Pyridine derivatives

Abstract

The present application provides novel pyridine compounds and pharmaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. These compounds are useful in inhibiting CYP17 activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with CYP17 activity. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer, such as prostate cancer.

What is claimed is: 
     
         1 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein A is of the structure: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 2 , R 3 , R 4 , R 5 , and R 6  are, independently, selected from the group consisting of H, halogen, OH, CN, optionally substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, H 2 NC(O)—, (C 1  to C 4  alkyl)-NHC(O)—, (C 1  to C 4  alkyl) 2 NC(O)—, HC(O)NH—, (C 1  to C 4  alkyl)-C(O)NH—, COOH, C 1  to C 6  alkylsulfonyl and —C(O)O(C 1  to C 4  alkyl); 
 with the proviso that 3, 4 or 5 of R 2 , R 3 , R 4 , R 5 , and R 6  are hydrogen; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein A is an optionally substituted pyridine; 
         wherein A is of the structure: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 7 , R 8 , R 9 , R 10 , and R 11  are, independently, selected from the group consisting of H, halogen, OH, CN, optionally substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, H 2 NC(O)—, (C 1  to C 4  alkyl)-NHC(O)—, (C 1  to C 4  alkyl) 2 NC(O)—, HC(O)NH—, (C 1  to C 4  alkyl)-C(O)NH—, COOH, C 1  to C 6  alkylsulfonyl and —C(O)O(C 1  to C 4  alkyl); 
 with the proviso that 2, 3 or 4 of R 7 , R 8 , R 9 , R 10 , and R 11  are hydrogen; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         5 . The compound according to  claim 4 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein A is optionally substituted pyridone; 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         7 . The compound according to  claim 6 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 7 , R 8 , R 10  and R 11  are, independently, selected from the group consisting of H, halogen, OH, CN, optionally substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, H 2 NC(O)—, (C 1  to C 4  alkyl)-NHC(O)—, (C 1  to C 4  alkyl) 2 NC(O)—, HC(O)NH—, (C 1  to C 4  alkyl)-C(O)NH—, COOH, C 1  to C 6  alkylsulfonyl and —C(O)O(C 1  to C 4  alkyl). 
 
       
     
     
         8 . The compound according to  claim 7 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 8 , wherein R 10  is C 1  to C 6  alkyl. 
     
     
         10 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein A is of the structure: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 13  and R 14  are, independently, selected from the group consisting of H, halogen, OH, CN, optionally substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, H 2 NC(O)—, (C 1  to C 4  alkyl)-NHC(O)—, (C 1  to C 4  alkyl) 2 NC(O)—, HC(O)NH—, (C 1  to C 4  alkyl)-C(O)NH—, COOH, C 1  to C 6  alkylsulfonyl and —C(O)O(C 1  to C 4  alkyl); and 
 R 15  is H or C 1  to C 6  alkyl; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         11 . The compound according to  claim 10 , wherein A is of the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 11 , wherein R 15  is H. 
     
     
         13 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein B is an optionally substituted pyridine; 
         wherein B is: 
       
       
         
           
           
               
               
           
         
         
           wherein, R 20 , R 21  and R 22  are independently selected from the group consisting of H, F, Cl, CH 3 , CF 3 , and CN; 
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         14 . The compound according to  claim 13 , wherein B is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 14 , wherein R 20 , R 21 , and R 22  are H. 
     
     
         16 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         wherein B is: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         17 . A compound of formula (I) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 Q is O or NH; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 wherein B is: 
 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         18 . A compound of formula (I-B) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         19 . A compound of formula (I-D) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 R Z  is C 1  to C 6  alkyl; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         20 . A compound of formula (I-E) of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is optionally substituted phenyl or optionally substituted heteroaryl; 
 B is optionally substituted heteroaryl; 
 R 1  is:
 (a) H, or C 1  to C 4  alkyl; or 
 (b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring; 
 
 R Z  is C 1  to C 6  alkyl; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         21 . The compound according to  claim 20 , which is of the formula (I-C): 
       
         
           
           
               
               
           
         
       
     
     
         22 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         23 . A kit comprising a compound according to  claim 1 . 
     
     
         24 . A method for regulating CYP17, said method comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof, wherein said regulation comprises inhibition of CYP17 activity. 
     
     
         25 . A method for treating a condition treatable by inhibiting CYP17 activity, said method comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need thereof. 
     
     
         26 . A method of treating cancer in a patient, said method comprising administering a compound of  claim 1  to said patient, wherein said cancer is prostate cancer. 
     
     
         27 . A method of reducing testosterone production in a patient, said method comprising administering a compound of  claim 1  to said patient.