Nitrogen-containing heterocyclic compounds as fxr modulators

Abstract

The present technology is directed to compounds, compositions, and methods related to modulation of FXR. In particular, the present compounds and compositions may be used to treat FXR-mediated disorders and conditions, including, e.g., liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, and atherosclerosis, and renal disease.

What is claimed is: 
     
         1 . A compound according to formula I 
       
         
           
           
               
               
           
         
         stereoisomers, and/or salts thereof wherein 
         L and M are independently selected from N and CR 7 , provided that at least one of L and M is N; 
         Z is a substituted or unsubstituted C 1 -C 4  alkylene group; 
         W is 
       
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         D is N or CR 9 ; 
         G 4  is CR 13 ; G 1 , G 2 , G 3  are selected from the group consisting of CH and CR 11 ; 
         Q is O, S, or NR 12 ; 
         R 1  and R 2  are independently H, OH, halo, CN, carboxyl, NR a R b , or a substituted or unsubstituted alkyl, alkoxy, or hydroxyalkyl group; 
         R 3  is a substituted or unsubstituted alkyl or cycloalkyl group; 
         R 4  is CN, SO 3 H, CONR a R b , SO 2 NR a R b , NHSO 2 R b , SO 2 NHCOR a , CO 2 R c , or a substituted or unsubstituted tetrazolyl or 1,2,4-oxadiazol-5(4H)-one-3-yl group; 
         R 7  is H, OH, halo, CN, carboxyl, amido, NR a R b , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, or aminoalkyl group; 
         R 9  is H, halo, or a substituted or unsubstituted C 1 -C 6  alkyl, or O—(C 1 -C 6  alkyl) group; 
         R 10  at each occurrence is independently halo, CO 2 R c , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group, or, when n is 2 or 3, two of the R 10  groups together may be a substituted or unsubstituted C2-C5 alkylene, heteroalkylene, alkenylene or heteroalkenylene group having 2 separate points of attachment to the same carbon or different carbons of the nitrogen containing ring to which it is attached; 
         R 11  at each occurrence is independently OH, halo, CF 3 , CN, carboxyl, NR a R b , or a substituted or unsubstituted alkyl, alkoxy group, or phenyl group;
 R 12  is H or a substituted or unsubstituted C 1 -C 6  alkyl group; and 
 
         R 13  is halo, or a substituted or unsubstituted C 1 -C 6  alkyl, or O—(C 1 -C 6  alkyl) group; 
         R a  at each occurrence is independently H, or a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO 2 -alkyl group; 
         R b  at each occurrence is H or a substituted or unsubstituted alkyl, or haloalkyl group; 
         R c  is H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl group; 
         n is 0, 1, 2, 3, or 4; and 
         r and t are each independently 1, 2, or 3. 
       
     
     
         2 . The compound of  claim 1 , wherein Z is an unsubstituted C 1 -C 4  alkylene group. 
     
     
         3 . The compound of  claim 2 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein X is 
       
         
           
           
               
               
           
         
         wherein q is 0, 1, or 2. 
       
     
     
         5 . The compound of  claim 4  according to Formula IA or Formula IB: 
       
         
           
           
               
               
           
         
         wherein
 r is 1 or 2; and 
 t is 2. 
 
       
     
     
         6 . The compound of  claim 5  according to Formula IA, wherein L is N. 
     
     
         7 . The compound of  claim 6  wherein n is 2 or 3 and two of the R 10  groups together are a substituted or unsubstituted C2-C5 alkylene, heteroalkylene, alkenylene or heteroalkenylene group having 2 separate points of attachment to the same carbon or different carbons of the nitrogen containing ring to which it is attached. 
     
     
         8 . The compound of  claim 7  wherein two of the R 10  groups together are a substituted or unsubstituted C2-C5 alkylene group having 2 separate points of attachment to the same carbon or different carbons of the nitrogen containing ring to which it is attached. 
     
     
         9 . The compound of  claim 5  according to formula IA, wherein L is CR 7 . 
     
     
         10 . The compound of  claim 9 , wherein n is 0. 
     
     
         11 . The compound of  claim 9 , wherein n is 1 or 2. 
     
     
         12 . The compound of  claim 11  wherein R 10  at each occurrence is independently halo, CO 2 R c , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group. 
     
     
         13 . The compound of  claim 3  according to Formula IB, wherein M is CR 7 . 
     
     
         14 . The compound of  claim 13 , wherein n is 0. 
     
     
         15 . The compound of  claim 13 , wherein n is 1 or 2. 
     
     
         16 . The compound of  claim 15  wherein R 10  at each occurrence is independently halo, CO 2 R c , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group. 
     
     
         17 . The compound of  claim 5 , wherein R 4  is CO 2 H, CN, CONH 2 , SO 2 NH 2 , or a substituted or unsubstituted CO 2 —C 1 -C 6  alkyl, CO 2 —C 3 -C 6  cycloalkyl, CONH—C 1 -C 6  alkyl, CONH—C 3 -C 6  cycloalkyl, NH—SO 2 —C 1 -C 6  alkyl, or tetrazolyl group. 
     
     
         18 . The compound of  claim 17 , wherein R 4  is CO 2 H, CONH 2 , or a tetrazolyl group. 
     
     
         19 . The compound of  claim 5 , wherein R 1  and R 2  are independently halo, CN, CO 2 R e , NR e R f , or a substituted or unsubstituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  hydroxyalkyl group; and
 wherein R e  and R f  at each occurrence are independently H or a substituted or unsubstituted C 1 -C 6  alkyl group.   
     
     
         20 . The compound of  claim 19 , wherein R 1  and R 2  are both Cl. 
     
     
         21 . The compound of  claim 5 , wherein R 3  is a substituted or unsubstituted C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl group. 
     
     
         22 . The compound of  claim 5 , wherein R 3  is an isopropyl or cyclopropyl group. 
     
     
         23 . The compound of  claim 5 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein R 11  at each occurrence is independently halo, CF 3 , or a substituted or unsubstituted alkyl, alkoxy, or phenyl group. 
     
     
         25 . The compound of  claim 23 , wherein R 13  is F, or a substituted or unsubstituted C 1 -C 3  alkyl, or O—(C 1 -C 3  alkyl) group. 
     
     
         26 . The compound of  claim 25 , wherein R 13  is F, CH 3 , or O—CH 3 . 
     
     
         27 . The compound of  claim 23 , wherein q is 0. 
     
     
         28 . A compound selected from the group consisting of compounds II-17, II-30, II-36, II-37, II-38, II-39, II-43, II-44, II-45, I-46, II-47, II-48, II-49, I-50, II-51, III-08, IV-10, and VI-11. 
     
     
         29 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1  for treating an FXR-mediated disorder or condition selected from the group consisting of liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, atherosclerosis, and renal disease. 
     
     
         31 . The pharmaceutical composition of  claim 30  wherein the disorder or condition is a liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis. 
     
     
         32 . A method of treatment comprising administering an effective amount of a compound of of  claim 1 , or administering a pharmaceutical composition comprising an effective amount of a compound of  claim 1 , to a subject suffering from an FXR-mediated disorder or condition selected from the group consisting of liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, atherosclerosis, and renal disease. 
     
     
         33 . The method of  claim 32 , wherein the disorder or condition is a liver disease selected from the group consisting of primary biliary cirrhosis (PB C), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis. 
     
     
         34 . A method comprising modulating FXR by contacting FXR with an effective amount of a compound of  claim 1 .