Phosphorous derivatives as kinase inhibitors

Abstract

The invention features compounds of the general formula: 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 , —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 . The compound of  claim 1  in which X 1  is N. 
     
     
         3 . The compound of  claim 2  in which X 3  is N and X 4  is CRC. 
     
     
         4 . The compound of  claim 2  in which X 3  is CR d  and X 4  is CRC. 
     
     
         5 . The compound of  claim 1  in which X 1  is CR b . 
     
     
         6 . The compound of  claim 5  in which X 3  is N and X 4  is CRC. 
     
     
         7 . The compound of  claim 5  in which X 3  is CR d  and X 4  is CRC. 
     
     
         8 . The compound of any of  claim 1 ,  2 ,  4 ,  5  or  7  in which R d  is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl. 
     
     
         9 . The compound of  claim 1  in which X 3  is CR d  and X 4  is CR e  wherein R d  and R e , together with the atoms to which they are attached, form 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. 
     
     
         10 . The compound of any of  claims 1 - 9  in which s is 1, 2, 3 or 4, and each of the substituents W is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2  and —P(═O)(R 3 ) 2 , wherein each R 1  and R 2  moiety may be further substituted or unsubstituted. 
     
     
         11 . The compound of  claim 10  in which at least one substituent R a  is —OR 2  and R 2  is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. 
     
     
         12 . The compound of  claim 10  or  11  in which at least one substituent R a  is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl moiety, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1-3 substituents independently selected from halo, —CN, —NO 2 , —OR 2 , —NR 1 R 2 , —NR 1 —NR 1 R 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 ), —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 ;
 wherein each Y is independently a bond, —O—, —S— or —NR 1 —. 
 
     
     
         13 . The compound of  claim 12  in which the heterocyclic or heteroaryl substituent R a  is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of any of  claims 10 - 13  in which at least one substituent R a  is —P(═O)(R 3 ) 2  in which each R 3  is, independently, a C1-C4 alkyl moiety. 
     
     
         15 . The compound of any of  claims 1 - 14  in which L is NH, Ring E is aryl, and each R g  is independently selected from halo, —R′, —OR 2 , —S(O) r R 2  and —P(═O)(R 3 ) 2 . 
     
     
         16 . The compound of  claim 15  in which Ring E contains at least one moiety R g  in the ortho position, relative to the ring atom attached to L. 
     
     
         17 . The compound of  claim 15  in which Ring E contains at least one moiety R g  in the meta position, relative to the ring atom attached to L. 
     
     
         18 . The compound of  claim 15  in which Ring E contains at least one moiety R g  in the para position, relative to the ring atom attached to L. 
     
     
         19 . The compound of any of  claims 15 - 18  in which at least one moiety R g  is —P(═O)(R 3 ) 2  and is —P(═O)(R 3 ) 2  is —P(═O)(CH 3 ) 2  or —P(═O)(CH 2 CH 3 ) 2 . 
     
     
         20 . The compound of  claim 13  in which L is NH; X 1  is N; X 3  is CR d ; X 4  is CR e ; Ring A is aryl and optionally contains up to two additional R a  moieties; and Ring E is aryl and contains 1-3 R g  moieties, one of which being an ortho, meta or para —P(═O)(R 3 ) 2  moiety. 
     
     
         21 . A pharmaceutical composition containing a compound of any of  claims 1 - 20  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 
     
     
         22 . A method for inhibiting cellular proliferation in a subject, said method comprising administering to said subject a compound of any of  claims 1 - 20  in an amount effective to inhibit said cellular proliferation.