Sulfonyl-substituted bicyclic compounds as ppar modulators for the treatment of non-alcoholic steatohepatitis

Abstract

Disclosed herein are new methods of treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and other fibrotic diseases of the liver in a subject by modulating PPARδ with sulfonyl-substituted bicyclic compounds and compositions as pharmaceuticals.

1 . A method for the treatment of NASH comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a salt, ester, or prodrug thereof, wherein:
 A is a saturated or unsaturated hydrocarbon chain or a heteroatom-comprising hydrocarbon chain having from 3 to 5 atoms, forming a five- to seven-membered ring; 
 T is selected from the group consisting of —C(O)OH, —C(O)NH 2 , and tetrazole; 
 G 1  is selected from the group consisting of —(CR 1 R 2 ) n —, -Z(CR 1 R 2 ) n —, —(CR 1 R 2 ) n Z-, —(CR 1 R 2 ) r Z(CR 1 R 2 ) s —; 
 Z is O, S or NR; 
 n is 0, 1, or 2; 
 r and s are independently 0 or 1; 
 R 1  and R 2  are independently selected from the group consisting of hydrogen, halo, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower alkoxy, and lower perhaloalkyl or together may form an optionally substituted cycloalkyl; 
 X 1 , X 2 , and X 3  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, halogen, perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, and NH 2 ; 
 G 2  is selected from the group consisting of a saturated or unsaturated cycloalkyl or heterocycloalkyl linker, optionally substituted with X 4  and X 5 ; 
 X 4  and X 5  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, halogen, lower perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH 2 , and CO 2 R, or X 4  and X 5  together may form a cycloalkyl; 
 R is selected from the group consisting of optionally substituted lower alkyl and hydrogen; 
 G 3  is selected from the group consisting of a bond, a double bond, —(CR 3 R 4 ) m —, carbonyl, and —(CR 3 R 4 ) m CR 3 ═CR 4 —; 
 m is 0, 1, or 2; 
 R 3  and R 4  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted aryl, lower perhaloalkyl, cyano, and nitro; 
 G 4  is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloheteroaryl, optionally substituted cycloalkenyl, and —N═(CR 5 R 6 ); and 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted cycloheteroalkyl. 
 
     
     
         2 . The method as recited in  claim 1 , wherein T is —C(O)OH. 
     
     
         3 . The method as recited in  claim 2 , wherein A comprises a chain having three atoms and forming a five-membered ring. 
     
     
         4 . The method as recited in  claim 2 , wherein the compound has the structural Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method as recited in  claim 1 , wherein:
 G 1  is —(CR 1 R 2 ) n —;   With the proviso that if A is a 5 carbon chain, n is 0 or 1;   G 2  has the structure:   
       
         
           
           
               
               
           
         
         Y 1  and Y 2  are independently selected from the group consisting of N and C—X 6 ; 
         X 4  and X 5  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, halogen, lower perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH 2 , and CO 2 R, or X 4  and X 5  together may form a cycloalkyl; 
         R is selected from the group consisting of lower alkyl and hydrogen; 
         p is 1, 2 or 3; 
         W is selected from the group consisting of —CX 4 X 5 — and N—X 7 ; 
         X 4  and X 5  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, halogen, lower perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH 2 , and CO 2 R; 
         X 6  is selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, cyano, halogen, lower perhaloalkyl and NH 2  or null when forming a double bond with an adjacent ring atom; and 
         X 7  is selected from the group consisting of hydrogen, alkyl, hydroxy, and lower perhaloalkyl, or null when forming a double bond with Y 2 . 
       
     
     
         6 . The method as recited in  claim 5 , wherein A comprises a chain having three atoms and forms a five-membered ring. 
     
     
         7 . The method as recited in  claim 5 , wherein G 3  is selected from the group consisting of a bond and methylene. 
     
     
         8 . The method as recited in  claim 5 , wherein:
 p is 2;   W is CX 4 X 5 ; and   Y 1  is N.   
     
     
         9 . The method as recited in  claim 9 , wherein G 4  is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         10 . The method as recited in  claim 9 , wherein G 4  is singly or doubly substituted with halogen, lower alkyl, lower perhaloalkyl, lower perhaloalkoxy or mono- or di-haloalkoxy. 
     
     
         11 . The method as recited in  claim 8 , wherein Y 2  is N. 
     
     
         12 . The method as recited in  claim 11 , wherein G 4  is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl. 
     
     
         13 . The method as recited in  claim 12 , wherein G 4  is optionally substituted phenyl or optionally substituted pyridinyl. 
     
     
         14 . The method as recited in  claim 13 , wherein G 4  is singly or doubly substituted with halogen, lower alkyl, lower perhaloalkyl, or lower perhaloalkoxy or mono- or di-haloalkoxy. 
     
     
         15 . The method as recited in  claim 12 , wherein X 1 , X 2 , and X 3  are each independently selected from the group consisting of hydrogen, lower alkyl, perhaloalkyl, and halogen. 
     
     
         16 . The method as recited in  claim 15 , wherein X 1 , X 2 , and X 3  are independently selected from the group consisting of hydrogen and methyl. 
     
     
         17 . The method as recited in  claim 1 , wherein the compound has the structural formula: 
       
         
           
           
               
               
           
         
         wherein G 1  is selected from the group consisting of —(CR 1 R 2 ) n — and —(CR 1 R 2 ) n O—. 
       
     
     
         18 . The method as recited in  claim 17 , wherein R 1  and R 2  are hydrogen. 
     
     
         19 . The method as recited in  claim 18 , wherein G 1  is —(CH 2 ) n —, and n is 0 or 1. 
     
     
         20 . The method as recited in  claim 19 , wherein at least one of X 4  and X 5  is not hydrogen. 
     
     
         21 . The method as recited in  claim 20 , wherein said at least one of X 4  and X 5  is lower alkyl. 
     
     
         22 . The method as recited in  claim 21 , wherein said at least one of X 4  and X 5  is methyl. 
     
     
         23 . The method as recited in  claim 22 , wherein one X 4  and one X 5  are methyl. 
     
     
         24 . The method as recited in  claim 23 , wherein X 4  and X 5  are methyl and are attached to the piperazine ring at the 2 and 6 positions. 
     
     
         25 . The method as recited in  claim 24 , wherein the X 4  and X 5  methyl groups are oriented cis to each other. 
     
     
         26 . The method as recited in  claim 17 , wherein X 1 , X 2 , and X 3  are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, and optionally substituted lower alkoxy. 
     
     
         27 . The method as recited in  claim 17 , wherein G 3  is selected from the group consisting of a bond and methylene. 
     
     
         28 . The method as recited in  claim 17 , wherein G 4  has a structural formula of: 
       
         
           
           
               
               
           
         
       
       wherein:
 q is 1 to 3; 
 X 8  and X 9  are independently selected from the group consisting of hydrogen, alkyl, halogen, lower perhaloalkyl, lower perhaloalkoxy or mono- or di-haloalkoxy, hydroxy, alkoxy, nitro, cyano, NH 2 , and CO 2 R; and 
 R is selected from the group consisting of lower alkyl and hydrogen. 
 
     
     
         29 . A method for the treatment of NASH comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of Compounds 1 and 2, or a salt thereof. 
     
     
         30 . The method as recited in  claim 29 , wherein said compound is (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid tosylate. 
     
     
         31 . A method of preventing or reducing hepatic fibrosis comprising the administration of a compound selected from the group consisting of Compounds 1 and 2, or a salt thereof. 
     
     
         32 . A method of preparing a liver for surgery comprising the administration of an effective amount of a compound selected from the group consisting of Compounds 1 and 2, or a salt thereof prior to surgery. 
     
     
         33 . The method as recited in  claim 32  wherein said surgery is liver transplant surgery. 
     
     
         34 . The method as recited in  claim 32 , wherein said compound is (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid tosylate. 
     
     
         35 . The method as recited in  claim 32 , wherein said administration achieves the effect of reducing fibrosis in said liver.