Tgr5 modulators and methods of use thereof

Abstract

The invention relates to compounds of Formula A:or a salt, solvate, hydrate, or prodrug thereof. The compounds of Formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, liver disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.

What is claimed: 
     
         1 . A compound according to formula A: 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, hydrate, or prodrug thereof, wherein R 1  is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
 R 2  is hydrogen or α-hydroxy; 
 R 3  is hydrogen, hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, or halogen; 
 R 5  is unsubstituted or substituted alkyl, or aryl; 
 R 6  is hydrogen, unsubstituted or substituted alkyl, or R 5  and R 6  taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms; 
 R 7  is hydrogen, substituted or unsubstituted alkyl, or hydroxy; 
 R 8  is hydrogen, substituted or unsubstituted alkyl; 
 R 9  is hydrogen, substituted or unsubstituted alkyl or taken together R 8  and R 9  form a carbonyl; 
 R 10  is R 3  or SO 3 H; 
 m is an integer 0, 1, 2, 3, 4, or 5; and 
 n is an integer 0, 1, 2, 3, 4, or 5. 
 
     
     
         2 . The compound according to  claim 1  having the formula III: 
       
         
           
           
               
               
           
         
         or a salt, solvate, hydrate, or prodrug thereof, wherein 
         R 1  is hydrogen, hydroxy, or halogen; 
         R 2  is hydrogen or α-hydroxy; 
         R 3  is hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H; 
         R 5  is unsubstituted or substituted alkyl, or aryl; 
         R 6  is hydrogen or R 5  and R 6  taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms; 
         R 7  is hydrogen, unsubstituted or substituted alkyl or hydroxy; 
         R 8  is hydrogen, unsubstituted or substituted alkyl; 
         R 9  is hydrogen, unsubstituted or substituted alkyl or R 8  and R 9  taken together with the carbon to which they are attached form a carbonyl; 
         R 10  is R 3  or SO 3 H; 
         m is an integer 0, 1, 2, 3, 4, or 5; and 
         n is an integer 0, 1, 2, 3, 4, or 5. 
       
     
     
         3 . The compound according to  claim 2  having the formula IIIA: 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, hydrate, or prodrug thereof,
 wherein R 1  is hydrogen, hydroxy, or halogen; 
 R 3  is hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H; 
 R 5  is unsubstituted or substituted alkyl, or aryl; 
 R 6  is hydrogen or R 5  and R 6  taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms; 
 R 7  is hydrogen, unsubstituted or substituted alkyl or hydroxy; 
 R 8  is hydrogen, unsubstituted or substituted alkyl; 
 R 9  is hydrogen, unsubstituted or substituted alkyl or R 8  and R 9  taken together with the carbon to which they are attached form a carbonyl; 
 R 10  is R 3  or SO 3 H; 
 m is an integer 0, 1, 2, 3, 4, or 5; and 
 n is an integer 0, 1, 2, 3, 4, or 5. 
 
     
     
         4 . The compound according to  claim 3 , wherein R 8  and R 9  taken together with the carbon to which they are attached form a carbonyl. 
     
     
         5 . The compound according to  claim 4 , wherein R 10  is R 3 . 
     
     
         6 . The compound according to  claim 5 , wherein R 3  is selected from hydroxyl, NH(CH 2 ) 2 SO 3 H, and NHCH 2 CO 2 H. 
     
     
         7 . The compound according to  claim 6 , wherein R 6  is hydrogen. 
     
     
         8 . The compound according to  claim 7 , wherein R 5  is in the S-configuration. 
     
     
         9 . The compound according to  claim 8 , wherein R 5  is unsubstituted alkyl. 
     
     
         10 . The compound according to  claim 9 , wherein R 5  is methyl. 
     
     
         11 . A Compound Ih3e having the chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, hydrate, glycine or taurine amino acid conjugate or prodrug thereof. 
     
     
         12 . The compound according to  claim 3 , wherein the compound is selected from Compounds Ig3e, Ih3e, Ii3e, Ig4e, Ih4e, Ii4e, Ig5e, Ih5e, and Ii5e. 
     
     
         13 . The compound according to  claim 2  selected from Compounds Ib3e, Ic3e, Id3e, Ie3e, If3e, Ig3e, Ih3e, Ii3e, Il3e, Im3e, In3e, Ia4e, Ib4e, Ic4e, Id4e, Ie4e, If4e, Ig4e, Ih4e, Ii4e, Il4e, Im4e, In4e, Ia5e, Ib5e, Ic5e, Id5e, Ie5e, If5e, Ig5e, Ih5e, Ii5e, Il5e, Im5e, In5e, Ia9e, Ib9e, Ic9e, Id9e, Ie9e, If9e, Ig9e, Ih9e, Ii9e, Il9e, Im9e, In9e, Ia10e, Ib10e, Ic10e, Id10e, Ie10e, If10e, Ig10e, Ih10e, Ii10e, Il10e, Im10e, In10e, Ia11e, Ib11e, Idle, Id11e, Id11e, If11e, Ig11e, Ih11e, Ii11e, Il11e, Im11e, In11e, Ia15e, Ib15e, Ic15e, Id15e, Ie15e, If15e, Ig15e, Ih15e, Ii15e, Il15e, Im15e, In15e, Ia16e, Ib16e, Ic16e, Id16e, Ie16e, If16e, Ig16e, Ih16e, Ii16e, Il16e, Im16e, In16e, Ia17e, Ib17e, Ic17e, Id17e, Ie17e, If17e, Ig17e, Ih17e, Ii17e, Il17e, Im17e, and In17e. 
     
     
         14 . The compound according to  claim 1 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         15 . A pharmaceutically acceptable composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         16 . A method of treating or preventing disease in a subject comprising administering a compound of formula A: 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, hydrate, or prodrug thereof, wherein R 1  is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
 R 2  is hydrogen or α-hydroxy; 
 R 3  is hydrogen, hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, or halogen; 
 R 5  is unsubstituted or substituted alkyl, or aryl; 
 R 6  is hydrogen, unsubstituted or substituted alkyl, or R 5  and R 6  taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms; 
 R 7  is hydrogen, substituted or unsubstituted alkyl, or hydroxy; 
 R 8  is hydrogen, substituted or unsubstituted alkyl; 
 R 9  is hydrogen, substituted or unsubstituted alkyl or taken together R 8  and R 9  form a carbonyl; 
 R 10  is R 3  or SO 3 H; 
 m is an integer 0, 1, 2, 3, 4, or 5; and 
 n is an integer 0, 1,2, 3, 4, or 5, further wherein the disease is selected from metabolic disease, inflammatory disease, liver disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease. 
 
     
     
         17 . A kit for treating or preventing disease in a subject, wherein the kit comprises a compound according to  claim 1  or a salt, solvate, hydrate, or prodrug thereof.