Heteroarylaminopyrazole derivatives useful for the treatment of diabetes

Abstract

The present invention relates to heteroarylaminopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.

1 . A heteroarylaminopyrazole compound of Formula (I) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
       
         is a substituted heterocyclic aromatic ring radical selected from 
       
     
     
       
         
         
             
             
         
       
       R is H, or (C 1 -C 6 )alkyl; 
       R 1  is H,
 (C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl, 
 (C 3 -C 6 )alkenyl, 
 (C 3 -C 6 )alkynyl, 
 (C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo, 
 (C 1 -C 3 )haloalkyl, or 
 phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano; 
 
       R 2  is H,
 halo, 
 (C 1 -C 6 )alkyl, 
 pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, halo, and (C 1 -C 6 )alkyl, 
 phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,
 pyrimidyl, 
 
 thienyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo, 
 benzothienyl, optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo, 
 or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo; 
 
       R 3  is (C 1 -C 6 )alkyl,
 (C 3 -C 6 )cycloalkyl, 
 (C 2 -C 3 )haloalkyl or 
 phenyl optionally substituted with up to four substituents selected from the group consisting of
 (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy, 
 halo, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 3 )haloalkoxy, 
 (C 1 -C 6 )alkylthio, and 
 cyano; 
 
 
       R 4  is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 6 )alkylthio, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, or 
 halo; 
 
       n=0, 1, 2, or 3; 
       X is CO 2 R 7 , CONR 5 R 6 , or SO 2 NH 2 ; 
       R 5  is H, (C 1 -C 6 )alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo; 
       R 6  is H or (C 1 -C 6 )alkyl;
 or 
 
       R 5  and R 6 , taken together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C 1 -C 3 )alkyl; 
       R 7  is H,
 (C 1 -C 6 )alkyl, 
 benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of
 halo, 
 (C 1 -C 6 )alkyl, 
 (C 1 -C 3 )alkoxy, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, and 
 (C 1 -C 6 )alkylthio; 
 
 phenyl optionally substituted with up to two substituents selected from the group consisting of
 (C 1 -C 6 )alkyl, 
 halo, 
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, and 
 (C 1 -C 6 )alkylthio; 
 
 
       and pharmaceutically acceptable salts thereof; 
       provided that the compound of Formula (I) is not 
     
     
       
         
         
             
             
         
       
     
   
   
       2 . The compound of  claim 1 ,
 wherein   
     
       
         
         
             
             
         
       
       
         is a substituted heterocyclic aromatic ring radical is 
       
     
     
       
         
         
             
             
         
       
       R is H, or (C 1 -C 6 )alkyl; 
       R 1  is H,
 (C 1 -C 6 )alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [tri(C 1 -C 4 )alkyl]silyl, 
 (C 3 -C 6 )alkenyl, 
 (C 3 -C 6 )alkynyl, 
 (C 3 -C 6 )cycloalkyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 3 )alkyl, CF 3 , and halo, 
 (C 1 -C 3 )haloalkyl, or 
 phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and cyano; 
 
       R 2  is H,
 halo, 
 (C 1 -C 6 )alkyl, 
 pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, halo, and (C 1 -C 6 )alkyl, 
 phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo,
 pyrimidyl, 
 
 thienyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo, 
 benzothienyl, optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo, 
 or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, cyano and halo; 
 
       R 3  is (C 1 -C 6 )alkyl,
 (C 3 -C 6 )cycloalkyl, 
 (C 2 -C 3 )haloalkyl or 
 phenyl optionally substituted with up to four substituents selected from the group consisting of
 (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy, 
 halo, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 3 )haloalkoxy, 
 (C 1 -C 6 )alkylthio, and 
 cyano; 
 
 
       R 4  is (C 1 -C 6 )alkyl optionally substituted with one (C 1 -C 4 )alkoxy,
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 6 )alkylthio, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, or 
 halo; 
 
       n=0, 1, 2, or 3; 
       X is CO 2 R 7 , CONR 5 R 6 , or SO 2 NH 2 ; 
       R 5  is H, (C 1 -C 6 )alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo; 
       R 6  is H or (C 1 -C 6 )alkyl;
 or 
 
       R 5  and R 6 , taken together with N atom to which they are attached, may form a piperidine, morpholine, thiomorpholine, or piperazine ring said piperazine optionally substituted on N with (C 1 -C 3 )alkyl; 
       R 7  is H,
 (C 1 -C 6 )alkyl, 
 benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of
 halo, 
 (C 1 -C 6 )alkyl, 
 (C 1 -C 3 )alkoxy, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, and 
 (C 1 -C 6 )alkylthio; 
 
 phenyl optionally substituted with up to two substituents selected from the group consisting of
 (C 1 -C 6 )alkyl, 
 halo, 
 (C 1 -C 6 )alkoxy, 
 (C 1 -C 3 )haloalkyl, 
 (C 1 -C 3 )haloalkoxy, and 
 (C 1 -C 6 )alkylthio; 
 
 
       and pharmaceutically acceptable salts thereof. 
     
   
   
       3 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 
   
   
       4 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents. 
   
   
       5 . The pharmaceutical composition of  claim 4 , wherein said pharmaceutical agent is selected from the group consisting of PPAR ligands, insulin secretagogues, sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, biguanides, protein tyrosine phosphatase-1B, dipeptidyl peptidase IV, 11beta-HSD inhibitors, anti-obesity drugs, HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates. 
   
   
       6 . A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       7 . The method of  claim 6 , wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes. 
   
   
       8 . A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       9 . A method of treating diabetes-related disorders comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       10 . The method of  claim 9 , wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 
   
   
       11 . A method of treating or preventing secondary causes of diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       12 . The method of  claim 11 , wherein said secondary cause is selected from the group consisting of glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. 
   
   
       13 . A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutical agents. 
   
   
       14 . The method of  claim 13 , wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents. 
   
   
       15 . The method of  claim 14 , wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes. 
   
   
       16 . A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutical agents. 
   
   
       17 . The method of  claim 16 , wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents. 
   
   
       18 . A method of treating diabetes-related disorders comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutical agents. 
   
   
       19 . The method of  claim 18 , wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 
   
   
       20 . The method of  claim 19 , wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents. 
   
   
       21 . A method of treating or preventing secondary causes of diabetes comprising the step of administering a subject in need thereof a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutical agents. 
   
   
       22 . The method of  claim 21 , wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents 
   
   
       23 . A method of treating diabetes, Syndrome X, diabetes-related disorders or secondary causes of diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  in combination with one or more agents selected from the group consisting of HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates. 
   
   
       24 . The method of  claim 23 , wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 
   
   
       25 . The method of any one of  claims 13  to  24 , wherein the compound of  claim 1  and one or more pharmaceutical agents are administered as a single pharmaceutical dosage formulation. 
   
   
       26 . A method of treating cardiovascular disease comprising the step of administering to a subject in need thereof a therapeutically effective amount of a polypeptide of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       27 . The method of  claim 26 , wherein said cardiovascular disease is selected from atherosclerosis, coronary heart disease, coronary artery disease, and hypertension. 
   
   
       28 . A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 3 . 
   
   
       29 . A method of stimulating insulin secretion in a subject in need thereof by administering to said subject a compound of  claim 1  or a pharmaceutical composition of  claim 3 .