Di-substituted pyrazole compounds for the treatment of diseases

Abstract

Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating a condition, disease, or disorder associated with abnormal activation of the SREBP pathway, including metabolic disorders such as obesity, cancer, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) wherein the compound is according to Formula (I).

1 . A Compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl rings are substituted with one R 1a  and additionally optionally substituted with a second R 1a  and additionally optionally substituted with a third R 1a ; and wherein the pyridinonyl is substituted on the nitrogen with R 1b  and is additionally optionally substituted with 1, 2, or 3 R 1a ; 
         each R 1a  is independently halo, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; 
         R 1b  is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; 
         R 20  is 
       
       
         
           
           
               
               
           
         
          where 0, 1, or 2 of X 1 -X 4  are nitrogen and the remaining are carbon; 
         each R 2b  is independently halo, alkyl, haloalkyl, —NO 2 , or cyano; 
         R 2c  is —NO 2  or NH 2 ; 
         R 3  is hydrogen or alkyl; 
         R 4  is hydrogen or alkyl; 
         R 5a  and R 6a  are independently hydrogen or alkyl; and 
         R 5b  and R 6b  are independently alkyl; haloalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl; and 
         wherein each cycloalkyl, either alone or as part of another group, is independently optionally substituted with one or two groups independently selected from the group consisting of alkyl, halo, and haloalkyl; or 
         a pharmaceutically acceptable salt thereof; 
         provided that the compound is not 4-(1-(3-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline: 4-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline; or 4-(1-(3-chloropyridin-4-yl)-1H-pyrazol-4-yl)aniline. 
       
     
     
         2 . The Compound of  claim 1 , wherein R 1  is phenyl, pyridinonyl, or pyridinyl; where the phenyl and pyridinyl are optionally substituted with 1 or 2 R 1a  and where the pyridinonyl is substituted on the nitrogen with R 1b  and is additionally optionally substituted with 1 R 1a ; or a pharmaceutically acceptable salt thereof. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The Compound of  claim 1 , wherein R 3  and R 4  are both hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The Compound of  claim 1 , wherein R 3  and R 4  are both methyl, R 3  is hydrogen and R 4  is methyl, or R 3  is hydrogen and R 4  is methyl; or a pharmaceutically acceptable salt thereof. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The Compound of  claim 1 , wherein the R 2  ring is substituted with a first R 2b ; and when the R 2  ring is phenyl or pyridinyl, R 2  is additionally optionally substituted with a second R 2b ; or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The Compound of  claim 1 , wherein the first R 2b  is halo; or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The Compound of  claim 1 , wherein the first R 2b  is chloro or fluoro; or a pharmaceutically acceptable salt thereof. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The Compound of  claim 1 , wherein the first R 2b  is —CH 3 ; or a pharmaceutically acceptable salt thereof. 
     
     
         22 . (canceled) 
     
     
         23 . The Compound of  claim 1 , wherein R 2c  is —NO 2 ; or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The Compound of  claim 1 , wherein R 2c  is —NH 2 ; or a pharmaceutically acceptable salt thereof. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . The Compound of  claim 1 , wherein R 1  is substituted with one R 1a ; or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The Compound of  claim 27 , wherein R 1a  is alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The Compound of  claim 1 , wherein R 1b  is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The Compound of  claim 1 , wherein R 1b  is alkyl, haloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl where the heterocycloalkylalkyl is optionally substituted with an alkyl group on a ring nitrogen of the heterocycloalkyl ring; or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The compound of  claim 1 , wherein the compound is selected from the following compounds: 4-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine,
 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline,   5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,   4-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine,   3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline,   6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine,   4-(4-(5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-2-propylpyridine,   3-chloro-5-nitro-2-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine,   5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine,   5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,   5-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-aminophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,   5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-amino-2-fluorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-amino-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile,   5-(4-(4-nitro-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-amino-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,   2-methyl-3-nitro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine,   2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine, and   5-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine;   or a pharmaceutically acceptable salt thereof.   
     
     
         32 . A pharmaceutical composition comprising a Compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating a condition, disease, or disorder associated with abnormal activation of the SREBP pathway comprising administering to a patient in need thereof a therapeutically effective amount of the Compound of  claim 1 . 
     
     
         34 . The method of  claim 33  wherein the condition, disease, or disorder is selected from metabolic syndrome, hypertension, type 2 diabetes, dyslipidemia, obesity, pancreatic B-cell dysfunction, atherosclerosis, a cell proliferative disease, reducing body weight, a metabolic disease, hyperlipidemia, a lipoprotein related disease, combined hyoerlipidemia (elevated cholesterol and triglycerides), Frederickson Type IIb, familial combined hyperlipidemia (inherited form of combined hyperlipidemia), familial hypertriglyceridemia, Frederickson Type IV, hyperlipoproteinemia Type V, mixed hyperlipidemia, Aquired hyperlipidemia, Fatty Liver Disease, Nonalcoholic Steatohepatitis, Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, Tissue Inflammation such as Cutaneous Psoriasis (associated with Metabolic syndrome), coronary artery disease (atherosclerosis), Post Myocardial Infarction management, Peripheral vascular disease, cerebrovascular disease—thrombotic, Type II Diabetes Mellitus, Diabetic Nephropathy, cancer, Hepatocellular Carcinoma, Glioblastoma Multiforme, Prostate Cancer, Post menopausal Breast Carcinoma, Pancreatic Adenocarcinoma, Ovarian cancer, B cell lymphoma, lung cancer, digestive and gastrointestinal cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, stomach (gastric) cancer, esophageal cancer, gall bladder cancer, appendix cancer, renal cancer, cancer of the central nervous system, skin cancer, a lymphoma, choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a blood cancer; or wherein the patient is in need of increased thermogenesis or in need of reducing body weight. 
     
     
         35 . The method of  claim 33  wherein the condition, disease, or disorder is selected from metabolic syndrome, hypertension, type 2 diabetes, dyslipidemia, obesity, pancreatic B-cell dysfunction, atherosclerosis, Hepatocellular Carcinoma, Glioblastoma Multiforme, Prostate Cancer, post-menopausal Breast Carcinoma, Pancreatic Adenocarcinoma, Ovarian cancer, B cell lymphoma, lung cancer, digestive and gastrointestinal cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, stomach (gastric) cancer, esophageal cancer, gall bladder cancer, appendix cancer, renal cancer, cancer of the central nervous system, skin cancer, a lymphoma, choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a blood cancer; or wherein the patient is in need of increased thermogenesis or in need of reducing body weight. 
     
     
         36 . The compound of  claim 1 , of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         37 . The compound of  claim 38 , of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The compound of  claim 38 , of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         39 . The compound of  claim 38 , of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         40 . The compound of  claim 38 , of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.