consisting of -C1-C6 alkyl, and -C1-C6 alkyl substituted with one or more groups selected from -C1-C6 alkoxy, and -O(CH2)2OCH3, with the proviso that R 50A and R50B However, they cannot both be C1-C6 alkyl, or R 50A and R 50B taken together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. The integer o' is an integer selected from the group consisting of 1, 2, and 3. The substituent R 60 is selected from the group consisting of 5-6 membered heterocyclyl, pyridinyl and thiazolyl, and o is an integer selected from the group consisting of 0, 1, 2 and 3.

[0145] Substituent R of Formula I 10c is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0146] Substituent R 40b and R 40d one of the substituents is H, and the other substituent is chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, It is selected from the group consisting of halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl.

[0147] A further embodiment is a compound according to formula IIa:

[0148] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and R of formula IIa 10a , and R 40d each of which is as described above for Formula II.

[0149] In some embodiments, R of Formula II or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -CH2NR50A R 50B Selected from R 50A and R 50B are each independently selected from methyl, and C1-C6 alkyl substituted with one or more groups selected from methoxy and -O(CH2)2OCH3.

[0150] In some embodiments, R of Formula II, or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -CH2NR 50A R 50B and R 50A and R 50B together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, -forms a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl, and azabicyclo[3.2.1]octanyl, and the heterocyclyl is selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -Optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorpholinyl, and the heterocyclyl is oxo, cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, and optionally substituted with one or more substituents independently selected from the group consisting of -CF3, methyl, fluoro, and acetyl. In some embodiments, the 4- to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3 and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorpholinyl; and azabicyclo[3.2.1]octanyl. In some embodiments, the 4- to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; and dioxothiomorpholinyl.

[0151] In some embodiments, R of Formula II, or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -CH2NR 50A R 50B and R 50A and R 50Btogether with the nitrogen to which they are attached form a 4- to 7-membered heterocyclyl selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorpholinyl, wherein the 4- to 7-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, —NHC(O)CH3, —C(O)NH2, —SO2CH3, —CF3, methyl, fluoro, and acetyl.

[0152] In some embodiments, R of Formula II, or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -CH2NR 50A R 50B -CHNR 50A R 50B is -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0153] [ka] is selected from the group consisting of:

[0154] In some embodiments, R of Formula II, or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -CH2NR 50A R 50B -CHNR 50A R 50B is -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0155] [ka] is selected from the group consisting of:

[0156] In some embodiments, R of Formula II, or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a is -(CH2) o R 60 and R 60 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and pyridinyl, and o is as defined above. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, R 60 is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl, and o is 0. In some embodiments, —(CH)R 60 teeth,

[0157] [ka] In some embodiments, —(CH)R 60 teeth,

[0158] [ka] is selected from the group consisting of:

[0159] In some embodiments, R of a compound of Formula II or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a are -OCH3, -CH2OCH3-CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0160] [ka] -CH2NR 50A R 50B , -(CH2) o R 60and C(O)N(CH2CH2OCH3)2, R 50A 、 R 50B and R 60 is as defined above in any embodiment herein.

[0161] In some embodiments, R of Formula II or Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10a are -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0162] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0163] [ka] and C(O)N(CH2CH2OCH3)2.

[0164] In some embodiments, R of Formula II or Formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 10a are -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0165] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2,

[0166] -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0167] [ka] and C(O)N(CH2CH2OCH3)2.

[0168] In some embodiments, R of Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10c are chloro, fluoro, and iodo.

[0169] In some embodiments, R of Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 10c is chloro.

[0170] In some embodiments, the substituent R 40b and R 40d One of the groups is H and the other substituent is selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.

[0171] In some embodiments, R 40b is H and R 40d are chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, It is selected from the group consisting of -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl.

[0172] In some embodiments, R 40d is H and R 40b are chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, It is selected from the group consisting of -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl.

[0173] In some embodiments, R 40d is H and R 40b is selected from the group consisting of fluoro, —CF3, —CHF2, and —OCF3.

[0174] In some embodiments, R 40d is H and R 40b is -CF3.

[0175] Some embodiments are compounds of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0176] [ka] -CH2NR 50A R 50B , -(CH2) o R 60 and C(O)N(CH2CH2OCH3)2; R 50A and R 50B are each independently selected from the group consisting of —C1-C6 alkyl and —C1-C6 alkyl substituted with one or more groups selected from —C1-C6 alkoxy and —O(CH2)2OCH3, or 50A and R 50Btogether with the nitrogen to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl; R 60 is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; o is 0, R 10c is selected from the group consisting of chloro, fluoro, and iodo; R 40b and R 40d One of the groups is H and the other is R 40b and R 40d the other is selected from the group consisting of fluoro, -CF3, -CHF2, -OCF3; However, R 50A and R 50B but not both are C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0177] Some embodiments are compounds of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0178] [ka] -CH2NR 50A R 50B , -(CH2) o R 60 and C(O)N(CH2CH2OCH3)2; R 50A and R 50Bare each independently selected from methyl and C1-C6 alkyl substituted with one or more groups selected from methoxy and —O(CH2)2OCH3, or 50A and R 50B taken together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclyl selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorpholinyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, —NHC(O)CH3, —C(O)NH2, —SO2CH3, —CF3, methyl, fluoro, and acetyl; R 60 is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl o is 0, R 10c is selected from the group consisting of chloro, fluoro, and iodo; R 40d is H and R 40b Fluoro, -CF3, -CHF2, and -OCF3, However, R 50A and R 50B but not both are methyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0179] Some embodiments are compounds of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0180] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0181] [ka] and —C(O)N(CH2CH2OCH3)2; R 10c is selected from the group consisting of chloro, fluoro, and iodo; R 40d is H and R 40b Fluoro, -CF3, -CHF2, and -OCF3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0182] Some embodiments are compounds of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0183] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0184] [ka] and C(O)N(CH2CH2OCH3)2; R 10c is selected from the group consisting of chloro, fluoro, and iodo; R 40d is H and R40b Fluoro, -CF3, -CHF2, and -OCF3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0185] Some embodiments are compounds of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0186] [ka] CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0187] [ka] and C(O)N(CH2CH2OCH3)2; R 10c But it's Chloro. R 40d is H and R 40b is -CF3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0188] Some embodiments are compounds of Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3,

[0189] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0190] [ka] and —C(O)N(CH 2 CH 2 OCH 3 ) 2 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0191] Some embodiments are compounds of Formula IIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 10a But -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3-CH2NHC(O)CH3,

[0192] [ka] CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0193] [ka] and C(O)N(CH2CH2OCH3)2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0194] Some embodiments are compounds selected from the group consisting of:

[0195] [Table 4-1]

[0196] [Table 4-2]

[0197] [Table 4-3]

[0198] [Table 4-4]

[0199] [Table 4-5]

[0200] [Table 4-6]

[0201] [Table 4-7]

[0202] [Table 4-8] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0203] Some embodiments are compounds selected from the group consisting of:

[0204] [Table 5-1]

[0205] [Table 5-2]

[0206] [Table 5-3] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0207] In one embodiment,

[0208] [Table 6] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0209] In one embodiment, the present disclosure provides a compound of formula III:

[0210] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0211] Substituent R of Formula III 100a teeth, -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3,

[0212] [ka] -(CH2) p’ NR 500A R 500B , -(CH2) p R 600 and C(O)N(CH2CH2OCH3)2. 5A and R 5Bare each independently selected from the group consisting of -C1-C6 alkyl, -C1-C6 alkoxy, and -C1-C6 alkyl substituted with one or more groups selected from -O(CH2)2OCH3. 500A and R 500B taken together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxyamido, The substituent R forms a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. The integer p' is an integer selected from the group consisting of 1, 2, and 3. 600 is selected from the group consisting of 5-6 membered heterocyclyl, pyridinyl and thiazolyl, and p is an integer selected from the group consisting of 0, 1, 2 and 3.

[0213] Substituent R of Formula III 100c is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0214] Substituent R of Formula III 400b and R 400d Each of Y 1 and Z 1 independently selected from the group consisting of: 400b Y 1 If R 400d is Z 1 and R 400b Z 1 If R 400d is Y 1 The substituent Y 1 is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl. 1 teeth, -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) q’ NR7A R 7B , and -(CH2) q R 8 R 7A and R 7B are each independently selected from C1 to C6 alkyl. 7A and R 7B together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl optionally substituted with one or more independently selected C1-C6 alkyls. The integer q' is an integer selected from the group consisting of 1, 2, and 3. The substituent R 8 is selected from the group consisting of 5-6 membered heterocycles optionally substituted with methyl; and q' is an integer selected from the group consisting of 0, 1, 2, and 3.

[0215] A further embodiment is a compound according to formula IIIa:

[0216] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and R of formula IIIa 100a , and R 400d each of which is as described above for Formula III.

[0217] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a But -CH2NR 500A R 500B Selected from R 500A and R 500B each of which is methyl, and methoxy, and -C1-C6 alkyl substituted with one or more groups selected from -O(CH2)2OCH3.

[0218] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,100a But -CH2NR 500A R 500B and R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy.

[0219] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a But -CH2NR 500A R 500B and R 500A and R 500B together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, -forms a 4-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl, and azabicyclo[3.2.1]octanyl, and the heterocyclyl is selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -Optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 4-8 membered heterocyclyl is oxo, cyano, hydroxyl, methoxy, It is optionally substituted with one or more substituents independently selected from the group consisting of -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl. In some embodiments, the 4-8-membered heterocyclyl is optionally substituted with one or more methyl substituents. In some embodiments, the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorpholinyl; and azabicyclo[3.2.1]octanyl.

[0220] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a But -CH2NR 500A R 500B and R 500A and R 500B together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, -forms a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of acylamino, carboxamido, -SO2CH3, -CF3, C1-C6 alkyl, halo, and acyl. In some embodiments, the 6-membered heterocyclyl is selected from the group consisting of piperazinyl optionally substituted with one or more C1-C6 alkyl substituents, and morpholinyl optionally substituted with one or more C1-C6 alkyl substituents.

[0221] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a But -CH2NR500A R 500B -CHNR 500A R 500B is -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0222] [ka] In some embodiments, -CHNR 500A R 500B teeth, -(CH2)N(CH2CH2OCH3)2,

[0223] [ka] is selected from the group consisting of:

[0224] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a is -(CH2) p R 600 and R 600 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and piperidinyl, and m is as defined above. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, -(CH) p R 600 teeth,

[0225] [ka] is selected from the group consisting of:

[0226] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a-CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)2NHCO2CH3,

[0227] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0228] [ka] is selected from the group consisting of:

[0229] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a is -CH3 and -CH2NR 500A R 500B and R 500A and R 500B is as previously described in any embodiment described herein. In some embodiments, R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy; or 500A and R 500B taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl.

[0230] In some embodiments, R of Formula III, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100a is -CH3, -(CH2)N(CH2CH2OCH3)2,

[0231] [ka] is selected from the group consisting of:

[0232] In some embodiments, R of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 100c is chloro.

[0233] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 400b But, Y 1 and R 400d But Z 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0234] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 400d But, Y 1 and R 400b But Z 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0235] In some embodiments, Y of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 1 is -CF3.

[0236] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CHNR 7A R 7B and R 7A and R 7B is as previously described herein. In some embodiments, R 7A and R 7B Each of R is methyl. 7A and R 7Btogether with the nitrogen to which they are attached, In some embodiments, R 7A and R 7B taken together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl optionally substituted with one or more C1-C6 alkyl and morpholinyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R 7A and R 7B taken together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl. -CH2NR 7A R 7B is -CH2N(CH3)2,

[0237] [ka] is selected from the group consisting of:

[0238] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -(CH2) q R 8 and R 8 is as previously described herein. In some embodiments, R 8 is a 6-membered heterocycle optionally substituted with methyl. In some embodiments, R 8 is 4-methylpiperidinyl. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, -(CH) q R 8 teeth,

[0239] [ka] is.

[0240] In some embodiments, Z of Formula I 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B , and -(CH2) q R 8 and R 7A , R 7B , R 8 , and p is as described in any embodiment herein.

[0241] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B , and -(CH2) q R 8 and R 7A , R 7B , R 8 , and p is as described in any embodiment herein.

[0242] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B , and -(CH2) q R 8 and R 7A and R 7B Each of R is methyl. 7A and R 7Btogether with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl, R 8 is 4-methylpiperidinyl.

[0243] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0244] [ka] is selected from the group consisting of:

[0245] In some embodiments, Z of Formula III 1 or R of formula IIIa 400d or a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0246] [ka] Y of formula III is selected from the group consisting of 1 are chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, It is selected from the group consisting of -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl.

[0247] In some embodiments, Z of Formula III 1 or R of formula IIIa 400dor a pharmaceutically acceptable salt, solvate, or prodrug thereof is -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0248] [ka] Y of formula III is selected from the group consisting of 1 is -CF3.

[0249] In some embodiments, R of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof 400d -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0250] [ka] R of formula III is selected from the group consisting of 400b is -CF3.

[0251] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, R 100a -CH3 and -CH2NR 500A R 500B is selected from the group consisting of R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy, or 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 100c But it's Chloro. R 400b and R 400d Each of the1 and Z 1 independently selected from the group consisting of: 400b Y 1 If R 400d is Z 1 and R 400b Z 1 If R 400d is Y 1 and Y 1 is selected from the group consisting of chloro, fluoro, iodo, bromo, —CF3, —CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, —OCF3, —SO2(C1-C6)alkyl, cyano, and —CO2(C1-C6)alkyl; Z 1 is -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B , and -(CH2) q R 8 and R 7A and R 7B is methyl, or 7A and R 7B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl; R 8 is 4-methylpiperidinyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0252] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, R 100a -CH3 and -CH2NR 500A R 500B is selected from the group consisting of R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy, or 500A and R500B together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 100c But it's Chloro. R 400b and R 400d Each of the 1 and Z 1 independently selected from the group consisting of: 400b Y 1 If R 400d is Z 1 and R 400b Z 1 If R 400d is Y 1 and Y 1 is -CF3, Z 1 is -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B , and -(CH2) q R 8 and R 7A and R 7B is methyl, or 7A and R 7B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl; R 8 is 4-methylpiperidinyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0253] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, R 100a -CH3, -(CH2)N(CH2CH2OCH3)2,

[0254] [ka] is selected from the group consisting of R 100c But it's Chloro. R 400b and R 400d Each of the 1 and Z 1 independently selected from the group consisting of: 400b Y 1 If R 400d is Z 1 and R 400b Z 1 If R 400d is Y 1 and Y 1 is CF3 and Z 1 is -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0255] [ka] The present invention describes a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0256] Some embodiments are compounds of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, R 100a -CH3, -(CH2)N(CH2CH2OCH3)2,

[0257] [ka] is selected from the group consisting of R 100c But it's Chloro. R 400b is CF3, R 400d is -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0258] [ka] The present invention describes a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0259] Some embodiments are compounds of Formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, R 100a -CH3, -(CH2)N(CH2CH2OCH3)2,

[0260] [ka] is selected from the group consisting of R 400d But -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2,

[0261] [ka] The present invention describes a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0262] Some embodiments describe compounds of formula IIIa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: During the ceremony, Some embodiments are compounds selected from the group consisting of:

[0263] [Table 7-1]

[0264] [Table 7-2] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0265] Some embodiments are compounds selected from the group consisting of:

[0266] [Table 8] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0267] Additional compounds that are mitochondrial uncouplers, but that may not necessarily have the unexpected properties of the other compounds disclosed herein, include:

[0268] [Table 9-1]

[0269] [Table 9-2]

[0270] [Table 9-3] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0271] The compounds of the embodiments described herein may have one or more asymmetric carbon atoms and therefore can exist in the form of optical isomers as well as racemic or non-racemic mixtures thereof. In the embodiments described herein, the compounds may be utilized as single isomers or as mixtures of stereochemically isomeric forms. Diastereoisomers, i.e., non-superimposable stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation. Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by treatment with an optically active acid or base to form diastereoisomeric salts. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Diastereomeric mixtures can be separated by crystallization followed by liberation of the optically active base from the salt. Another method for separating optical isomers involves the use of a chiral chromatography column optimally selected to maximize the separation of the enantiomers. Yet another available method involves the synthesis of covalently bonded diastereomeric molecules by reacting the compounds of the present invention with activated optically pure acids or optically pure isocyanates. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds. The optically active compounds of the present invention can also be obtained by utilizing optically active starting materials. These isomers may be in the form of free acids, free bases, esters, or salts.

[0272] The compounds according to the embodiments described herein may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not important, so long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein can be prepared from inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. In some embodiments, the salt is a hydrochloride salt. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acid classes, including, but not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, maleic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, algenic acid, β-hydroxybutyric acid, malonic acid, galactic acid, and galacturonic acid. Pharmaceutically acceptable base addition salts of the compounds described herein can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines , substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed diamines and mixed triamines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, etc. Also included are amines where two or three of the substituents together with the amino nitrogen form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, etc. It should also be understood that other carboxylic acid derivatives, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, etc., are useful in the preparation of pharmaceutically acceptable salts.

[0273] Acceptable salts can be obtained using standard procedures well known in the art, for example, by treating a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of organic acids (e.g., carboxylic acids) can also be made.

[0274] Compounds according to embodiments described herein may have a prodrug form. Any compound that is converted in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are well known in the art (see, for example, Medicinal Chemistry: Principles and Practice, FD King, ed., The Royal Society of Chemistry, Cambridge, UK, 1994; Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, B. Testa, JM Mayer, VCHA and Wiley-VCH, Zurich, Switzerland, 2003; The Practice of Medicinal Chemistry, C. Wermuth, 2004). nd ed., Academic Press, San Diego, CA, 1999). Some prodrugs of the present invention include those in which the 2-hydroxy of the benzamide is substituted with, but not limited to,

[0275] [ka] and —CH 2 OAc.

[0276] In some embodiments, a prodrug of a compound according to any of the embodiments described herein can take the form of a carbamate. For example, the 2-hydroxy group of a benzamide according to any of the embodiments described can be converted at the same position to a carbamate group, —OC(O)NR 9 R 10 can be converted to R 9 and R 10 are each independently selected from the group consisting of hydrogen and optionally substituted C1-C6-alkyl, or R 9 and R 10 taken together with the nitrogen to which they are attached form an optionally substituted C3-C6-heterocyclyl.

[0277] The present invention also encompasses isolated compounds, which refer to compounds that represent at least 10%, preferably at least 20%, more preferably at least 50%, and most preferably at least 80% of the compounds present in a mixture.

[0278] In some embodiments of the present invention, one or more hydrogen atoms are replaced by deuterium.It is well established that deuteration of bioactive compounds provides the advantage of maintaining the pharmacological profile of their hydrogen counterparts, while favorably affecting their metabolic results.In the compound of the present invention, selectively replacing one or more hydrogen atoms with deuterium can improve the safety, tolerability and efficacy of the compound compared with its all-hydrogen counterpart.

[0279] Methods for incorporating deuterium into compounds are well established. Using metabolic studies established in the art, compounds of the invention can be tested to identify sites for selective placement of deuterium isotopes where the isotope is not metabolized. Furthermore, these studies identify sites of metabolism as positions where deuterium atoms are placed.

[0280] Some embodiments describe pharmaceutical compositions comprising a compound according to embodiments described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

[0281] The compounds or pharmaceutically acceptable salts thereof can be formulated for oral, intravenous, intramuscular, subcutaneous, or parenteral administration for the therapeutic or prophylactic treatment of the diseases, disorders, or infections described herein. For oral or parenteral administration, the compounds of the present invention can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. Pharmaceutical compositions containing the compounds of the present invention contain from about 0.1 to about 99% by weight, more usually from about 10 to about 30%, of the active compound.

[0282] The pharmaceutical preparations disclosed herein are prepared according to standard procedures and administered at dosages selected to reduce, prevent, or eliminate infection (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., and Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, NY, the contents of which are incorporated herein by reference for a general description of methods for administering various agents for human treatment). The pharmaceutical compositions of the invention can be delivered using controlled-release delivery systems (e.g., capsules) or sustained-release delivery systems (e.g., bioerodible matrices).

[0283] Pharmaceutically acceptable pharmaceutical compositions of the present invention comprise one or more compounds of the present invention together with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients (collectively referred to herein as "carrier" substances), and optionally other active ingredients. Pharmaceutical compositions may contain common carriers and excipients such as cornstarch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid. Pharmaceutical compositions may contain croscarmellose sodium, microcrystalline cellulose, cornstarch, sodium starch glycolate, and alginic acid.

[0284] Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

[0285] Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone oil, talc, waxes, oils and colloidal silica.

[0286] Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, etc. may also be used. It may also be desirable to add coloring agents to make the dosage form more aesthetically pleasing or to aid in product identification.

[0287] For oral use, solid preparations such as tablets and capsules are particularly useful. Sustained-release preparations or enteric-coated preparations can also be designed. For application to children and the elderly, suspensions, syrups, and chewable tablets are particularly suitable. For oral administration, the pharmaceutical composition is, for example, in the form of a tablet, capsule, suspension, or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a therapeutically effective amount of the active ingredient. Examples of such dosage units are tablets and capsules. For therapeutic purposes, tablets and capsules can contain, in addition to the active ingredient, conventional carriers such as binders, for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth; fillers, for example, calcium phosphate, glycine, lactose, corn starch, sorbitol, or sucrose; lubricants, for example, magnesium stearate, polyethylene glycol, silica, talc; disintegrants, for example, potato starch, flavorings or colorings, or acceptable wetting agents. Oral liquid preparations are generally in the form of aqueous or oily solutions, suspensions, emulsions, syrups or elixirs, and may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents, flavoring agents, etc. Examples of additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fat, lecithin, methylcellulose, methyl or propyl parahydroxybenzoate, propylene glycol, sorbitol, or sorbic acid.

[0288] For intravenous (IV) use, the compounds according to the present invention can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion. Intravenous fluids include, but are not limited to, saline or Ringer's solution. Intravenous administration can be achieved using, but is not limited to, a syringe, a minipump, or an intravenous line.

[0289] Preparations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.These solutions or suspensions can be prepared from sterile powders or granules with one or more of the carriers mentioned for use in preparations for oral administration.The compounds can be dissolved in polyethylene glycol, propylene glycol, ethanol, corn oil, benzyl alcohol, sodium chloride, and / or various buffer solutions.

[0290] For intramuscular preparations, a sterile preparation of the compound or a suitable soluble salt form of the compound, e.g., the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection (WFI), saline, or 5% glucose. A suitable insoluble form of the compound can be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base (e.g., an ester of a long-chain fatty acid such as ethyl oleate).

[0291] The dose of an intravenous, intramuscular, or parenteral formulation of the compound can be administered as a bolus or by slow infusion. A bolus is a dose administered in less than 30 minutes. In a preferred embodiment, the bolus is administered in less than 15 minutes or less than 10 minutes. In a more preferred embodiment, the bolus is administered in less than 5 minutes. In an even more preferred embodiment, the bolus is administered within 1 minute. An infusion is a dose administered at a rate of 30 minutes or more. In a preferred embodiment, the infusion is for 1 hour or more. In another embodiment, the infusion is substantially constant.

[0292] For topical use, the compounds of the present invention may also be prepared in a suitable form for application to the skin or mucous membranes of the nose and throat, and may take the form of a cream, ointment, liquid spray or inhalant, lozenge, or throat paint. Such topical formulations may further contain compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.

[0293] For application to the eye or ear, the compounds of the invention may be provided in liquid or semi-liquid form formulated in a hydrophobic or hydrophilic base as an ointment, cream, lotion, paint or powder.

[0294] For rectal administration, the compounds of the present invention can be administered in the form of suppositories mixed with a conventional carrier such as cocoa butter, wax or other glycerides.

[0295] Alternatively, the compounds of the present invention may be in powder form for reconstitution in a suitable pharmaceutically acceptable carrier at the time of delivery. In another embodiment, the unit dosage form of the compound may be a solution of the compound, or preferably its salt, in a suitable diluent in a sterile, sealed ampoule or sterile syringe. The concentration of the compound in the unit dosage may vary, for example, from about 1% to about 50%, depending on the compound used and its solubility and the dosage desired by the physician.

[0296] In some embodiments, the pharmaceutical compositions described herein are at therapeutically effective dosage levels. In some embodiments, the pharmaceutical compositions are for administration to patients, e.g., humans and the elderly, at therapeutically effective levels of 0.001 to 100 mg per kg of body weight per day. Therapeutically effective amounts are generally about 0.5 mg to 10 g per patient per day, which may be administered in single or multiple doses. In some embodiments, therapeutically effective amounts have lower limits of 0.5 mg, 10 mg, 1 mg, 500.0 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, 5000 mg, 5500 mg, 6000 mg, 6500 mg, 7000 mg, 7500 mg, 8000 mg, 8500 mg, 9000 mg, 9500 mg, and 100 mg. 000mg, and upper limits are between 10000mg, 9500mg, 9000mg, 8500mg, 8000mg, 7500mg, 7000mg, 6500mg, 6000mg, 5500mg, 5000mg, 4500mg, 4000mg, 3500mg, 3000mg, 2500mg, 2000mg, 1500mg, 1000mg, 500.0mg, 100mg, 10mg, and 0.5mg. In some embodiments, the therapeutically effective amount is about 0.5 mg to 2500 mg per patient per day, in some embodiments about 0.5 mg to 200 mg per patient per day, in some embodiments about 0.5 mg to 500 mg per patient per day, in some embodiments about 0.5 mg to 1000 mg per patient per day, and in some other embodiments about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in solid dosage forms containing about 0.5 mg to 500 mg of active ingredient, or about 1 mg to 250 mg of active ingredient. Pharmaceutical compositions may be provided in solid dosage forms containing, for example, about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, or 1000 mg of active ingredient.For oral administration, the composition may be provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000, and 2000 milligrams of active ingredient, for symptomatic adjustment of dosage to the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times, or four times per day.

[0297] Unexpected properties Mitochondrial uncouplers with improved PK profiles Some embodiments describe mitochondrial uncoupling agents provided herein that have improved pharmacokinetic (PK) profiles, such as significantly increased systemic exposure (i.e., due to increased solubility and absorption) consistent with dramatically improved efficacy, and significantly reduced half-lives consistent with a once-daily oral dosing regimen, and elimination of toxicity risk factors due to accumulation over long-term use for chronic conditions or disorders.

[0298] A common feature of conventional benzamide compounds with mitochondrial uncoupling activity is low systemic exposure. As shown in Table 1, niclosamide ethanolamine exhibited only approximately 1800 h post-dose in a 24-hour period after administration of 50 mg / kg. * Compound 31 in WO 2016 / 081599 and compound 27 in U.S. Pat. No. 10,227,315 each have an oral exposure of approximately 2400 hr after oral administration of 20 mg / kg over a 24-hour period. * ng / ml, and approximately 3000 hours after oral administration of 10 mg / kg *These compounds have a systemic exposure of only ng / ml (Table 1). To overcome the poor pharmacokinetic properties of previously disclosed compounds, such as low systemic exposure and short half-lives, studies in animal models have required the compounds to be mixed with food, and high doses of the compounds have been required to achieve efficacy (e.g., 1500 ppm niclosamideethanolamine (NEN) in the diet, equivalent to 150 mg / kg / day (Tao, et al. 2014 and WO 2012 / 068274), or 600-750 ppm in the diet, equivalent to 60-75 mg / kg / day (compound 28 in U.S. Pat. No. 10,227,315)). Neither the high doses required nor the need to mix the compound into food are compatible with therapeutic development in humans.

[0299] As exemplified in Table 1, novel compounds (e.g., compounds 2, 9, and 78) unexpectedly exhibited significantly increased systemic exposure without compromising uncoupling activity, with increases of 20- to 160-fold relative to conventional uncoupling agents with the best systemic exposure.

[0300] [Table 10]

[0301] Table 2 provides additional compounds with dramatically increased systemic exposure (see Example B3).

[0302] [Table 11] +++: 10,000-30,000, ++++: 30,001-60,000, +++++: 60,001-120,000, ++++++: >120,000

[0303] As shown in Table 3, the mitochondrial uncoupling activity of compound 49 of US Pat. No. 10,227,315 is lower compared to the analogous compounds of the present invention.

[0304] [Table 12]

[0305] Dramatically improved metabolic stability and half-life characteristics Some embodiments describe compounds presented herein that have improved metabolic stability and half-life.

[0306] One major reason that previously known mitochondrial uncouplers, such as DNP, exhibit a narrow therapeutic index is due to their long half-lives. For example, DNP has a half-life measured in days to weeks, leading to toxic levels accumulating in the body during long-term use to treat chronic conditions or disorders. Excretion characteristics are also important in the development of orally administered drugs. The drug must not only have sufficient exposure, but also be eliminated at a rate that is neither too short nor too long. On the one hand, it is important that oral drugs have a sufficiently long half-life in patients so that the drug can be administered at regular intervals (e.g., once a day instead of once an hour). On the other hand, the half-life of the compound cannot be too long, as this could result in toxic accumulation of the drug in the patient's body. For drugs administered orally once daily, a half-life of approximately 8 to 12 hours is considered a desirable characteristic, but a half-life of more than 48 hours is incompatible with once-daily oral administration and may lead to toxic accumulation of the drug. For example, Compound 2 of U.S. Patent No. 10,227,315 exhibits an extremely long half-life (66.9 hours, Table 4, Example B8).This long half-life correlates with extremely high metabolic stability (rat microsome metabolic stability, half-life 2,131.8 minutes).In other words, the extremely long half-life of Compound 2 of U.S. Patent No. 10,227,315 is mainly caused by the inability of liver metabolic enzymes to efficiently metabolize these compounds.

[0307] As shown in Table 4, compound 17 of the present invention unexpectedly has a dramatically reduced metabolic stability (from 2,132 minutes to 145 minutes, Example B7) and a concomitantly reduced oral half-life (from 66.9 hours to 8.6 hours, Example B8). The structural modification does not reduce mitochondrial uncoupling activity and is therefore expected to have a better toxicity profile when used to treat chronic conditions or disorders requiring long-term use.

[0308] [Table 13]

[0309] The half-lives in a rat liver microsome stability assay were determined for several compounds described herein (Example B7) and compared to compounds 2, 53, and 54 in U.S. Pat. No. 10,227,315 (Table 5). The compounds of the present invention exhibit dramatically improved metabolic stability (favorable half-lives that are less likely to cause toxicity when used to treat chronic conditions or disorders requiring long-term use) without reducing uncoupling activity (see Tables 5 and 8).

[0310] [Table 14-1]

[0311] [Table 14-2]

[0312] MMP-retaining compounds Some embodiments describe mitochondrial uncouplers provided herein that effectively increase OCR without reducing or significantly reducing MMP. These compounds are referred to in this disclosure as MMP-preserving uncouplers.

[0313] Mechanistically, conventional mitochondrial uncouplers transport protons across the inner mitochondrial membrane into the mitochondrial matrix. Because the mitochondrial membrane potential is supported by a proton gradient across the membrane, conventional uncouplers necessarily require a rapid dissipation of the mitochondrial membrane potential to sustain their mitochondrial uncoupling action (Figure 3). Prior to this disclosure, all mitochondrial uncouplers (referred to herein as conventional uncouplers) tested possessed the properties of increasing OCR and decreasing MMP, and the concentrations resulting in OCR increase and MMP disappearance correlated (Figure 4). Figure 4 shows that the conventional uncoupler, FCCP, exhibited a C of less than 3. 10%TMRE / C min-OCR where C 10%TMRE is the concentration that results in 10% MMP retention (or 90% MMP loss, as measured by TMRE staining), and C min-OCR is the minimum concentration that results in an increase in OCR. Therefore, the activity of reducing MMPs is considered to be a second characteristic of mitochondrial uncoupling. Because MMPs are important for cell survival and normal cell function in many tissues and organs, this seemingly inherent property of conventional mitochondrial uncoupling agents to eliminate MMPs poses a major safety obstacle to their therapeutic development.

[0314] In some embodiments, the mitochondrial uncouplers described herein represent a fundamentally different category of mitochondrial uncouplers that effectively induce mitochondrial uncoupling (increasing mitochondrial oxygen consumption in the presence of oligomycin) without significantly reducing mitochondrial membrane potential across a wide concentration range (Figures 5 and 6, Example B2). Figure 5 shows that compound 25 does not appear to reduce MMP across a wide concentration range where OCR increases and reaches a maximum level. The C of compound 25 10%TMRE / C min-OCR The ratio of C to MMP is greater than 25. Figure 6 shows that compound 64 effectively induces mitochondrial uncoupling over a wide concentration range without significantly reducing MMP. 10%TMRE / C min-OCR The ratio is 10 to 25.

[0315] After determining the mitochondrial uncoupling activity of the mitochondrial uncouplers described herein (Example B1), a mitochondrial membrane potential assay was performed on the mitochondrial uncouplers using a standard TMRE (tetramethylrhodamine ethyl ester) staining method with cultured mammalian cells (Example B2). The results were categorized into three groups, with Compound 25-like compounds designated as MMP-retaining uncouplers (C 10%TMRE / C min-OCR Compound 64-like compounds are MMP-retaining uncouplers (C between 10 and 25). 10%TMRE / C min-OCR ), and conventional uncouplers (C below 3 10%TMRE / C min-OCR The results are summarized in Table 6.

[0316] [Table 15] C 10%TMRE is the concentration that results in 10% MMP retention (or 90% MMP loss as measured by TMRE staining), and C min-OCR is the minimum concentration that results in an OCR increase.

[0317] Mechanistically, chemical uncouplers are lipophilic weak acids or bases that localize to the inner mitochondrial membrane and transport protons across the membrane into the mitochondrial matrix through protonation and deprotonation cycles (Figures 3 and 7A). Because mitochondrial membrane potential (MMP) is supported by a proton gradient across the membrane, it is highly unexpected that compounds can uncouple mitochondrial oxidation (transport protons) without significantly reducing MMP. We analyzed benzothiazole derivatives of benzamide uncouplers that exhibit MMP-sparing activity. All of them contain tertiary or secondary amine groups with pKas greater than 10.0. The amine groups are positively charged in the cellular environment, where the pH is generally below 8.0.

[0318] Without being bound by theory, we propose that the mechanism of action of MMP-retained uncouplers is as shown in Figure 7B. Essentially, MMP-retained uncoupler molecules consist of two functional moieties (Figure 7C). The first moiety functions as a conventional uncoupler, transporting protons from the mitochondrial intermembrane space to the mitochondrial matrix (Figure 7B). The second moiety is a positively charged functional group that is poorly impermeable to the inner mitochondrial membrane. This feature allows for asymmetric distribution and orientation of the compound across the inner mitochondrial membrane, resulting in a higher concentration of charged molecules in the intermembrane space than in the mitochondrial matrix, with the positively charged moiety distributed primarily on the outer surface of the membrane (facing the intermembrane space, Figure 7B). As mitochondrial uncoupling occurs and the resulting proton gradient across the membrane decreases, the loss of membrane potential due to the reduced proton gradient is compensated for by the asymmetric positive charge distribution across the membrane provided by the MMP-retained uncoupler. Thus, the overall mitochondrial membrane potential is minimally affected over a wide concentration range of the uncoupler.

[0319] Figure 7D shows the structural features of all MMP-retaining uncouplers listed in Table 6, where the positive charge is provided by a tertiary or secondary amine. By modifying the amine-containing moiety, we were able to fine-tune the MMP-retaining activity. 10%TMRE / C min-OCR We found that reducing the ratio of MMP-containing uncouplers from >25 to between 10 and 25 significantly reduced the ratio. Some modifications of the amine-containing moiety could further reduce the ratio to near 3, which corresponds to the ratio of typical conventional mitochondrial uncouplers. Figure 7E shows a specific example of an MMP-retaining uncoupler, with the conventional uncoupler components shown in frame.

[0320] Improved in vivo safety profile Some embodiments describe that MMP-retaining uncouplers exhibit a significantly improved safety profile compared to conventional uncouplers, such as the benchmark conventional uncoupler DNP.

[0321] DNP is a conventional mitochondrial uncoupler that was previously used in humans to treat obesity. However, it exhibited high levels of toxicity and a narrow therapeutic window. It was subsequently withdrawn from the market for human use. The toxicity profiles of MMP-retaining uncouplers, Compound 25 and Compound 64, were compared with those of DNP as examples. Compound 25 and Compound 64 have excellent oral absorption, systemic exposure, and efficacy in reducing blood glucose and hepatic steatosis in animal models (Tables 2, 5, and 9).

[0322] Some embodiments demonstrate that MMP-retaining uncouplers exhibit significantly improved acute toxicity profiles. Figure 8 (Example B9) shows that Compound 64 and Compound 25 have LD50 (lethal dose, 50% animal death) / MED (minimum effective dose) ratios of greater than 400 and 200, respectively, while DNP has an LD50 / MED ratio of 30.

[0323] Some embodiments demonstrate MMP-retaining uncouplers that exhibit significantly improved short-term (10-day) toxicity profiles. Figures 9-10 (Example B10) show that the ratio of NOAEL (No Observed Adverse Effect Level) to MED for compound 64 is greater than 40 (between 40 and 57 using different parameters), the NOAEL / MED ratio for compound 25 is greater than 19, while the NOAEL / MED ratio for DNP is reported to be less than 3.

[0324] Some embodiments describe methods for preparing MMP-retaining uncouplers from conventional mitochondrial uncouplers by adding a positively charged side chain to the conventional uncoupler, for example, by adding a tertiary amine (or secondary amine)-containing side chain (Figure 7D), as shown in Figure 7C. As shown in Figure 7E, a tertiary amine-containing moiety was added to the conventional uncoupler (in-frame structure). This modification results in a C of the conventional uncoupler (3). 10%TMRE / C min-OCR ) with MMP-retaining uncouplers (listed in Table 2 and having a C of greater than 25 10%TMRE / C min-OCR effectively converting it to a

[0325] Some embodiments are of the formula: (R A ) u -R B mitochondrial membrane-retaining uncoupler compounds, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, In the formula, R A and R B is covalently bonded, Each R A is independently a secondary or tertiary amine-containing moiety; u is an integer selected from the group consisting of 1 and 2; R B is R A a conventional mitochondrial uncoupler prior to covalent attachment to the mitochondrial membrane-retaining uncoupler compound,

[0326] [ka] isn't it.

[0327] Some embodiments provide a method for preparing a mitochondrial membrane-retaining mitochondrial uncoupling agent, comprising: 1. Identifying conventional mitochondrial uncouplers; 2. Designing a compound that covalently attaches at least one moiety that can be positively charged in a cellular environment to a conventional mitochondrial uncoupler; 3. preparing a compound of Step 2, wherein the compound is a mitochondrial membrane-retaining uncoupler compound.

[0328] In some embodiments, the moiety that can be positively charged in a cellular environment is a secondary or tertiary amine moiety.

[0329] Some embodiments provide a method for preparing a mitochondrial membrane-retaining mitochondrial uncoupling agent, comprising: 1. Identifying conventional mitochondrial uncouplers; 2. Designing a compound that covalently attaches at least one secondary or tertiary amino moiety to a conventional mitochondrial uncoupler; 3. preparing a compound of Step 2, wherein the compound is a mitochondrial membrane-retaining uncoupler compound.

[0330] In some embodiments, a secondary or tertiary amino moiety or R A -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -CH2NHSO2CH3,

[0331] [ka] -(CH2) r’ NR 5000A R 5000B , (CH2) m’ NR 5A R 5B , -(CH2) o’ NR 50A R 50B , -(CH2) p’ NR 500A R 500B , -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B , -(CH2)O(CH2)2NR 2000A R 2000B , -(CH2) q’ NR 7A R 7B , and -(CH2) t’ NR 70000A R 70000B and R 5000A , R 5000B , R 5A , R 5B , R 50A , R 50B , R 500A , R 500B , R2A , R 2B , R 2000A , R 2000B , R 7A , R 7B , R 7000A , R 7000B , r', m', o', p', q', and t' are as previously described in any embodiment described herein.

[0332] In some embodiments, a secondary or tertiary amino moiety or R A -CH2NHSO2CH3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NHC(O)CH2CH3,

[0333] [ka] -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3,

[0334] [ka] C(O)N(CH2CH2OCH3)2, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3,

[0335] [ka] is selected from the group consisting of:

[0336] In some embodiments, a secondary or tertiary amino moiety or R A teeth,

[0337] [ka] is selected from the group consisting of:

[0338] In some embodiments, a conventional mitochondrial uncoupler or R B is selected from the group consisting of conventional mitochondrial uncoupling agents described herein. In some embodiments, a conventional mitochondrial uncoupling agent or R B is selected from the group consisting of conventional mitochondrial uncouplers described in U.S. Pat. No. 10,227,3158, U.S. Patent Application No. 15 / 527,808 and Childress, ES, et al. (2018) J. Med. Chem., 61(11), 4641-4655.

[0339] In some embodiments, a conventional mitochondrial uncoupler or R B teeth,

[0340] [ka] is selected from the group consisting of:

[0341] In some embodiments, a secondary or tertiary amino moiety or R A , conventional mitochondrial uncouplers or R B , and mitochondrial membrane-retaining uncoupler compounds (R A ) u -R B are as listed in Table 7.

[0342] [Table 16-1]

[0343] [Table 16-2]

[0344] [Table 16-3]

[0345] [Table 16-4]

[0346] [Table 16-5]

[0347] [Table 16-6]

[0348] Treatment method In some embodiments, a method of treating a mitochondrial-associated condition or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to an embodiment described herein.

[0349] In some embodiments, the mitochondrial-associated condition or disorder has one or more underlying causative factors selected from the group consisting of hyperglycemia, abnormal accumulation of lipids in cells, abnormal accumulation of lipids in tissues, abnormal lipid metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis. In some embodiments, the mitochondrial-associated condition or disorder has one or more underlying causative factors selected from the group consisting of hyperglycemia, lipid accumulation, insulin resistance, altered cell metabolism, fibrosis, abnormal TGF-beta activation, or abnormal cell proliferation.

[0350] In some embodiments, the mitochondrial-associated condition or disorder has one or more underlying symptoms selected from the group consisting of hyperglycemia, abnormal accumulation of lipids in cells, abnormal accumulation of lipids in tissues, abnormal lipid metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis. In some embodiments, the mitochondrial-associated condition or disorder has one or more underlying causative factors selected from the group consisting of hyperglycemia, lipid accumulation, insulin resistance, altered cell metabolism, fibrosis, abnormal TGF-beta activation, or abnormal cell proliferation.

[0351] In some embodiments, the mitochondrial-associated condition or disorder is a metabolic disease, cancer, an autoimmune disease, pulmonary fibrosis, a skin disorder, an infectious disease, or a neurodegenerative disease. In some embodiments, the mitochondrial-associated condition or disorder is a metabolic disease, cancer, and an autoimmune disease, or an infectious disease.

[0352] In some embodiments, the mitochondrial-related condition or disorder is a metabolic disease, hi some embodiments, the metabolic disease is selected from the group consisting of type 2 diabetes, diseases characterized by insulin resistance or hyperglycemia, obesity or obesity-related complications, and diseases characterized by abnormal lipid accumulation.

[0353] In some embodiments, methods of treating a metabolic disease or disorder characterized by insulin resistance or abnormal tissue lipid accumulation, or a disease or disorder in which insulin resistance or abnormal tissue lipid accumulation is a symptom, or cancer or hyperplasia, in a subject in need thereof, comprise administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to embodiments described herein. In some embodiments, the metabolic disease or disorder is type 2 diabetes, or a disease characterized by insulin resistance or hyperglycemia.

[0354] In some embodiments, the metabolic disease or disorder described in any embodiment herein is a complication caused by type 2 diabetes selected from the group consisting of diabetes-induced cardiovascular disease, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart disease, nephropathy, retinopathy, neuropathy, and diabetic heart failure. In some embodiments, the metabolic disease or disorder is obesity or an obesity-related complication.

[0355] In some embodiments, the metabolic disease or disorder described in any of the embodiments herein is non-alcoholic fatty liver disease (NAFLD) and includes at least one prognostic stage of the disease selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and NAFLD-induced hepatocellular carcinoma (HCC). In some embodiments, the metabolic disease or disorder is alcoholic fatty liver disease or a complication caused by alcoholic fatty liver disease. In some embodiments, the complication of alcoholic fatty liver disease includes alcoholic hepatitis, cirrhosis, or a combination thereof.

[0356] In some embodiments, the metabolic disease or disorder is dyslipidemia or a complication caused by dyslipidemia.

[0357] In some embodiments, the cancer is a primary cancer selected from the group consisting of hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer. In some embodiments, the cancer is a metastatic cancer originating from a primary tumor of another tissue type. In some embodiments, the metastatic site is selected from the group consisting of liver, lung, and intraperitoneal cavity.

[0358] In some embodiments, a compound of the embodiments described herein is administered in combination with a second agent indicated for the aforementioned disorders or diseases, either simultaneously with, before, or after the administration of the second agent. In some embodiments, the second agent is an antidiabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 agonists, SGLT2 inhibitors, and DPP-4 inhibitors. In some embodiments, the second agent is an anti-obesity agent. In some embodiments, the second agent is an anti-non-alcoholic fatty liver disease agent. In some embodiments, the second agent is an anti-alcoholic fatty liver disease agent. In some embodiments, the second agent is an anti-dyslipidemic agent.

[0359] In some embodiments, the compound of the embodiments described herein is administered in combination with a second anti-non-alcoholic fatty liver disease agent.In some embodiments, the compound of the present invention is administered in combination with a second anti-alcoholic fatty liver disease agent.In some embodiments, the compound of the present invention is administered in combination with a second anti-dyslipidemic agent.

[0360] In some embodiments, the compound may be administered in combination with a second anti-cancer agent or anti-cancer regimen. In some embodiments, the second anti-cancer agent is a cancer immunotherapeutic agent. In some embodiments, the cancer immunotherapeutic agent is selected from the group consisting of antibodies against PD-1 / PD-L1, antibodies against other immune checkpoint proteins, CAR-T cells, and other therapeutic immune cells. In some embodiments, the compound may be administered before, simultaneously with, or after the administration of the second antimetabolic disease agent or anti-cancer agent.

[0361] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the compounds described herein are used as veterinary medicines to treat diabetes or a diabetes-related disorder, and the subject is a mammal.

[0362] Some embodiments are directed to methods for long-term disease management of a metabolic disease or disorder, comprising administering to a subject in need of such long-term management an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, methods for long-term disease management of a metabolic disease or disorder or for long-term disease management of cancer comprise administering to a subject in need of such long-term management an effective amount of a compound or pharmaceutical composition according to any of the embodiments described herein. In some embodiments, the metabolic disease or disorder is obesity, obesity-related complications, type 2 diabetes, or type 2 diabetes-related complications. In some embodiments, the cancer is any primary or metastatic tumor.

[0363] In some embodiments, the present disclosure describes the use of a compound according to any of the embodiments described herein in the manufacture of a medicament for the treatment of diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, or a disease in which insulin resistance or abnormal accumulation of lipids in tissues is a symptom, or an associated disorder or complication, including, but not limited to, hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD-induced hepatocellular carcinoma (HCC). In some embodiments, the compounds of the embodiments herein may be used to manufacture a medicament for the treatment of cancer, a disease in which cell proliferation (hyperplasia) is a symptom, or a cancer- or hyperplasia-related complication.

[0364] Some embodiments herein are directed to methods of treating or preventing a metabolic disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0365] Some embodiments herein provide methods for treating and alleviating symptoms of one or more complications of the above-mentioned metabolic disorders, including, but not limited to, obesity (characterized by excessive accumulation of lipids in adipocytes), pre-type 2 diabetes (characterized by insulin resistance, usually caused by ectopic accumulation of lipids in liver and muscle cells), type 2 diabetes (characterized by insulin resistance and hyperglycemia), non-alcoholic or alcoholic fatty liver disease (characterized by abnormal accumulation of lipids in the liver), dyslipidemia (characterized by abnormal lipid deposition in tissues other than adipose tissue), and hypertension, cardiovascular disease, nephropathy, and neuropathy, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject. These diseases or disorders can be caused by dietary, environmental, medical, and / or genetic factors. The methods described herein can also be used for the prevention of the above-mentioned metabolic disorders in subjects with risk factors, including, but not limited to, dietary, environmental, medical, and genetic predispositions. Additionally, some embodiments provide methods for long-term chronic disease management and longevity management by reducing insulin resistance or lowering blood glucose levels.

[0366] In some embodiments, the metabolic disease or disorder is type 2 diabetes or a related disease that results in insulin resistance or hyperglycemia, hi some embodiments, the metabolic disease or disorder is obesity or one or more obesity-related complications.

[0367] In some embodiments, the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH) and cirrhosis, or alcoholic fatty liver disease (AFLD). In some embodiments, the metabolic disease or disorder is hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD-induced hepatocellular carcinoma (HCC).

[0368] In some embodiments, the metabolic disease or disorder is one or more complications of type 2 diabetes, including, but not limited to, type 2 diabetes-induced hypertension, cardiovascular disease, nephropathy, atherosclerosis, dyslipidemia, retinopathy, neurodegenerative disorders, diabetic heart failure, and neuropathy. In some embodiments, the metabolic disease or disorder is type 2 prediabetes. In some embodiments, the metabolic disease or disorder is dyslipidemia.

[0369] In some embodiments, the disease being treated may be a mitochondrial disorder. In some embodiments, the metabolic disorder can be LHON (leber heredity optic neuropathy), MELAS (mitochondrial myopathy, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy and ragged red muscle fiber), Leigh syndrome, MILS (maternally inherited Leigh Syndrome), NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa), FBSN (familial bilateral striatal necrosis), or KSS (Kearns Sayre Syndrome).

[0370] Some embodiments are directed to methods of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the cancer can be a primary cancer or a metastatic cancer. In some embodiments, the cancer is a primary cancer, including, but not limited to, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer. In some embodiments, the cancer is a metastatic liver cancer derived from a primary tumor of another tissue type. In some embodiments, the cancer is a metastatic lung cancer derived from a primary tumor of another tissue type. In some embodiments, the cancer is a metastatic cancer to other sites, including the peritoneal cavity.

[0371] Some embodiments are directed to methods of treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the autoimmune disease is celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

[0372] Some embodiments are directed to a method of treating or preventing a skin disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein, in some embodiments, the skin disorder is eczema, dyshidrotic eczema, seborrheic eczema, psoriasis, rosacea, dermatitis, and atopic dermatitis.

[0373] Some embodiments are directed to methods of treating or preventing a non-viral parasitic infectious disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to the subject. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is an enveloped virus infection. In some embodiments, the viral infection is selected from the group consisting of SARS-CoV-2, corana virus infection, and Ebola virus infection.

[0374] In some embodiments, the disease being treated may be a cardiac disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject. In some embodiments, the cardiac disorder may be hypertension or cardiovascular disease. In some embodiments, the disease being treated may be a central nervous system (CNS) disease. In some embodiments, the CNS disease may be stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotropic lateral sclerosis (ALS).

[0375] In some embodiments, the disease to be treated may be a disorder associated with increased production of reactive oxygen species (ROS), which involves administering to a subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. Increased ROS has been associated with aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), mitochondrial diseases, and various cancers.

[0376] The compounds and pharmaceutical compositions described herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation spray, ocular, nasal, vaginal, rectal, sublingual, or topical routes of administration, and can be formulated, alone or in combination, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each route of administration. The compounds and pharmaceutical compositions described herein can also be formulated as controlled-release formulations.

[0377] The compounds described herein may be administered topically and can be formulated into a variety of topically administrable pharmaceutical compositions containing the active ingredient and a dermatologically and / or ophthalmologically acceptable base. Such pharmaceutical compositions can be formulated, for example, as a solution, suspension, spray, lotion, gel, paste, medicated stick, balm, shampoo, bar soap, liquid soap, cream, or ointment. In one embodiment, the pharmaceutical composition is in the form of an ointment that can be applied in or around the eye of a mammal, including a human.

[0378] In some embodiments, the dermatologically and / or ophthalmologically acceptable base comprises a pharmaceutically acceptable ointment base. Examples of suitable ointment bases include, but are not limited to, oily ointment bases such as petrolatum (e.g., liquid petrolatum or white petrolatum), Plastibase, hard paraffin, white soft paraffin, yellow soft paraffin, liquid paraffin, emulsifying wax, microcrystalline wax, white wax, yellow wax, carnauba wax, wool wax (wool wax), mineral oil, olive oil, refined lanolin, anhydrous lanolin, and water-soluble ointment bases such as polyethylene glycol (e.g., polyethylene glycol 400 or polyethylene glycol 3350), propylene glycol, polyoxyethylene, polyoxypropylene, or any combination thereof.

[0379] In some embodiments, the dermatologically and / or ophthalmically acceptable base comprises one or more polymers as a suspending agent. Useful polymers include, but are not limited to, water-soluble polymers such as cellulose-based polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. The dermatologically and / or ophthalmically acceptable base may also comprise a dermatologically and / or ophthalmically acceptable mucoadhesive polymer, such as carboxymethylcellulose, carbomer (acrylic acid polymer), carbopol (acrylic acid or copolymer cross-linked with polyalkenyl polyether), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, or dextran.

[0380] In some embodiments, the dermatologically and / or ophthalmically acceptable base comprises one or more viscosity enhancing agents. Examples of suitable viscosity enhancing agents include, but are not limited to, methylcellulose, xanthan gum, tragacanth gum, carboxymethylcellulose, silica, silicone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, hydroxypropyl methylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, acacia, cornstarch, gelatin, or combinations thereof.

[0381] In some embodiments, the dermatologically and / or ophthalmically acceptable base comprises one or more dermatologically and / or ophthalmically acceptable pH adjusting or buffering agents, including, but not limited to, acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane, and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffering agents are included in amounts necessary to maintain the pH of the composition within a dermatologically and / or ophthalmologically acceptable range.

[0382] In some embodiments, the dermatologically and / or ophthalmically acceptable vehicle comprises one or more dermatologically and / or ophthalmically acceptable salts in an amount necessary to bring the osmolality of the composition into a dermatologically and / or ophthalmically acceptable range, including, but not limited to, those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, such as, for example, sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0383] In some embodiments, the dermatologically and / or ophthalmologically acceptable vehicle comprises one or more dermatologically and / or ophthalmologically acceptable preservatives to inhibit microbial activity. Suitable preservatives include, but are not limited to, mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0384] In further embodiments, the dermatologically and / or ophthalmically acceptable base contains one or more dermatologically and / or ophthalmologically acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include isohexadecane, cyclomethicone, copolymers of ethylene glycol and propylene glycol, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0385] In further embodiments, the dermatologically and / or ophthalmologically acceptable vehicle contains one or more dermatologically and / or ophthalmologically acceptable penetration enhancers to enhance physical stability or for other purposes. Penetration enhancers are substances that facilitate passage of a topically applied compound into the stratum corneum of the skin and thence into the epidermis and dermis. Examples include, but are not limited to, dimethyl isosorbide, ethoxydiglycol, 1-dodecylazacycloheptan-2-one, propylene glycol, oleyl alcohol, polyoxyethylene esters, sorbitan mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) and its derivatives, ethanol, glyceryl monoethyl ether, monoglycerides, isopropyl myristate, lauryl alcohol, lauric acid, lauryl lactate, terpinol, menthol, D-limonene, beta-cyclodextrin, DMSO (dimethyl sulfoxide), polysorbates, fatty acids (e.g., oleic acid), bile salts, N-methylpyrrolidone, polyglycosylated glycerides ... butan-2-one (Azone®), cyclopentadecalactone (CPE-215®), alkyl-2-(N,N-disubstituted amino)-alkanoate esters (NexAct®), 2-(n-nonyl)-1,3-dioxolane (DEPA®), and penetration enhancers such as those set forth in U.S. Pat. Nos. 3,909,816, 4,405,616, 4,801,586, 4,861,764, 4,886,783, 4,983,396, 5,118,845, 5,196,410, 8,486,374, and 8,741,265 (each of which is expressly incorporated herein by reference in its entirety).

[0386] In further embodiments, the dermatologically and / or ophthalmologically acceptable base contains one or more dermatologically and / or ophthalmologically acceptable permability enhancers to enhance physical stability or for other purposes. Various classes of compounds may serve as suitable permability enhancers in accordance with the present invention. The first category includes fatty acids and their salts and esters, including mono-, di-, and triglycerides. Medium-chain-length fatty acids, particularly C8 and C10 acids, and their salts and esters are particularly useful. Suitable examples include sodium caprylate, sodium caprate, CAPMUL® glycerides (available from Abitec, Columbus, Ohio), LABRASOL® glycerides (PEG-8 caprylic / capric glycerides, available from Gattefosse SAS, Saint Priest, Cedex, France), GELUCIRE® 44 / 14 (PEG-32 glyceryl laurate EP, available from Gattefosse), other glycerides and fatty acid esters, CREMOPHOR® (BASF, Ludwigshafen, Germany), D-α-tocopheryl polyethylene glycol 1000 succinate, vegetable oils, polyoxylglycerides, and medium chain mono- and diacylglycerides.

[0387] One example of this class, CAPMUL® MCM L8 (glycerol monocaprylate) (available from Abitec, Columbus, Ohio), is composed of mono- and diglycerides of medium-chain fatty acids (primarily caprylic acid, with some capric acid) and up to 7% free glycerol. It contains at least 44% alpha monoglycerides (as caprylate).

[0388] Other examples of this class of enhancers include GATTEFOSSE Compositions 61A-61H, proprietary to Gattefosse SAS, which generally consist of mixtures containing varying amounts of one or more of medium chain mono-, di-, or triglycerides, polysorbate derivatives, polyoxyl castor oil derivatives, polyethylene glycol derivatives including polyethylene glycol glycerides, polyoxyl ethers, vegetable oils, glycerin, and similar GRAS (Generally Regarded as Safe) lipid components. These components are part of individual commercial products such as CAPRYOL™ 90, CAPRYOL™ PGMC, LAUROGLYCOL™ 90, GELUCIRE® 44 / 14, Plurol Oleique CC497, LABRASOL®, LABRAFIL® M1944CS (apricot kernel oil PEG-6 ester), Transcutol HP, Peceol, and Maisine 35-1, all of which are available from Gattefosse SAS.

[0389] Although not directly in this class, glycerol itself has been found to provide excellent permeability enhancement, particularly for neuraminidase inhibitors, a result that was unexpected since glycerol is not considered a permeability enhancer.

[0390] The second category of enhancers includes surfactants with a steroid structure, such as bile salts. Examples of suitable compounds include sodium cholate, sodium deoxycholate, glycocholic acid, glycoursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and steroid detergents / bile salts. Other surfactants, including cationic, anionic, and nonionic surfactants, may also be suitable permeation enhancers. Examples include polysorbate 80, hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, tetradecyl-β-D-maltoside, octylglucoside, glycyrrhetinic acid, 3-(N,N-dimethylpalmitylammonio)propanesulfonate, and sodium lauryl sulfate.

[0391] Cyclodextrins may also be used as suitable promoters, examples of which include β-cyclodextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

[0392] Various other compounds can also be used as enhancers, including sodium salicylate, ethylenediamine tetraacetic acid (EDTA), citric acid, chitosan and chitosan derivatives, N-trimethylchitosan chloride, monocarboxymethyl-chitosan, palmitoylcarnitine chloride, acylcarnitines, ethylene glycol tetraacetic acid (EGTA), 3-alkylamido-2-alkoxypropyl-phosphocholine derivatives, alkanoylcholines, N-acetylated amino acids (α- and non-α-amino acid based), mucoadhesive polymers, phospholipids, piperine, 1-methylpiperazine, α-amino acids, and mineral oil.

[0393] Thus, a wide variety of enhancer compounds may be selected from the group consisting of fatty acids, fatty acid esters, fatty acid salts, glycerol, surfactants, cyclodextrins, sodium salicylate, ethylenediaminetetraacetic acid, citric acid, chitosan, chitosan derivatives, N-trimethylchitosan chloride, monocarboxymethyl-chitosan, palmitoylcarnitine chloride, acylcarnitines, ethylene glycol tetraacetic acid, 3-alkylamido-2-alkoxypropyl-phosphocholine derivatives, alkanoylcholines, N-acetylated amino acids, mucoadhesive polymers, phospholipids, piperine, 1-methylpiperazine, α-amino acids, and mineral oil.

[0394] The permeation enhancer and polar agent can be mixed in any ratio, as long as a therapeutically effective amount of the polar agent and a permeation-enhancing amount of the enhancer compound are provided. The enhancement of the skin bioavailability of topically administered polar agents can depend on the nature and concentration of the enhancer compound formulated with the agent. Therefore, it is contemplated that the required therapeutic amount can be contained in a single dosage form or can be divided into one or more doses intended for simultaneous or sequential application.

[0395] Permeation enhancers act relatively independently of the concentration of the polar drug. Different permeation enhancers can achieve either optimal or maximum enhancement over a wide concentration range, depending on their specific inherent enhancement capabilities. Enhancers often have a nonlinear dose-response relationship between the concentration of enhancer present and the amount of increased polar drug absorption. The amount of enhancer utilized in oral dosage forms with polar drugs is initially based on the enhancement properties observed in Caco-2 cell assays at various fixed enhancer concentrations. Based on these results, the effective in vivo dose of the enhancer compound for human formulations can be estimated, verified, and optimized to achieve a desired pharmacokinetic in vivo profile without undue experimentation using methods well known to those skilled in the formulation arts.

[0396] It will be apparent to those skilled in the art of formulation that, in formulating the compositions of the present invention, a more effective enhancer compound will require less polar agent than a less effective permeation enhancer to achieve the target pharmacokinetic profile. Taking these considerations and variables into account, the amount of enhancer may be at least about 0.1% by weight of the combined weight of the enhancer and polar agent, more preferably at least about 50% by weight, and more preferably at least 70% by weight of the combined weight of the enhancer and polar agent. The amount is preferably up to 95% by weight, more preferably up to 80% by weight, and more preferably up to 75% by weight of the combined weight of the enhancer and polar agent. Thus, as shown in the examples, a typical dosage form may contain a wide range of enhancer compound concentrations, depending on the compound itself and its efficacy in enhancing the permeability of polar agents after oral administration. Concentrations as low as 0.001% to 20% by weight have been demonstrated to be effective in enhancing the permeability of polar agents.

[0397] In yet other embodiments, the dermatologically and / or ophthalmically acceptable base optionally contains one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, the antioxidant optionally enhances chemical stability.

[0398] In addition to those listed above, any other surfactants, moisturizers, gelling agents, preservatives, colorants or pigments, antioxidants, radical scavengers, emulsifiers, humectants, pH adjusters, chelating agents, or other dermatologically acceptable excipients generally known to those skilled in the art as being useful in topical compositions are contemplated as being useful in the compositions described herein. Furthermore, any non-toxic, inert, and effective topical carrier can be used to formulate the compositions described herein.

[0399] The well-known carrier that is used to formulate other topical therapeutic compositions for human administration can be used in these compositions.The examples of such components that are well known to those skilled in the art can be found in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, NJ (2001), CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004), and "Inactive Ingredient Guide", Center for Drug Evaluation and Research (CDER) Office of the Food and Drug Administration (FDA), http: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm, and the contents of these are incorporated herein by reference in their entirety. Examples of such useful pharmaceutically acceptable excipients, carriers, and diluents include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those preferred for use herein.

[0400] These additional inactive ingredients, as well as effective formulation and administration procedures, are well known in the art and are described in standard textbooks such as, for example, Goodman and Gillman's: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990) and Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, PA. (1990), both of which are incorporated herein by reference in their entireties.

[0401] The compositions may be used immediately or may be stored for later use in any type of container known to those skilled in the art, such as, for example, pouches, jars, bottles, tubes, ampoules, pre-filled syringes, etc. Finally, the compositions may be sterilized by any method known to those skilled in the art, such as, for example, gamma irradiation.

[0402] The compounds and pharmaceutical compositions described herein can be administered at prophylactically effective dosage levels to prevent the above conditions and disorders, as well as other conditions and disorders characterized by insulin resistance or hyperglycemia.

[0403] The pharmaceutical compositions and compounds of the embodiments herein can be administered in a wide variety of dosage forms, including, for example, solid and liquid dosage forms. Solid dosage forms may include powders, tablets, pills, capsules, suppositories, or dispersible granules. A solid carrier may be one or more substances that function as diluents, flavoring agents, solvents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powder form, the carrier may be a finely divided solid, including lactose, hydroxypropylmethylcellulose, and PVP, mixed with an appropriate amount of the active ingredient. Suitable carriers for powder and tablet forms include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatin, tragacanth, methylcellulose, and sodium carboxymethylcellulose.

[0404] Liquid dosage forms include, for example, solutions, suspensions, and emulsions. Also included are pharmaceutical compositions in solid form that are intended to be converted into liquid form immediately before ingestion. These forms may contain, in addition to the active ingredient, artificial colorants, flavors, stabilizers, buffers, natural or artificial sweeteners, dispersants, thickeners, solubilizers, etc.

[0405] The solution or mixture can be administered directly to the nasal cavity using conventional means such as drops or spray. The pharmaceutical composition can be prepared in individual or multi-dose forms. Multi-dose forms include droppers, pipettes or atomizers that deliver a predetermined amount of the pharmaceutical composition.

[0406] Pharmaceutical compositions and compounds of embodiments herein may be provided in individual dosage units containing an appropriate amount of the active ingredient. The individual doses may be provided in a package or as a kit that includes a measuring device (e.g., a device for measuring the oral or injectable dose (i.e., a measuring cup, needle, or syringe). The kit may also include other materials (e.g., buffers, diluents, filters, and a package insert containing instructions for use). A label may be present on the kit to indicate that the pharmaceutical composition is to be used for a particular treatment and may also indicate directions for use.

[0407] If necessary, the pharmaceutical compositions of the present invention may further comprise one or more additional active agents. Where appropriate, any of the active agents may be administered in the form of the compound itself and / or in the form of a salt, polymorph, ester, amide, prodrug, derivative, etc., provided that the salt, polymorph, ester, amide, prodrug, or derivative is pharmacologically suitable. Where appropriate, salts, esters, amides, prodrugs, and other derivatives of active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry, for example, as described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For any active agents that may exist in enantiomeric forms, the active agent may be incorporated into the pharmaceutical compositions of the present invention either as a racemate or in an enantiomerically enriched form.

[0408] The dosage of the active compound administered will depend on the condition being treated, the particular compound, and other clinical factors such as the age, sex, weight, and health of the subject being treated, the route of administration of the compound, and the type of pharmaceutical composition administered (tablet, gel cap, capsule, solution, suspension, inhaler, aerosol, elixir, lozenge, injectable, patch, ointment, cream, etc.). It should be understood that the present disclosure has application for both human and veterinary use. The amount of compound or its active salt or derivative required for therapeutic use will ultimately be at the discretion of the attending physician or clinician.

[0409] As described above, the compounds of the present invention are useful for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders, and conditions described herein. The dosage of the compound as an active ingredient in the pharmaceutical composition of the present invention can be varied to obtain a suitable dosage form. The active ingredient can be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage will depend on the desired therapeutic effect, the route of administration, and the duration of treatment. Dosages will vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, any special diets the patient follows, concomitant medications, and other factors recognized by those skilled in the art. Generally, dosages of 0.001 to 100 mg per kg of body weight per day are administered to patients, e.g., humans and the elderly. The therapeutically effective amount is generally about 0.5 mg to 10 g per patient per day, which can be administered in single or multiple doses. In some embodiments, the therapeutically effective amount has lower limits of 0.5 mg, 10 mg, 1 mg, 500.0 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, 5000 mg, 5500 mg, 6000 mg, 6500 mg, 7000 mg, 7500 mg, 8000 mg, 8500 mg, 9000 mg, 9500 mg, and 10 000mg, and upper limits are between 10000mg, 9500mg, 9000mg, 8500mg, 8000mg, 7500mg, 7000mg, 6500mg, 6000mg, 5500mg, 5000mg, 4500mg, 4000mg, 3500mg, 3000mg, 2500mg, 2000mg, 1500mg, 1000mg, 500.0mg, 100mg, 10mg, and 0.5mg. In some embodiments, the therapeutically effective amount is about 0.5 mg to 2500 mg per patient per day, in some embodiments about 0.5 mg to 200 mg per patient per day, in some embodiments about 0.5 mg to 500 mg per patient per day, in some embodiments about 0.5 mg to 1000 mg per patient per day, and in some other embodiments about 5 mg to 50 mg per patient per day.The pharmaceutical compositions of the present invention may be provided in solid dosage forms containing about 0.5 mg to 500 mg of active ingredient, or about 1 mg to 250 mg of active ingredient. The pharmaceutical compositions may be provided in solid dosage forms containing, for example, about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, or 1000 mg of active ingredient. For oral administration, the pharmaceutical compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000, and 2000 milligrams of active ingredient, for symptomatic adjustment of dosage to the patient being treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times or four times per day.

[0410] definition Molecular terms, as used in this application, have their ordinary meaning unless otherwise specified.

[0411] The articles "a" and "an," as used herein, unless otherwise indicated, mean "one or more" or "at least one." That is, the reference to any element of the invention by the indefinite article "a" or "an" does not exclude the possibility that more than one of that element is present.

[0412] The term "acylamino" refers to a nitrogen radical adjacent to an acyl group.

[0413] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 17 Alkyl" or "C 1~17 "Alkyl" (or alkylene) is C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C16 and C 17 It is intended to include alkyl groups. Further, for example, "C1-C6 alkyl" or "C 1~6 "Alkyl" means an alkyl having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted, where at least one hydrogen has been replaced with another chemical group. In some embodiments, one of the more hydrogen atoms is replaced with a chemical group selected from hydroxyl and dimethylamino. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl). Examples of substituted alkyls include: These include, but are not limited to, -CH2N(CH3)2, -CH2CH2N(CH3)2, and -CH2CH2CH2N(CH3)2.

[0414] "Alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to three, carbon-carbon double bonds that may occur at any stable point along the chain. For example, "C2-C6 alkenyl" or "C 2~6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. 2~17 The term "alkenyl" refers to any of the C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 and C 17It is intended to include alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0415] "Alkynyl" is intended to include a hydrocarbon chain in either a straight or branched configuration with one or more, preferably one to three, carbon-carbon triple bonds which may occur at any stable point along the chain. For example, "C2-C6 alkynyl" is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0416] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. 1~6 "Alkoxy" (or alkyloxy) is intended to include C, C, C, C, C, and C alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.

[0417] An "aryl" group refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, thiazolyl, phenyl, and naphthyl. 10 aryl" or "C 6~10 "Aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "C6-C 10 Aryl, "C 6~10An "aryl" or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups selected from -OH, -OCH3, -Cl, -F, -Br, -I, -CN, -NO2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -OCF3, -C(O)CH3, -SCH3, -S(O)CH3, -S(O)2CH3, -CH3, -CH2CH3, -CO2H, and -CO2CH3.

[0418] The term "benzyl," as used herein, refers to a methyl group in which one of the hydrogen atoms has been replaced with a phenyl group, the phenyl group optionally being substituted with 1 to 5, preferably 1 to 3, substituents independently selected from methyl, trifluoromethyl (-CF), hydroxyl (-OH), methoxy (-OCH), halogen, cyano (-CN), nitro (-NO), -COMe, -COEt, and -COH. Representative examples of benzyl groups include, but are not limited to, PhCH-, 4-MeO-CHCH-, 2,4,6-trimethyl-CHCH-, and 3,4-di-Cl-CHCH-.

[0419] The term "carboxamido" refers to a carbonyl radical adjacent to an amino group.

[0420] As used herein, "compound" generally refers to any type of substance or agent that is considered a drug or a candidate for use as a drug, as well as combinations and mixtures of the above. When referring to the compounds of the present invention, unless otherwise specified, the term "compound" is intended to encompass not only the specified molecular entity, but also its pharmaceutically acceptable, pharmacologically active analogs (including, but not limited to, salts, polymorphs, esters, amides, prodrugs, adducts, conjugates, active metabolites, etc.) when such modifications to the molecular entity are appropriate.

[0421] As used herein, "conventional mitochondrial uncoupling agents" describes mitochondrial uncoupling agents that have the properties of increasing OCR and decreasing MMP, and the concentrations that increase OCR and the concentrations that eliminate MMP are correlated.

[0422] As used herein, a "derivative" of a compound refers to a chemical compound that can be produced in one or more steps from another compound of similar structure. Non-limiting examples include replacement of an H with an alkyl, acyl, or amino group.

[0423] As used herein, "effective amount" or "therapeutically effective amount" means an amount sufficient to produce a selected effect, such as alleviating the symptoms of a disease or disorder. In the context of administering a compound in the form of a combination, such as multiple compounds, the amount of each compound may be different when administered in combination with another compound than when the compound is administered alone. Thus, the effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amount of each compound may vary. The term "more effective" means that the selected effect is alleviated to a greater extent by one treatment compared to the second treatment being compared.

[0424] The terms "formula" and "structure" are used interchangeably herein.

[0425] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, and trichloromethyl.

[0426] As used herein, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Unless otherwise specified, a heteroaryl group can be unsubstituted or substituted with 1 to 5 groups selected from -OH, -OCH3, -Cl, -F, -Br, -I, -CN, -NO2-NH2, -NH(CH3), -N(CH3)2, -CF3, -OCF3, -C(O)CH3, -SCH3, -S(O)CH3-S(O)2CH3, -CH3-CH2CH3, -CO2H, and -CO2CH3. Nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N→O and S(O)→O). p (wherein p is 0, 1 or 2).

[0427] The terms "heterocyclyl," "heterocyclic," or "heterocyclyl ring" refer to a single or fused heterocyclic ring system having 3 to 12 ring members, including O, N, NH, -N(R Z R is defined as a saturated or partially unsaturated ring containing 1 to 4 heteroatoms or heterogroups selected from -S(O)-, -S(O)-, or -S(O)2-; Zis selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and optionally substituted heterocyclyl. In preferred embodiments, the heterocyclyl is a ring system having 3 to 7 ring members. Examples of heterocyclyl groups include, but are not limited to, azetindinyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl, tetrahydrofuranyl, and azabicyclo[3.2.1]octanyl. Unless otherwise specified, a heteroaryl group can be unsubstituted or substituted with at least one group selected from oxo, cyano, hydroxyl, alkoxy, -acylamino, carboxamido, -SOCH, -CF, C-C alkyl, halo, and acyl.

[0428] The term "infectious disease" as used herein refers to a bacterial infection or a viral infection. Infectious diseases do not include infections caused by parasites. In some embodiments, the viral infection is an enveloped virus. Examples of enveloped viruses include SARS-CoV-2, corana virus, and Ebola virus.

[0429] The term "mitochondrial-related conditions or disorders" is defined as a pathological condition caused by mitochondrial dysfunction and is reviewed and summarized in "A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine," Annu Rev Genet. 2005;39:359; "The Rise of Mitochondria in Medicine," Mitochondrion 2016,30:105-16; and "Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocrine Reviews 2020,41(491-517)," all of which are incorporated herein by reference. These conditions include, but are not limited to, genetic mitochondrial diseases, various types of cancer, autism, neurodegenerative diseases, neuromuscular diseases, immune diseases, metabolic diseases, aging, and age-related noncommunicable chronic diseases.

[0430] "MMP-sparing compounds" or "mitochondrial membrane potential-sparing compounds" are defined as mitochondrial uncouplers that effectively increase OCR without significantly reducing MMP.

[0431] The term "mitochondrial uncoupling," also known as "uncoupling," refers to the process by which protons enter the mitochondrial matrix via a pathway independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. This process can be pharmacologically induced by small-molecule mitochondrial protonophores, which shuttle protons directly across the inner mitochondrial membrane into the matrix. The primary pathway for energy production in aerobic cells involves the oxidation of nutrients (including fats, carbohydrates, and amino acids) in mitochondria, which promotes proton efflux from the mitochondrial matrix. This process creates pH and electrochemical gradients across the inner mitochondrial membrane. Protons normally re-enter the mitochondrial matrix via ATP synthase, resulting in ATP production. Protons can also re-enter the mitochondrial matrix via a pathway independent of ATP synthase, which "uncouples" nutrient oxidation and proton efflux from ATP production.

[0432] The phrase "ophthalmically acceptable" is used herein to refer to compounds, materials, pharmaceutical compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the eye of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0433] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, pharmaceutical 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, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0434] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those prepared from organic acids such as, for example, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0435] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Company, Easton, PA, 1990, the disclosure of which is incorporated herein by reference.

[0436] As used herein, the term "pharmaceutically acceptable carrier" includes any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions (e.g., oil / water emulsions or water / oil emulsions), and various types of wetting agents. The term also encompasses any agent approved by a regulatory agency of the U.S. federal government or listed in the U.S. Pharmacopoeia for use in animals, including humans.

[0437] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug, or may demonstrate increased palatability, or may be easier to formulate.

[0438] The terms "subject," "individual," or "patient" are used interchangeably and, as used herein, are intended to include human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals, e.g., non-human primates, sheep, dogs, cats, cows, and horses, are preferred. Preferred subjects include human patients in need of an enhanced immune response. The method is particularly suitable for treating human patients with a disease or disorder described herein.

[0439] The terms "administration of" and / or "administering" a compound should be understood to mean providing a compound described herein, or a prodrug thereof, to an individual in need of treatment.

[0440] As used herein, the term "treating" or "treatment" refers to the administration of a compound or agent to a subject having or at risk of developing a disorder for the purpose of curing, alleviating, mitigating, treating, delaying the onset of, preventing, or ameliorating the disorder, the symptoms of the disorder, a disease state secondary to the disorder, or the predisposition to the disorder. [Example]

[0441] Processes for preparing compounds of the present invention, such as those of Formula A, I, Ia, II, IIa, III, and IIIa, or processes for preparing intermediates useful for preparing compounds of Formula A, I, Ia, II, IIa, III, and IIIa, or other formulas of the present disclosure, are provided as further embodiments of the present invention or are known in the art. The following text may exemplify specific compounds and corresponding synthetic routes, but is not intended to limit the scope of the present invention to such specific references or examples. Various modifications may be made by those skilled in the art, taking into account practical and economic considerations such as the source of reagents and the specific conditions of the reaction.

[0442] [Table 17]

[0443] Example 1 5-chloro-2-hydroxy-3-((methoxymethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (1)

[0444] [ka] To a stirred solution of methyl 5-chloro-3-(hydroxymethyl)-2-methoxybenzoate (106 mg, 0.46 mmol) in DCM (5 mL) was added DIPEA (240 μL, 1.38 mmol), MOMCl (105 μL, 1.38 mmol), followed by DMAP (3 mg, 0.023 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was complete, DCM and saturated ammonium chloride solution were added. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-((methoxymethoxy)methyl)benzoate (122 mg, 97%) as a yellow oil. 1 H NMR (300MHHz, chloroform-d) δ7.72(d,J=2.8Hz,1H),7.58(d,J=2.9Hz,1H),4.73(s,2H),4.64(s,2H),3.90(s,3H),3.83(s,3H),3.40(s,3H).

[0445] To a stirred solution of methyl 5-chloro-2-methoxy-3-((methoxymethoxy)methyl)benzoate (122 mg, 0.445 mmol) in MeOH (5 mL) was added 2.2 mL of 1 N KOH solution. The resulting mixture was stirred at 60 °C overnight. After the mixture was cooled to room temperature, the reaction was partitioned between ethyl acetate and 2% citric acid. The ethyl acetate layer was washed with brine, dried over Na SO , and concentrated in vacuo. To this residue were added HBTU (98 mg, 0.258 mmol), DMF (3 mL), and DIPEA (187 μL, 1.075 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (47 mg, 0.215 mmol) was added. The resulting reaction was heated at 120 °C for 24 hours. The mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. Purification by column chromatography afforded 5-chloro-2-hydroxy-3-((methoxymethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2yl)benzamide as a yellow solid (37 mg, 39%). 1H NMR (400 MHz, chloroform-d) δ 8.16 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 4.80 (s, 2H), 4.78 (s, 2H), 3.47 (s, 3H). MS (ESI) [M+Na] + Required value m / z 469.02, observed value m / z 468.55.

[0446] Example 2 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (2)

[0447] [ka] To a stirred solution of 5-chloro-2-methoxybenzoic acid (5.59 g, 30 mmol) in sulfuric acid (10.2 mL) and TFA (20.4 mL) at room temperature was added NBS (5.87 g, 33 mmol). The pale solution was stirred at room temperature overnight. The resulting pale suspension was carefully poured onto crushed ice. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure. The pale yellow residue was suspended in a minimum amount of DCM. The solid was collected, washed with cold DCM, and dried under vacuum to give 3-bromo-5-chloro-2-methoxybenzoic acid as a white solid (8.00 g, 100%). 1 H NMR (300 MHz, acetone) δ 7.86 (d, 1H, J = 3.0 Hz), 7.78 (d, 1H, J = 3.0 Hz), 3.91 (s, 3H).

[0448] To a stirred solution of 3-bromo-5-chloro-2-methoxybenzoic acid (6 g, 22.6 mmol) in DMF (30 mL) was added potassium carbonate (31 g, 226 mmol), followed by CHCl (1.4 mL, 22.6 mmol). The mixture was stirred at room temperature for 24 hours. Water was added and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to give a pale yellow oil (6.18 g, 97%).

[0449] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc) (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tribasic potassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed overnight under N. After cooling, the reaction was added with saturated NH.sub.4Cl solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1 H NMR (300 MHz, chloroform) δ 7.62 (d, 1H, J = 3.0 Hz), 7.32 (d, 1H, J = 3.0 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).

[0450] To a flame-dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%). 1H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0451] To a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (236 mg, 0.805 mmol) in 2-methoxyethanol (10 mL) was added 2N NaOH solution (7 mL). The resulting mixture was stirred at 75° C. overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N HCl, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with ether to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (204 mg, 93%) as a yellow oil. 1 H NMR(300MHz,cdcl3)δ10.02(brs,1H),7.86(d,J=2.8Hz,1H),7.66(d,J=1.4Hz,1 H),4.62(s,2H),3.87(s,3H),3.75-3.67(m,2H),3.66-3.56(m,2H),3.41(s,3H). MS(ESI)[M+Na] + Required value m / z 297.05, observed value m / z 296.6.

[0452] 5-Chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (90 mg, 0.328 mmol) was dissolved in DMF (3 mL). HBTU (149 mg, 0.394 mmol) was added, followed by DIPEA (286 μL, 1.64 mmol). The resulting mixture was stirred at room temperature for 15 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (72 mg, 0.328 mmol) was added. The resulting mixture was stirred at 130 °C for 24 hours. Saturated NH4Cl solution was added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow powder (34 mg, 30%). 1 H NMR (300MHz, acetone) δ8.37(s,1H),8.02(s,1H),7.81(d,J=8.3Hz,1H),7.69(d,J=8 .4Hz,1H),7.41(s,1H),4.91(s,2H),3.87(s,3H),3.53(brs,2H),2.94(brs,2H). MS(ESI)[M+Na] + Required value m / z 483.04, observed value m / z 483.1.

[0453] Example 3 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (3) and 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (3A)

[0454] [ka] To a stirred solution of 5-chloro-2-methoxybenzoic acid (5.59 g, 30 mmol) in sulfuric acid (10.2 mL) and TFA (20.4 mL) at room temperature was added NBS (5.87 g, 33 mmol). The pale solution was stirred at room temperature overnight. The resulting pale suspension was carefully poured onto crushed ice. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure. The pale yellow residue was suspended in a minimum amount of DCM. The solid was collected, washed with cold DCM, and dried under vacuum to give 3-bromo-5-chloro-2-methoxybenzoic acid as a white solid (8.00 g, 100%). 1 H NMR (300 MHz, acetone) δ 7.86 (d, 1H, J = 3.0 Hz), 7.78 (d, 1H, J = 3.0 Hz), 3.91 (s, 3H).

[0455] To a stirred solution of 3-bromo-5-chloro-2-methoxybenzoic acid (6 g, 22.6 mmol) in DMF (30 mL) was added potassium carbonate (31 g, 226 mmol), followed by CHCl (1.4 mL, 22.6 mmol). The mixture was stirred at room temperature for 24 hours. Water was added and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to give a pale yellow oil (6.18 g, 97%).

[0456] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc) (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tribasic potassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed overnight under N. After cooling, the reaction was added with saturated NH.sub.4Cl solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1H NMR (300 MHz, chloroform) δ 7.62 (d, 1H, J = 3.0 Hz), 7.32 (d, 1H, J = 3.0 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).

[0457] To a flame-dried flask were added NBS (492 mg, 2.767 mmol), AIBN (57 mg, 0.346 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (495 mg, 2.306 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (588 mg, 87%). 1 H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0458] To a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (500 mg, 1.71 mmol) in THF (6 mL) at 0° C. was added 2-methoxy-N-methylethan-1-amine (370 μL, 3.41 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was partitioned between NaHCO and ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give methyl 5-chloro-2-methoxy-3-(((2-methoxyethyl)(methyl)amino)methyl)benzoate (437 mg, 85%) as a yellow oil. 1 H NMR (300MHz, chloroform-d) δ7.67(s,2H),3.91(s,3H),3.81(s,2H),3.61(s,2H),3.52(t,J=5.7Hz,2H),3.34(s,3H),2.64(t,J=5.7Hz,2H),2.29(s,3H). MS(ESI)[M+H] + Required value m / z 302.12, observed value m / z 301.60.

[0459] To a stirred solution of methyl 5-chloro-2-methoxy-3-(((2-methoxyethyl)(methyl)amino)methyl)benzoate (352 mg, 1.17 mmol) in MeOH (5 mL) was added 5.0 mL of 1N KOH solution. The resulting mixture was stirred at 50° C. overnight. The solvent was evaporated, and 4N HCl in dioxane (2 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (532 mg, 1.404 mmol), DMF (5 mL), and DIPEA (1.02 mL, 5.85 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (255 mg, 1.17 mmol) was added. The resulting reaction was heated at 130° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography afforded 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (220 mg, 40%). 1 H NMR (300MHz, methanol-d4) δ8.24(s,1H),7.93(s,1H),7.84(d,J=8.4Hz,1H),7.69(d,J=9.0Hz,1H), 7.31(s,1H),4.31(s,2H),3.78(t,J=6.0Hz,2H),3.44(s,3H),3.35(t,J=6.0Hz,2H),2.85(s,3H). MS(ESI)[M+H] + Required value m / z 474.09, observed value m / z 473.55.

[0460] To a stirred solution of 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (126 mg, 0.266 mmol) in THF (5 mL) was added 4.0 N HCl in dioxane (70 μL, 0.266 mmol). The mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure, and the resulting residue was washed with diethyl ether to give 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (135 mg, 100%).

[0461] Example 4 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (4)

[0462] [ka] To a stirred solution of 5-chloro-2-methoxy-3-methylbenzoic acid (1.80 g, 8.99 mmol) in DMF (10 mL) was added potassium carbonate (12.4 g, 89.9 mmol), followed by CHCl (0.56 mL, 8.99 mmol). The mixture was stirred at room temperature for 24 hours. Water was added and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to give methyl 5-chloro-2-methoxy-3-methylbenzoate as a pale yellow oil (1.13 g, 63%). 1 H NMR(300MHz,cdcl3)δ7.52(d,J=2.7Hz,1H),7.22(d,J=2.7Hz,1H),3.83(s,3H),3.74(s,3H),2.21(s,3H).

[0463] To a stirred solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (241 mg, 1.12 mmol) in anhydrous DCM (5 mL) at −78° C., BBr3 (1.0 M in DCM, 2.25 mL) was added dropwise. After the addition, the reaction was slowly warmed to room temperature, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was cooled in an ice bath, and MeOH and water were added to quench the reaction. The mixture was partitioned between DCM and water. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to afford methyl 5-chloro-2-hydroxy-3-methylbenzoate as a pale yellow solid (220 mg, 98%), which was used in the next step without further purification.

[0464] To a stirred solution of methyl 5-chloro-2-hydroxy-3-methylbenzoate (220 mg, 1.1 mmol) in anhydrous DCM (5 mL) was added pyridine (443 μL, 5.5 mmol), (Boc)O (504 mg, 2.30 mmol), and DMAP (13 mg, 0.11 mmol). The resulting mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give methyl 2-((tert-butoxycarbonyl)oxy)-5-chloro-3-methylbenzoate (290 mg, 88%) as a colorless oil. 1 H NMR(300MHz,cdcl3)δ7.80(dd,J=2.7,0.6Hz,1H),7.40(dd,J=2.7,0.7Hz,1H),3.89(s,3H),2.26(s,3H),1.58(s,9H).

[0465] To a flame-dried flask was added NBS (205 mg, 1.156 mmol), AIBN (24 mg, 0.145 mmol), and a solution of methyl 2-((tert-butoxycarbonyl)oxy)-5-chloro-3-methylbenzoate (289 mg, 0.963 mmol) in CCl4 (5 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 3-(bromomethyl)-2-((tert-butoxycarbonyl)oxy)-5-chlorobenzoate as a colorless oil (220 mg, 62%). 1 H NMR (300MHz, cdcl3) δ7.95(d,J=2.2Hz,1H),7.61(d,J=2.3Hz,1H),4.45(s,2H),3.91(s,3H),1.58(s,9H).

[0466] To a stirred solution of methyl 3-(bromomethyl)-2-((tert-butoxycarbonyl)oxy)-5-chlorobenzoate (220 mg, 0.582 mmol) in 2-methoxyethanol (10 mL) was added 2N NaOH solution (5 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N HCl, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with ether to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)benzoic acid (145 mg, 92%) as a white oil. 1 H NMR(300MHz,cdcl3)δ10.76(s,2H),7.67(d,J=2.6Hz,1H),7.59(d,J=2.5Hz,1H),4 .61(s,2H),3.79(dd,J=5.9,2.7Hz,2H),3.72(dd,J=5.9,2.8Hz,2H),3.49(s,3H). MS(ESI)[M+Na] + Required value m / z 283.03, observed value m / z 282.55.

[0467] 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)benzoic acid (65 mg, 0.249 mmol) was dissolved in THF (3.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (26 μL, 0.299 mmol). The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in dioxane (5.0 mL), and 2-chloro-4-(trifluoromethyl)aniline (35 μL, 0.25 mmol) was added. The mixture was refluxed overnight. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (35 mg, 35%) as a white solid. 1 H NMR(500MHz,cdcl3)δ10.25(s,1H),10.20(s,1H),8.76(d,J=8.6Hz,1H),7.96(d,J=2.6Hz,1H),7.69(d,J=1.7Hz,1H) ,7.58(dd,J=8.8,2.1Hz,1H),7.36(d,J=2.6Hz,1H),4.73(s,2H),3.82-3.76(m,2H),3.66-3.62(m,2H),3.45(s,3H). MS(ESI)[M+Na] + Required value m / z 460.03, observed value m / z 459.95.

[0468] Example 5 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (5)

[0469] [ka] 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)benzoic acid (77 mg, 0.28 mmol, Example 2) was dissolved in DCM (3.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (40 μL, 0.34 mmol). The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (59 μL, 0.34 mmol) and 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (65 mg, 0.28 mmol) were added. The mixture was stirred at room temperature for 48 hours, after which silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (27 mg, 34% yield) as a white solid. 1 H NMR(500MHz,cdcl3)δ8.13(d,J=2.8Hz,1H),7.83(d,J=8.8Hz,1H),7.73(d,J=2.8Hz,2H),7.34(ddd,J=8. 8,2.4,0.8Hz,1H),4.66(s,2H),3.99(s,3H),3.75-3.72(m,2H),3.62(dd,J=3.9,2.5Hz,2H),3.41(s,3H). MS(ESI)[M+H] + Required value m / z 491.07, observed value m / z 491.10.

[0470] A solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (27 mg, 0.055 mmol) in DMF (3 mL) was mixed with sodium ethoxide (18 mg, 0.275 mmol), and the resulting suspension was heated at 140 °C overnight. After completion of the reaction, 1N HCl was added to the reaction and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (13 mg, 50%) as a yellow solid. 1 H NMR(500MHz,cdcl3)δ8.13(d,J=2.8Hz,1H),7.83(d,J=8.8Hz,1H),7.73(d,J=2.8Hz,2H),7.34(ddd ,J=8.8,2.4,0.8Hz,1H),4.66(s,2H),3.75-3.72(m,2H),3.62(dd,J=3.9,2.5Hz,2H),3.41(s,3H). MS(ESI)[M+H] + Required value m / z 477.05, observed value m / z 477.30.

[0471] Example 6 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide (6)

[0472] [ka] 5-Chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (90 mg, 0.33 mmol, Example 2) was dissolved in DCM (3.0 mL), followed by the addition of catalytic amounts of DMF (10 μL) and oxalyl chloride (34 μL, 0.39 mmol). The reaction was stirred at room temperature for 30 minutes, concentrated in vacuo, and the 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride residue was redissolved in THF (3.0 mL). In a separate flask, 5-(trifluoromethyl)pyrazin-2-amine (54.0 mg, 0.33 mmol) was dissolved in THF (3.0 mL), followed by the addition of NaH (16.0 mg, 0.439 mmol, 60% in mineral oil). The mixture was stirred for 10 minutes and then added dropwise to a flask containing freshly prepared 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride at room temperature. The reaction was stirred at room temperature for 2 hours, after which silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide as a white solid (32.0 mg, 23% yield). 1 H NMR(300MHz,cdcl3)δ10.54(s,1H),9.82(d,J=1.1Hz,1H),8.67(s,1H),8.11(d,J=2.8Hz,1H),7. 71(d,J=2.8Hz,1H),4.68(s,2H),3.95(s,3H),3.79-3.71(m,2H),3.67-3.59(m,2H),3.43(s,3H). MS(ESI)[M+H] + Required value m / z 420.10, observed value m / z 420.30.

[0473] A solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide (32 mg, 0.076 mmol) in DMF (3 mL) was mixed with sodium ethanethiolate (32 mg, 0.382 mmol), and the resulting suspension was heated at 130 °C overnight. After completion of the reaction, 1N HCl was added to the reaction mixture and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide (18 mg, 62%) as a yellow solid. 1 H NMR (300 MHz, acetone) δ 9.66 (s, 1H), 8.82 (s, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 4.74 (s, 2H), 3.88-3.74 (m, 2H), 3.74-3.61 (m, 2H), 3.41 (s, 3H). MS (ESI) [M+H] + Required value m / z 406.08, observed value m / z 406.20.

[0474] Example 7 5-chloro-2-hydroxy-3-((2-hydroxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (7)

[0475] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol, Example 2), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc) (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tribasic potassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed overnight under N. After cooling, the reaction was added with saturated NH.sub.4Cl solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1 H NMR (300 MHz, chloroform) δ 7.62 (d, 1H, J = 3.0 Hz), 7.32 (d, 1H, J = 3.0 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).

[0476] To a flame-dried flask were added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 mg, 0.93 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%). 1 H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0477] To a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (222 mg, 0.76 mmol) in 2-(tert-butoxy)ethan-1-ol (4 mL) was added 2N NaOH solution (2 mL). The resulting mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N HCl, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with ether to give 3-((2-(tert-butoxy)ethoxy)methyl)-5-chloro-2-methoxybenzoic acid as a yellow oil (100%). MS(ESI)[MH] - Required value m / z 315.10, observed value m / z 315.60.

[0478] To a stirred solution of 3-((2-(tert-butoxy)ethoxy)methyl)-5-chloro-2-methoxybenzoic acid (240 mg, 0.76 mmol) in DMF (5 mL) was added HBTU (345 mg, 0.91 mmol) and DIPEA (662 μL, 3.8 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (165 mg, 0.76 mmol) was added. The resulting reaction was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography gave 3-((2-(tert-butoxy)ethoxy)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (27 mg, 10%). 1 H NMR (300MHz, acetone) δ8.35(s,1H),7.96(s,1H),7.72(dd,J=19.4,8.5Hz,2H),7.41(s,1H),4.89(s,2H),4.06(s,2H),3.82(s,2H),1.15(s,9H). MS(ESI)[M+H] + Required value m / z 503.10, observed value m / z 503.20.

[0479] To a stirred solution of 3-((2-(tert-butoxy)ethoxy)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (27 mg, 0.054 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the remaining residue was subjected to flash column chromatography to give 5-chloro-2-hydroxy-3-((2-hydroxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (19 mg, 83%). 1 H NMR (300MHz, acetone) δ8.35(s,1H),7.96(s,1H),7.72(dd,J=19.4,8.5Hz,2H),7.41(s,1H),4.89(s,2H),4.06(s,2H),3.82(s,2H). MS(ESI)[M+H] + Required value m / z 447.04, observed value m / z 447.10.

[0480] Example 8 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (8)

[0481] [ka] To a flame-dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 3-(bromomethyl)-5-chloro-2-methoxybenzoate as a colorless oil (236 mg, 87%). 1 H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0482] To a stirred solution of 3-(bromomethyl)-5-chloro-2-methoxybenzoate (180 mg, 0.614 mmol) in 2-methoxyethanol (5 mL) was added 2N NaOH solution (4 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N HCl, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with ether to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (170 mg, 100%) as a yellow oil. 1 H NMR(300MHz,cdcl3)δ10.02(brs,1H),7.86(d,J=2.8Hz,1H),7.66(d,J=1.4Hz,1 H),4.62(s,2H),3.87(s,3H),3.75-3.67(m,2H),3.66-3.56(m,2H),3.41(s,3H). MS(ESI)[M+Na]+Required value m / z 297.05, Actual value m / z 296.6.

[0483] 5-Chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (85 mg, 0.31 mmol) was dissolved in DCM (3.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (32 μL, 0.372 mmol). The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (162 μL, 0.93 mmol) and 6-fluorobenzo[d]thiazol-2-amine (52 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 48 hours, after which silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-methoxy-3-((2-methoxyethoxy)methyl)benzamide (52 mg, 41%) as a white solid. MS(ESI)[M+H] + Required value m / z 425.08, observed value m / z 425.10.

[0484] A solution of 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-methoxy-3-((2-methoxyethoxy)methyl)benzamide (52 mg, 0.123 mmol) in DMF (3 mL) was mixed with sodium ethanethiolate (52 mg, 0.613 mmol), and the resulting suspension was heated at 130 °C overnight. After completion of the reaction, 1N HCl was added to the reaction and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (20 mg, 40%) as a yellow solid. 1 H NMR (300MHz, acetone) δ8.05(s,1H),7.77(dd,J=8.4,2.5Hz,1H),7.61(s,1H),7. 47(s,1H),7.20(t,J=8.8Hz,1H),4.79(s,2H),3.83-3.72(m,4H),3.47(s,3H). MS(ESI)[M+H] + Required value m / z 411.06, observed value m / z 411.10.

[0485] Example 9 5-chloro-2-hydroxy-3-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (9)

[0486] [ka] To a flame-dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 3-(bromomethyl)-5-chloro-2-methoxybenzoate as a colorless oil (236 mg, 87%). 1H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0487] To a stirred solution of methyl 3-(bromomethyl)-5-chloro-2-methoxybenzoate (270 mg, 0.921 mmol) in methanol (10 mL) was added 2N NaOH solution (7 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N HCl, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with ether to give 5-chloro-2-methoxy-3-(methoxymethyl)benzoic acid (217 mg, 83%) as a yellow oil, which was used in the next step without further purification. MS (ESI) [MH] - Required value m / z 229.02, observed value m / z 229.40.

[0488] 5-Chloro-2-methoxy-3-(methoxymethyl)benzoic acid (217 mg, 0.94 mmol) was dissolved in DCM (5.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (97 μL, 1.13 mmol). The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (197 μL, 1.13 mmol) and 6-(trifluoromethyl)benzo[d]thiazol-2-amine (206 mg, 0.94 mmol) were added. The mixture was stirred at room temperature for 48 hours, after which the reaction was quenched by the addition of silica gel. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give 5-chloro-2-methoxy-3-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (165 mg, 45%) as a yellow solid. MS(ESI)[M+H] + Required value m / z 431.05, observed value m / z 431.10.

[0489] A solution of 5-chloro-2-methoxy-3-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (100 mg, 0.23 mmol) in DMF (5 mL) was mixed with sodium ethanethiolate (97 mg, 1.16 mmol), and the resulting suspension was heated at 130 °C overnight. After completion of the reaction, 1N HCl was added to the reaction and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-3-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (90 mg, 94%) as a white solid. 1 H NMR(300MHz,cdcl3)δ8.16(s,1H),8.13(d,J=2.6Hz,1H),7.87(d,J=8.6Hz, 1H),7.73(d,J=8.9Hz,1H),7.49(d,J=2.6Hz,1H),4.67(s,2H),3.55(s,3H). MS(ESI)[MH] - Required value m / z 415.02, observed value m / z 415.40.

[0490] Example 10 5-chloro-2-hydroxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (10) and 5-chloro-2-hydroxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (10A)

[0491] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (280 mg, 1.0 mmol, Example 2), 3-pyridineboronic acid (184 mg, 1.5 mmol), PdCl(dpppf)-DCM (81 mg, 0.1 mmol), and 2 M sodium carbonate (2 mL) in dioxane (5 mL) was heated at 75° C. overnight under nitrogen. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-(pyridin-3-yl)benzoate (140 mg, 52%) as a white solid. 1 H NMR(300MHz,cdcl3)δ8.74(d,J=40.1Hz,2H),7.95(d,J=6.3Hz,1H),7.81(d,J=1.5Hz,1H),7.47(brs,J=17.7Hz,2H),3.96(s,3H),3.52(s,3H). MS(ESI)[M+H] + Required value m / z 278.06, observed value m / z 278.20.

[0492] To a stirred solution of methyl 5-chloro-2-methoxy-3-(pyridin-3-yl)benzoate (140 mg, 0.505 mmol) in MeOH (4 mL) was added 2.5 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 10% citric acid was added to the residue to pH = 3. The mixture was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated to give 5-chloro-2-methoxy-3-(pyridin-3-yl)benzoic acid (132 mg, 100%), which was used directly in the next step as a yellow solid without further purification. MS (ESI) [M+H] + Required value m / z 264.04, observed value m / z 264.20.

[0493] 5-Chloro-2-methoxy-3-(pyridin-3-yl)benzoic acid (132 mg, 0.50 mmol) was dissolved in DCM (3.0 mL) and THF (3.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (52 μL, 0.60 mmol), respectively. The reaction was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (104 μL, 0.60 mmol) and 6-(trifluoromethyl)benzo[d]thiazol-2-amine (109 mg, 0.50 mmol) were added. The mixture was stirred at room temperature for 48 hours, after which the reaction was quenched by the addition of silica gel. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give 5-chloro-2-methoxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (20 mg, 10%) as a yellow solid. 1 H NMR (300 MHz, acetone) δ 8.88 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 17.8, 9.1 Hz, 2H), 7.63 (s, 1H), 7.60-7.46 (m, 1H), 3.28 (s, 3H). MS (ESI) [M+H] + Required value m / z 464.05, observed value m / z 464.20.

[0494] To a stirred solution of 5-chloro-2-methoxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (20 mg, 0.043 mmol) in anhydrous DCM (5 mL) at −78° C., BBr3 (1.0 M in DCM, 129 μL) was added dropwise. After the addition, the reaction was slowly warmed to room temperature, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was cooled in an ice bath, and MeOH and water were added to quench the reaction. The mixture was partitioned between DCM and water. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (12 mg, 63%) as a yellow solid. 1 H NMR (300 MHz, acetone) δ 8.88 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 17.8, 9.1 Hz, 2H), 7.63 (s, 1H), 7.60-7.46 (m, 1H). MS (ESI) [M+H] + Required value m / z 450.03, observed value m / z 450.10.

[0495] To a stirred solution of 5-chloro-2-hydroxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (12 mg, 0.0267 mmol) in THF (5 mL) was added 2.0 N HCl in ether (15 μL, 0.0267 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to give 5-chloro-2-hydroxy-3-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (13 mg, 100%). MS (ESI) [M+H] + Required value m / z 450.03, observed value m / z 450.10.

[0496] Example 11 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (11) and 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (11A)

[0497] [ka] Methyl 3-(dibromomethyl)-5-chloro-2-methoxybenzoate (370 mg, 1 mmol, Example 41) was dissolved in 4 mL of concentrated sulfuric acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to give methyl 5-chloro-3-formyl-2-methoxybenzoate (220 mg, 96%) as a white solid. 1 H NMR(300MHz,cdcl3)δ10.33(s,1H),8.00(d,J=2.6Hz,1H),7.91(d,J=3.1Hz,1H),3.98(s,4H),3.94(s,4H).

[0498] To a stirred solution of methyl 5-chloro-3-formyl-2-methoxybenzoate (220 mg, 0.965 mmol) in MeOH (10 mL) was added (2S,6R)-2,6-dimethylmorpholine (238 μL, 1.93 mmol), NaBHCN (121 mg, 1.93 mmol), and acetic acid (138 μL, 2.41 mmol). The resulting mixture was stirred at room temperature overnight. Saturated NaHCO was added and extracted twice with DCM. The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column chromatography to give methyl 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-methoxybenzoate as a yellow oil (232 mg, 75% yield). MS (ESI) [M+H] +Required value m / z 328.20, observed value m / z 328.40.

[0499] To a stirred solution of methyl 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-methoxybenzoate (232 mg, 0.71 mmol) in MeOH (4 mL) was added 3.5 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 4N HCl in dioxane (2 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (322 mg, 0.852 mmol), DMF (5 mL), and DIPEA (618 μL, 3.55 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (154 mg, 0.71 mmol) was added. The resulting reaction was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (77 mg, 35%) as a white solid. 1 H NMR (300MHz, acetone) δ8.41(s,1H),8.00-7.90(m,2H),7.76(dd,J=8.5,2.4Hz,1H),7.36-7.29(m,1H) ,4.27(s,2H),4.02-3.93(m,2H),3.39-3.33(m,4H),2.51(t,J=11.4Hz,2H),1.23(d,J=6.3Hz,6H). MS(ESI)[M+H] + Required value m / z 500.10, observed value m / z 500.30.

[0500] To a stirred solution of 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (77 mg, 0.154 mmol) in THF (5 mL) was added 2.0 N HCl in ether (77 μL, 0.154 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to give 5-chloro-3-((cis-2,6-dimethylmorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (82 mg, 100%) as a yellow solid. MS (ESI) [M+H] + Required value m / z 500.10, observed value m / z 500.30.

[0501] Example 12 5-chloro-2-hydroxy-3-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (12) and 5-chloro-2-hydroxy-3-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (12A)

[0502] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (277 mg, 0.99 mmol, Example 2), 2-tributylstannyl thiazole (346 μL, 1.1 mmol), and Pd(PPh3)4 (35 mg, 0.03 mmol) in dioxane (2 mL) was heated to 150 °C under nitrogen in a microwave for 20 minutes. After cooling to room temperature, the mixture was filtered through Celite, washed with ethyl acetate, and concentrated in vacuo. The resulting solid was purified by flash column chromatography to give methyl 5-chloro-2-methoxy-3-(thiazol-2-yl)benzoate (237 mg, 85%) as a yellow solid. MS (ESI) [M+H] + Required value m / z 284.01, observed value m / z 284.0.

[0503] To a stirred solution of methyl 5-chloro-2-methoxy-3-(thiazol-2-yl)benzoate (237 mg, 0.837 mmol) in MeOH (5 mL) and THF (4 mL) was added 4.0 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 10% citric acid was added to the residue to pH = 3. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To the residue were added HBTU (379 mg, 1.0 mmol), DMF (5 mL), and DIPEA (729 μL, 4.185 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (182 mg, 0.837 mmol) was added. The resulting reaction was heated at 120 °C for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 5-chloro-2-hydroxy-3-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (177 mg, 47%) as a yellow solid. 1 H NMR(300MHz,cdcl3)δ8.28(d,J=2.6Hz,1H),8.07(s,1H),7.88-7.74(m,3H),7.62(d,J=8.5Hz,1H),7.42(d,J=3.4Hz,1H). MS(ESI)[M+H] + Required value m / z 455.99, observed value m / z 456.2.

[0504] To a stirred solution of 5-chloro-2-hydroxy-3-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (177 mg, 0.389 mmol) in THF (5 mL) was added 2N HCl in ether (195 μL, 0.389 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to give 5-chloro-2-hydroxy-3-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (191 mg, 100%). MS (ESI) [M+H] + Required value m / z 455.99, observed value m / z 456.2.

[0505] Example 13 5-chloro-2-hydroxy-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide (13)

[0506] [ka] A mixture of 2-methyl-4-(trifluoromethyl)aniline (525 mg, 3 mmol), NHSCN (228 mg, 3 mmol), and TFA (574 μL, 7.5 mmol) in ethyl acetate (5 mL) was refluxed overnight. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(2-methyl-4-(trifluoromethyl)phenyl)thiourea (347 mg, 50%) as a yellow solid. MS (ESI) [M+H] + Required value m / z 235.05, observed value m / z 235.30.

[0507] At 0 °C, a solution of Br (76 μL, 1.48 mmol) in CHCl (2 mL) was added dropwise to a stirred solution of 1-(2-methyl-4-(trifluoromethyl)phenyl)thiourea (347 mg, 1.48 mmol) in CHCl (5 mL). After the addition was complete, the mixture was heated to reflux overnight. After cooling to room temperature, the precipitated white solid was filtered, collected, neutralized by the addition of ammonia, and further extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 4-methyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (125 mg, 37%) as a white solid, which was used in the next step without further purification. MS (ESI) [M+H] + Required value m / z 233.04, observed value m / z 233.20.

[0508] To a stirred solution of 4-methyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (97 mg, 0.418 mmol) and (Boc)O (262 mg, 1.2 mmol) in anhydrous DCM (4 mL) was added DMAP (5 mg, 0.0418 mmol). The resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, ethyl acetate was added and washed sequentially with saturated NH4Cl, water, saturated sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl N-tert-butoxycarbonyl-N-(4-(methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate (180 mg, 100%) as a yellow solid, which was used in the next step without further purification. MS (ESI) [M+H] + Required value m / z 433.14, observed value m / z 433.4.

[0509] A mixture of tert-butyl N-tert-butoxycarbonyl-N-(4-(methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate (180 mg, 0.417 mmol), NBS (82 mg, 0.459 mmol), and AIBN (7 mg, 0.0417 mmol) in CCl4 (5 mL) was refluxed under nitrogen for 2.5 h. After cooling to room temperature, the mixture was concentrated and the residue was chromatographed to give tert-butyl N-(4-(bromomethyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-N-tert-butoxycarbonylcarbamate (210 mg, 98%) as a yellow solid. MS (ESI) [M+H] + Required value m / z 511.05, observed value m / z 511.20.

[0510] To a stirred solution of tert-butyl N-(4-(bromomethyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-N-tert-butoxycarbonylcarbamate (210 mg, 0.411 mmol) in 2-methoxyethan-1-ol (8 mL) was added 1N NaOH (4 mL). The resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate (86 mg, 52%) as a colorless oil. MS (ESI) [M+H] + Required value m / z 407.13, observed value m / z 407.3.

[0511] To a stirred solution of tert-butyl (4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate (86 mg, 0.212 mmol) in DCM (4 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, excess TFA was evaporated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to give 4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine as a pale yellow solid (62 mg, 97%), which was used in the next step without further purification. MS (ESI) [M+H] + Required value m / z 307.07, observed value m / z 307.20.

[0512] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol, Example 2), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc) (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tribasic potassium phosphate (1.9 g, 8.96 mmol) was refluxed overnight in toluene (10 mL) and water (1 mL) under N. After cooling, the reaction was added with saturated NH.sub.4Cl solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1 H NMR (300 MHz, chloroform) δ 7.62 (d, 1H, J = 3.0 Hz), 7.32 (d, 1H, J = 3.0 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).

[0513] To a stirred solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (43 mg, 0.20 mmol) in MeOH (5 mL) was added 1.0 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. After completion of the reaction, 1N HCl was added to the reaction and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 5-chloro-2-methoxy-3-methylbenzoic acid as a residue (white solid, 40 mg, 100%), which was used in the next step without further purification.

[0514] 5-Chloro-2-methoxy-3-methylbenzoic acid (40 mg, 0.20 mmol) was dissolved in DCM (3.0 mL), followed by the addition of catalytic amounts of DMF (1 drop) and oxalyl chloride (21 μL, 0.243 mmol). The reaction was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (43 μL, 0.243 mmol) and 4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine (62 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 48 hours, after which the reaction was quenched by the addition of silica gel. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 5-chloro-2-methoxy-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide (20 mg, 21%) as a white solid. MS(ESI)[M+H] + Required value m / z 489.08, observed value m / z 489.20.

[0515] A solution of 5-chloro-2-methoxy-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide (20 mg, 0.04 mmol) in DMF (5 mL) was mixed with sodium ethanethiolate (17 mg, 0.205 mmol), and the resulting suspension was heated at 130 °C overnight. After completion of the reaction, 1N HCl was added to the reaction mixture and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-hydroxy-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide (15 mg, 55%) as a white solid. 1 H NMR(300MHz,cdcl3)δ7.95(s,2H),7.58(s,1H),7.29(s,1H),4.96(s,2H),3.98-3.86(m,2H),3.84-3.73(m,2H),3.64(s,3H),2.28(s,3H). MS(ESI)[M+H] + Required value m / z 475.06, observed value m / z 475.20.

[0516] Example 14 5-Chloro-2-hydroxy-3-(tetrahydrofuran-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (14)

[0517] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (275 mg, 0.98 mmol, Example 2), furan-3-ylboronic acid (218 mg, 1.96 mmol), Pd(PPh3)4 (56 mg, 0.049 mmol), and sodium carbonate (312 mg, 2.95 mmol) in dioxane (3 mL) and water (1 mL) was irradiated in a microwave at 100 °C for 1 h under nitrogen. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(furan-3-yl)-2-methoxybenzoate (250 mg, 96%) as a colorless oil. MS (ESI) [M+H] + Required value m / z 267.03, observed value m / z 267.20.

[0518] A mixture of methyl 5-chloro-3-(furan-3-yl)-2-methoxybenzoate (267 mg, 1.0 mmol) and Pd—C (27 mg) in MeOH (5 mL) was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated to give methyl 2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (238 mg, 100%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI) [M+H] + Required value m / z 237.1, observed value m / z 237.3.

[0519] A mixture of methyl 2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (238 mg, 1 mmol) and NCS (134 mg, 1.0 mmol) in acetonitrile (5 mL) was refluxed for 24 h. After cooling to room temperature, the solvent was concentrated, and the residue was directly applied to a column to give methyl 5-chloro-2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (85 mg, 31%) as a colorless oil. 1H NMR(300MHz,cdcl3)δ7.66-7.60(m,1H),7.42(d,J=2.7Hz,1H),4.11-4.03(m,2H),3.9 0(s,3H),3.86-3.74(m,5H),3.72-3.64(m,1H),2.44-2.29(m,1H),1.98-1.84(m,1H). MS(ESI)[M+H] + Required value m / z 271.07, observed value m / z 271.2.

[0520] To a stirred solution of 5-chloro-2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (85 mg, 0.315 mmol) in MeOH (5 mL) was added 2.0 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 4N HCl in dioxane (1 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (143 mg, 0.378 mmol), DMF (5 mL), and DIPEA (274 μL, 1.575 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (68 mg, 0.315 mmol) was added. The resulting reaction was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 5-chloro-2-hydroxy-3-(tetrahydrofuran-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (14 mg, 10%) as a white solid. 1 H NMR (400MHz, acetone) δ8.42(s,1H),8.12(d,J=2.6Hz,1H),7.91(d,J=8.5Hz,1H),7.83(dd,J=8.5,1.4Hz, 1H),7.47(d,J=2.6Hz,1H),4.09-3.96(m,2H),3.88-3.71(m,3H),2.37-2.31(m,1H),1.98-1.84(m,1H). MS(ESI)[M+H] + Required value m / z 443.04, observed value m / z 443.3.

[0521] Example 15 5-Chloro-2-hydroxy-3-(tetrahydrofuran-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (15)

[0522] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (253 mg, 0.90 mmol, Example 2), furan-2-ylboronic acid (132 mg, 1.17 mmol), Pd(PPh3)4 (52 mg, 0.045 mmol), and sodium carbonate (287 mg, 2.7 mmol) in dioxane (3 mL) and water (1 mL) was irradiated in a microwave at 100 °C for 1 h under nitrogen. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(furan-2-yl)-2-methoxybenzoate (131 mg, 55%) as a colorless oil. MS (ESI) [M+H] + Required value m / z 267.03, observed value m / z 267.20.

[0523] A mixture of methyl 5-chloro-3-(furan-2-yl)-2-methoxybenzoate (131 mg, 0.5 mmol) and Pd—C (15 mg) in MeOH (5 mL) was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-(tetrahydrofuran-2-yl)benzoate (95 mg, 70%) as a colorless oil. 1H NMR(300MHz,cdcl3)δ7.71(d,J=2.8Hz,1H),7.62(dd,J=2.8,0.6Hz,1H),5.13(t,J=7.2Hz,1H),4.16-4.08(m ,1H),3.99-3.90(m,1H),3.93(s,3H),3.84(s,3H),2.52-2.38(m,1H),2.07-1.96(m,2H),1.73-1.65(m,1H). MS(ESI)[M+H] + Required value m / z 271.07, observed value m / z 271.2.

[0524] To a stirred solution of 5-chloro-2-methoxy-3-(tetrahydrofuran-2-yl)benzoate (95 mg, 0.352 mmol) in MeOH (5 mL) was added 2.0 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 4N HCl in dioxane (1 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (160 mg, 0.422 mmol), DMF (5 mL), and DIPEA (306 μL, 1.76 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (76 mg, 0.352 mmol) was added. The resulting reaction was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2-hydroxy-3-(tetrahydrofuran-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a white solid (15 mg, 10%). 1 H NMR (500MHz, acetone) δ8.42(s,1H),8.11(s,1H),7.91(d,J=8.3Hz,1H),7.82(d,J=8.5Hz,1H),7.56(s,1H),5.12( t,J=7.1Hz,1H),4.17-4.10(m,1H),3.94-3.85(m,1H),2.55-2.45(m,1H),2.03-1.91(m,2H),1.78-1.66(m,1H). MS(ESI)[M+H]+ Required value m / z 443.04, observed value m / z 443.3.

[0525] Example 16 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (16) and 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (16A)

[0526] [ka] To a flame-dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl (10 mL). The suspension was refluxed overnight in the dark. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%). 1 H NMR (300MHz, cdcl3) δ7.76(d,J=2.7Hz,1H),7.54(d,J=2.7Hz,1H),4.51(s,2H),3.96(s,3H),3.94(s,3H).

[0527] To a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (132 mg, 0.45 mmol) in THF (4 mL) at 0 °C, morpholine (78 μL, 0.90 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction was partitioned between DCM and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography to give methyl 5-chloro-2-methoxy-3-(morpholinomethyl)benzoate (110 mg, 83%) as a colorless oil. 1H NMR(500MHz,cdcl3)δ7.68(d,J=2.8Hz,1H),7.58(d,J=2.7Hz,1H),3.90(s,3H),3.82(s,3H),3.70(t,4H),3.52(s,2H),2.47(t,J=4.1Hz,4H). MS(ESI)[M+H] + Required value m / z 300.10, observed value m / z 300.30.

[0528] To a stirred solution of methyl 5-chloro-2-methoxy-3-(morpholinomethyl)benzoate (110 mg, 0.368 mmol) in MeOH (3 mL) was added 2.0 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 4N HCl in dioxane (1 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (168 mg, 0.442 mmol), DMF (5 mL), and DIPEA (320 μL, 1.84 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (80 mg, 0.368 mmol) was added. The resulting reaction mixture was heated at 120 °C for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (75 mg, 43%) as a yellow solid. 1 H NMR (400MHz, dmso) δ8.39(s,1H),7.80(dd,J=9.5,5.7Hz,2H),7.67(d,J=8.6Hz,1H),7.37(d,J=2.9Hz,1H),4.23(s,2H),3.81(brs,4H),3.17(brs,4H). MS(ESI)[M+H] + Required value m / z 472.07, observed value m / z 472.20.

[0529] To a stirred solution of 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (32 mg, 0.068 mmol) in THF (5 mL) was added 4.0 N HCl in dioxane (20 μL, 0.075 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to give 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (100%). MS (ESI) [M+H] + Required value m / z 472.07, observed value m / z 472.20.

[0530] Example 17 5-chloro-2-hydroxy-3-(2-morpholinoethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (17) and 5-chloro-2-hydroxy-3-(2-morpholinoethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (17A)

[0531] [ka] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (445 mg, 1.6 mmol, Example 2), potassium trifluoro(vinyl)borate (322 mg, 2.4 mmol), Pd(dppf)Cl (40 mg, 0.05 mmol), and sodium carbonate (339 mg, 3.2 mmol) was refluxed overnight in dioxane (10 mL) and water (1 mL) under N. After cooling, the reaction was added with saturated NH.sub.4Cl solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-vinylbenzoate (320 mg, 89%) as a colorless oil. 1H NMR(300MHz,cdcl3)δ7.69(d,J=2.7Hz,1H),7.63(d,J=2.7Hz,1H),6.99(dd,J=17.7,11.1Hz ,1H),5.79(dd,J=17.7,0.8Hz,1H),5.43(dd,J=11.1,0.8Hz,1H),3.93(s,3H),3.83(s,3H).

[0532] To a stirred solution of methyl 5-chloro-2-methoxy-3-vinylbenzoate (270 mg, 1.19 mmol) at 0 °C, 9-BBN (3.1 mL, 1.55 mmol, 0.5 M in THF) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was cooled to 0 °C, and 1 mL of 50% HO solution was added, followed by 1 mL of 3 M NaOH solution. The mixture was stirred on an ice bath for 2 hours. The reaction was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-3-(2-hydroxyethyl)-2-methoxybenzoate (110 mg, 50%) as a colorless oil. 1 H NMR (400MHz, d2o) δ7.65(s,1H),7.37(s,1H),3.90(s,3H),3.85-3.78(m,5H),2.88(t,J=6.3Hz,2H). MS(ESI)[M+H] + Required value m / z 245.06, observed value m / z 245.20.

[0533] To a stirred solution of methyl 5-chloro-3-(2-hydroxyethyl)-2-methoxybenzoate (110 mg, 0.451 mmol) in DCM (3 mL) at 0 °C, TEA (95 μL, 0.677 mmol) and MsCl (42 μL, 0.54 mmol) were added. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between DCM and saturated NH Cl solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-(2-((methylsulfonyl)oxy)ethyl)benzoate (119 mg, 83%) as a colorless oil.1 H NMR(500MHz,cdcl3)δ7.71(d,J=2.7Hz,1H),7.37(d,J=2.7Hz,1H),4.41(t, J=6.8Hz,2H),3.92(s,3H),3.83(s,3H),3.08(t,J=6.8Hz,2H),2.93(s,3H).

[0534] To a stirred solution of methyl 5-chloro-2-methoxy-3-(2-((methylsulfonyl)oxy)ethyl)benzoate (119 mg, 0.369 mmol) in DMF (3 mL) was added morpholine (160 μL, 1.84 mmol). The resulting mixture was stirred at 80° C. overnight. The reaction was partitioned between water and DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-chloro-2-methoxy-3-(2-morpholinoethyl)benzoate (91 mg, 83%) as a yellow oil. 1 H NMR(300MHz,cdcl3)δ7.65(d,J=2.3Hz,1H),7.35(d,1H),3.91(s,3H),3.82(s,3 H),3.78-3.69(m,4H),2.86-2.79(m,2H),2.64-2.56(m,2H),2.57-2.49(m,4H). MS(ESI)[M+H] + Required value m / z 314.12, observed value m / z 314.20.

[0535] To a stirred solution of methyl 5-chloro-2-methoxy-3-(2-morpholinoethyl)benzoate (91 mg, 0.29 mmol) in MeOH (3 mL) was added 1.5 mL of 1N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and 4N HCl in dioxane (1 mL) was added to the residue. After the mixture was stirred for an additional 10 minutes, it was concentrated and dried under vacuum. To this residue were added HBTU (132 mg, 0.35 mmol), DMF (5 mL), and DIPEA (253 μL, 1.45 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (64 mg, 0.29 mmol) was added. The resulting reaction was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2-hydroxy-3-(2-morpholinoethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (56 mg, 40%) as a yellow solid. 1 H NMR (300MHz, acetone) δ8.41-8.36(m,1H),7.94-7.86(m,2H),7.77-7.70(m,1H),7.24(d,J=2.9Hz,1H),4.04(brs,4H),3.40-3.02(m,8H). MS(ESI)[M+H] + Required value m / z 486.10, observed value m / z 486.20.

[0536] To a stirred solution of 5-chloro-2-hydroxy-3-(2-morpholinoethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (36 mg, 0.074 mmol) in THF (5...

Claims

1. A compound of formula A, 【Chemical 1】 wherein R of formula A １０００ａ but, -CH ３ , -CH ２ CH ３ , -C １ ~C ６ Alkyl, —C ３ ~C ６ Cycloalkyl, —OCH ３ , -CH ２ OCH ３ , -CH ２ OCH ２ OCH ３ , -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 -(CH ２ )NHCO ２ CH ３ 、 【Chemistry 2】 - (CH ２ ) ｒ’ NR ５０００Ａ R ５０００Ｂ , -(CH ２ ) ｒ R ６０００ , and C(O)N(CH ２ CH ２ OCH ３ ) ２ is selected from the group consisting of Substituent R ５０００Ａ and R ５０００Ｂ each independently represents -C １ ~C ６ Alkyl, and -C １ ~C ６ Alkoxy and —O(CH ２ ) ２ OCH ３ -C substituted with one or more groups selected from １ ~C ６ alkyl, or R ５０００Ａ and R ５０００Ｂ together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO ２ CH ３ , -CF ３ , C １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and acyl; R ６０００ is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; r' is an integer selected from the group consisting of 1, 2, and 3; r is an integer selected from the group consisting of 0, 1, 2, and 3; R of Formula I １０００ｃ is selected from the group consisting of chloro, fluoro, iodo, and bromo; R ４０００ｂ and R ４０００ｄ Each of the １０００ and Z １０００ independently selected from the group consisting of: ４０００ｂ Y １０００ If R ４０００ｄ is Z １０００ and R ４０００ｂ Z １０００ If R ４０００ｄ Is Y １０００ and Y １０００ is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, —OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano and —CO ２ (C １ ~C ６ ) alkyl; Z １０００ が、H、-CH ２ OCH ３ 、-CH ２ OCH ２ CH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSO ２ CH ３ 、 -(CH ２ )O(CH ２ ) ２ NR ２０００Ａ R ２０００Ｂ ,-(EH ２ ) ｓ R ３０００ 、-CH ２ OCH ２ Arr １ 、OCH ３ CH ２ NHC(O)H ２ CH ３ 、 -CH ２ NHC(O)CH ２ OCH ３ , -CH ２ NHSO ２ CH ３ , -(CH ２ ) ｔ’ NR ７０００Ａ R ７０００Ｂ , and -(CH ２ ) ｔ R ８０００ is selected from the group consisting of R ２０００Ａ and R ２０００Ｂ But together with the nitrogen to which they are attached, forming a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups; R ３０００ is a 5- or 6-membered heterocycle; Ar １ But C １ ~C ６ a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from alkyl, halo, hydroxyl and alkoxy; R ７０００Ａ and R ７０００Ｂ Each of the groups independently represents C １ ~C ６ alkyl, or R ７０００Ａ and R ７０００Ｂ together with the nitrogen to which they are attached, １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R ８０００ is selected from the group consisting of a 5- to 6-membered heterocycle optionally substituted with methyl; s is an integer selected from the group consisting of 0, 1, 2, and 3; t' is an integer selected from the group consisting of 1, 2, and 3; t is an integer selected from the group consisting of 0, 1, 2, and 3; however, R ５０００Ａ and R ５０００Ｂ But both are C １ ~C ６ It is not alkyl, Z １０００ is H, then R １０００ａ is C １ ~C ６ Alkyl, —C ３ ~C ６ Cycloalkyl, CH ３ or CH ２ CH ３ Not a compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. A compound of formula I, 【Chemistry 3】 During the ceremony, R １ａ but, -CH ３ 、-CH ２ CH ３ 、-OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH ２ ) ２ OH、-H ２ O(CH ２ ) ２ OCH ３ 、 -(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、-(CH ２ )NHCO ２ CH ３ 、 【Chemistry 4】 - (CH ２ ) ｍ’ NR ５Ａ R ５Ｂ , -(CH ２ ) ｍ R ６ , and C(O)N(CH ２ CH ２ OCH ３ ) ２ is selected from the group consisting of R ５Ａ and R ５Ｂ each independently represents -C １ ~C ６ Alkyl, and -C １ ~C ６ Alkoxy, and -O(CH ２ ) ２ OCH ３ -C substituted with one or more groups selected from １ ~C ６ alkyl, or R ５Ａ and R ５Ｂ together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO ２ CH ３ , -CF ３ , C １ ~C ６ form a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and acyl; R ６ is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; m' is an integer selected from the group consisting of 1, 2, and 3; m is an integer selected from the group consisting of 0, 1, 2, and 3; R １ｃ is selected from the group consisting of chloro, fluoro, iodo, and bromo; R ４ｂ and R ４ｄ are each independently selected from the group consisting of Y and Z, with the proviso that R ４ｂ If Y, then R ４ｄ is Z and R ４ｂ When is Z, R ４ｄ is Y, Y is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, —OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano, and -CO ２ (C １ ~C ６ ) alkyl; Zが、-CH ２ OH、-H ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ NHCH ３ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、 -CH ２ O (CH ２ ) ２ NHSO ２ CH ３ , -(CH ２ ) O(CH ２ ) ２ NR ２Ａ R ２Ｂ , -(CH ２ ) ｎ R ３ , -CH ２ OCH ２ Ar, and OCH ３ is selected from the group consisting of R ２Ａ and R ２Ｂ But together with the nitrogen to which they are attached, forming a 4- to 8-membered heterocyclic ring optionally substituted with one or more methyl groups; R ３ is selected from the group consisting of a 5- to 6-membered heterocycle and phenoxy; n is an integer selected from the group consisting of 0, 1, 2, and 3; Ar is -C １ ~C ６ a compound which is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, hydroxy, and alkoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. R １ａ But -CH ３ , -CH ２ CH ３ and -CH ２ NR ５Ａ R ５Ｂ 3. The compound of claim 2 selected from the group consisting of:

4. R ５Ａ and R ５Ｂ each independently being C substituted with one or more methoxy groups; １ ~C ６ alkyl, or R ５Ａ and R ５Ｂ together with the nitrogen to which they are attached, １ ~C ６ 4. The compound of claim 3, which forms a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl.

5. R １ａ が、-CH ３ 、-CH ２ CH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、 【Chemistry 5】 3. The compound of claim 2 selected from the group consisting of:

6. R １ｃ The compound of claim 2, wherein is chloro.

7. R ４ｂ is Y and R ４ｄ The compound of claim 2, wherein is Z.

8. R ２Ａ and R ２Ｂ and R 1 and R 2 together with the nitrogen to which they are attached form a 6-membered heterocyclyl optionally substituted with a methyl group.

9. R ２Ａ and R ２Ｂ The compound of claim 2, wherein together with the nitrogen to which they are attached form a heterocyclyl selected from piperazinyl or 4-methylpiperazinyl.

10. R ３ The compound of claim 2, wherein is a five-membered heterocycle.

11. R ３ The compound of claim 2, wherein is tetrahydrofuranyl.

12. The compound of claim 2 , wherein n is 0.

13. - (CH ２ ) ｎ R ３ but, 【Chemistry 6】 3. The compound of claim 2, wherein:

14. 3. The compound of claim 2, wherein Ar is selected from the group consisting of 5-6 membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.

15. Ar is phenyl, 【Chemistry 7】 15. The compound of claim 14 selected from the group consisting of:

16. Y is CF ３ 3. The compound of claim 2, wherein:

17. Zが、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、-CH ２ O(CH ２ ) ２ OH、-H ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH) ３ ) ２ 、 -CH ２ O (CH ２ ) ２ NHSO ２ CH ３ , -(CH ２ ) O(CH ２ ) ２ NR ２Ａ R ２Ｂ , -(CH ２ ) ｍ R ３ , -CH ２ OCH ２ Ar and OCH ３ is selected from the group consisting of R ２Ａ and R ２Ｂ together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R ３ is tetrahydrofuranyl, 3. The compound of claim 2, wherein Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxyl, and methoxy.

18. R ４ｄ が、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSO ２ CH ３ 、 【Chemistry 8】 and OCH ３ and R ４ｂ But, -CF ３ 3. The compound of claim 2 selected from the group consisting of:

19. R １ａ But -CH ３ , -CH ２ CH ３ and -CH ２ NR ５Ａ R ５Ｂ is selected from the group consisting of R ５Ａ and R ５Ｂ each independently being C substituted with one or more methoxy groups; １ ~C ６ alkyl, or R ５Ａ and R ５Ｂ together with the nitrogen to which they are attached, １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R １ｃ But it's Chloro. Y is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, —OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano, and —CO ２ (C １ ~C ６ ) alkyl; Zが、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、-CH ２ O(CH ２ ) ２ OH、-H ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH) ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSS ２ CH ３ ,-(EH ２ )O(CH ２ ) ２ NR ２Ａ R ２Ｂ ,-(EH ２ ) ｍ R ３ 、-CH ２ OCH ２ Ar-OCH ３ selected from the group R ２Ａ and R ２Ｂ together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R ３ is tetrahydrofuranyl, The compound of claim 2, wherein Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy. or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. R １ａ But -CH ３ , -CH ２ CH ３ and -CH ２ NR ５Ａ R ５Ｂ is selected from the group consisting of R ５Ａ and R ５Ｂ each of which is independently substituted with one or more groups selected from methoxy １ ~C ６ alkyl, or R ５Ａ and R ５Ｂ together with the nitrogen to which they are attached, １ ~C ６ forming a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R １ｃ But it's Chloro. Y is CF ３ and Zが、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、-CH ２ O(CH ２ ) ２ OH、-H ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH) ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSS ２ CH ３ ,-(EH ２ )O(CH ２ ) ２ NR ２Ａ R ２Ｂ ,-(EH ２ ) ｍ R ３ 、-CH ２ OCH ２ Ar-OCH ３ selected from the group R ２Ａ and R ２Ｂ together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperazinyl or 4-methylpiperazinyl R ３ is tetrahydrofuranyl, 3. The compound of claim 2, wherein Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxyl, and methoxy. or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

21. R １ａ が、-CH ３ 、-CH ２ CH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、 【Chemistry 9】 is selected from the group consisting of R １ｃ But it's Chloro. Y is CF ３ and Zが、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、-CH ２ O(CH ２ ) ２ OH、-H ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH) ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSS ２ CH ３ 、 【Chemistry 10】 and OCH ３ The compound of claim 2 selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

22. R ４ｂ is Y and R ４ｄ The compound of claim 21 , wherein is Z.

23. Formula Ia: 【Chemistry 11】 wherein, R １ａ is, -CH ３ , -CH ２ CH ３ , -(CH ２ )N(CH ２ CH ２ OCH ３ ) ２ , 【Chemistry 12】 is selected from the group consisting of R ４ｄ が、CH ２ OH、-H ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ NHCH ３ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、 -CH ２ O(CH ２ ) ２ NHSO ２ CH ３ 、 【Chemistry 13】 and -OCH ３ The compound of claim 2 selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

24. R ４ｄ が、-CH ２ OCH ２ CH ３ 、-CH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSO ２ CH ３ 、 【Chemistry 14】 and -OCH ３ 24. The compound of claim 23 selected from the group consisting of: 【Request 25】 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

26. 【Table 2】 26. The compound of claim 25, a pharmaceutically acceptable salt, solvate, or prodrug thereof, the hydrochloride salt.

27. A compound of formula II, 【Chemistry 15】 During the ceremony, R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 -(CH ２ )NHCO ２ CH ３ 、 【Chemistry 16】 - (CH ２）ｏ’ NR ５０Ａ R ５０Ｂ , -(CH ２ ) ｏ R ６０ , and C(O)N(CH ２ CH ２ OCH ３ ) ２ is selected from the group consisting of R ５０Ａ and R ５０Ｂ each independently represents -C １ ~C ６ Alkyl, and -C １ ~C ６ Alkoxy and —O(CH ２ ) ２ OCH ３ -C substituted with one or more groups selected from １ ~C ６ alkyl, or R ５０Ａ and R ５０Ｂ together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO ２ CH ３ , -CF ３ , C １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and acyl; R ６０ is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; o' is an integer selected from the group consisting of 1, 2, and 3; o is an integer selected from the group consisting of 0, 1, 2, and 3; R １０ｃ is selected from the group consisting of chloro, fluoro, iodo, and bromo; R ４０ｂ and R ４０ｄ is H, and R ４０ｂ and R ４０ｄ The other is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, -OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano and —CO ２ (C １ ~C ６ ) alkyl; However, R ５０Ａ and R ５０Ｂ But both are C １ ~C ６ The compound, which cannot be alkyl, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

28. R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ OH、-H ２ O(CH) ２ ) ２ OCH ３ 、 -(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 【Chemistry 17】 -CH ２ NR ５０Ａ R ５０Ｂ , -(CH ２ ) ｏ R ６０ , and C(O)N(CH ２ CH ２ OCH ３ ) ２ 28. The compound of claim 27 selected from the group consisting of:

29. R ５０Ａ and R ５０Ｂ each independently represents methyl, and methoxy and —O(CH ２ ) ２ OCH ３ C substituted with one or more groups selected from １ ~C ６ alkyl, or R ５０Ａ and R ５０Ｂ together with the nitrogen to which they are attached form azetindinyl; pyrrolidinyl; cyano, hydroxyl, methoxy, -NHC(O)CH ３ , -C(O)NH ２ , -SO ２ CH ３ , -CF ３ pyrrolidinyl substituted with one or more substituents selected from the group consisting of - and methyl; piperidinyl; -CF ３ 28. The compound of claim 27, wherein the compound forms a 4-8 membered heterocyclyl selected from the group consisting of piperidinyl substituted with one or more substituents selected from the group consisting of fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; and dioxothiomorphyl.

30. -CH ２ NR ５０Ａ R ５０Ｂ が、-CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemistry 18】 30. The compound of claim 29 selected from the group consisting of:

31. R ６０ 28. The compound of claim 27, wherein is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl, and o is 0.

32. - (CH ２ ) ０ R ６０ but, 【Chemistry 19】 28. The compound of claim 27 selected from the group consisting of:

33. R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ OH、-H ２ O(CH) ２ ) ２ OCH ３ 、 -(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 【Chemistry 20】 -CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ 、 -(CH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemical 21】 and C(O)N(CH ２ CH ２ OCH ３ ) ２ 28. The compound of claim 27 selected from the group consisting of:

34. R ４０ｂ and R ４０ｄ is H, and R ４０ｂ and R ４０ｄ The other is fluoro, —CF ３ , -CHF ２ , and -OCF ３ 28. The compound of claim 27 selected from the group consisting of:

35. R ４０ｄ is H and R ４０ｂ Fluoro, -CF ３ , -CHF ２ , and -OCF ３ 35. The compound of claim 34, selected from the group consisting of:

36. R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ OH、-H ２ O(CH) ２ ) ２ OCH ３ ,-(EH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)H ３ 、 【Chemical 22】 -CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemical 23】 and -C(O)N(CH ２ CH ２ OCH ３ ) ２ is selected from the group consisting of R １０ｃ is selected from the group consisting of chloro, fluoro, and iodo; R ４０ｄ is H and R ４０ｂ Fluoro, -CF ３ , -CHF ２ , and -OCF ３ 28. The compound of claim 27, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

37. R １０Ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ Oh, -CH ２ O(CH ２ ) ２ OCH ３ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 【Chemistry 24】 -CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemistry 25】 and C(O)N(CH ２ CH ２ OCH ３ ) ２ 37. The compound of claim 36, selected from the group consisting of:

38. R １０ｃ is chloro, and R ４０ｂ But, -CF ３ 38. The compound of claim 37, wherein:

39. A compound of formula IIa, 【Chemical 26】 During the ceremony, R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、 -CH ２ O(CH ２ ) ２ OH、-CH ２ O(CH ２ ) ２ OCH ３ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 【Chemical 27】 CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemical Formula 28】 and C(O)N(CH ２ CH ２ OCH ３ ) ２ 28. The compound of claim 27, which is a compound of formula IIa selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

40. R １０ａ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ Oh, -CH ２ O(CH ２ ) ２ OCH ３ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、 【Chemical Formula 29】 -CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH) ２ ) ２ OCH ３ 、 【Chemistry 30】 -C(O)N(CH ２ CH ２ OCH ３ ) ２ 40. The compound of claim 39, selected from the group consisting of: 【Request 41】 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】 【Table 3-7】 【Table 3-8】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 【Request 42】 【Table 4】 42. The compound of claim 41, selected from the group consisting of a pharmaceutically acceptable salt, solvate, or prodrug thereof.

43. A compound of formula III, 【Chemical 31】 During the ceremony, R １００ａ が、-CH ３ 、-OCH ３ 、-CH ２ OCH ３ 、 -CH ２ OCH ２ OCH ３ 、-CH ２ O(CH) ２ ) ２ OH、-H ２ O(CH) ２ ) ２ OCH ３ ,-(EH ２ )NH(CH ２ ) ２ OCH ３ 、 -CH ２ NHC(O)CH ３ 、-(CH ２ )NHCO ２ CH ３ 、 【Chemical 32】 - (CH ２ ) ｐ’ NR ５００Ａ R ５００Ｂ , (CH ２ ) ｐ R ６００ , and C(O)N(CH ２ CH ２ OCH ３ ) ２ is selected from the group consisting of R ５００Ａ and R ５００Ｂ each independently represents -C １ ~C ６ Alkyl, and -C １ ~C ６ Alkoxy, and -O(CH ２ ) ２ OCH ３ -C substituted with one or more groups selected from １ ~C ６ alkyl, or R ５００Ａ and R ５００Ｂ together with the nitrogen to which they are attached, form oxo, cyano, hydroxyl, alkoxy, acylamino, carboxamido, -SO ２ CH ３ , -CF ３ , C １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and acyl; R ６００ is selected from the group consisting of 5- to 6-membered heterocyclyl, pyridinyl, and thiazolyl; p' is an integer selected from the group consisting of 1, 2, and 3; p is an integer selected from the group consisting of 0, 1, 2, and 3; R １００ｃ is selected from the group consisting of chloro, fluoro, iodo, and bromo; R ４００ｂ and R ４００ｄ Each of the １ and Z １ independently selected from the group consisting of: ４００ｂ Y １ If R ４００ｄ is Z １ and R ４００ｂ Z １ If R ４００ｄ Is Y １ and Y １ is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, —OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano, and -CO ２ (C １ ~C ６ ) alkyl; Z １ が、-CH ２ NHC(O)CH ２ CH ３ 、 -CH ２ NHC(O)CH ２ OCH ３ , -CH ２ NHSO ２ CH ３ , -(CH ２ ) ｑ’ NR ７Ａ R ７Ｂ , and -(CH ２ ) ｑ R ８ is selected from the group consisting of R ７Ａ and R ７Ｂ Each of the groups independently represents C １ ~C ６ alkyl, or R ７Ａ and R ７Ｂ together with the nitrogen to which they are attached, one or more independently selected C １ ~C ６ forming a 4- to 8-membered heterocyclyl optionally substituted with alkyl; R ８ is selected from the group consisting of a 5- to 6-membered heterocycle optionally substituted with methyl; q' is an integer selected from the group consisting of 1, 2, and 3; a compound wherein q is an integer selected from the group consisting of 0, 1, 2 and 3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

44. R １００ａ But -CH ３ and -CH ２ NR ５００Ａ R ５００Ｂ 44. The compound of claim 43, selected from the group consisting of:

45. R ５００Ａ and R ５００Ｂ each independently being C substituted with one or more methoxy groups; １ ~C ６ alkyl, or R ５００Ａ and R ５００Ｂ together with the nitrogen to which they are attached, １ ~C ６ 45. The compound of claim 44, which forms a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl.

46. R １００ａ が、-CH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、 【Chemical 33】 44. The compound of claim 43, selected from the group consisting of:

47. R １００ｃ 44. The compound of claim 43, wherein is chloro.

48. R ４００ｂ is Y and R ４００ｄ is Z.

49. R ７Ａ and R ７Ｂ each is methyl, or R ７Ａ and R ７Ｂ together with the nitrogen to which they are attached 44. The compound of claim 43, which forms a 6-membered heterocyclyl optionally substituted with a methyl group.

50. R ７Ａ and R ７Ｂ But together with the nitrogen to which they are attached, 44. The compound of claim 43, wherein the heterocyclyl is selected from the group consisting of 4-methylpiperazinyl and morpholinyl.

51. R ８ 44. The compound of claim 43, wherein is a 6-membered heterocycle optionally substituted with methyl.

52. R ８ The compound of claim 43, wherein is 4-methylpiperidinyl.

53. 44. The compound of claim 43, wherein q is 0.

54. Z １ But -CH ２ NHC(O)CH ２ CH ３ , -CH ２ NHC(O)CH ２ OCH ３ , -CH ２ NHSO ２ CH ３ , -CH ２ NR ７Ａ R ７Ｂ , and -(CH ２ ) ｑ R ８ is selected from the group consisting of R ７Ａ and R ７Ｂ each is methyl, or R ７Ａ and R ７Ｂ But together with the nitrogen to which they are attached, forming a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl; And R ８ The compound of claim 43, wherein is 4-methylpiperidinyl.

55. Z １ but, -CH ２ NHC(O)CH ２ CH ３ 、-CH ２ NHC(O)CH ２ OCH ３ 、-CH ２ NHSO ２ CH ３ 、-CH ２ N(CH ３ ) ２ 、 【Chemical 34】 44. The compound of claim 43, selected from the group consisting of:

56. Y １ But CF ３ 44. The compound of claim 43, wherein:

57. Z １ が、-CH ２ NHC(O)CH ２ CH ３ 、-CH ２ NHC(O)CH ２ OCH ３ 、-CH ２ NHSO ２ CH ３ 、 -CH ２ N(CH ３ ) ２ 、 【Chemistry 35】 and Y is selected from the group consisting of １ But, -CF ３ 44. The compound of claim 43, wherein:

58. R １００ａ But -CH ３ and -CH ２ NR ５００Ａ R ５００Ｂ is selected from the group consisting of R ５００Ａ and R ５００Ｂ each independently being C substituted with one or more methoxy groups; １ ~C ６ alkyl, or R ５００Ａ and R ５００Ｂ together with the nitrogen to which they are attached, １ ~C ６ forming a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R １００ｃ But it's Chloro. Y １ is chloro, fluoro, iodo, bromo, -CF ３ , -CHF ２ , Fluoro (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, —OCF ３ , -SO ２ (C １ ~C ６ ) alkyl, cyano and —CO ２ (C １ ~C ６ ) alkyl; Z １ が、-CH ２ NHC(O)CH ２ OCH ３ 、 -CH ２ NHC(O)CH ２ CH ３ , -CH ２ NHSO ２ CH ３ , -CH ２ NR ７Ａ R ７Ｂ , and -(CH ２ ) ｑ R ８ is selected from the group consisting of R ７Ａ and R ７Ｂ each is methyl, or R ７Ａ and R ７Ｂ But together with the nitrogen to which they are attached, forming a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl; R ８ is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

59. R １００ａ But -CH ３ and -CH ２ NR ５００Ａ R ５００Ｂ is selected from the group consisting of R ５００Ａ and R ５００Ｂ each independently being C substituted with one or more methoxy groups; １ ~C ６ alkyl, or R ５００Ａ and R ５００Ｂ together with the nitrogen to which they are attached, １ ~C ６ forming a 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R １００ｃ But it's Chloro. Y １ But, -CF ３ and Z １ が、-CH ２ NHC(O)CH ２ OCH ３ 、 -CH ２ NHC(O)CH ２ CH ３ , -CH ２ NHSO ２ CH ３ , -CH ２ NR ７Ａ R ７Ｂ , and -(CH ２ ) ｑ R ８ is selected from the group consisting of R ７Ａ and R ７Ｂ each is methyl, or R ７Ａ and R ７Ｂ But together with the nitrogen to which they are attached, forming a heterocyclyl selected from the group consisting of 4-methylpiperazinyl and morpholinyl; R ８ is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

60. R １００ａ が、-CH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、 【Chemical 36】 is selected from the group consisting of R １００ｃ But it's Chloro. Y １ But CF ３ and Z １ が、-CH ２ NHC(O)CH ２ OCH ３ 、-CH ２ NHC(O)CH ２ CH ３ 、-CH ２ NHSO ２ CH ３ 、-CH ２ N(CH ３ ) ２ 、 【Chemical 37】 44. The compound of claim 43, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

61. R ４００ｂ But Y １ and R ４００ｄ But Z １ 61. The compound of claim 60, wherein:

62. A compound of formula IIIa, 【Chemical Formula 38】 R １００ａ が、-CH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、 【Chemical 39】 is selected from the group consisting of R ４００ｄ が、-CH ２ NHC(O)CH ２ CH ３ 、-CH ２ NHC(O)CH ２ OCH ３ 、-CH ２ NHSO ２ CH ３ 、-CH ２ N(CH ３ ) ２ 、 【Chemistry 40】 44. The compound of claim 43, which is a compound of formula IIIa selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 【Request 63】 【Table 5-1】 【Table 5-2】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

64. 64. A pharmaceutical composition comprising a compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

65. 65. A method for treating a mitochondrial-related condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

66. 66. The method of claim 65, wherein the mitochondrial-associated condition or disorder has one or more underlying causative factors selected from the group consisting of hyperglycemia, abnormal accumulation of lipids in cells, abnormal accumulation of lipids in tissues, abnormal lipid metabolism, abnormal mitochondrial metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis.

67. 66. The method of claim 65, wherein the mitochondrial-associated condition or disorder has one or more underlying symptoms selected from the group consisting of hyperglycemia, abnormal accumulation of lipids in cells, abnormal accumulation of lipids in tissues, abnormal lipid metabolism, abnormal mitochondrial metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis.

68. 68. The method of any one of claims 65 to 67, wherein the mitochondrial-related condition or disorder is selected from the group consisting of metabolic diseases, cancer, autoimmune diseases, pulmonary fibrosis, skin disorders, infectious diseases, and neurodegenerative diseases.

69. 69. The method of claim 68, wherein the metabolic disease is selected from the group consisting of type 2 diabetes, diseases characterized by insulin resistance or hyperglycemia, obesity or obesity-related complications, and diseases characterized by abnormal accumulation of lipids.

70. 69. The method of claim 68, wherein the metabolic disease is a complication caused by type 2 diabetes selected from the group consisting of diabetes-induced cardiovascular disease, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart disease, nephropathy, retinopathy, neuropathy, and diabetic heart failure.

71. 69. The method of claim 68, wherein the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD) and at least one prognostic stage of the disease is selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and NAFLD-induced hepatocellular carcinoma (HCC).

72. 69. The method of claim 68, wherein the metabolic disease or disorder is alcoholic fatty liver disease or one or more complications caused by alcoholic fatty liver disease, and the one or more complications caused by alcoholic fatty liver disease are selected from the group consisting of alcoholic hepatitis, cirrhosis, and combinations thereof.

73. 69. The method of claim 68, wherein the metabolic disease or disorder is dyslipidemia or one or more complications caused by dyslipidemia.

74. 69. The method of claim 68, wherein the cancer is a primary cancer selected from the group consisting of hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer.

75. 69. The method of claim 68, wherein the cancer is a metastatic cancer derived from a primary tumor of another tissue type.

76. 69. The method of claim 68, wherein the pharmaceutical composition is administered in combination with a second agent indicated for the metabolic disorder.

77. 77. The method of claim 76, wherein the second agent is an antidiabetic agent selected from the group consisting of metformin, insulin, an insulin analog, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, an alpha-glucosidase inhibitor, a GLP-1 agonist, a DPP-4 inhibitor, and an SGLT2 inhibitor.

78. 77. The method of claim 76, wherein the second agent is selected from the group consisting of an anti-obesity agent, an anti-non-alcoholic fatty liver disease agent, an anti-non-alcoholic fatty liver disease agent, and an anti-dyslipidemic agent.

79. 76. The method of claim 74 or 75, wherein the pharmaceutical composition is administered in combination with a second anti-cancer agent or anti-cancer regimen.

80. 80. The method of claim 79, wherein the second anti-cancer agent is a cancer immunotherapy (immunoncological) agent.

81. 81. The method of claim 80, wherein the cancer immunological therapeutic agent is selected from the group consisting of antibodies against PD-1 / PD-L1, antibodies against other immune checkpoint proteins, CAR-T cells, and other therapeutic immune cells.

82. 69. The method of claim 68, wherein the skin disorder is selected from eczema, dyshidrotic eczema, seborrheic eczema, psoriasis, rosacea, dermatitis, and atopic dermatitis.

83. 69. The method of claim 68, wherein the infectious disease is a bacterial infection.

84. 69. The method of claim 68, wherein the infectious disease is a viral infection.

85. 85. The method of claim 84, wherein the viral infection is selected from a SARS-CoV-2 infection, a coronavirus infection, and an Ebola virus infection.

86. A method for treating a metabolic disease or disorder characterized by hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues, or a disease or disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues is a symptom, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described in claim 64.

87. 65. A method for treating cancer or hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

88. 65. A method for treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of claim 64.

89. 65. A method for treating or preventing a skin disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

90. 65. A method of treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

91. 65. A method for treating or preventing a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

92. 65. A method for treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 64.

93. 93. The method of any one of claims 65 to 92, wherein the subject is a mammal or a human.

94. 94. The method of claim 93, wherein the subject is a human.

95. 95. The method of any one of claims 65 to 94, wherein the pharmaceutical composition is administered orally, intravenously, subcutaneously, intramuscularly, transdermally, intraperitoneally, or by other pharmacologically acceptable routes.

96. 65. A method for the long-term disease management of a metabolic disease or disorder or for the long-term disease management of cancer, comprising administering to a subject in need of such long-term management an effective amount of the pharmaceutical composition of claim 64.

97. 64. Use of the compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment of a metabolic disease or disorder characterized by hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues, a disease or disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues is a symptom, cancer, hyperplasia, or a cancer- or hyperplasia-related complication, diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, a skin disorder, or a bacterial or viral infection.

98. 1. A method for preparing a mitochondrial membrane-retaining mitochondrial uncoupling agent, comprising:

1. Identifying a conventional mitochondrial uncoupler; 2. Designing a compound that covalently attaches at least one secondary or tertiary amino moiety to a conventional mitochondrial uncoupling agent; 3. Preparing the compound of step 2, wherein the compound is a mitochondrial membrane-retaining uncoupler compound.

99. formula: (R Ａ ) ｕ -R Ｂ mitochondrial membrane-retaining uncoupler compounds, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, In the formula, R Ａ and R Ｂ are covalently bonded, Each R Ａ is independently a secondary or tertiary amine-containing moiety; u is an integer selected from the group consisting of 1 and 2; R Ｂ But, R Ａ a conventional mitochondrial uncoupler prior to covalent attachment to a mitochondrial membrane-retaining uncoupler compound, wherein said mitochondrial membrane-retaining uncoupler compound is 【Chemistry 41】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, that is not a mitochondrial membrane-retaining uncoupler compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

100. R Ａ が、-CH ２ NHSO ２ CH ３ 、-CH ２ N(CH ３ ) ２ 、-(CH ２ ) ２ N(CH ３ ) ２ 、-(CH ２ )NH(CH ２ ) ２ OCH ３ 、-CH ２ NHC(O)CH ３ 、-CH ２ NHC(O)CH ２ CH ３ 、 【Chemistry 42】 -CH ２ N(CH) ３ )(CH ２ ) ２ OCH ３ ,-(EH ２ )N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ N(CH) ３ )(CH ２ ) ２ O(CH ２ ) ２ OCH ３ 、 【Chemistry 43】 C(O)N(CH ２ CH ２ OCH ３ ) ２ 、-CH ２ O(CH ２ ) ２ N(CH ３ ) ２ 、-CH ２ O(CH ２ ) ２ NHSO ２ CH ３ 、 【Chem. 44】 98. The compound of claim 97, selected from the group consisting of:

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