Mitochondrial uncoupling agents for treatment of metabolic diseases and cancer

Abstract

The present application discloses different classes of mitochondrial uncoupling compounds having significantly improved pharmacokinetic properties and conventional mitochondrial uncoupling compounds, pharmaceutical compositions containing the compounds and / or prodrugs, and diseases that are useful in the treatment of diseases associated with mitochondrial dysfunction or benefits by modulation of mitochondrial activity. Methods of using the compounds, prodrugs, and pharmaceutical compositions in treatment of diseases, including diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), mitochondrial genetic diseases, neurodegenerative diseases, cancer, autoimmune diseases, and infectious diseases.

Description

Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 374,927, filed on September 8, 2022, the entire content of which is incorporated herein by reference. Summary of the Invention

[0002] The present disclosure relates to novel mitochondrial uncoupling compounds that preserve mitochondrial membrane potential and 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 metabolism - related diseases, including diabetes, non - alcoholic fatty liver disease (NAFLD), non - alcoholic steatohepatitis (NASH), cancer, autoimmune diseases, dyslipidemia, and infectious diseases.

[0003] Some embodiments of the present disclosure relate to compounds of Formula A: Wherein R of Formula A 1000a is selected from the group consisting of -CH3, -CH2CH3, -C1 - C6 alkyl, -C3 - C6 cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, (CH2) r’ NR 5000A R 5000B 、-(CH2) r R 6000 and C(O)N(CH2CH2OCH3)2; Substituents 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, R 5000A and R 5000B together with the nitrogen to which they are attached form a 4 - to 8 - membered heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1 - C6 alkyl, halogen, and acyl; R 6000 is selected from the group consisting of a 5 - to 6 - membered heterocyclic group, pyridyl, 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 chlorine, fluorine, iodine and bromine; R 4000b and R 4000d are each independently selected from the group consisting of Y 1000 and Z 1000 provided that when R 4000b is Y 1000 then R 4000d is Z 1000 and when R 4000b is Z 1000 then R 4000d is Y 1000 ; Y 1000 is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl; Z 1000 is selected from the group consisting of 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 ; Alternatively, R 2000A and R 2000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocycle optionally substituted by one or more methyl groups; R 3000 is a 5- to 6-membered heterocycle; Ar 1 is a 5- to 6-membered aryl or heteroaryl optionally substituted by one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl, halogen, hydroxy and alkoxy; R7000A 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- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 8000 is selected from the group consisting of 5- to 6-membered heterocycles 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; provided that R 5000A and R 5000B are not both C1-C6 alkyl; and when Z 1000 is H, R 1000a is not C1-C6 alkyl, -C3-C6 cycloalkyl, CH3, or CH2CH3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0004] Some embodiments of the present disclosure relate to compounds of Formula I: wherein: R 1a is selected from the group consisting of -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) m’ NR 5A R 5B 、(CH2) m R 6 and C(O)N(CH2CH2OCH3)2; R 5A and R 5B 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 R 5A and R 5BTogether with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl; R 6 Selected from the group consisting of 5- to 6-membered heterocyclic groups, pyridyl 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 Selected from the group consisting of chlorine, fluorine, iodine and bromine; and R 4b and R 4d are each independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4d is Y; Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl; Z 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, -(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 heterocycle optionally substituted with one or more methyl groups; R 3 Selected from the group consisting of 5- to 6-membered heterocyclic groups and phenoxy; n is an integer selected from the group consisting of 0, 1, 2 and 3; and Ar is a 5-6 membered aryl or heteroaryl optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of -C1-C6 alkyl, halogen, hydroxy and alkoxy; Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0005] Some embodiments of the present disclosure relate to compounds of Formula II: Wherein: R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) o’ NR 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 R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl; R 60 is selected from the group consisting of a 5- to 6-membered heterocyclic group, pyridyl, 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 chlorine, fluorine, iodine, and bromine; and R 40b and R 40d one of which is H, and the other of R 40b and R 40d is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano, and -CO2(C1-C6) alkyl; Provided that R 50A and R 50B are not both C1-C6 alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0006] Some embodiments of the present disclosure relate to compounds of formula III: Wherein: R 100a is selected from the group consisting of -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, - -(CH2) p’ NR 500A R 500B 、-(CH2) p R 600 and C(O)N(CH2CH2OCH3)2; R 500A and R 500B 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, R 500A and R 500B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl; R 600 is selected from the group consisting of a 5- to 6-membered heterocyclic group, pyridyl, 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 chlorine, fluorine, iodine, and bromine; R 400b and R 400d are each independently selected from the group consisting of Y 1 and Z 1 provided that when R 400b is Y 1 then R 400d is Z 1 and when R 400b is Z 1 then R 400d is Y 1 ; Y 1selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z 1 selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) q’ NR 7A R 7B and -(CH2) q R 8 ; 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- to 8-membered heterocyclic group optionally substituted with one or more independently selected C1-C6 alkyl; R 8 is selected from the group consisting of 5- to 6-membered heterocycles optionally substituted with methyl; q' is an integer selected from the group consisting of 1, 2, and 3; and q is an integer selected from the group consisting of 0, 1, 2, and 3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0007] Embodiments herein describe pharmaceutical compositions that comprise a compound according to any embodiment herein, or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier or diluent.

[0008] Some embodiments describe methods of treating mitochondrial-related disorders or conditions in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the mitochondrial-related disorder or condition has one or more potential causal 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-β activation, and abnormal fibrosis. In some embodiments, the mitochondrial-related disorder or condition is selected from the group consisting of metabolic diseases, cancers, autoimmune diseases, pulmonary fibrosis, dermatological diseases, infectious diseases, and neurodegenerative diseases.

[0009] In some embodiments, the mitochondrion-related disorder or condition 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 and is selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative diseases, 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), wherein 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, wherein 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 agent indicative of a metabolic disease. In some embodiments, the second agent is an anti-diabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, glinides, thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors. In some embodiments, the second agent 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.

[0010] In some embodiments, the mitochondrion-related disorder or condition 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 an immuno-oncology agent. In some embodiments, the immunocological 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.

[0011] In some embodiments, the mitochondrion-related disorder or condition is a dermatological disease selected from the group consisting of eczema, dyshidrosis, seborrheic eczema, psoriasis, rosacea, dermatitis, and atopic dermatitis.

[0012] In some embodiments, the mitochondrial-related disorder or condition 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 SARS-CoV-2 infection, coronavirus infection, and Ebola virus infection.

[0013] Some embodiments describe methods of treating a metabolic disease or disorder characterized by hyperglycemia or insulin resistance or abnormal accumulation of lipids in a tissue, or a disease or disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipids in a tissue is a symptom, in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0014] Some embodiments describe methods of treating cancer or hyperplasia in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0015] Some embodiments describe methods of treating fibrosis in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0016] Some embodiments describe methods of treating or preventing an autoimmune disease in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0017] Some embodiments describe methods of treating or preventing a dermatological disease in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0018] Some embodiments describe methods of treating fibrosis in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0019] Some embodiments describe methods of treating or preventing a bacterial infection in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0020] Some embodiments describe methods of treating or preventing a viral infection in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0021] Some embodiments herein describe methods in which the subject is a mammal or a human. In some embodiments, the subject is a human.

[0022] Some embodiments of the present disclosure describe methods in which the pharmaceutical composition is administered orally, intravenously, subcutaneously, intramuscularly, transdermally, intraperitoneally, or by other pharmaceutically acceptable routes.

[0023] Some embodiments describe methods for long-term disease management of metabolic diseases or disorders or for long-term disease management of cancer, which comprise administering to a subject in need of such long-term management an effective amount of a compound or pharmaceutical composition described herein.

[0024] Some embodiments describe the use of a compound described herein in the preparation of a medicament for treating a metabolic disease or disorder. In some embodiments, the metabolic disease or disorder may be selected from diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, a disease characterized by hyperglycemia or insulin resistance or abnormal lipid accumulation in tissues, or related conditions or complications.

[0025] Some embodiments describe a method for preparing a mitochondrial membrane potential (MMP)-retaining mitochondrial uncoupler, which comprises: 1. Identifying a conventional mitochondrial uncoupler; 2. Designing a compound that covalently links at least one secondary or tertiary amino moiety to the conventional mitochondrial uncoupler; and 3. Preparing the compound of step 2, wherein the compound is a mitochondrial membrane-retaining uncoupler compound.

[0026] Some embodiments describe a mitochondrial membrane-retaining uncoupler compound of the following formula: (R A ) u -R B ; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R A and R B are covalently linked; each R A is independently a moiety containing a secondary or tertiary amine; u is an integer selected from the group consisting of 1 and 2; and R B is a conventional mitochondrial uncoupler before being covalently linked to R A ; provided that the mitochondrial membrane-retaining uncoupler compound is not BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1A 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. Mitochondrial uncoupling, by reducing the metabolic output of metabolites and ROS, will contribute to the elimination of the pathogenic factors of these diseases.

[0028] Figure 2 shows the oxygen consumption rate (OCR) of two representative compounds over time. Compound 16 ( Figure 2A ) and Compound 69 ( Figure 2B ). Oligo represents oligomycin, Comp.A represents Compound 16, Comp.B represents Compound 69, Rot / AA represents rotenone / antimycin. The measurements were performed using a Seahorse XF-24 instrument. The compounds were injected into the assay medium in the indicated order, with oligomycin at 2.5 μM; both Comp.A and Comp.B at a concentration of 1.0 μM; rotenone at 2.0 μM, and antimycin A at 2.0 μM.

[0029] Figure 3 Shows the molecular mechanism of conventional mitochondrial uncoupling. Dissipating the mitochondrial membrane potential is an inherent property of conventional mitochondrial uncoupling agents. As shown, the outer mitochondrial membrane, inner mitochondrial membrane, electron transport complexes I-IV, ATP synthase, chemical uncoupling agents (U-, UH), and mitochondrial matrix are shown. Conventional uncoupling agents are weak lipophilic weak acids located in the inner mitochondrial membrane (shown in the deprotonated form U - and the protonated form UH). U - binds protons (protonation) on the outer side of the inner mitochondrial membrane and releases protons into the mitochondrial matrix (deprotonation). As a result, mitochondrial uncoupling agents catalyze proton translocation across the inner membrane without ATP synthesis, leading to the "ineffective" oxidation of acetyl-CoA (the final metabolite of lipid oxidation and glucose metabolism). Since MMP is established by the proton gradient across the inner mitochondrial membrane, conventional mitochondrial uncoupling is associated with simultaneous dissipation of MMP.

[0030] Figure 4 shows the effects of a representative conventional mitochondrial uncoupling agent, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), on the oxygen consumption rate and mitochondrial membrane potential. FCCP simultaneously increases the oxygen consumption rate ( Figure 4A ) and dissipates the mitochondrial membrane potential ( Figure 4B ). Figure 4A Shows the cellular oxygen consumption rate (OCR) measured using C2C12 cells by Seahorse OCR assay (Seahorse OCR assay). Figure 4AThe rhombus represents DMSO (vehicle control), the triangle represents 3.0 μM FCCP, the square represents 6.0 μM FCCP, the X represents 12.0 μM FCCP, the * represents 18.0 μM FCCP, and the circle represents 24 μM FCCP. Oligo is oligomycin at 2.5 μM; AA is antimycin A at 2 μM; Rot is rotenone at 2 μM. Figure 4B Shows mitochondrial membrane potential (MMP) measured by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining, in the presence of FCCP at the indicated concentrations. Fluorescence intensity indicates MMP. The C 10％TMRE / C min-OCR ratio is less than 3, 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.

[0031] Figure 5 shows the effects of the representative MMP-maintaining mitochondrial uncoupler compound 25 (#25) on oxygen consumption rate and mitochondrial membrane potential. Compound 25 effectively uncouples mitochondria (induces OCR, Figure 5A ) without reducing MMP ( Figure 5B ). Figure 5A Shows the cellular oxygen consumption rate measured using C2C12 cells by Seahorse OCR assay. Figure 5A The rhombus in Figure 5B represents the vehicle control, the square represents 1.0 μM of compound 25 (#25), the triangle represents 3.0 μM of compound 25, the X represents 6.0 μM of compound 25, the * represents 9.0 μM of compound 25, and the circle represents 12.0 μM of compound 25. Oligo is oligomycin at 2.5 μM; AA is antimycin A at 2 μM; Rot is rotenone at 2 μM. 10％TMRE / C min-OCR ratio is greater than 25), representing an MMP-maintaining uncoupler that does not cause an observable decrease in MMP when uncoupling mitochondria.

[0032] Figure 6 shows the effects of compound 64 (#64) on oxygen consumption rate ( Figure 6A ) and mitochondrial membrane potential ( Figure 6B ). Compound 64 increases OCR without significantly dissipating the mitochondrial membrane potential. Figure 6AShows the cellular oxygen consumption rate measured in C2C12 cells at the indicated concentrations using Seahorse OCR. Figure 6A The diamonds in Figure 6A represent vehicle-treated controls, the squares represent compound 64 (#64) at 0.3 μM, the triangles represent compound 64 at 1.0 μM, the Xs represent compound 64 at 2.0 μM, the *s represent compound 64 at 3.0 μM, and the circles represent compound 64 at 4.0 μM. Oligo is oligomycin at 2.5 μM; AA is antimycin A at 2 μM; Rot is rotenone at 2 μM. Figure 6B Shows the mitochondrial membrane potential (MMP) measured by fluorescence microscopy in the presence of the indicated concentrations of compound 64 (#64) using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilC1(5) staining. Fluorescence intensity indicates MMP. Compound 64 represents an MMP-maintaining uncoupler that does not significantly reduce MMP while uncoupling mitochondria (C 10％TMRE / C min-OCR ratio between 10 and 25).

[0033] Figure 7 shows the mechanism of action of a conventional mitochondrial uncoupler ( Figure 7A ) and a schematic of the proposed mechanism of action of an MMP-maintaining uncoupler ( Figure 7B ), as well as a figure and example of how a conventional uncoupler can be converted to an MMP-maintaining uncoupler ( Figure 7C -E). Figure 7A and Figure 7B show mitochondrial electron transport chain complexes I, II, III, IV, ATP synthase, and uncouplers (UH or U - ). Conventional uncouplers allow proton translocation across the inner mitochondrial membrane, resulting in loss of MMP ( Figure 7A ). The presence and asymmetric distribution of the positively charged side chain of the MMP-maintaining uncoupler result in an electrogradient that compensates for the loss of MMP due to proton translocation ( Figure 7B ). Figure 7C and Figure 7D show a general method for creating a new MMP-maintaining uncoupler by adding a positively charged side chain to a conventional uncoupler ( Figure 7C ), for example, obtaining an MMP-maintaining uncoupler by adding a side chain containing a tertiary (or secondary) amine ( Figure 7D ), where N is nitrogen; and X and Y are optimally substituted side chains. Figure 7E Shows an example of an MMP-maintaining uncoupler that shows the conventional uncoupling component in the box.

[0034] Figure 8AShow the acute lethal dose (acute LD50 or LD50) that causes 50% death of test animals and 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 MMP maintain the minimum effective dose (MED) of the uncoupler, compound 64 (#64, Figure 8B ) and compound 25 (#25, Figure 8C ). Compounds 64 and 25 showed a significantly improved acute toxicity profile over DNP. Acute toxicity tests were performed on C57Bl6 mice (male, 6 weeks old, n = 6). Compounds 64 and 25 were prepared as a fine suspension in 0.5% CMC-Na / 1% Tween80 aqueous solution. The compound suspension was administered orally by gavage at 100 - 400 μL to the required dose (mg / kg) according to body weight and tested under feeding conditions. Drinking water was provided to the mice throughout the test period. The behavior of the mice was monitored every 15 - 30 minutes and the LD50 was determined. The MED was determined in diabetic and steatosis mouse models (Table 9).

[0035] Figure 9 shows the safety profile of compound 64 (#64) compared to DNP. Figure 9A Show 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 USCDC). Figure 9B Show the MED, intermediate NOAEL, and NOAEL / MED of compound 64 calculated by oral dose. Figure 9C Show the MED, intermediate NOAEL, and NOAEL / MED of compound 64 over DNP calculated by Cmax (maximum blood concentration). Figure 9DShow the MED, intermediate NOAEL, and NOAEL / MED of compound 64 calculated by AUC (area under the curve). The figure shows that MMP maintains the uncoupler compound 64 exhibits a significantly improved short-term safety profile relative to the conventional uncoupler DNP. A 10-day toxicology study was conducted in CD-1 mice to determine the NOAEL of compound 64, where animals (n = 5) were administered 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 steatosis mouse models (Table 9).

[0036] Figure 10 shows the safety profile of compound 25 (#25), Figure 10A show the MED, intermediate NOAEL, and NOAEL / MED of compound 25 calculated by oral dose. Figure 10B show the MED, intermediate NOAEL, and NOAEL / MED of compound 25 on DNP calculated by Cmax (maximum blood concentration). Figure 10C show the MED, intermediate NOAEL, and NOAEL / MED of compound 25 calculated by AUC (area under the curve). The figure shows that MMP maintains the uncoupler, compound 25 exhibits a significantly improved short-term safety profile on the conventional uncoupler DNP. A 10-day toxicology study was conducted in CD-1 mice to determine the NOAEL of compound 25, where animals (n = 5) were administered 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 steatosis mouse models (Table 9).

[0037] Figure 11 shows the efficacy of compound 25 (#25) and compound 64 (#64) in reducing blood glucose and glycated hemoglobin A1C in the db / db diabetic mouse model. Figure 11A is a graph of blood glucose levels in mice treated with vehicle and mice treated with compound 25. Figure 11B is a graph of glycated hemoglobin A1C in mice treated with vehicle and mice treated with compound 25. Figure 11C is a graph of blood glucose levels in mice treated with vehicle and mice treated with compound 64. Figure 11DGraph of glycated hemoglobin A1C in mice treated with vehicle and in mice treated with compound 64. BKS db / 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 s.d., ***p < 0.001. In each group, n = 6. "Vehicle", vehicle-treated control group.

[0038] 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 D) in an HFD-induced diabetic / steatohepatitis mouse model (n = 6 per group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p < 0.05, ***p < 0.001. In each group, n = 6. #25: Mice treated with compound 25 (5 mg / kg / day, daily gavage) for three weeks. "Vehicle", vehicle-treated control group. Figure 12A -B, light-colored bars, initial levels; dark-colored bars, levels after 3-week vehicle or drug treatment.

[0039] Figure 13 shows the effects of compound 64 on blood glucose ( Figure 13A ) and plasma insulin levels ( Figure 13B ) in an HFD-induced diabetic / steatohepatitis mouse model (n = 6 per group). Statistical significance (P) was determined by Student's t-test. All error bars are s.d., *p < 0.05, ***p < 0.001. In each group, n = 6. #64: Mice treated with compound 64 (5 mg / kg / day, daily gavage) for two weeks. "Vehicle", vehicle-treated control group. Figure 13A , dark-colored bars, initial levels; light-colored bars, levels after 2-week vehicle or drug treatment.

[0040] 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 s.d., *p < 0.05. In each group, n = 6. #25: Treated with compound 25 (5 mg / kg / day, daily gavage) for 3 weeks; "Vehicle", vehicle-treated control group.

[0041] Figure 15 shows the effects of compound 25 and compound 64 on high-fat diet-induced hepatic steatosis. Representative hepatic histological images from mice stained with H&E are as indicated: Figure 15A , "Normal", liver sections from healthy C57 / Bl6 mice not fed with HFD; Figure 15B , HFD, liver sections from mice fed with HFD; Figure 15C , HFD+#25, liver sections from mice fed with HFD followed by treatment with compound 25 for 3 weeks (P.O. dose 5 mg / kg, daily gavage); and Figure 15D , HFD+#64, liver sections from mice fed with HFD followed by treatment with compound 64 for 3 weeks (P.O. dose 5 mg / kg, daily gavage). N = 6 in each group.

[0042] Figure 16 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 protocol 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 plus 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, middle panel); compound 25 (TGFβ+#25, right panel) prevents TGFβ-induced differentiation of LX-2 cells.

[0043] Figure 17 shows the inhibitory effect of compound 64 on the differentiation of hepatic stellate cells into myofibroblast-like cells. Figure 17A 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 plus 1 ng / mL compound 64. TGF-β treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form a "ring" - shaped morphology after TGF-β treatment (TGF-β, middle panel); compound 64 (TGFβ+#64, right panel) prevents TGFβ-induced differentiation of LX-2 cells. Figure 17B is a Western blot analysis showing that compound 64 blocks the activation of the TGF-β signaling pathway as evidenced by the loss of Smad2 / 3 phosphorylation. LX-2 cells were treated with vehicle (control), TGF-β alone, or TGF-β plus the indicated concentration of compound 64 for 6 hours. Then the cells were harvested and subjected to Western blot analysis with antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH as shown.

[0044] Figure 18 shows the efficacy of compound 25 in reducing liver fibrosis as determined by histological and molecular analyses.Figure 18A Microscopic images of liver sections of CCl4-treated mice stained with H&E (upper left panel); CCl4 plus compound 25 (7.5 mg / kg / day)-treated mice stained with H&E (lower left panel); CCl4-treated mice stained with Sirius red (fibrotic collagen stained, upper right panel) and CCl4 plus compound 25 (7.5 mg / kg / day)-treated mice stained with Sirius red (fibrotic collagen stained, lower left panel). Figure 18B Depicts fibrosis and lipofuscin scores of 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 hepatic fibrosis and lipofuscin abundance in each mouse are presented in different color shades. Lipofuscin is an intracellular aggregate of highly oxidized proteins and indigestible lipids. Lipofuscin mainly accumulates in the lysosomes of senescent cells and cells under pathological conditions. Figure 18C Shows immunoblot analysis of collagen expression (Col1a1) in mice treated with vehicle, CCl4 alone, CCl4 + compound 25 (CCl4+#25). The fibrosis score for each sample is listed between the immunoblots as shown. GAPDH was used as an internal control, n = 7; treatment duration, 6 weeks. Histology and molecular markers show that compound 25 reduces fibrosis in CCl4-treated animals.

[0045] Figure 19 shows immunoblot analysis of the inhibitory effect of compound 6464 on TGF-β activation in T cells. Figure 19A Is an immunoblot analysis of human Jurkat cells treated with vehicle alone (first lane), TGF-β alone (second lane), TGF-β plus 0.5, 1.0, or 2.0 μM compound 64 (third to fifth lanes) for 6 hours. Figure 19B Is an immunoblot analysis of murine primary T cells (B) treated with vehicle alone (first lane), TGF-β alone (second lane), or TGF-β plus different concentrations of 1.0 or 2.0 μM compound 64 (third and fourth lanes) for 6 hours. Immunoblot analysis was performed using antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as shown. Loss of Smad2 / 3 phosphorylation indicates the efficacy of compound 64 in blocking TGF-β activation in T cells.

[0046] Figure 20 shows that combination therapy of compound 64 with a PD-1 antibody is effective in treating metastatic cancer in mice. Figure 20AThis is an experimental design (see Example B12). Briefly, on day 7, C57 / Bl6 mice with intrahepatic transplantation of MC38 cancer cells (day 0) were treated differently: PD-1 or isotype, and the mice were treated on the designated days with a PD-1 antibody or its isotype antibody (control) by intraperitoneal (IP) injection (the PD-1 antibody has a half-life of more than 1 week in mice); #64 or vehicle, and the mice were treated with compound #64 or vehicle by daily gavage. Figure 20B This is a table Figure 20A describing the experimental results described in

[0047] Figure 21 showing the antiviral activity (EC50), cytotoxicity (TC50), and selectivity index (SI) of compounds 64, 25, and 57 against enveloped viruses. Each row represents the experimental results of the indicated compound on host cells infected or not infected with the indicated virus. The EC50 is the concentration of the compound that reduces the virus-induced cytopathic effect (CPE) by 50%. The TC50 is the concentration of the compound that results in 50% cell viability of uninfected cells; the SI is the ratio between the TC50 and the EC50. The experiment was conducted as follows. As shown, host cells (Vero 760 or MRC-5) were seeded in 96-well flat-bottom tissue culture plates and allowed to adhere overnight. After incubation overnight, the cells were infected with virus (SARS-CoV-2 or alpha coronavirus 229E) or not, and the diluted test compound was added to each well. After incubation at 37 °C, 5% CO2 for three or six days, cell viability was determined. The percentage reduction in CPE of virus-infected wells and the percentage of cell viability of uninfected drug control wells were measured to calculate and determine the EC50 and TC50 values. The SI was calculated accordingly. Detailed Description

[0048] The following factors make mitochondria an ideal target for treating a variety of important diseases: (1) Mitochondria are the final sites where lipid or glucose metabolites are consumed (oxidized); (2) Mitochondria are crucial in regulating the abundance of metabolic intermediates that serve as building blocks for the biosynthesis essential for cell growth and proliferation of cancer cells, as well as viral envelope production and assembly; (3) Mitochondria are the major sites of ROS production in neurons and many other cells ( Figure 1 ).

[0049] Mitochondrial uncoupling is a unique way to regulate mitochondrial activity and function. Substantially, mitochondrial uncoupling is the process of decoupling the activity of the mitochondrial electron transport chain from ATP synthesis. Mechanistically, mitochondrial uncoupling is caused by the action of mitochondrial uncoupling agents that carry protons across the inner mitochondrial membrane into the mitochondrial matrix, independent of ATP synthase (Terada, H. (1990) Environmental Health Perspectives 87, 213 - 218). The technical definition of a mitochondrial uncoupling agent is an increase in the oxygen consumption rate (OCR) of cells in the presence of an ATP synthase inhibitor such as oligomycin. Thus, mitochondrial uncoupling agents result in inefficient mitochondrial oxidation and increased electron transport chain flux. As a result, mitochondrial uncoupling agents can promote glucose or lipid catabolism in cells, reduce the production output of small molecule building blocks, and reduce electron stall in the electron transport chain, thus reducing electron leakage and mitochondrial ROS production. Through these actions, mitochondrial uncoupling agents represent an effective strategy for treating a variety of important diseases.

[0050] Mitochondria and metabolic diseases. Metabolic diseases are a series of diseases characterized by symptoms of abnormal glucose and / or lipid metabolism, such as obesity, type 2 diabetes, alcoholic fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis. These diseases are associated with age-, environment- or gene-related decreases in mitochondrial function (such as reduced oxidative capacity). Importantly, these diseases also share a common pathogenic factor, namely the abnormal accumulation of intracellular lipids in the cells of various tissues and insulin resistance in most cases. 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 the cells of the liver, muscle or adipose tissue. Type 2 diabetes is characterized by insulin resistance caused by hyperglycemia usually caused by ectopic fat accumulation and insulin resistance in the cells of the liver, muscle or adipose tissue. Alcoholic fatty liver disease is characterized by ectopic lipid accumulation and liver injury, liver inflammation and fibrosis in hepatocytes. The various stages of alcoholic fatty liver disease (or NAFLD) include hepatosteatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) caused by NAFLD, mainly due to ectopic lipid accumulation in hepatocytes that causes liver injury, inflammation and fibrosis. Various types of dyslipidemia are partly caused by ectopic accumulation of lipids in liver, muscle or heart cells due to the redistribution of lipids from adipose tissue to other tissues.

[0051] Mitochondrial uncoupling agents that reduce energy efficiency and enhance futile lipid oxidation will effectively reduce cellular lipid accumulation. Since ectopic intracellular lipid accumulation in the liver and muscle and excessive accumulation in adipose tissue are the root causes of insulin resistance in various forms of metabolic diseases (Samuel V.T. et al., Lancet, 2010, 375:2267-77), the applicant and others have demonstrated in animal models that small molecule (chemical) mitochondrial uncoupling agents are effective in preventing and treating metabolic diseases (Tao, H., Zhang, Y., Zeng, X., Shulman, G.I., and Jin, S. (2014) Nature Medicine, 20, 1263-1269; Perry, R.J., Zhang, D., Zhang, X.M., Boyer, J.L., and Shulman, G.I. (2015) Science, 347(6227), 1253-6), resulting in: (1) reduced lipid accumulation in various tissues, including adipose tissue, (2) reduced insulin resistance, (3) reduced blood glucose concentration, and (4) improved blood glucose control and slowed disease progression. Importantly, treating metabolic diseases with mitochondrial uncoupling agents has many attractive features; for example, since they correct the cause of insulin resistance (ectopic lipid accumulation), this approach can cure some metabolic diseases.

[0052] Cancer is a group of diseases characterized by the uncontrolled growth and proliferation of cells of various tissue types, arising from a combination of gene mutations in oncogenes and tumor suppressor genes. It is well recognized that one requirement for tumorigenesis is an alteration in cellular metabolism. Cancer cells require not only energy but also building blocks (metabolic intermediates) for the biosynthesis of macromolecules such as DNA and RNA to support rapid cell growth and proliferation. Metabolism in cancer cells has changed in a way that can meet both the energy requirements and the requirements for various metabolic intermediates (building blocks) needed for macromolecule biosynthesis (VanderHeiden, M.G., Cantley, L.C., and Thompson, C.B. (2009) Science, 324(5930), 1029-33). Thus, most cancers exhibit a unique cellular metabolic pattern called the Warburg effect or aerobic glycolysis, which prevents the complete oxidation of glucose or lipids and allows the production of glucose metabolites for macromolecule biosynthesis (Vander Heiden et al., 2009).

[0053] Mitochondrial uncoupling reduces energy efficiency, thereby disrupting the energy requirements of cancer cells. In addition, mitochondrial uncoupling promotes the complete mitochondrial oxidation of glucose and lipids, thereby reducing the production of metabolic intermediates necessary for macromolecular biosynthesis required for cell proliferation. In addition, mitochondrial uncoupling may lead to AMPK activation, which is a known event that inhibits cell growth. In fact, the existing literature shows that mitochondrial uncoupling agents exhibit anti-cancer activity (U.S. Patent 10,227,315). Targeting cancer cells through mitochondrial uncoupling, which deprives them of energy and biosynthetic metabolic intermediates that are absolutely necessary for cancer cell growth and proliferation, has proven to be an effective anti-cancer strategy (Alasadi, A. et al., (2018) Cell Death Dis., 9(2), 215).

[0054] 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-attaching immune cells need to expand (proliferate), 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 will potentially inhibit the activation and expansion of self-attacking immune cells.

[0055] Neurodegenerative diseases are a large class of neurological disabilities such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, which are characterized by the relatively selective death of neuronal subtypes. A large body of evidence suggests that impaired mitochondrial function is one of the pathogenic factors of these diseases, and mitochondrial ROS production is one of the most important (Elfawy, H.A., and Das, B. (2019) Life Sci., 218, 165-184.).

[0056] Mitochondrial uncoupling agents increase mitochondrial electron transport chain flux and reduce electron stalling in electron transport chain complexes, so they can effectively reduce mitochondrial ROS. Therefore, mitochondrial uncoupling is considered a powerful antioxidant strategy and can have therapeutic potential for treating neurodegenerative diseases.

[0057] Declines in mitochondrial function and capacity are associated with normal aging and with the development of a wide range of age-related diseases. Some proven anti-aging and lifespan-extending methods, such as calorie restriction, are highly associated with improvements in mitochondrial function (Sun, N. et al. (2016) Mol. Cell, 61(5), 654–666). The modulation of mitochondrial function by mitochondrial uncoupling has been proposed as an anti-aging strategy (Caldeira da Silva, C.C. et al. (2008) Aging Cell, 7(4), 552-60).

[0058] Mitochondria are archaea that have formed a symbiotic relationship with the host cell. Bacterial plasma membranes contain an electron transport chain and ATP synthase similar to that of mitochondria, and thus compounds that affect mitochondrial uncoupling can be useful inhibitors of bacterial growth and effective as antibiotics (U.S. Patent 10,227,315).

[0059] Despite the attractive beneficial features of mitochondrial uncoupling, there are currently no FDA-approved drugs in the United States with a mitochondrial uncoupling mechanism of action for the treatment of the above diseases. There are major obstacles to the development of mitochondrial uncoupling agents as therapeutic agents. The discovery of new synthetic mitochondrial uncoupling agents with better druggable characteristics is crucial for the development of mitochondrial uncoupling therapeutics.

[0060] Benzamide mitochondrial uncoupling agents have been developed (International Patent Publication Nos. WO 2012 / 068274, WO 2016 / 081599, U.S. Patent 10,227,315, and Tao et al., 2014) for potential therapeutic applications. A major limitation of existing benzamide compounds is poor pharmacokinetic properties and low systemic exposure. For example, to overcome the poor pharmacokinetic properties of low systemic exposure and short half-life of previously disclosed compounds, studies in animal models required the compound to be mixed with food, and high doses of the compound were required to achieve efficacy (e.g., 1500 ppm niclosamide ethanolamine (NEN) in the diet, equivalent to 150 mg / kg / day (Tao et al. 2014, and WO 2012 / 068274); or 600-750 ppm of Compound 27 in the diet (in US10,227,315), equivalent to 60-75 mg / kg / day). Neither the high doses required nor the necessity of mixing the compound with food meets the needs of human therapeutic development.

[0061] Another limitation of available mitochondrial uncoupling agents is the safety issue, as some mitochondrial uncoupling agents are known to have a narrow therapeutic index. For example, the most well-known mitochondrial uncoupling agent 2,4-dinitrophenol was previously used in humans but was withdrawn from the market due to its narrow therapeutic window. The ratio of concentration (in cells) / dose (in vivo) between the toxicity and efficacy of 2,4-dinitrophenol is only about 3-fold. Thus, new properties that allow mitochondrial uncoupling agents to improve the safety margin are considered crucial for the therapeutic development of mitochondrial uncoupling agents.

[0062] Various embodiments provide novel benzamide mitochondrial uncoupling agents that are effective in inducing mitochondrial uncoupling (increasing mitochondrial oxygen consumption in the presence of oligomycin) over a wide concentration range without significantly reducing the mitochondrial membrane potential (see below). These compounds are referred to herein as mitochondrial membrane potential-maintaining (MMP-maintaining) compounds (MMP-maintaining).

[0063] Compared to the benchmark conventional mitochondrial uncoupling agent DNP, these MMP-maintaining compounds exhibit a significantly improved safety profile. These compounds show a wider therapeutic index when used to treat metabolic diseases.

[0064] Various embodiments provide new benzamide mitochondrial uncoupling agents that show significantly improved pharmacokinetic properties, such as a significantly increased systemic exposure (some of these compounds have an AUC increase of more than 100-fold compared to some of the previously disclosed druggable benzamide mitochondrial uncoupling agents with the highest reported systemic exposure).

[0065] Various embodiments describe the use of these compounds for the prevention and treatment of bacterial infections; dermatological diseases; 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.

[0066] Various embodiments provide the use of these compounds for treating disease symptoms such as hyperglycemia, insulin resistance, abnormal lipid accumulation, fibrosis, and abnormal TGF-β activation.

[0067] Various embodiments describe the use of these compounds alone or in combination with another agent for the prevention and treatment of diseases. Compound

[0068] In one embodiment, the present disclosure describes a compound of formula A: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0069] The substituent R of formula A1000a selected from the group consisting of -CH3, -CH2CH3, -C1-C6 alkyl, -C3-C6 cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, (CH2) r’ NR 5000A R 5000B 、-(CH2) r R 6000 and C(O)N(CH2CH2OCH3)2. The substituents 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; provided that R 5000A and R 5000B are not both C1-C6 alkyl. Alternatively, R 5000A and R 5000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, 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- to 6-membered heterocyclic groups, pyridyl, and thiazolyl; and r is an integer selected from the group consisting of 0, 1, 2, and 3.

[0070] The substituent R of formula I 1000c is selected from the group consisting of chlorine, fluorine, iodine, and bromine.

[0071] The substituents R of formula A 4000b and R 4000d are each independently selected from the group consisting of Y 1000 and Z 1000 provided that when R 4000b is Y, R 4000d is Z, and when R 4000b is Z, R 4000d is Y. The substituent Y 1000 is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl. The substituent Z 1000Selected from the group consisting of H, -CH2OCH2CH3, -CH2OCH3, -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 and the group consisting of -(CH2) 1000 Provided that when Z 1000a is H, R 2000A and R 2000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocycle optionally substituted with one or more methyl groups. Substituent R 3000 is a 5- to 6-membered heterocycle, and s is an integer selected from the group consisting of 0, 1, 2, and 3. Substituent Ar 1 is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl, halogen, hydroxy, and alkoxy. R 7000A and R 7000B are each independently selected from C1-C6 alkyl. Alternatively, R 7000A and R 7000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, and q' is an integer selected from the group consisting of 1, 2, and 3. Substituent R 8000 is selected from the group consisting of 5- to 6-membered heterocycles optionally substituted with methyl, and t is an integer selected from the group consisting of 0, 1, 2, and 3.

[0072] In some embodiments, R 4000d is selected from the group consisting of H, R 4d as described in paragraph

[0078] and R 400d as described in paragraph

[0149] .

[0073] In some embodiments, the compound of formula A is a compound selected from the group consisting of compounds of formula I, compounds of formula II, and compounds of formula III as defined herein.

[0074] In some embodiments, the compound of formula A is selected from the group consisting of the compounds described in any one of paragraphs

[0089] ,

[0120] , and

[0156] .

[0075] In one embodiment, the present disclosure describes a compound of formula I: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0076] The substituent R of formula I 1a is selected from the group consisting of -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) m’ NR 5A R 5B 、-(CH2) m R 6 and C(O)N(CH2CH2OCH3)2. The substituents R 5A and R 5B 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. Alternatively, R 5A and R 5B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, the one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, 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 a 5- to 6-membered heterocyclic group, pyridyl, and thiazolyl; and r is an integer selected from the group consisting of 0, 1, 2, and 3.

[0077] The substituent R of formula I 1c is selected from the group consisting of chlorine, fluorine, iodine, and bromine.

[0078] The substituent R of formula I 4b and R 4d are each independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4dis Y. The substituent Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl. The substituent Z 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, -(CH2)O(CH2)2NR 2A R 2B 、-(CH2) n R 3 、-CH2OCH2Ar and -OCH3. The substituents R 2A and R 2B together with the nitrogen to which they are attached form a 4- to 8-membered heterocycle optionally substituted with one or more methyl groups. The substituent R 3 is selected from the group consisting of 5- to 6-membered heterocyclic groups and phenoxy groups; and the integer n is an integer selected from the group consisting of 0, 1, 2, and 3. The substituent Ar is a 5- to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, hydroxyl, and alkoxy.

[0079] Additional embodiments describe compounds according to formula Ia: or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1a and R 4d of formula Ia are each as previously described for formula I.

[0080] In some embodiments, R 1a of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from -CH2NR 5A R 5B ; wherein 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.

[0081] In some embodiments, R 1a of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR 5A R 5B ; wherein R 5A and R 5BEach independently selected from C1-C6 alkyl substituted by one or more methoxy groups.

[0082] In some embodiments, R of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof 1a is selected from the group consisting of -CH2NR 5A R 5B ; wherein R 5A and R 5B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted by one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl and azabicyclo[3.2.1]octyl; wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is optionally substituted by one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluorine and acetyl. In some embodiments, the 4-8 membered heterocyclic group is optionally substituted by one or more methyl substituents. In some embodiments, the 4- to 8-membered heterocyclic group is selected from the group consisting of azetidinyl; pyrrolidinyl; pyrrolidinyl substituted by one or more substituents selected from the group consisting of cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted by one or more substituents selected from the group consisting of -CF3 and fluorine; piperazinyl substituted by one or more substituents selected from the group consisting of oxo, methyl and acetyl; morpholinyl; morpholinyl substituted by one or more methyl substituents; dioxothiomorpholinyl and azabicyclo[3.2.1]octyl.

[0083] In some embodiments, R of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof 1a is selected from the group consisting of -CH2NR 5A R 5B ; wherein R 5A and R 5BTogether with the nitrogen to which they are attached, form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl. In some embodiments, the 6-membered heterocyclic group is selected from the group consisting of piperidinyl optionally substituted with one or C1-C6 alkyl substituents, and morpholinyl optionally substituted with one or C1-C6 alkyl substituents.

[0084] In some embodiments, R of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof 1a is selected from the group consisting of -CH2NR 5A R 5B ; wherein -CH2NR 5A R 5B is selected from the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, ; In some embodiments, -CH2NR 5A R 5B is selected from the group consisting of -(CH2)N(CH2CH2OCH3)2, ;

[0085] 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 ; wherein R 6 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and piperidinyl, and m is as described above. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, -(CH2) m R 6 is selected from the group consisting of ;

[0086] In some embodiments, R of formula I or formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof 1aSelected from the group consisting of -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)2NHCO2CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and the group consisting thereof.

[0087] In some embodiments, R of formula I or formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 1a is selected from the group consisting of -CH3, -CH2CH3 and -CH2NR 5A R 5B wherein R 5A and R 5B are as described in any of the embodiments previously described herein. In some embodiments, R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 5A and R 5B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl.

[0088] In some embodiments, R of formula I or formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, and the group consisting thereof.

[0089] In some embodiments, R of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof 1c is chlorine.

[0090] Some embodiments describe a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 4b is Y and R 4d is Z.

[0091] Some embodiments describe a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R4d is Y and R 4b is Z.

[0092] In some embodiments, Y of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is -CF3.

[0093] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is -(CH2)O(CH2)2NR 2A R 2B , where R 2A and R 2B are as previously described herein. In some embodiments, R 2A and R 2B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with methyl. In some embodiments, R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from piperazinyl or 4-methylpiperazinyl.

[0094] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is -(CH2) n R 3 , where 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. In some embodiments, R 3 is tetrahydrofuranyl. In some embodiments, R 3 is selected from the group consisting of and phenoxy. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, -(CH2) n R 3 is selected from the group consisting of In some embodiments, -(CH2) n R 3 is

[0095] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4dis -CH2OCH2Ar, where Ar is as described previously herein. In some embodiments, Ar is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxyl, 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, fluorine, chlorine, hydroxyl, and methoxy. In some embodiments, Ar is selected from the group consisting of phenyl, and the like.

[0096] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate, or prodrug thereof 4d 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, -(CH2)O(CH2)2NR 2A R 2B -(CH2) n R 3 , -CH2OCH2Ar, and OCH3; where R 2A R 2B , R 3 , n, and Ar are as described in any embodiment herein.

[0097] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate, or prodrug thereof 4d is selected from the group consisting of -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; where R 2A R 2B , R 3 , n, and Ar are as described in any embodiment herein.

[0098] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is selected from the group consisting of -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; wherein R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R 3 is tetrahydrofuranyl; and Ar is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy and methoxy.

[0099] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d 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, and -OCH3.

[0100] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3.

[0101] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4dSelected 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, and -OCH3, and Y in formula I is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano and -CO2(C1-C6) alkyl.

[0102] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d 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, and -OCH3, and Y is -CF3.

[0103] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3, and Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano and -CO2(C1-C6) alkyl.

[0104] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or R of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof 4d is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, a group consisting of -OCH3, and Y is -CF3.

[0105] Some embodiments describe compounds of formula I, wherein: R 1a is selected from the group consisting of -CH3, -CH2CH3, and -CH2NR 5A R 5B ; R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more groups selected from methoxy; or, R 5A and R 5B together with the nitrogen to which they are attached form a 4-8 membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 1c is chlorine; R 4b and R 4d are each independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4d is Y; Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z is selected from the group consisting of -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; wherein R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R 3 is tetrahydrofuranyl; and Ar is a 5 to 6 membered aryl or heteroaryl optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy.

[0106] Some embodiments describe a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 1a is selected from the group consisting of -CH3, -CH2CH3, and -CH2NR 5A R 5B ; where R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more groups selected from methoxy; or, R 5A and R 5B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 1c is chlorine; R 4b and R 4d are each independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4d is Y; Y is CF3; and Z is selected from the group consisting of -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; where R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R 3 is tetrahydrofuranyl; and Ar is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy.

[0107] Some embodiments describe a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, ; R 1c is chlorine; R 4b and R4d Each is independently selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4d is Y; Y is CF3; and Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3.

[0108] Some embodiments describe a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, ; R 1c is chlorine; R 4b is CF3; and R 4d is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3.

[0109] Some embodiments describe a compound of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, ; and R 4d 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, and -OCH3.

[0110] Some embodiments describe a compound of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R1a selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, ; and R 4d selected from the group consisting of -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3.

[0111] Some embodiments describe compounds selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0112] Some embodiments describe compounds selected from the group consisting of:

[0113] In one embodiment, the compound is or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0114] In one embodiment, the present disclosure describes a compound of formula II: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0115] The substituent R of formula I 10a selected from OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) o’ NR 50A R50B , -(CH2) o R 60 and the group consisting of C(O)N(CH2CH2OCH3)2. The substituents 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. Provided that R 50A and R 50B are not both C1-C6 alkyl; or, R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, 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 a 5- to 6-membered heterocyclic group, pyridyl, and thiazolyl; and o is an integer selected from the group consisting of 0, 1, 2, and 3.

[0116] The substituent R of formula I 10c is selected from the group consisting of chlorine, fluorine, iodine, and bromine.

[0117] The substituent R 40b and R 40d one of which is H and the other substituent is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl.

[0118] Another embodiment describes a compound according to formula IIa: or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a and R 40d of formula IIa are each as previously described for formula II.

[0119] In some embodiments, R 10a of formula II or formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from -CH2NR 50A R 50B ; wherein 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.

[0120] In some embodiments, R of formula II or formula IIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 10a is selected from the group consisting of -CH2NR 50A R 50B ; wherein R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxyamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl and azabicyclo[3.2.1]octyl; wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxyamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl and dioxothiomorpholinyl; wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluorine and acetyl. In some embodiments, the 4- to 8-membered heterocyclic group is selected from the group consisting of azetidinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, 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 fluorine; 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]octyl. In some embodiments, the 4- to 8-membered heterocyclic group is selected from the group consisting of azetidinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, 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 fluorine; 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.

[0121] In some embodiments, R of formula II or IIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 10a is selected from the group consisting of -CH2NR 50A R 50B ; wherein R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl and dithiamorpholinyl; wherein the 4- to 7-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluorine and acetyl.

[0122] In some embodiments, R of formula II or IIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 10a is selected from the group consisting of -CH2NR 50A R 50B ; wherein -CH2NR 50A R 50B is selected from the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, .

[0123] In some embodiments, R of formula II or IIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 10a is selected from the group consisting of -CH2NR 50A R 50B ; wherein -CH2NR 50A R 50B is selected from the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, .

[0124] In some embodiments, R of formula II or IIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 10a is -(CH2) o R 60 ; wherein R 60is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and pyridinyl; and o is as described 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, -(CH2)0R 60 is selected from the group consisting of In some embodiments, -(CH2)0R 60 is selected from the group consisting of consisting of.

[0125] In some embodiments, R of formula II or formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NR 50A R 50B 、-(CH2) o R 60 and C(O)N(CH2CH2OCH3)2, wherein R 50A 、R 50B and R 60 is as previously defined by any embodiment herein.

[0126] In some embodiments, R of formula II or formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 10a is -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, C(O)N(CH2CH2OCH3)2.

[0127] In some embodiments, R of formula II or formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 10a-OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2.

[0128] In some embodiments, R of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof 10c is chlorine, fluorine and iodine.

[0129] In some embodiments, R of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof 10c is chlorine, fluorine and iodine.

[0130] In some embodiments, substituent R 40b and R 40d one of which is H, and the other substituent is selected from the group consisting of fluorine, -CF3, -CHF2 and -OCF3.

[0131] In some embodiments, R 40b is H and R 40d is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl.

[0132] In some embodiments, R 40d is H and R 40b is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl.

[0133] In some embodiments, R 40d is H and R 40b is selected from the group consisting of fluorine, -CF3, -CHF2 and -OCF3.

[0134] In some embodiments, R 40d is H and R 40b is -CF3.

[0135] Some embodiments describe a compound of formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -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 R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl; R 60 is selected from the group consisting of a 5- to 6-membered heterocyclic group, pyridyl, and thiazolyl; o is 0; R 10c is selected from the group consisting of chlorine, fluorine, and iodine; and R 40b and R 40d one of which is H, and R 40b and R 40d the other of which is selected from the group consisting of fluorine, -CF3, -CHF2, and -OCF3. Provided that R 50A and R 50B are not both C1-C6 alkyl.

[0136] Some embodiments describe a compound of formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NR 50A R50B , -(CH2) o R 60 and the group consisting of C(O)N(CH2CH2OCH3)2; 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; or, R 50A and R 50B together with the nitrogen to which they are attached form a 4-7 membered heterocyclic group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl and dioxothiomorpholinyl; wherein said heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluorine and acetyl; R 60 is selected from the group consisting of tetrahydrofuranyl, pyridinyl and thiazolyl; o is 0; R 10c is selected from the group consisting of chlorine, fluorine, iodine; and R 40d is H and R 40b is selected from the group consisting of fluorine, -CF3, -CHF2 and -OCF3. Provided that R 50A and R 50B are not both methyl.

[0137] Some embodiments describe a compound of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, C(O)N(CH2CH2OCH3)2; R 10c is selected from the group consisting of chlorine, fluorine, iodine; and R 40d is H and R 40bis selected from the group consisting of fluorine, -CF3, -CHF2, and -OCF3.

[0138] Some embodiments describe a compound of formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2; R 10c is selected from the group consisting of chlorine, fluorine, and iodine; and R 40d is H and R 40b is selected from the group consisting of fluorine, -CF3, -CHF2, and -OCF3.

[0139] Some embodiments describe a compound of formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2; R 10c is chlorine; and R 40d is H and R 40b is -CF3.

[0140] Some embodiments describe a compound of formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R10a selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2.

[0141] Some embodiments describe a compound of formula IIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 10a selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2.

[0142] Some embodiments describe a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0143] Some embodiments describe a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0144] One embodiment describes a compound, namely or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0145] In one embodiment, the present disclosure describes a compound of Formula III: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0146] The substituent R of Formula III 100a is selected from the group consisting of -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) p’ NR 500A R 500B 、-(CH2) p R 600 and C(O)N(CH2CH2OCH3)2. The substituents R 5A and R 5B 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. Alternatively, R 500A and R 500B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxyamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl. The integer p' is an integer selected from the group consisting of 1, 2, and 3. The substituent R 600 is selected from the group consisting of a 5- to 6-membered heterocyclic group, pyridyl, and thiazolyl; and p is an integer selected from the group consisting of 0, 1, 2, and 3.

[0147] The substituent R of Formula III 100c is selected from the group consisting of chlorine, fluorine, iodine, and bromine.

[0148] The substituent R of Formula III 400b and R 400d are each independently selected from Y1 and Z 1 A group consisting of, provided that when R 400b is Y 1 then R 400d is Z 1 and when R 400b is Z 1 then R 400d is Y 1 . The substituent Y 1 is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl. The substituent Z 1 is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) q’ NR 7A R 7B and -(CH2) q R 8 R 7A and R 7B are each independently selected from C1-C6 alkyl. Alternatively, R 7A and R 7B together with the nitrogen to which they are attached form a 4-8 membered heterocyclic group optionally substituted with one or more independently selected C1-C6 alkyl groups. 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 the following 5- to 6-membered heterocycles optionally substituted with methyl, and the integer q' is an integer selected from the group consisting of 0, 1, 2, and 3.

[0149] Additional embodiments describe a compound according to formula IIIa: or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 100a and R 400d of formula IIIa are each as previously described for formula III.

[0150] In some embodiments, R 100a of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from -CH2NR 500A R 500B ; wherein R 500A and R 500B are each independently selected from methyl; and C1-C6 alkyl substituted with one or more groups selected from methoxy and -O(CH2)2OCH3.

[0151] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 100a is selected from the group consisting of -CH2NR 500A R 500B ; wherein R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups.

[0152] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 100a is selected from the group consisting of -CH2NR 500A R 500B ; wherein R 500A and R 500B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl and azabicyclo[3.2.1]octanyl; wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl. In some embodiments, the 4-8 membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluorine and acetyl. In some embodiments, the 4-8 membered heterocyclic group is optionally substituted with one or more methyl substituents. In some embodiments, the 4- to 8-membered heterocyclic group is selected from the group consisting of azetidinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, 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 fluorine; 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 substituents; dioxothiomorpholinyl and azabicyclo[3.2.1]octanyl.

[0153] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 100a is selected from the group consisting of -CH2NR500A R 500B a group consisting of; wherein R 500A and R 500B together with the nitrogen to which they are attached form a 6 - membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, SO2CH3, -CF3, C1 - C6 alkyl, halogen, and acyl. In some embodiments, the 6 - membered heterocyclic group is selected from the group consisting of piperazinyl optionally substituted with one or a C1 - C6 alkyl substituent, and morpholinyl optionally substituted with one or a C1 - C6 alkyl substituent.

[0154] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 100a is selected from the group consisting of -CH2NR 500A R 500B a group consisting of; wherein -CH2NR 500A R 500B is selected from the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, a group consisting of. In some embodiments, -CH2NR 500A R 500B is selected from the group consisting of -(CH2)N(CH2CH2OCH3)2, a group consisting of.

[0155] 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 wherein R 600 is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and piperidinyl, and m is as described above. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, -(CH2) p R 600 is selected from the group consisting of a group consisting of.

[0156] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate, or prodrug thereof 100aSelected from the group consisting of -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)2NHCO2CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and the group consisting of.

[0157] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 100a is selected from the group consisting of -CH3 and -CH2NR 500A R 500B and the group consisting of, wherein R 500A and R 500B are as described in any of the embodiments previously described herein. In some embodiments, R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl.

[0158] In some embodiments, R of formula III or formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, and the group consisting of.

[0159] In some embodiments, R of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 100c is chlorine.

[0160] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 400b is Y 1 and R 400d is Z 1 .

[0161] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 400d is Y 1 and R400b is Z 1 .

[0162] In some embodiments, Y of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 is -CF3.

[0163] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is -CH2NR 7A R 7B , where R 7A and R 7B are as previously described herein. In some embodiments, R 7A and R 7B are each methyl. In some embodiments, R 7A and R 7B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with methyl. In some embodiments, R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of a piperazinyl group optionally substituted with one or more C1-C6 alkyl groups and a morpholinyl group optionally substituted with one or more C1-C6 alkyl groups. In some embodiments, R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl. In some embodiments, -CH2NR 7A R 7B is selected from the group consisting of -CH2N(CH3)2, and the like.

[0164] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is -(CH2) q R 8 . Where 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, -(CH2) q R 8 is

[0165] In some embodiments, Z of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 , wherein R 7A , R 7B , R 8 and p are as described in any embodiment herein.

[0166] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 , wherein R 7A , R 7B , R 8 and p are as described in any embodiment herein.

[0167] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 , wherein R 7A and R 7B are each methyl. In an alternative embodiment, R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and R 8 is 4-methylpiperidinyl.

[0168] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, .

[0169] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, . And Y of formula III 1 is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl.

[0170] In some embodiments, Z of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 1 , or R of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, . And Y of formula III 1 is -CF 3. .

[0171] In some embodiments, R of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, ; and R of formula III 400b is -CF3.

[0172] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 100aSelected from the group consisting of -CH3 and -CH2NR 500A R 500B ; R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl; R 100c is chlorine; R 400b and R 400d are each independently selected from the group consisting of Y 1 and Z 1 , provided that when R 400b is Y 1 , then R 400d is Z 1 , and when R 400b is Z 1 , then R 400d is Y 1 . Y 1 is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl; Z 1 is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 , where R 7A and R 7B are each methyl; or R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and R 8 is 4-methylpiperidinyl.

[0173] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 100a is selected from the group consisting of -CH3 and -CH2NR 500A R 500B ; R500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl; R 100c is chlorine; R 400b and R 400d are each independently selected from the group consisting of Y 1 and Z 1 , provided that when R 400b is Y 1 , then R 400d is Z 1 , and when R 400b is Z 1 , then R 400d is Y 1 , Y 1 is -CF3; Z 1 is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 , where R 7A and R 7B are each methyl; or R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and R 8 is 4-methylpiperidinyl.

[0174] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, ; R 100c is chlorine; R 400b and R 400d are each independently selected from the group consisting of Y 1 and Z 1 , provided that when R 400b is Y 1 then R400d is Z 1 and when R 400b is Z 1 then R 400d is Y 1 ; Y 1 is CF3; and Z 1 is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2N(CH3)2, .

[0175] Some embodiments describe a compound of formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, . R 100c is chlorine; R 400b is CF3; and R 400d is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2N(CH3)2, .

[0176] Some embodiments describe a compound of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, ; and R 400d is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, .

[0177] Some embodiments describe a compound of formula IIIa or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0178] Some embodiments describe a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0179] Some embodiments describe compounds selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0180] Additional compounds that act as mitochondrial uncoupling agents but do not necessarily have the unexpected properties of the other compounds disclosed herein include: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0181] The compounds of the embodiments described herein may have one or more asymmetric carbon atoms and can therefore exist in the form of optical isomers as well as in the form of their racemic or non-racemic mixtures. The compounds may be used in the embodiments described herein as a single isomer or as a mixture of stereoisomeric forms. Diastereoisomers, i.e., non-overlapping stereoisomers, can be separated by conventional methods 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, dimethylbenzoyltartaric acid and camphorsulfonic acid. Mixtures of diastereoisomers can be separated by crystallization, followed by release of the optically active base from these salts. Alternative methods for separating optical isomers include using an optimally selected chiral chromatographic column to maximize the separation of enantiomers. Another available method involves the synthesis of covalently linked diastereoisomeric molecules by reacting the compounds of the invention with an activated form of an optically pure acid or an optically pure isocyanate. 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 invention can also be obtained by utilizing optically active starting materials. These isomers can be in the form of free acids, free bases, esters or salts.

[0182] Compounds according to 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 addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein can be prepared from inorganic acids 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. Suitable organic acids can be selected from organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes, examples of which include, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, maleic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, p-aminobenzenesulfonic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, malonic acid, galactose, and galacturonic acid. Pharmaceutically acceptable base addition salts of the compounds described herein can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, bis(substituted alkyl)amines, tris(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, bis(substituted alkenyl)amines, tris(substituted alkenyl)amines, cycloalkylamines, bis(cycloalkyl)amines, tris(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, bis(cycloalkenyl)amines, tris(cycloalkenyl)amines, substituted cycloalkenyls, disubstituted cycloalkenylamines, trisubstituted cycloalkenyls, arylamines, diarylamines, triarylamines, heteroarylamines, bis(heteroaryl)amines, tris(heteroaryl)amines, heterocyclic amines, bis(heterocyclic)amines, tris(heterocyclic)amines, mixed diamines and triamines in which 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 such amines in which 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, tris(isopropyl)amine, tris(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, penicillin G, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.It should also be understood that other carboxylic acid derivatives can be used to prepare pharmaceutically acceptable salts, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

[0183] 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 that provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of organic acids (such as carboxylic acids) can also be prepared.

[0184] Compounds according to the embodiments described herein can have prodrug forms. 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, F.D. King, ed., The Royal Society of Chemistry, Cambridge, UK, 1994; Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, B. Testa, J.M. Mayer, VCHA and Wiley-VCH, Zurich, Switzerland, 2003; The Practice of Medicinal Chemistry, C.G. Wermuth, 2 nd ed., Academic Press, San Diego, CA, 1999). Some prodrugs of the present invention include compounds according to any of the embodiments described herein, wherein the 2-hydroxy group of the benzamide is converted to, for example, but not limited to and a group such as -CH2OAc.

[0185] In some embodiments, the 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 the benzamide according to any of the described embodiments can be converted to a carbamate group -OC(O)NR 9 R 10 . 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 together with the nitrogen to which they are attached form an optionally substituted C3-C6 heterocyclic group.

[0186] The present invention also includes isolated compounds. An isolated compound refers to 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.

[0187] In some embodiments of the present invention, one or more hydrogen atoms are replaced by deuterium. It is recognized that deuteration of a bioactive compound provides the advantage of maintaining the pharmacological profile of its hydrogen counterpart while positively affecting its metabolic outcome. In the compounds of the present invention, selective replacement of one or more hydrogens with deuterium can improve the safety, tolerability, and efficacy of the compound compared to its fully hydrogenated counterpart.

[0188] Methods for incorporating deuterium into compounds are well recognized. Using established metabolic studies in the art, the compounds of the present invention can be tested to identify sites for the selective placement of deuterium isotopes where the isotope will not be metabolized. Additionally, these studies identify metabolic sites as locations where deuterium atoms will be placed.

[0189] Some embodiments describe pharmaceutical compositions comprising: a compound, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof according to the embodiments described herein; and a pharmaceutically acceptable carrier or diluent.

[0190] The compound or its pharmaceutically acceptable salt can be formulated for oral, intravenous, intramuscular, subcutaneous, or parenteral administration for the treatment 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, etc. A pharmaceutical composition containing a compound of the present invention will contain from about 0.1 to about 99% by weight of the active compound, more typically from about 10 to about 30% by weight of the active compound.

[0191] The pharmaceutical formulations disclosed herein are prepared according to standard procedures and are administered in a dose selected to reduce, prevent, or eliminate the 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, N.Y., the contents of which are incorporated herein by reference for a general description of methods of administering various agents for human therapy). The pharmaceutical compositions of the present invention can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodible matrices).

[0192] The pharmaceutically acceptable drug compositions of the present invention comprise one or more compounds of the present invention and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients (collectively referred to herein as "carrier" materials) and other active ingredients as required. The drug compositions may contain common carriers and excipients such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. The drug compositions may contain sodium carboxymethyl starch cross-linked, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

[0193] Tablet binders that may be included are gum arabic, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, sucrose, starch and ethylcellulose.

[0194] Lubricants that may be used include magnesium stearate or other metal stearates, stearic acid, silicone fluid, talc, wax, oil and colloidal silica.

[0195] Flavoring agents such as peppermint, wintergreen oil, cherry flavoring, etc. may also be used. It may also be desirable to add coloring agents to make the dosage form more aesthetically pleasing in appearance or to aid in the identification of the product.

[0196] For oral use, solid dosage forms such as tablets and capsules are particularly useful. Sustained release or enteric coated formulations may also be designed. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are particularly suitable. For oral use, the drug compositions are in the form of, for example, tablets, capsules, suspensions or liquids. The drug compositions are preferably prepared in dosage unit form containing a therapeutically effective amount of the active ingredient. Examples of such dosage units are tablets and capsules. For therapeutic purposes, in addition to the active ingredient, tablets and capsules may also contain conventional carriers such as binders such as gum arabic, gelatin, polyvinylpyrrolidone, sorbitol or tragacanth; fillers such as calcium phosphate, glycine, lactose, corn starch, sorbitol or sucrose; lubricants such as magnesium stearate, polyethylene glycol, silica or talc; disintegrants such as potato starch, flavoring agents or coloring agents or acceptable wetting agents. Oral liquid preparations are generally in the form of aqueous or oily solutions, and suspensions, emulsions, syrups or elixirs may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents. Examples of additives for liquid preparations include gum arabic, almond oil, ethanol, fractionated coconut oil, gelatin, glucose syrup, glycerol, hydrogenated edible fat, lecithin, methylcellulose, methyl or propyl p-hydroxybenzoate, propylene glycol, sorbitol or sorbic acid.

[0197] For intravenous (IV) use, the compounds according to the invention can be dissolved or suspended in any conventional intravenous fluid and administered by infusion. Intravenous fluids include, but are not limited to, saline or Ringer's solution. Intravenous administration can be achieved by using, but not limited to, syringes, small pumps or intravenous lines.

[0198] 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 having one or more of the carriers of the preparations for oral administration. The compounds can be dissolved in polyethylene glycol, propylene glycol, ethanol, corn oil, benzyl alcohol, sodium chloride and / or various buffers.

[0199] For intramuscular preparations, a sterile preparation of the compound or a suitable soluble salt of the compound, such as in the form of a hydrochloride salt, can be administered with a pharmaceutical diluent such as Water-for-Injection (WFI), saline or 5% dextrose. Suitable insoluble forms of the compound can be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base (such as esters of long-chain fatty acids, such as ethyl oleate).

[0200] The dose of the intravenous, intramuscular or parenteral preparation 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 in one minute or less. An infusion is a dose administered at a rate of 30 minutes or greater. In a preferred embodiment, the infusion is for 1 hour or longer. In another embodiment, the infusion is at a substantially constant rate.

[0201] For topical use, the compounds of the invention can also be prepared in a suitable form for application to the skin or the mucous membranes of the nose and throat and can take the form of creams, ointments, liquid sprays or inhalants, lozenges or throat paints. Such topical preparations can also include chemical compounds, such as dimethyl sulfoxide (DMSO), to facilitate the surface penetration of the active ingredient.

[0202] For application to the eye or ear, the compounds of the invention can be in liquid or semi-liquid form, formulated in a hydrophobic or hydrophilic base in the form of an ointment, cream, emulsion, coating or powder.

[0203] For rectal administration, the compounds of the invention can be administered in the form of suppositories mixed with conventional carriers such as cocoa butter, wax or other glycerides.

[0204] Alternatively, the compounds of the invention may be in powder form for reconstitution in a suitable pharmaceutically acceptable carrier upon 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, airtight sealed ampoule or a 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, its solubility and the dose required by the physician.

[0205] In some embodiments, the pharmaceutical compositions described herein are at a therapeutically effective dosage level. In some embodiments, the pharmaceutical composition is administered to a patient, such as a human and an elderly person, at a therapeutically effective level of from 0.001 to 100 mg / kg body weight per day. The therapeutically effective amount is generally from about 0.5 mg to 10 g per day, which can be administered in a single dose or multiple doses. In some embodiments, the therapeutically effective amount is between a lower limit 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 10000 mg; and an upper limit of 10000 mg, 9500 mg, 9000 mg, 8500 mg, 8000 mg, 7500 mg, 7000 mg, 6500 mg, 6000 mg, 5500 mg, 5000 mg, 4500 mg, 4000 mg, 3500 mg, 3000 mg, 2500 mg, 2000 mg, 1500 mg, 1000 mg, 500.0 mg, 100 mg, 10 mg and 0.5 mg. In some embodiments, the therapeutically effective amount will be from about 0.5 mg to 2500 mg / patient / day; in some embodiments from about 0.5 mg to 200 mg / patient / day; in some embodiments from about 0.5 mg to 500 mg / patient / day; in some embodiments from about 0.5 mg to 1000 mg / patient / day; and in still some other embodiments from about 5 mg to 50 mg / patient / day. The pharmaceutical compositions of the present invention can be provided in solid dosage forms, such as containing from about 0.5 mg to 500 mg of the active ingredient, or containing from about 1 mg to 250 mg of the active ingredient. The pharmaceutical composition can be provided in solid dosage formulations 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 the active ingredient. For oral administration, the composition can be provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000 and 2000 milligrams of the active ingredient, for symptom adjustment of the dose for the patient to be treated. The compound can be administered according to a regimen of 1 to 4 times a day, such as once, twice, three times or four times a day. Unexpected property Mitochondrial uncoupling agent with improved PK profile

[0206] Some embodiments describe the mitochondrial uncoupling agents depicted herein, which have an improved pharmacokinetic (PK) profile, e.g., a significantly increased systemic exposure (i.e., via increased solubility and absorption) consistent with significantly improved efficacy, and a significantly reduced half-life consistent with once-daily oral administration regimens, and eliminate the toxic risk factors due to accumulation from long-term use for long-term conditions or disorders.

[0207] A common feature of existing benzamide compounds with mitochondrial uncoupling activity is low systemic exposure. As shown in Table 1, niclosamide ethanolamine has an oral exposure of only about 1800 hr*ng / ml after 24 hours at a dose of 50 mg / kg. Compound 31 in International Patent Publication No. WO 2016 / 081599 and Compound 27 in U.S. Patent 10,227,315 have systemic exposures of only about 2400 hr*ng / ml after oral administration at 20 mg / kg and about 3000 hr*ng / ml after oral administration at 10 mg / kg, respectively, over a 24-hr period (Table 1). To overcome the poor pharmacokinetic properties of low systemic exposure and short half-life of previously disclosed compounds, studies in animal models required mixing the compounds with food and high doses of the compounds to achieve efficacy (e.g., 1500 ppm niclosamide ethanolamine (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 (Compound 28 in US10,227,315), equivalent to 60 - 75 mg / kg / day). Neither the required high doses nor the necessity of mixing the compounds with food is compatible with the needs of human therapeutic development.

[0208] As shown in Table 1, the new compounds (e.g., Compounds 2, 9, 78) unexpectedly exhibit a significantly increased systemic exposure without compromising uncoupling activity, a 20- to 160-fold increase relative to existing uncoupling agents with the best systemic exposure. Table 1

[0209] Table 2 provides additional compounds with a significantly increased systemic exposure (see Example B3). Compound number Oral exposure (AUC, hr*ng / ml, 24 hrs) after gavage at 10 mg / kg 2 ++++++ 3 +++ 4 ++++ 9 ++++++ 11 +++++ 13 ++++ 14 ++++++ 15 ++++++ 16 +++ 17 +++ 23 +++ 25 +++ 26 +++ 27 ++++ 32 ++++ 64 +++ 65 +++++ 66 ++++ 68 ++++ 69 +++ 78 ++++ 97 +++ +++ : 10,000 - 30,000; +++++ : 30,001 - 60,000; ++++++ : 60,001 - 120,000; +++++++ : >120,000

[0210] As shown in Table 3, compared with the similar compounds of the present invention, Compound 49 in US Patent 10,227,315 has lower mitochondrial uncoupling activity. Table 3 Significantly improved metabolic stability and half-life characteristics

[0211] Some embodiments describe compounds described herein having improved metabolic stability and half-life.

[0212] A key reason that previously known mitochondrial uncoupling agents such as DNP exhibit a narrow therapeutic index is due to their long half-life. For example, DNP has a half-life in the range of days to weeks, resulting in the accumulation of toxic levels in the body during long-term use for treating chronic conditions or disorders. For developing drugs for oral use, excretion characteristics are also important. A drug not only needs to have sufficient exposure, but also needs to be excreted at a rate that is neither too short nor too long. On the one hand, it is important that an oral drug should have a sufficiently long half-life in a patient so that the drug can be administered at certain intervals (e.g., once a day instead of once an hour); on the other hand, the half-life of a compound cannot be too long because this may lead to the accumulation of drug toxicity in the patient. For a drug administered orally once a day, a half-life of about 8 - 12 hours is considered an advantageous property, while a half-life exceeding 48 hours is not suitable for once-daily oral administration and may lead to the accumulation of drug toxicity. For example, Compound 2 of US Patent 10,227,315 exhibits an extremely long half-life (66.9 hours, Table 4, Example B8). The long half-life is associated with extreme metabolic stability (rat microsomal metabolic stability, half-life 2,131.8 minutes). In other words, the extremely long half-life of Compound 2 of US Patent 10,227,315 is mainly caused by the inability of liver metabolic enzymes to effectively metabolize these compounds.

[0213] As shown in Table 4, Compound 17 of the present invention unexpectedly has significantly reduced metabolic stability (from 2,132 minutes to 145 minutes, Example B7), and is accompanied by a reduced oral half-life (from 66.9 hours to 8.6 hours, Example B8). The structural modification does not reduce the mitochondrial uncoupling activity, and thus is expected to have better toxicological properties when used for treating chronic conditions or disorders that require long-term use. Table 4

[0214] The half-lives of the various compounds described herein were determined in a rat liver microsome stability assay (Example B7) and compared to Compounds 2, 53, and 54 in U.S. Patent 10,227,315 (Table 5). The compounds of the present invention exhibit significantly improved metabolic stability (a favorable half-life is less likely to cause toxicity when used to treat chronic conditions or conditions that require long-term use) without reducing uncoupling activity (see Tables 5 and 8). Table 5 MMP-maintaining compound

[0215] Some embodiments describe the mitochondrial uncoupling agents described herein that effectively increase OCR without reducing or significantly reducing MMP. These compounds are referred to in this disclosure as MMP-maintaining uncoupling agents.

[0216] Mechanistically, conventional mitochondrial uncoupling agents transport protons across the inner mitochondrial membrane into the mitochondrial matrix. Since the transmembrane proton gradient supports the mitochondrial membrane potential, conventional uncoupling agents inevitably need to rapidly dissipate the mitochondrial membrane potential to maintain mitochondrial uncoupling ( Figure 3 ). Prior to this disclosure, all mitochondrial uncoupling agents tested (referred to herein as conventional uncoupling agents) had the property of increasing OCR and reducing MMP, and the concentrations that result in increased OCR and MMP dissipation were correlated (Figure 4). Figure 4 shows the conventional uncoupling agent FCCP, whose C 10％TMRE / C min-OCR ratio is less than 3, where C 10％TMRE is the concentration that results in 10% MMP retention (or 90% MMP loss, measured by TMRE staining), and C min-OCR is the minimum concentration that results in increased OCR. Thus, the activity of reducing MMP is considered to be the second hallmark of mitochondrial uncoupling. Since MMP is essential for cell survival and normal function of cells in many tissues and organs, this seemingly inherent property of conventional mitochondrial uncoupling agents to dissipate MMP represents a major safety obstacle in therapeutic development.

[0217] In some embodiments, the mitochondrial uncoupling agents described herein represent a substantially different class of mitochondrial uncoupling agents that effectively induce mitochondrial uncoupling (increase mitochondrial oxygen consumption in the presence of oligomycin) without significantly reducing the mitochondrial membrane potential over a wide concentration range (Figures 5 and 6, Example B2). Figure 5 shows that Compound 25 does not appear to reduce MMP over a wide concentration range where OCR increases and reaches a maximum level. The C 10％TMRE / C min-OCRThe ratio exceeds 25. Figure 6 shows that compound 64 effectively induces mitochondrial uncoupling within a wide concentration range without significantly reducing MMP. The C 10％TMRE / C min-OCR ratio is between 10 and 25.

[0218] After determining the mitochondrial uncoupling activity (Example B1) of the mitochondrial uncoupling agents described herein, the mitochondrial membrane potential of the mitochondrial uncoupling agents was measured using a standard TMRE (tetramethylrhodamine ethyl ester) staining method for culturing mammalian cells (Example B2). The results were divided into three groups, and the compound 25-like compounds were designated as MMP-maintaining uncoupling compounds (C 10％TMRE / C min-OCR > 25); the compound 64-like compounds were designated as MMP-maintaining uncoupling compounds (C 10％TMRE / C min-OCR between 10 and 25), and conventional uncoupling agents (C 10％TMRE / C min-OCR less than or equal to 3). The compounds are summarized in Table 6. Table 6 C 10％TMRE is the concentration that results in 10% MMP maintenance (or 90% MMP loss, measured by TMRE staining), and C min-OCR is the minimum concentration that results in an increase in OCR.

[0219] Mechanistically, chemical uncoupling agents are lipophilic weak acids or weak bases that localize in the inner mitochondrial membrane and transport protons across the membrane into the mitochondrial matrix through protonation and deprotonation cycles ( Figure 3 and Figure 7A ). Since the transmembrane proton gradient supports the mitochondrial membrane potential (MMP), it is highly unexpected that the compounds can uncouple mitochondrial oxidation (transporting protons) without significantly reducing MMP. We analyzed benzothiazole derivatives of benzamide uncoupling agents, which exhibited MMP-maintaining activity. They all contain a tertiary or secondary amine group with a pKa exceeding 10.0. In a cellular environment where the pH is typically below 8.0, the amine group becomes positively charged.

[0220] Without wishing to be bound by theory, we propose a mechanism of action for MMP-maintaining uncoupling agents, as Figure 7B shown. Substantially, the MMP-maintaining uncoupling agent molecule consists of two functional parts ( Figure 7C ). The first part acts as a conventional uncoupling agent, which transports protons from the mitochondrial intermembrane space to the mitochondrial matrix ( Figure 7B)。The second part is a positively charged functional group that has poor permeability to the inner mitochondrial membrane. This feature allows for the asymmetric distribution and orientation of the compound on the inner mitochondrial membrane, where the concentration of charged molecules in the intermembrane space is higher than that in the mitochondrial matrix, and the positively charged portion is mainly distributed at the outer surface of the membrane (facing the intermembrane space, Figure 7B )。As mitochondrial uncoupling occurs and thus the transmembrane proton gradient decreases, the loss of membrane potential caused by the reduction of the proton gradient is compensated by the asymmetric positive charge distribution across the membrane provided by the MMP-maintaining uncoupler. Therefore, the overall mitochondrial membrane potential is minimally affected over a wide concentration range of the uncoupler.

[0221] Figure 7D Show the structural features of all MMP-maintaining uncouplers listed in Table 6, where the positive charge is provided by a tertiary or secondary amine. We note that by modifying the amine-containing moiety, the MMP-maintaining activity can be fine-tuned, reducing the C 10％TMRE / C min-OCR ratio from >25 to between 10 and 25. Some modifications of the amine-containing moiety can even reduce the ratio to close to 3, i.e., equal to the ratio of typical conventional mitochondrial uncouplers. Figure 7E Show specific examples of MMP-maintaining uncouplers, where the conventional uncoupler components are shown in the box. Improved in vivo safety profile

[0222] Some embodiments describe that compared with conventional uncouplers (e.g., the bench-mark conventional uncoupler DNP), the MMP-maintaining uncouplers exhibit a significantly improved safety profile.

[0223] DNP is a conventional mitochondrial uncoupler that was used in humans before being used for obesity treatment. However, it exhibits a high level of toxicity and has a narrow therapeutic window. Subsequently, the drug was withdrawn from the market and is no longer used in humans. The toxicological profiles of the MMP-maintaining uncouplers use Compound 25 and Compound 64 as examples and compare them with the toxicological profile of DNP. 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).

[0224] Some embodiments show that the MMP-maintaining uncouplers exhibit a significantly improved acute toxicity profile. Figure 8 (Example B9) shows that Compound 64 and Compound 25 have LD50 (lethal dose, 50% of animals die) / MED (minimum effective dose) ratios of 400 and 200, respectively, while the LD50 / MED ratio of DNP is 30.

[0225] Some embodiments show that MMP-maintaining uncouplers exhibit a significantly improved short-term (10-day) toxicological profile. Figures 9-10 (Example B10) show that the ratio of the NOAEL (No Observed Adverse Effect Level) to the MED for Compound 64 exceeds 40 (between 40-57 using different parameters), the NOAEL / MED ratio for Compound 25 exceeds 19, while the reported NOAEL / MED ratio for DNP is less than 3.

[0226] Some embodiments describe methods for preparing MMP-maintaining uncouplers from conventional mitochondrial uncouplers by adding a positively charged side chain to a conventional uncoupler, such as Figure 7C described, for example, by adding a side chain containing a tertiary amine (or secondary amine) ( Figure 7D ). As Figure 7E shown, the tertiary amine-containing moiety is added to the conventional uncoupler (the structure in the box). This modification effectively converts the conventional uncoupler (C 10％TMRE / C min-OCR ratio of 3) into an MMP-maintaining uncoupler (listed in Table 2, where the C 10％TMRE / C min-OCR ratio exceeds 25).

[0227] Some embodiments describe mitochondrial membrane-maintaining uncoupler compounds of the following formula: (R A ) u -R B ; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R A and R B are covalently linked; R A are each independently a moiety containing a secondary or tertiary amine; u is an integer selected from the group consisting of 1 and 2; and R B is a conventional mitochondrial uncoupler before being covalently linked to R A ; provided that the mitochondrial membrane-maintaining uncoupler compound is not

[0228] Some embodiments describe methods for preparing mitochondrial membrane-maintaining mitochondrial uncouplers, including 1. Identifying a conventional mitochondrial uncoupler; 2. Designing a compound that covalently links at least one moiety that will become positively charged in a cellular environment to the conventional mitochondrial uncoupler; and 3. Preparing the compound of step 2, wherein the compound is a mitochondrial membrane-maintaining uncoupler compound. In some embodiments, the moiety that can become positively charged in a cellular environment is a secondary or tertiary amine moiety.

[0229] Some embodiments describe a method of preparing a mitochondrion membrane-retaining mitochondrial uncoupler, comprising 1. identifying a conventional mitochondrial uncoupler; 2. designing a compound that covalently links at least one secondary or tertiary amino moiety to the conventional mitochondrial uncoupler; and 3. preparing the compound of step 2, wherein the compound is a mitochondrion membrane-retaining uncoupler compound.

[0230] In some embodiments, the secondary amino or tertiary amino moiety or R A is selected from the group consisting of -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -CH2NHSO2CH3, -(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 wherein R 5000A , R 5000B , R 5A , R 5B , R 50A , R 50B , R 500A , R 500B , R 2A , R 2B , R 2000A , R 2000B , R 7A , R7B , R 7000A , R 7000B , r’, m’, o’, p’, q’ and t’ are as described in any of the previous embodiments described herein.

[0231] In some embodiments, the secondary or tertiary amino moiety or R A is selected from the group consisting of -CH2NHSO2CH3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NHC(O)CH2CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, C(O)N(CH2CH2OCH3)2, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and the group consisting of.

[0232] In some embodiments, the secondary or tertiary amino moiety or R A is selected from the group consisting of and the group consisting of.

[0233] In some embodiments, a conventional mitochondrial uncoupler or R B is selected from the group consisting of the conventional mitochondrial uncouplers described herein. In some embodiments, a conventional mitochondrial uncoupler or R B is selected from the group consisting of the conventional mitochondrial uncouplers described in U.S. Patent No. 10,227,3158, U.S. Patent Application No. 15 / 527,808, and Childress, E.S. et al. (2018) J. Med. Chem., 61(11), 4641 - 4655.

[0234] In some embodiments, a conventional mitochondrial uncoupler or R B is selected from the group consisting of and the group consisting of.

[0235] In some embodiments, the secondary or tertiary amino moiety or R A ; a conventional mitochondrial uncoupler or R B; and the mitochondrial membrane maintains the uncoupling agent compound (R A ) u -R B as described in Table 7. Table 7 Treatment method

[0236] In some embodiments, a method of treating a mitochondria-related disorder or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to the embodiments described herein.

[0237] In some embodiments, the mitochondria-related disorder or condition 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-β activation, and abnormal fibrosis. In some embodiments, the mitochondria-related disorder or condition has one or more underlying causative factors selected from the group consisting of hyperglycemia, lipid accumulation, insulin resistance, altered cell metabolism, fibrosis, abnormal TGF-β activation, or abnormal cell proliferation.

[0238] In some embodiments, the mitochondria-related disorder or condition 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-β activation, and abnormal fibrosis. In some embodiments, the mitochondria-related disorder or condition has one or more underlying causative factors selected from the group consisting of hyperglycemia, lipid accumulation, insulin resistance, altered cell metabolism, fibrosis, abnormal TGF-β activation, or abnormal cell proliferation.

[0239] In some embodiments, the mitochondria-related disorder or condition is a metabolic disease, cancer, autoimmune disease, pulmonary fibrosis, dermatological disease, infectious disease, or neurodegenerative disease. In some embodiments, the mitochondria-related disorder or condition is a metabolic disease, cancer, and autoimmune disease, or an infectious disease.

[0240] In some embodiments, the mitochondrial-related disorder or disease is a metabolic disease. In 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.

[0241] In some embodiments, a method of treating a metabolic disease or disorder characterized by insulin resistance or abnormal lipid accumulation in a tissue, or a disease or disorder in which insulin resistance or abnormal lipid accumulation in a tissue is a symptom, or treating cancer or hyperplasia in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to the embodiments described herein. In some embodiments, the metabolic disease or disorder is type 2 diabetes, or a disease characterized by insulin resistance or hyperglycemia.

[0242] In some embodiments, the metabolic disease or disorder described in any of the embodiments herein is a complication caused by type 2 diabetes and is selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative diseases, atherosclerosis, hypertension, coronary heart disease, nephropathy, retinopathy, neuropathy, and diabetic heart failure. In some embodiments, the metabolic disease or disorder is obesity or obesity-related complications.

[0243] In some embodiments, the metabolic disease or disorder described in any of the embodiments herein is non-alcoholic fatty liver disease (NAFLD) and comprises 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 complications of alcoholic fatty liver disease include alcoholic hepatitis, cirrhosis, or a combination thereof.

[0244] In some embodiments, the metabolic disease or disorder is dyslipidemia, or a complication caused by dyslipidemia.

[0245] 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 derived from a primary tumor of another tissue type. In some embodiments, the metastatic site is selected from the group consisting of the liver, lung, and peritoneal cavity.

[0246] In some embodiments, the compounds of the embodiments described herein are administered in combination with a second agent while, before, or after administering the second agent for treating the above-mentioned disorder or disease. In some embodiments, the second agent is an anti-diabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, glinides, thiazolidinediones, α-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-nonalcoholic 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-dyslipidemia agent.

[0247] In some embodiments, the compounds of the embodiments described herein are administered in combination with a second anti-nonalcoholic fatty liver disease agent. In some embodiments, the compounds of the present invention are administered in combination with a second anti-alcoholic fatty liver disease agent. In some embodiments, the compounds of the present invention are administered in combination with a second anti-dyslipidemia agent.

[0248] In some embodiments, the compound can be administered in combination with a second anti-cancer agent or anti-cancer regimen. In some embodiments, the second anti-cancer agent is an immuno-oncology agent. In some embodiments, the immuno-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 can be administered before, simultaneously with, or after administering the second anti-metabolic disease or anti-cancer agent.

[0249] In some embodiments, the subject is a mammalian animal. In some embodiments, the subject is a human. In some embodiments, the compounds described herein are used as veterinary drugs for treating diabetes or diabetes-related diseases, and the subject is a mammal.

[0250] Some embodiments relate to methods for the long-term disease management of metabolic diseases or disorders, which include administering to a subject in need of such long-term management an effective amount of the compounds or pharmaceutical compositions described herein. In some embodiments, the methods for the long-term disease management of metabolic diseases or disorders or for the long-term disease management of cancer include 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 tumor or metastatic tumor.

[0251] In some embodiments, the present disclosure describes the use of a compound according to any of the embodiments described herein in the preparation of a medicament for treating diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, or a disease or related disorder or complication characterized by insulin resistance or abnormal lipid accumulation in tissues (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 can be used to manufacture a medicament for treating cancer, a disease characterized by cell proliferation (hyperplasia), or a cancer- or hyperplasia-related complication.

[0252] Some embodiments herein relate to a method of treating or preventing a metabolic disease or disorder in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0253] Some embodiments herein provide a method of treating and alleviating the symptoms of obesity (characterized by excessive lipid accumulation in adipocytes), prediabetes type 2 (characterized by insulin resistance usually caused by ectopic lipid accumulation in liver and muscle cells), diabetes type 2 (characterized by insulin resistance and hyperglycemia), non-alcoholic fatty liver disease or alcoholic fatty liver disease (characterized by abnormal lipid accumulation in the liver), dyslipidemia (characterized by abnormal lipid deposition in tissues other than fat), and one or more complications of the above metabolic diseases (including but not limited to hypertension, cardiovascular disease, kidney disease, and neuropathy), which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. These diseases or conditions can be caused by dietary, environmental, medical, and / or genetic factors. The methods described herein can also be used to prevent the above metabolic diseases in subjects having risk factors, including but not limited to dietary, environmental, medical, and genetic susceptibilities. In addition, some embodiments provide a method for long-term chronic disease management and lifespan management by reducing insulin resistance or reducing blood glucose levels.

[0254] In some embodiments, the metabolic disease or disorder is diabetes type 2, or a related disease leading to insulin resistance or hyperglycemia. In some embodiments, the metabolic disease or disorder is obesity or one or more obesity-related complications.

[0255] 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).

[0256] In some embodiments, the metabolic disease or disorder is one or more complications of type 2 diabetes, including but not limited to hypertension, cardiovascular disease, kidney disease, atherosclerosis, dyslipidemia, retinopathy, neurodegenerative diseases, diabetic heart failure, and neuropathy caused by type 2 diabetes. In some embodiments, the metabolic disease or disorder is type 2 diabetes. In some embodiments, the metabolic disease or disorder is dyslipidemia.

[0257] In some embodiments, the disease to be treated can be a mitochondrial disorder. In some embodiments, the metabolic disorder can be LHON (Leber hereditary optic neuropathy), MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy and ragged-red fibers), Leigh syndrome, MILS (maternally inherited Leigh syndrome), NARP (neurogenic weakness, ataxia, and retinitis pigmentosa), FBSN (familial bilateral striatal necrosis), or KSS (Kearns Sayre syndrome).

[0258] Some embodiments relate 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 primary cancer or metastatic cancer. In some embodiments, the cancer is primary cancer, including but not limited to hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, lung cancer. In some embodiments, the cancer is metastatic liver cancer originating from a primary tumor of other tissue types. In some embodiments, the cancer is metastatic lung cancer originating from a primary tumor of other tissue types. In some embodiments, the cancer is metastatic cancer that has metastasized to other sites including the peritoneal cavity.

[0259] Some embodiments relate to methods of treating or preventing autoimmune diseases 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.

[0260] Some embodiments relate to methods of treating or preventing dermatological diseases 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 dermatological disease is eczema, dyshidrosis, seborrheic eczema, psoriasis, rosacea dermatitis, and atopic dermatitis.

[0261] Some embodiments relate to methods of treating or preventing an infectious disease of a non-viral parasite in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. 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, coronavirus infection, and Ebola virus infection.

[0262] In some embodiments, the disease to be treated can be a cardiac disorder, which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the cardiac disease can be hypertension or cardiovascular disease. In some embodiments, the disease to be treated can be a central nervous system (CNS) disease. In some embodiments, the CNS disease can be stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, or ALS (amyotrophic lateral sclerosis).

[0263] In some embodiments, the disease to be treated can be a condition associated with increased production of ROS (reactive oxygen species), which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. Increased ROS is associated with aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), mitochondrial diseases, and various cancers.

[0264] 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 implantation), by inhalation spray, eye, nose, vagina, rectum, sublingual, or topical administration routes, and can be formulated singly or together in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route. The compounds and pharmaceutical compositions described herein can also be formulated as controlled-release formulations.

[0265] The compounds described herein can be administered topically and can be formulated into a variety of topically administrable pharmaceutical compositions, which comprise an active ingredient and a dermatologically acceptable matrix and / or an ophthalmically acceptable matrix. Such pharmaceutical compositions can be formulated, for example, as solutions, suspensions, sprays, lotions, gels, pastes, medicated sticks, balms, shampoos, soap bars, liquid soaps, creams, or ointments. In one embodiment, the pharmaceutical composition is in the form of an ointment that can be administered in or around the eyes of a mammal, including a human.

[0266] In some embodiments, dermatologically and / or ophthalmologically acceptable matrices include pharmaceutically acceptable ointment bases. Examples of suitable ointment bases include, but are not limited to, oleaginous 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 beeswax, yellow beeswax, carnauba wax, wool wax (lanolin), mineral oil, olive oil, purified 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.

[0267] In some embodiments, dermatologically and / or ophthalmologically acceptable matrices include one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers such as cellulose polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Dermatologically and / or ophthalmologically acceptable matrices may also include dermatologically and / or ophthalmologically acceptable mucoadhesive polymers such as carboxymethylcellulose, carbomer (acrylic polymer), carbopol (copolymer cross-linked with polyalkenyl polyether or acrylic acid), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, or dextran.

[0268] In some embodiments, dermatologically and / or ophthalmologically acceptable matrices include one or more viscosity promoters. Examples of suitable viscosity promoters 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, gum arabic, chitosan, gum acacia, corn starch, gelatin, or combinations thereof.

[0269] In some embodiments, dermatologically and / or ophthalmologically acceptable matrices include one or more dermatologically and / or ophthalmologically acceptable pH regulators or buffers, 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 tromethamine; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within a dermatologically and / or ophthalmologically acceptable range.

[0270] In some embodiments, a dermatologically and / or ophthalmologically acceptable matrix includes one or more dermatologically and / or ophthalmologically acceptable salts in an amount that renders the osmolality of the composition within a dermatologically and / or ophthalmologically acceptable range. Such salts include, but are not limited to, salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; specific salts include, for example, sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0271] In some embodiments, a dermatologically and / or ophthalmologically acceptable matrix includes one or more dermatologically and / or ophthalmologically acceptable preservatives that inhibit microbial activity. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercuric borate (merfen) and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0272] In additional embodiments, a dermatologically and / or ophthalmologically acceptable matrix includes one or more dermatologically and / or ophthalmologically acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include isocetane, cyclomethicone, copolymers of ethylene glycol and propylene glycol, polyoxyethylene fatty acid glycerides, and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene ether alkyl ethers and alkyl phenyl ethers such as octoxynol 10, octoxynol 40.

[0273] In additional embodiments, a dermatologically and / or ophthalmologically acceptable matrix includes one or more dermatologically and / or ophthalmologically acceptable penetration enhancers to enhance physical stability or for other purposes. A penetration enhancer is a substance that enhances the passage of a topically applied compound through the stratum corneum of the skin, through the stratum corneum and into the epidermis and dermis. Examples include, but are not limited to, isosorbide dimethyl ester, ethoxydiglycol, 1-dodecylazacycloheptan-2-one, propylene glycol, oleyl alcohol, polyoxyethylene esters, sorbitan mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) and its derivatives, ethanol, glycerol monoethyl ether, monoglycerides, isopropyl myristate, lauryl alcohol, lauric acid, lauryl lactate, terpineol, menthol, D-limonene, β-cyclodextrin, DMSO (dimethyl sulfoxide), polysorbates, fatty acids (such as oleic acid), bile salts, N-methylpyrrolidone, glycosylated glycerides, 1-dodecylazacycloheptan-2-one Cyclopentadecanolide (CPE-215), alkyl-2-(N,N-disubstituted amino)-alkanoates 2-(n-nonyl)-1,3-dioxolane and penetration enhancers, such as those shown in U.S. Patent 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 hereby expressly incorporated by reference in its entirety.

[0274] In additional embodiments, the dermatologically and / or ophthalmologically acceptable matrix includes one or more dermatologically and / or ophthalmologically acceptable penetration enhancers to enhance physical stability or for other purposes. A variety of classes of compounds can be used as suitable penetration enhancers according to the present invention. The first class includes fatty acids and their salts and esters, including glycerol monoesters, diesters, and triesters. Medium-chain length fatty acids, particularly C8 and C10 acids and their salts and esters, are particularly useful. Suitable specific examples include sodium caprylate, sodium caprate, glycerol esters (available from Abitec, Columbus, Ohio), glycerol esters (PEG-8 caprylic / capric glycerides, available from Gattefosse SAS, Saint Priest, Cedex, France), 44 / 14 (PEG-32 glyceryl laurate EP, available from Gattefosse), other glycerol esters and fatty acid esters, (BASF, Ludwigshafen, Germany), D-α-tocopheryl polyethylene glycol 1000 succinate, vegetable oils, polyoxyglycerol esters, and medium-chain glycerol monoesters and diesters.

[0275] An example of this class MCM L8 (glycerol monocaprylate) (available from Abitec, Columbus, Ohio) consists of glycerol monoesters and diesters of medium-chain fatty acids (primarily caprylic acid, some capric acid) and up to 7% free glycerol. It contains at least 44% α-monoglyceride (as caprylate).

[0276] Other examples of this class of enhancers include GATTEFOSSE Compositions 61A to 61H, which are proprietary to Gattefosse SAS but generally consist of mixtures containing one or more of medium-chain glycerol monoesters, diesters, or triesters, polysorbate derivatives, polyethylene glycol castor oil derivatives, polyethylene glycol derivatives including polyethylene glycol glycerol esters, polyethylene glycol ethers, vegetable oils, glycerol, and similar GRAS (Generally Recognized as Safe) lipid components. These components are part of individual commercial products, such as CAPRYOL TM 90, CAPRYOL TMPGMC, LAUROGLYCOL TM 90、 44 / 14, Plurol Oleique CC497, M1944CS (PEG-6 Almond Oil Ester), Transcutol HP, Peceol and Maisine 35-1, all of which are available from Gattefosse SAS.

[0277] Although not falling directly within this class, glycerol itself has been found to confer excellent permeability enhancement, particularly for neuraminidase inhibitors. This result was not expected as glycerol is not considered a penetration enhancer.

[0278] A second class of enhancers includes surfactants having a steroid structure, such as bile salts. Examples of suitable compounds include sodium cholate, sodium deoxycholate, glycocholate, glycochenodeoxycholate, taurocholate, taurodeoxycholate and steroid detergents / bile salts. Other surfactants may also be suitable penetration enhancers, including cationic, anionic and nonionic surfactants. Examples include polysorbate 80, cetyl dimethyl benzyl ammonium chloride, N-cetylpyridinium bromide, dodecyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, tetradecyl-β-D-maltoside, octyl glucoside, glycyrrhetinic acid, 3-(N,N-dimethylpalmitoylammonio) propane sulfonate and sodium lauryl sulfate.

[0279] Cyclodextrins can also be used as suitable enhancers. Examples include β-cyclodextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin and hydroxypropyl-γ-cyclodextrin.

[0280] A variety of other compounds can also be used as enhancers. Examples include sodium salicylate, ethylenediaminetetraacetic acid (EDTA), citric acid, chitosan and chitosan derivatives, N-trimethyl chitosan chloride, monocarboxymethyl chitosan, palmitoyl carnitine chloride, acyl carnitines, ethylene glycol tetraacetic acid (EGTA), 3-alkamino-2-alkoxypropyl-phosphocholine derivatives, alkanoylcholines, N-acetylated amino acids (based on α- and non-α amino acids), mucoadhesive polymers, phospholipids, piperine, 1-methylpiperazine, α-amino acids and mineral oil.

[0281] Accordingly, the penetration enhancer compounds can 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-trimethyl chitosan chloride, mono-carboxymethyl chitosan, palmitoyl carnitine chloride, acyl carnitine, ethylene glycol tetraacetic acid, 3-alkylamino-2-alkoxypropyl-phosphocholine derivatives, alkanoyl choline, N-acetylated amino acids, mucoadhesive polymers, phospholipids, piperine, 1-methyl piperazine, α-amino acids, and mineral oil.

[0282] The penetration enhancer and the polar agent can be mixed in any ratio as long as a therapeutically effective amount of the polar agent and a penetration enhancing amount of the penetration enhancer compound are provided. Enhancement of the dermal bioavailability of the topically applied polar agent can depend on the nature and concentration of the penetration enhancer compound of the formulation reagent. Accordingly, the desired therapeutic amount can be included in a single dosage form or divided into one or more doses intended for simultaneous or sequential administration.

[0283] The penetration enhancer acts relatively independently of the concentration of the polar agent. Different penetration enhancers can achieve optimal or maximal enhancement over a wide concentration range, depending on their specific inherent enhancing potential. Generally, the enhancer has a non-linear dose-response relationship between the concentration of the enhancer present and the increased absorption of the polar agent. The amount of the enhancer used in an oral dosage form with a polar agent is initially based on the enhancing properties observed in Caco-2 cell assays at different fixed enhancer concentrations. Based on these results, the effective in vivo amount of the enhancer compound for human formulations can be estimated, demonstrated, and optimized without undue experimentation using methods well known to those skilled in the art of formulation to achieve the desired in vivo pharmacokinetic profile.

[0284] In formulating the compositions of the present invention, it will be apparent to those skilled in the art of formulation that a more effective enhancer compound will require less of the polar agent to achieve the target pharmacokinetic profile compared to a less effective penetration enhancer. Taking these considerations and variations into account, the amount of the enhancer can be at least about 0.1 wt% of the total weight of the enhancer and the polar agent, more preferably at least about 50 wt%, and more preferably at least 70 wt% of the total weight of the enhancer and the polar agent. The amount is preferably at most 95 wt% of the total weight of the enhancer and the polar agent, more preferably at most 80 wt%, and more preferably at most 75 wt%. Accordingly, as shown in the examples, typical dosage forms can contain a wide range of concentrations of the enhancer compound, depending on the compound itself and its efficacy in enhancing the permeability of the polar agent after oral administration. Concentrations as low as 20% and as high as 0.001% by weight have been shown to be effective in enhancing the permeability of the polar agent.

[0285] In other embodiments, the dermatologically and / or ophthalmologically acceptable matrix includes one or more antioxidants to enhance chemical stability when needed. By way of example only, suitable antioxidants include butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherols. In certain embodiments, the antioxidant enhances chemical stability when needed.

[0286] In addition to those enumerated above, any other surfactant, humectant, gelling agent, preservative, coloring agent or pigment, antioxidant, free radical scavenger, emulsifier, wetting agent, pH adjuster, chelating agent, or other dermatologically acceptable excipients commonly known to those of ordinary skill in the art that can be used in topical compositions are considered to be useful in the compositions described herein. In addition, any non-toxic, inert, and effective topical carrier can be used to formulate the compositions described herein.

[0287] Well-known carriers for formulating other topical therapeutic compositions for human administration will be useful in these compositions. Examples of such components well-known to those skilled in the art are described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide”, U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, http: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm, the contents of which are incorporated herein by reference in their entirety. Examples of such useful pharmaceutically acceptable excipients, carriers, and diluents include distilled water, normal saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are those preferably used herein.

[0288] These additional other inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as 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 entirety.

[0289] The composition can be used immediately or stored for later use in any type of container known to those skilled in the art, such as a pouch, jar, bottle, tube, ampoule, and pre-filled syringe. Finally, the composition can be sterilized by any method known to those skilled in the art, such as gamma radiation.

[0290] The compounds and pharmaceutical compositions described herein can be administered at prophylactically effective dose levels to prevent the above-mentioned diseases and disorders, as well as other diseases and disorders characterized by insulin resistance or hyperglycemia.

[0291] The pharmaceutical compositions and compounds of the embodiments herein can be administered in a wide range of dosage forms, including, for example, solid dosage forms and liquid dosage forms. Solid dosage forms can include powders, tablets, pills, capsules, suppositories, or dispersible granules. The solid carrier can be one or more substances used as a diluent, flavor additive, solvent, lubricant, suspending agent, binder, preservative, tablet disintegrating substance, or encapsulating material. In powder form, the carrier can be a finely ground solid (including lactose, hydroxypropyl methylcellulose, 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, stiffener, gelatin, tragacanth, methylcellulose, and sodium carboxymethylcellulose.

[0292] Liquid dosage forms include, for example, solutions, suspensions, and emulsions. Also included are pharmaceutical compositions in solid form, which means they are converted to liquid form shortly before consumption. In addition to the active ingredient, these forms can also include artificial colors, flavors, stabilizers, buffers, natural or artificial sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0293] Solutions or mixtures can be administered directly to the nasal cavity using conventional means such as drops or sprays. The pharmaceutical composition can be produced in single or multi-dose forms. Multi-dose forms will include a dropper, pipette or nebulizer for delivering a predetermined volume of the pharmaceutical composition.

[0002] The pharmaceutical compositions and compounds of the embodiments herein can be provided in single-dose units containing a suitable amount of the active ingredient. The single dose can be provided in a package or as a kit including a measuring device such as a device for measuring an oral or injectable dose (i.e., a measuring cup, needle or syringe). The kit can also include other materials such as buffers, diluents, filters and package inserts with instructions for use. A label can be present on the kit to indicate that the pharmaceutical composition is for a particular therapy and can also indicate instructions for use.

[0294] If desired, the pharmaceutical compositions of the present invention can further comprise one or more additional active agents. Where appropriate, any active agent can be administered in the form of the compound itself and / or in the form of salts, polymorphs, esters, amides, prodrugs, derivatives, etc., provided that the salt, polymorph, ester, amide, prodrug or derivative is pharmaceutically suitable. Where appropriate, salts, esters, amides, prodrugs and other derivatives of the active agent can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and are described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For any active agent that can exist in enantiomeric forms, the active agent can be incorporated into the present pharmaceutical composition as a racemate or in an enantiomerically enriched form.

[0295] The dose of the one or more active compounds administered will depend on the condition being treated, the particular compound and other clinical factors such as the age, sex, weight and health status of the subject being treated, the route of administration of the one or more compounds and the type of pharmaceutical composition being administered (tablets, gel caps, capsules, solutions, suspensions, inhalants, aerosols, elixirs, lozenges, injections, patches, ointments, creams, etc.). It should be understood that the present disclosure applies to use in humans and animals. The amount of the compound or its active salt or derivative required for use in treatment will ultimately be determined by the attending physician or clinician.

[0296] As described above, the compounds of the present invention can be used for preventing, treating, controlling, ameliorating or reducing the risk of the diseases, disorders and conditions described herein. The dosage of the compound as the active ingredient in the pharmaceutical compositions of the present invention can vary so as to obtain a suitable dosage form. The active ingredient can be administered to a patient (animal and human) in need of such treatment in a dosage that will provide optimal pharmaceutical efficacy. The dosage selected depends on the desired therapeutic effect, the route of administration and the duration of treatment. The dosage will vary with the patient depending on the nature and severity of the disease, the patient's body weight, the particular diet followed by the patient, co-administered drugs, and other factors that will be recognized by those skilled in the art. Generally, a dosage level of from 0.001 to 100 mg / kg body weight per day is administered to a patient, such as a human and an elderly person. A therapeutically effective amount is generally from about 0.5 mg to 10 g per day, which can be administered in a single dose or multiple doses. In some embodiments, the therapeutically effective amount is between a lower limit 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 10000 mg; and an upper limit of 10000 mg, 9500 mg, 9000 mg, 8500 mg, 8000 mg, 7500 mg, 7000 mg, 6500 mg, 6000 mg, 5500 mg, 5000 mg, 4500 mg, 4000 mg, 3500 mg, 3000 mg, 2500 mg, 2000 mg, 1500 mg, 1000 mg, 500.0 mg, 100 mg, 10 mg and 0.5 mg. In some embodiments, the therapeutically effective amount will be from about 0.5 mg to 2500 mg / patient / day; in some embodiments from about 0.5 mg to 200 mg / patient / day; in some embodiments from about 0.5 mg to 500 mg / patient / day; in some embodiments from about 0.5 mg to 1000 mg / patient / day; and in still some other embodiments from about 5 mg to 50 mg / patient / day. The pharmaceutical compositions of the present invention can be provided in solid dosage forms, for example, containing from about 0.5 mg to 500 mg of the active ingredient, or containing from about 1 mg to 250 mg of the active ingredient. The pharmaceutical compositions can 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 the active ingredient.For oral administration, the composition can be provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000, and 2000 milligrams of the active ingredient, for symptom adjustment of the dose for the patient to be treated. The compound can be administered according to a regimen of 1 to 4 times per day, such as once, twice, three times, or four times a day. Definitions

[0297] Unless otherwise indicated, when used in this application, molecular terms have their common meanings.

[0298] Unless otherwise indicated, as used herein, "a / an" means "one or more" or "at least one". That is, the reference to any element of the present invention by the indefinite article "a" or "an" does not exclude the possibility of the presence of more than one element.

[0299] The term "acylamino" denotes a nitrogen radical adjacent to an acyl group.

[0300] As used herein, the term "alkyl" is intended to include 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 intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 and C 17 alkyl. Additionally, for example, "C1-C6 alkyl" or "C 1-6 alkyl" represents an alkyl group having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or at least one hydrogen is replaced by another chemical group. In some embodiments, one or more hydrogen atoms are replaced by a chemical group selected from hydroxy 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, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl). Examples of substituted alkyl groups include, but are not limited to, -CH2N(CH3)2, -CH2CH2N(CH3)2, and -CH2CH2CH2N(CH3)2.

[0301] "Alkenyl" is intended to include hydrocarbon chains having a straight-chain or branched-chain configuration with a specified number of carbon atoms and one or more, preferably one to three, carbon-carbon double bonds that can 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 alkenyls. The term "C 2-17 alkenyl" is intended to include C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , and C 17 alkenyls. Examples of alkenyls include, but are not limited to, vinyl, 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.

[0302] "Alkynyl" is intended to include hydrocarbon chains having a straight-chain or branched-chain configuration with one or more, preferably one to three, carbon-carbon triple bonds that can occur at any stable point along the chain. For example, "C2-C6 alkynyl" is intended to include C2, C3, C4, C5, and C6 alkynyls; for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0303] The term "alkoxy / alkoxy" or "alkyloxy / alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" or "C 1-6 alkoxy" (or alkoxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxys. Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy.

[0304] "Aryl" refers to monocyclic or polycyclic aromatic hydrocarbons, including, for example, thiazolyl, phenyl, and naphthyl. "C6-C 10 aryl" or "C 6-10 aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "C6-C 10 aryl", "C 6-10 aryl", or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups selected from -OH, -OCH3, -CI, -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.

[0305] As used herein, the term "benzyl" means a methyl group in which one hydrogen atom is replaced by a phenyl group, wherein the phenyl group may optionally be substituted with one to five, preferably one to three substituents independently selected from methyl, trifluoromethyl (-CF3), hydroxy (-OH), methoxy (-OCH3), halogen, cyano (-CN), nitro (-NO2), -CO2Me, -CO2Et, and -CO2H. Representative examples of benzyl include, but are not limited to, PhCH2-, 4-MeO-C6H4CH2-, 2,4,6-tri-methyl-C6H2CH2-, and 3,4-di-Cl-C6H3CH2-.

[0306] The term "carboxamido" denotes a carbonyl radical adjacent to an amino group.

[0307] As used herein, "compound" means any type of substance or agent that is commonly regarded as a drug or a candidate for use as a drug, as well as combinations and mixtures thereof. When referring to the compounds of the present invention, unless otherwise specified, the term "compound" is intended to cover not only the designated 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., where such modifications of the molecular entity are appropriate.

[0308] As used herein, "conventional mitochondrial uncouplers" describe mitochondrial uncouplers that have the property of increased OCR and decreased MMP, and the concentration of which is associated with increased OCR and dissipation of MMP.

[0309] As used herein, a "derivative" of a compound means a compound that can be prepared from another compound of similar structure in one or more steps. Non-limiting examples include substitution of H by alkyl, acyl, or amino.

[0310] 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 case of administering a compound in the form of a combination of, for example, multiple compounds, the amount of each compound when administered in combination with one or more other compounds may be different from the amount when the compound is administered alone. Thus, the effective amounts of the compounds in a combination are collectively referred to as the overall combination, although the actual amounts of each compound may vary. The term "more effective" means that the selected effect is alleviated to a greater extent by one treatment relative to a second treatment with which it is compared.

[0311] The terms "formula" and "structure" are used interchangeably herein.

[0312] The term "halo or halogen" refers to fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl and trichloromethyl.

[0313] As used herein, the term "heteroaryl" means a stable monocyclic and polycyclic aromatic hydrocarbon containing at least one heteroatom ring member (such as sulfur, oxygen or nitrogen). Heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, dihydroindolyl, benzodioxolanyl and benzodioxane. Unless otherwise specified, heteroaryl may be unsubstituted or substituted with 1-5 groups selected from -OH, -OCH3, -CI, -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. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→0 and S(O) p , where p is 0, 1 or 2).

[0314] The terms "heterocyclic group", "heterocycle" or "heterocyclic ring" are defined as a saturated or partially unsaturated ring containing one to four heteroatoms or hetero groups selected from O, N, NH, -N(R Z )-, -S(O)- or -S(O)2- in a monocyclic or fused heterocyclic system having 3 to 12 ring members, where R Z is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, optionally substituted heterocyclic group. In a preferred embodiment, the heterocyclic group is a ring system having 3 to 7 ring members. Examples of heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorpholinyl, tetrahydrofuryl and azabicyclo[3.2.1]octyl. Unless otherwise specified, heteroaryl may be unsubstituted or substituted with at least one group selected from oxo, cyano, hydroxy, alkoxy, acylamino, carboxyamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl.

[0315] As used herein, the term "infectious disease" refers to a bacterial or viral infection. Infectious diseases include infections caused by parasitic organisms. In some embodiments, the viral infection is an enveloped virus. Examples of enveloped viruses include SARS-CoV-2, coronaviruses, and Ebola virus.

[0316] The term "mitochondrial-related disorder or disease" is defined as a pathological condition caused by mitochondrial dysfunction, as 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), which are hereby incorporated by reference in their entirety. These disorders include, but are not limited to, inherited mitochondrial diseases, various types of cancer, autism, neurodegenerative diseases, neuromuscular diseases, immunological diseases, metabolic diseases, aging, and age-related non-communicable chronic diseases.

[0317] An "MMP-maintaining compound" or "mitochondrial membrane potential-maintaining compound" is defined as a mitochondrial uncoupler that effectively increases OCR without significantly reducing MMP.

[0318] The term "mitochondrial uncoupling", also known as "uncoupling", refers to the process by which protons enter the mitochondrial matrix through a pathway independent of ATP synthase, thereby decoupling nutrient oxidation from ATP production. This process can be pharmacologically induced by small molecule mitochondrial proton carriers, which directly transfer protons across the inner mitochondrial membrane into the matrix. The major energy-producing pathway in aerobic cells involves the oxidation of nutrients (including fats, carbohydrates, and amino acids) in the mitochondria, which promotes proton efflux from the mitochondrial matrix. This process generates a pH and electrochemical gradient across the inner mitochondrial membrane. Protons typically re-enter the mitochondrial matrix via ATP synthase, which results in ATP production. Protons can also re-enter the mitochondrial matrix via a pathway independent of ATP synthase, which "decouples" nutrient oxidation and proton efflux from ATP production.

[0319] The term "ophthalmologically acceptable" as used herein refers to those compounds, materials, pharmaceutical compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with the eyes of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0320] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, pharmaceutical compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0321] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali metal 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 salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as 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 hydroxyethanesulfonic acid.

[0322] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is given in Remington’s Pharmaceutical Sciences, 18 th Edition, Mack Publishing Company, Easton, PA, 1990, the disclosure of which is incorporated herein by reference.

[0323] As used herein, the term "pharmaceutically acceptable carrier" includes any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsion (e.g., oil / water or water / oil emulsion) and various types of wetting agents. The term also includes any pharmaceutical agent approved by the regulatory agencies of the federal government of the United States or listed in the United States Pharmacopeia for use in animals (including humans).

[0324] "Prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because in some cases they can be administered more readily than the parent drug. For example, they may be bioavailable by oral administration when the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug, or may exhibit increased palatability, or be more easily formulated.

[0325] 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, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals such as non-human primates, sheep, dogs, cats, cows, and horses are preferred. Preferred subjects include human patients in need of enhanced immune response. The methods are particularly applicable to treating human patients suffering from the diseases or disorders described herein.

[0326] The term "administration" and / or "administering" of a compound shall be understood to mean providing to an individual in need of treatment a compound or a prodrug thereof as described herein.

[0327] As used herein, the terms "treating" or "treatment" refer to administering a compound or agent to a subject suffering from a disorder or at risk of developing a disorder, with the aim of curing, alleviating, relieving, remedying, delaying the onset, preventing, or improving the disorder, the symptoms of the disorder, the disease state secondary to the disorder, or the susceptibility to the disorder. Examples

[0328] Methods for preparing the compounds of the invention such as those of formulae A, I, Ia, II, IIa, III, and IIIa, or for preparing intermediates useful for preparing compounds of formulae A, I, Ia, II, IIa, III, and IIIa or other formulae of the present disclosure are provided as further embodiments of the invention or are known in the art. While the following text may illustrate specific compounds and corresponding synthetic routes, it is not intended to limit the scope of the invention to such specific references or examples. Given practical and economic considerations, those skilled in the art can make various modifications, such as the source of the reagents and the specific conditions of the reactions.

[0329] Chemical Abbreviations: Example 1 5-Chloro-2-hydroxy-3-((methoxymethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (1)

[0330] 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 overnight at room temperature. After completion of the reaction, 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 HNMR (300 MHz, Chloroform-d) δ 7.72 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 4.73 (s, 2H), 4.64 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.40 (s, 3H).

[0331] 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 1N KOH solution. The resulting mixture was stirred overnight at 60 °C. After cooling the mixture to room temperature, the reaction was partitioned between ethyl acetate and 2% citric acid. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. To this residue was added HBTU (98 mg, 0.258 mmol), DMF (3 mL) and DIPEA (187 μL, 1.075 mmol). The mixture was stirred for 10 minutes, 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 h, the mixture was cooled to room temperature, and then separated between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2-hydroxy-3-((methoxymethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (37 mg, 39%) as a yellow solid. 11H 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] + The required value m / z 469.02, the measured value m / z 468.55. Example 2 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (2)

[0332] At room temperature, NBS (5.87 g, 33 mmol) was added 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). 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 the minimum amount of DCM. The solid was collected, washed with cold DCM, and dried in vacuo to give 3-bromo-5-chloro-2-methoxybenzoic acid as a white solid (8.00 g, 100%). 1 1H 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).

[0333] 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 CH3I (1.4 mL, 22.6 mmol). The mixture was stirred at room temperature for 24 h. Water was added and the mixture was 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 was removed in vacuo to give a pale yellow oil (6.18 g, 97%).

[0334] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc)₂ (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol) and tripotassium phosphate (1.9 g, 8.96 mmol) was refluxed overnight under N₂ in toluene (10 mL) and water (1 mL). After the reaction was cooled, 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 methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1 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).

[0335] To a flame dried flask was added a solution of NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl₄ (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 (236 mg, 87%) as a colorless oil. 1 ¹H NMR (300 MHz, cdcl₃) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0336] 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. 11H NMR (300 MHz, CDCl3) δ 10.02 (brs, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 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] + Calculated m / z 297.05, found m / z 296.6.

[0337] 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 min 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 h. 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 (34 mg, 30%) as a yellow powder. 1 1H NMR (300 MHz, acetone) δ 8.37 (s, 1H), 8.02 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 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] + Calculated m / z 483.04, found m / z 483.1. 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)

[0338] At room temperature, NBS (5.87 g, 33 mmol) was added 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). 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 the minimum amount of DCM. The solid was collected, washed with cold DCM, and dried in vacuo 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).

[0339] 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 CH3I (1.4 mL, 22.6 mmol). The mixture was stirred at room temperature for 24 h. Water was added and the mixture was 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 was removed in vacuo to give a pale yellow oil (6.18 g, 97%).

[0340] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (756 mg, 2.7 mmol), methylboronic acid (324 mg, 5.4 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tripotassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed under N2 overnight. After the reaction was cooled, 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 methyl 5-chloro-2-methoxy-3-methylbenzoate as a yellow oil (520 mg, 91%). 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).

[0341] To a flame-dried flask was added a solution of NBS (492 mg, 2.767 mmol), AIBN (57 mg, 0.346 mmol) and methyl 5-chloro-2-methoxy-3-methylbenzoate (495 mg, 2.306 mmol) in CCl4 (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 (588 mg, 87%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0342] At 0 °C, 2-methoxy-N-methylethan-1-amine (370 μL, 3.41 mmol) was added to a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (500 mg, 1.71 mmol) in THF (6 mL). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was partitioned between NaHCO3 and ethyl acetate. The aqueous layer was further extracted with ethyl acetate twice. 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 1H NMR (300 MHz, Chloroform-d) δ 7.67 (s, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.61 (s, 2H), 3.52 (t, J = 5.7 Hz, 2H), 3.34 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 2.29 (s, 3H). MS (ESI) [M+H] + Calculated m / z 302.12, found m / z 301.60.

[0343] 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 dioxane (2 mL) of 4N HCl was added to the residue. The mixture was stirred for an additional 10 minutes, then concentrated and dried under vacuum. To this residue was 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, then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (255 mg, 1.17 mmol) was added. The resulting reaction mixture was heated at 130 °C for 24 h. 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 gave 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (220 mg, 40%) as a yellow solid. 1 HNMR (300 MHz, Methanol-d4) δ 8.24 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.31 (s, 1H), 4.31 (s, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.44 (s, 3H), 3.35 (t, J = 6.0 Hz, 2H), 2.85 (s, 3H). MS (ESI) [M+H] + Calculated m / z 474.09, found m / z 473.55.

[0344] 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 4.0N HCl in dioxane (70 μL, 0.266 mmol). The mixture was stirred at room temperature for 20 min. The solvent was removed under reduced pressure, and the resulting residue was washed with ether to give 5-chloro-2-hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (135 mg, 100%) as a yellow solid. Example 4 5-Chloro-N-(2-bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (4)

[0345] 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), and then CH3I (0.56 mL, 8.99 mmol). The mixture was stirred at room temperature for 24 h. Water was added and the mixture was 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 was removed in vacuo to give methyl 5-chloro-2-methoxy-3-methylbenzoate (1.13 g, 63%) as a pale yellow oil. 1 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 2.7 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.21 (s, 3H).

[0346] At -78 °C, BBr3 (1.0 M in DCM, 2.25 mL) was added dropwise to a stirred solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (241 mg, 1.12 mmol) in anhydrous DCM (5 mL). After addition, the reaction was slowly warmed to room temperature and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was cooled in an ice bath and the reaction was quenched by adding MeOH and water. The mixture was separated between DCM and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give methyl 5-chloro-2-hydroxy-3-methylbenzoate (220 mg, 98%) as a pale yellow solid, which was used in the next step without further purification.

[0347] To a stirred solution of methyl 5-chloro-2-hydroxy-3-methylbenzoate (220 mg, 1.1 mmol) in anhydrous DCM (5 mL) were added pyridine (443 μL, 5.5 mmol), (Boc)2O (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. 11H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 2.7, 0.6 Hz, 1H), 7.40 (dd, J = 2.7, 0.7 Hz, 1H), 3.89 (s, 3H), 2.26 (s, 3H), 1.58 (s, 9H).

[0348] To a flame-dried flask was added a solution of NBS (205 mg, 1.156 mmol), AIBN (24 mg, 0.145 mmol) and 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 (220 mg, 62%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 1.58 (s, 9H).

[0349] 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 overnight at room temperature 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 1H NMR (300 MHz, CDCl3) δ 10.76 (s, 2H), 7.67 (d, J = 2.6 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 4.61 (s, 2H), 3.79 (dd, J = 5.9, 2.7 Hz, 2H), 3.72 (dd, J = 5.9, 2.8 Hz, 2H), 3.49 (s, 3H). MS (ESI) [M+Na] + Calculated m / z 283.03, found m / z 282.55.

[0350] 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)benzoic acid (65 mg, 0.249 mmol) was dissolved in THF (3.0 mL), and then a catalytic amount of DMF (1 drop) and oxalyl chloride (26 μL, 0.299 mmol) were added respectively. The reaction mixture was stirred at room temperature for 30 min 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 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide as a white solid (35 mg, 35%). 1 1H NMR (500 MHz, CDCl3) δ 10.25 (s, 1H), 10.20 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 8.8, 2.1 Hz, 1H), 7.36 (d, J = 2.6 Hz, 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] + Calculated m / z 460.03, found m / z 459.95. Example 5 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (5)

[0351] 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)benzoic acid (77 mg, 0.28 mmol, Example 2) was dissolved in DCM (3.0 mL), and then a catalytic amount of DMF (1 drop) and oxalyl chloride (40 μL, 0.34 mmol) were added respectively. The reaction mixture 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, then 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 as a white solid (27 mg, 34% yield). 1 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 2H), 7.34 (ddd, J = 8.8, 2.4, 0.8 Hz, 1H), 4.66 (s, 2H), 3.99 (s, 3H), 3.75–3.72 (m, 2H), 3.62 (dd, J = 3.9, 2.5 Hz, 2H), 3.41 (s, 3H). MS (ESI) [M+H] + Calculated m / z 491.07, found m / z 491.10.

[0352] 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 mixture, and the mixture was 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 as a yellow solid (13 mg, 50%). 11H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 2H), 7.34 (ddd, J = 8.8, 2.4, 0.8 Hz, 1H), 4.66 (s, 2H), 3.75–3.72 (m, 2H), 3.62 (dd, J = 3.9, 2.5 Hz, 2H), 3.41 (s, 3H). MS (ESI) [M+H] + Calculated m / z 477.05, found m / z 477.30. Example 6 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide (6)

[0353] 5-Chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (90 mg, 0.33 mmol, Example 2) was dissolved in DCM (3.0 mL), and then catalytic amounts of DMF (10 μL) and oxalyl chloride (34 μL, 0.39 mmol) were added respectively. The reaction mixture was stirred at room temperature for 30 minutes, concentrated in vacuo, and the residue of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride was redissolved in THF (3.0 mL). In another flask, 5-(trifluoromethyl)pyrazin-2-amine (54.0 mg, 0.33 mmol) was dissolved in THF (3.0 mL), and then NaH (16.0 mg, 0.439 mmol, 60% in mineral oil) was added. After the mixture was stirred for 10 minutes, it was added dropwise to the flask containing freshly prepared 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then 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 (32.0 mg, 23% yield) as a white solid. 1 1H NMR (300 MHz, CDCl3) δ 10.54 (s, 1H), 9.82 (d, J = 1.1 Hz, 1H), 8.67 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 2.8 Hz, 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]+ The required value of m / z is 420.10, and the measured value of m / z is 420.30.

[0354] 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 the mixture was 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-methoxy-3-((2-methoxyethoxy)methyl)-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide as a yellow solid (18 mg, 62%). 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] + The required value of m / z is 406.08, and the measured value of m / z is 406.20. Example 7 5-chloro-2-hydroxy-3-((2-hydroxyethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (7)

[0355] 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)2 (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tripotassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed under N2 overnight. After the reaction was cooled, saturated NH4Cl solution was added, and the mixture was 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 as a yellow oil (520 mg, 91%). 11H 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).

[0356] To a flame-dried flask was added a solution of NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and methyl 5-chloro-2-methoxy-3-methylbenzoate (201 mg, 0.93 mmol) in CCl4 (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 (236 mg, 87%) as a colorless oil. 1 1H NMR (300 MHz, cdcl3) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0357] 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 h 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 (100%) as a yellow oil. MS (ESI) [M-H] - Calculated m / z 315.10, found m / z 315.60.

[0358] 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 mixture was heated at 120 °C for 24 h. 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 HNMR(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] + Calculated m / z 503.10, found m / z 503.20.

[0359] 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 overnight at room temperature. The solvent was evaporated and the remaining residue was treated by flash column 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] + Calculated m / z 447.04, found m / z 447.10. Example 8 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (8)

[0360] To a flame-dried flask was added a solution of NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl4 (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 (236 mg, 87%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0361] To a solution of methyl 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 overnight at room temperature 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 1H NMR (300 MHz, CDCl3) δ 10.02 (brs, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 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] + Calculated m / z 297.05, found m / z 296.6.

[0362] 5-Chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (85 mg, 0.31 mmol) was dissolved in DCM (3.0 mL), and then a catalytic amount of DMF (1 drop) and oxalyl chloride (32 μL, 0.372 mmol) were added respectively. The reaction mixture 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, and then 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] + Calculated m / z 425.08, found m / z 425.10.

[0363] 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, 1 N HCl was added to the reaction mixture, and the mixture was 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 (300 MHz, acetone) δ 8.05 (s, 1H), 7.77 (dd, J = 8.4, 2.5 Hz, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.20 (t, J = 8.8 Hz, 1H), 4.79 (s, 2H), 3.83–3.72 (m, 4H), 3.47 (s, 3H). MS (ESI) [M+H] + Calculated m / z 411.06, found m / z 411.10. Example 9 5-Chloro-2-hydroxy-3-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (9)

[0364] To a flame-dried flask was added a solution of NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl4 (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 (236 mg, 87%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0365] 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) [M-H] - Calculated m / z 229.02, found m / z 229.40.

[0366] 5-Chloro-2-methoxy-3-(methoxymethyl)benzoic acid (217 mg, 0.94 mmol) was dissolved in DCM (5.0 mL), and then a catalytic amount of DMF (1 drop) and oxalyl chloride (97 μL, 1.13 mmol) were added respectively. The reaction mixture was stirred at room temperature for 30 min 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 h, and then 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-(methoxymethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (165 mg, 45%) as a yellow solid. MS (ESI) [M+H] + Calculated m / z 431.05, found m / z 431.10.

[0367] 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 mixture, and the mixture was 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 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 4.67 (s, 2H), 3.55 (s, 3H). MS (ESI) [M-H] - Calculated m / z 415.02, found m / z 415.40. 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)

[0368] 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), PdCl2(dpppf)-DCM (81 mg, 0.1 mmol), and 2M 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. 11H NMR (300 MHz, CDCl3) δ 8.74 (d, J = 40.1 Hz, 2H), 7.95 (d, J = 6.3 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.47 (brs, J = 17.7 Hz, 2H), 3.96 (s, 3H), 3.52 (s, 3H). MS (ESI) [M+H] + Calculated m / z 278.06, found m / z 278.20.

[0369] 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 overnight at room temperature. 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%) as a yellow solid, which was used in the next step without further purification. MS (ESI) [M+H] + Calculated m / z 264.04, found m / z 264.20.

[0370] 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 a catalytic amount of DMF (1 drop) and oxalyl chloride (52 μL, 0.60 mmol). The reaction mixture 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 and then 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-(pyridin-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (20 mg, 10%) as a yellow solid. 1 1H 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] +The required value of m / z is 464.05, and the measured value of m / z is 464.20.

[0371] At -78 °C, BBr3 (1.0 M in DCM, 129 μL) was added dropwise 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). After addition, the reaction was slowly warmed to room temperature and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was cooled in an ice bath and quenched by adding MeOH and water. The mixture was separated between DCM and water. The organic layer was washed with water and 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 as a yellow solid (12 mg, 63%). 1 1H 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] + The required value of m / z is 450.03, and the measured value of m / z is 450.10.

[0372] 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 min. The resulting precipitate was filtered and washed with 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] + The required value of m / z is 450.03, and the measured value of m / z is 450.10. 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)

[0373] 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 h. 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 1H NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 3.1 Hz, 1H), 3.98 (s, 4H), 3.94 (s, 4H).

[0374] 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), NaBH3CN (121 mg, 1.93 mmol), and acetic acid (138 μL, 2.41 mmol). The resulting mixture was stirred at room temperature overnight. Saturated NaHCO3 was added and the mixture was 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 (232 mg, 75% yield) as a yellow oil. MS (ESI) + Calculated m / z 328.20, found m / z 328.40.

[0375] 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 1 N KOH solution. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated and 4N HCl in dioxane (2 mL) was added to the residue. The mixture was stirred for an additional 10 minutes, then concentrated and dried under vacuum. To this residue was added HBTU (322 mg, 0.852 mmol), DMF (5 mL) and DIPEA (618 μL, 3.55 mmol). The mixture was stirred for 10 minutes, then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (154 mg, 0.71 mmol) was added. The resulting reaction mixture was heated at 120 °C for 24 h. 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-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 (300 MHz, acetone) δ 8.41 (s, 1H), 8.00–7.90 (m, 2H), 7.76 (dd, J = 8.5, 2.4 Hz, 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 = 11.4 Hz, 2H), 1.23 (d, J = 6.3 Hz, 6H). MS (ESI) [M+H] + Calculated m / z 500.10, found m / z 500.30.

[0376] 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 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] + Calculated m / z 500.10, found m / z 500.30. 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)

[0377] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (277 mg, 0.99 mmol, Example 2), 2-tributylstannylthiazole (346 μL, 1.1 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in dioxane (2 mL) was heated in a microwave under nitrogen to 150 °C 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 to give methyl 5-chloro-2-methoxy-3-(thiazol-2-yl)benzoate (237 mg, 85%) as a yellow solid. MS(ESI) [M+H] + Calculated m / z 284.01, found m / z 284.0.

[0378] 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. The mixture was stirred for an additional 10 minutes, then concentrated and dried under vacuum. To this residue was added HBTU (379 mg, 1.0 mmol), DMF (5 mL) and DIPEA (729 μL, 4.185 mmol). The mixture was stirred for 10 minutes, then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (182 mg, 0.837 mmol) was added. The resulting reaction mixture was heated at 120 °C for 24 h. 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-(thiazol-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (177 mg, 47%) as a yellow solid. 1 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 2.6 Hz, 1H), 8.07 (s, 1H), 7.88–7.74 (m, 3H), 7.62 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 3.4 Hz, 1H). [M+H] +Calculated value m / z 455.99, measured value m / z 456.2.

[0379] 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 (195 μL, 0.389 mmol) in ether. The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with ether to afford 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] + Calculated value m / z 455.99, measured value m / z 456.2. Example 13 5-Chloro-2-hydroxy-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide (13)

[0380] A mixture of 2-methyl-4-(trifluoromethyl)aniline (525 mg, 3 mmol), NH4SCN (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 afford 1-(2-methyl-4-(trifluoromethyl)phenyl)thiourea as a yellow solid (347 mg, 50%). MS (ESI) [M+H] + Calculated value m / z 235.05, measured value m / z 235.30.

[0381] At 0 °C, a solution of Br2 (76 μL, 1.48 mmol) in CHCl3 (2 mL) was added dropwise to a stirred solution of 1-(2-methyl-4-(trifluoromethyl)phenyl)thiourea (347 mg, 1.48 mmol) in CHCl3 (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 and collected, neutralized by adding 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 as a white solid (125 mg, 37%), which was used in the next step without further purification. MS(ESI)[M+H] + Calculated m / z 233.04, found m / z 233.20.

[0382] To a stirred solution of 4-methyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (97 mg, 0.418 mmol) and (Boc)2O (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 h. After the reaction was complete, ethyl acetate was added and the mixture was washed successively 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-(4-(methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate as a yellow solid (180 mg, 100%), which was used in the next step without further purification. MS(ESI)[M+H] + Calculated m / z433.14, found m / z 433.4.

[0383] A mixture of tert-butyl 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)carbamate as a yellow solid (210 mg, 98%). MS(ESI)[M+H] + Calculated m / z 511.05, found m / z 511.20.

[0384] To a stirred solution of N-(4-(bromomethyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-N-(tert-butoxycarbonyl)carbamic acid tert-butyl ester (210 mg, 0.411 mmol) in 2-methoxyethanol (8 mL) was added 1 N 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 afford 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] + Calculated m / z 407.13, found m / z 407.3.

[0385] 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 h. After completion of the reaction, the 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 afford 4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine (62 mg, 97%) as a pale yellow solid, which was used in the subsequent step without further purification. MS (ESI) [M+H] + Calculated m / z 307.07, found m / z 307.20.

[0386] 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)2 (24 mg, 0.11 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol), and tripotassium phosphate (1.9 g, 8.96 mmol) in toluene (10 mL) and water (1 mL) was refluxed overnight under N2. After the reaction was cooled, saturated NH4Cl solution was added and the mixture was 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 afford methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil. 1 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).

[0387] 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 1 N KOH solution. The resulting mixture was stirred overnight at room temperature. After completion of the reaction, 1 N HCl was added to the reaction mixture, and the mixture was 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.

[0388] 5-Chloro-2-methoxy-3-methylbenzoic acid (40 mg, 0.20 mmol) was dissolved in DCM (3.0 mL), and then a catalytic amount of DMF (1 drop) and oxalyl chloride (21 μL, 0.243 mmol) were added respectively. The reaction mixture 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, and then 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-N-(4-((2-methoxyethoxy)methyl)-6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3-methylbenzamide as a white solid (20 mg, 21%). MS (ESI) [M+H] + Calculated m / z 489.08, found m / z 489.20.

[0389] 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, 1 N HCl was added to the reaction mixture, and the mixture was 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 as a white solid (15 mg, 55%). 11H NMR (300 MHz, CDCl3) δ 7.95 (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] + Calculated m / z 475.06, found m / z 475.20. Example 14 5-Chloro-2-hydroxy-3-(tetrahydrofuran-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (14)

[0390] 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 a mixture of dioxane (3 mL) and water (1 mL) was irradiated under nitrogen at 100 °C in a microwave for 1 h. 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] + Calculated m / z 267.03, found m / z 267.20.

[0391] 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 h. 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] + Calculated m / z 237.1, found m / z 237.3.

[0392] 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 subjected to column separation to give methyl 5-chloro-2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (85 mg, 31%) as a colorless oil. 1 H NMR (300 MHz, cdcl3) δ 7.66–7.60 (m, 1H), 7.42 (d, J = 2.7 Hz, 1H), 4.11–4.03 (m, 2H), 3.90 (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] + Calculated m / z 271.07, found m / z 271.2.

[0393] To a stirred solution of methyl 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 overnight at room temperature. The solvent was evaporated and dioxane (1 mL) of 4N HCl was added to the residue. The mixture was stirred for an additional 10 minutes and then concentrated and dried under vacuum. To this residue was 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 mixture was heated at 120 °C for 24 h. 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-3-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (14 mg, 10%) as a white solid. 1 H NMR (400 MHz, acetone) δ 8.42 (s, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.5, 1.4 Hz, 1H), 7.47 (d, J = 2.6 Hz, 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] +The required value of m / z is 443.04, and the measured value of m / z is 443.3. Example 15 5-Chloro-2-hydroxy-3-(tetrahydrofuran-2-yl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (15)

[0394] 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 under microwave at 100 °C under nitrogen for 1 h. 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] + The required value of m / z is 267.03, and the measured value of m / z is 267.20.

[0395] 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 at room temperature under a hydrogen atmosphere for 6 h. The reaction mixture was filtered and the filtrate was concentrated. 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. 1 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 2.8 Hz, 1H), 7.62 (dd, J = 2.8, 0.6 Hz, 1H), 5.13 (t, J = 7.2 Hz, 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] + The required value of m / z is 271.07, and the measured value of m / z is 271.2.

[0396] 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 1 N KOH solution. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated and 1 mL of dioxane of 4 N HCl was added to the residue. The mixture was stirred for an additional 10 minutes and then concentrated and dried under vacuum. To this residue was 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 mixture was heated at 120 °C for 24 h. 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 (15 mg, 10%) as a white solid. 1 H NMR (500 MHz, acetone) δ 8.42 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 5.12 (t, J = 7.1 Hz, 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] + Calculated m / z 443.04, found m / z 443.3. 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)

[0397] To a flame-dried flask was added a solution of NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol), and methyl 5-chloro-2-methoxy-3-methylbenzoate (201 g, 0.93 mmol) in CCl4 (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 (236 mg, 87%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0398] At 0 °C, morpholine (78 μL, 0.90 mmol) was added to a stirred solution of methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate (132 mg, 0.45 mmol) in THF (4 mL), and the mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture 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 to give methyl 5-chloro-2-methoxy-3-(morpholinomethyl)benzoate (110 mg, 83%) as a colorless oil. 1 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.70 (t, 4H), 3.52 (s, 2H), 2.47 (t, J = 4.1 Hz, 4H). MS (ESI) [M+H] + Calculated m / z 300.10, found m / z 300.30.

[0399] 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 overnight at room temperature. The solvent was evaporated and 1 mL of dioxane of 4N HCl was added to the residue. The mixture was stirred for an additional 10 minutes and then concentrated and dried under vacuum. To this residue was 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 h. 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 methyl 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (75 mg, 43%) as a yellow solid. 1 1H NMR (400 MHz, dmso) δ 8.39 (s, 1H), 7.80 (dd, J = 9.5, 5.7 Hz, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.9 Hz, 1H), 4.23 (s, 2H), 3.81 (brs, 4H), 3.17 (brs, 4H). MS (ESI) [M+H] + Calculated m / z 472.07, found m / z 472.20.

[0400] To a stirred solution of methyl 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 20 μL of 4.0N HCl in dioxane (0.075 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with ether to give methyl 5-chloro-2-hydroxy-3-(morpholinomethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (100%). MS (ESI) [M+H] + Calculated m / z 472.07, found m / z 472.20. 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)

[0401] 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)Cl2 (40 mg, 0.05 mmol), and sodium carbonate (339 mg, 3.2 mmol) was refluxed overnight under N2 in dioxane (10 mL) and water (1 mL). After the reaction was cooled, saturated NH4Cl solution was added and the mixture was 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. 1 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 6.99 (dd, J = 17.7, 11.1 Hz, 1H), 5.79 (dd, J = 17.7, 0.8 Hz, 1H), 5.43 (dd, J = 11.1, 0.8 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H).

[0402] At 0 °C, 9-BBN (3.1 mL, 1.55 mmol, 0.5 M in THF) was added dropwise to a stirred solution of methyl 5-chloro-2-methoxy-3-vinylbenzoate (270 mg, 1.19 mmol). After addition was complete, the mixture was stirred at room temperature overnight. The reaction was cooled to 0 °C, 1 mL of 50% H2O2 solution was added, followed by 1 mL of 3 M NaOH solution. The mixture was stirred on an ice bath for 2 h. The reaction 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-(2-hydroxyethyl)-2-methoxybenzoate (110 mg, 50%) as a colorless oil. 1 1H NMR (400 MHz, D2O) δ 7.65 (s, 1H), 7.37 (s, 1H), 3.90 (s, 3H), 3.85–3.78 (m, 5H), 2.88 (t, J = 6.3 Hz, 2H). MS (ESI) [M+H]+ The required value of m / z is 245.06, and the measured value of m / z is 245.20.

[0403] At 0 °C, TEA (95 μL, 0.677 mmol) and MsCl (42 μL, 0.54 mmol) were added to a stirred solution of methyl 5-chloro-3-(2-hydroxyethyl)-2-methoxybenzoate (110 mg, 0.451 mmol) in DCM (3 mL). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between DCM and saturated NH4Cl 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 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 4.41 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 2.93 (s, 3H).

[0404] Morpholine (160 μL, 1.84 mmol) was added 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). The resulting mixture was stirred at 80 °C overnight. The reaction mixture 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 give methyl 5-chloro-2-methoxy-3-(2-morpholinoethyl)benzoate (91 mg, 83%) as a yellow oil. 1 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 2.3 Hz, 1H), 7.35 (d, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 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] + The required value of m / z is 314.12, and the measured value of m / z is 314.20.

[0405] 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 overnight at room temperature. The solvent was evaporated and 1 mL of dioxane of 4N HCl was added to the residue. The mixture was stirred for an additional 10 minutes and then concentrated and dried under vacuum. To this residue was 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 mixture was heated at 120 °C for 24 h. 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 as a yellow solid (56 mg, 40%). 1 H NMR (300 MHz, acetone) δ 8.41–8.36 (m, 1H), 7.94–7.86 (m, 2H), 7.77–7.70 (m, 1H), 7.24 (d, J = 2.9 Hz, 1H), 4.04 (brs, 4H), 3.40–3.02 (m, 8H). MS (ESI) [M+H] + Calculated m / z 486.10, found m / z 486.20.

[0406] 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 mL) was added 4.0N HCl in dioxane (21 μL, 0.082 mmol). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with ether to give 5-chloro-2-hydroxy-3-(2-morpholinoethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (100%). MS (ESI) [M+H] + Calculated m / z 486.10, found m / z 486.20. Example 18 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2-hydroxybenzamide (18)

[0407] Methyl 3-bromo-5-chloro-2-methoxybenzoate (6.18 g, 22.07 mmol, Example 2), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (16.6 g, 66.21 mmol), Pd(dppf)Cl2 (968 mg, 1.32 mmol), and Cs2CO3 (21.5 g, 66.21 mmol) were added to a flask. The flask was evacuated and refilled with N2 three times. Subsequently, toluene (75 mL) and water (25 mL) were added to the flask under N2. The mixture was stirred overnight at 80 °C under N2. Saturated NH4Cl solution was added, and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column chromatography to afford methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-chloro-2-methoxybenzoate (1.51 g, 20% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.34 (brs, 2H), 2.82 (t, J = 6.9 Hz, 2H), 1.41 (s, 9H). MS (ESI) [M+Na]+ calcd for m / z 366.11, found m / z 365.95.

[0408] Methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-chloro-2-methoxybenzoate (1.12 g, 3.26 mmol) was dissolved in 4N HCl in dioxane (5 mL), and the resulting mixture was stirred at room temperature for 2 h. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM. The organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was filtered, and the solvent was removed in vacuo to afford methyl 3-(2-aminoethyl)-5-chloro-2-methoxybenzoate (475 mg, 60%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 2.92 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.1 Hz, 2H), 1.61 (s, 2H). MS (ESI) [M+H] + Calcd for m / z 244.08, found m / z 244.30.

[0409] To a stirred solution of methyl 3-(2-aminoethyl)-5-chloro-2-methoxybenzoate (100 mg, 0.411 mmol) in MeOH (3 mL) was added formaldehyde (122 μL, 1.64 mmol, 37% wt% in H2O), NaBH3CN (103 mg, 1.64 mmol), and acetic acid (117 μL, 2.06 mmol). The resulting mixture was stirred overnight at room temperature. Saturated NaHCO3 was added and the mixture was extracted twice with DCM. The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column chromatography to afford methyl 5-chloro-3-(2-(dimethylamino)ethyl)-2-methoxybenzoate as a yellow oil (88 mg, 82% yield). 1 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.34 (s, 6H). MS (ESI) [M+H] + Calculated m / z 272.10, found m / z 272.05.

[0410] To a stirred solution of methyl 5-chloro-3-(2-(dimethylamino)ethyl)-2-methoxybenzoate (82 mg, 0.3 mmol) in MeOH (3 mL) was added 1N KOH (1 mL) solution. The mixture was stirred overnight at room temperature. 1N HCl was added to adjust the pH to 1. The mixture was concentrated in vacuo. The residue was dissolved in DCM (3 mL), and then catalytic amounts of DMF (1 drop) and oxalyl chloride (32 μL, 0.36 mmol) were added respectively. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (157 μL, 0.90 mmol) and 2-chloro-4-(trifluoromethyl)aniline (42 μL, 0.30 mmol) were added. The mixture was stirred at room temperature for 48 h, and then silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to afford 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2-methoxybenzamide as a white solid (124 mg, 95%). 11H NMR (300 MHz, CDCl3) δ 10.61 (s, 1H), 8.85 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.71 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 3.92 (s, 3H), 3.04–2.79 (m, 2H), 2.77–2.49 (m, 2H), 2.42 (s, 6H). MS (ESI) [M+H] + Calculated m / z 435.09, found m / z 435.0.

[0411] At -78 °C, BBr3 (1.0 M in DCM, 0.635 mL) was added dropwise to a stirred solution of 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2-methoxybenzamide (69 mg, 0.16 mmol) in anhydrous DCM (5 mL). After addition, the reaction was slowly warmed to room temperature and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was cooled in an ice bath and quenched with MeOH and water. The mixture was separated between DCM and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2-hydroxybenzamide as a yellow solid (56 mg, 85%). 1 1H NMR (300 MHz, CDCl3) δ 12.50 (s, 1H), 8.96–8.83 (m, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.55 (dd, J = 8.7, 1.5 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 2.91 (s, 4H), 2.62 (s, 6H). MS (ESI) [M+H] + Calculated m / z 421.07, found m / z 421.20. Example 19 3-((4-Acetylpiperazin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (19) and 3-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (19A)

[0412] At 0 °C, 1-(piperazin-1-yl)ethan-1-one (225 mg, 1.754 mmol) was added to a stirred solution of methyl 3-(bromomethyl)-5-chloro-2-methoxybenzoate (257 mg, 0.88 mmol, Example 2) in THF (5 mL), and the mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture 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 afford methyl 3-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-methoxybenzoate (265 mg, 89%) as a colorless oil. 1 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.57–3.52 (m, 2H), 3.48 (s, 2H), 3.42–3.37 (m, 2H), 2.43–2.36 (m, 4H), 2.00 (s, 3H).

[0413] To a stirred solution of methyl 3-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-methoxybenzoate (265 mg, 0.78 mmol) in MeOH (5 mL) was added 4.0 mL of 1 N KOH solution. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and dioxane (2 mL) of 4 N HCl was added to the residue. The mixture was stirred for an additional 10 minutes and then concentrated and dried under vacuum. To this residue was added HBTU (356 mg, 0.94 mmol), DMF (5 mL), and DIPEA (680 μL, 3.9 mmol). The mixture was stirred for 10 minutes, and then 6-(trifluoromethyl)benzo[d]thiazol-2-amine (170 mg, 0.78 mmol) was added. The resulting reaction mixture was heated at 120 °C for 24 h. 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-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (101 mg, 30%) as a yellow solid. 11H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 2.6 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.26–7.20 (m, 1H), 3.57–3.52 (m, 2H), 3.48 (s, 2H), 3.42–3.37 (m, 2H), 2.43–2.36 (m, 4H), 2.00 (s, 3H). MS (ESI) [M+H] + Calculated m / z 513.10, found m / z 513.30.

[0414] To a stirred solution of 3-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (101 mg, 0.197 mmol) in THF (5 mL) was added 2N HCl (100 μL, 0.2 mmol) in ether. The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was filtered and washed with ether to afford 3-((4-acetylpiperazin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (100%) as a yellow solid. MS (ESI) [M+H] + Calculated m / z 513.10, found m / z 513.30. Example 20 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide (20) and 5- 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide hydrochloride (20A)

[0415] At 0 °C, POCl3 (167 mg, 1.09 mmol, 101.49 μL) was added to a solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (200 mg, 728.08 μmol, Example 2) and 6-(trifluoromethyl)pyridin-3-amine (118 mg, 728.08 μmol) in pyridine (2 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (3 mL) and extracted with DCM (3 mL × 3). The combined organic layers were washed with 5 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (prep-TLC) (SiO2, petroleum ether / ethyl acetate = 3:1) to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide as a white solid (117 mg, 212.32 μmol, 29.16% yield, 76% purity). MS (ESI) [M+H] + Calculated m / z 419.09, found m / z 419.2.

[0416] NaSEt (38 mg, 453.68 μmol) was added to a solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide (95 mg, 226.84 μmol) in DMF (2 mL), and the mixture was stirred at 160 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions) to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide as a brown solid (32.99 mg, 73.67 μmol, 32.48% yield, 98.537% purity, HCl). MS (ESI) [M+H] + Calculated m / z 405.08, found m / z 405.0. 1 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.93 (d, J = 2.19 Hz, 1H), 8.37 (dd, J = 8.33, 2.19 Hz, 1H), 7.90 (d, J = 2.19 Hz, 1H), 7.74 (d, J = 8.77 Hz, 1H), 7.52 (d, J = 2.63 Hz, 1H), 4.53 (s, 2H), 3.60 - 3.66 (m, 2H), 3.51 - 3.56 (m, 2H), 3.22 (dt, J = 3.29, 1.43 Hz, 3H). Example 21 5-Chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(2-(trifluoromethyl)pyrimidin-5-yl)benzamide (21)

[0417] Using a method similar to that of Example 20, 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-N-(2-(trifluoromethyl)pyrimidin-5-yl)benzamide was obtained. MS(ESI)[M+H] + Required value m / z 406.07, found m / z 406.0. 1 H NMR(400MHz, METHANOL-d4) δ ppm 9.35(s, 2H), 8.00(d, J = 2.43Hz, 1H), 7.64(s, 1H), 4.64(s, 2H) 3.73(dd, J = 5.62, 3.42Hz, 2H), 3.60 - 3.66(m, 2H), 3.40(s, 3H). Example 22 5-Chloro-2-hydroxy-3-(((2-methoxyethyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzoyl amine (22)

[0418] A solution of 5-chloro-2-hydroxybenzoic acid (10 g, 57.95 mmol) and 6,7,8,9-tetraazacyclodecane (16.2 g, 115.90 mmol) in TFA (100 mL) was stirred at 100 °C for 12 h, then cooled to 20 °C, and then HCl (100 mL, 3M) was added. The reaction mixture was stirred for an additional 1 h and then concentrated under reduced pressure. The white residue was suspended in water (50 mL). The solid was collected and dried under vacuum to obtain 5-chloro-3-formyl-2-hydroxybenzoic acid (6 g, crude) as a white solid. 1 H NMR(400MHz, DMSO-d6) δ ppm 10.30(s, 1H), 8.02(br d, J = 2.45Hz, 1H), 7.83(br d, J = 2.93Hz)

[0419] A mixture of 5-chloro-3-formyl-2-hydroxybenzoic acid (2 g, 9.97 mmol), 6-(trifluoromethyl)benzo[d]thiazol-2-amine (2.1 g, 9.97 mmol), EDCI (2.2 g, 11.97 mmol), and HOBt (2.0 g, 14.96 mmol) in DCM (20 mL) was heated at 50 °C for 8 h. The reaction mixture was concentrated to remove the solvent, then H2O (20 mL) was added and NaOH (3 M) was added until the pH was ~9 - 10. The reaction mixture was extracted with ethyl acetate (30 mL × 2), then concentrated to remove ethyl acetate. The residue was diluted with ethyl acetate (30 mL), the solid precipitated, filtered, and concentrated under reduced pressure to give 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (580 mg, 5.8% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.43 (s, 1H), 7.95 (d, J = 3.09 Hz, 1H), 7.86 (d, J = 8.38 Hz, 1H), 7.70 (br d, J = 8.60 Hz, 1H), 7.49 (d, J = 3.31 Hz, 1H). MS (ESI) [M+H] + Calculated m / z 400.99, found m / z 401.1.

[0420] To a solution of 2-methoxyethylamine (22 mg, 299.43 μmol) and 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (100 mg, 249.53 μmol) in MeOH (4 mL) was added acetic acid (3 mg, 49.91 μmol, 2.85 μL) to make the pH ~5 - 6. The mixture was stirred at 20 °C for 2 h, then NaBH3CN (94 mg, 1.50 mmol) was added. The mixture was stirred at 20 °C for another 10 h. The reaction mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC (HCl conditions) to give 5-chloro-2-hydroxy-3-(((2-methoxyethyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a brown solid (28.30 mg, 57.02 μmol, 22.85% yield, 100% purity, HCl). 11H NMR (400 MHz, methanol-d4) δ ppm 8.27 (s, 1H), 8.20 (d, J = 2.45 Hz, 1H), 7.74 - 7.82 (m, 2H), 7.63 (d, J = 2.45 Hz, 1H), 4.31 (s, 2H), 3.67 - 3.72 (m, 2H), 3.44 (s, 3H), 3.28 (d, J = 4.89 Hz, 2H). MS (ESI) [M+H] + Calculated m / z 460.06, found m / z 460.2. Example 23 5-Chloro-2-hydroxy-3-(pyrrolidin-1-ylmethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (23)

[0421] 5-Chloro-2-hydroxy-3-(pyrrolidin-1-ylmethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide was prepared in a similar manner as described in Example 22. MS (ESI) [M+H] + Calculated m / z 456.07, found m / z 456.2. 1 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 - 8.32 (m, 2H), 7.73 - 7.83 (m, 2H), 7.70 (s, 1H), 4.46 (s, 2H), 3.51 - 3.63 (m, 2H), 3.25 - 3.30 (m, 2H), 2.15 - 2.28 (m, 2H), 1.99 - 2.11 (m, 2H) Example 24 5-Chloro-2-hydroxy-3-(((2-(2-methoxyethoxy)ethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (24) and 5-chloro-2-hydroxy-3-(((2-(2-methoxyethoxy)ethyl)(methyl)amino)methyl)-N-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride (24A)

[0422] To a solution of 2-(2-methoxyethoxy)ethylamine (53 mg, 449.15 μmol, 44.21 μL) and 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (150 mg, 374.29 μmol) in toluene (3 mL) was added acetic acid (22 mg, 374.29 μmol, 21.41 μL) to pH ~5-6. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to remove the solvent, then MeOH (3 mL) and NaBH3CN (141 mg, 2.25 mmol) were added. The mixture was stirred at 20 °C for another 12 h, then (HCHO)n (101 mg, 1.12 mmol) was added, and the mixture was stirred at 20 °C for another 12 h. The reaction mixture was concentrated to remove the solvent. Then it was purified by preparative HPLC (HCl conditions) to give 5-chloro-2-hydroxy-3-(((2-(2-methoxyethoxy)ethyl)(methyl)amino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (55.74 mg, 100.01 μmol) as a white solid in 26.72% yield, 99.478% purity, HCl). MS (ESI) [M+H]+ calcd m / z 518.1, found m / z 518.2. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 8.20 - 8.30 (m, 2H), 7.74 - 7.83 (m, 2H), 7.71 (br d, J = 2.21 Hz, 1H), 4.62 (br d, J = 11.25 Hz, 1H), 4.35 (br d, J = 12.57 Hz, 1H), 3.90 (br d, J = 4.41 Hz, 2H), 3.67 - 3.75 (m, 2H), 3.58 - 3.65 (m, 2H), 3.51 (br s, 1H), 3.44 (br s, 1H), 3.41 (s, 3H), 2.92 (s, 3H). Example 25 3-((Bis(2-methoxyethyl)amino)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benz amide (25) and 3-((Bis(2-methoxyethyl)amino)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)benzamide hydrochloride (25A)

[0423] To a solution of bis(2-methoxyethyl)amine (40 mg, 299.43 μmol, 44.21 μL) and 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (100 mg, 249.53 μmol, Example 22) in toluene (3 mL) was added acetic acid (3 mg, 49.91 μmol, 2.85 μL) to pH ~5-6. The mixture was stirred at 75 °C for 12 h. The reaction mixture was concentrated to remove the solvent, then MeOH (3 mL) and NaBH3CN (94 mg, 1.5 mmol) were added. The mixture was stirred at 20 °C for an additional 5 h. The reaction mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC (HCl conditions) to afford 3-((bis(2-methoxyethyl)amino)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (98.93% purity, HCl) as a brown solid, 47.28 mg. MS (ESI) [M+H]+ calcd for m / z 518.1, found m / z 518.1. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 8.26 (s, 1H), 8.15 (d, J = 2.44 Hz, 1H), 7.73 - 7.80 (m, 2H), 7.56 (d, J = 2.45 Hz, 1H), 4.52 (s, 2H), 3.74 - 3.80 (m, 4H), 3.44 - 3.50 (m, 4H), 3.41 (s, 6H).

[0424] Compound 26-37 was prepared in a similar manner to compound 25 in Example 25: Example 26 5-Chloro-2-hydroxy-3-(piperidin-1-ylmethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (26)

[0425] MS (ESI) [M+H] + Calcd for m / z 470.08, found m / z 470.0. 11H NMR (400 MHz, METHANOL-d4) δ ppm 8.24 - 8.29 (m, 2H), 7.74 - 7.82 (m, 2H), 7.68 (d, J = 2.45 Hz, 1H), 4.36 (s, 2H), 3.46 - 3.59 (m, 2H), 3.02 - 3.18 (m, 2H), 1.96 (br d, J = 14.18 Hz, 2H), 1.77 (br d, J = 13.69 Hz, 3H), 1.56 (br s, 1H). Example 27 3-(azetidin-1-ylmethyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (27)

[0426] MS (ESI) [M+H] + Calculated m / z 442.85, found m / z 442.1. 1 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.28 (s, 1H) 8.24 (d, J = 2.65 Hz, 1H) 7.74 - 7.84 (m, 2H) 7.65 (d, J = 2.21 Hz, 1H) Example 28 5-chloro-2-hydroxy-3-((4-methylpiperazin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (28)

[0427] MS (ESI) [M+H] + Calculated m / z 485.09, found m / z 485.0. 1 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.27 (s, 1H), 8.25 (d, J = 2.93 Hz, 1H), 7.74 - 7.82 (m, 3H), 4.50 (s, 2H), 3.43 - 3.88 (m, 8H), 3.02 (s, 3H) Example 29 5-chloro-2-hydroxy-3-((3-oxopiperazin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (29)

[0428] MS (ESI) [M+H] +Calculated value m / z 485.06, measured value m / z 485.0. 1 H NMR(400MHz, METHANOL-d4) δ ppm 8.28 - 8.31(m, 2H), 7.76 - 7.84(m, 2H), 7.72(d, J=2.63Hz, 1H), 4.53(s, 2H), 3.95(s, 2H), 3.60(br s, 4H) Example 30 5-Chloro-2-hydroxy-3-((3-hydroxypyrrolidin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (30)

[0429] MS(ESI)[M + H] + Calculated value m / z 472.06, measured value m / z 472.0. 1 H NMR(400MHz, DMSO-d6) δ ppm 8.41(s, 1H), 8.05(d, J=2.87Hz, 1H), 7.70 - 7.85(m, 3H), 4.43(br d, J=2.20Hz, 1H), 4.39(s, 2H), 3.41 - 3.50(m, 2H), 3.32 - 3.40(m, 1H), 3.15. Example 31 5-Chloro-2-hydroxy-3-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (31)

[0430] MS(ESI)[M + H] + Calculated value m / z 486.08, measured value m / z 486.0. 1 H NMR(400MHz, METHANOL-d4) δ ppm 8.23(br d, J=16.63Hz, 2H), 7.77(q, J=8.64Hz, 2H), 7.69(s, 1H), 4.41 - 4.59(m, 2H), 3.47 - 3.87(m, 2H), 3.34 - 3.45(m, 1.5H), 3.22(d, J=11.74Hz, 0.5H), 1.97 - 2.30(m, 2H), 1.46(s, 3H). Example 32 5-Chloro-2-hydroxy-3-((3-methoxypyrrolidin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide amine (32)

[0431] MS(ESI)[M+H] + Calculated m / z 486.08, found m / z 486.1. 1 H NMR(400MHz,METHANOL-d4)δppm 8.19 - 8.28(m,2H),7.77(q,J=8.53Hz,2H),7.69(br s,1H),4.43 - 4.55(m,2H),4.16 - 4.24(m,1H),3.56 - 3.74(m,2H),3.32 - 3.50(m,5H),2.30 - 2.48(m,1H),2.06 - 2.21(m,1H). Example 33 3-((3-Acetamidopyrrolidin-1-yl)methyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (33)

[0432] MS(ESI)[M+H] + Calculated m / z 513.09, found m / z 513.0. 1H NMR(400MHz,DMSO-d6)δppm 8.45(s,1H)8.24(br d,J=5.07Hz,1H)8.11(d,J=2.65Hz,1H)7.84 - 7.91(m,2H)7.77 - 7.83(m,1H)4.44(s,2H)4.40(br d,J=6.39Hz,1H)3.47 - 3.63(m,2H)3.32 - 3.44(m,1H)3.18 - 3.27(m,1H)2.27 - 2.39(m,1H)1.89 - 2.01(m,1H)1.84(s,3H) Example 34 1-(5-Chloro-2-hydroxy-3-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamoyl)benzyl)pyrrolidine-2-carboxamide (34)

[0433] MS(ESI)[M+H] + Calculated m / z 499.07, found m / z 498.9.1 H NMR (400 MHz, METHANOL-d4) δ ppm 8.28 (s, 1H), 8.23 (d, J = 2.65 Hz, 1H), 7.74 - 7.84 (m, 2H), 7.67 (d, J = 2.43 Hz, 1H), 4.45 - 4.58 (m, 2H), 4.33 (dd, J = 9.37, 6.73 Hz, 1H), 3.73 (br s, 1H), 3.42 - 3.50 (m, 2H), 2.51 - 2.67 (m, 1H), 1.99 - 2.28 (m, 2H) Example (35) 5-Chloro-3-((1,1-dioxothiomorpholino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide Amine (35)

[0434] MS (ESI) [M + H] + Calculated m / z 520.03, found m / z 520.0. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 8.27 - 8.31 (m, 2H), 7.73 - 7.84 (m, 3H), 4.59 (s, 2H), 3.91 (br d, J = 5.73 Hz, 4H), 3.57 (br s, 4H) Example 36 5-Chloro-3-((3-cyanopyrrolidin-1-yl)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (36)

[0435] MS (ESI) [M + H] + Calculated m / z 481.06, found m / z 480.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (s, 1H) 7.78 - 7.86 (m, 2H) 7.69 (br d, J = 8.38 Hz, 1H) 7.38 (d, J = 2.87 Hz, 1H) 4.25 (br s, 2H) 3.62 (br s, 1H) 3.49 - 3.56 (m, 4H) 2.16 - 2.36 (m, 2H) Example 37 5-Chloro-2-hydroxy-3-((3-(methylsulfonyl)pyrrolidin-1-yl)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (37)

[0436] MS(ESI)[M+H] + Calculated m / z 534.05, found m / z 534.0. 1H NMR(400MHz, METHANOL-d4) δ ppm 8.22 - 8.30 (m, 2H), 7.74 - 7.84 (m, 2H), 7.70 (br d, J = 2.45Hz, 1H), 4.51 - 4.58 (m, 2H), 4.16 - 4.27 (m, 1H), 3.83 - 3.99 (m, 2H), 3.60 (br s, 2H), 3.10 (s, 3H), 2.50 - 2.69 (m, 2H) Example 38 (E)-5-Chloro-2-hydroxy-3-((hydroxyimino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (38)

[0437] To a solution of 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (100 mg, 249.53 μmol) in EtOH (3 mL) was added NH2OH·HCl (17.34 mg, 249.53 μmol) and Na2CO3 (52.89 mg, 499.05 μmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (basic conditions) to give the title compound (E)-5-chloro-2-hydroxy-3-((hydroxyimino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (30.95 mg, 70.19 μmol, 28.13% yield, 94.297% purity). 1 1H NMR(400MHz, METHANOL-d4) δ ppm 8.38 (br s, 1H), 8.30 (br s, 1H), 8.05 (br s, 1H), 7.87 (br s, 1H), 7.72 (br d, J = 16.63Hz, 2H). MS(ESI)[M+H] + Calculated m / z 416.00, found m / z 416.00. Example 39 (E)-5-Chloro-2-hydroxy-3-((methoxyimino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (39)

[0438] (E)-5-Chloro-2-hydroxy-3-((methoxyimino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide was prepared in a similar manner to compound 38. MS (ESI) [M+H]+ requires 430.02 m / z, found m / z 430.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (br s, 1H), 8.41 (br s, 1H), 8.01 (br s, 1H), 7.83 (br s, 2H), 7.76 (br d, J = 0.98 Hz, 1H), 3.94 (br s, 3H). Example 40 3-(Acetamidomethyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (40)

[0439] To a solution of (E)-5-chloro-2-hydroxy-3-((hydroxyimino)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (320 mg, 769.65 μmol, Example 40) in TFA (6 mL) was added Zn (251 mg, 3.85 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to remove the solvent. The residue was diluted with water (3 mL), adjusted to pH 9 with 2 M NaOH, and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(aminomethyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (300 mg, crude) as a white solid.

[0440] At 0 °C, 3-(aminomethyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (20 mg, 49.78 μmol) and TEA (6 mg, 59.73 μmol, 8.31 μL) were dissolved in DCM (3 mL). The solution was stirred and acetyl chloride (3 mg, 39.82 μmol, 2.84 μL) was added. The resulting solution was warmed to 20 °C and maintained for 30 minutes. The reaction mixture was quenched by adding MeOH (3 mL), and then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions) to give 3-(acetamidomethyl)-5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a white solid (14 mg, 99.660% purity). 1 H NMR (400 MHz, METHANOL-d4) δ ppm 8.28 (s, 1H), 8.03 (d, J = 2.45 Hz, 1H), 7.73 - 7.86 (m, 2H), 7.43 (s, 1H), 4.39 (s, 2H), 2.03 (s, 3H). MS (ESI) [M+H] + Calculated value m / z 444.03, found value m / z 444.0. Example 41 5-chloro-2-hydroxy-N 1 ,N 1 -bis(2-methoxyethyl)-N 3 -(6-(trifluoromethyl)benzo[d]thiazol-2-yl)phthalimide (41)

[0441] To a flame-dried flask was added a solution of NBS (2.99 g, 16.79 mmol), AIBN (173 mg, 1.05 mmol) and methyl 5-chloro-2-methoxy-3-methylbenzoate (1.13 g, 5.26 mmol) in CCl4 (20 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-(dibromomethyl)-2-methoxybenzoate as a yellow oil (1.59 g, 81%). 1 H NMR (300 MHz, cdcl3) δ 8.04 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.09 (s, 1H), 3.95 (s, 6H).

[0442] Methyl 5-chloro-3-(dibromomethyl)-2-methoxybenzoate (1.59 g, 4.27 mmol) was dissolved in 10 mL of concentrated sulfuric acid, and the mixture was stirred at room temperature for 2 h. 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 (673 mg, 71%) as a white solid. 1 1H NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 3.1 Hz, 1H), 3.98 (s, 4H), 3.94 (s, 4H).

[0443] To a stirred solution of methyl 5-chloro-3-formyl-2-methoxybenzoate (112 mg, 0.49 mmol) in acetone (3 mL) and water (3 mL) was added KMnO4 (310 mg, 1.96 mmol). The resulting mixture was stirred at room temperature for 3.5 h. After completion of the reaction as indicated by TLC, 0.8 g of sodium carbonate was added and the mixture was stirred for an additional 15 minutes. The mixture was then filtered and the pH of the filtrate was adjusted to 2 - 3 when a large amount of solid precipitated. The mixture was filtered and the solid was washed with water. The crude product was purified by recrystallization in ethanol to give 5-chloro-2-methoxy-3-(methoxycarbonyl)benzoic acid (90 mg, 76%) as a white solid. MS (ESI) [M+H] + Calculated m / z 245.02, found m / z 245.0.

[0444] 5-Chloro-2-methoxy-3-(methoxycarbonyl)benzoic acid (90 mg, 0.37 mmol) was dissolved in DCM (3.0 mL), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (38 μL, 0.44 mmol). The reactants were stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig's base (192 μL, 1.1 mmol) and bis(2-methoxyethyl)amine (55 μL, 0.37 mmol) were added. The mixture was stirred at room temperature for 48 h, then 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 methyl 3-(bis(2-methoxyethyl)carbamoyl)-5-chloro-2-methoxybenzoate (116 mg, 88%) as a colorless oil. 11H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 4.04 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.71–3.62 (m, 2H), 3.57–3.40 (m, 3H), 3.39 (s, 3H), 3.37–3.24 (m, 2H), 3.23 (s, 3H). MS (ESI) [M+H] + Calculated m / z 360.12, found m / z 360.10.

[0445] To a stirred solution of methyl 3-(bis(2-methoxyethyl)carbamoyl)-5-chloro-2-methoxybenzoate (116 mg, 0.323 mmol) in MeOH (3 mL) was added 2.0 mL of 1 N KOH solution. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1 N NaOH solution. The aqueous layer was acidified to pH = 1 and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to give 3-(bis(2-methoxyethyl)carbamoyl)-5-chloro-2-methoxybenzoic acid (115 mg, 100%) as a colorless oil, which was used in the next step without further purification. MS (ESI) [M+H] + Calculated m / z 346.11, found m / z 346.20.

[0446] 3-(Bis(2-methoxyethyl)carbamoyl)-5-chloro-2-methoxybenzoic acid (115 mg, 0.32 mmol) was dissolved in DCM (3.0 mL), and then catalytic amounts of DMF (1 drop) and oxalyl chloride (34 μL, 0.39 mmol) were added respectively. The reaction mixture 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 (170 μL, 0.98 mmol) and 6-(trifluoromethyl)benzo[d]thiazol-2-amine (71 mg, 0.32 mmol) were added. The mixture was stirred at room temperature for 48 hours, and then 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-N 1 ,N 1 -bis(2-methoxyethyl)-N 3 -(6-(trifluoromethyl)benzo[d]thiazol-2-yl) isophthalimide (95 mg, 58%). MS (ESI) [M+H] + Calculated m / z 546.11, found m / z 546.20.

[0447] 5-Chloro-2-methoxy-N 1 ,N 1 -bis(2-methoxyethyl)-N 3 -(6-(trifluoromethyl)benzo[d]thiazol-2-yl)phthalimide (95 mg, 0.174 mmol) in DMF (3 mL) was mixed with sodium ethanethiolate (74 mg, 0.872 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 the mixture was 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 1 ,N 1 -bis(2-methoxyethyl)-N 3 -(6-(trifluoromethyl)benzo[d]thiazol-2-yl)phthalimide (55 mg, 63%) as a yellow solid. 1 1H NMR (300 MHz, CDCl3) δ 8.18–7.95 (m, 5H), 3.71 (brs, 4H), 3.56 (brs, 4H), 2.95 (s, 3H), 2.87 (s, 3H). MS (ESI) [M+H] + Calcd m / z 532.09, found m / z 532.20. Example 42 5-Chloro-N-(6-(difluoromethyl)benzo[d]thiazol-2-yl)-2-hydroxy-3-((2-methoxyethoxy)methyl)benzamide (42)

[0448] At 0 °C, DIBAL-H (1 M, 53.99 mL) was added portionwise to a solution of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (3 g, 13.50 mmol) in THF (60 mL). The reaction mix...

Claims

1. A compound of formula A: wherein R of formula A 1000a is selected from the group consisting of -CH3, -CH2CH3, -C1-C6 alkyl, -C3-C6 cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, (CH2) r’ NR 5000A R 5000B 、-(CH2) r R 6000 and C(O)N(CH2CH2OCH3)2; Substituent R 5000A and R 5000B each independently is selected from the group consisting of -C1-C6 alkyl; and -C1-C6 alkyl substituted by one or more groups selected from -C1-C6 alkoxy and -O(CH2)2OCH3; or, R 5000A and R 5000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted by one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl; R 6000 selected from the group consisting of a 5- to 6-membered heterocyclic group, a pyridyl group, and a thiazolyl group; 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 chlorine, fluorine, iodine and bromine; R 4000b and R 4000d each independently selected from the group consisting of Y 1000 and Z 1000 provided that when R 4000b is Y 1000 then R 4000d is Z 1000 and when R 4000b is Z 1000 then R 4000d is Y 1000 ; Y 1000 selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano and -CO2(C1-C6) alkyl; Z 1000 selected from the group consisting of 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 and the group consisting of; R 2000A and R 2000B together with the nitrogen to which they are attached form a 4- to 8-membered heterocycle optionally substituted with one or more methyl groups; R 3000 is a 5- or 6-membered heterocycle; Ar 1 is a 5- to 6-membered aryl or heteroaryl optionally substituted by one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl, halogen, hydroxy and alkoxy; R 7000A and R 7000B 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- to 8-membered heterocyclic group optionally substituted with one or more substituents independently selected from C1-C6 alkyl; R 8000 selected from the group consisting of 5- to 6-membered heterocycles 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; provided that R 5000A and R 5000B are not all C1-C6 alkyl groups; and When Z 1000 is H, R 1000a is not a C1-C6 alkyl group, a -C3-C6 cycloalkyl group, CH3 or CH2CH3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. A compound of formula I: wherein: R 1a selected from the group consisting of -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) m’ NR 5A R 5B 、-(CH2) m R 6 and C(O)N(CH2CH2OCH3)2; R 5A and R 5B each independently is 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, R 5A and R 5B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl; R 6 is selected from the group consisting of 5- to 6-membered heterocyclic group, pyridyl 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 chlorine, fluorine, iodine and bromine; and R 4b and R 4d each independently is selected from the group consisting of Y and Z, provided that when R 4b is Y, R 4d is Z, and when R 4b is Z, R 4d is Y; Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z 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, -(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 an optionally 4- to 8-membered heterocycle substituted with one or more methyl groups; R 3 selected from the group consisting of a 5- to 6-membered heterocyclic group and a phenoxy group; n is an integer selected from the group consisting of 0, 1, 2, and 3; and Ar is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, and alkoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compound according to claim 2, wherein R 1a is selected from the group consisting of -CH3, -CH2CH3, and -CH2NR 5A R 5B and the group consisting thereof.

4. The compound according to claim 3, wherein R 5A and R 5B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 5A and R 5B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl.

5. The compound according to claim 2, wherein R 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, and the like.

6. The compound according to claim 2, wherein R 1c is chlorine.

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

8. The compound according to claim 2, wherein R 2A and R 2B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with methyl.

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

10. The compound according to claim 2, wherein R 3 is a 5-membered heterocycle.

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

12. The compound according to claim 2, wherein n is 0.

13. The compound according to claim 2, wherein -(CH2) n R 3 is 14. The compound according to claim 2, wherein Ar is selected from the group consisting of 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy.

15. The compound according to claim 14, wherein Ar is selected from the group consisting of phenyl, and the group consisting of.

16. The compound according to claim 2, wherein Y is CF3.

17. The compound according to claim 2, wherein Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B 、-(CH2) m R 3 , -CH2OCH2Ar, and OCH3; wherein R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of piperazinyl and 4-methylpiperazinyl; R 3 is a tetrahydrofuranyl group; and Ar is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy.

18. The compound according to claim 2, wherein R 4d selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and OCH3, and R 4b is selected from the group consisting of -CF3.

19. The compound according to claim 2, wherein R 1a selected from the group consisting of -CH3, -CH2CH3, and -CH2NR 5A R 5B ; R 5A and R 5B each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 5A and R 5B together with the nitrogen to which they are attached form a 4-8 membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 1c is chlorine; Y is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(C1-C6)alkyl; Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B 、-(CH2) m R 3 、-CH2OCH2Ar and OCH3; wherein R 2A and R 2B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of a piperazinyl group and a 4-methylpiperazinyl group; R 3 is a tetrahydrofuranyl group; Ar is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. The compound according to claim 2, wherein R 1a selected from the group consisting of -CH3, -CH2CH3 and -CH2NR 5A R 5B ; R 5A and R 5B each independently selected from C1-C6 alkyl substituted by one or more groups selected from methoxy; or, R 5A and R 5B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted by one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 1c is chlorine; Y is CF3; Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR 2A R 2B 、-(CH2) m R 3 、-CH2OCH2Ar and OCH3; R 2A and R 2B together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of a piperazinyl group or a 4-methylpiperazinyl group; R 3 is a tetrahydrofuranyl group; Ar is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, chlorine, hydroxy, and methoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

21. The compound according to claim 2, wherein R 1a selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, and R 1c is chlorine; Y is CF3; and Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and OCH3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

23. The compound of formula Ia according to claim 2 wherein R 1a is selected from the group consisting of -CH3, -CH2CH3, -(CH2)N(CH2CH2OCH3)2, and; R 4d 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, and -OCH3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

24. The compound according to claim 23, wherein R 4d selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and -OCH3.

25. The compound according to claim 2, which is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

26. The compound according to claim 25, which is its pharmaceutically acceptable salt, solvate or prodrug.

27. A compound of formula II: Wherein: R 10a selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH 2)o’ NR 50A R 50B 、-(CH2) o R 60 and C(O)N(CH2CH2OCH3)2; R 50A and R 50B each independently is 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, R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen, and acyl; R 60 selected from the group consisting of a 5- to 6-membered heterocyclic group, a pyridyl group, and a thiazolyl group; 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 selected from the group consisting of chlorine, fluorine, iodine and bromine; and R 40b and R 40d one of which is H, R 40b and R 40d and the other of which is selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluoro(C1-C6)alkyl, halo(C1-C6)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano and -CO2(C1-C6)alkyl; Provided that R 50A and R 50B are not both C1-C6 alkyl groups; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

28. The compound according to claim 27, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NR 50A R 50B 、-(CH2) o R 60 and C(O)N(CH2CH2OCH3)2.

29. The compound according to claim 27, wherein R 50A and R 50B are each independently selected from the group consisting of methyl; and C1-C6 alkyl substituted with one or more groups selected from methoxy and -O(CH2)2OCH3; or, R 50A and R 50B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group selected from the group consisting of azetidinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, 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 fluorine; 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; thiomorpholinyl 1,1-dioxide.

30. The compound according to claim 29, wherein -CH2NR 50A R 50B is selected from the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and the group consisting thereof.

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

32. The compound according to claim 27, wherein -(CH2)0R 60 is selected from the group consisting of the group consisting of 33. The compound according to claim 27, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and the group consisting of C(O)N(CH2CH2OCH3)2 34. The compound according to claim 27, wherein one of R 40b and R 40d is H, and the other of R 40b and R 40d is selected from the group consisting of fluorine, -CF3, -CHF2, and -OCF3.

35. The compound according to claim 34, wherein R 40d is H and R 40b is selected from the group consisting of fluorine, -CF3, -CHF2 and -OCF3.

36. The compound according to claim 27, wherein R 10a selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and -C(O)N(CH2CH2OCH3)2; R 10c selected from the group consisting of chlorine, fluorine, and iodine; and R 40d is H and R 40b is selected from the group consisting of fluorine, -CF3, -CHF2, and -OCF3; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

37. The compound according to claim 36, wherein R 10A is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and C(O)N(CH2CH2OCH3)2.

38. The compound according to claim 37, wherein R 10c is chlorine; and R 40b is -CF3.

39. The compound of formula IIa according to claim 27, wherein R 10a selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, a group consisting of and C(O)N(CH2CH2OCH3)2; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

40. The compound according to claim 39, wherein R 10a is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, and -C(O)N(CH2CH2OCH3)2.

41. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

42. The compound according to claim 41, which is selected from the group consisting of: its pharmaceutically acceptable salt, solvate or prodrug.

43. A compound of formula III: Wherein: R 100a selected from the group consisting of -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -(CH2)NHCO2CH3, -(CH2) p’ NR 500A R 500B 、(CH2) p R 600 and C(O)N(CH2CH2OCH3)2; R 500A and R 500B each independently is 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, R 500A and R 500B together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from the group consisting of oxo, cyano, hydroxy, alkoxy, acylamino, carboxylamino, -SO2CH3, -CF3, C1-C6 alkyl, halogen and acyl; R 600 selected from the group consisting of a 5- to 6-membered heterocyclic group, a pyridyl group, and a thiazolyl group; 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 selected from the group consisting of chlorine, fluorine, iodine, and bromine; R 400b and R 400d each independently selected from the group consisting of Y 1 and Z 1 provided that when R 400b is Y 1 then R 400d is Z 1 and when R 400b is Z 1 then R 400d is Y 1 ; Y 1 selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano and -CO2(C1-C6) alkyl; Z 1 selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2) q’ NR 7A R 7B and -(CH2) q R 8 and 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 heterocyclic group optionally substituted by one or more independently selected C1-C6 alkyl groups; R 8 selected from the group consisting of 5- to 6-membered heterocycles optionally substituted with methyl; q’ is an integer selected from the group consisting of 1, 2 and 3; and 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. The compound according to claim 43, wherein R 100a is selected from the group consisting of -CH3 and -CH2NR 500A R 500B and the group consisting thereof.

45. The compound according to claim 44, wherein R 500A and R 500B are each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents being independently selected from C1-C6 alkyl.

46. The compound according to claim 43, wherein R 100a is selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, and the like.

47. The compound according to claim 43, wherein R 100c is chlorine.

48. The compound according to claim 43, wherein R 400b is Y and R 400d is Z.

49. The compound according to claim 43, wherein R 7A and R 7B are each methyl; or, R 7A and R 7B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with methyl.

50. The compound according to claim 43, wherein R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl.

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

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

53. The compound according to claim 43, wherein q is 0.

54. The compound according to claim 43, wherein Z 1 is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 ; wherein R 7A and R 7B are each methyl; or R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and and R 8 is 4-methylpiperidinyl.

55. The compound according to claim 43, wherein Z 1 is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, and the like.

56. The compound according to claim 43, wherein Y 1 is CF3.

57. The compound according to claim 43, wherein Z 1 is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, ; and Y 1 is -CF3.

58. The compound according to claim 43, wherein: R 100a selected from the group consisting of -CH3 and -CH2NR 500A R 500B ; R 500A and R 500B each independently selected from C1-C6 alkyl substituted with one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted with one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 100c is chlorine; Y 1 selected from the group consisting of chlorine, fluorine, iodine, bromine, -CF3, -CHF2, fluorinated (C1-C6) alkyl, halogenated (C1-C6) alkyl, -OCF3, -SO2(C1-C6) alkyl, cyano and -CO2(C1-C6) alkyl; Z 1 selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 ; R 7A and R 7B are each methyl; or R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and R 8 is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

59. The compound according to claim 43, wherein: R 100a selected from the group consisting of -CH3 and -CH2NR 500A R 500B ; R 500A and R 500B each independently selected from C1-C6 alkyl substituted by one or more methoxy groups; or, R 500A and R 500B together with the nitrogen to which they are attached form a 6-membered heterocyclic group optionally substituted by one or more substituents, said one or more substituents independently selected from C1-C6 alkyl; R 100c is chlorine; Y 1 is -CF3; Z 1 selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR 7A R 7B and -(CH2) q R 8 ; R 7A and R 7B are each methyl; or R 7A and R 7B together with the nitrogen to which they are attached form a heterocyclic group selected from the group consisting of 4-methylpiperazinyl and morpholinyl; and R 8 is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

60. The compound according to claim 43, wherein R 100a selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, ; R 100c is chlorine; Y 1 is CF3; and Z 1 selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2N(CH3)2, and the group consisting of; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

61. The compound according to claim 60, wherein R 400b is Y 1 and R 400d is Z 1 .

62. The compound of formula IIIa according to claim 43, R 100a selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2, and; R 400d selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -CH2N(CH3)2, and the like; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

63. The compound according to claim 43, which is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

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

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

66. The method according to claim 65, wherein the mitochondrial - related disorder or condition has one or more underlying pathogenic 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 - β activation and abnormal fibrosis.

67. The method according to claim 65, wherein the mitochondrial-related disorder or condition has one or more potential 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-β activation, and abnormal fibrosis.

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

69. The method according to 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 lipid accumulation.

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

71. The method according to 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. The method according to 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 one or more complications caused by alcoholic fatty liver disease are selected from the group consisting of alcoholic hepatitis, cirrhosis, and combinations thereof.

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

74. The method according to 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. The method according to claim 68, wherein the cancer is a metastatic cancer derived from a primary tumor of other tissue types.

76. The method according to claim 68, wherein the pharmaceutical composition is administered in combination with a second agent indicating the metabolic disease.

77. The method according to claim 76, wherein the second agent is an anti-diabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors.

78. The method according to claim 76, wherein the second reagent is selected from the group consisting of anti-obesity agents, anti-nonalcoholic fatty liver disease agents, anti-nonalcoholic fatty liver disease agents, and anti-dyslipidemia agents.

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

80. The method according to claim 79, wherein the second anti-cancer agent is an immuno-oncology agent.

81. The method according to claim 80, wherein the immunoagent 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. The method according to claim 68, wherein the dermatological disease is selected from the group consisting of eczema, dyshidrosis, seborrheic eczema, psoriasis, rosacea, dermatitis, and atopic dermatitis.

83. The method according to claim 68, wherein the infectious disease is a bacterial infection.

84. The method according to claim 68, wherein the infectious disease is a viral infection.

85. The method according to claim 84, wherein the viral infection is selected from the group consisting of SARS-CoV-2 infection, coronavirus infection, and Ebola virus infection.

86. A method 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 thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 64.

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

88. 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 the composition of claim 64.

89. A method of treating or preventing a dermatological disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 64.

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

91. 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 the pharmaceutical composition according to claim 64.

92. 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 the pharmaceutical composition according to claim 64.

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

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

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

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

97. Use of a compound according to any one of claims 1 - 63 or a pharmaceutically acceptable salt or prodrug thereof in the preparation 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; or a disease or disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipids in tissues is a symptom; cancer; hyperplasia; or cancer - or hyperplasia - related complications; diabetes; obesity; non - alcoholic fatty liver disease; alcoholic fatty liver disease; dyslipidemia; dermatological diseases; or bacterial infections; or viral infections.

98. A method for preparing a mitochondrial membrane - retaining mitochondrial uncoupler, which comprises: (1). Identifying a conventional mitochondrial uncoupler; (2). Designing a compound that covalently links at least one secondary or tertiary amino moiety to the conventional mitochondrial uncoupler; and (3). Preparing the compound of step (2), wherein the compound is a mitochondrial membrane - retaining uncoupler compound.

99. A mitochondrial membrane - retaining uncoupler compound of the following formula: (R A ) u -R B ; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R A and R B are covalently linked; Each R A is independently a moiety containing a secondary or tertiary amine; u is an integer selected from the group consisting of 1 and 2; and R B Prior to covalent attachment to R A was a conventional mitochondrial uncoupler; Provided that the mitochondrial membrane maintaining uncoupling agent compound is not or a pharmaceutically acceptable salt, solvate or prodrug thereof.

100. The compound according to claim 97, wherein R A is selected from the group consisting of -CH2NHSO2CH3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -CH2NHC(O)CH2CH3, -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, -CH2N(CH3)(CH2)2O(CH2)2OCH3, C(O)N(CH2CH2OCH3)2, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, and the group consisting thereof.

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