Oxopyridine derivatives useful as aminocarboxymuconate semialdehyde decarboxylase (acmsd) inhibitors

Abstract

The present invention is related to a compound represented by the following structural formula: The present invention is also related a method of treating a subject with a disease which can be ameliorated by inhibition of aminocarboxymuconate semialdehyde decarboxylase (ACMSD).

1 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; 
 R 2  is -halo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:
 the (C 1 -C 5 )alkyl group represented by R 2  is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 1 -C 5 )alkyl group represented by R 2  are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy; 
 the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2  are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ; 
 each R a  and each R b  are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a  or R b  is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy; 
 R c  is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c  is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy; 
 i is 0, 1, or 2; 
 
 each R 3  is independently —H, —CH 3 , or F; 
 A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ; 
 each R 4  is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and 
 B is —COOH or tetrazolyl, 
 provided that the compound is other than 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1  and X 2  are each independently CH or N, and at least one of X 1  and X 2  is CH. 
     
     
         7 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1  and X 2  are each independently CH or N, and at least one of X 1  and X 2  is CH. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 - or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2  is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2  is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy and —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 — or pyrimidyl-CH 2 — group represented by R 2  is optionally and independently substituted with —CH 3 . 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —H, —CH 3 , —OCH 3 , F, Cl, or —CN;   R 2  is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl or benzyl, wherein the (C 1 -C 5 )alkyl represented by R 2  is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2  is optionally and independently substituted with —CH 3 ;   R 3  is —H, F, or —CH 3 ;   R 4  is F, Cl, —CH 3 , or methoxy; and   n is 0 or 1.   
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; 
 R 2  is -halo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:
 the (C 1 -C 5 )alkyl group represented by R 2  is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 1 -C 5 )alkyl group represented by R 2  are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy; 
 the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2  are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ; 
 each R a  and each R b  are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a  or R b  is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy; 
 R c  is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c  is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy; 
 i is 0, 1, or 2; 
 
 each R 3  is independently —H, —CH 3 , or F; 
 A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ; 
 each R 4  is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and 
 B is —COOH or tetrazolyl. 
 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1  and X 2  are each independently CH or N, and at least one of X 1  and X 2  is CH. 
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1  and X 2  are each independently CH or N, and at least one of X 1  and X 2  is CH. 
     
     
         23 . (canceled) 
     
     
         24 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         25 . (canceled) 
     
     
         26 . The pharmaceutical composition of  claim 16 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         27 . The pharmaceutical composition of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 2  is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 - or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2  is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2  is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy and —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 — or pyrimidyl-CH 2 — group represented by R 2  is optionally and independently substituted with —CH 3 . 
     
     
         28 . (canceled) 
     
     
         29 . The pharmaceutical composition of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —H, —CH 3 , —OCH 3 , F, Cl, or —CN;   R 2  is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl or benzyl, wherein the (C 1 -C 5 )alkyl represented by R 2  is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2  is optionally and independently substituted with —CH 3 ;   R 3  is —H, F, or —CH 3 ;   R 4  is F, Cl, —CH 3 , or methoxy; and   n is 0 or 1.   
     
     
         30 . (canceled) 
     
     
         31 . A method of treating a subject with a disease which can be ameliorated by inhibition of aminocarboxymuconate semialdehyde decarboxylase (ACMSD), comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 16 , wherein the disease is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a beta oxidation disease, a metabolic disease, a cancer, a vascular disease, an ocular vascular disease, a muscular eye disease, a renal disease, genetic lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia/reperfusion injury (IRI), Duchenne & Becker muscular dystrophy, diabetes (type I or type II), obesity, sarcopenia, Alpers's Disease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenic muscle weakness, ataxia, and retinitis pigmentosa, Pearson Syndrome, platinum-based chemotherapy induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum A, Wallerian degeneration, or HIV-induced lipodystrophy. 
     
     
         32 . A method of treating a subject with acute kidney injury, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         33 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         34 - 38 . (canceled)