Mitochondrial uncouplers for treatment of metabolic diseases and cancer

Abstract

The present application discloses a distinct class of mitochondrial uncoupling compounds as well as conventional mitochondrial uncoupling compounds with drastically improved pharmacokinetic properties, pharmaceutical compositions containing the compounds and / or the prodrugs and methods of using the compounds, prodrugs and pharmaceutical compositions in treating diseases related to mitochondrial dysfunctions or diseases benefiting from modulating mitochondrial activities, including diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), mitochondrial genetic diseases, neurodegenerative diseases, cancer, autoimmune diseases, and infectious diseases.

Description

MITOCHONDRIAL UNCOUPLERS FOR TREATMENT OF METABOLIC DISEASES AND CANCERCROSS REFERENCE TO RELATED APPLICATIONS(00011 This application claims priority to U.S. Provisional Application No. 63 / 374,927, filed on September 8, 2022, which is hereby incorporated by reference in its entirety.SUMMARY

[0002] The present disclosure relates to new mitochondrial uncoupling compounds that retain mitochondrial membrane potential as well as new mitochondrial uncoupling compounds with unexepctedly improved pharmacokinetic properties. Various embodiments described herein provide benzamide compounds, prodrugs of the compounds, pharmaceutical compositions containing the compounds and / or the prodrugs and methods of using the compounds, prodrugs and pharmaceutical compositions in the treatment of diseases related to metabolism including diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), Non- Alcoholic Steathohepatitis (NASH), cancer, autoimmune diseases, dyslipodemia, and infectious diseases.[0003| Some embodiments of the present disclosure are directed to a compound of Formula A:wherein R1000aof Formula A is selected from the group consisting of-CH3, -CH2CH3, -CI-CS alkyl, -C3-C6cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3,C(O)N(CH2CH2OCH3)2;SUBSTITUTE SHEET ( RULE 26 )each of substituents R5000AandR5000Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R5000Aand R5000Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R6000is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; r’ is an integer selected the group consisting of 1, 2 and 3; r is an integer selected from the group consisting of 0, 1, 2 and 3;Rloooc of Formula I is selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R4000band R4000dis independently selected from the group consisting of Y1000and Z1000, provided that when R4000bis Y1000, R4000dis z1000and when R4000bis z1000, R4000disyiooo.Y1000is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , - CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci- Ce)alkyl;Z1000is 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)2NR2000AR2000B, -(CH2)SR3000, -CI FOCI F Ar1, OCH3 CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2)t’NR7000AR7000B, and -(CH2)tR8000;R2OOOAanj R2000Bt|ienitrogen to which they are attached, form a 4 to 8- membered heterocyclic ring optionally substituted with one or more methyl groups;R3000is a 5 to 6-membered heterocyclic ring;Ar1is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl, halo, hydroxyl and alkoxy;-2-SUBSTITUTE SHEET ( RULE 26 )each of R7000Aand R7000Bis independently selected from Ci-Ce alkyl; alternatively, R7OOOAanj R7000BtOgetherwith the nitrogen to which they are attached, form a 4 to 8- membered heterocyclyl optionally substituted with one or more substituents independently selected from Ci-Ce alkyl;R8000is selected from the group consisting of a 5 to 6-membered heterocyclic ring 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; with the proviso thatR5000Aand R5000Bare not both Ci-Ce alkyl; and when Z1000is H; R1000ais not Ci- C6alkyl, -C3-C6cycloalkyl, CH3or CH2CH3;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0004] Some embodiments of the present disclosure are directed to a compound of Formula I:wherein:Rlais selected from the group consisting of -CH3, -CH2CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -(CH2)NH(CH2)2OCH3,SUBSTITUTE SHEET ( RULE 26 )each of R5AandR5Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R5Aand R5Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino, carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R6is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; m’ is an integer selected the group consisting of 1, 2 and 3; m is an integer selected the group consisting of 0, 1, 2 and 3;Rlcis selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R4band R4dis independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4bis Z, R4dis Y;Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl;Z is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3J-CH2O(CH2)2N(CH3)2J-CH2O(CH2)2NHSO2CH3J-(CH2)O(CH2)2NR2AR2B, -(CH2)nR3, -CH2OCH2Ar, and -OCH3;R2Aand R2Btogether with the nitrogen to which they are attached, form a 4 to 8- membered heterocyclic ring optionally substituted with one or more methyl groups;R3is selected from the group consisting of a 5 to 6-membered heterocyclic ring and phenoxy; n is an integer selected from the group consisting of 0 1, 2 and 3; and-4-SUBSTITUTE SHEET ( RULE 26 )Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from the group consisting of -Ci-Ce alkyl, halo, hydroxy, and alkoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof

[0005] Some embodiments of the present disclosure are directed to a compound of Formula II:wherein:R10ais selected from the group consisting of -OCH3, -CFFOCHa, -CH2OCH2OCH3,C(O)N(CH2CH2OCH3)2; each of R50AandR50Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R60is selected from the group consisting of 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; o’ is an integer selected from the group consisting of 1, 2 and 3; o is an integer selected from the group consisting of 0, 1, 2 and 3;R10cis selected from the group consisting of chloro, fluoro, iodo, and bromo; and-5-SUBSTITUTE SHEET ( RULE 26 )one of R40band R40dis H and the other of R40band R40dis selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl; with the proviso that R50Aand R50Bare not both Ci-Ce alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof100061 Some embodiments of the present disclosure are directed to a compound of Formula III:wherein:R100ais selected from the group consisting of -CH3, -OCH3, -CH2OCH3,each of R500Aand R500Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R500Aand R500Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl; R600is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; p’ is an integer selected the group consisting of 1, 2, and 3; p is an integer selected the group consisting of 0, 1, 2 and 3;SUBSTITUTE SHEET ( RULE 26 )R100cis selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R400band R400dis independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1;Y1is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl;Z1is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2)qNR7AR7B, and -(CH2)QR8; each ofR7AandR7Bis independently selected from Ci-Ce alkyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl;R8is selected from the group consisting of a 5 to 6-membered heterocyclic ring 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 a pharmaceutical composition comprising: a compound according to any embodiment described herein, or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier or diluent.10008] Some embodiments describe a method of treating a mitochondria-related condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments the mitochondria-related condition or disorder has and one or more underlying causal factors or symptoms selected from the group consisting of hyperglycemia, abnormal accumulation of lipid in cells, abnormal accumulation of lipid in tissues, abnormal lipid metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis. In some embodiments, the mitochondria-related condition or disorder is selected from the group consisting of a metabolic disease, cancer, an-7-SUBSTITUTE SHEET ( RULE 26 )autoimmune disease, pulmonary fibrosis, a dermatological disorder, an infectious disease, and a neurodegenerative disease.|0009] In some embodiments the metochondria-rel ted condition or disorder is a metabolic disease selected from the group consisting of type 2 diabetes, a disease characterized by insulin resistance or hyperglycemia; obesity or obesity related complications, and a disease characterized by abnormal lipid accumulation. In some embodiments the metabolic disease is a complication caused by type 2 diabetes, selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart diseases, 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 prognosis 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 is selected from the group consisting of alcoholic hepatitis, cirrhosis, and a combination thereof. In some embodiments the metabolic disease or disorder is dyslipidemia, or one or more complications caused by dyslipidemia. In some embodimets the pharmaceutical composition is administered in combination with a second agent indicated for the 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, meglit-inides, thiazolidinediones, alpha glucosidase inhibitors, GLP-1 agonists, DPP-4 inhibitors and SGLT2 inhibitors. In some embiodiments the second agent s selected from the group consisting of an anti-obesity agent, an anti- nonalcoholic fatty liver disease agent, an anti-nonalcoholic fatty liver disease agent and an anti-dyslipidemia agent.

[0010] In some embodiments the metochondria-related condition or disorder is a primary cancer selected from the group consisting of hepatocellular carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer. In some embodiments the cancer is a metastatic cancer originated from a primary tumor of other tissue types. In some mebodiments the pharmaceutical composition is administered in combination with a second anti-cancer agent or anti-cancer regimen. In some emodiments the second anti-cancer agent is an immunoncological agent. In some embodiments the immunocological agent is selected from-8-SUBSTITUTE SHEET ( RULE 26 )the group consisting of an antibody against PD-1 / PD-L1, an antibody against other immune check point proteins, CAR-T cells, and other therapeutic immune cells.10011] In some embodiments the metochondria-related condition or disorder is a dermatological disorder selected from eczema, dyshidrotic eczema, seborrheic eczema psoriasis, rosacea, dermatitis and atopic dermatitis.]0012| In some embodiments the metochondria-related condition or disorder is an infectious disease. In some embodiments the infectious disease is a bacterial infection. In some embodiments the infectious disease is viral infection. In some embodiments the viral infection is selected from SARS-CoV-2 infection, a corona viral infection, and Ebola viral infection.

[0013] Some embodiments describe a method of treating a metabolic disease or disorder characterized by hyperglycemia, or insulin resistance or by abnormal accumulation of lipid in tissue, a disease or a disorder in which hyperglycemia, or insulin resistance or abnormal accumulation of lipid in tissue is a symptom, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein.10014] Some embodiments describe a method of treating cancer or hyperplasia, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein.

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

[0016] . Some embodiments describe a method of treating or preventing autoimmune diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of oa pharmaceutical composition described herein.|0017] Some embodiments describe a method of treating or preventing a dermatological disorder, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

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

[0019] Some embodiments describe a method of treating or preventing a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.-9-SUBSTITUTE SHEET ( RULE 26 )[0020| Some embodiments describe a method of treating or preventing viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein

[0021] Some embodiments herein describe methods wherein the subject is a mammal or a human. In some embodiments, the subjet is a human.[0022| Some embodiments herein describe methods wherein the pharmaceutical composition is administered orally, intravenously, subcutaneously, intramuscularly, transdermally, intraperitoneally, or by other pharmacologically acceptable routes.

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

[0024] Some embodiments describe the use of a compound described herein in the manufacture of a medicament for treatment of a metabolic disease or disorder. In some embodiments, the metabolic disease or disorder may be selected from diabetes, obesity, nonalcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, a disease where hyperglycemia, or insulin resistance or abnormal lipid accumulation in tissue is a symptom, or related disorders or complications.

[0025] Some embodiments describe a method of preparing a mitochondrial membrane potential (MMP)-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 a conventional mitochondrial uncoupler; and3. 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 Formula:(RA)U-RB; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein RAand RBare covalently linked; each RAis independently a moiety containing a secondary or tertiary amine;-10-SUBSTITUTE SHEET ( RULE 26 )u is an integer selected from the group consisting of 1 and 2; andRBis a conventional mitochondrial uncoupler prior to being covalently linked to RA; provided the mitochondrial membrane-retaining uncoupler compound is notDESCRIPTION OF THE DRAWINGS

[0027] Figure 1 shows a schematic diagram illustrating the role of mitochondrial functions and dysfunctions in various diseases, including obesity, T2D (type 2 diabetes), NASH (non-alcoholic steatohepatitis), viral infection, cancer, cancer immune suppression (Cancer ME, cancer microenvironment), and neurodegenerative diseases. Mitochondrial uncoupling, by reducing metabolic output of metabolites and ROS, would help eliminate the causal factors of these diseases.

[0028] Figure 2 shows oxygen consumption rates (OCR) over time of two representative compounds. Compound 16 (Figure 2A) and Compound 69 (Figure 2B). Oligo represents oligomycin, Comp, A represents Compound 16, Comp, B represents compound 69, and Rot / A A represents Rotenone / Antimycin. The assay was performed with Seahorse XF-24 instrument. The compounds were injected into assay media in the order as indicated, Oligomycin at 2.5 pM; each of Comp. A and Comp.B at a concentration at 1.0 pM; Rotenone at 2.0 pM and Antimycin A at 2.0 pM.

[0029] Figure 3 shows the molecular mechanism of conventional mitochondrial uncoupling. Dissipating mitochondrial membrane potential is an intrinsic property for-11-SUBSTITUTE SHEET ( RULE 26 )conventional mitochondrial uncouplers. The mitochondrial outer membrane, inner membrane, electron transport complexes I- IV, ATP synthase, a chemical uncoupler (U-, UH), and mitochondrial matrix are shown as indicated. Conventional uncouplers are weak lipophilic weak acid localized in mitochondrial inner membrane (shown as the deprotonated form U" and protonated form UH). U" binds to a proton at the outer side of the mitochondrial inner membrane (protonation) and releases the proton into the mitochondrial matrix (deprotonated). As a result, the mitochondrial uncoupler catalyzes proton translocation across the inner membrane without ATP synthesis, leading to 'futile' oxidation of acetyl-CoA (an end metabolic product of lipid oxidation and glucose metabolism). As the MMP is established by the proton gradient across the mitochondrial inner membrane, conventional mitochondrial uncoupling is associated with a simultaneous MMP dissipation.(0030] Figure 4 shows the effect of a a representative conventional mitochondrial uncoupler, trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), on oxygen consumption rate and mitochondrial membrane potential. FCCP simultaneously increases oxygen consumption rate (Figure 4A) and dissipates mitochondrial membrane potential (Figure 4B). Figure 4A shows cellular oxygen consumption rates (OCR), determined by Seahorse OCR assay using C2C12 cells. The diamond in Figure 4A represents DMSO (vehicle treatment control), the triangle represents FCCP at 3.0 pM, the square represents FCCP at 6.0 pM, the X represents FCCP at 12.0 pM, the * represents FCCP at 18.0 pM, and the circle represents FCCP at 24 pM. Oligo is oligomycin 2.5 pM; AA isantimycin A 2 pM; Rot isrotenone 2 pM. Figure 4B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of FCCP at the indicated concentrations. The fluorescent intensity is indicative of MMP. FCCP has a ratio of CIO%TMRE / Cmin-OCR less than 3, where CIO%TMRE is the concentration leading to 10% MMP retention (or 90% MMP loss, measured by TMRE staining) and Cmin-ocR is the minimal concentration leading to OCR increase.

[0031] Figure 5 shows the effect of a representative MMP -retaining mitochondrial uncoupler, Compound 25 (#25), on oxygen consumption rate and mitochondrial membrane potential. Compound 25 effectively uncouples mitochondria (induces OCR, Figure 5 A) without reducing MMP (Figure 5B). Figure 5A shows cellular oxygen consumption rates determined by Seahorse OCR assay using C2C12 cells. The diamond in Figure 5A represents vehicle treatment control, the square represents Compound 25 (#25) at 1.0 pM, the triangle represents Compound 25 at 3.0 pM, the X represents Compound 25 at 6.0 pM, the *-12-SUBSTITUTE SHEET ( RULE 26 )represents Compound 25 at 9.0 pM, and the circle represents Compound 25 atl2.0 pM. Oligo, isoligomycin 2.5 pM; AA is antimycin A 2 pM; Rot isrotenone 2 pM. Figure 5B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of Compound 25(#25) at the indicated concentrations. The fluorescent intensity is indicative of MMP. Compound 25 represents the MMP -retaining uncouplers that do not cause observable MMP reduction while uncoupling mitochondria (with a ratio of CIO%TMRE I Cmin-ocR greater than 25).

[0032] Figure 6 shows the effect of Compound 64 (#64), on oxygen consumption rate (Figure 6A) and mitochondrial membrane potential (Figure 6B). Compound 64 increases OCR without drastically dissipating mitochondrial membrane potential. Figure 6A shows cellular oxygen consumption rates determined by Seahorse OCR assay using C2C12 cells at the indicated concentrations. The diamond in Figure 6A represents vehicle treatment control, the square represents Compound 64 (#64) at 0.3 pM, the triangle represents Compound 64 at 1.0 pM, the X represents Compound 64 at 2.0 pM, the * represents Compound 64 at 3.0 pM, and the circle represents Compound 64 at 4.0 pM. Oligo is oligomycin 2.5 pM; AA is antimycin A 2 pM; Rot is rotenone 2 pM. Figure 6B shows mitochondrial membrane potential (MMP) determined by fluorescence microscopy using two different dyes, tetramethylrhodamine ethyl ester (TMRE) staining and DilCl(5) staining, respectively, in the presence of Compound 64 (Comp #64) at the indicated concentrations. The fluorescent intensity is indicative of MMP. Compound 64 represents the MMP-retaining uncouplers that do not drastically reduce MMP while uncoupling mitochondria (with a ratio of CIO%TMRE / Cmin-ocR between 10 and 25).[00331 Figure 7 shows a schematic illustration of the mechanism of action of a conventional mitochondrial uncoupler (Figure 7A) and a proposed mechanism of action of an MMP-retaining uncoupler (Figure 7B), as well as diagrams and an example of how to convert a conventional uncoupler to an MMP-retaining uncoupler (Figure 7C-E). Figure 7A and Figure 7B show mitochondrial electron transport chain complexes I, II, III, IV, ATP synthase, as well as uncouplers (UH or U"). Conventional uncouplers allow proton translocation across the mitochondrial inner membrane, causing loss of MMP (Figure 7A). The presence of a positively charged side chain and the asymmetrical distribution of the MMP-retaining uncouplers 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 approach to create new MMP-retaining uncouplers by adding a positively charged side chain to a-13-SUBSTITUTE SHEET ( RULE 26 )conventional uncoupler (Figure 7C), for example, by adding a tertiary amine- (or secondary amine-) containing side chain to obtain an MMP -retaining uncoupler (Figure 7D), where N is nitrogen; and X and Y are optimally substituted side chains. Figure 7E shows an example of an MMP -retaining uncoupler, showing a conventional uncoupling component in the frame.

[0034] Figures 8A shows the acute lethal dose leading to the death of 50% of test animals (Acute LD50 or LD50) and the minimum efficacious dose (MED) of the conventional uncoupler DNP (US EP A, 2, 4-dinitrophenol. https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf, Figure 8A) and MMP -retaining uncouplers, Compound 64 (#64, Figure 8B) and Compound 25 (#25, Figure 8C). Compound 64 and Compound 25 exhibit drastically improved acute toxicity profiles over DNP. Acute toxicity tests were performed on C57B16 mice, male, 6 weeks old, n=6. Compounds 64 and 25 were prepared to a fine suspension in 0.5% CMC-Na / 1% Tween80 water solution. The tests were performed under fed condition, by oral gavage of 100-400 pL compound suspension according to the body weight to desired dosages (mg / kg). The mice were supplied with drinking water all through the testing time. Mouse behaviors were monitored every 15-30 minutes and LD50 were determined. MED was determined in diabetic and steatosis mouse models (Table 9).

[0035] Figures 9 shows the safety profile of Compound 64 (#64) compared to DNP. Figure 9A shows the NOAEL(no-observable-adverse-effect-level) / MED of DNP. https: / / www.atsdr.cdc.gov / ToxProfiles / tp64.pdf; (US EP A, 2, 4-dinitrophenol. https: / / www.epa.gov / sites / default / files / 2016-09 / documents / 2-4-dinitrophenol.pdf; and US CDC). Figure 9B shows the MED, intermediate NOAEL and NOAEL / MED of Compound 64 calculated by oral dosage. Figure 9C shows the MED, intermediate NOAEL and NOAEL / MED of Compound 64 over DNP calculated by Cmax (maximal blood concentration). Figure 9D shows the MED, intermediate NOAEL and NOAEL / MED of Compound 64 calculated byAUC (Area Under Curve). The Figures demonstrate that the MMP-retaining uncoupler, Compound 64 exhibits drastically improved short-term safety profiles over the conventional uncoupler DNP. A 10-day toxicology study in CD-I mice was performed to determine NOAEL of Compound 64, where animals (n=5) were administered once daily for 10 consecutive days. Clinical signs, body weights, food consumptions, rectal temperature, hematology, serum chemistry, plasma exposure, necropsies, tissue histopathology, were examined. MED was determined in diabetic and steatosis mouse models (Table 9)-14-SUBSTITUTE SHEET ( RULE 26 )

[0036] Figure 10 show the safety profile of Compound 25 (#25) Figure 10A shows the MED, intermediate NOAEL and NOAEL / MED of Compound 25 calculated by oral dosage. Figure 10B shows the MED, intermediate NOAEL and NOAEL / MED of Compound 25 over DNP calculated by Cmax (maximal blood concentration). Figure 10C shows the MED, intermediate NOAEL and NOAEL / MED of Compound 25 calculated byAUC (Area Under Curve). The Figures demonstrate that the MMP -retaining uncoupler, Compound 25 exhibits drastically improved short-term safety profiles over the conventional uncoupler DNP. A 10-day toxicology study in CD-I mice was performed to determine NOAEL of Compound 25, where animals (n=5) were administered once daily for 10 consecutive days. Clinical signs, body weights, food consumptions, rectal temperature, hematology, serum chemistry, plasma exposure, necropsies, tissue histopathology, were examined. 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 the blood glucose level of mice treated with vehicle and mice treated with Compound 25. Figure 1 IB is a graph of glycated hemoglobin A1C of mice treated with vehicle and mice treated with Compound 25. Figure 11C is a graph of the blood glucose level of mice treated with vehicle and mice treated with Compound 64. Figure 1 ID is a graph of glycated hemoglobin A1C of mice treated with vehicle and mice treated with Compound 64. BKS db / db mice were treated with or without 5mg / kg Compound 25 or Compound64 by daily oral gavage, for 3 weeks. Blood glucose and glycated hemoglobin A1C levels were measured. Statistical significance (P) was determined by the Student’s t- test. All error bars, s.d., ***p < 0.001. n=6 in each group. 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 HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by the Student’s t-test. All error bars, s.d., *p < 0.05, ***p < 0.001. n=6 in each group. #25: mice treated with Compound 25 (5mg / kg / day, daily gavage) for three weeks. Vehicle, vehicle-treated control group. Figure 12 A-B, Light bars, initial levels; dark 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 HFD-induced diabetic / fatty liver mouse model (n=6 in each group). Statistical significance (P) was determined by the Student’ s t-test.-15-SUBSTITUTE SHEET ( RULE 26 )All error bars, s.d., *p < 0.05, ***p < 0.001. n=6 in each group. #64: mice treated with Compound 64 (5mg / kg / day, daily gavage) for two weeks. Vehicle, vehicle-treated control group. Figure 13 A, Dark bars, initial levels; light bars, levels after 2-week vehicle or drug treatments.

[0040] Figure 14 shows the effects of Compound 25 on blood triglyceride (Figure 14A), total cholesterol (Figure 14B), and nori-HDI. cholesterol levels (Figure 14C) in high-fat diet induced diabetic / hepatic steatosis mice. Statistical significance (P) was determined by the Student’s t-test. All error bars, s.d., *p < 0.05, n=6 in each group. #25: treated with Compound 25 (5 mg / kg / day, daily gavage) for 3 weeks; vehicle, vehicle-treated control group.[0041[ Figure 15 shows the effects of Compound 25 and Compound 64 on hepatic steatosis induced by high-fat diet. Representative liver histology images with H&E staining from mice as indicated: Figure 15A, normal: the liver section from a healthy C57 / B16 mouse without HFD feeding; Figure 15B, HFD, the liver section from a mouse fed HFD; Figure 15C, HFD+#25, the liver sections from a mouse fed HFD following 3 weeks of Compound 25 treatment (P.O. dosing of 5 mg / kg, by daily gavage); and Figure 15D, HFD + #64, the liver sections from a mouse fed HFD following 3 weeks Compound 64 treatment (P.O. dosing of 5 mg / kg, by daily gavage). N=6 in each group.

[0042] Figure 16 shows the inhibitory effects of Compound 25 on hepatic stellate cell differentiation into myofibroblast-like cells. Figure 16A is a schematic representation of the experimental procedure (See procedure B5). Figure 16B is microscope images showing the cell morphology of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL of TGFP and TGFP plus 7.5 ng / mL of Compound 25. TGFP treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form the “ring”-shape morphology after TGFP treatment (TGFP, middle panel); Compound 25 (TGFp+#25, right panel) prevents TGFP-induced differentiation of LX-2 cells.

[0043] Figure 17 shows the inhibitory effects of Compound 64 on hepatic stellate cell differentiation into myofibroblast-like cells. Figure 17A. is microscope images showing cell morphology of LX-2 cells (human hepatic stellate cells) treated with vehicle, 10 ng / mL of TGFP and TGFP plus 1 ng / mL of Compound 64. TGF-P treatment induces the differentiation of LX-2 cells into myofibroblast-like cells, which form the “ring”-shape morphology after TGF-P treatment (TGF-P, middle panel); Compound64 (TGFp+#64, right panel) prevents TGFP-induced differentiation of LX-2 cells. Figure 17B is an immunoblotting analysis showing Compound 64 blocks activation of TGF-P signaling-16-SUBSTITUTE SHEET ( RULE 26 )pathway as evidenced by losing Smad2 / 3 phosphorylation. LX-2 cells were treated with either vehicle (control), or TGF-0 alone, or TGF-0 plus indicated concentrations of Compound 64 for 6 hrs. Cells were then harvested, and immunoblotting analyses were performed with antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated.

[0044] Figure 18 shows the efficacy of Compound 25 in reducing liver fibrosis determined by histology and molecular analysis. Figure 18A is microscope images of liver sections of CCL treated mice, subjected to H & E staining (top left panel); CCI4 plus Compound 25 (7.5 mg / kg / day) treated mice subjected to H & E staining (bottom left panel); CCL treated mice, subjected to Picrosirius Red staining(staining fibrotic collagen, top right panel) and CCL plus Compound 25 (7.5 mg / kg / day) treated mice subjected to Picrosirius Red staining (staining fibrotic collagen, bottom left panel. Figure 18B depicts fibrosis and lipofuscin scoring of vehicle (control), CCL alone, and CCL+ Compound 25 (CCL+25) treated mice. Each slice in a pie represents one mouse. The severity of liver fibrosis and abundance of lipofuscin in each mouse is presented with a different shade of color. Lipofuscin is an intracellular aggregate of highly oxidized proteins and lipids that cannot be digested. Lipofuscin mainly accumulate in lysosomes in aged cells and cells under pathological conditions. Figure 18C shows the immunoblotting analysis of collagen expression (Collal) in mice treated with vehicle, CCL alone, CCL+ Compound 25 (CCL+#25), with the fibrotic scores of each sample listed between the immunoblotting panels, as indicated. GAPDH serves as an internal control. n=7; duration of treatment, 6 weeks. Histological and molecular markers show Compound 25 reduces fibrosis in CCL treated animals.

[0045] Figure 19 is an immunoblotting analysis that shows the inhibitory effect of Compound 6464 on TGF-0 activation in T-cells. Figure 19A is an immunoblotting analysis of Human Jurkat cells treated with either vehicle alone (first lanes), TGF-0 alone (second lanes), TGF-0 plus Compound 64 at 0.5, 1.0 or 2.0 pM of compound (third through 5th lanes), as indicated, for 6 hours. Figure 19B is an immunoblotting analysis of mouse primary T-cells (B) were treated with either vehicle alone (first lanes), TGF-0 alone (second lanes), or TGF-0 plus varying concentrations of Compound 64 atl.O or 2.0 pM of compound (third and fourth lanes), as indicated, for 6 hours. Immunoblotting analyses were performed with antibodies against p-Smad2 / 3 (phosphorylated Smad2 / 3), Smad2 / 3, or GAPDH, as indicated.-17-SUBSTITUTE SHEET ( RULE 26 )Loss of Smad2 / 3 phosphorylation indicates the efficacy of Compound 64 in blocking TGF-P activation in T-Cells.

[0046] Figure 20 shows Compound 64 is efficacious in combinatory therapy with PD-1 antibody in treating metastatic cancer in mice. Figure 20A is the experimental design (see Example B 12). Briefly, C57 / B16 mice intrahepatically transplanted with MC38 cancer cells (day 0) were subject to various treatments starting on day 7: aPD-1 or isotype, mice were either treated with PD-1 antibody or its isotype antibody (control) by intraperitoneal (IP) injection on indicated days (PD-1 antibody has a half-life of over 1 week in mice); #64 or vehicle, mice were either treated with Compound #64 or vehicle by daily gavage. Figure 20B is a table depicting outcomes of the experiments described in Figure 20A and Example B12. aPD-1 +#64 represents mice treated with PD-1 antibody (IP) and #64 (daily gavage); aPD-1 represents mice treated with PD-1 antibody (IP) and vehicle (gavage); control, represents mice treated with isotype antibody (IP) and vehicle (gavage); n is number of mice in each group. Tumor-positive is the number of tumor- bearing mice in each group; tumor- free is thenumber of tumor-free mice in each group; tumor-free % is thepercentage of tumor- free animals in each group. Fisher Exact 2x2 test is theP value comparing each experimental group to control group using statistical analysis with Fisher Exact 2x2 test. P<0.05 is indicative of a statistically significant difference.

[0047] Figure 21 shows antiviral activity (EC50), cytotoxicity (TC50), and specificity index (SI) of Compounds 64, 25 and 57 against enveloped viruses. Each row represents results from experiments of the indicated compound on the host cells infected with or without the indicated virus. EC50 isthe compound concentration that reduces virus- induced cytopathic effects (CPE) by 50%. TC50 isthe compound concentration that leads to 50% of cell viability of uninfected cells; SI is the ratio between TC50 and EC50. The experiments were performed as follows. The host cells, either Vero 760 or MRC-5, as indicated, were seeded in 96-well flat-bottom tissue culture plates and allowed to adhere overnight. Following overnight incubation, the cells were either infected with virus (either SARS-CoV-2 or alpha coronavirus 229E) or uninfected, and diluted test compounds were added to each well. Following incubation at 37°C, 5% CO2 for three days or six days, cell viability was determined. Percent of CPE reduction of the virus-infected wells and the percent of cell viability of uninfected drug control wells, were measured to calculate and determine the EC50 and TC50 values. SI, was calculated accordingly.-18-SUBSTITUTE SHEET ( RULE 26 )DETAILED DESCRIPTION10048] The following factors make mitochondria an ideal target for treating a number of important diseases: (1) mitochondria are the ultimate site where lipid or glucose metabolites are consumed (oxidized); (2) mitochondria are critical in regulating the abundance of metabolic intermediates that become building blocks of biosynthesis essential for cell growth and proliferation of cancer cells, as well as for viral envelop production and assembly; (3) mitochondria are the major production site of ROS in neurons and many other cells (Figure 1).[0049J Mitochondrial uncoupling is a unique way to modulate mitochondrial activity and functions. In essence, mitochondrial uncoupling is a process by which the activity of mitochondrial electron transport chain is de-coupled from ATP synthesis. Mechanistically, mitochondrial uncoupling is caused by the action of mitochondrial uncouplers that carry protons across the mitochondrial inner membrane into the mitochondrial matrix, independent of the ATP synthase (Terada, H. (1990) Environmental Health Perspectives 87, 213-218). The technical definition of mitochondrial uncouplers is an increase of oxygen consumption rate (OCR) by cells in the presence of an ATP synthase inhibitor such as oligomycin. As a result, mitochondrial uncouplers lead to futile mitochondrial oxidation and increase electron transport chain flux. Consequently, mitochondrial uncouplers could facilitate glucose or lipid catabolism in cells, reduce small molecule building block production output, and reduce electron stall in electron transport chain, hence reduce electron leakiness and mitochondrial ROS production. Through these actions, mitochondrial uncouplers represent an effective strategy for potential treatment of a number of important diseases.|0050] Mitochondria and metabolic diseases. Metabolic diseases are a family of diseases characterized by symptoms of abnormal glucose and / or lipid metabolism, such as obesity, type 2 diabetes, alcoholic fatty liver disease, non-alcoholic fatty liver diseases, nonalcoholic steatohepatitis. These diseases are associated with age-, environmental-, or genetic- related decrease in mitochondrial functions such as reduced oxidative capacity. Importantly, these diseases also share a common causal factor, namely abnormal accumulation of intracellular lipid in cells of various tissues as well as insulin resistance in most cases. For example, obesity is characterized by excessive fat accumulation in cells of adipose tissue. Metabolic syndrome is characterized with insulin resistance in peripheral tissues, usually caused by ectopic fat accumulation in cells of liver, muscle, or adipose tissue. Type 2-19-SUBSTITUTE SHEET ( RULE 26 )diabetes is characterized by insulin resistance usually caused by ectopic fat accumulation in cells of liver, muscle, or adipose tissue, and hyperglycemia caused by insulin resistance. Alcoholic fatty liver disease is characterized by ectopic lipid accumulation in liver cells and liver damage, liver inflammation, and fibrosis. The various stages of non-alcoholic liver fatty liver disease (orNAFLD), include hepatosteatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and NAFLD induced hepatocellular carcinoma (HCC), has a primary cause of ectopic lipid accumulation in liver cells which lead to liver damage, inflammation, and fibrosis. The various types of dyslipidemia are partly caused by ectopic accumulation of lipid in cells of liver, muscle, or heart, as a result of redistribution of lipid from adipose tissue to other tissues.10051] Mitochondrial uncouplers, which reduce energy efficiency and boost futile lipid oxidation, would effectively reduce cellular accumulation of lipid. As ectopic intracellular accumulation of lipid in the liver and muscle, as well as excessive accumulation of lipid in adipose tissue are the fundamental cause of insulin resistance in various forms of metabolic diseases (Samuel V.T., et al., Lancet, 2010, 375:2267-77), applicant and others have demonstrated in animal models, that small molecule (chemical) mitochondrial uncouplers are efficacious 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), leading to: (1) reduction of lipid accumulation in various tissues, including adipose tissue, (2) reduction in insulin resistance, (3) reduction in blood glucose concentrations, and (4) improvement in glycemic control and slowdown in disease progression. Importantly, using mitochondrial uncouplers for treating metabolic diseases has a number of appealing features; for example, since they correct the cause of insulin resistance (ectopic lipid accumulation), such an approach may provide a cure for some metabolic diseases.|0052] Cancer is a family of diseases characterized by uncontrolled growth and proliferation of cells of various tissue types, resulting from a combination of genetic mutations in oncogenes and tumor suppressor genes. It is well-accepted that one requirement of tumorigenesis is the alteration of cell metabolism. Cancer cells require not only energy but also the building blocks (metabolic intermediates) for biosynthesis of macromolecules such as DNA and RNA to support rapid cell growth and proliferation. Metabolism in cancer cells is changed in such a way it could support both the energy need and the need of the various metabolic intermediates (building blocks) for biosynthesis of macromolecules (Vander Heiden, M. G , Cantley, L. C., and Thompson, C. B. (2009) Science, 324(5930), 1029-33). As-20-SUBSTITUTE SHEET ( RULE 26 )a result, most cancers exhibit a unique cellular metabolic pattern called the Warburg effect, or aerobic glycolysis, which prevents the complete oxidation of glucose or lipid and allows for production of glucose metabolites for biosynthesis of macromolecules (Vander Hei den, et al., 2009).

[0053] Mitochondrial uncoupling reduces energy efficiency thereby undermining the energy requirement of cancer cells. In addition, mitochondrial uncoupling promotes the complete mitochondrial oxidation of glucose and lipid, thereby diminishing the production of metabolic intermediates essential for biosynthesis of macromolecules required for cell proliferation. Moreover, mitochondrial uncoupling could lead to AMPK activation, a known event for inhibiting cell growth. Indeed, prior documents showed that mitochondrial uncouplers exhibit anti-cancer activities (U. S. Patent 10,227,315). Targeting cancer cells through mitochondrial uncoupling would deprive energy as well as biosynthetic metabolic intermediates that are absolutely essential for cancer cell growth and proliferation, which is proven to be an effective anti-cancer strategy (Alasadi, A. et al., (2018) Cell Death Dis., 9(2), 215)

[0054] Autoimmune diseases are conditions where the body’s immune system attacks their own healthy organs. The common autoimmune diseases include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. To activate and sustain the autoimmune activity, the body’s own self-attaching immune cells need amplification (proliferation) which requires metabolic changes similar to the Warburg effect observed in cancer cells to provide sufficient building blocks for biosynthesis (Ganeshan, K., et al. (2014) Annual Review of Immunology, 32, 609-634). Therefore, mitochondrial uncoupling would potentially inhibit the activation and amplification of self-attacking immune cells.

[0055] Neurodegenerative diseases are a large group of disabling disorders of the nervous system such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, characterized by the relative selective death of neuronal subtypes. There is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases, with mitochondrial ROS production as one of the most important one (Elfawy, H. A., and Das, B. (2019) Life Sci., 218, 165-184.)|0056] Mitochondrial uncouplers increase mitochondrial electron transport chain flux and decrease the electron stall in the complexes of the electron transport chain, thus they could effectively reduce mitochondrial ROS. Therefore, mitochondrial uncoupling is-21-SUBSTITUTE SHEET ( RULE 26 )considered a powerful anti-oxidant strategy and could have therapeutic potential for treating neurodegenerative diseases.|0057] A decline in mitochondrial function and capacity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Some proven ant-aging and pro-longevity approaches, such as calorie restriction, highly correlate with improvement in mitochondrial functions (Sun, N., et al. (2016) Mol. Cell, 61(5), 654-666). Modulation of mitochondrial functions by mitochondrial uncoupling has been proposed as anti-aging strategy (Caldeira da Silva, C. C., et al. (2008) Aging Cell, 7(4), 552-60).

[0058] Mitochondria are ancient bacteria that formed a symbiotic relationship with host cells. Bacterial plasma membrane contains electron transport chain and ATP synthase that are similar to those of mitochondria, therefore compounds that impact mitochondrial uncoupling could be useful inhibitors of bacterial growth and effective as antibiotics (US Patent 10,227,315).[00591 Despite the appealing beneficial features of mitochondrial uncoupling, noU. S. FDA approved drug is currently being used in humans with the mechanism of action of mitochondrial uncoupling for treating the above mentioned diseases in United States. There are major hurdles for developing mitochondrial uncouplers as therapeutics. Discovery of new synthetic mitochondrial uncouplers with better druggable features is critical for developing mitochondrial uncoupling therapeutics.

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

[0061] Another limitation of the available mitochondrial uncouplers is safety concerns, because some mitochondrial uncouplers are known to have a narrow therapeutic-22-SUBSTITUTE SHEET ( RULE 26 )index. For example, the most famous mitochondrial uncoupler, 2, 4- dinitrophenol , was previously used in humans but was withdrawn from the market due to its narrow therapeutic window. 2, 4- Dinitrophenol has a ratio of concentration (in cells) / dosage in vivo), between toxicity and efficacy, is merely a factor of about 3. Therefore, new properties that allow mitochondrial uncouplers that improve the safety margin are considered critical for therapeutic development of mitochondrial uncouplers.

[0062] Various embodiments provide new benzamide mitochondrial uncouplers that effectively induce mitochondrial uncoupling (increase mitochondrial oxygen consumption in the presence of oligomycin) without significantly decreasing mitochondrial membrane potential (vide infra) over wide concentration ranges. These compounds are referred to herein as mitochondrial membrane potential-retaining (MMP -retaining) compounds (MMP-retaining).

[0063] These MMP-retaining compounds exhibit drastically improved safety profiles compared to the bench mark conventional mitochondrial uncoupler, DNP. These compounds exhibit a wider therapeutic index when used for treating metabolic diseases.

[0064] Various embodiments provide new benzamide mitochondrial uncouplers that show markedly improved pharmacokinetic properties, such as markedly increased systemic exposure (with some compounds having more than 100 fold increase in AUC than some previously disclosed druggable benzamide mitochondrial uncouplers with the highest reported systemic exposure).

[0065] Various embodiments describe the use of these compounds for the prevention and treatment of bacterial infections; dermatological disorders; viral infection; metabolic diseases or disorders , including, but not limited to, obesity, metabolic syndrome, type 2 diabetes, alcoholic fatty liver disease, non-alcoholic fatty liver diseases, dyslipidemia, and primary cancer of various tissue origins, and metastatic cancer.|0066] Various embodiments provide the use of these compounds for treatment of disease symptoms such as hyperglycemia, insulin resistance, aberrant lipid accumulation, fibrosis, and aberrant TGF-P activation.|0067] Various embodiments describe the use of these compounds for the prevention and treatment of the diseases alone or in combination with another agent.-23-SUBSTITUTE SHEET ( RULE 26 )Compounds

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

[0069] The substituent R1000aof Formula A is selected from the group consisting of-CH3, -CH2CH3, -Ci-C6alkyl, -C3-C6cycloalkyl, -OCH3, -CH2OCH3, -CH2OCH2OCH3,C(O)N(CH2CH2OCH3)2. Each of substituents R5000Aand R5000B, is independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3;with the proviso that R5000Aand R5000Bare not both Ci-Ce alkyl. Alternatively R5000Aand R5000Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. Integer r’ is an integer selected the group consisting of 1, 2 and 3. Substituent R6000is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; and r is an integer selected from the group consisting of 0, 1, 2, and 3.

[0070] Substituent R1000cof Formula I is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0071] Each of substituents R4000band R4000dof Formula A is independently selected from the group consisting of Y1000and Z1000, provided that when R4000bis Y, R4000dis Z and when R4000bis Z, R4000dis Y. Substituent Y1000is selected from the group consisting of-24-SUBSTITUTE SHEET ( RULE 26 )chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, - SO2(Ci-Ce)alkyl, cyano, and -CO2(Ci-C6)alkyl. Substituent Z1000is selected 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)2NR2000AR2000B, -(CH2)SR3000, -CH2OCH2Ar', -OCH3 CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2)t’NR7000AR7000B, and -(CH2)tR8000provided that when Z1000is H; R1000ais not Ci- G, alkyl, -C3-C6 cycloalkyl, -CH3 or -CH2CH3. Substituents R2000Aand R2000Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclic ring optionally substituted with one or more methyl groups. Substituent R3000is a 5 to 6-membered heterocyclic ring and s is an integer selected from the group consisting of 0, 1, 2 and 3. Substituent Ar1is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl, halo, hydroxyl, and alkoxy. Each of R7000AandR7000Bis independently selected fromCi-Ce alkyl. Alternatively R7000Aand R7000Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from Ci-Ce alkyl and t’ is an integer selected from the group consisting of 1, 2, and 3. Substituent R8000is selected from the group consisting of a5 to 6-membered heterocyclic ring optionally substituted with methyl, and t is an integer selected from the group consisting of 0, 1, 2 and 3.

[0072] In some embodiments R4000dis selected from the group consisting of H, R4das described in paragraph

[0078] and R400das described in paragraph

[0149] ,

[0073] In some embodiments the compound of Formula A is a compound selected from the group consisting of a compound of Formula I, a compound of Formula II and a compound of Formula III as defined herein.|0074] In some embodiments a compound of Formula A is selected from the group consisting of a compound as described in any of paragraphs

[0089] ,

[0120] and

[0156] ,

[0075] In one embodiment, the present disclosure describes a compound of Formula I:-25-SUBSTITUTE SHEET ( RULE 26 )or a pharmaceutically acceptable salt, solvate, or prodrug thereof.[00761 The substituent Rlaof Formula I is selected from the group consisting of-CH3, -CH2CH3, -0CH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -Each of substituents R5AandR5B, is independently selected from the group consisting of -Ci- Ch> alkyl; and -C1-C6 alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3. Alternatively R5Aand R5Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3,-CF3, Ci-Ce alkyl, halo, and acyl. Integer m’ is an integer selected the group consisting of 1, 2 and 3. Substituent R6is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; and m is an integer selected from the group consisting of 0, 1, 2 and 3.

[0077] Substituent Rlcof Formula I is selected from the group consisting of chloro, fluoro, iodo, and bromo.

[0078] Each of substituents R4band R4dof Formula I is independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4bis Z, R4dis Y. Substituent Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 ,-CHF2, fluoro(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(C1-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl. Substituent Z is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3,-26-SUBSTITUTE SHEET ( RULE 26 )-CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR2AR2B, -(CH2)nR3, -CFFOCFFAr, and OCH3. Substituents R2Aand R2Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclic ring optionally substituted with one or more methyl groups. Substituent R3is selected from the group consisting of a 5 to 6- membered heterocyclic ring and phenoxy; and n is an integer selected from the group consisting of 0 1, 2 and 3. Substituent Ar is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl, halo, hydroxy, and alkoxy.

[0079] Further embodiments describe the compound according to Formula la:or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of Rlaand R4dof Formula la is as described previously for Formula I.

[0080] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from -CH2NR5AR5B; wherein each of R5Aand R5Bis independently selected from methyl; and Ci-Ce alkyl substituted with one or more groups selected from methoxy, and -O(CH2)2OCH3.10081| In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR5AR5B; wherein each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy.[00821 In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR5AR5B; wherein R5Aand R5Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,-acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl,-27-SUBSTITUTE SHEET ( RULE 26 )dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl; wherein the heterocyclyl is optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,-acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy,-NHC(0)CH3, -C(0)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl. In some embodiments the 4-8-membered heterocyclyl is optionally substituted with one or more methyl substituents. In some embodiments the 4 to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(0)CH3, - C(0)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl.

[0083] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR5AR5B; wherein R5Aand R5Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino, carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 6-membered heterocyclyl is selected from the group consisting piperidinyl optionally substituted with one or Ci-Ce alkyl substituents, and morpholinyl optionally substituted with one or Ci-Ce alkyl substituents.

[0084] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR5AR5B; wherein -CH2NR5AR5Bis selected from the group consisting ofSUBSTITUTE SHEET ( RULE 26 )

[0085] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)mR6; wherein R6is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl and piperidinyl and m is as previously described. In some embodiments m is 0. In some embodiments m is 1. In some embodiments -(CH2)mR6is selected from the group|0086] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 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)2NHCO2CH3,SUBSTITUTE SHEET ( RULE 26 )

[0087] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH3, -CH2CH3 and -CH2NR5AR5Bwherein R5Aand R5Bare as previously described in any embodiment described herein. In some embodiments, each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.

[0088] In some embodiments, Rlaof Formula I, or of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the groupSUBSTITUTE SHEET ( RULE 26 )

[0089] In some embodiments, Rlcof Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro.

[0090] Some embodiments describe a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R4bis Y and R4dis Z.|0091] Some embodiments describe a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R4dis Y and R4bis Z.[00921 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 R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)O(CH2)2NR2AR2Bwherein R2Aand R2Bare as previously described herein. In some embodiments R2Aand R2Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with a methyl group. In some embodiments R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from piperazinyl or a 4- methyl piperazinyl.[00941 In some embodiments, Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)nR3, wherein R3is as previously described herein. In some embodiments R3is a 5-membered heterocyclic ring. In some embodiments R3is selected from the group consisting of tetrahydrofuranyl, and phenoxy. In some embodiments R3is tetrahydrofuranyl. In some embodiments R3is selected from the group consisting ofand phenoxy. In some embodiments n is 0. In some embodiments n is 1. In some embodiments -(CH2)nR3is selected from the group consistingSUBSTITUTE SHEET ( RULE 26 )[00951 In some embodiments, Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -CH2OCH2Ar, wherein Ar is as previously described herein. In some embodiments 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, fluoro, chloro, hydroxy, and methoxy. In some embodiments Ar is selected from the group consisting of thiazolyl, phenyl, and phenyl substituted with one or more groups independently selected from methyl, fluoro, chloro, hydroxy, and methoxy.In some embodiments Ar is selected from the group consisting of, phenyl,

[0096] In some embodiments, Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, CH2O(CH2)2NHCH3,-CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2 NR2AR2B, -(CH2)nR3, -CH2OCH2Ar and OCH3; wherein R2AR2B, R3, n and Ar are as described in any embodiment herein.

[0097] In some embodiments, Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2OCH2CH -CH2O(CH2)2N(CH3)2, -CH2-CFLOCJTAr and OCH3; wherein R2AR2B, R3, n and Ar are as described in any embodiment herein.

[0098] In some embodiments, Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 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)2NR2AR2B, -(CH2)nR3, -CFLOCJTAr and OCH3; wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinyl; R3is tetrahydrofuranyl; and Ar is a 5 to 6-membered aryl or heteroaryl group-32-SUBSTITUTE SHEET ( RULE 26 )optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.|0099] In some embodiments Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2OH,-CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3,[0100} In some embodiments Z of Formula I, or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group

[0101] In some embodiments Z of Formula I or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3,SUBSTITUTE SHEET ( RULE 26 )f Formula I is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci- Ce)alkyl, cyano, and -CO2(Ci-Ce)alkyl.

[0102] In some embodiments Z of Formula I or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2OH, -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3,

[0103] In some embodiments Z of Formula I or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the grouphe group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci- C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl.

[0104] In some embodiments Z of Formula I or R4dof Formula la, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3,SUBSTITUTE SHEET ( RULE 26 )10105] Some embodiments describe a compound of Formula I wherein:Rlais selected from the group consisting of -CH3, -CH2CH3and -CH2NR5AR5B; each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more groups selected from methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 4-8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;Rlcis chloro; each of R4band R4dis independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4bis Z, R4dis Y;Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci- Ce)alkyl;Z is selected from the group consisting of -CH2OCH2CH3,-CH2OCH3, - CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2J-CH2O(CH2)2NHSO2CH3, - (CH2)O(CH2)2NR2AR2B, -(CH2)nR3, -CH2OCH2Ar and -OCH3; wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinyl; R3is tetrahydrofuranyl; and Ar is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.(0106] Some embodiments describe a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:SUBSTITUTE SHEET ( RULE 26 )Rlais selected from the group consisting of -CH3, -CH2CH3 and -CH2NR5AR5B; wherein each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more groups selected from methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;Rlcis chloro; each of R4band R4dis independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4bis Z, R4dis Y; Y is CF3; and Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CFLCXCFb^OH, - CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR2AR2B, -(CH2)nR3, -CFLOCFLAr and -OCH3; wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinyl; R3is tetrahydrofuranyl; and Ar is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy, and methoxy.

[0107] Some embodiments describe a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:Rlais selected from the group consisting of -CH3, -CH2CH3, -Rlcis chloro; each of R4band R4dis independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4bis Z, R4dis Y; Y is CF3; and Z is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -SUBSTITUTE SHEET ( RULE 26 )[01081 Some embodiments describe a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:Rlcis chloro;R4bis CF3; andR4dis selected from the group consisting of -CH2OCH2CHa, -CH2OCH3,

[0109] Some embodiments describe a compound of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Rlais selected from theH, --37-SUBSTITUTE SHEET ( RULE 26 )CH2OCH2CH3, -CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2NHCH3, -(0110] Some embodiments describe a compound of Formula la or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Rlais selected from the group consisting of(0111] Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof|0H2] Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

[0114] In one embodiment, the present disclosure describes a compound ofFormula II:-49-SUBSTITUTE SHEET ( RULE 26 )or a pharmaceutically acceptable salt, solvate, or prodrug thereof.[01151 The substituent R10aof Formula I is selected from the group consisting of-(CH2)O’NR50AR50B, -(CH2)OR60, and C(O)N(CH2CH2OCH3)2. Each of substituents R50Aand R50B, is independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3, with the proviso that R50Aand R50Bare not both Ci-Ce alkyl; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. Integer o’ is an integer selected the group consisting of 1, 2 and 3.Substituent R60is selected from the group consisting 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; and o is an integer selected from the group consisting of 0 1, 2 and 3.Substituent R10cof Formula I is selected from the group consisting of chloro, fluoro, iodo, and bromo.[01171 One of substituent R40band R40dis H and the other substituent is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl.[01181 Further embodiments describe the compound according to Formula Ila:-50-SUBSTITUTE SHEET ( RULE 26 )or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of R10a, and R40dof Formula Ila is as described previously for Formula II.[0119| In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from - CH2NR50AR50B; wherein each of R50Aand R50Bis independently selected from methyl; and Ci-Ce alkyl substituted with one or more groups selected from methoxy, and -O(CH2)2OCH3.

[0120] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR50AR50B; wherein R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,-acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl; wherein the heterocyclyl is optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,-acylamino, carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorphylinyl; wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3,-CF3, methyl, fluoro, and acetyl. In some embodiments the 4 to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, - NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro;SUBSTITUTE SHEET ( RULE 26 )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; dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl. In some embodiments the 4 to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(0)CH3, -C(0)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorphylinyl.

[0121] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR50AR50B; wherein R50Aand R50Btogether with the nitrogen to which they are attached, form a 4-7 membered heterocyclyl selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorphylinyl; wherein the 4-7 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(0)CH3, -C(0)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl.[0122 | In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR50AR50B; wherein -CH2NR50AR50Bis selected from the group consistingSUBSTITUTE SHEET ( RULE 26 )

[0123] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR50AR50B; wherein -CH2NR50AR50Bis selected from the group consisting

[0124] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)OR60; wherein R60is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiazolyl, and pyridinyl and o is as previously described. In some embodiments o is 0. In some embodiments o is 1. In some embodiments R60is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl and o is 0. In some embodiments -(CH2)o R60isSUBSTITUTE SHEET ( RULE 26 )selected from the group consistingIn some embodiments -(CH2)o R60is selected from the group consisting of

[0125] In some embodiments R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3,C(O)N(CH2CH2OCH3)2, wherein R50AR50B, and R60are as previously defined by any embodiment herein.|0126] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -OCH3, -CH2OCH3,SUBSTITUTE SHEET ( RULE 26 )

[0127] In some embodiments, R10aof Formula II, or of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -OCH3, -CH2OCH3,SUBSTITUTE SHEET ( RULE 26 )C(O)N(CH2CH2OCH3)2.

[0128] In some embodiments, R10cof Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro, fluoro, and iodo.

[0129] In some embodiments, R10cof Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro.

[0130] In some embodiments one of substituent R40band R40dis H and the other substituent is selected from the group consisting of fluoro, -CF3 , -CHF2, and -OCF3.

[0131] In some embodiments, R40bis H and R40dis selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-Ce)alkyl, -OCF3,-SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl.

[0132] In some embodiments, R40dis H and R40bis selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -OCF3,-SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-C6)alkyl.

[0133] In some embodiments R40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.

[0134] In some embodiments R40dis H and R40bis -CF3.[0135| Some embodiments describe a compound of Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR10ais selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3,each of R50AandR50Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 7-membered heterocyclyl optionally substituted with one or moreSUBSTITUTE SHEET ( RULE 26 )substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R60is selected from the group consisting of 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; o is 0;R10cis selected from the group consisting of chloro, fluoro, iodo; and one of R40band R40dis H and the other of R40band R40dis selected from the group consisting of fluoro, -CF , -CHF2, -OCF3; with the proviso that R50Aand R50Bare not both Ci-Ce alkyl.|0136] Some embodiments describe a compound of Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR10ais selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3,each of R50Aand R50Bis independently selected from methyl; and Ci-Ce alkyl substituted with one or more groups selected from methoxy, and -O(CH2)2OCH3; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4-7- membered heterocyclyl selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, and dioxothiomorphylinyl; wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(O)CH , -C(O)NH2, - SO2CH3, -CF3, methyl, fluoro, and acetyl;R60is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl o is 0;R10cis selected from the group consisting of chloro, fluoro, iodo; andR40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3;-57-SUBSTITUTE SHEET ( RULE 26 )with the proviso that R50Aand R50Bare not both methyl.[0137| Some embodiments describe a compound of Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinC(O)N(CH2CH2OCH3)2;R10cis selected from the group consisting of chloro, fluoro, iodo; andR40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.-58-SUBSTITUTE SHEET ( RULE 26 )[O138| Some embodiments describe a compound of Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR10cis selected from the group consisting of chloro, fluoro, iodo; andR40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.[0139 j Some embodiments describe a compound of Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R10ais selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, - CH2O(CH2)2OCH3,-59-SUBSTITUTE SHEET ( RULE 26 )R10cis chloro; andR40dis H and R40bis -CF3.|0140] Some embodiments describe a compound of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR10ais selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3,SUBSTITUTE SHEET ( RULE 26 )C(O)N(CH2CH2OCH3)2.

[0141] Some embodiments describe a compound of Formula Ila or a pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinSUBSTITUTE SHEET ( RULE 26 )

[0142] Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.|0143] Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.|0144] One embodiment describes a compound that isSUBSTITUTE SHEET ( RULE 26 )or a pharmaceutically acceptable salt, solvate, or prodrug thereof.[01451 In one embodiment, the present disclosure describes a compound ofFormula III:Ill or a pharmaceutically acceptable salt, solvate, or prodrug thereof

[0146] The substituent R100aof Formula III is selected from the group consisting of-(CH2)p’NR500AR500B, -(CH2)pR600, and C(O)N(CH2CH2OCH3)2. Each of substituents R5AandR5B, is independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3.Alternatively R500Aand R500Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido,-SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. Integer p’ is an integer selected the group consisting of 1, 2 and 3. Substituent R600is selected from the group consisting of 5 to 6--75-SUBSTITUTE SHEET ( RULE 26 )membered heterocyclyl, pyridinyl and thiazolyl; and p is an integer selected from the group consisting of 0, 1, 2, and 3.[0147| Substituent R100cof Formula III is selected from the group consisting of chloro, fluoro, iodo, and bromo.10148] Each of substituents R400band R400dof Formula III is independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1. Substituent Y1is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, - SO2(Ci-Cs)alkyl, cyano, and -CO2(Ci-Ce)alkyl. Substituent Z1is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2)q’NR7AR7B, and -(CH2)qR8. Each ofR7AandR7Bis independently selected from Ci-Ce alkyl. Alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl. Integer q’ is an integer selected from the group consisting of 1, 2, and 3. Substituent R8is selected from the group consisting of a 5 to 6-membered heterocyclic ring optionally substituted with methyl, and q’ is an integer selected from the group consisting of 0, 1, 2 and 3.

[0149] Further embodiments describe the compound according to Formula Illa:TTTIlla or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of R100a, and R4°0dof Formula Illa is as described previously for Formula III.[01501 In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from - CH2NR500AR500B; wherein each of R500Aand R500Bis independently selected from is independently selected from methyl; and Ci-Ce alkyl substituted with one or more groups selected from methoxy, and -O(CH2)2OCH3.-76-SUBSTITUTE SHEET ( RULE 26 )[O151 | In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR500AR500B; wherein each of R500Aand R500Bis independently selected from Ci-C6alkyl substituted with one or more methoxy.

[0152] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR500AR500B; wherein R500Aand R500Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is selected from the group consisting of azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl; wherein the heterocyclyl is optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl. In some embodiments the 4-8-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, methoxy, -NHC(O)CH3, -C(O)NH2, -SO2CH3, -CF3, methyl, fluoro, and acetyl. In some embodiments the 4-8-membered heterocyclyl is optionally substituted with one or more methyl substituents. In some embodiments the 4 to 8-membered heterocyclyl is selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3, - C(O)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorphylinyl, and azabicyclo[3.2.1]octanyl.10153] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR500AR500B; wherein R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more-77-SUBSTITUTE SHEET ( RULE 26 )substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy,-acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl In some embodiments the 6-membered heterocyclyl is selected from the group consisting piperazinyl optionally substituted with one or Ci-Ce alkyl substituents, and morpholinyl optionally substituted with one or Ci-Ce alkyl substituents.

[0154] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NR500AR500B; wherein -CH2NR500AR500Bis selected from the groupembodiments -CH2NR500AR500Bis selected from the group consisting of|0155] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)PR600; wherein R600is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,SUBSTITUTE SHEET ( RULE 26 )thiazolyl and piperidinyl and m is as previously described. In some embodiments p is 0. In some embodiments p is 1. In some embodiments -(CH2)PR600is selected from the group[O156| In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH3, -OCH3, -CH2OCH3, -CH2OCH2OCH3, -CH2O(CH2)2OH, -SUBSTITUTE SHEET ( RULE 26 )

[0157] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH3, and -CH2NR500AR500Bwherein R500Aand R500Bare as previously described in any embodiment described herein. In some embodiments, each of R500Aand R5°°BJSindepencientiy selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6- membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.

[0158] In some embodiments, R100aof Formula III, or of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group

[0159] In some embodiments, R100cof Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is chloro.[0160| Some embodiments describe a compound of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R400bis Y1and R400dis Z1.

[0161] Some embodiments describe a compound of Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R400dis Y1and R400bis Z1.

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

[0163] In some embodiments, Z'of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -CH2NR7AR7Bwherein R7Aand R7Bare as previously described herein. In some embodiments each of R7Aand R7Bis methyl. In some embodiments R7Aand R7Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with a methyl group. In some embodiments R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl-80-SUBSTITUTE SHEET ( RULE 26 )selected from the group consisting of piperazinyl optionally substituted with one or more Ci- Cc> alkyl and morpholinyl optionally substituted with one or more Ci-Ce alkyl. In some embodiments R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl. In some embodiments-CH2NR7AR7Bis selected from the group consisting

[0164] In some embodiments, Z1of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is -(CH2)qR8, wherein R8is as previously described herein. In some embodiments R8is a 6-membered heterocyclic ring optionally substituted with methyl. In some embodiments R8is 4-methylpiperidinyl. In some embodiments q is 0. In some embodiments q is 1. In some embodiments -(CH2)qR8is

[0015] In some embodiments, Z1of Formula I, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, - CH2NR7AR7B, and -(CH2)qR8, wherein R7A, R7B, R8, and p are as described in any embodiment herein.

[0166] In some embodiments, Z1of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, - CH2NR7AR7B, and -(CH2)qR8wherein R7A, R7B, R8, and p are as described in any embodiment herein.

[0167] In some embodiments, Z1of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, - CH2NR7AR7B, and -(CH2)qR8, wherein each of R7Aand R7Bis methyl. Alternatively-81-SUBSTITUTE SHEET ( RULE 26 )embodiments R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; and R8is 4-methylpiperidinyl.|0168] In some embodiments , Z1of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -|0169] In some embodiments , Z1of Formula III, or R400clof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group 3, -CH2NHSO2CH3, -Formula III is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci- C6)alkyl, -OCF3,-SO2(Ci-Ce)alkyl, cyano, and -CO2(Ci-Ce)alkyl.

[0170] In some embodiments , Z1of Formula III, or R400dof Formula Illa, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group 3, -CH2NHSO2CH3, -Formula III is -CF3.

[0171] In some embodiments, R400dof Formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is selected from the group consisting of - , -CH2NHSO2CH3, -CH2N(CH3)2,of Formula III is -CF3.|0172] Some embodiments describe a compound of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof-82-SUBSTITUTE SHEET ( RULE 26 )wherein:R100ais selected from the group consisting of -CH3, and -CH2NR500AR500B; each of R500Aand R500Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;R1°°Cjgchloro- each of R400band R400dis independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1.Y1is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci- C6)alkyl;Z1is selected from the group consisting of -CH2NHC(O)CH2OCH3, - CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR7AR7B, and -(CH2)qR8, wherein each of R7Aand R7Bis methyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; and R8is 4-methylpiperidinyl.(0173| Some embodiments describe a compound of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:R100ais selected from the group consisting of -CH3, and -CH2NR500AR500B; each of R500Aand R500Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;R1°°Cjs chloro- each of R400band R400dis independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1.-83-SUBSTITUTE SHEET ( RULE 26 )Y1is -CF3;Z1is selected from the group consisting of-CH2NHC(O)CH2OCH3, - CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR7AR7B, and -(CH2)qR8, wherein each of R7Aand R7Bis methyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; and R8is 4-methylpiperidinyl

[0174] Some embodiments describe a compound of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:R100ais selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,R1°°C js chloro- each of R400band R400dis independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1; Y1is CF3; and Z1is selected from the group consisting of -CH2NHC(O)CH2OCH3, -

[0175] Some embodiments describe a compound of Formula III or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:R100ais selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,Rl°°c jschloj-Q--84-SUBSTITUTE SHEET ( RULE 26 )R400bis CF3; and

[0176] Some embodiments describe a compound of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:R100ais selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,

[0177] Some embodiments describe a compound of Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:|0178] Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.[O179| Some embodiments describe a compound selected from the group consisting of:SUBSTITUTE SHEET ( RULE 26 )

[0180] Additional compounds that are mitochondrial uncouplers but may not necessarily have the unexpected properties of the other compounds disclosed herein include:SUBSTITUTE SHEET ( RULE 26 )SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0181] The compounds of embodiments described herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The compounds can be utilized in embodiments described herein as a single isomer or as a mixture of stereochemical isomeric forms. Diastereoisomers, i.e., non-superimposable stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization or sublimation. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. The mixture of diastereomers can be separated by crystallizationSUBSTITUTE SHEET ( RULE 26 )followed by liberation of the optically active bases from these salts. An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form 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 the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

[0182] Compounds according to embodiments described herein may be in the form of pharmaceutically acceptable salts. A pharmaceutically acceptable salt of the compounds described herein includes acid addition salts and base addition salts. Pharmaceutically-acceptable salt embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of the compounds described herein may be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. In some embodiments the salt is a hydrochloride salt. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, malonic, galactic, and galacturonic acid. Pharmaceutically-acceptable base addition salts for compounds described herein can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di (substituted alkenyl) amines, tri (substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cyclo alkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine,-93-SUBSTITUTE SHEET ( RULE 26 )trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the preparation of pharmaceutically acceptable salts, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

[0183] Acceptable salts may 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 affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of organic (e g., carboxylic) acids can also be made.

[0184] Compounds of according to embodiments described herein may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent is a prodrug within the scope and spirit of the 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, 2nded., Academic Press, San Diego, CA, 1999). Some prodrugs of the present invention include a compound according to any embodiment described herein in which the 2--94-SUBSTITUTE SHEET ( RULE 26 )hydroxy of the benzamide is converted to a group such as, but not limited to,10185] In some embodiments, a prodrug of a compound according to any embodiment described herein may take the form of a carbamate. For instance, the 2-hydroxy group of a benzamide according to any embodiment described may converted to a carbamate group, -OC(O)NR9R10at the same position. Each of R9and R10is independently selected from the group consisting of hydrogen, and optionally substituted Ci-Ce-alkyl; alternatively R9and R10taken together with the nitrogen to which they are attached form an optionally substituted Cs- -heterocyclyl.[0186| The invention also embraces isolated compounds. An isolated compound refers to a compound which represents at least 10%, preferably at least 20%, more preferably at least 50% and most preferably at least 80% of the compound present in the mixture.

[0187] In some embodiments of the invention, one or more hydrogen atoms is replaced by a deuterium. It is well established that deuteration of physiologically active compounds offer the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively impacting their metabolic outcome. Selective replacement of one or more hydrogen with deuterium, in a compound of the present invention, could improve the safety, tolerability and efficacy of the compound when compared to its all hydrogen counterpart.

[0188] Methods for incorporation of deuterium into compounds is well established. Using metabolic studies establish in the art, the compound of the present invention can be tested to identify sites for selective placement of a deuterium isotope, wherein the isotope will not be metabolized. Moreover these studies identify sites of metabolism as the location where a deuterium atom would be placed.10189] Some embodiments describe a pharmaceutical composition comprising: a compound according to an embodiment described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier or diluent.(0190] Compounds, or pharmaceutically acceptable salts thereof, can be formulated for oral, intravenous, intramuscular, subcutaneous or parenteral administration for the therapeutic or prophylactic treatment of diseases, disorders or infections described herein.-95-SUBSTITUTE SHEET ( RULE 26 )For oral or parenteral administration, compounds of this invention can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like. The pharmaceutical compositions comprising a compound of this invention will contain from about 0.1 to about 99% by weight of the active compound, and more generally from about 10 to about 30%.10191 | The pharmaceutical preparations disclosed herein are prepared in accordance with standard procedures and are administered at dosages that are 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 the methods for administering various agents for human therapy). The pharmaceutical compositions of the invention can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices).[0192| The pharmaceutically acceptable pharmaceutical compositions of the present invention comprise one or more compounds of the invention in association with 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 if desired other active ingredients. The pharmaceutical compositions may contain common carriers and excipients, such as com starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. The pharmaceutical compositions may contain croscarmellose sodium, microcrystalline cellulose, com starch, sodium starch glycolate and alginic acid.[0193| Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.[01941 Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.[01951 Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. It may also be desirable to add a coloring agent to make the dosage form more aesthetic in appearance or to help identify the product.[01961 For oral use, solid formulations such as tablets and capsules are particularly useful. Sustained release or enterically coated preparations may also be devised. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are-96-SUBSTITUTE SHEET ( RULE 26 )especially suitable. For oral administration, the pharmaceutical compositions are in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a therapeutically effective amount of the active ingredient. Examples of such dosage units are tablets and capsules. For therapeutic purposes, the tablets and capsules which can contain, in addition to the active ingredient, conventional carriers such as binding agents, for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth; fillers, for example, calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose; lubricants, for example, magnesium stearate, polyethylene glycol, silica, or talc, disintegrants, for example, potato starch, flavoring or coloring agents, or acceptable wetting agents. Oral liquid preparations generally are in the form of aqueous or oily solutions, 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 acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, methyl or propyl parahydroxybenzoate, propylene glycol, sorbitol, or sorbic acid.10197] For intravenous (IV) use, a compound according to the invention can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion. Intravenous fluids include, without limitation, physiological saline or Ringer's solution. Intravenous administration may be accomplished by using, without limitation, syringe, minipump or intravenous line.|0198] Formulations 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 mentioned for use in the formulations for oral administration. The compounds can be dissolved in polyethylene glycol, propylene glycol, ethanol, com oil, benzyl alcohol, sodium chloride, and / or various buffers.

[0199] For intramuscular preparations, a sterile formulation of a compound or a suitable soluble salt form of the compound, for example the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as Water-for-Inj ection (WFI), physiological saline or 5% glucose. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g., an ester of a long chain fatty acid such as ethyl oleate.-97-SUBSTITUTE SHEET ( RULE 26 )[0200| A dose of an intravenous, intramuscular or parental formulation of a compound may be administered as a bolus or by slow infusion. A bolus is a dose that is administered in less than 30 minutes. In a preferred embodiment, a bolus is administered in less than 15 or less than 10 minutes. In a more preferred embodiment, a bolus is administered in less than 5 minutes. In an even more preferred embodiment, a bolus is administered in one minute or less. An infusion is a dose that is administered at a rate of 30 minutes or greater In a preferred embodiment, the infusion is one hour or greater. In another embodiment, the infusion is substantially constant.(0201] For topical use the compounds of the present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints. Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.

[0202] For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.1 203] For rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.

[0204] Alternatively, the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery. In another embodiment, the unit dosage form of the compound can be a solution of the compound or preferably a salt thereof in a suitable diluent in sterile, hermetically sealed ampoules or sterile syringes. The concentration of the compound in the unit dosage may vary, e.g. from about 1 percent to about 50 percent, depending on the compound used and its solubility and the dose desired 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 at a therapeutically effective levels of between 0.001 to 100 mg / kg. of body weight daily for administration to a patient, e.g., humans and elderly humans. The therapeutically effective amount will generally be about 0.5 mg to 10g per patient per day which may be administered in single 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,-98-SUBSTITUTE SHEET ( RULE 26 )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 about 0.5 mg to 2500 mg per patient per day; in some embodiments about 0.5 mg to 200 mg per patient per day; in some embodiments about 0.5 mg to 500 mg per patient per day; in some embodiments about 0.5 mg to 1000 mg per patient per day; and in yet some other embodiments about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising for example about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg or 1000 mg of active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 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 the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times or four times per day.Unexpected PropertiesMitochondrial uncouplers with improved PK profile|0206] Some embodiments describe mitochondrial uncouplers depicted herein that have improved pharmacokinetic (PK) profiles, such as markedly increased systemic exposure (i.e. through increased solubility and absorption) consistent with drastically improved potency, and markedly reduced half-lives consistent with a once-daily oral administration regimen and elimination of the toxicity risk factor due to accumulation over prolonged use for chronic conditons or disorders.

[0207] A common feature of prior benzamide compounds with mitochondrial uncoupling activity is low systemic exposure. As shown in Table 1, niclosamide ethanolamine has an oral exposure of merely about 1800 hr*ng / ml in a 24 hr period after 50 mg / kg dosage. Compound 31 in International Patent Publication Number WO 2016 / 081599 and Compound 27 in US Patent 10,227,315 have systemic exposure of only about 2400-99-SUBSTITUTE SHEET ( RULE 26 )hr*ng / ml after 20 mg / kg oral administration and about 3000 hr*ng / ml after 10 mg / kg oral administration in 24 hr period of time respectively (Table 1). In order to overcome the poor pharmacokinetic properties of low systemic exposure and short half-life of the previously disclosed compounds, studies in animal models required the compound to be mixed with food, and high doses of the compounds were required to achieve efficacy (e g. 1500 ppm niclosamide ethanolamine (NEN) in diet, equivalent to 150 mg / kg / day (Tao, et al. 2014, and WO 2012 / 068274); or 600-750 ppm (Compound 28 in US10,227,315) in diet, equivalent of 60-75 mg / kg / day ). Neither the high doses required nor the need to mix the compound in food, is compatible with therapeutic development in humans.[0208| As exemplified in Table 1, the new compounds (e.g., Compounds 2, 9, 78) unexpectedly exhibit significantly increased systemic exposure without compromising uncoupling activity, with 20- to 160- fold increase over the prior uncouplers with the best systemic exposure.Table 1SUBSTITUTE SHEET ( RULE 26 )[0209| Table 2 provides additional compounds with drastically increased systemic exposure (See Example B3).Table 2-101-SUBSTITUTE SHEET ( RULE 26 )+++: 10,000-30,000; ++++: 30,001- 60,000; +++++: 60,001-120,000; ++++++:>120,000

[0210] As noted in Table 3, Mitochondrial uncoupling activity of Compound 49 in U.S. Patent 10,227,315 is low compared to similar compounds of the present invention.Table 3:-102-SUBSTITUTE SHEET ( RULE 26 )Drastically Improved Metabolic Stability and Half-life Properties[0211| Some embodiments describe compounds depicted herein with improved metabolic stability and half-life.[0212J One key reason previously known mitochondrial uncouplers such as DNP exhibit a narrow therapeutic index is due to their long-half life. For example, DNP has a half- life measured in days to weeks, leading to accumulation of toxic levels in the body during prolonged use to treat chronic conditions or disorders. For development of orally administered drugs, excretion properties are also important. Not only does a drug need to have sufficient exposure, but it also needs to be excreted at a rate that is not too short nor to long. On the one hand, it is important that an oral drug should have sufficiently long half-life in patients so the drug can be administered at certain intervals (e.g. once daily instead of once every hour); on the other hand, the half-life of a compound cannot be too long as this could lead to toxic accumulation of the drug inside the patient. For once-daily orally administered drugs, a half-life around 8-12 hrs is considered a favorable property, while half-lives exceeding 48 hrs are incompatible for once-daily oral administration and could lead to toxic accumulation of the drug. For example, Compound 2 of US Patent 10,227,315 exhibits an extremely long half-life (66.9 hrs, Table 4, Example B8). The long half-life correlated with extreme metabolic stability (rat microsome metabolic stability, half-life 2,131.8 minutes). In-103-SUBSTITUTE SHEET ( RULE 26 )other words, the extremely long half-life of Compound 2 of US Patent 10,227,315 is mainly caused by the liver metabolic enzymes inability to efficiently metabolize these compounds.|0213] As shown in Table 4, Compound 17 of the present invention unexpectedly has drastically decreased metabolic stability (from 2,132 minutes to 145 minutes, Example B7), and concomitant decreased oral half-life (from 66.9 hrs to 8.6 hrs, Example B8). The structural modification does not decrease the mitochondrial uncoupling activity thus are expected to have better toxicology properties when used to treat chronic conditions or disorders, which require prolonged use .Table 4|0214] Half-lives in rat liver microsomal stability assay were determined (Example B7) for a number of compounds described herein and compared with Compound 2, Compound 53, and 54 in U. S. Patent 10,227,315 (Table 5). The compounds of the present invention exhibited drastically improved metabolic stability (favorable half-life less likely to cause toxicity when used to treat chronic conditions or disorders, which require prolonged use) without decreased uncoupling activity (see Table 5 and Table 8).-104-SUBSTITUTE SHEET ( RULE 26 )Table 5SUBSTITUTE SHEET (RULE 26)MMP-retaining compounds10215] Some embodiments describe mitochondrial uncouplers depicted herein that effectively increases OCR without reducing or significantly reducing MMP. These compounds are referred to as MMP -retaining uncouplers in this disclosure.

[0216] Mechanistically, conventional mitochondrial uncouplers transport protons across the mitochondrial inner membrane into the mitochondrial matrix. As mitochondrial membrane potential is supported by proton gradient across the membrane, conventional uncouplers inevitably require rapid dissipation of mitochondrial membrane potential to sustain mitochondrial uncoupling action (Figure 3). Prior to the present disclosure, all mitochondrial uncouplers (herein referred to as conventional uncouplers) tested, had properties that increase OCR and decreased MMP, and the concentrations leading to OCR increase and MMP dissipation correlate (Figure 4). Figure 4 shows a conventional uncoupler, FCCP, has a ratio of CIO%TMRE / Cmin-ocR less than 3, where CIO%TMRE is the concentration leading to 10% MMP retention (or 90% MMP loss, measured by TMRE staining) and-106-SUBSTITUTE SHEET ( RULE 26 )OCR is the minimal concentration leading to OCR increase. As such, the activity for decreasing MMP is considered a second hallmark of mitochondrial uncoupling. As MMP is critical for cell survival and normal functions of cells in many tissues and organs, this seemingly inherent property of conventional mitochondrial uncouplers on dissipating MMP represents a major safety hurdle for therapeutic development.[0217| In some embodiments, the mitochondrial uncouplers described herein represent a fundamentally different category of mitochondrial uncouplers which effectively induce mitochondrial uncoupling (increase mitochondrial oxygen consumption in the presence of oligomycin) without significantly decreasing 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 maximal levels. The ratio of CIO%TMRE / Cmin-ocR for Compound 25 is over 25. Figure 6 shows that Compound 64 effectively induces mitochondrial uncoupling without significantly decreasing MMP over a wide concentration range. The ratio of CIO%TMRE / Cmin-ocR for Compound 64 is between 10 to 25.|0218] After determining the mitochondrial uncoupling activity of a mitochondrial uncoupler described herein (Example Bl), a mitochondrial membrane potential assay was performed on the mitochondrial uncoupler, using the standard TMRE (tetramethylrhodamine ethyl ester) staining method with cultured mammalian cells (Example B2). Results are categorized into three groups, the Compound 25-like compounds are denoted as MMP -Retaining Uncoupling Compounds (CIO%TMRE / Cmin-OCR>25); The Compound 64-like compounds are denoted as MMP -Retaining Uncoupling Compounds (Cio%TMRE / Cmin-ocR between 10 to 25), and Conventional Uncouplers (CIO%TMRE / Cmin-ocR less or equal to 3). The results are summarized in Table 6.Table 6-107-SUBSTITUTE SHEET ( RULE 26 )CW%TMRE is the concentration leading to 10% MMP retention (or 90% MMP loss, measured by TMRE staining) and Cmin-ocR is the minimal concentration leading to OCR increase

[0219] Mechanistically, chemical uncouplers are lipophilic weak acids or weak bases that localize in mitochondrial inner membrane and transport protons across the membrane into mitochondrial matrix through a protonation and deprotonation cycle (Figure 3 and Figure 7A). As mitochondrial membrane potential (MMP) is supported by proton gradient across the membrane, it is highly unexpected that a compound could uncouple mitochondrial oxidation (transport protons) without significantly decreasing MMP. We analyzed the benzothiazole derivatives of benzamide uncouplers that exhibit MMP -retaining-108-SUBSTITUTE SHEET ( RULE 26 )activity. They all contain a tertiary amine or secondary amine group, which have a pKa over 10.0. The amine groups become positively charged in cellular environment where the pH is generally below 8.010220] Without wishing to be bound by theory, we propose the mechanism of action for the MMP- retaining uncouplers, is as illustrated in Figure 7B. In essence, a MMP- retaining uncoupler molecule consists of two functional parts (Figure 7C). The first part functions as a conventional uncoupler, which transports proton from the mitochondrial intermembrane space to the mitochondrial matrix (Figure 7B). The second part is a positively charged functional group that is poorly impermeable to the mitochondrial inner membrane. This feature allows an asymmetrical distribution and orientation of the compounds across mitochondrial inner membrane, with higher concentration of the charged molecules in the intramembrane space than in the mitochondrial matrix, as well as with the positively charged moiety primarily distributed at the outer surface of the membrane (facing the intermembrane space, Figure 7B). As mitochondrial uncoupling occurs and consequently reduction of proton gradient across the membrane, the loss of membrane potential due to proton gradient reduction is compensated by the asymmetrical positive charge distribution across the membrane provided by MMP-retaining uncouplers. Hence, the overall mitochondrial membrane potential is minimally impacted over a wide concentration range of the uncouplers.[0221 J Figure 7D illustrates the structural feature of the all the MMP-retaining uncouplers listed in Table 6 in which the positive charge is provided by a tertiary amine or a secondary amine. We notice that by modifying the amine containing moiety, one could finetune the MMP-retaining activity, reducing the ratio of Cio%TMRE / Cmin-ocR from >25 to a ratio between 10 to 25. Some modification of the amine-containing moiety could even reduce the ratio close to 3, a ratio equal to that of a typical conventional mitochondrial uncoupler. Figure 7E shows a specific example of the MMP-retaining uncoupler, with the conventional uncoupler component shown in the frame. Improved in vivo safety profiles|0222] Some embodiments describe MMP- retaining uncouplers exhibit markedly improved safety profiles compared with conventional uncouplers such as the bench mark conventional uncoupler DNP.[02231 DNP is a conventional mitochondrial uncoupler once used in humans before for obesity treatment. However, it exhibited high levels of toxicity and had a narrow-109-SUBSTITUTE SHEET ( RULE 26 )therapeutic window. It was subsequently withdrawn from market for use in humans. The toxicology profiles of the MMP-retaining uncouplers using Compound 25 and Compound 64 as examples, and compared them with those of DNP. Compounds 25 and Compound 64 have excellent oral absorption, systemic exposure, and efficacy in reducing blood glucose and liver steatosis in animal models (Tables 2, 5, and 9).I0224| Some embodiments show MMP-retaining uncouplers exhibit markedly improved acute toxicity profiles. Figure 8 (Example B9) shows Compound 64 and Compound 25 have LD50 (lethal dose, 50% animal death) / MED (minimal efficacious dosage) ratios over 400 and 200 respectively, while the LD50 / MED ratio of DNP is 30.[02251 Some embodiments show MMP-retaining uncouplers exhibiting markedly improved short-term (10-day) toxicology profiles. Figure 9-10 (Example B10) show that the ratio ofNOAELs (no-observable-adverse-effect-level) over MED of Compounds 64 is over 40 (between 40-57 using different parameters), NOAEL / MED ratio of Compound 25 is over 19, while NOAEL / MED ratio of DNP is reportedly less than 3.[0226 [ Some embodiments describe a method of preparing MMP-retaining uncouplers from conventional mitochondrial uncouplers by adding a positively charged side chain to the conventional uncouplers, as illustrated in Figure 7C, for example, by adding a tertiary amine (or secondary amine) containing side chain (Figure 7D). As shown in Figure 7E, a tertiary amine-containing moiety was added to a conventional uncoupler (the structure in the Frame). This modification effectively converts the conventional uncoupler (with the ratio of Cio%TMRE / Cmin-ocR of 3) to an MMP-retaining uncoupler (listed in Table 2, with the ratio of Cio%TMRE / Cmin-ocROver 25).

[0227] Some embodiments describe a mitochondrial membrane-retaining uncoupler compound of the Formula:(RA)U-RB; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein RAand RBare covalently linked; each RAis independently a moiety containing a secondary or tertiary amine; u is an integer selected from the group consisting of 1 and 2; andRBis a conventional mitochondrial uncoupler prior to being covalently linked to RA; provided the mitochondrial membrane-retaining uncoupler compound is not-110-SUBSTITUTE SHEET ( RULE 26 )

[0228] Some embodiments describe a method of preparing a mitochondrial membrane-retaining mitochondrial uncoupler comprising1. identifying a conventional mitochondrial uncoupler;2. designing a compound that covalently links at least one moiety capable of becoming positively charge in a cellular environment, to a conventional mitochondrial uncoupler; and3. preparing the compound of step 2, wherein the compound is a mitochondrial membrane retaining uncoupler compound.In some embodiments the moiety capable of becoming positively charge in a cellular environment is a secondary or tertiary amine moiety.[0229| Some embodiments describe a method of preparing a mitochondrial membrane-retaining mitochondrial uncoupler comprising1. identifying a conventional mitochondrial uncoupler;2. designing a compound that covalently links at least one secondary or tertiary amino moiety to a conventional mitochondrial uncoupler; and3. preparing the compound of step 2, wherein the compound is a mitochondrial membrane retaining uncoupler compound.-111-SUBSTITUTE SHEET ( RULE 26 )

[0230] In some embodiments the secondary or tertiary amino moiety or RAis selected from the group consisting of -(CH2)NH(CH2)2OCH3, -CH2NHC(O)CH3, -previously described in any embodiment described herein.[02311 In some embodiments the secondary or tertiary amino moiety or RAis selected from the group consisting of -CH2NHSO2CH3, -CH2N(CH3)2, -(CH2)2N(CH3)2, --112-SUBSTITUTE SHEET ( RULE 26 )[02321 In some embodiments the secondary or tertiary amino moiety or RAis-113-SUBSTITUTE SHEET ( RULE 26 )[0233} In some embodiments the conventional mitochondrial uncoupler or RBis selected from the group consisting of a conventional mitochondrial uncoupler as described herein. In some embodiments the conventional mitochondrial uncoupler or RBis selected from the group consisting of a conventional mitochondrial uncoupler as described in: U. S. Patent No. 10,227,3158, U. S. Patent Application No. 15 / 527,808 and Childress, E. S., et al. (2018) i Med. Chem., 61(11), 4641- 4655.[0234} In some embodiments the conventional mitochondrial uncoupler or RBis selected from the group consisting of[0235| In some embodiments the secondary or tertiary amino moiety or RA; the conventional mitochondrial uncoupler or RB; and the mitochondrial membrane-retaining uncoupler compound (RA)U-RBare as described in Table 7.-114-SUBSTITUTE SHEET ( RULE 26 )Table 7-115-SUBSTITUTE SHEET (RULE 26)-116-SUBSTITUTE SHEET (RULE 26)-117-SUBSTITUTE SHEET (RULE 26)-118-SUBSTITUTE SHEET (RULE 26)-119-SUBSTITUTE SHEET (RULE 26)-120-SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)Methods of Treatment10236] In some embodiments, a method of treating a mitochondria-related condition or diorder, in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition according to embodiments described herein.

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

[0238] In some embodiments, the mitochondria-related condition or disorder has and one or more underlying symptoms selected from the group consisting of hyperglycemia, abnormal accumulation of lipid in cells, abnormal accumulation of lipid in tissues, abnormal lipid metabolism, insulin resistance, abnormal cell proliferation, abnormal TGF-beta activation, and abnormal fibrosis. In some embodiments, the mitochondria-related condition or disorder has and one or more underlying causal factors selected from the group consisting of hyperglycemia, lipid accumulation, insulin resistance, altered cellular metabolism, fibrosis, aberrant TGF-beta activation, or aberrant cell proliferation.

[0239] In some embodiments, the mitochondria-related condition or disorder is a metabolic disease, cancer, an autoimmune disease, pulmonary fibrosis, a dermatological disorder, an infectious disease or a neurodegenerative disease. In some embodiments, the mitochondria-related condition or disorder is a metabolic disease, cancer, and autoimmune disease, or infectious disease.[02401 In some embodiments, the mitochondria-related condition or disorder is a metabolic disease. In some embodiments the metabolic disease is selected from the group consisting of type 2 diabetes, a disease characterized by insulin resistance or hyperglycemia; obesity or obesity related complications, and a disease characterized by abnormal lipid accumulation.

[0241] In some embodiments, a method of treating a metabolic disease or disorder characterized by insulin resistance or by abnormal accumulation of lipid in tissue, or a-122-SUBSTITUTE SHEET ( RULE 26 )disease or a disorder in which insulin resistance or abnormal accumulation of lipid in 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 a pharmaceutical composition according to embodiments described herein. In some embodiments, the metabolic disease or disorder is type 2 diabetes, or a disease characterized by insulin resistance or hyperglycemia.

[0242] In some embodiments, a metabolic disease or disorder described in any embodiment herein is a complication caused by type 2 diabetes, selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart diseases, 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, a metabolic disease or disorder described in any embodiment herein is non-alcoholic fatty liver disease (NAFLD), comprising at least one prognosis stage of this disease selected from the group consisting of hepatic steatosis, nonalcoholic 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 diseases. In some embodiments, the complication of alcoholic fatty liver disease comprises 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 carcinoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, and lung cancer. In some embodiments, the cancer is a metastatic cancer originated from a primary tumor of other tissue types. In some embodiments, the metastatic sites are selected from the group consisting of liver, lung and the intraperitoneal cavity.

[0246] In some embodiments, the compound of embodiments described herein is administered in combination with a second agent indicated for the above-mentioned disorders or diseases, either concomitant with, prior to, or after the administration of the second agent. In some embodiments, the second agent is an anti-diabetic agent selected from the group consisting of metformin, insulin, insulin analogs, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha glucosidase inhibitors, GLP-1 agonists, SGLT2 inhibitors and DPP--123-SUBSTITUTE SHEET ( RULE 26 )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 anti-alcoholic fatty liver disease agent. In some embodiments, the second agent is an anti-dyslipidemia agent.[0247 j In some embodiments, a compound of embodiments described herein, is administered in combination with a second anti- non-alcoholic fatty liver disease agent. In some embodiments, a compound of the invention is administered in combination with a second anti- alcoholic fatty liver disease agent. In some embodiments, a compound of the invention is administered in combination with a second anti- dyslipidemia agent.[02481 In some embodiments, the compound may be administered in combination with a second anti-cancer agent or anti-cancer regimen. In some embodiment the second anti-cancer agent s an immunoncological agent. In some embodiments the immunocological agent is selected from the group consisting of an antibody against PD-1 / PD-L1, an antibody against other immune check point proteins, CAR-T cells, and other therapeutic immune cells. In some embodiments, the compound may be administered prior to, concomitantly with, or subsequently to administration of 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 compound described herein is used as a veterinarian drug to treat diabetes or a diabetes-associated disease, and the subject is a mammalian animal.

[0250] Some embodiments are directed to a method for long-term disease management of a metabolic disease or disorder comprising administering to a subject in need of such long-term management an effective amount of a compound or a pharmaceutical composition described herein. In some embodiments, a method for long-term disease management of a metabolic disease or disorder, or for long-term disease management of cancer, comprises administering to a subject in need of such long-term management an effective amount of a compound or a 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 manufacture of a medicament for treatment of diabetes, obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease, dyslipidemia, or a disease where insulin resistance or abnormal lipid-124-SUBSTITUTE SHEET ( RULE 26 )accumulation in tissue is a symptom, or related disorders or complications, including, but not limited to, hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD induced hepatocellular carcinoma (HCC). In some embodiments, the compound of embodiments herein may be used to manufacture a medicament for the treatment of cancer, a disease where cell proliferation (hyperplasia) is a symptom, or cancer or hyperplasia related complications.[0252J Some embodiments herein are directed to a method of treating or preventing a metabolic disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0253] Some embodiments herein provide for a method of treating and alleviating the symptoms of obesity (characterized by excessive accumulation of lipid in adipocytes), pre-type 2 diabetes (characterized by insulin resistance usually caused by ectopic accumulation of lipid in cells of liver and muscle), type 2 diabetes (characterized by insulin resistance and hyperglycemia), non-alcoholic fatty liver diseases or alcoholic fatty liver disease (characterized by abnormal accumulation of lipid in liver), dyslipidemia (characterized by abnormal lipid deposit in tissue other than adipose), and one or more complications of the above mentioned metabolic disorders, including, but not limited to, hypertension, cardiovascular diseases, nephropathy, and neuropathy comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. These diseases or disorders may be caused by dietary, environmental, medical and / or genetic factors. The methods described herein may also be used for prevention of the above-mentioned metabolic diseases for a subject with risk factors including, but not limited to, dietary, environmental, medical, and genetic predispositions. In addition, some embodiments provide a method for long-term chronic disease management and longevity management by reducing insulin resistance or reducing glucose levels in the blood.

[0254] In some embodiments, the metabolic disease or disorder is type 2 diabetes, or related diseases leading to insulin resistance or hyperglycemia. In some embodiments, the metabolic disease or disorder is obesity or one or more obesity related complications.10255] In some embodiments, the metabolic disease or disorder is non-alcoholic fatty liver disease, (NAFLD), including nonalcoholic steatohepatitis (NASH) and cirrhosis, or alcoholic fatty liver disease (AFLD). In some embodiments, the metabolic disease or disorder-125-SUBSTITUTE SHEET ( RULE 26 )is hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, or NAFLD induced hepatocellular carcinoma (HCC).|0256] In some embodiments, the metabolic diseases or disorder is one or more complications of type 2 diabetes including, but not limited to, type 2 diabetes induced hypertension, cardiovascular disease, nephropathy, atherosclerosis, dyslipidemia, retinopathy, neurodegenerative disorders, diabetic heart failure, and neuropathy. In some embodiments, the metabolic disease or disorder is pre-type 2 diabetes. In some embodiments, the metabolic disease or disorder is dyslipidemia.

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

[0258] Some embodiments are directed to a method 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 may be primary cancer or metastatic cancer. In some embodiments, the cancer is primary cancer including but not limited to hepatocellular carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, lymphoma, melanoma, ovarian cancer, lung cancer. In some embodiments, the cancer is metastatic liver cancer originated from the primary tumor of other tissue types. In some embodiments, the cancer is metastatic lung cancer originated from the primary tumor of other tissue types. In some embodiments, the cancer is metastatic cancer to other sites including intraperitoneal cavity.

[0259] Some embodiments are directed to a method 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, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

[0260] Some embodiments are directed to a method of treating or preventing a dermatological disorder in a subject in need thereof, comprising administering to the subject a-126-SUBSTITUTE SHEET ( RULE 26 )therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the dermatological disorder is eczema, dyshidrotic eczema, seborrheic eczema psoriasis, rosacea, dermatitis and atopic dermatitis.|0261] Some embodiments are directed to a method of treating or preventing an infectious disease of non-viral parasites 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 infectious disease is a viral infections. In some embodiments the viral infection is an envelope viral infection. In some embodiments the viral infection is selected from the group consisting of SARS- CoV-2 , a corana virus infection and an Ebola viral infection.

[0262] In some embodiments, the disease to be treated may be a heart disorder comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the heart disorder may be hypertension or cardiovascular disease. In some embodiments, the disease to be treated may be a central nervous system (CNS) disease. In some embodiments, the CNS disease may be stroke, Alzheimer’s, Parkinson’s, Huntington’s, or ALS (amyotropic lateral sclerosis).

[0263] In some embodiments, the disease to be treated may be a disorder associated with increased ROS (reactive oxygen species) production comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. Increased ROS has been associated with aging, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS (amyotropic lateral sclerosis), mitochondrial diseases, and various cancers.[02641 The compounds and pharmaceutical compositions described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, ophthalmic, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The compounds and pharmaceutical compositions described herein may also be formulated as a controlled-release formulation.

[0265] The compounds described herein may be administered topically and can be formulated into a variety of topically administrable pharmaceutical compositions comprising an active ingredient and a dermatologically acceptable base and / or an ophthalmically-127-SUBSTITUTE SHEET ( RULE 26 )acceptable base. Such pharmaceutical compositions can be formulated, e.g., as solutions, suspensions, spray, lotions, gels, pastes, medicated sticks, balms, shampoos, soap bars, liquid soaps, creams or ointments. In one embodiment, the pharmaceutical composition is the form of an ointment that can be applied in or around the eye of a mammal, including a human.

[0266] In some embodiments, a dermatologically and / or ophthalmically acceptable base includes a pharmaceutically acceptable ointment base. 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 bees wax, yellow bees wax, carnauba wax, wool wax (wool fat), 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 combinations thereof.

[0267] In some embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers, e g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers. A dermatologically and / or ophthalmically acceptable base can also include a dermatologically and / or ophthalmically acceptable mucoadhesive polymer, e.g., carboxymethylcellulose, carbomer (acrylic acid polymer), carbopol (copolymers or acrylic acid crosslinked with a polyakenyl polyether), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, or dextran.

[0268] In some embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more viscosity enhancing agents. Examples of suitable viscosity enhancing agents include, but are not limited to, methyl cellulose, xanthan gum, gum tragacanth, carboxymethyl cellulose, silica, silicone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans, acacia, com starch, gelatin, or combinations thereof.

[0269] In some embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable pH adjusting agents or buffering agents, including, but not limited to, acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium, lactate and tris--128-SUBSTITUTE SHEET ( RULE 26 )hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in a dermatologically and / or ophthalmically acceptable range.[0270 j In some embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable salts in an amount required to bring osmolality of the composition into a dermatologically and / or ophthalmically acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; specific salts include, e.g., sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0271] In some embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable preservatives to inhibit microbial activity. Suitable preservatives include, but are not limited to, mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.[02721 In further embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable surfactants to enhance physical stability, or for other purposes. Suitable nonionic surfactants include isohexadecane, cyclomethicone, copolymers of ethylene glycol and propylene glycol, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.|0273| In further embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable penetration enhancers to enhance physical stability, or for other purposes. Penetration enhancers are substances which enhance passage of topically-applied compounds into the stratum, comeum of the skin and therefrom into the epidermis and dermis. Examples include, but are not limited to: dimethyl isosorbide, ethoxy diglycol, 1- dodecylazacycloheptan-2-one, propylene glycol, oleyl alcohol, polyoxyethylene ester, sorbitan mono-9-octadecenoate, poly(oxy-l,2-ethanediyl) and derivatives thereof, ethanol, glyceryl monoethyl ether, monoglycerides, isopropylmyristate, lauryl alcohol, lauric acid, lauryl lactate, terpinol, menthol, D-limonene, beta-cyclodextrin, DMSO (dimethyl sulfoxide),-129-SUBSTITUTE SHEET ( RULE 26 )polysorbates, fatty acids (e g., oleic), bile salts, N-methylpyrrolidone, polyglycosylated glycerides, l-dodecylazacycloheptan-2-one (Azone®), Cyclopentadecalactone (CPE-215®), Alkyl -2-(N,N-disubstituted amino)-alkanoate ester (NexAct®), 2-(n-nonyl)- 1,3 -di oxolane (DEP A®), and penetration enhancers shown for example in U.S. Pat. Nos. 3,909,816; 4,405,616; 4,801,586; 4,861,764; 4,886,783; 4,983,396; 5,118,845; 5,196,410, 8486,374 and 8,741,265, each of which is hereby expressly incorporated herein by reference in its entirety.

[0274] In further embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more dermatologically and / or ophthalmically acceptable permability enhancers to enhance physical stability, or for other purposes. A variety of classes of compounds may serve as suitable permeability enhancers according to the invention. A first category includes fatty acids and salts and esters thereof, including mono-, di-, and triglycerides. Medium chain length fatty acids, especially C8 and CIO acids, and their salts and esters are particularly useful. Suitable specific examples include sodium caprylate, sodium caprate, CAPMUL® glycerides (available from Abitec of Columbus, Ohio), LABRASOL® glycerides (PEG-8 caprylic / capric glycerides, available from Gattefosse SAS of Saint Priest, Cedex, France), GELUCIRE® 44 / 14 (PEG-32 glyceryl laurate EP, available from Gattefosse), other glycerides & fatty acid esters, CREMOPHOR® (BASF, Ludwigshafen, Germany), D-a-tocopheryl polyethylene glycol 1000 succinate, vegetable oils, polyoxylglycerides, and medium chain mono- and diacylglycerides.

[0275] One example of this class, CAPMUL® MCM L8 (glycerol monocaprylate) (available from Abitec of Columbus, Ohio), is composed of mono- and diglycerides of medium chain fatty acids (mainly caprylic, with some capric) and 7% maximum free glycerol. It contains at least 44% alpha monoglycerides (as caprylate).[0276| Other examples of this class of enhancers include GATTEFOSSE compositions 61 A through 61H which are proprietary to Gattefosse SAS, but generally are composed of mixtures containing one or more of medium chain mono-, di-, or triglycerides, polysorbate derivatives, polyoxyl castor oil derivatives, polyethylene glycol derivatives including polyethylene glycol glycerides, polyoxyl ethers, vegetable oils, glycerin, and similar GRAS (generally regarded as safe) lipidic components in varying amounts. These components are part of individual commercial products such as CAPRYOL™ 90, CAPRYOL™ PGMC, LAUROGLYCOL™ 90, GELUCIRE® 44 / 14, Plurol Oleique CC497, LABRASOL®, LABRAFIL® M1944CS (apricot kernel oil PEG-6 esters), Transcutol HP, Peceol, and Maisine 35-1, all of which are available from Gattefosse SAS.-130-SUBSTITUTE SHEET ( RULE 26 )[0277| While not falling directly within this class, glycerol itself has been found to impart excellent permeability enhancement, particularly for neuraminidase inhibitors. This result was not anticipated as glycerol is not considered a permeability enhancer.|0278] A second category of enhancers includes surfactants having a steroidal structure, such as bile acid salts. Examples of suitable compounds include sodium cholate, sodium deoxycholate, glycocholate, glycoursodeoxycholate, taurocholate, taurodeoxycholate, and steroid detergents / bile salts. Other surfactants may also be suitable permeability enhancers, including cationic, anionic, and nonionic surfactants. Examples include polysorbate 80, hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, tetradecyl-P-D-maltoside, octylglucoside, glycyrrhetinic acid, 3-(N,N- dimethylpalmitylammonio)propane-sulfonate, and sodium lauryl sulfate.

[0279] Cyclodextrins may also be used as suitable enhancers. Examples include P-cyclodextrin, hydroxypropyl-P-cyclodextrin, y-cyclodextrin, and hydroxypropyl-y- cyclodextrin.10280] A variety of other compounds may also be used as enhancers. Examples include sodium salicylate, ethylenediamine tetraacetic acid (EDTA), citric acid, chitosan & chitosan derivatives, N-trimethyl chitosan chloride, monocarboxymethyl-chitosan, palmitoyl carnitine chloride, acyl carnitines, ethylene glycol tetraacetic acid (EGTA), 3-alkylamido-2- alkoxypropyl-phosphocholine derivatives, alkanoylcholines, N-acetylated amino acids (based on a- and non-a-amino acids), mucoadhesive polymers, phospholipids, piperine, 1- methylpiperazine, a-amino acids, and mineral oil.

[0281] Thus a wide variety of enhancer compounds may be selected from the group consisting of fatty acids, fatty acid esters, fatty acid salts, glycerol, surfactants, cyclodextrins, sodium salicylate, ethylenediamine tetraacetic acid, citric acid, chitosan, chitosan derivatives, N-trimethyl chitosan chloride, monocarboxymethyl-chitosan, palmitoyl carnitine chloride, acyl carnitines, ethylene glycol tetraacetic acid, 3-alkylamido-2- alkoxypropyl-phosphocholine derivatives, alkanoylcholines, N-acetylated amino acids, mucoadhesive polymers, phospholipids, piperine, 1 -methylpiperazine, a-amino acids, and mineral oil.10282] The permeability enhancer and the polar agent may be mixed in any proportion so long as there is provided a therapeutically effective amount of the polar agent and a permeability-enhancing amount of the enhancer compound. Enhancement in dermal bioavailability of topically administered polar agents can depend on the nature and-131-SUBSTITUTE SHEET ( RULE 26 )concentration of the enhancer compound with which the agent is formulated. It is thus contemplated that the required therapeutic amount may be contained in a single dosage form or divided between one or more dosages intended for application at the same time or in sequence.[0283 j The permeability enhancers act relatively independently of the concentration of polar agent. Differing permeability enhancers can reach either optimal or maximum enhancement over a wide concentration range depending on their particular inherent enhancement potential. Often, enhancers have a non-linear dose response relationship between concentration of enhancer present and amount of increased polar agent absorption. The amount of enhancer to be utilized in an oral dosage form with a polar agent is initially based upon the enhancement properties observed in Caco-2 cell assays at varying fixed enhancer concentrations. Based upon those results, an effective in vivo amount of enhancer compound for a human formulation can be estimated, demonstrated and optimized without undue experimentation using methods well known to those skilled in the formulation art, to achieve a desired pharmacokinetic in vivo profile.

[0284] In formulating the composition of this invention, it will be apparent to those skilled in the formulation art that more effective enhancer compounds would require less polar agent than less effective permeability enhancers to achieve a target pharmacokinetic profile. Given those considerations and variations, the amount of enhancer may be at least about 0.1 wt % of the combined weight of enhancer and polar agent, more preferably at least about 50 wt %, and more preferably at least 70 wt % of the combined weight of enhancer and polar agent. The amount is preferably at most 95 wt %, more preferably at most 80 wt %, and more preferably at most 75 wt % of the combined weight of the enhancer and polar agent. Thus, as shown in the examples, a typical dosage form may contain a wide range of concentrations of enhancer compounds depending on the compound itself and its efficacy in enhancing the permeability of polar agents following oral administration. Concentrations as low as 0.001% by weight up to 20% have been demonstrated to be effective in enhancement of the permeability of polar agents.

[0285] In yet other embodiments, a dermatologically and / or ophthalmically acceptable base includes one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.-132-SUBSTITUTE SHEET ( RULE 26 )

[0286] In addition to those enumerated above, any other surfactant, moisturizer, gelling agent, preservative, colorant or pigment, antioxidant, radical scavenger, emulsifier, humectant, pH modifier, chelating agent, or other dermatologically acceptable excipient commonly known to those of ordinary skill in the art as useful in topical compositions is contemplated as useful in the compositions described herein. Further, any non-toxic, inert, and effective topical carrier may be used to formulate the compositions described herein.

[0287] Well-known carriers used to formulate other topical therapeutic compositions for administration to humans will be useful in these compositions. Examples of such components that are well known to those of skill 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 hereby incorporated by reference in their entirety. Examples of such useful pharmaceutically acceptable excipients, carriers and diluents include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those preferred for use herein.

[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 by reference herein in their entirety.

[0289] The composition may be used immediately or stored for later use in any type of container known to one of skill in the art such as, for example, pouch, jar, bottle, tube, ampule and pre-filled syringe. Finally, the composition may be sterilized by any method known to one of skill in the art such as, for example, y radiation.

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

[0291] The pharmaceutical compositions and compounds of embodiments herein can be administered in a wide range of dosage-forms including, for example, solid dosage-133-SUBSTITUTE SHEET ( RULE 26 )forms and liquid dosage forms. Solid dosage forms may include powders, tablets, pills, capsules, suppositories, or dispersible granules. A solid carrier can be one or more substances that function as a diluting agent, flavor additive, solvent, lubricant, suspension agent, binder, preservative, tablet-disintegrating substance or encapsulating material. In powdered form, the carrier may be a finely pulverized solid including lactose, hydroxypropylmethylcellulose and PVP, mixed with an appropriate amount of the active ingredient. Appropriate carriers for powder and tablet forms include for example magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatins, tragacanth, methylcellulose, and sodium carboxymethylcellulose.[02921 Liquid dosage forms include for example solutions, suspensions, and emulsions. Also included are pharmaceutical compositions in solid form that are meant to be converted to liquid form shortly prior to consumption. These forms may include, in addition to the active ingredients, artificial colors, flavors, stabilizers, buffers, natural or artificial sweeteners, dispersing agents, thickeners, dissolving agents and the like.[0293| Solutions or mixtures may be administered directly to the nasal cavity using conventional means, such as drops or sprays. The pharmaceutical composition may be produced in individual or multi-dose forms. Multi-dose forms would include a dropper, pipette or atomizer that delivers a predetermined volume of the pharmaceutical composition.

[0002] The pharmaceutical compositions and compounds of embodiments herein may be provided in individual dosage units that contain a suitable amount of the active ingredient. The individual doses may be provided in a package, or as a kit that includes a measuring device, e.g., a device for measuring oral or injectable dosages (i.e., a measuring cup, needle, or syringe). The kit can also include, other materials such buffers, diluents, filters, and package inserts with instructions for use. A label may be present on the on the kit to indicate that the pharmaceutical composition is used for a specific therapy, and may also indicate directions for use.

[0294] If desired, the pharmaceutical compositions of the present invention may further comprise one or more additional active agents. Where it is appropriate, any of the active agents may be administered in the form of the compound per se, and / or in the form of a salt, polymorph, ester, amide, prodrug, derivative, or the like, provided the salt, polymorph, ester, amide, prodrug or derivative is suitable pharmacologically. Where it is appropriate, salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms-134-SUBSTITUTE SHEET ( RULE 26 )and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For any active agents that may exist in enantiomeric forms, the active agent may be incorporated into the present pharmaceutical compositions either as the racemate or in enantiomerically enriched form.|0295] The dosage of the active compound(s) being administered will depend on the condition being treated, the particular compound, and other clinical factors such as age, sex, weight, and health of the subject being treated, the route of administration of the compound(s), and the type of pharmaceutical composition being administered (tablet, gel cap, capsule, solution, suspension, inhaler, aerosol, elixir, lozenge, injection, patch, ointment, cream, etc.) It is to be understood that the present disclosure has application for both human and animal use. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will be ultimately at the discretion of the attendant physician or clinician.|0296] As described above, the compounds of the invention are useful for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of the compound as an active ingredient in the pharmaceutical compositions of this invention may be varied so that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.001 to 100 mg / kg. of body weight daily are administered to the patient, e.g., humans and elderly humans. The therapeutically effective amount will generally be about 0.5 mg to 10g per patient per day which may be administered in single 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 about 0.5 mg to 2500 mg per patient per day; in some embodiments about 0.5 mg to 200 mg per patient per day; in some embodiments about 0.5 mg to 500 mg-135-SUBSTITUTE SHEET ( RULE 26 )per patient per day; in some embodiments about 0.5 mg to 1000 mg per patient per day; and in yet some other embodiments about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising for example about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg or 1000 mg of active ingredient. For oral administration, the pharmaceutical compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of 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 the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times or four times per day.DEFINITIONS

[0297] Molecular terms, when used in this application, have their common meaning unless otherwise specified.10298] The articles "a" and "an" as used herein mean "one or more" or "at least one," unless otherwise indicated. That is, reference to any element of the present invention by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present.

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

[0300] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C17- alkyl" or "C1.17 alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, and C17 alkyl groups. Additionally, for example, "Ci-Ce alkyl" or "Ci-6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. In some embodiments the one of more hydrogen atoms is replaced by a chemical group selected from hydroxyl, and dimethylamino. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl). Examples of substituted alkyl includes, but is not limited to, -CH2N(CH3)2, -CH2CH2N(CH3)2, and -CH2CH2CH2N(CH3)2.-136-SUBSTITUTE SHEET ( RULE 26 )[03011 "Alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to three, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2-C6 alkenyl" or "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and G> alkenyl groups. The term "C2-17 alkenyl", is intended to include C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, C13, C14, C15, Ci6, and C17 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 2- butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-methyl-2 -propenyl, and 4-methyl- 3 -pentenyl.

[0302] “Alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. For example, "C2-C6 alkynyl" is intended to include C2, C3, C4, C5, and C<, alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.[03031 The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "Ci-Ce alkoxy" or "Ci-6 alkoxy" (or alkyloxy), is intended to include Ci, C2, C3, C4, C5, and Ce, alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.

[0304] "Aryl" groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, thiazolyl, phenyl, and naphthyl. "Cs-Cio aryl" or " Ce-io aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", " Cg-Cw aryl," " Ce-io 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] The term "benzyl," as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted by one to five, preferably one to three, substituents independently selected from methyl, trifluoromethyl (-CF3), hydroxyl (-OH), methoxy (-OCH3), halogen, cyano (-CN), nitro (-NO2), -CO2Me, -CO2Et, and -CO2H. Representative examples of benzyl group include, but are not limited to, PI1CH2-, 4-MeO-C6H4CH2-, 2,4,6-tri-methyl-C6H2CH2-, and 3,4-di-Cl-C5H3CH2-.

[0306] The term “carboxyamido” denotes a carbonyl radical adjacent to an amino group.-137-SUBSTITUTE SHEET ( RULE 26 )[0307| A "compound," as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above. When referring to a compound of the invention, and unless otherwise specified, the term "compound" is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, polymorphs, esters, amides, prodrugs, adducts, conjugates, active metabolites, and the like, where such modifications to the molecular entity are appropriate.

[0308] A “conventional mitochondrial uncoupler” as used herein describes a mitochondrial uncoupler that has properties that increase OCR and decreased MMP, and the concentrations for increasing OCR and dissipating MMP correlate.

[0309] As used herein, a "derivative" of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps. Non-limiting examples include replacement of H by an alkyl, acyl, or amino group.[0310| As used herein, an "effective amount" or "therapeutically effective amount" means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder. In the context of administering compounds in the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with another compound(s), may be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, 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 the second treatment to which it is being compared.]0311] The terms "formula" and "structure" are used interchangeably herein.|0312] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluorom ethyl, and tri chloromethyl.|0313] As used herein, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,-138-SUBSTITUTE SHEET ( RULE 26 )imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Unless otherwise specified, heteroaryl groups 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 -CO2CH3The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein 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, wherein p is 0, 1 or 2).[0314| The term “heterocyclyl,” “heterocyclic” or “heterocyclyl ring” is defined as a saturated or partially unsaturated ring containing one to four hetero atoms or hetero groups selected from O, N, NH, -N(RZ)-, -S(O)- or -S(O)2- , wherein Rzis selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, optionally substituted heterocyclyl, in a single or fused heterocyclic ring system having from three to twelve ring members. In a preferred embodiment, a heterocyclyl is a ring system having three to seven ring members Examples of a heterocyclyl group include, without limitation, azetindinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholinyl, dioxothiomorphylinyl, tetrahydrofuranyl and azabicyclo[3.2.1]octanyl. Unless otherwise specified, heteroaryl groups may be unsubstituted or substituted with at least one groups selected from oxo, cyano, hydroxyl, alkoxy, -acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl.

[0315] The term “infectious disease” as described herein referes to a bacterial infection, or viral infection. Infectious diseases do not include infections caused by parasitic organism. In some embodiments the viral infection is an envelope virus. Examples of envelope viruses include SARS-CoV-2 , corana viruses and Ebola viruses.

[0316] The term “mitochondria-related condition or disorder” is defined as pathologic conditions caused by mitochondrial malfunction 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 Noncommuni cable Chronic Diseases? Endocrine Reviews 2020,41(491-517), all of which are incorporated herein by reference. These conditions include, but are not limited to: genetic mitochondrial diseases, various types of cancer, autisim, neurodegenerative diseases, neuromuscular diseases, immunological diseases, metabolic diseases, aging, and aging- related noncommuni cable chronic diseases.-139-SUBSTITUTE SHEET ( RULE 26 )[0317| An “MMP -retaining compound” or a “mitochondrial membrane potentialretaining compound” is defined as a mitochondrial uncoupler that effectively increases OCR without significantly reducing MMP.

[0318] The term, "mitochondrial uncoupling", also referred to as "uncoupling", refers to the process whereby protons enter the mitochondrial matrix via a pathway independent of ATP synthase and thereby uncouple nutrient oxidation from ATP production. This process can be pharmacologically induced by small molecule mitochondrial protonophores, which directly shuttle protons across the mitochondrial inner membrane into the matrix. The primary pathway for energy production in aerobic cells involves the oxidation of nutrients (including fats, carbohydrates, and amino acids) in mitochondria, which promotes the efflux of protons out of the mitochondrial matrix. This process creates a pH and electrochemical gradient across the mitochondrial inner membrane. Protons normally re-enter the mitochondrial matrix via ATP synthase, which results in ATP production. Protons can also re-enter the mitochondrial matrix via pathways independent of ATP synthase, which 'uncouples' nutrient oxidation and proton efflux from ATP production.

[0319] The phrase " opthalmically acceptable" is employed herein to refer to those compounds, materials, pharmaceutical compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the eyes of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0320] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, pharmaceutical compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.|0321] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic-140-SUBSTITUTE SHEET ( RULE 26 )acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

[0322] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base 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 the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18thEdition, Mack Publishing Company, Easton, PA, 1990, the disclosure of which is hereby incorporated by reference.

[0323] As used herein, the term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil / water or water / oil emulsion, and various types of wetting agents. The term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.

[0324] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug, or may demonstrate increased palatability, or be easier to formulate.

[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 includes all vertebrates, e g. mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses. Preferred subjects include human patients in need of enhancement of an immune response. The methods are particularly suitable for treating human patients having a disease or disorder described herein.-141-SUBSTITUTE SHEET ( RULE 26 )[0326| The terms “administration of’ and or “administering a” compound should be understood to mean providing a compound described herein or a prodrug thereof to the individual in need of treatment.|0327] The term “treating” or “treatment” as used herein refers to administration of a compound or agent to a subject who has a disorder or is at risk of developing the disorder with the purpose to cure, alleviate, relieve, remedy, delay the onset of, prevent, or ameliorate the disorder, the symptom of the disorder, the disease state secondary to the disorder, or the predisposition toward the disorder.EXAMPLES103281 Processes for preparing compounds of the present invention, such as Formulas A, I, la, II, Ila, in and Illa, or for preparing intermediates useful for preparing compounds of Formulas A, I, la, II, Ha, III and Illa or other formulas of the present disclosure are provided as further embodiments of the invention or are known in the art. While the following text may exemplify specific compounds and corresponding routes of synthesis, it is not intended to limit the scope of the invention to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of practical and economic considerations, such as the source of the agents and specific conditions of reactions.I0329 | Chemical Abbreviations:-142-SUBSTITUTE SHEET ( RULE 26 )Example 1 -chloro-2-hydroxy-3-((methoxymethoxy)methyl)-A-(6-(trifluoromethyl)benzo[6?]thiazol-2- yl)benzamide(l)SUBSTITUTE SHEET ( RULE 26 )[0330| To a stirred solution of methyl 5-chl oro-3 -(hydroxymethyl)-2- methoxybenzoate (106 mg, 0.46 mmol) in DCM (5 mL) was added DIPEA (240 pL, 1.38 mmol), MOMC1 (105 pL, 1.38 mmol) and followed by DMAP (3 mg, 0.023 mmol). The reaction mixture was stirred at rt overnight. After the reaction was completed, DCM and sat. Ammonia chloride solution were added. The organic layer was dried and concentrated, the residue was purified via silica gel column chromatography to give methyl 5-chloro-2- methoxy-3-((methoxymethoxy)methyl)benzoate (122 mg, 97%) as yellow oil. ’H NMR (300 MHz, Chloroform-d) 5 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 IN KOH solution. The resulting mixture was stirred at 60 °C overnight. After the mixture was cooled to rt, 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 pL, 1.075 mmol). The mixture was stirred for 10 minutes and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (47 mg, 0.215 mmol) was added. The resulting reaction was heated at 120 °C for 24 h. the mixture was cooled to rt, then separated between ethyl acetate and water. The organic layer was washed with brine, dried over NazSCL and concentrated in vacuo. Purification by column chromatography gave the 5-chloro-2-hydroxy- 3-((methoxymethoxy)methyl)-A-(6-(trifluoromethyl)benzo[<7]thiazol-2 yl)benzamide as a yellow solid (37 mg, 39%).XHNMR (400 MHz, Chloroform-d) 8 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]+requires m / z 469.02, found m / z 468.55.-144-SUBSTITUTE SHEET ( RULE 26 )Example 25-chloro-2 -hydroxy-3 -((2 -methoxy ethoxy )methyl)-JV-(6-(trifluoromethyl)benzo[ ]thiazol-2- yl)benzamide (2)

[0332] To a stirred solution of 5-chloro-2-methoxybenzoic acid (5.59g, 30 mmol) in sulfuric acid (10.2 mL) and TFA (20.4 mL) at rt was added NBS (5.87g, 33 mmol). The pale solution was stirred at rt 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 light yellow residue was suspended in a minimum amount of DCM. The solid was collected, washed with cold DCM and dried under vacuum to yield 3 -bromo-5-chloro-2-m ethoxybenzoic acid as a white solid (8.00g, 100%). ‘H NMR (300 MHz, acetone) 6 7.86 (d, 1H, J=3.0Hz), 7.78(d, 1H, J=3.0Hz), 3.91(s, 3H).

[0333] To a stirred solution of 3 -bromo-5-chloro-2 -methoxybenzoic acid (6g, 22.6 mmol) in DMF (30 mL) was added potassium carbonate (31g, 226 mmol) followed by CH3I-145-SUBSTITUTE SHEET ( RULE 26 )(1.4 mL, 22.6 mmol). The mixture was stirred at rt for 24 h. Water was added and extracted with ethyl acetate two times. The combined organic layer was washed with water and brine and dried over sodium sulfate The organic layer was filtered and the solvent removed in vacuo to yield a pale yellow oil (6.18g, 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 potassium phosphate tribasic (1.9g, 8.96 mmol) was refluxed in toluene(10 mL) and water (1 mL) under N2 overnight. After the reaction was cooled, saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over NajSCh and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5 -chi oro-2-m ethoxy-3 -methylbenzoate (520 mg, 91%) as a yellow oil. 'H NMR (300 MHz, chloroform) 5 7.62 (d, 1H, J=3.0Hz), 7.32(d, 1H, J=3.0Hz), 3.92(s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).[0335| To a flame dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201g, 0.93 mmol) in CCI4 (10 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%).1H NMR (300 MHz, cdcl3) 5 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-chl oro-3 -(bromomethyl)-2- methoxybenzoate (236 mg, 0.805 mmol) in 2-methoxyethanol (10 mL) was added 2NNaOH 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 HC1 dried over sodium sulfate and concentrated in vacuo. The residure was triturated with ether to give 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (204 mg, 93%) as yellow oil.XHNMR (300 MHz, cdcl3) 5 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]+requires 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 pL, 1.64 mmol). The resulting mixture was stirred at rt for 15mins, then 6-(trifluoromethyl)benzo[r / ]thiazol-2-amine (72 mg, 0.328 mmol) was added. The-146-SUBSTITUTE SHEET ( RULE 26 )resulting mixture was stirred at 130 °C for 24h. Saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over NazSCri and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-A-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow powder (34 mg, 30%). 'H NMR (300 MHz, acetone) 6 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]+requires m / z 483.04, found m / z 483.1.Example 35-chloro-2-hydroxy-3-(((2 -methoxy ethyl)(methyl)amino)methyl)-A-(6- (trifluoromethyl)benzo[< / ]thiazol-2-yl)benzamide (3) and 5-chloro-2-hydroxy-3-(((2- methoxyethyl)(methyl)amino)methyl)-JV-(6-(trifluoromethyl)benzo[tZ]thiazol-2-yl)benzamide hydrochloride (3 A)-147-SUBSTITUTE SHEET ( RULE 26 )

[0338] To a stirred solution of 5-chloro-2-methoxybenzoic acid (5.59g, 30 mmol) in sulfuric acid (10.2 mL) and TFA (20.4 mL) at rt was added NBS (5.87g, 33 mmol). The pale solution was stirred at rt overnight. The resulting pale suspension was carefully poured onto crushed ice. The mixture was extracted with ethyl acetate. The ethyl acetate layer dried over NazSCh and concentrated under reduced pressure. The light yellow residue was suspend in minimum amount of DCM. The solid was collected, washed with cold DCM and dried under vacuum to yield the 3-bromo-5-chloro-2-methoxybenzoic acid as a white solid (8.00g, 100%). 'l l NMR (300 MHz, acetone) S 7.86 (d, 1H, J=3.0Hz), 7.78(d, 1H, J=3.0Hz), 3.91(s, 3H).

[0339] To a stirred solution of 3 -bromo-5-chloro-2 -methoxybenzoic acid (6g, 22.6 mmol) in DMF (30 mL) was added potassium carbonate (31g, 226 mmol) followed by CH3I (1.4 mL, 22.6 mmol). The mixture was stirred at rt for 24 h. Water was added and extracted with ethyl acetate two times. The combined organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to yield a pale yellow oil (6.18g, 97%).-148-SUBSTITUTE SHEET ( RULE 26 )[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 potassium phosphate tribasic (1.9g, 8.96 mmol) was refluxed in toluene(10 mL) and water (1 mL) under N2 overnight. After the reaction was cooled, saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5 -chi oro-2-methoxy-3 -methylbenzoate (520 mg, 91%) as a yellow oil. 'H NMR (300 MHz, chloroform) 8 7.62 (d, 1H, J=3.0Hz), 7.32(d, 1H, J=3.0Hz), 3 92(s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).[0341[ To a flame dried flask was added NBS (492 mg, 2.767 mmol), AIBN (57 mg, 0.346 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (495 mg, 2.306 mmol) in CC14 (10 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (588 mg, 87%). 'H NMR (300 MHz, cdcl3) 6 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, to a stirred solution of methyl 5-chl oro-3 -(bromomethyl)-2- methoxybenzoate (500 mg, 1.71 mmol) in THF (6 mL) was added 2-methoxy-JV- methylethan- 1 -amine (370 pL, 3.41 mmol). The mixture was stirred at rt for 16 h. After completion of the reaction, the mixture was partitioned between NaHCCh and ethyl acetate. The aqueous layer was further extracted with ethyl acetate two times. The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduce pressure to afford methyl 5-chloro-2-methoxy-3-(((2- methoxyethyl)(methyl)amino)methyl)benzoate (437 mg, 85%) as a yellow oil.XH NMR (300 MHz, Chloroform-d) 8 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]+requires 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 IN KOH solution. The resulting mixture was stirred at 50 °C overnight. The solvent was evaporated out and 4N HC1 in dioxane (2 mL) was added to the residue. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (532 mg, 1.404 mmol), DMF (5 mL) and DIPEA-149-SUBSTITUTE SHEET ( RULE 26 )(1.02 mL, 5.85 mmol). The mixture was stirred for 10 minutes and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (255 mg, 1.17 mmol) was added. The resulting reaction was heated at 130 °C for 24hs. After cooling to rt, the mixture was separated between ethyl acetate and water. The organic layer was washed with brine, dried over NazSCh and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2- hydroxy-3-(((2-methoxyethyl)(methyl)amino)methyl)-Ar-(6-(trifluoromethyl)benzo[<7]thiazol- 2-yl)benzamide as a yellow solid (220 mg, 40%). 'H NMR (300 MHz, Methanol-d4) 8 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=6.0Hz, 2H), 3.44 (s, 3H), 3.35 (t, J=6.0Hz, 2H), 2 85 (s, 3H). MS (ESI) [M+H]+requires 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)-A-(6-(trifluoromethyl)benzo[< / ]thiazol-2-yl)benzamide (126 mg, 0.266 mmol) in THF (5 mL) was added 4. ON HC1 in dioxane (70 pL, 0.266 mmol). The mixture was stirred at rt for 20mins. The solvent was removed under reduce pressure and the resulting residue was washed with diethyl ether to afford 5-chloro-2-hydroxy-3-(((2- methoxyethyl)(methyl)amino)methyl)-A-(6-(trifluoromethyl)benzo[< / ]thiazol-2-yl)benzamide hydrochloride as a yellow solid (135 mg, 100%).Example 45-chloro-2V-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-3-((2- m ethoxy ethoxy )methyl)benzamide (4)-150-SUBSTITUTE SHEET ( RULE 26 )

[0345] To a stirred solution of 5 -chi oro-2-methoxy-3 -methylbenzoic acid (1.80g, 8.99 mmol) in DMF (10 mL) was added potassium carbonate (12.4g, 89.9 mmol) followed by CH3I (0.56 mL, 8.99 mmol). The mixture was stirred at rt for 24 h. Water was added and extracted with ethyl acetate two times. The combined organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to yield methyl 5-chloro-2-methoxy-3-methylbenzoate as a pale yellow oil (1.13g, 63%). 'HNMR (300 MHz, cdch) S 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, to a stirred solution of methyl 5-chloro-2-methoxy-3- methylbenzoate (241 mg, 1.12 mmol) in anhydrous DCM (5 mL) was added BBn (1.0M in DCM, 2.25 mL) dropwise. After addition, the reaction was allowed to warm to rt slowly and the mixture was stirred at rt for 2h. After completion of the reaction, the reaction mixture was cooled in an ice bath and MeOH and water were added to quench the reaction. The mixture was separated between DCM and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to afford methyl 5-chl oro-2 -hy droxy-3 - methylbenzoate as pale yellow solid (220 mg, 98%), which was used in the next step without further purification.10347] To a stirred solution of methyl 5-chl oro-2-hy droxy-3 -methylbenzoate (220 mg, 1.1 mmol) in anhydrous DCM (5 mL) was added pyridine (443 pL, 5.5 mmol), (Boc)2O (504 mg, 2.30 mmol) and DMAP (13 mg, 0.11 mmol). The resulting mixture was stirred at rt-151-SUBSTITUTE SHEET ( RULE 26 )for 2 days. After completion of the reaction, solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield methyl 2-((tert- butoxycarbonyl)oxy)-5-chloro-3-methylbenzoate (290 mg, 88%) as a colorless oil. 'H NAIR (300 MHz, cdch) 5 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).103481 To a flame dried flask was added NBS (205 mg, 1.156 mmol), AIBN (24 mg, 0.145 mmol) and a solution of methyl 2-(( / er / -butoxycarbonyl)oxy)-5-chloro-3- methylbenzoate (289 mg, 0.963 mmol) in CCL (5 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 3-(bromomethyl)-2-(( / er / - butoxycarbonyl)oxy)-5-chlorobenzoate as a colorless oil (220 mg, 62%). 'H MR (300 MHz, cdch) 5 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-(bromomcthyl)-2-(( / e / 7- butoxycarbonyl)oxy)-5-chlorobenzoate (220 mg, 0.582 mmol) in 2-methoxyethanol (10 mL) was added 2N NaOH solution (5 mL). The resulting mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was washed with 2N HC1 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. 'H NMR (300 MHz, cdch) 5 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]+requires m / z 283.03, found m / z 282.55.[0350| 5-chl oro-2 -hydroxy-3 -((2-methoxyethoxy)methyl)benzoic acid (65 mg,0.249 mmol) was dissolved in THF (3.0 mL), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (26 pL, 0.299 mmol) respectively. The reaction was allowed to stir at rt for 30 min and was concentrated in vacuo. The residue was re-dissolved in dioxane(5.0 mL) and 2-chloro-4-(trifluoromethyl)aniline (35 pL, 0.25 mmol) was added. The mixture was refluxed overnight. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield -chloro-A-(2-chloro-4- (trifluoromethyl)phenyl)-2-hydroxy-3 -((2 -m ethoxy ethoxy)methyl)benzamide (35 mg, 35%) as a white solid.LH NMR (500 MHz, cdch) 5 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),-152-SUBSTITUTE SHEET ( RULE 26 )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]+requires m / z 460.03, found m / z 459.95.Example 55-chloro-2-hydroxy-3-((2 -methoxy ethoxy )methyl)-iV-(6-(tri fluoromethoxy )benzo[c / ]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), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (40 pL, 0.34 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig’s base (59 pL, 0.34 mmol) and 6- (trifluoromethoxy)benzo[t / ]thiazol-2-amine (65 mg, 0.28 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-jV-(6--153-SUBSTITUTE SHEET ( RULE 26 )(trifluoromethoxy )benzo[ ]thiazol-2-yl)benzamide (27 mg, 34% yield) as a white solid. 'H NMR (500 MHz, cdch) 5 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]+requires m / z 491.07, found m / z 491.10.[0352| A solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-jV-(6- (trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (27 mg, 0.055 mmol,) in DMF (3 mL) is mixed with sodium ethoxide (18 mg, 0.275 mmol) and the resulting suspension is heated at 140 °C overnight. After completion of the reaction, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)- / V-(6- (trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (13 mg, 50%) as a yellow solid. 'H NMR (500 MHz, cdch) 5 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]+requires m / z 477.05, found m / z 477.30.Example 65-chloro-2-hydroxy-3-((2 -methoxy ethoxy )methyl)- / V-(5-(trifluoromethyl)pyrazin-2- yl)benzamide (6)-154-SUBSTITUTE SHEET ( RULE 26 )

[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), followed by the addition of catalytic amount of DMF (10 pL) and oxalyl chloride (34 pL, 0.39 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes, concentrated in vacuo, and the 5-chloro-2- methoxy-3-((2-methoxyethoxy)methyl)benzoyl chloride residue was re-dissolved 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) followed by addition of NaH (16.0 mg, 0.439 mmol, 60% in mineral oil) The mixture was stirred for 10 minutes before it was added dropwise at rt to the flask containing the freshly prepared 5-chloro-2-methoxy-3-((2- methoxyethoxy)methyl)benzoyl chloride. The reaction was stirred at rt for 2h before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-3-((2- methoxyethoxy)methyl)-A-(5-(trifluoromethyl)pyrazin-2-yl)benzamide as a white solid (32.0 mg, 23% yield). ‘H NMR (300 MHz, cdch) 8 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]+requires m / z 420.10, found m / z 420.30.10354] A solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)-A-(5- (trifluoromethyl)pyrazin-2-yl)benzamide (32 mg, 0.076 mmol) in DMF (3 mL) is mixed with sodium ethanethiolate (32 mg, 0.382 mmol) and the resulting suspension is heated at 130 °C overnight. After completion of the reaction, IN HC1 was added to the reaction and extractedSUBSTITUTE SHEET ( RULE 26 )with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-2-hydroxy-3-((2-methoxyethoxy)methyl)-A-(5- (trifluoromethyl)pyrazin-2-yl)benzamide (18 mg, 62%) as a yellow solid.XHNMR (300 MHz, acetone) 8 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]+requires m / z 406.08, found m / z 406.20.Example 75-chloro-2-hydroxy-3-((2-hydroxy ethoxy )methyl)-A-(6-(trifluoromethyl)benzo|T ]thiazol-2- yl)benzamide (7)[03551 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 potassium phosphate tribasic (1.9g, 8.96-156-SUBSTITUTE SHEET ( RULE 26 )mmol) was refluxed in toluene(10 mL) and water (1 mL) under N2 overnight. After the reaction was cooled, saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil.XH NMR (300 MHz, chloroform) 8 7.62 (d, 1H, J=3.0Hz), 7.32(d, 1H, J=3.0Hz), 3.92(s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).

[0356] To a flame dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0 093 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201 mg, 0.93 mmol) in CCL (10 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%). 'H NMR (300 MHz, cdch) 8 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).[0357J To a stirred solution of methyl 5-chl oro-3 -(bromomethyl)-2- methoxybenzoate (222 mg, 0.76 mmol) in 2-(terZ-butoxy)ethan-l-ol (4 mL) was added 2N NaOH solution (2 mL). The resulting mixture was stirred at rt for 4h and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was washed with 2N HC1 dried over sodium sulfate and concentrated in vacuo. The residure was triturated with ether to give 3-((2-(to7-butoxy)ethoxy)methyl)-5-chloro-2-methoxybenzoic acid as a yellow oil (100%). MS (ESI) [M-H]' requires m / z 315.10, found m / z 315.60.|0358] To a stirred solution of 3-((2-(terLbutoxy)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 pL, 3.8 mmol). The mixture was stirred for 10 minutes and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (165 mg, 0.76 mmol) was added. The resulting reaction was heated at 120 °C for 24 h. After cooled to rt, the mixture was separated 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-JV-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)benzamide as a yellow solid (27 mg, 10%).1HNMR (300 MHz, acetone) 8 8.35 (s, 1H), 7.96 (s, 1H), 7.72 (dd, J= 19.4, 8.5 Hz, 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]+requires m / z 503.10, found m / z 503.20.

[0359] To a stirred solution of 3-((2-(Ze / 7-butoxy)ethoxy)methyl )-5-chloro-2- hydroxy-A-(6-(trifluoromethyl)benzo[ ]thiazol-2-yl)benzamide (27 mg, 0.054 mmol) in-157-SUBSTITUTE SHEET ( RULE 26 )DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at rt overnight. The solvent was evaporated out and the remaining residue was subjected to flash column to afford 5- chloro-2-hydroxy-3-((2-hydroxyethoxy)methyl)-Ar-(6-(trifluoromethyl)benzo[<7]thiazol-2- yl)benzamide as a yellow solid (19 mg, 83%).XHNMR (300 MHz, acetone) 8 8.35 (s, 1H), 7.96 (s, 1H), 7.72 (dd, J= 19.4, 8.5 Hz, 2H), 7.41 (s, 1H), 4.89 (s, 2H), 4.06 (s, 2H), 3.82 (s, 2H). MS (ESI) [M+H]+requires m / z 447.04, found m / z 447.10.Example 85-chloro-jV-(6-fluorobenzo[tZ]thiazol-2-yl)-2-hydroxy-3-((2- m ethoxy ethoxy )methyl)benzamide (8)SUBSTITUTE SHEET ( RULE 26 )

[0360] To a flame dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201g, 0.93 mmol) in CC14 (10 mL). The suspension was refluxed in the dark overnight The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 3-(bromomethyl)-5-chloro-2 -methoxybenzoate as a colorless oil (236 mg, 87%). H NVIR (300 MHz, cdch) 87.76 (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).10361] To a stirred solution of 3 -(bromomethyl)-5-chl oro-2 -methoxybenzoate (180 mg, 0.614 mmol) in 2-methoxyethanol (5 mL) was added 2N NaOH solution (4 mL). The resulting mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was washed with 2N HC1 dried over sodium sulfate and concentrated in vacuo. The residure was triturated with ether to give 5- chloro-2-methoxy-3-((2-methoxy ethoxy )methyl)benzoic acid (170 mg, 100%) as yellow oil. 'H NMR (300 MHz, cdch) 8 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]+requires m / z 297.05, found m / z 296.6.10362] 5-chloro-2-methoxy-3-((2 -methoxyethoxy )methyl)benzoic acid (85 mg,0.31 mmol) was dissolved in DCM (3.0 mL), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (32 pL, 0.372 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and was concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig’s base (162 pL, 0.93 mmol) and 6- fluorobenzo[<7]thiazol-2-amine (52 mg, 0.31 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-A- (6-fluorobenzo[<7]thiazol-2-yl)-2-methoxy-3-((2-methoxy ethoxy )methyl)benzamide (52 mg, 41%) as a white solid. MS (ESI) [M+H]+requires m / z 425.08, found m / z 425.10.

[0363] A solution of 5-chloro-A-(6-fluorobenzo[t ]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, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-;V-(6-fluorobenzo[c / ]thiazol-2-yl)-2-hydroxy-3- ((2-methoxy ethoxy )methyl)benzamide (20 mg, 40%) as a yellow solid.LH NMR (300 MHz,-159-SUBSTITUTE SHEET ( RULE 26 )acetone) 5 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]+requires m / z 411 06, found m / z 411 10.Example 95-chloro-2-hydroxy-3-(methoxymethyl)- / V-(6-(trifluoromethyl)benzo[tZ]thiazol-2- yl)benzamide (9)

[0364] To a flame dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201g, 0.93 mmol) in CC14 (10 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 3-(bromomethyl)-5-chloro-2 -methoxybenzoate as a colorless oil (236 mg, 87%). 'H NMR (300 MHz, cdch) 57.76 (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).-160-SUBSTITUTE SHEET ( RULE 26 )[0365| To a stirred solution of methyl 3-(bromomethyl)-5-chloro-2- methoxybenzoate (270 mg, 0.921 mmol) in methanol (10 mL) was added 2NNaOH solution (7 mL). The resulting mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was washed with 2N HC1 dried over sodium sulfate and concentrated in vacuo. The residure was triturated with ether to give 5-chloro-2-methoxy-3-(methoxymethyl)benzoic acid (217 mg, 83%) as yellow oil which was used in the next step without further purification. MS (ESI) [M-H]' requires 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), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (97 pL, 1.13 mmol) respectively. The reaction was allowed to stir at rt for 30 min and concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig’s base (197 pL, 1.13 mmol) and 6-(trifluoromethyl)benzo[tZ]thiazol-2-amine (206 mg, 0.94 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-3-(methoxymethyl)-7V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (165 mg, 45%) as a yellow solid. MS (ESI) [M+H]+requires m / z 431.05, found m / z 431.10.

[0367] A solution of 5-chloro-2-methoxy-3-(methoxymethyl)-A-(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, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-2-hydroxy-3-(methoxymethyl)-7V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (90 mg, 94%) as a white solid. 'H NMR (300 MHz, cdch) 8 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]' requires m / z 415.02, found m / z 415.40.-161-SUBSTITUTE SHEET ( RULE 26 )Example 105-chloro-2-hydroxy-3-(pyri din-3-yl )-Af-(6-(tri fluoromethyl )benzo[<7]thiazol -2- yl)benzamide(lO) and 5-chloro-2-hydroxy-3-(pyridin-3-yl)-A-(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-pyridine boronic acid (184 mg, 1.5 mmol), PdC12(dpppf)-DCM(81 mg, 0.1 mmol) and 2M sodium carbonate (2 m ) in dioxane (5 m ) was heated to 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 via silica gel column chromatography to give methyl 5 -chi oro-2-m ethoxy-3 -(pyri din-3 -yl)benzoate (140 mg, 52%) as a white solid. 'H NMR (300 MHz, cdch) 5 8.74 (d, J= 40.1 Hz, 2H), 7.95 (d, J= 6.3 Hz, 1H), 7.81 (d, J= 1.5-162-SUBSTITUTE SHEET ( RULE 26 )Hz, 1H), 7.47 (brs, J= 17.7 Hz, 2H), 3.96 (s, 3H), 3.52 (s, 3H). MS (ESI) [M+H]+requires 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 IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 10% citric acid was added to the residue to pH=3. The mixture was extracted with DCM two times. The combined organic layer was dried over sodium sulfate and concentrated to afford 5-chloro-2-methoxy-3-(pyridin-3-yl)benzoic acid (132 mg, 100%) which was used directly in the next step without further purification as a yellow solid. MS (ESI) [M+H]+requires 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 pL, 0.60 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and then concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig’s base (104 pL, 0.60 mmol) and 6- (trifluoromethyl)benzo[4 / ]thiazol-2-amine (109 mg, 0.50 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-3-(pyridin-3-yl)- / V-(6-(trifluoromethyl)benzo[ ]thiazol-2- yl)benzamide (20 mg, 10%) as a yellow solid. 'H NMR (300 MHz, acetone) 5 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]+requires m / z 464.05, found m / z 464.20.[0371| At -78 °C, To a stirred solution of 5-chloro-2-methoxy-3-(pyridin-3-yl)-A- (6-(trifluoromethyl)benzo[tZ]thiazol-2-yl)benzamide (20 mg, 0.043 mmol) in anhydrous DCM (5 mL) was added BBr, (1.0M in DCM, 129 pL) dropwise. After addition, the reaction was allowed to warm to rt slowly and the mixture was stirred at rt for 2h. After completion of the reaction, the reaction mixture was cooled in an ice bath and MeOH and water was added to quench the reaction. The mixture was separated between DCM and water. The organic layer was washed with water, brine and dried over sodium sulfate, concentrated in vacuo. The residue was purified via silica gel column chromatography to afford 5-chloro-2-hydroxy-3- (pyridin-3-yl)-A-(6-(trifluoromethyl)benzo[ ]thiazol-2-yl)benzamide (12 mg, 63%) as a yellow solid. H NMR (300 MHz, acetone) 5 8.88 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 8.22 (s,-163-SUBSTITUTE SHEET ( RULE 26 )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]+requires m / z 450.03, found m / z 450.10.|0372] To a stirred solution of 5-chloro-2-hydroxy-3-(pyridin-3-yl)-A-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (12 mg, 0.0267 mmol) in THF (5 mL) was added 2. ON HC1 in ether (15 pL, 0.0267 mmol). The mixture was stirred at rt for 20mins. The resulting precipitate was fdtered and washed with diethyl ether to afford 5-chloro-2-hydroxy- 3-(pyridin-3-yl)-M-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (13 mg, 100%). MS (ESI) [M+H]+requires m / z 450.03, found m / z 450.10.Example 115-chloro-3-((c / s-2,6-dimethylmorpholino)methyl)-2-hydroxy- / V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide(l 1) and 5-chloro-3-((c7.s-2,6- dimethylmorpholino)methyl)-2-hydroxy-JV-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)benzamide hydrochloride (11 A)-164-SUBSTITUTE SHEET ( RULE 26 )[03731 Methyl 3-(dibromomethyl)-5-chloro-2-methoxybenzoate (370 mg, 1 mmol, Example 41) was dissolved in 4 mL concentrated sulfuric acid and the mixture was stirred at rt for 2h. The reaction mixture was poured into ice water and extracted with ethyl acetate two times. The combined organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was purified via silica gel column chromatography to give methyl 5-chloro-3-formyl-2-methoxybenzoate (220 mg, 96%) as a white solid. 'H NMR (300 MHz, cdch) 5 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-chl oro-3 -formyl-2-methoxybenzoate (220 mg, 0.965 mmol) in MeOH (10 mL) was added (25,6A)-2,6-dimethylmorpholine (238 pL, 1.93 mmol), NaBTLCN (121 mg, 1.93 mmol) and acetic acid (138 pL, 2.41 mmol). The resulting mixture was stirred at rt overnight. Saturated NaHCOs was added and extracted with DCM two times. The combined organic layer was concentrated in vacuo and the residue was purified via silica gel column chromatography to yield methyl 5-chloro-3-((cA-2,6- dimethylmorpholino)methyl)-2-methoxybenzoate as a yellow oil (232 mg, 75% yield). MS (ESI) [M+H]+requires m / z 328.20, found m / z 328.40.SUBSTITUTE SHEET ( RULE 26 )[03751 To a stirred solution of methyl 5-chloro-3-((c7.s-2,6- dimethylmorpholino)methyl)-2 -methoxybenzoate (232 mg, 0.71 mmol) in MeOH (4 mL) was added 3.5 mL IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (2 mL) was added to the residue. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (322 mg, 0.852 mmol), DMF (5 mL) and DIPEA (618 pL, 3.55 mmol). The mixture was stirred for 10 minutes and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (154 mg, 0.71 mmol) was added. The resulting reaction was heated at 120 °C for 24 h. After cooling to rt, the mixture was separated 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-((cA- 2,6-dimethylmorpholino)methyl)-2-hydroxy- / V-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)benzamide as a white solid (77 mg, 35%). 'H NMR (300 MHz, acetone) 8 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]+requires m / z 500.10, found m / z 500.30.|0376] To a stirred solution of 5-chloro-3-((cA-2,6-dimethylmorpholino)methyl)- 2-hydroxy-A-(6-(trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (77 mg, 0.154 mmol) in THF (5 mL) was added 2. ON HC1 in ether (77 pL, 0.154 mmol). The mixture was stirred at rt for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to afford - chi oro-3 -((cis-2, 6-dimethylmorpholino)m ethyl)-2-hy droxy-.V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide hydrochloride as a yellow solid (82 mg, 100%). MS (ESI) [M+H]+requires m / z 500.10, found m / z 500.30.Example 125-chloro-2-hydroxy-3-(thiazol-2-yl)-A-(6-(trifluoromethyl)benzo[<7]thiazol-2- yl)benzamide(12) and 5-chloro-2-hydroxy-3-(thiazol-2-yl)-A-(6- (trifluoromethyl)benzo[ ]thiazol-2-yl)benzamide hydrochloride (12A)-166-SUBSTITUTE SHEET ( RULE 26 )

[0377] A mixture of methyl 3-bromo-5-chloro-2-methoxybenzoate (277 mg, 0.99 mmol, Example 2), 2-tributylstannylthiazole (346 pL, 1.1 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in dioxane (2 m ) was heated to 150 °C for 20 minutes in a microwave under nitrogen. After cooling to rt, the mixture was filtered through celite, washed with ethyl acetate and concentrated in vacuo. The resulting solid was purified by flash column to obtain methyl 5 -chi oro-2-m ethoxy-3 -(thiazol -2 -yl)benzoate (237 mg, 85%) as a yellow solid. MS (ESI) [M+H]+requires 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 mb IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 10% citric acid was added to the residue to pH=3. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (379 mg, 1.0 mmol), DMF (5 mL) and DIPEA (729 pL, 4.185 mmol). The mixture was stirred for 10 minutess and then 6-(trifluoromethyl)benzo[tZ]thiazol-2-amine (182 mg, 0.837 mmol) was added. The resulting reaction was heated at 120 °C for 24h. After cooling to rt, the mixture was separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column-167-SUBSTITUTE SHEET ( RULE 26 )chromatography gave 5-chloro-2-hydroxy-3-(thiazol-2-yl)- / V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a yellow solid (177 mg, 47%). 'H NMR (300 MHz, cdch) 5 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). MS (ESI) [M+H]+requires m / z 455.99, found m / z 456.2.103791 To a stirred solution of 5-chloro-2-hydroxy-3-(thiazol-2-yl)- / V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (177 mg, 0.389 mmol) in THF (5 mL) was added 2N HC1 in ether (195 pL, 0.389 mmol). The mixture was stirred at rt for 20 minutess. The resulting precipitate was filtered and washed with diethyl ether to afford 5-chloro-2- hydroxy-3-(thiazol-2-yl)-iV-(6-(trifluoromethyl)benzo[t7]thiazol-2-yl)benzamide hydrochloride as a yellow solid (191 mg, 100%). MS (ESI) [M+H]+requires m / z 455.99, found m / z 456.2.Example 135-chloro-2-hydroxy-iV-(4-((2-methoxy ethoxy )methyl)-6-('tri fluoromethyl )benzo[c / ]thiazol-2- yl)-3 -methylbenzamide (13)SUBSTITUTE SHEET ( RULE 26 )[0380 | A mixture of 2-methyl-4-(trifluoromethyl)aniline (525 mg, 3 mmol), NH4SCN (228 mg, 3 mmol) and TFA (574 pL, 7.5 mmol) in ethyl acetate (5 mL) was refluxed overnight. After cooling to rt, 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 via silica gel column chromatography to give l-(2-m ethyl - 4-(trifluoromethyl)phenyl)thiourea (347 mg, 50%) as a yellow solid. MS (ESI) [M+H]+requires m / z 235.05, found m / z 235.30.-169-SUBSTITUTE SHEET ( RULE 26 )[03811 At 0 °C, a solution of Bn (76 pL, 1.48 mmol)in CHCh (2 mL) was added dropwise to a stirred solution of l-(2-methyl-4-(trifluoromethyl)phenyl)thiourea (347 mg, 1.48 mmol) in CHCh (5 mL). After completion of the addition, the mixture was heated to reflux overnight. After cooling to rt, the precipitated out white solid was filtered and collected, neutralized by addition ammoniaand further extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 4-methyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (125 mg, 37%) as a white solid which was used in the next step without further purification. MS (ESI) [M+H]+requires m / z 233.04, found m / z 233.20.[0382[ To a stirred solution of 4-rnethyl-6-(trifluoromethyl)benzo[<7]thiazol-2- amine (97 mg, 0.418 mmol) and (Boc O (262 mg, 1.2 mmol) in anhydrous DCM (4 mL) was added DMAP (5 mg, 0.0418 mmol). The resulting mixture was stirred at rt for 5h. After completion of the reaction, ethyl acetate was added and washed sequentially with saturated NH4CI, water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the tert-butyl N-tert- butoxycarbonyl-JV- (4-(m ethyl )-6-(trifluoromethyl)benzo / r / / thiazol-2-yl)carbamate (180 mg, 100%) as a yellow solid which was used in the next step without further purification. MS (ESI) [M+H]+requires m / z 433.14, found m / z 433.4.[0383| A mixture of tert-butyl A-tert-butoxycarbonyl-A- (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 CCI4 (5 mL) was refluxed for 2.5h under nitrogen. After cooling to rt, the mixture was concentrated and the residue was subjected to chromatography to afford tert-butyl A-(4-(bromomethyl)-6-(trifluoromethyl)benzo[ ]thiazol- 2-yl)-A-tert-butoxycarbonylcarbamate (210 mg, 98%) as a yellow solid. MS (ESI) [M+H]+requires m / z 511.05, found m / z 511.20.|0384] To a stirred solution of tert-butyl A-(4-(bromomethyl)-6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)-A-tert-butoxycarbonylcarbamate (210 mg, 0.411 mmol) in 2-methoxyethan-l-ol (8 mL) was added IN NaOH (4 mL). The resulting mixture was stirred at rt 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 via silica gel column chromatography to give te / 7-butyl (4-((2-methoxyethoxy)methyl)-6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)carbamate (86 mg, 52%) as a colorless oil. MS (ESI) [M+H]+requires m / z 407.13, found m / z 407.3.-170-SUBSTITUTE SHEET ( RULE 26 )[0385| To a stirred solution of Zc / 7-butyl (4-((2-methoxyethoxy)methyl)-6- (trifluoromethyl)benzo[<i]thiazol-2-yl)carbamate (86 mg, 0.212 mmol) in DCM (4 mL) was added TFA (3 mL), the resulting mixture was stirred at rt for 2h After completion of the reaction, the excess of TFA was evaporated out 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 as a pale yellow solid (62 mg, 97%) which was used in the subsequent step without further purification. MS (ESI) [M+H]+requires 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 potassium phosphate tribasic (1.9g, 8.96 mmol) was refluxed in toluene(10 mL) and water (1 mL) under N2 overnight. After the reaction was cooled, saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-methylbenzoate (520 mg, 91%) as a yellow oil.XH NMR (300 MHz, chloroform) 5 7.62 (d, 1H, J=3.0Hz), 7.32(d, 1H, J=3.0Hz), 3.92(s, 3H), 3.82 (s, 3H), 2.30 (s, 3H).[03871 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 IN KOH solution. The resulting mixture was stirred at rt overnight. After completion of the reaction, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressureto afford 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.[0388J 5-chloro-2-methoxy-3-methylbenzoic acid (40 mg, 0.20 mmol) was dissolved in DCM (3.0 mL), followed by the addition of acatalytic amount of DMF (1 drop) and oxalyl chloride (21 pL, 0.243 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig’s base (43 pL, 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 rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to-171-SUBSTITUTE SHEET ( RULE 26 )yield 5-chloro-2-methoxy-JV-(4-((2-methoxy ethoxy )methyl)-6- (trifluoromethyl)benzo[J]thiazol-2-yl)-3-methylbenzamide (20 mg, 21%) as a white solid. MS (ESI) [M+H]+requires m / z 489 08, found m / z 489 20.|0389] A solution of 5-chloro-2-methoxy-JV-(4-((2-methoxy ethoxy )methyl)-6-(trifluoromethyl)benzo[ ]thiazol -2 -yl)-3 -methylbenzamide (20 mg, 0.04 mmol) in DMF (5 mL) is mixed with sodium ethanethiolate (17 mg, 0.205 mmol) and the resulting suspension is heated at 130 °C overnight. After completion of the reaction, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give the 5-chloro-2-hydroxy- / V-(4-((2- methoxy ethoxy )methyl)-6-(trifluoromethyl)benzo[<7]thiazol-2-yl)-3 -methylbenzamide (15 mg, 55%) as a white solid.XHNMR (300 MHz, cdcl3) 57.95 (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]+requires m / z 475.06, found m / z 475.20.Example 145-chl oro-2 -hydroxy-3-(tetrahydrofuran-3-yl)- / V-(6-(trifluorornethyl)benzo[d]thi azol -2- yl)benzamide (14)-172-SUBSTITUTE SHEET ( RULE 26 )[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(PPhi)4 (56 mg, 0.049 mmol) and sodium carbonate (312 mg, 2.95 mmol) in dioxane (3 mL) and water (1 mL) was irradiated under microwave at 100 °C for Ih under nitrogen. After cooling to it, 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 via silica gel column chromatography to give methyl 5-chl oro-3 -(furan-3-yl)-2 -methoxybenzoate (250 mg, 96%) as a colorless oil. MS (ESI) [M+H]+requires 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 at rt under hydrogen atmosphere for 5h. The reaction mixture was filtered and the filtrate was concentrated to afford 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]+requires 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 24h. After cooling to rt, the solvent was concentrated and the residue was subjected to column directly to afford methyl 5-chloro-2-methoxy-3-(tetrahydrofuran-3-yl)benzoate (85 mg, 31%) as a colorless oil. 'HNMR (300 MHz, cdch) 8 7.66 - 7.60 (m, IH), 7.42 (d, J= 2.7 Hz, IH), 4.11-173-SUBSTITUTE SHEET ( RULE 26 )- 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]+requires m / z 271.07, found m / z 271.2.|0393] To a stirred solution of 5-chloro-2-methoxy-3-(tetrahydrofuran-3- yl)benzoate (85 mg, 0.315 mmol) in MeOH (5 mL) was added 2.0 mL IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (1 mL) was added to the residue The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (143 mg, 0.378 mmol), DMF (5 mL) and DIPEA (274 pL. 1.575 mmol). The mixture was stirred for 10 minutes and then 6-(trifluoromethyl)benzo[<7]thiazol-2-amine (68 mg, 0.315 mmol) was added. The resulting reaction was heated at 120 °C for 24h. After cooling to rt, the mixture was separated 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-hy droxy-3 -(tetrahy drofuran-3 -y 1 )- N- (6 - (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a white solid (14 mg, 10%). 'H NMR (400 MHz, acetone) 6 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]+requires m / z 443.04, found m / z 443.3.Example 155-chl oro-2 -hy droxy-3-(tetrahydrofuran-2-yl)- / V-(6-(trifluoromethyl)benzo[ ]thi azol -2- yl)benzamide (15)-174-SUBSTITUTE SHEET ( RULE 26 )

[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 for Ih under nitrogen. After cooling to rt, 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 via silica gel column chromatography to give methyl 5-chl oro-3 -(furan -2 -yl)-2 -methoxybenzoate (131 mg, 55%) as a colorless oil. MS (ESI) [M+H]+requires m / z 267.03, found m / z 267.20.

[0395] A mixture of methyl 5-chl oro-3 -(furan-2-yl)-2-methoxybenzoate (131 mg, 0.5 mmol) and Pd-C (15 mg) in MeOH (5 mL) was stirred at rt under hydrogen atmosphere for 6h. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3- (tetrahydrofuran-2-yl)benzoate (95 mg, 70%) as a colorless oil. 'H NMR. (300 MHz, cdch) 8 7.71 (d, 7= 2.8 Hz, IH), 7.62 (dd, 7= 2.8, 0.6 Hz, IH), 5.13 (t, 7= 7.2 Hz, IH), 4.16 - 4.08 (m, IH), 3.99 - 3.90 (m, IH), 3.93 (s, 3H), 3.84 (s, 3H), 2.52 - 2.38 (m, IH), 2.07 - 1.96 (m, 2H), 1.73 - 1.65 (m, IH). MS (ESI) [M+H]+requires m / z 271.07, found m / z 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 IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (1 mL) was added to the residue. The mixture was stirred for another 10 minutes-175-SUBSTITUTE SHEET ( RULE 26 )before it was concentrated and dried under vacumn. To this residue was added HBTU (160 mg, 0.422 mmol), DMF (5 mL) and DIPEA (306 pL, 1.76 mmol). The mixture was stirred for 10 minutes and then 6-(trifluoromethyl)benzo[<7]thiazol-2-amine (76 mg, 0.352 mmol) was added. The resulting reaction was heated at 120 °C for 24h. After cooling to rt, the mixture was separated 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-chl oro-2-hydroxy-3-(tetrahydrofuran-2-yl)-A-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide as a white solid (15 mg, 10%). 'H NMR (500 MHz, acetone) 5 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]+requires m / z 443.04, found m / z 443.3.Example 165-chloro-2-hydroxy-3-(morpholinomethyl)-jV-(6-(trifluoromethyl)benzo[6?]thiazol-2- yl)benzamide(16) and 5-chl oro-2 -hy droxy-3-(morpholinomethyl)-A'-(6- (trifluoromethyl)benzo[6?]thiazol-2-yl)benzarnide hydrochloride (16A)-176-SUBSTITUTE SHEET ( RULE 26 )[0397| To a flame dried flask was added NBS (183 mg, 1.03 mmol), AIBN (15 mg, 0.093 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (201g, 0.93 mmol) in CCh (10 mL). The suspension was refluxed in the dark overnight. The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(bromomethyl)-2-methoxybenzoate as a colorless oil (236 mg, 87%). 'l l NMR (300 MHz, cdch) 57.76 (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, to a stirred solution of methyl 5-chl oro-3 -(bromomethyl)-2- methoxybenzoate (132 mg, 0.45 mmol) in THF (4 mL) was added morpholine (78 pL, 0.90 mmol) and the mixture was stirred at rt for 6h. After completion of the reaction, the reaction was partitioned between DCM and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column to afford methyl 5 -chi oro-2-m ethoxy-3 -(morpholinomethyl)benzoate (110 mg, 83%) as a colorless oil.-177-SUBSTITUTE SHEET ( RULE 26 )XHNMR (500 MHz, cdcl3) 8 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]+requires 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 IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (1 mL) was added to the residue. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (168 mg, 0.442 mmol), DMF (5 mL) and DIPEA (320 pL, 1.84 mmol) The mixture was stirred for 10 minutes and then 6-(trifluoromethyl)benzo[tZ]thiazol-2-amine (80 mg, 0.368 mmol) was added. The resulting reaction mixturewas heated at 120 °C for 24h. After cooling to rt, the mixture was separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography gave 5-chloro-2-hydroxy-3-(morpholinomethyl)-7V- (6-(trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (75 mg, 43%) as a yellow solid. ’H NMR (400 MHz, dmso) 8 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]+requires m / z 472.07, found m / z 472.20.[04(H)] To a stirred solution of 5-chloro-2-hydroxy-3-(morpholinomethyl)-A-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (32 mg, 0.068 mmol) in THF (5 mL) was added 4. ON HC1 in dioxane (20 pL, 0.075 mmol). The mixture was stirred at rt for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to afford 5- chloro-2-hydroxy-3-(morpholinomethyl)-7V-(6-(trifluoromethyl)benzo[<7]thiazol-2- yl)benzamide hydrochloride as a yellow solid (100%). MS (ESI) [M+H]+requires m / z 472.07, found m / z 472.20.-178-SUBSTITUTE SHEET ( RULE 26 )Example 175-chloro-2-hydroxy-3-(2-morpholinoethyl)-A-(6-(trifluoromethyl)benzo[< / ]thiazol-2- yl)benzamide(17) and 5-chl oro-2 -hy droxy-3-(2-morpholinoethyl)-A-(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)C12, (40-179-SUBSTITUTE SHEET ( RULE 26 )mg, 0.05 mmol), and sodium carbonate (339 mg, 3.2 mmol) was refluxed in dioxane (10 mL) and water (1 mL) under N2 overnight. After the reaction was cooled, saturated NH4CI solution was added and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3- vinylbenzoate (320 mg, 89%) as a colorless oil.XHNMR (300 MHz, cdch) 57.69 (d, J= 2.7 Hz, 1H), 7.63 (d, .7= 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, to a stirred solution of methyl 5-chloro-2-methoxy-3- vinylbenzoate (270 mg, 1.19 mmol) was added 9-BBN (3.1 mL, 1.55 mmol, 0.5M in THF) dropwise. After completion of the addition, the mixture was allowed to stir at rt overnight. The reaction was cooled to 0 °C and 1 mL of 50% H2O2 solution was added followed by 1 mL of 3M NaOH solution. The mixture was stirred over an ice bath for 2h. The reaction was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(2-hydroxyethyl)-2-methoxybenzoate (110 mg, 50%) as a colorless oil. 'H NMR (400 MHz, d2o) 5 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]+requires m / z 245.06, found m / z 245.20.

[0403] At 0 °C, to a stirred solution of methyl 5-chl oro-3 -(2 -hydroxy ethyl)-2- methoxybenzoate (110 mg, 0.451 mmol) in DCM (3 mL) was added TEA (95 pL, 0.677 mmol) and MsCl (42 pL, 0.54 mmol). The resulting mixture was stirred at 0 °C for Ih. The reaction mixture was partitioned between DCM and saturated NH4CI solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-(2- ((methylsulfonyl)oxy)ethyl)benzoate (119 mg, 83%) as a colorless oil. 'H NMR (500 MHz, cdch) 8 7.71 (d, J= 2.7 Hz, IH), 7.37 (d, J= 2.7 Hz, IH), 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] To a stirred solution of methyl 5-chloro-2-methoxy-3-(2- ((methylsulfonyl)oxy)ethyl)benzoate (119 mg, 0.369 mmol) in DMF (3 mL) was added morpholine (160 pL, 1.84 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was partitioned between water and DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give methyl 5-chloro-2-methoxy-3-(2-morpholinoethyl)benzoate-180-SUBSTITUTE SHEET ( RULE 26 )(91 mg, 83%) as a yellow oil. 'H NMR (300 MHz, cdch) 57.65 (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]+requires m / z 314 12, found m / z 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 IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (1 mL) was added to the residue. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (132 mg, 0.35 mmol), DMF (5 mL) and DIPEA (253 pL, 1. 45 mmol). The mixture was stirred for 10 minutes and then 6-(trifluoromethyl)benzo[t / ]thiazol-2-amine (64 mg, 0.29 mmol) was added. The resulting reaction was heated at 120 °C for 24h. After cooling to rt, the mixture was separated 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)- / V-(6- (trifluoromethyl)benzo[< ]thiazol-2-yl)benzamide (56 mg, 40%) as a yellow solid. H NMR (300 MHz, acetone) 6 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]+requires m / z 486.10, found m / z 486.20.

[0406] To a stirred solution of 5-chloro-2-hydroxy-3-(2-morpholinoethyl)- / V-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (36 mg, 0.074 mmol) in THF (5 mL) was added 4. ON HC1 in dioxane (21 pL, 0.082 mmol). The mixture was stirred at rt for 20 minutes. The resulting precipitate was filtered and washed with diethyl ether to afford 5- chloro-2-hydroxy-3-(2-morpholinoethyl)-A-(6-(trifluoromethyl)benzo[c ]thiazol-2- yl)benzamide hydrochloride as a yellow solid (100%). MS (ESI) [M+H]+requires m / z 486.10, found m / z 486.20.Example 185-chloro- / V-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2- hydroxybenzamide (18)-181-SUBSTITUTE SHEET ( RULE 26 )[0407| Methyl 3-bromo-5-chloro-2-methoxybenzoate (6.18g, 22.07 mmol, Example 2), potassium (2-((fer / -butoxycarbonyl)amino)ethyl)trifluoroborate (16.6g, 66.21 mmol), Pd(dppf)C12 (968 mg, 1.32 mmol) and CS2CO3 (21.5g, 66.21 mmol) were added to a flask. This 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 at 80 °C under N2 overnight. Saturated NH4CI solution was added and the resulting mixture was extracted with ethyl acetate two times. The combined organic layer was concentrated in vacuo and the residue was purified via silica gel column chromatography to yield methyl 3- (2-((ter / -butoxycarbonyl)amino)ethyl)-5-chloro-2-methoxybenzoate as a yellow oil (1.51g, 20% yield). 1H NMR (300 MHz, cdcl3) 5 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]+requires m / z 366.11, found m / z 365.95.

[0408] Methyl 3 -(2-((tert-butoxy carbonyl )ami no)ethyl )-5-chl oro-2 - methoxybenzoate (1.12g, 3.26 mmol) was dissolved in 4N HC1 in dioxane (5 mL) and the-182-SUBSTITUTE SHEET ( RULE 26 )resulting mixture was stirred at rt for 2h. Saturated NaHCCh solution was added and 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 removed in vacuo to yield methyl 3-(2-aminoethyl)-5-chloro-2-methoxybenzoate as a pale yellow oil (475 mg, 60%). 1H NMR (500 MHz, cdcl3) 8 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]+requires 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 pL, 1.64 mmol, 37% wt in H2O), NaBHsCN (103 mg, 1.64 mmol) and acetic acid (117 pL, 2.06 mmol). The resulting mixture was stirred at rt overnight. Saturated NaHCCh was added and extracted with DCM two times. The combined organic layer was concentrated in vacuo and the residue was purified via silica gel column chromatography to yield methyl 5-chloro-3-(2- (dimethylamino)ethyl)-2-methoxybenzoate as a yellow oil (88 mg, 82% yield). 'H NMR (300 MHz, cdcl3) 87.66 (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]+requires m / z 272.10, found m / z 272.05.

[0410] To a stirred solution of methyl 5-chl oro-3 -(2-(dimethylamino)ethyl)-2- methoxybenzoate (82 mg, 0.3 mmol) in MeOH (3 mL) was added IN KOH (1 mL) solution. The mixture was stirred at rt overnight. IN HC1 was added to adjust the pH to 1. The mixture was concentrated in vacuo. The residue was dissolved in DCM (3 mL) followed by the addition of catalytic amount of DMF (1 drop) and oxalyl chloride (32 pL, 0.36 mmol) respectively. The reaction was allowed to stir at rt for 2h then concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig’s base (157 pL, 0.90 mmol) and 2- chloro-4-(trifluoromethyl)aniline (42 pL, 0.30 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5- chloro- / V-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2- methoxybenzamide (124 mg, 95%) as a white solid. 'H NMR (300 MHz, cdch) 8 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= 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]+requires m / z 435.09, found m / z 435.0.

[0411] At -78 °C, to a stirred solution of 5-chloro-7V-(2-chloro-4- (trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)-2-methoxybenzamide (69 mg, 0.16-183-SUBSTITUTE SHEET ( RULE 26 )mmol) in anhydrous DCM (5 mL) was added BBr3(1.0M in DCM, 0.635 m ) dropwise. After addition, the reaction was allowed to warm to rt slowly and the mixture was stirred at rt for 2h. After completion of the reaction, the reaction mixture was cooled in an ice bath and MeOH and water were added to quench the reaction. The mixture was separated between DCM and water. The organic layer was washed with water, brine and dried over sodium sulfate, concentrated in vacuo. The residue was purified via silica gel column chromatography to afford 5-chloro-A-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2- (dimethylamino)ethyl)-2-hydroxybenzamide (56 mg, 85%) as a yellow solid.LH NMR (300 MHz, cdcl3) 5 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]+requires m / z 421.07, found m / z 421.20.Example 193 -((4-acetylpiperazin-l-yl)methyl)-5-chl oro-2 -hydroxy -N-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (19) and 3-((4-acetylpiperazin-l- yl)methyl)-5-chloro-2-hydroxy-A-(6-(trifluoromethyl)benzo[< / ]thiazol-2-yl)benzamide hydrochloride (19A)-184-SUBSTITUTE SHEET ( RULE 26 )|0412] At 0 °C, to a stirred solution of methyl 3-(bromomethyl)-5-chloro-2- methoxybenzoate (257 mg, 0.88 mmol, Example 2) in THF (5 mL) was added 1 -(piperazin- 1- yl)ethan-l-one (225 mg, 1.754 mmol) and the mixture was stirred at rt for 6h. After completion of the reaction, the reaction was partitioned between DCM and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column to afford methyl 3-((4-acetylpiperazin-l-yl)methyl)-5- chloro-2-methoxybenzoate (265 mg, 89%) as a colorless oil. 'H NMR (300 MHz, cdch) 5 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-l-yl)methyl)-5- chloro-2-methoxybenzoate (265 mg, 0.78 mmol) in MeOH (5 mL) was added 4.0 mL IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (2 mL) was added to the residue. The mixture was stirred for another 10 minutes before it was concentrated and dried under vacumn. To this residue was added HBTU (356 mg, 0.94 mmol), DMF (5 mL) and DIPEA (680 pL, 3.9 mmol). The mixture was stirred for 10 minutes and then 6-(trifluoromethyl)benzo[tZ]thiazol-2-amine (170 mg, 0.78 mmol) was added. The resulting reaction was heated at 120 °C for 24h. After cooling to rt, the mixture was separated 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-l-yl)methyl)-5-chloro-2-hydroxy-A-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (101 mg, 30%) as a yellow solid. 'H NMR (300 MHz, cdch) 5 8.19 (d, J= 2.6 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J= 8.6 Hz, 1H), 7.70 (d, J-185-SUBSTITUTE SHEET ( RULE 26 )= 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]+requires m / z 513.10, found m / z 513.30.|0414] To a stirred solution of 3-((4-acetylpiperazin-l-yl)methyl)-5-chloro-2- hydroxy- / V-(6-(trifluoromethyl)benzo[^ / ]thiazol-2-yl)benzamide (101 mg, 0.197 mmol) in THF (5 mL) was added 2N HC1 in ether (100 pL, 0.2 mmol). The mixture was stirred at rt for 20 minutess. The resulting precipitate was fdtered and washed with diethyl ether to afford 3- ((4-acetylpiperazin- l-yl)methyl )-5-chloro-2-hydroxy-A',-(6-(trifluoromethyl)benzo[<7]thiazol- 2-yl)benzamide hydrochloride as a yellow solid (100%). MS (ESI) [M+H]+requires m / z 513 10, found m / z 513 30.Example 205-chloro-2-hydroxy-3-((2 -methoxy ethoxy )methyl)-JV-(6-(trifluoromethyl)pyri din-3- yl)benzamide (20) and 5-chloro-2-hydroxy-3-((2-methoxy ethoxy )methyl)-jV-(6- (trifluoromethyl)pyridin-3-yl)benzamide hydrochloride (20A)(0415] To a solution of 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (200 mg, 728.08 pmol, Example 2), 6-(trifluoromethyl)pyridin-3-amine (118 mg, 728.08 pmol) in pyridine (2 mL) was added POCh (167 mg, 1.09 mmol, 101.49 pL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (3 mL) and extracted with DCM (3 mL x 3). The combined organic layers were washed with brine 5 mL, dried over NazSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate = 3:1) to afford 5-chloro-2--186-SUBSTITUTE SHEET ( RULE 26 )methoxy-3-((2-methoxyethoxy)methyl)-A-(6-(trifluoromethyl)pyridine-3-ylbenzamide (117 mg, 212.32 pmol, 29.16% yield, 76% purity) as a white solid. MS (ESI) [M+H]+requires m / z 419.09, found m / z 4192|0416] To 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)- / V-(6- (trifluoromethyl)pyridine-3-ylbenzamide (95 mg, 226.84 pmol) in DMF (2 mL) was added NaSEt (38 mg, 453.68 pmol) and the mixture was stirred at 160 °C for 2h The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition) to afford 5-chloro-2-hydroxy-3-((2- methoxyethoxy)methyl)-Ar-(6-(trifluoromethyl)pyridin-3-yl)benzamide (32.99 mg, 73 67 pmol, 32.48% yield, 98.537% purity, HC1) as a brown solid. MS (ESI) [M+H]+requires m / z 405.08, found m / z 405.0.XHNMR (400 MHz, METHANOL-d4) 5 ppm 8.93 (d, J = 2.19 Hz, 1 H), 8.37 (dd, J = 8.33, 2.19 Hz, 1 H), 7.90 (d, J = 2.19 Hz, 1 H), 7.74 (d, J = 8.77 Hz, 1 H), 7.52 (d, J = 2.63 Hz, 1 H), 4.53 (s, 2 H), 3.60 - 3.66 (m, 2 H), 3.51 - 3.56 (m, 2 H), 3.22 (dt, J = 3.29, 1.43 Hz, 3 H).Example 215-chl oro-2 -hy droxy-3-((2-methoxy ethoxy)methyl)-A-(2-(trifluoromethyl)pyrimidin-5- yl)benzamide (21)|0417] Using a method similar to Example 20, 5-chloro-2-hydroxy-3-((2- methoxyethoxy)methyl)- / V-(2-(trifluoromethyl)pyrimidin-5-yl)benzamide was obtained. MS (ESI) [M+H]+requires m / z 406.07, found m / z 406.0. 'HNMR (400 MHz, METHANOL-d4) 5 ppm 9.35 (s, 2 H), 8.00 (d, J = 2.43 Hz, 1 H), 7.64 (s, 1 H), 4.64 (s, 2 H) 3.73 (dd, J = 5.62, 3.42 Hz, 2 H), 3.60 - 3.66 (m, 2 H), 3.40 (s, 3 H).-187-SUBSTITUTE SHEET ( RULE 26 )Example 225-chloro-2-hydroxy-3-(((2-methoxyethyl)amino)methyl)-A-(6- (trifluoromethy l)b cnzo[t / ] th i azol -2-y l)b enzami de (22)|0418] A solution of 5-chloro-2-hydroxybenzoic acid (10 g, 57.95 mmol), and6,7,8,9-tetrazatricyclodecane (16.2 g, 115.90 mmol) in TFA (100 mL) was stirred at 100 °C for 12 h, then cooled to 20 °C, followed by addition of HCI (100 mL, 3M). The reaction mixture was stirred for another 1 h, then concentrated under reduced pressure. The white residue was suspend in water (50 mL). The solid was collected and dried under vacuum to obtained 5-chloro-3-formyl-2 -hydroxybenzoic acid (6 g, crude) as a white solid. 'H NMR (400 MHz, DMSO-dg) 8 ppm 10.30 (s, 1 H), 8.02 (br d, J = 2.45 Hz, 1 H), 7.83 (br d, J = 2.93 Hz, 1 H)|0419| A mixture of 5-chloro-3-formyl-2 -hydroxybenzoic acid (2 g, 9.97 mmol), 6-(trifluoromethyl)benzo[<7]thiazol-2-amine (2.1 g, 9.97 mmol) and EDCI (2.2 g, 11.97 mmol), 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 solvent, then H2O (20 mL) was added and NaOH (3M) was added until the pH was- 9-10. The reaction mixture was extracted with ethyl acetate (30 mL x 2), then concentrated to remove ethyl acetate. The residue was diluted with ethyl acetate (30 mL), solid precipitated, filtered and concentrated under reduced pressure to give 5-chloro-3-formyl-2-hydroxy-A-(6-(trifluoromethyl)benzo[ri]thiazol-2- yl)benzamide (580 mg, 5.8% yield) as a yellow solid.LH NMR (400 MHz, DMSO-de) 8 ppm-188-SUBSTITUTE SHEET ( RULE 26 )10.34 (s, 1 H), 8.43 (s, 1 H), 7.95 (d, J = 3.09 Hz, 1 H), 7.86 (d, J = 8.38 Hz, 1 H), 7.70 (br d, J = 8.60 Hz, 1 H), 7.49 (d, J = 3.31 Hz, 1 H). MS (ESI) [M+H]+requires m / z 400.99, found m / z 401.1.|0420] To a solution of 2-methoxyethanamine (22 mg, 299.43 pmol), 5-chloro-3- formyl-2-hydroxy-A-(6-(trifluoromethyl)benzo[J]thiazol-2-yl)benzamide (100 mg, 249.53 pmol) in MeOH (4 mb) was added acetic acid (3 mg, 49.91 pmol, 2.85 pL) to make pH ~ 5- 6. The mixture was stirred at 20 °C for 2 h, then NaBFECN (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 solvent. The residue was purified by prep-HPLC (HC1 condition) to afford 5-chloro- 2-hydroxy-3-(((2-methoxyethyl)amino)methyl)-jV-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)benzamide (28.30 mg, 57.02 pmol, 22.85% yield, 100% purity, HC1) as a brown solid. 'H NMR (400 MHz, METHANOL-d4) 8 ppm 8.27 (s, 1 H), 8.20 (d, J = 2.45 Hz, 1 H), 7.74 - 7.82 (m, 2 H), 7.63 (d, J = 2.45 Hz, 1 H), 4.31 (s, 2 H), 3.67 - 3.72 (m, 2 H), 3.44 (s, 3 H), 3.28 (d, J = 4.89 Hz, 2 H). MS (ESI) [M+H]+requires m / z 460.06, found m / z 460.2Example 235-chloro-2-hydroxy-3-(pyrrolidin-l-ylmethyl)-JV-(6-(trifluoromethyl)benzo[< / ]thiazol-2-yl) benzamide (23)

[0421] 5-chl oro-2 -hydroxy-3-(pyrrolidin-l-ylmethyl)-7V-(6-(trifluoromethyl)benzo[d]thiazol-2-yl) benzamide was made in a similar manner as the described in Example 22. MS (ESI) [M+H]+requires m / z 456.07, found m / z 456.2. 'H NMR (400 MHz, METHANOL-d4) 8 ppm 8.16 - 8.32 (m, 2 H), 7.73 - 7.83 (m, 2 H), 7.70 (s, 1 H), 4.46 (s, 2 H), 3.51 - 3.63 (m, 2 H), 3.25 - 3.30 (m, 2 H), 2.15 - 2.28 (m, 2 H), 1.99 - 2.11 (m, 2 H)Example 245-chloro-2-hydroxy-3-(((2-(2 -methoxy ethoxy)ethyl)(methyl)amino)methyl)-JV-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (24) and 5-chloro-2-hydroxy-3-(((2-(2--189-SUBSTITUTE SHEET ( RULE 26 )methoxy ethoxy)ethyl)(methyl)amino)methyl)-7V-(6-(trifluoromethyl)benzo[< ]thi azol -2- yl)benzamide hydrochloride (24A)44.21 pL), 5-chloro-3-formyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[<7]thiazol-2- yl)benzamide (150 mg, 374.29 pmol) in toluene (3 mL) was added acetic acid (22 mg, 374.29 pmol, 21.41 pL) to pH ~ 5-6. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to remove solvent then MeOH (3 mL), and NaBHsCN (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 solvent, then purified by prep-HPLC (HC1 condition) to afford 5-chloro-2-hydroxy-3-(((2-(2- methoxyethoxy)ethyl)(methyl)amino)methyl)-A-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)benzamide (55.74 mg, 100.01 pmol, 26.72% yield, 99.478% purity, HC1) as a white solid. MS (ESI) [M+H]+ requires m / z 518.1, found m / z 518.2.XHNMR (400 MHz, METHANOL- d4) 5 ppm 8.20 - 8.30 (m, 2 H), 7.74 - 7.83 (m, 2 H), 7.71 (br d, J = 2.21 Hz, 1 H), 4.62 (br d, J = 11.25 Hz, 1 H), 4.35 (br d, J = 12.57 Hz, 1 H), 3.90 (br d, J = 4.41 Hz, 2 H), 3.67 - 3.75 (m, 2 H), 3.58 - 3.65 (m, 2 H), 3.51 (br s, 1 H), 3.44 (br s, 1 H), 3.41 (s, 3 H), 2.92 (s, 3 H).-190-SUBSTITUTE SHEET ( RULE 26 )Example 253-((bis(2 -methoxy ethyl)amino)methyl)-5-chloro-2 -hydroxy -N-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (25) and 3-((bis(2- methoxyethyl)amino)methyl)-5-chloro-2-hydroxy-A-(6-(trifluoromethyl)benzo[t ]thiazol-2- yl)benzamide hydrochloride (25A)

[0423] To a solution of bis(2-methoxyethyl)amine (40 mg, 299.43 pmol, 44.21 pL) and 5-chloro-3-formyl-2-hydroxy-A-(6-(trifluoromethyl)benzo[< / ]thiazol-2-yl)benzamide (100 mg, 249.53 pmol, Example 22) in toluene (3 mL) was added acetic acid (3 mg, 49.91 pmol, 2.85 pL) to pH ~ 5-6. The mixture was stirred at 75 °C for 12 h. The reaction mixture was concentrated to remove solvent, then MeOH (3 mL) and NaBHsCN (94 mg, 1.5 mmol) were added. The mixture was stirred at 20 °C for another 5h The reaction mixture was concentrated to remove solvent. The residue was purified by prep-HPLC (HC1 condition) to afford 3-((bis(2-methoxyethyl)amino)methyl)-5-chloro-2-hydroxy-A-(6- (trifluoromethyl)benzo[c / ]thiazol-2-yl)benzamide (98.93% purity, HC1) 47.28 mg as a brown solid. MS (ESI) [M+H]+ requires m / z 518.1, found m / z 518.1. 'H NMR (400 MHz, METHANOL-O 5 ppm 8.26 (s, 1 H), 8.15 (d, J = 2.44 Hz, 1 H), 7.73 - 7.80 (m, 2 H), 7.56 (d, J= 2.45 Hz, 1 H), 4.52 (s, 2 H), 3.74 - 3.80 (m, 4 H), 3.44 - 3 50 (m, 4 H), 3.41 (s, 6 H).

[0424] Compounds 26-37 were made in a similar manner as Compound 25 in Example 25:-191-SUBSTITUTE SHEET ( RULE 26 )Example 265-chloro-2-hydroxy-3-(piperidin- l-ylmethyl)- / V-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)benzamide (26)[0425| MS (ESI) [M+H]+requires m / z 470.08, found m / z 470.0. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 8.24 - 8.29 (m, 2 H), 7.74 - 7.82 (m, 2 H), 7.68 (d, J = 2.45 Hz, 1 H), 4.36 (s, 2 H), 3.46 - 3.59 (m, 2 H), 3.02 - 3.18 (m, 2 H), 1.96 (br d, J = 14.18 Hz, 2 H), 1.77 (br d, J = 13.69 Hz, 3 H), 1.56 (br s, 1 H).Example 273-(azetidin-l-ylmethyl)-5-chloro-2-hydroxy-A-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)benzamide (27)10426] MS (ESI) [M+H]+requires m / z 442.85, found m / z 442.1. 'H NMR (400 MHz, METHANOL-c / 4) 5 ppm 8.28 (s, 1 H) 8.24 (d, J=2.65 Hz, 1 H) 7.74 - 7.84 (m, 2 H) 7.65 (d, J=2.21 Hz, 1 H)Example 285-chloro-2-hydroxy-3-((4-methylpiperazin-l-yl)methyl)-A-(6- (trifluoromethy l)b enzo[t / J th i azol -2-y l)b enzami de (28)

[0427] MS (ESI) [M+H]+requires m / z 485.09, found m / z 485.0. 'H NMR (400 MHz, METI IANOL-<74) 8 ppm 8.27 (s, 1 H), 8.25 (d, J = 2.93 Hz, 1 H), 7.74 - 7.82 (m, 3 H), 4.50 (s, 2 H), 3.43 - 3.88 (m, 8 H), 3.02 (s, 3 H)-192-SUBSTITUTE SHEET ( RULE 26 )Example 295-chloro-2-hydroxy-3-((3-oxopiperazin-l-yl)methyl)- / V-(6-(trifluoromethyl)benzo[< / ]thiazol- 2-yl)benzamide (29)[0428| MS (ESI) [M+H]+requires m / z 485.06, found m / z 485.0. 'H NMR (400 MHz, METHANOL-J4) 5 ppm 8.28 - 8.31 (m, 2 H), 7.76 - 7.84 (m, 2 H), 7.72 (d, J = 2.63 Hz, 1 H), 4.53 (s, 2 H), 3.95 (s, 2 H), 3.60 (br s, 4 H)Example 305-chloro-2-hydroxy-3-((3-hydroxypyrrolidin-l-yl)methyl)-A-(6-(trifluoromethyl)benzo[c / ]thiazol-2-yl (benzamide (30)

[0429] MS (ESI) [M+H]+requires m / z 472.06 found m / z 472.0.1H NMR (400MHz, DMSO-676) 5 ppm 8.41 (s, 1 H), 8.05 (d, J= 2.87 Hz, 1 H), 7.70 - 7.85 (m, 3 H), 4.43 (br d, J= 2.20 Hz, 1 H), 4.39 (s, 2 H), 3.41 - 3.50 (m, 2 H), 3.32 - 3.40 (m, 1 H), 3.15.Example 315-chloro-2-hydroxy-3-((3 -hydroxy-3 -methylpyrrolidin- l -yl)mcthyl)-Af-(6- (trifluoromethyl(benzo[c / ]thiazol-2-yl)benzamide (31)|0430] MS (ESI) [M+H]+requires m / z 486.08 found m / z 486.0.LH NMR (400 MHz, METHANOL-d4) 8 ppm 8.23 (br d, J = 16.63 Hz, 2 H), 7.77 (q, J = 8.64 Hz, 2 H), 7.69 (s, 1 H), 4.41 - 4.59 (m, 2 H), 3.47 - 3 87 (m, 2 H), 3.34 - 3.45 (m, 1.5 H), 3.22 (d, J = 11.74 Hz, 0.5 H), 1.97 - 2.30 (m, 2 H), 1.46 (s, 3 H).-193-SUBSTITUTE SHEET ( RULE 26 )Example 325-chloro-2-hydroxy-3-((3-methoxypyrrolidin-l-yl)methyl)-A-(6-(trifluoromethy l)b cnzo[t / ] th i azol -2-y l)b enzami de (32)[04311 MS (ESI) [M+H]+requires m / z 486.08 found m / z 486.1.LH NMR (400 MHz, METHANOL-d4) 8 ppm 8.19 - 8.28 (m, 2 H), 7.77 (q, J = 8.53 Hz, 2 H), 7.69 (br s, 1 H), 4.43 - 4.55 (m, 2 H), 4.16 - 4.24 (m, 1 H), 3.56 - 3.74 (m, 2 H), 3.32 - 3.50 (m, 5 H), 2.30 - 2.48 (m, 1 H), 2.06 - 2.21 (m, 1 H).Example 333-((3-acetamidopyrrolidin-l-yl)methyl)-5-chloro-2-hydroxy-A-(6-(trifluoromethy l)b enzo[t / J th i azol -2-y l)b enzami de (33 )

[0432] MS (ESI) [M+H]+ requires m / z 513.09 found m / z 513.0. 1HNMR (400 MHz, DMSO-d6) 8 ppm 8.45 (s, 1 H) 8.24 (br d, J=5.07 Hz, 1 H) 8.11 (d, J=2.65 Hz, 1 H)7.84 - 7.91 (m, 2 H) 7.77 - 7.83 (m, 1 H) 4.44 (s, 2 H) 4.40 (br d, J=6.39 Hz, 1 H) 3.47 - 3.63 (m, 2 H) 3.32 - 3.44 (m, 1 H) 3.18 - 3.27 (m, 1 H) 2.27 - 2.39 (m, 1 H) 1.89 - 2.01 (m, 1 H)1.84 (s, 3 H)Example 34 l-(5-chloro-2-hydroxy-3-((6-(trifluoromethyl)benzo|X]thiazol-2- yl)carbamoyl)benzyl)pyrrolidine-2-carboxamide (34)[0433[ MS (ESI) [M+H]+requires m / z 499.07 found m / z 498.9.LH NMR (400MHz, METHANOL-t74) 8 ppm 8.28 (s, 1 H), 8.23 (d, J = 2.65 Hz, 1 H), 7.74 - 7.84 (m, 2 H),-194-SUBSTITUTE SHEET ( RULE 26 )7.67 (d, J= 2.43 Hz, 1 H), 4.45 - 4.58 (m, 2 H), 4.33 (dd, J= 9.37, 6.73 Hz, 1 H), 3.73 (br s, 1 H), 3.42 - 3.50 (m, 2 H), 2.51 - 2.67 (m, 1 H), 1.99 - 2.28 (m, 2 H)Example (35)5-chloro-3-((l,l-dioxidothiomorpholino)methyl)-2-hydroxy-A-(6- (trifluoromethyl)benzo[c / ]thiazol-2-yl (benzamide (35)

[0434] MS (ESI) [M+H]+requires m / z 520.03 found m / z 520.0.LH NMR (400MHz, METHANOL-c / 4) 5 ppm 8.27 - 8.31 (m, 2 H), 7.73 - 7.84 (m, 3 H), 4.59 (s, 2 H), 3.91(br d, J= 5.73 Hz, 4 H), 3.57 (br s, 4 H)Example 365-chloro-3-((3-cyanopyrrolidin-l-yl)methyl)-2-hydroxy-A-(6- (trifluoromethy l)b enzo[t / J th i azol -2-y l)b enzami de (36)[0435| MS (ESI) [M+H]+requires m / z 481.06 found m / z 480.9. 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.42 (s, 1 H) 7.78 - 7.86 (m, 2 H) 7.69 (br d, J=8.38 Hz, 1 H) 7.38 (d, J=2.87 Hz, 1 H) 4.25 (br s, 2 H) 3.62 (br s, 1 H) 3.49 - 3.56 (m, 4 H) 2.16 - 2.36 (m, 2 H)Example 375-chloro-2-hydroxy-3-((3-(methylsulfonyl)pyrrolidin-l-yl)methyl)- / V-(6- (trifluoromethy l)b enzo[<7] th i azol -2-y l)b enzami de (37)

[0436] MS (ESI) [M+H]+requires m / z 534.05 found m / z 534.0. 1H NMR (400MHz, METHANOL-J4) 6 ppm 8.22 - 8.30 (m, 2 H), 7.74 - 7.84 (m, 2 H), 7.70 (br d, J= 2.45SUBSTITUTE SHEET ( RULE 26 )Hz, 1 H), 4.51 - 4.58 (m, 2 H), 4.16 - 4.27 (m, 1 H), 3.83 - 3.99 (m, 2 H), 3.60 (br s, 2 H),3.10 (s, 3 H), 2.50 - 2.69 (m, 2 H)Example 38(E)-5-chloro-2-hydroxy-3-((hydroxyimino)methyl)-7V-(6-(trifluoromethyl)benzo[t7]thiazol-2- yl)benzamide (38)

[0437] To a solution of 5-chloro-3-formyl-2-hydroxy-JV-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (100 mg, 249.53 pmol) in EtOH (3 mL) was added NH2OH.HCI (17.34 mg, 249.53 pmol) and Na2CO3(52.89 mg, 499.05 pmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (basic condition) to afford the title compound (E)-5-chloro-2-hydroxy-3-((hydroxyimino)methyl)-7V- (6-(trifluoromethyl)benzo[tZ]thiazol-2-yl)benzamide (30.95 mg, 70.19 pmol, 28.13% yield, 94.297% purity) as a yellow solid. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 8.38 (br s, 1 H), 8.30 (br s, 1 H), 8.05 (br s, 1 H), 7.87 (br s, 1 H), 7.72 (br d, J = 16.63 Hz, 2 H). MS (ESI) [M+H]+requires m / z 416.00, found m / z 416.00.Example 39(£)-5-chloro-2-hydroxy-3-((methoxyimino)methyl)-AL(6-(trifluoromethyl)benzo[<i]thiazol-2- yl)benzamide (39)-196-SUBSTITUTE SHEET ( RULE 26 )

[0438] (E)-5-chl oro-2 -hy droxy-3-((methoxyimino)methyl)-A-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide was made in a similar manner as compound 38. MS (ESI) [M+H]+ requires 430 02m / z found m / z 430.0.JH NMR (400 MHz, DMSO-de) 6 ppm 8.52 (br s, 1 H), 8.41 (br s, 1 H), 8.01 (br s, 1 H), 7.83 (br s, 2 H), 7.76 (br d, J = 0.98 Hz, 1 H), 3.94 (br s, 3 H).Example 403-(acetamidomethyl)-5-chloro-2-hydroxy- V-(6-(trifluoromethyl)benzo[< / ]thiazol-2- yl)benzamide (40)|0439j To a solution of (E)-5-chloro-2-hydroxy-3-((hydroxyimino)methyl)-A-(6- (trifluoromethyl)benzo[ ]thiazol-2-yl)benzamide (320 mg, 769.65 pmol, 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 solvent. The residue was diluted with water (3 mL) and adjusted to pH 9 with 2M NaOH, then extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (15 mL), dried over N 2SC>4, fdtered and concentrated under reduced pressure to afford 3-(aminomethyl)-5-chloro-2-hydroxy-2V- (6-(trifluoromethyl)benzo[t / ]thiazol-2-yl)benzamide (300 mg, crude) as a white solid.

[0440] 3-(aminomethyl)-5-chloro-2-hydroxy-A-(6- (trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (20 mg, 49.78 pmol) and TEA (6 mg, 59.73 pmol, 8.31 pL) was dissolved in DCM (3 mL) at 0 °C. The solution wasstirred and acetyl chloride (3 mg, 39.82 pmol, 2.84 pL) was added. The resulting solution was warmed to 20 °C for 30 minutes. The reaction mixture was quenched by addition of MeOH (3 mL), then concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (HC1 condition) to afford 3-(acetamidomethyl)-5-chloro-2-hydroxy-Ar-(6--197-SUBSTITUTE SHEET ( RULE 26 )(trifluoromethyl)benzo[c / ]thiazol-2-yl)benzarriide (14 mg, 99.660% purity) as a white solid.XH NMR (400 MHz, METHANOL-^) 5 ppm 8.28 (s, 1 H), 8.03 (d, J= 2.45 Hz, 1 H), 7.73 - 7.86 (m, 2 H), 7.43 (s, 1 H), 4.39 (s, 2 H), 2.03 (s, 3 H) MS (ESI) [M+H]+requires m / z 444.03, found m / z 444.0.Example 415-chloro-2-hydroxy-JV1,7V1-bis(2-methoxyethyl)-JV3-(6-(trifluoromethyl)benzo[t / ]thiazol-2- yl)isophthalamide (41)SUBSTITUTE SHEET ( RULE 26 )[04411 To a flame dried flask was added NBS (2.99g, 16.79 mmol), AIBN (173 mg, 1.05 mmol) and a solution of methyl 5-chloro-2-methoxy-3-methylbenzoate (1.13g, 5.26 mmol) in CC14 (20 mL). The suspension was refluxed in the dark overnight The mixture was cooled to rt and concentrated. The residue was purified via silica gel column chromatography to give methyl 5-chloro-3-(dibromomethyl)-2-methoxybenzoate as a yellow oil (1.59g, 81%). 'H NMR (300 MHz, cdcl3) 6 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 (1.59g, 4.27 mmol) was dissolved in 10 mL concentrated sulfuric acid and the mixture was stirred at rt for 2h. The reaction mixture was poured into ice water and extracted with ethyl acetate two times. The combined organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was purified via silica gel column chromatography to give methyl 5-chloro-3-formyl-2 -methoxybenzoate (673 mg, 71%) as a white solid. 'H NMR (300 MHz, cdcl3) 5 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 KMnCU (310 mg, 1.96 mmol). The resulting mixture was stirred at rt for 3.5h. After completion of the reaction as indicated by TLC, 0.8g sodium carbonate was added and stirred for another 15minutes. The mixture was then filtered and the pH of the filtrate was adjusted to 2-3 when a large amount of solid was precipitated. The mixture was filtered and the solid was washed with water. The crude product was purified through recrystallization in ethanol to give 5-chloro-2-methoxy-3- (methoxycarbonyl)benzoic acid (90 mg, 76%) as a white solid. MS (ESI) [M+H]+requires 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 pL, 0.44 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig’s base (192 pL, 1.1 mmol) and bis(2-methoxyethyl)amine (55 pL, 0.37 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield methyl 3 -(bi s(2 -methoxy ethyl)carbam oyl)-5- chloro-2-methoxybenzoate (116 mg, 88%) as a colorless oil. 'H NMR (300 MHz, cdcl3) 5 7.81 (d, J= Hz, 1H), 7.42 (d, J= 2.7 Hz, 1H), 4.04 (M, 1H), 3.93 (s, 3H), 3.88 (s, 3H),-199-SUBSTITUTE SHEET ( RULE 26 )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]+requires 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 m IN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and the residue was portioned between ethyl acetate and IN NaOH solution. The aqueous layer was acidified to pH=l and extracted with ethyl acetate. This organic phase was dried over over sodium sulfate and concentrated in vacuo to afford 3-(bis(2- methoxyethyl)carbamoyl)-5-chloro-2-methoxybenzoic acid (115 mg, 100%) as a colorless oil which used in the next step without further purification. MS (ESI) [M+H]+requires 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), followed by the addition of a catalytic amount of DMF (1 drop) and oxalyl chloride (34 pL, 0.39 mmol) respectively. The reaction was allowed to stir at rt for 30 minutes and concentrated in vacuo. The residue was redissolved in THF (5.0 mL), and Hunig’s base (170 pL, 0.98 mmol) and 6- (trifluoromethyl)benzo[d]thiazol-2-amine (71 mg, 0.32 mmol) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. The solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-A1,A1-bis(2-methoxyethyl)- / V3-(6-(trifluoromethyl)benzo

[0006] thiazol- 2-yl)isophthalamide (95 mg, 58%) as a colorless oil. MS (ESI) [M+H]+requires m / z 546.11, found m / z 546.20.

[0447] A solution of 5-chloro-2-methoxy-A1,A1-bis(2-methoxyethyl)- / V3-(6- (trifluoromethyl)benzo[t / ]thiazol-2-yl)isophthalamide (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, IN HC1 was added to the reaction and extracted with ethyl acetate two times. The combined ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-chloro-2-hydroxy-A1,A1-bis(2- methoxyethyl)-A3-(6-(trifluoromethyl)benzo[ ]thiazol-2-yl)isophthalamide (55 mg, 63%) as a yellow solid.XHNMR (300 MHz, cdcl3) 5 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]+requires m / z 532.09, found m / z 532.20.-200-SUBSTITUTE SHEET ( RULE 26 )Example 425-chloro-2V-(6-(difluoromethyl)benzo[<i]thiazol-2-yl)-2-hydroxy-3-((2- methoxyethoxy)methyl)benzamide (42)

[0448] To a solution of ethyl 2-anii nobeiizo[c / ]tlii azol e-6-carboxyl ale (3 g, 13.50 mmol) in THF (60 mL) was added portion wise DIBAL-H (1 M, 53.99 mb) at 0 °C. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was quenched by addition saturated sodium potassium tartrate (30 mL), and then diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (200 mL), dried over NazSO-i, filtered and concentrated under reduced pressure to give (2-aminobenzo[< / ]thiazol-6-yl)methanol (2.4 g, crude) as a yellow solid. ’H NMR (400 MHz, DMSO-6 / 6) 8 ppm 7.57 (s, 1 H), 7.38 (s, 2 H), 7.27 (d, J= 8.31 Hz, 1 H), 7.14 (dd, J= 8.07,-201-SUBSTITUTE SHEET ( RULE 26 )1.22 Hz, 1 H), 5.09 (t, J= 5.87 Hz, 1 H), 4.47 (d, J= 5.87 Hz, 2 H). MS (ESI) [M+H]+requires m / z 181.04, found m / z 181.2.|0449] To a solution of (2-aminobenzo[< ]thiazol-6-yl)methanol (1 g, 5.55 mmol) in ethyl acetate (30 mL) was added MnCb (4.8 g, 55.49 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered with diatomite filter and concentrated under reduced pressure to give the crude product 2-aminobenzo[d]thiazole-6-carbaldehyde (900 mg, crude) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 5 ppm 9.87 (s, 1 H), 8.23 (d, J = 1.47 Hz, 1 H), 8.05 (br s, 2 H), 7.75 (dd, J= 8.31, 1.47 Hz, 1 H), 7.44 (d, J= 8.31 Hz, 1 H). MS (ESI) [M+H]+requires m / z 179.02, found m / z 179.1.

[0450] To a stirred solution of 5-chloro-2-methoxybenzoic acid (10 g, 53.59 mmol) in H2SO4 (18.25 mL, purity 98%) and TFA (36.50 mL) at 20 °C was added NBS (10.5 g, 58.95 mmol). The pale solution was stirred at 20 °C for 12 h. The resulting pale suspension was carefully poured onto crushed ice (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3), dried over NazSCU and concentrated under reduced pressure. The light yellow residue was suspend in DCM (50 mL). The solid was collected, washed with cold DCM (50 mL) and dried under vacuum to afford 3-bromo-5-chloro-2 -methoxybenzoic acid (10 g, crude) as a white solid. 'H NMR (400 MHz, DMSO-de) 5 ppm 7.96 (t, J = 2.32 Hz, 1 H), 7.69 (t, I = 2.32 Hz, 1 H), 3.78 (d, J = 2.43 Hz, 3 H)

[0451] To a stirred solution of 3 -bromo-5-chloro-2 -methoxybenzoic acid (5 g, 18.83 mmol) in DMF (25 mL) was added K2CO3 (26 g, 188.33 mmol) followed by CH3I (2.7g, 18.83 mmol, 1.2 mL). The mixture was stirred at 20 °C for 12 h. H2O (50 mL) was added and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (100 mL) and dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo to afford methyl 3-bromo-5-chloro -2 -methoxybenzoate (4.7 g, purity 88.4%) as yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.03 (d, J = 2.93 Hz, 1 H), 7.74 (d, J = 2.45 Hz, 1 H), 3.87 (s, 3 H), 3.81 (s, 3 H). MS (ESI) [M+H]+requires m / z 278.93, found m / z 281.0.

[0452] A mixture of methyl 3-bromo-5-chloro-2 -methoxybenzoate (2 g, 7.16 mmol), potassium trifluoro (methyl)boranuide (1 g, 8.59 mmol), K2CO3 (3 g, 21.47 mmol), Pd(dppf)C12 (1 g, 1.43 mmol) in dioxane (20 mL), H2O (2 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated to remove solvent. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford methyl 5-chloro- 2-methoxy-3-methyl-benzoate (1.2 g, 5.31 mmol, 74.23% yield, 95% purity) as yellow oil.-202-SUBSTITUTE SHEET ( RULE 26 )[04531 To a flame dried flask was added NBS (1.2 g, 6.71 mmol), AIBN (91 mg, 559.06 pmol) and a solution of methyl 5-chloro-2-methoxy-3-methyl-benzoate (1.2 g, 5.59 mmol) in CCL (10 mL). The suspension was stirred at 80 °C for 12 h. The reaction mixture was concentrated to remove solvent. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to afford methyl 3-(bromomethyl)-5- chloro-2-methoxybenzoate (1.5 g, 3.58 mmol, 63.98% yield, 70% purity) as yellow oilXH NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.69 (d, J = 2.93 Hz, 1 H), 7.46 (d, J = 2.93 Hz, 1 H), 4.44 (s, 2 H), 3.88 (s, 3 H), 3.86 (s, 3 H).[0454| To a stirred solution of methyl 3-(bromomethyl)-5-chloro-2- methoxybenzoate (1 g, 3.41 mmol) in 2-methoxyethanol (19.3 g, 253.63 mmol, 20 mL) was added 2NNaOH (15 mL). The resulting mixture was stirred at 75 °C for 12 h then concentrated in vacuo. The residue was diluted with water (5 mL) and adjusted to pH 9 with 2M NaOH, then extracted with ethyl acetate (5 mL x 3). The clear solution was acidified with IN HC1 to pH 5 and then extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (20 mL) and dried over Na2 Ch, filtered and concentrated under reduced pressure to afford 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (500 mg, purity:80%) as yellow oil. 'H NMR (400 MHz, CHLOROFORM-d) 6 ppm 7.90 - 8.00 (m, 1 H), 7.63 - 7.73 (m, 1 H), 4.63 (s, 2 H), 3.92 - 3.94 (m, 3 H), 3.72 (dd, J = 5.62, 3.67 Hz, 2 H), 3.59 - 3.65 (m, 2 H), 3.42 (s, 3 H). [M-H]’ requires m / z 273.0, found m / z 272.9.

[0455] To a solution of 2-aminobenzo[r / ]thiazole-6-carbaldehyde (162 mg, 910.09 pmol), 5-chloro-2-methoxy-3-((2-methoxyethoxy)methyl)benzoic acid (250 mg, 910.09 pmol) in DCM (4 mL) was added EDCI (209.36 mg, 1.09 mmol) and HOBt (184 mg, 1.37 mmol). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (neutral condition) to afford 5-chloro-A-(6-formylbenzo[ ]thiazol-2-yl) -2 -m ethoxy-3 -((2- methoxyethoxy)methyl)benzamide (80 mg, 97% purity) as a yellow solid. [M+H]+requires m / z 435.07, found m / z 435.1[0456| To a solution of 5-chloro-JV-(6-formylbenzo[t / ]thiazol-2-yl) -2-methoxy-3- ((2 -methoxyethoxy )methyl)benzamide (50 mg, 114.97 pmol) in DCM (2 mL) was added BAST (406 mg, 1.84 mmol, 402.95 pL). The mixture was stirred at 50 °C for another 12 h. The reaction mixture was quenched by addition sat.NaHCCL (8 mL), and extracted with ethyl acetate (8 mL x 3). The combined organic layer was washed with brine (10 mL), dried over NazSCh, filtered and concentrated under reduced pressure to give a residue. The residue was-203-SUBSTITUTE SHEET ( RULE 26 )purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 3: 1) to afford 5-chloro- / V-(6- (difluoromethyl)benzo[d]thiazol-2-yl)-2-methoxy-3-((2-methoxyethoxy)methyl)benzamide (40 mg, 72.67 pmol, 63.20% yield, 83% purity) as a white solid. [M+H]+requires m / z 457.07, found m / z 457.2

[0457] To a solution of 5-chloro- / V-(6-(difluoromethyl)benzo[d]thiazol-2-yl)-2- methoxy-3-((2-methoxyethoxy)methyl)benzamide (40 mg, 87.55 pmol) in DMF (2 mL) was added ethyl sulfanyl sodium (22 mg, 262.65 pmol). The mixture was stirred at 160 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (3 mL) and extracted with DCM (3 mL x 3). The combined organic layers were washed with brine (5 mL), dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, Petroleum ether / Ethyl acetate = 0:1). The residue was purified by prep-HPLC (HC1 condition) to afford 5-chloro-A'-(6-(difluorornethyl)benzo[<7]thiazol-2-yl)-2-hydroxy-3-((2- methoxyethoxy)methyl)benzamide (5.22 mg, 99.157% purity) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.28 (s, 1 H), 7.99 (br s, 1 H), 7.76 (br s, 1 H), 7.67 - 7.73 (m, 1 H), 7.52 (s, 1 H), 6.98 - 7.33 (m, 1 H), 4.56 (s, 2 H), 3.65 (dd, J = 5.62, 3.67 Hz, 2 H), 3.52 (dd, J = 5.62, 3.67 Hz, 2 H), 3.28 (s, 3 H). [M+H]+requires m / z 443.06, found m / z 442.9Example 435-fluoro-2-hydroxy-3-((2-methoxyethoxy)methyl)- / V-(6-(trifluoromethylbenzo[<7]thiazol-2- yl)benzamide (43)-204-SUBSTITUTE SHEET ( RULE 26 )

[0458] To a stirred solution of 5-fluoro-2 -methoxybenzoic acid (5 g, 29.39 mmol) in H2SO4 (10 mL) (98%) and TFA (20 mL) at 20°C was added NBS (5.7 g, 32.33 mmol). The pale solution was stirred at 20°C for 12 h. The resulting pale suspension was carefully poured onto crushed ice (500 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine 1000 mL, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford 3-bromo-5-fluoro-2 -methoxybenzoic acid (7 g) as a yellow solid. 'H NMR (400 MHz, DMSO- r,) 5 ppm 7.77 (dd, J= 7.89, 3.07 Hz, 1 H), 7.50 (dd, 7= 8.77, 3.07 Hz, 1 H), 3.76 - 3.80 (s, 3 H).(0459] To a stirred solution of 3 -bromo-5-fluoro-2-m ethoxybenzoic acid (7 g, 28.11 mmol) in DMF (20 mL) was added K2CO3 (38.8 g, 281.09 mmol) followed by Mel (3.9 g, 28.11 mmol, 1.75 mL). The mixture was stirred at 20°C for 12. Water (100 mL) was added and the extracted with ethyl acetate (150 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over sodium sulfate. The organic...

Claims

CLAIMSWhat Is Claimed Is :1 . A compound of F ormul a A :wherein R1000aof Formula A is selected from the group consisting of-CH3, -CH2CH3, -C1-C6alkyl, -C3-C6cycloalkyl, -0CH3, -CH2OCH3, -CH2OCH2OCH3,C(O)N(CH2CH2OCH3)2; each of substituents R5000AandR5000Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R5000Aand R5000Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R6000is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; r’ is an integer selected the group consisting of 1, 2 and 3; r is an integer selected from the group consisting of 0, 1, 2 and 3;Rloooc of Formula I is selected from the group consisting of chloro, fluoro, iodo, and bromo;-295-SUBSTITUTE SHEET ( RULE 26 )each of R4000band R4000dis independently selected from the group consisting of Y1000and Z1000, provided that when R4000bis Y1000, R4000dis z1000and when R4000bis z1000, R4000disyiooo.Y1000is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , - CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci- Ce)alkyl;Z1000is selected from the group consisting of H, -CH2OCH3, -CH2OCH2CH3,R2OOOAANC| R2OOOB togetherwith the nitrogen to which they are attached, form a 4 to 8-membered heterocyclic ring optionally substituted with one or more methyl groups;R3000is a 5 to 6-membered heterocyclic ring;Ar1is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl, halo, hydroxyl and alkoxy; each of R7000Aand R7000Bis independently selected from Ci-Ce alkyl; alternatively R7OOOAanj R7000Btogether with the nitrogen to which they are attached, form a 4 to 8- membered heterocyclyl optionally substituted with one or more substituents independently selected from Ci-Ce alkyl;R8000is selected from the group consisting of a 5 to 6-membered heterocyclic ring 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; with the proviso thatR5000Aand R5000Bare not both Ci-Ce alkyl; and-296-SUBSTITUTE SHEET ( RULE 26 )when Z1000is H; R1000ais not Ci- C6alkyl, -C3-C6cycloalkyl, CH3or CH2CH3;or a pharmaceutically acceptable salt, solvate, or prodrug thereof,2. A compound of F ormul a I :each of R5AandR5Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R5Aand R5Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R6is selected from the group consisting of 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; m’ is an integer selected the group consisting of 1, 2 and 3; m is an integer selected the group consisting of 0, 1, 2 and 3;-297-SUBSTITUTE SHEET ( RULE 26 )Rlcis selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R4band R4dis independently selected from the group consisting of Y and Z, provided that when R4bis Y, R4dis Z and when R4his Z, R4dis Y;Y is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-C6)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano, and -CO2(Ci-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)2NR2AR2B, -(CH2)nR3, -CH2OCH2Ar, and OCH3;R2Aand R2Btogether with the nitrogen to which they are attached, form a 4 to8-membered heterocyclic ring optionally substituted with one or more methyl groups;R3is selected from the group consisting of a 5 to 6-membered heterocyclic ring and phenoxy; n is an integer selected from the group consisting of 0 1, 2, and 3; andAr is a 5-6 membered aryl or heteroaryl group optionally substituted with one or more substituents, independently selected from the group consisting of -Ci-Ce alkyl, halo, hydroxy, and alkoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compound of claim 2, wherein Rlais selected from the group consisting of -CH3, -CH2CH3 and -CH2NR5AR5B.

4. The compound of claim 3, wherein each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.

5. The compound of claim 2, wherein Rlais selected from the group consisting of-298-SUBSTITUTE SHEET ( RULE 26 )6. The compound of claim 2 wherein Rlcis chloro.

7. The compound of claim 2 wherein R4bis Y and R4dis Z.

8. The compound of claim 2 wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with a methyl group.

9. The compound of claim 2 wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from piperazinyl or a 4-methyl piperazinyl.

10. The compound of claim 2 wherein R3is a 5-membered heterocyclic ring.

11. The compound of claim 2 wherein R3is tetrahydrofuranyl.

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

13. The compound of claim 2 wherein -(CH2)nR is.

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

15. The compound of claim 14 wherein Ar is selected from the group consisting16. The compound of claim 2 wherein Yis CF317. The compound of claim 2, wherein Z is selected from the group consisting of - CH2OCH2CH3,-CH2OCH3, -CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2J-CH2O(CH2)2NHSO2CH3, -(CH2)O(CH2)2NR2AR2B, -(CH2)mR3, -CH2OCH2Ar and OCH3; wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinylR3is tetrahydrofuranyl; and-299-SUBSTITUTE SHEET ( RULE 26 )Ar is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxyl and methoxy.

18. The compound of claim 2 whereinR4dis selected from the group consisting of -CH2OCH2CH3, -CH2OCH3,19. The compound of claim 2 whereinRlais selected from the group consisting of -CH3, -CH2CH3 and -CH2NR5AR5B; each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 4-8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;Rlcis chloroY is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-Cg)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci-Ce)alkyl, cyano, and -CC>2(Ci- 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)2NR2AR2B, -(CH2)mR3, -CH2OCH2Ar and OCH3; wherein R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl and 4-methyl piperazinyl;-300-SUBSTITUTE SHEET ( RULE 26 )R3is tetrahydrofuranyl;Ar is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxy and methoxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. The compound of claim 2 whereinRlais selected from the group consisting of -CH3, -CH2CH3 and -CH2NR5AR5B; each of R5Aand R5Bis independently selected from Ci-Ce alkyl substituted with one or more groups selected from methoxy; alternatively, R5Aand R5Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;Rlcis chloroY is CF3;Z is selected from the group consisting of -CH2OCH2CH3,-CH2OCH , - CH2O(CH2)2OH, -CH2O(CH2)2OCH3, -CH2O(CH2)2N(CH3)2, -CH2O(CH2)2NHSO2CH3, - (CH2)O(CH2)2NR2AR2B, -(CH2)mR3, -CH2OCH2Ar and OCH3;R2Aand R2Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of piperazinyl or a 4-methyl piperazinylR3is tetrahydrofuranyl;Ar is a 5 to 6-membered aryl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, chloro, hydroxyl, and methoxy or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

21. The compound of claim 2 wherein-301-SUBSTITUTE SHEET ( RULE 26 )Rlais selected from the group consisting of -CH3, -CH2CH3, -Rlcis chloro;Y is CF3; andZ is selected from the group consisting of -CH2OCH2CH3, -CH2OCH3, -or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

22. The compound of claim 21 whereinR4bis Y and R4dis Z.

23. The compound of claim 2 of Formula la-302-SUBSTITUTE SHEET ( RULE 26 )wherein Rlais selected from the group consisting of -CH3, -CH2CH3, -R4dis selected from the group consisting of CH2OH, -CH2OCH2CH3, -CH2OCH3,or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

24. The compound of claim 23 whereinR4dis selected from the group consisting of -CH2OCH2CH3, -CH2OCH3,25. The compound of claim 2selected from the group consisting of:-303-SUBSTITUTE SHEET ( RULE 26 )-304-SUBSTITUTE SHEET (RULE 26)-305-SUBSTITUTE SHEET (RULE 26)-306-SUBSTITUTE SHEET (RULE 26)-307-SUBSTITUTE SHEET (RULE 26)-308-SUBSTITUTE SHEET (RULE 26)-309-SUBSTITUTE SHEET (RULE 26)-310-SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

26. The compound of claim 25 that is-311-SUBSTITUTE SHEET ( RULE 26 )pharmaceutically acceptable salt, solvate, or prodrug thereof.

27. A compound of Formula II:wherein:R10ais selected from the group consisting of -OCH3, -CH2OCH3, -CH2OCH2OCH3,C(O)N(CH2CH2OCH3)2; each of R50AandR50Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-Ce alkoxy, and -O(CH2)2OCH3; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;-312-SUBSTITUTE SHEET ( RULE 26 )R60is selected from the group consisting of 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; o’ is an integer selected from the group consisting of 1, 2, and 3; o is an integer selected from the group consisting of 0, 1, 2, and 3;R10cis selected from the group consisting of chloro, fluoro, iodo, and bromo; and one of R40band R40dis H and the other of R40band R40dis selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3 , -CHF2, fluoro(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano and -CO2(Ci-C6)alkyl; with the proviso that R50Aand R50Bare not both Ci-Ce alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof28. The compound of claim 27 wherein R10ais selected from the group consistingC(O)N(CH2CH2OCH3)229. The compound of claim 27, wherein each of R50AandR50Bis independently selected from the group consisting of methyl; and Ci-Ce alkyl substituted with one or more groups selected from methoxy, and -CXCFL^OCFF; alternatively R50Aand R50Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl selected from the group consisting of azetindinyl; pyrrolidinyl; pyrrolidinyl substituted with one or more substituents selected from the group consisting of cyano, hydroxyl, methoxy, -NHC(O)CH3,-C(O)NH2, -SO2CH3, -CF3 and methyl; piperidinyl; piperidinyl substituted with one or more substituents selected from the group consisting of -CF3, and fluoro; piperazinyl substituted with one or more substituents selected from the group consisting of oxo, methyl, and acetyl; morpholinyl; morpholinyl substituted with one or more methyl groups; dioxothiomorphylinyl.

30. The compound of claim 29 wherein -CH2NR50AR50Bis selected from the group consisting of the group consisting of -CH2N(CH3)(CH2)2OCH3, -(CH2)N(CH2CH2OCH3)2, --313-SUBSTITUTE SHEET ( RULE 26 )31. The compound of claim 27 wherein R60is selected from the group consisting of tetrahydrofuranyl, thiazolyl, and pyridinyl and o is 0.

32. The compound of claim 27 wherein -(CH2)o R‘ is selected from the group consisting33. The compound of claim 27 wherein R10ais selected from the group consisting-314-SUBSTITUTE SHEET ( RULE 26 )and C(O)N(CH2CH2OCH3)2.

34. The compound of claim 27 wherein one of R40band R40dis H and the other of R40band R40dis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.

35. The compound of claim 34 wherein R40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3.

36. The compound of claim 27, wherein-315-SUBSTITUTE SHEET ( RULE 26 )C(O)N(CH2CH2OCH3)2;R10cis selected from the group consisting of chloro, fluoro, iodo; andR40dis H and R40bis selected from the group consisting of fluoro, -CF3, -CHF2, and -OCF3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof37. The compound of claim 36 wherein R10Ais selected from the group consisting-316-SUBSTITUTE SHEET ( RULE 26 )38. The compound of claim 37 wherein R10cis chloro; and R40bis -CF3.

39. The compound of claim 27 of Formula Ila-317-SUBSTITUTE SHEET ( RULE 26 )C(O)N(CH2CH2OCH3)2; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

40. The compound of claim 39 wherein R10ais selected from the group consisting-318-SUBSTITUTE SHEET ( RULE 26 )-C(O)N(CH2CH2OCH3)2.

41. A compound selected from the group consisting of:-319-SUBSTITUTE SHEET ( RULE 26 )-320-SUBSTITUTE SHEET (RULE 26)-321-SUBSTITUTE SHEET (RULE 26)-322-SUBSTITUTE SHEET (RULE 26)-323-SUBSTITUTE SHEET (RULE 26)-324-SUBSTITUTE SHEET (RULE 26)-325-SUBSTITUTE SHEET (RULE 26)-326-SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

42. The compound of claim 41 selected from the group consisting ofpharmaceutically acceptable salt, solvate, or prodrug thereof.

43. A compound of Formula III:wherein:-327-SUBSTITUTE SHEET ( RULE 26 )R100ais selected from the group consisting of -CH3, -OCH3, -CH2OCH3,each of R500AandR500Bis independently selected from the group consisting of -Ci-Ce alkyl; and -Ci-Ce alkyl substituted with one or more groups selected from -Ci-G> alkoxy, and -O(CH2)2OCH3; alternatively R500Aand R500Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more substituents, independently selected from the group consisting of oxo, cyano, hydroxyl, alkoxy, acylamino , carboxyamido, -SO2CH3, -CF3, Ci-Ce alkyl, halo, and acyl;R600is selected from the group consisting of a 5 to 6-membered heterocyclyl, pyridinyl and thiazolyl; p’ is an integer selected from the group consisting of 1, 2, and 3; p is an integer selected the group consisting of 0, 1, 2 and 3;R100cis selected from the group consisting of chloro, fluoro, iodo, and bromo; each of R400band R400dis independently selected from the group consisting of Y1and Z1, provided that when R400bis Y1, R400dis Z1and when R400bis Z1, R400dis Y1;Y1is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci-Ce)alkyl, cyano, and -CO2(Ci-C6)alkyl;Z1is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3, -CH2NHSO2CH3, -(CH2)qNR7AR7B, and -(CH2)qR8; each ofR7AandR7Bis independently selected from Ci-Ce alkyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a 4 to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl;R8is selected from the group consisting of a 5 to 6-membered heterocyclic ring optionally substituted with methyl;-328-SUBSTITUTE SHEET ( RULE 26 )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 of claim 43 wherein R100ais selected from the group consisting of -CH3, and -CH2NR500AR500B45. The compound of claim 44 wherein each of R500Aand R500Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl.

46. The compound of claim 43 wherein R100ais selected from the group consisting47. The compound of claim 43 wherein R100cis chloro.

48. The compound of claim 43 wherein R400bis Y and R400dis Z.

49. The compound of claim 43 wherein each of R7Aand R7Bis methyl; alternatively, R7Aand R7Btogether with the nitrogen to which they are attached, form a6-membered heterocyclyl optionally substituted with a methyl group.

50. The compound of claim 43 wherein R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl.

51. The compound of claim 43 wherein R8is a 6-membered heterocyclic ring optionally substituted with methyl.

52. The compound of claim 43 wherein R8is 4-methylpiperidinyl.

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

54. The compound of claim 43 wherein Z1is selected from the group consisting of -CH2NHC(O)CH2CH3, -CH2NHC(O)CH2OCH3,-CH2NHSO2CH3, -CH2NR7AR7B, and -(CH2)qR8;-329-SUBSTITUTE SHEET ( RULE 26 )wherein each of R7Aand R7Bis methyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of,4-methylpiperazinyl, and morpholinyl; and and R8is 4-methylpiperidinyl.

55. The compound of claim 43 wherein Z1is selected from the group consisting of56. The compound of claim 43 wherein Y1is CF3.

57. The compound of claim 43 wherein is Z1is selected from the group consisting58. The compound of claim 43 wherein:R100ais selected from the group consisting of -CH3, and -CH2NR500AR500B; each of R500Aand R500Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;R100cis chloro;Y1is selected from the group consisting of chloro, fluoro, iodo, bromo, -CF3, -CHF2, fluoro(Ci-C6)alkyl, halo(Ci-Ce)alkyl, -OCF3, -SO2(Ci-C6)alkyl, cyano and -CO2(Ci-C6)alkyl;Z1is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR7AR7B, and -(CH2)qR8;-330-SUBSTITUTE SHEET ( RULE 26 )each of R7Aand R7Bis methyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; andR8is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof59. The compound of claim 43 wherein:R100ais selected from the group consisting of -CH3, and -CH2NR500AR500B; each of R500Aand R500Bis independently selected from Ci-Ce alkyl substituted with one or more methoxy; alternatively, R500Aand R500Btogether with the nitrogen to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more substituents, independently selected from Ci-Ce alkyl;R1°°C is chloro-Y1is -CF3;Z1is selected from the group consisting of -CH2NHC(O)CH2OCH3, -CH2NHC(O)CH2CH3, -CH2NHSO2CH3, -CH2NR7AR7B, and -(CH2)qR8; each of R7Aand R7Bis methyl; alternatively R7Aand R7Btogether with the nitrogen to which they are attached, form a heterocyclyl selected from the group consisting of, 4-methylpiperazinyl, and morpholinyl; andR8is 4-methylpiperidinyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

60. The compound of claim 43 whereinR100ais selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,RI°°C jschioj-o--331-SUBSTITUTE SHEET ( RULE 26 )Y1is CF3; andor a pharmaceutically acceptable salt, solvate, or prodrug thereof.

61. The compound of claim 60 wherein R400bis Y1and R400dis Z1.

62. The compound of claim 43 of Formula IllaR100ais selected from the group consisting of -CH3, -(CH2)N(CH2CH2OCH3)2,or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

63. The compound of claim 43 selected from the group consisting of-332-SUBSTITUTE SHEET ( RULE 26 )-333-SUBSTITUTE SHEET (RULE 26)-334-SUBSTITUTE SHEET (RULE 26)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

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

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

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

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

69. The method of claim of 68, wherein the metabolic disease is selected from the group consisting of type 2 diabetes, a disease characterized by insulin resistance or hyperglycemia; obesity or obesity related complications, and a disease characterized by abnormal lipid accumulation.SUBSTITUTE SHEET ( RULE 26 )70. The method of claim 68, wherein the metabolic disease is a complication caused by type 2 diabetes, selected from the group consisting of diabetes-induced cardiovascular diseases, neurodegenerative disorders, atherosclerosis, hypertension, coronary heart diseases, nephropathy, retinopathy, neuropathy and diabetic heart failure.

71. The method of claim 68, wherein the metabolic disease or disorder is nonalcoholic fatty liver disease (NAFLD), wherein at least one prognosis 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 of claim 68, wherein the metabolic disease or disorder is alcoholic fatty liver disease, or one or more complications caused by alcoholic fatty liver disease, wherein the one or more complications caused by alcoholic fatty liver disease is selected from the group consisting of alcoholic hepatitis, cirrhosis, and a combination thereof.

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

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

75. The method of claim 68, wherein the cancer is a metastatic cancer originated from a primary tumor of other tissue types.

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

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

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

79. The method of either of claims 74 or 75, wherein the pharmaceutical composition is administered in combination with a second anti-cancer agent or anti-cancer regimen.-336-SUBSTITUTE SHEET ( RULE 26 )80. The method of claim 79, wherein the second anti-cancer agent is an immunoncological agent.

81. The method of claim 80 wherein the immunocological agent is selected from the group consisting of an antibody against PD-1 / PD-L1, an antibody against other immune check point proteins, CAR-T cells, and other therapeutic immune cells.

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

83. The method of claim 68, wherein the infectious disease is a bacterial infection84. The method of claim 68, wherein the infectious disease is viral infection.

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

86. A method of treating a metabolic disease or disorder characterized by hyperglycemia or insulin resistance, or by abnormal accumulation of lipid in tissue, or a disease or a disorder in which hyperglycemia or insulin resistance or abnormal accumulation of lipid in tissue is a symptom, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according 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 a pharmaceutical composition according to claim 64.

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

89. A method of treating or preventing a dermatological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 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 a pharmaceutical composition according to claim 64.-337-SUBSTITUTE SHEET ( RULE 26 )91. A method of treating or preventing a bacterial infection in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a 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 a pharmaceutical composition according to claim 6493. The method of claim of any of claims 65 to 92, wherein the subject is a mammal or a human.

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

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

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

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

98. A method of preparing a mitochondrial 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 a conventional mitochondrial uncoupler; and-338-SUBSTITUTE SHEET ( RULE 26 )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 Formula:(RA)U-RB; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein RAand RBare covalently linked; each RAis independently a moiety containing a secondary or tertiary amine; u is an integer selected from the group consisting of 1 and 2; andRBis a conventional mitochondrial uncoupler prior to being covalently linked to RA; provided the mitochondrial membrane-retaining uncoupler compound is nota pharmaceutically acceptable salt, solvate, or prodrug thereof.

100. The compound of claim 97 wherein RAis selected from the group consisting of: RAis selected from the group consisting of -CH2NHSO2CH3, -CH2N(CHs)2, -(CH2)2N(CH3)2, --339-SUBSTITUTE SHEET ( RULE 26 )-340-SUBSTITUTE SHEET (RULE 26)

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