Substituted benzofused derivatives and their use as vanilloid receptor ligands

Abstract

The present invention relates to substituted benzofused derivatives, which can be used as vanilloid receptor ligands, method of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a tautomer thereof, 
       wherein
 X and Y are independently O, S(O) m , or NR e ; 
 R 1  and R 2  are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR 9  or S(O) m ; 
 R 3  and R 4  are independently hydrogen, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl or —NR 9 R 10 , or R 3  and R 4  together form an oxo group; 
 R 5 , R 6  and R 7  are independently hydrogen, nitro, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 ; and 
 R 8  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 ; or 
 each occurrence of R 9  and R 10  may be the same or different and is independently hydrogen, —OR a , —SR a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR a R b , —C(=L)-R a , —C(O)O—R a , —C(O)NR a R b , —S(O) m —R a  or —S(O) m —NR a R b , or R 9  and R 10  taken together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R a  and R b  independently is hydrogen, —OR c , —SR c , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —C(=L)-R c , —C(O)O—R c , —C(O)NR c R d , —S(O) m —R c , —S(O) m —NR c R d , —NR c R d , or a protecting group, or R a  and R b  taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R c  and R d  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or R c  and R d  taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R e  is independently hydrogen or substituted or unsubstituted alkyl; 
 each occurrence of L is independently O, S, or NR e ; 
 each occurrence of m is independently 0, 1, or 2; and 
 n is an integer from 0 to 4. 
 
     
     
         2 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein X is O. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein Y is O. 
     
     
         15 - 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein R 3  and R 4  are independently hydrogen, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl or —NR 9 R 10 . 
     
     
         20 . The compound of  claim 19 , wherein R 3  and R 4  are hydrogen. 
     
     
         21 . The compound of  claim 1 , wherein each occurrence of R 5  is independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, —OR 9 , —NR 9 R 10  or —S(O) m R 9 . 
     
     
         22 . The compound of  claim 21 , wherein each occurrence of R 5  is independently hydrogen, halogen, unsubstituted alkyl, and —OR 9 , where R 9  is unsubstituted alkyl or alkyl substituted with halogen. 
     
     
         23 . The compound of  claim 21 , wherein each occurrence of R 5  is independently hydrogen or halogen. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The compound of  claim 14 , wherein R 6  and R 7  are hydrogen. 
     
     
         28 . The compound of  claim 1 , wherein R 6  and R 7  are hydrogen, and X and Y are O. 
     
     
         29 - 44 . (canceled) 
     
     
         45 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a tautomer thereof, 
       wherein
 X and Y are independently O, —S(O) m , or NR e ; 
 R 3  and R 4  are independently hydrogen, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl or —NR 9 R 10 , or R 3  and R 4  together form an oxo group; 
 R 5 , R 6  and R 7  are independently hydrogen, nitro, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 ; and 
 R 8  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 ; or 
 each occurrence of R 9  and R 10  may be the same or different and is independently hydrogen, —OR a , —SR a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR a R b , —C(=L)-R a , —C(O)O—R a , —C(O)NR a R b , —S(O) m —R a  or —S(O) m —NR a R b , or R 9  and R 10  taken together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R a  and R b  independently is hydrogen, —OR c , —SR c , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —C(=L)-R c , —C(O)O—R c , —C(O)NR c R d , —S(O) m —R c , —S(O) m —NR c R d , —NR c R d , or a protecting group, or R a  and R b  taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R c  and R d  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or R c  and R d  taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R e  is independently hydrogen or substituted or unsubstituted alkyl; 
 each occurrence of L is independently O, S, or NR e ; 
 each occurrence of m is independently 0, 1, or 2; and 
 n is an integer from 0 to 4. 
 
     
     
         46 . The compound of  claim 45 , wherein X and Y are O and R 6  and R 7  are hydrogen. 
     
     
         47 . (canceled) 
     
     
         48 . The compound of  claim 45 , wherein Y is O and R 6  and R 7  are hydrogen. 
     
     
         49 - 56 . (canceled) 
     
     
         57 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a tautomer thereof, 
       wherein
 X and Y are independently O, —S(O) m , or NR e ; 
 R 3  and R 4  are independently hydrogen, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl or —NR 9 R 10 , or R 3  and R 4  together form an oxo group; 
 each occurrence of R 5  is independently nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —OR 9 , —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , or —C(O)NR 9 R 10 ; 
 R 6  is independently hydrogen, nitro, cyano, halogen, —OR 9 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 ; 
 each occurrence of R 9  and R 10  may be the same or different and is independently hydrogen, —OR a , —SR a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR a R b , —C(=L)-R a , —C(O)O—R a , —C(O)NR a R b , —S(O) m —R a  or —S(O) m —NR a R b , or R 9  and R 10  taken together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 one of R 11 -R 14  is N and the remaining R 11 -R 14  groups are CH or CR a ; 
 each occurrence of R 15  and R 16  is independently hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —OR 9 , —NR 9 R 10 , —C(=L)-R 9 , —C(O)O—R 9 , —C(O)NR 9 R 10 , —S(O) m —R 9 , or —S(O) m —NR 9 R 10 . 
 each occurrence of R a  and R b  independently is hydrogen, —OR c , —SR c , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —C(=L)-R c , —C(O)O—R c , —C(O)NR c R d , —S(O) m —R c , —S(O) m —NR c R d , —NR c R d , or a protecting group, or R a  and R b  taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R c  and R d  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or R c  and R d  taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR e  or S; 
 each occurrence of R e  is independently hydrogen or substituted or unsubstituted alkyl; 
 each occurrence of L is independently O, S, or NR e ; 
 each occurrence of m is independently 0, 1, or 2; 
 n is an integer from 0 to 4; and 
 p and q are independently 0, 1, 2, or 3. 
 
     
     
         58 . The compound of  claim 57 , wherein X and Y are O and R 6  and R 7  are hydrogen. 
     
     
         59 . (canceled) 
     
     
         60 . The compound of  claim 57 , wherein Y is O and R 6  and R 7  are hydrogen. 
     
     
         61 - 65 . (canceled) 
     
     
         66 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         67 . The pharmaceutical composition according to  claim 66 , wherein the pharmaceutically acceptable excipient is a carrier or diluent. 
     
     
         68 - 85 . (canceled) 
     
     
         86 . The compound of  claim 28 , wherein R 1  and R 2  are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring. 
     
     
         87 . The compound of  claim 1 , wherein
 R 6  and R 7  are hydrogen,   X and Y are O, and   R 8  is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic group.   
     
     
         88 . The compound of  claim 87 , wherein R 1  and R 2  are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring. 
     
     
         89 . The compound of  claim 1 , wherein
 R 6  and R 7  are hydrogen,   Y is O, and   R 8  is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic group.   
     
     
         90 . A pharmaceutical composition comprising a compound according to  claim 14  and a pharmaceutically acceptable excipient. 
     
     
         91 . The pharmaceutical composition according to  claim 90 , wherein the pharmaceutically acceptable excipient is a carrier or diluent. 
     
     
         92 . A pharmaceutical composition comprising a compound according to  claim 27  and a pharmaceutically acceptable excipient. 
     
     
         93 . The pharmaceutical composition according to  claim 90 , wherein the pharmaceutically acceptable excipient is a carrier or diluent.