Inhibiting fatty acid synthase (fasn)

Abstract

The present disclosure is directed to inhibitors of FASN. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of FASN. For instance, the disclosure is concerned with compounds and compositions for inhibition of FASN, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of FASN, and methods of synthesis of these compounds.

1 . A method of inhibiting fatty acid synthase, comprising:
 administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I),   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is 6-10 membered aryl or 6-10 membered heteroaryl containing 1-2 N atoms; 
 R 1  is C 1-3  aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 10 atom, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O and N,
 wherein R 1  is optionally substituted with —OH or —NH 2 ; 
 
 R 2  is —CO 2 R 3 , —SO 2 NHCOR 3 , or an optionally substituted group selected from the group consisting of 3-4 membered cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein an optionally substituted group of R 2  is optionally substituted with 1-6 R d ; 
 each R a  is independently halogen; 
 each R b  is independently C 1-3  aliphatic; 
 R c  is hydrogen or halogen; 
 R c′  is hydrogen or halogen; 
 R c″  is hydrogen, halogen, —CO 2 H, or tetrazole; 
 each R d  is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , —SO 2 NHCOR 3 , —P(O)R 4 OR 3 , —CH 2 CO 2 R 3 , or an optionally substituted group selected from the group consisting of C 1-3  aliphatic, 4-membered cycloalkyl, and 5-membered heteroaryl containing 1-4 N atoms;
 wherein an optionally substituted group of R d  is optionally substituted with halogen, oxo, OH, or C 1-3  aliphatic; 
 
 each R 3  is independently hydrogen or C 1-3  alkyl optionally substituted with fluoro; 
 R 4  is C 1-6  aliphatic; 
 m is 0-4; and 
 n is 0-6. 
 
     
     
         2 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein the compound is selected from the group consisting of 4-{4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl}-3-methylbenzoic acid; (S)-4′-(6-(1-hydroxycyclopropane-1-carbonyl)-6-azaspiro[2.5]octan-1-yl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; 6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; 5-chloro-6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(2′-methoxy-4′-(2H-tetrazol-5-yl)-1′,2′,3′,4′,5′,6′-hexahydro-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; and 4-[4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl]quinoline-2-carboxylic acid; or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A method of inhibiting fatty acid synthase, comprising:
 administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (II)   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is 6-10 membered aryl or 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; 
 R 1  is C 1-6  aliphatic, 3-6 membered cycloalkyl, 4-6-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; wherein R 1  is optionally substituted with halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ), —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3  alkyl optionally substituted with halogen or —CO 2 R 3 ; 
 R 2  is —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ), —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of 3-7 membered cycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R 2  is optionally substituted with 1-6 R d ; 
 each R a  is independently halogen, —CN, —NO 2 , —OR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ), —SR 3 , —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3  aliphatic optionally substituted with halogen; 
 each R b  is independently C 1-6  aliphatic optionally substituted with halogen; 
 R c  is hydrogen or halogen; 
 R c′  is hydrogen or halogen; 
 each R d  is independently halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ )N(R 4 )(R 4′ ), —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), —COR 5 , —N(R 4 )COR 5 , —N(R 4 )SOR 5 , —N(R 4 )SO 2 R 5 , —SOR 5 , —SO 2 R 5 , —N(R 4 )CO 2 R 3 , —N(R 4 )C(O)N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of C 1-6  aliphatic and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R d  is optionally substituted with halogen, —OH, —NH 2 , —CN, oxo, or C 1-3  alkyl; 
 each R 3  is independently hydrogen or C 1-6  aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo; 
 each R 4  is independently hydrogen, —OH, —CN, or C 1-6  aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo; 
 each R 4′  is independently hydrogen, or C 1-6  aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo; 
 each R 5  is independently hydrogen or C 1-6  aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo; 
 
           m is 0-4; and 
           n is 0-6. 
         
       
     
     
         12 . The method of  claim 11 , wherein the compound is a compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1-3  aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;
 wherein R 1  is optionally substituted with —OH or NH 2 ; 
 
 R 2  is —CO 2 H or an optionally substituted group selected from the group consisting of phenyl and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S,
 wherein an optionally substituted group of R 2  is optionally substituted with 1-6 R d ; 
 
 each R a  is independently halogen; 
 each R d  is independently halogen, —OR 3 , —CO 2 R 3 , —S(O) 2 NH 2 , or an optionally substituted group selected from the group consisting of C 1-3  aliphatic, and 5-7 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;
 wherein an optionally substituted group of R d  is optionally substituted with halogen or C 1-3  aliphatic; 
 
 each R 3  is independently hydrogen or C 1-3  alkyl; and 
 n is 0-4. 
 
       
     
     
         13 . The method of  claim 11 , wherein R 1  is 3-4 membered cycloalkyl or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S; wherein R 1  is optionally substituted with —OH or NH 2 ; and
 R 2  is an optionally substituted group selected from the group consisting of phenyl and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein an optionally substituted group of R 2  is optionally substituted with 1-6 R d . 
 
     
     
         14 . The method of  claim 11 , wherein the compound is a compound of formula (IV) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1-3  aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; and wherein R 1  is optionally substituted with —OH or —NH 2;    
 each R a  is independently halogen; 
 each R d  is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , or an optionally substituted group selected from the group consisting of C 1-3  aliphatic and 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 
 
         wherein an optionally substituted group of R d  is optionally substituted with halogen or C 1-3  aliphatic;
 each R 3  is independently hydrogen or C 1-3  alkyl; and 
 n is 0-4. 
 
       
     
     
         15 . The method of  claim 11 , wherein the compound is a compound of formula (VI-A) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is 3-membered cycloalkyl optionally substituted with —OH, or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; 
 each R d  is independently halogen, —CO 2 H, —OR 3 , C 1-3  aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and 
 each R 3  is independently hydrogen or C 1-3  alkyl. 
 
       
     
     
         16 . The method of  claim 11 , wherein the compound is a compound of formula (V) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is 3-membered cycloalkyl optionally substituted with —OH, or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; 
 each R d  is independently halogen, —CO 2 H, —OR 3 , C 1-3  aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of 0, N and S; and 
 each R 3  is independently hydrogen or C 1-3  alkyl. 
 
       
     
     
         17 . The method of  claim 11 , wherein m is 0 and n is 0. 
     
     
         18 . The method of  claim 11 , wherein:
 R 1  is 4-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; and   each R d  is independently —CO 2 R 3 , —OR 3 , or 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.   
     
     
         19 . The method of  claim 11 , wherein R 1  is selected from the group consisting of methyl, ethyl, 
       
         
           
           
               
               
           
         
       
     
     
         20 . A method of inhibiting fatty acid synthase, comprising:
 administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is phenyl or naphthyl; 
 R 1  is methyl, ethyl, tetrahydrofuranyl, oxazolyl, triazolyl, cyclobutyl, or cyclopropyl optionally substituted with —CH 2 CO 2 H, —OH, or —NH 2;    
 R 2  is —CO 2 H, cyclobutyl, benzoxazolyl, indolyl, indazolyl, benzimidazolyl, quinolinyl, phenyl, naphthyl, pyridyl, or isoquinolinyl; 
 each R a  is independently fluoro or chloro; 
 each R b  is independently methyl; 
 R c  is hydrogen or fluoro; 
 R c′  is hydrogen or fluoro; 
 R c″  is hydrogen or —CO 2 H; 
 m is 0-1; and 
 n is 0-3.