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 - 42 . (canceled) 
     
     
         43 . A compounds of Formula I, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is NR b1  or CR b ; 
         X 2  is NR c1 ; 
         X 3  is NR d1  or CR d ; 
         X 4  is NR e1  or CR e ; 
         Ring A is an aryl, a 5- or a 6-membered heteroaryl ring which contains 1 to 4 heteroatoms selected from N, O and S(O) r ; 
         each R a , R b , R d  and R e  is independently 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  or —NR 1 SO 2 NR 1 R 2 , and R b1 , R c1 , R d1  and R e1  are absent; 
         each Y is independently a bond, —O—, —S— or —NR 1 —; 
         alternatively, two adjacent substituents selected from R b , R b1 , R c1 , R d , R d1 , R e  and R e1 , or two adjacent R a  moieties, together with the atoms to which they are attached, form a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which ring contains 0-4 heteroatoms selected from N, O and S(O) r  and which is substituted with one to four R f  moieties; 
         each R f  moiety is independently halo, ═O, ═S, —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  or —NR 1 SO 2 NR 1 R 2 ; or alternatively two adjacent R f  moieties, together with the atoms to which they are attached, form an optionally substituted 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring which contains 0-4 heteroatoms selected from N, O and S(O) r ; 
         at least one of R a , R b , R d , R e , R f , R b1 , R c1 , R d1  and R e1 , when present, is or contains —P(═O)(R 3 ) 2  or a ring system containing the moiety —P(═O)(R 3 )— as a ring member; 
         r is 0, 1 or 2; 
         s is 1, 2, 3, 4 or 5; 
         n is 0 or 1; 
         each Y is independently a bond, —O—, —S— or —NR 1 —; 
         each R 1  and R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl; 
         each R 3  is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R 3  moieties combine to form a ring system including a phosphorous atom; 
         each R 3a  is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; 
         alternatively, each NR 1 R 2  moiety may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which is 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 moiety is optionally substituted. 
       
     
     
         44 . The compound of  claim 43 , having the Formula VII: 
       
         
           
           
               
               
           
         
         wherein Ring A, R a , R f , n, X 1 , X 2 , X 3  and X 4  are as defined in  claim 43 ; 
         t is 1, 2, 3 or 4; and 
         Ring F is an aryl, a carbocyclyl, a 5- or 6- or 7-membered heteroaryl or heterocyclyl ring substituted with 1-4 R f  groups. 
       
     
     
         45 . The compound of  claim 43 , having the Formula II: 
       
         
           
           
               
               
           
         
         wherein R 3 , R a , n, Ring A, X 1 , X 2 , X 3  and X 4  are as defined in  claim 43  and m is 0, 1, 2, 3 or 4. 
       
     
     
         46 . The compound of  claim 43  in which X 1  is N. 
     
     
         47 . The compound of  claim 46  in which X 3  is N and X 4  is CR e . 
     
     
         48 . The compound of  claim 46  in which X 3  is CR d  and X 4  is CR e . 
     
     
         49 . The compound of  claim 43  in which X 1  is CR b . 
     
     
         50 . The compound of  claim 49  in which X 3  is N and X 4  is CR e . 
     
     
         51 . The compound of  claim 49  in which X 3  is CR d  and X 4  is CR e . 
     
     
         52 . The compound of  claim 43  in which R d  is selected from Cl, F, C 1 -C 4  alkyl, trihaloalkyl, cycloalkyl, C 2 -C 4  alkenyl, and alkynyl. 
     
     
         53 . The compound of  claim 43  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. 
     
     
         54 . The compound of  claim 43  in which s is 1, 2, 3 or 4, and each of the substituents R a  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. 
     
     
         55 . The compound of  claim 54  in which at least one substituent R a  is —OR 2  and R 2  is selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl. 
     
     
         56 . The compound of  claim 54  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 , —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 ; and wherein each Y is independently a bond, —O—, —S— or —NR 1 —. 
     
     
         57 . The compound of  claim 56  in which the heterocyclic or heteroaryl substituent R a  is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         58 . The compound of  claim 54  in which at least one substituent R a  is —P(═O)(R 3 ) 2  in which each R 3  is, independently, a C 7 -C 4  alkyl moiety. 
     
     
         59 . The compound of  claim 43  in which R a  is H, halo, C 1 -C 4  alkyl, C 7 -C 4  haloalkyl, C 7 -C 4  alkoxy, C 1 -C 4  haloalkoxy or —P(O)(R 3 ) 2 . 
     
     
         60 . The compound of  claim 43  in which R d  is F, Cl, C7-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 , or R f  is H, —CH 3  or halo. 
     
     
         61 . A method for treating an ALK-driven cancer in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound of  claim 43 , or a pharmaceutically acceptable salt thereof. 
     
     
         62 . A pharmaceutical composition containing a compound of  claim 43 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.