Phosphorous derivatives as kinase inhibitors

Abstract

The invention features compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.

1 . A compound of the formula VIa: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is NR b1  or CR b ; 
 X 3  is NR d1  or CR d ; 
 X 4  is NR e1  or CR e ; 
 Ring A and Ring E are each an independently selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from N, O and S(O) r ; 
 each occurrence of R a , R b , R d , R e , and R g  is independently selected from the group consisting of halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2  and —NR 1 SO 2 NR 1 R 2 ; or alternatively, each R a  and R g  may also be an independently selected moiety, —P(═O)(R 3 ) 2  or a ring system containing the moiety —P(═O)(R 3 )— as a ring member; 
 R b1 , R d1  and R e1  are absent; 
 or alternatively two adjacent substituents selected from R d , R d1 , R e , and R e1 , or two adjacent R a  moieties, can form, with the atoms to which they are attached, a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r  and which may bear up to four substituents; 
 at least one of R a  and R g  is or contains a moiety, —P(═O)(R 3 ) 2  or a ring system containing the moiety —P(═O)(R 3 )— as a ring member; 
 L is O or NH; 
 r is 0, 1 or 2; 
 s is 1, 2, 3, 4 or 5; 
 p is 1, 2, 3 or 4; 
 each occurrence of Y is independently a bond, —O—, —S— or —NR 1 —; 
 each occurrence of R 1  and R 2  is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety; 
 each occurrence of R 3  is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety, or two adjacent R 3  moieties combine to form a ring system including a phosphorous atom; 
 each occurrence of R 3a  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, and heteroaryl; 
 alternatively, each NR 1 R 2  moiety may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; and 
 each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic moieties is optionally substituted. 
 
     
     
         2 - 22 . (canceled) 
     
     
         23 . A method for treating cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of formula VIa: 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  is NR b1  or CR b ; 
 X 3  is NR d1  or CR d ; 
 X 4  is NR e1  or CR e ; 
 Ring A and Ring E are each an independently selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from N, O and S(O) r ; 
 each occurrence of R a , R b , R d , R e , and R g  is independently selected from the group consisting of halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2  and —NR 1 SO 2 NR 1 R 2 ; or alternatively, each R a  and R g  may also be an independently selected moiety, —P(═O)(R 3 ) 2  or a ring system containing the moiety —P(═O)(R 3 )— as a ring member; 
 R b1 , R d1  and R e1  are absent; 
 or alternatively two adjacent substituents selected from R d , R d1 , R e , and R e1 , or two adjacent R a  moieties, can form, with the atoms to which they are attached, a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r  and which may bear up to four substituents; 
 at least one of R a  and R g  is or contains a moiety, —P(═O)(R 3 ) 2  or a ring system containing the moiety —P(═O)(R 3 )— as a ring member; 
 L is O or NH; 
 r is 0, 1 or 2; 
 s is 1, 2, 3, 4 or 5; 
 p is 1, 2, 3 or 4; 
 each occurrence of Y is independently a bond, —O—, —S— or —NR 1 —; 
 each occurrence of R 1  and R 2  is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety; 
 each occurrence of R 3  is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety, or two adjacent R 3  moieties combine to form a ring system including a phosphorous atom; 
 each occurrence of R 3a  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, and heteroaryl; 
 alternatively, each NR 1 R 2  moiety may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; and 
 each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic moieties is optionally substituted. 
 
     
     
         24 . A method for making the compound 
       
         
           
           
               
               
           
         
       
       wherein the method comprises reacting the compound 
       
         
           
           
               
               
           
         
       
       with the compound 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 24 , wherein the compound 
       
         
           
           
               
               
           
         
       
       is formed by a method comprising reacting the compound 
       
         
           
           
               
               
           
         
       
       with the compound 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 25 , wherein the compound 
       
         
           
           
               
               
           
         
       
       is formed by a method comprising reacting the compound 
       
         
           
           
               
               
           
         
       
       with the compound 
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound, which is 
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound, which is