TRIAZOLOPYRIDINONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS

Abstract

The present invention discloses triazolopyridinone 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.

We claim: 
     
         1 . A compound that is an inhibitor of stearoyl-CoA desaturase having the structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, optionally substituted C 1-20  alkyl, optionally substituted C 1-5  lower alkyl, optionally substituted C 3-20  cycloalkyl, optionally substituted C 2-20  alkenyl, optionally substituted C 2-20  alkynyl, optionally substituted C 1-20  alkoxy, optionally substituted monocyclic aryl, or optionally substituted monocyclic heteroaryl; 
 R 2  is hydrogen, optionally substituted C 1-20  alkyl, optionally substituted C 1-6  lower alkyl, optionally substituted C 3-20  cycloalkyl, optionally substituted C 2-20  alkenyl, optionally substituted C 2-20  alkynyl, optionally substituted C 1-20  alkoxy; 
 X is a moiety selected from: —O—C(O)—, —NR′—C(O)—, —C(O)—NR′—, or —O—C(O)—NR′—, wherein R′ is hydrogen or C 1-6  lower alkyl; 
 L 1  is a covalent bond or -Lk-Y-, wherein Lk is optionally substituted linear or branched C 1-4  alkylene and Y is selected from a covalent bond, —O—, —S—, or —NR″—, wherein R″ is hydrogen or C 1-6  lower alkyl; and 
 L 2  is a covalent bond or -Lk′-Y′-, wherein Lk′ is optionally substituted linear or branched C 1-4  alkylene and Y′ is selected from a covalent bond, —O—, —S—, or —NR″—, wherein R″ is hydrogen or C 1-6  lower alkyl. 
 
     
     
         2 . The compound of  claim 1  wherein
 R 1  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 lower alkyl, halogen, CF 3 , —OCF 3 , and —OCH 3 ; and 
 L 1  is methylene. 
 
     
     
         3 . The compound of  claim 1  wherein X is —NR′—C(O)—. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is optionally substituted monocyclic aryl. 
     
     
         5 . The compound of  claim 4 , selected from the group consisting of:
 2-(3,4-dichlorobenzyl)-N-hexyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide;   2-(3,4-dichlorobenzyl)-N-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide; and   2-(4-chloro-3-(trifluoromethyl)benzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.   
     
     
         6 . The compound of  claim 3 , wherein L 1  is -Lk-Y-, wherein Lk is optionally substituted C 2-3  alkylene and Y is a covalent bond or —O—. 
     
     
         7 . The compound of  claim 6 , selected from the group consisting of
 2-(3-(2,5-dichlorophenoxy)propyl)-N-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide; and   (S)-N-butyl-2-(1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)-3-oxo-2,3-dihydro-1,2,41-triazolo[4,3-a]pyridine-6-carboxamide.   
     
     
         8 . The compound of  claim 1  wherein X is —C(O)—NR′—. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is optionally substituted monocyclic aryl. 
     
     
         10 . The compound of  claim 9 , selected from the group consisting of:
 N-(2-(4-chloro-3-(trifluoromethyl)benzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-hydroxyacetamide; and   N-(2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,3-dihydroxypropanamide.   
     
     
         11 . The compound of  claim 8 , wherein L 1  is -Lk-Y-, wherein Lk is optionally substituted C 2-3  alkylene and Y is a covalent bond or —O—. 
     
     
         12 . The compound of  claim 11 , namely 2-hydroxy-N-(3-oxo-2-(3-(o-tolyloxy)propyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)acetamide. 
     
     
         13 . The compound of  claim 1 , wherein X is —O—C(O)—. 
     
     
         14 . The compound of  claim 13 , selected from the group consisting of:
 ethyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate; and   2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid.   
     
     
         15 . The compound of  claim 1 , wherein X is —O—C(O)—NR′—. 
     
     
         16 . The compound of  claim 15 , selected from the group consisting of:
 tert-butyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate; and   butyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate.   
     
     
         17 . The compound of  claim 1 , wherein R 2  is optionally substituted alkyl. 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof. 
     
     
         19 . A method for treating a disease or condition in a mammal that can be treated with a stearoyl-CoA desaturase inhibitory compound comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1  or a pharmaceutically acceptable salt, ester, prodrug, solvate, or hydrate thereof. 
     
     
         20 . The method of  claim 19 , 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.