PTERIDINONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS

Abstract

The present invention discloses pteridinone derivatives for use as inhibitors of stearoyl-CoA desaturase having the structure of Formula I: The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.

1 . A compound that is an inhibitor of stearoyl-CoA desaturase having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —X 1 —NR 5  or, —X 2 —C(O)NR 4 R 5  wherein
 R 4  is hydrogen or C 1-4  lower alkyl, and 
 R 5  is hydrogen, aryl, heteroaryl, —C(═NH)NH 2 , —C(═O)R 6  or —S(═O) 2 R 6 ,
 wherein 
 R 6  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 1-4  alkenyl, C 1-4  alkoxy, 5 or 6 membered optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl; 
 
 X 1  is optionally substituted linear or branched C 1-4  alkylene; and 
 X 2  is optionally substituted linear or branched C 2-4  alkylene; 
 
 R 2  is optionally substituted mono or bicyclic heterocyclyl, optionally substituted mono or bicyclic aryl, or mono or bicyclic heteroaryl, 
 R 1  is 5 or 6 membered optionally substituted monocyclic cycloalkyl, 5 or 6 membered optionally substituted monocyclic heterocycle, or 5 or 6 membered optionally substituted monocyclic heteroaryl, 
 with the proviso that R 3  is not 2-thiazolyl; and 
 Y is (CH 2 ) P , where P is 0, 1, or 2, 
 or a pharmaceutically acceptable salt, ester, prodrug, solvate, or hydrate thereof. 
 
   
   
       2 . The compound of  claim 1 , wherein
 R 2  is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 2 O)NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 , and   further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;   R 3  is 5 or 6 membered monocyclic cycloalkyl, 5 or 6 membered monocyclic heterocycle, or 5 or 6 membered monocyclic heteroaryl wherein the cycloalkyl, heterocycle, or heteroaryl moiety may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 2 °, C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 , and   R 20  and R 22  are independently selected from the group consisting of hydrogen, C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl,   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6  alkyl, CF 3 , aryl, and heteroaryl.   
   
   
       3 . The compound of  claim 2 , wherein
 R 2  is phenyl which may be optionally substituted at the 3, 4, or 5 position with 1 to 3 substituents selected from the group consisting of halogen, CF 3 , —OCF 3 , and —OCH 3 ; and   Y is methylene.   
   
   
       4 . The compound of  claim 3 , wherein R 1  is —X 1 —NR 4 R 5 . 
   
   
       5 . The compound of  claim 4 , wherein R 5  is —C(O)R 6 . 
   
   
       6 . The compound of  claim 5 , wherein R 3  is 5 or 6 membered optionally substituted monocyclic heteroaryl. 
   
   
       7 . The compound of  claim 6 , selected from the group consisting of:
 N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-6-(6-methoxy(3-pyridyl))-7-oxo-8-hydropteridin-8-yl)ethyl]acetamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)-8-hydropteridin-8-yl)ethyl]carboxamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)(8-hydropteridin-8-yl))ethyl]benzamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)(8-hydropteridin-8-yl))ethyl]-3-thienylcarboxamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)(8-hydropteridin-8-yl))ethyl](4-fluorophenyl)carboxamide;   N-[2-(2-{[(3-chlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)-8-hydropteridin-8-yl)ethyl]acetamide;   N-(2-{7-oxo-2-[benzylamino]-6-(3-pyridyl)-8-hydropteridin-8-yl}ethyl)acetamide;   N-[2-(2-{[(4-fluorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)-8-hydropteridin-8-yl)ethyl]acetamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(3-pyridyl)-8-hydropteridin-8-yl)ethyl]acetamide;   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-(2-thienyl)-8-hydropteridin-8-yl)ethyl]acetamide;   N-[2-(2-{[(3,4-difluorophenyl)methyl]amino}-7-oxo-6-(2-thienyl)-8-hydropteridin-8-yl)ethyl]acetamide; and   N-[2-(2-{[(3,4-dichlorophenyl)methyl]amino}-7-oxo-6-pyrimidin-2-yl-8-hydropteridin-8-yl)ethyl]acetamide.   
   
   
       8 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof. 
   
   
       9 . A method for treating a disease or condition in a mammal that can be treated with an stearoyl-CoA desaturase inhibitory compound comprising administering to a mammal in need thereof a therapeutically effective dose of a compound having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —X 1 —NR 4 R 5  or, —X 2 —C(O)NR 4 R 5  wherein
 R 4  is hydrogen or C 1-4  lower alkyl, and 
 R 5  is hydrogen, aryl, heteroaryl, —C(═NH)NH 2 , —C(═O)R 6  or —S(═O) 2 R 6 ,
 wherein 
 R 6  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 1-4  alkenyl, C 1-4  alkoxy, 5 or 6 membered optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl; 
 
 X 1  is optionally substituted linear or branched C 1-4  optionally substituted alkylene; and 
 X 2  is optionally substituted linear or branched C 2-4  optionally substituted alkylene; 
 
 R 2  is optionally substituted mono or bicyclic heterocyclyl, optionally substituted mono or bicyclic aryl, or mono or bicyclic heteroaryl, 
 R 3  is hydrogen, optionally substituted C 1-4  alkyl, 5 or 6 membered optionally substituted monocyclic cycloalkyl, 5 or 6 membered optionally substituted monocyclic aryl, 5 or 6 membered optionally substituted monocyclic heterocycle, or 5 or 6 membered optionally substituted monocyclic heteroaryl, 
 with the proviso that R 3  is not 2-thiazolyl or 2-methoxyphenyl; and 
 Y is (CH 2 ) P , where P is 0, 1, or 2, 
 
     or a pharmaceutically acceptable salt, ester, prodrug, solvate, or hydrate thereof. 
   
   
       10 . The method of  claim 9 , wherein the disease state is selected from the group consisting of coronary artery disease, atherosclerosis, heart disease, hypertension, and peripheral vascular disease, cancer, cerebrovascular diseases (including, but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy), dyslipidemia, obesity, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, and other diabetic complications.