Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

Abstract

The present invention relates to the synthesis of a new class of indeno[1,2-c]pyrazol-4-ones of formula (I): that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk1-7 and their regulatory subunits know as cyclins A-G. This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.

What is claimed is:  
     
         1 . A compound according to formula (I):  
       
         
           
           
               
               
           
         
         3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one  
         or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:  
         X is selected from the group: O, S, and NR;  
         R is selected from the group: H, C 1-4  alkyl, and NR 5 R 5a ;  
         R 1  is selected from the group: H, C 1-10  alkyl substituted with 0-3 R c , C 2-10  alkenyl substituted with 0-3 R c , C 2-10  alkynyl substituted with 0-3 R c , —NHR 4 , C 3-10  carbocycle substituted with 0-5 R a , and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;  
         R 2  is selected from the group: H, C 1-10  alkyl substituted with 0-3 R c , C 2-10  alkenyl substituted with 0-3 R c , C 2-10  alkynyl substituted with 0-3 R c , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R a , and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;  
         R 3  is selected from the group: H, halo, —CN, NO 2 , C 1-4  haloalkyl, NR R 5a , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 1-4  alkyl, phenyl, benzyl, C 1-4  alkyl substituted with 1-3 R c , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ; and  
         provided that if R 3  is phenyl, it is substituted with 1-5 R a ;  
         R 4  is independently at each occurrence selected from the group: H, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;  
         provided that at least one R 3  is present and that this R 3  is selected from the group: C 1-4  alkyl substituted with 1-3 R 6 , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ;  
         R a  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , SO 2 NR 3 R 3a , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;  
         alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH 2 O— or —OCH 2 CH 2 O—;  
         R b  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , and SO 2 R 3b ;  
         R c  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 5 NR 5 R 5a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;  
         R 3a  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
         alternatively, R 3  and R 3a , together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R 3c ;  
         R 3b  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
         R 3c  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3b , NHC(O)NR 3 R 3b , NHC(S)NR 3 R 3b , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , SO 2 NR 3 R 3b , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;  
         R 5  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;  
         R 5a  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;  
         R 5b  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;  
         R 6  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 3-10  carbocycle substituted with 0-5 R 5 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 5 ; and  
         m is selected from 0, 1, 2, and 3.  
       
     
     
         2 . A compound according to  claim 1 , wherein: 
 X is selected from the group: O, S, and NR;    R is selected from the group: H, C 1-4  alkyl, and NR 5 R 5a ;    R 1  is selected from the group: H, C 1-5  alkyl substituted with 0-3 R c , C 2-5  alkenyl substituted with 0-3 R c , C 2-5  alkynyl substituted with 0-3 R c , —NHR 4 , C 3-6  carbocycle substituted with 0-5 R a , and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;    R 2  is selected from the group: H, C 1-5  alkyl substituted with 0-3 R c , C 2-5  alkenyl substituted with 0-3 R c , C 2-5  alkynyl substituted with 0-3 R c , —(CF 2 ) m CF 3 , C 3-6  carbocycle substituted with 0-5 R a , and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;    R 3  is selected from the group: H, halo, —CN, NO 2 , C 1-4  haloalkyl, NR R 5a , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 1-4  alkyl, phenyl, benzyl, C 1-4  alkyl substituted with 1-3 R c , CS-1O alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ; and    provided that if R 3  is phenyl, it is substituted with 1-5 R a ;    R 4  is independently at each occurrence selected from the group: H, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    provided that at least one R 3  is present and that this R 3  is selected from the group: C 1-4  alkyl substituted with 1-3 R 6 , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ;    R a  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    alternatively, when two R a 's are present on adjacent carbon atoms they combine to form —OCH 2 O— or —OCH 2 CH 2 O—;    R b  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , and SO 2 R 3b ;    R c  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , NR 5 NR 5 R 5a , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    R 3a  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    alternatively, R 3  and R 3a , together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R 3c ;    R 3b  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 3c  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3b , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3b , NHC(O)NR 3 R 3b , NHC(S)NR 3 R 3b , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , SO 2 NR 3 R 3b , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    R 5  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 5a  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;    R 5b  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 6  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 3-10  carbocycle substituted with 0-5 R 5 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 5 ; and    m is selected from 0, 1, 2, and 3.    
     
     
         3 . A compound according to  claim 2 , wherein: 
 X is selected from the group: O and S;    R 1  is selected from the group: H, C 1-5  alkyl substituted with 0-3 R c , C 2-5  alkenyl substituted with 0-3 R c , —NHR 4 , C 3-6  carbocycle substituted with 0-5 R a , and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;    R 2  is selected from the group: H, C 1-5  alkyl substituted with 0-3 R c , C 2-5  alkenyl substituted with 0-3 R c , —(CF 2 ) m CF 3 , C 3-6  carbocycle substituted with 0-5 R a , and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;    R 3  is selected from the group: H, halo, —CN, NO 2 , Cl- 4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 1-4  alkyl, phenyl, benzyl, C 1-4  alkyl substituted with 1-3 R c , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ; and    provided that if R 3  is phenyl, it is substituted with 1-5 R a ;    R 4  is independently at each occurrence selected from the group: H, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    provided that at least one R 3  is present and that this R 3  is selected from the group: C 1-4  alkyl substituted with 1-3 R 6 , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ;    R a  is independently at each occurrence selected from the group: halo, —CN, N 3 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)R 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 ,    CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    alternatively, when two R a 's are present on adjacent carbon atoms they combine to form —OCH 2 O— or —OCH 2 CH 2 O—;    R b  is independently at each occurrence selected from the group: halo, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , and SO 2 R 3b ;    R c  is independently at each occurrence selected from the group: halo, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 5 NR 5 R 5a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    R 3a  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    alternatively, R 3  and R 3a , together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R 3c ;    R 3b  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 3c  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3b , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3b , NHC(O)NR 3 R 3b , NHC(S)NR 3 R 3b , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , SO 2 NR 3 R 3b , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    R 5  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 5a  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;    R 5b  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 6  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 3-10  carbocycle substituted with 0-5 R 5 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 5 ; and    m is selected from 0, 1, 2, and 3.    
     
     
         4 . A compound according to  claim 3 , wherein: 
 X is selected from the group: O and S;    R 1  is selected from the group: H, C 1-5  alkyl substituted with 0-2 R c , —NHR 4 , C 3-6  carbocycle substituted with 0-5 R a , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R b ;    R 2  is selected from the group: H, C 1-5  alkyl substituted with 0-3 R c , —(CF 2 ) m CF 3 , C 3-6  carbocycle substituted with 0-5 R a , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-3 R b ;    R 3  is selected from the group: H, halo, —CN, NO 2 , C 1-4  haloalkyl, NR 5 R 5a , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 1-4  alkyl, phenyl, benzyl, C 1-4  alkyl substituted with 1-3 R c , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ; and    provided that if R 3  is phenyl, it is substituted with 1-5 R a ;    R 4  is independently at each occurrence selected from the group: H, —CN, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    provided that at least one R 3  is present and that this R 3  is selected from the group: C 1-4  alkyl substituted with 1-3 R 6 , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ;    R a  is independently at each occurrence selected from the group: halo, —CN, N 3 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3, CONR   3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    alternatively, when two R a 's are present on adjacent carbon atoms they combine to form —OCH 2 O— or —OCH 2 CH 2 O—;    R b  is independently at each occurrence selected from the group: halo, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , and SO 2 R 3b ;    R c  is independently at each occurrence selected from the group: halo, C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 5 NR 5 R 5a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;    R 3a  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    alternatively, R 3  and R 3a , together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R 3c ;    R 3b  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;    R 3c  is independently at each occurrence selected from the group: halo, —CN, N 3 , NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3b , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3b , NHC(O)NR 3 R 3b , NHC(S)NR 3 R 3b , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , SO 2 NR 3 R 3b , SO 2 R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;    R 5  is independently selected from the group: H and C 1-4  alkyl;    R 5a  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;    R 5b  is independently selected from the group: H and C 1-4  alkyl;    R 6  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R 5a , NHC(S)NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 3-10  carbocycle substituted with 0-5 R 5 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 5 ; and    m is selected from 0, 1, 2, and 3.    
     
     
         5 . A compound according to  claim 1 , wherein the compound is selected from: 
 (a) 3-(4-methoxyphenyl)-5(2-benzoylhydrazinecarboxamido)indeno [1,2-c]pyrazol-4-one;    (b) 3-(4-methoxyphenyl)-5-(2-isonicotinoylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (c) 3-(4-methoxyphenyl)-5-(2-nictinoylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (d) 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (e) 3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (f) 3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (g) 3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (h) 3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (i) 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl) hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;    (j) 3-(4-methoxyphenyl)-5-(2-phenethylacetylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;    (k) 3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; and    (l) 3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;    or pharmaceutically acceptable salt thereof.    
     
     
         6 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 .  
     
     
         7 . A method of treating cancer and proliferative diseases comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or prodrug form thereof.  
     
     
         8 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 .  
     
     
         9 . A method of treating cancer and proliferative diseases comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or prodrug form thereof.  
     
     
         10 . A compound according to formula (II)  
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: 
 X is selected from the group: O and NR;  
 R is selected from the group: H, C 1-4  alkyl, NR 3 R 3a , and C 1-4  alkyl substituted with 1-3 R c ;  
 R 3  is selected from the group: H, halo, —CN, NO 2 , C 1-4  haloalkyl, NR 5 R 5a , NR 5 NR 5 R 5a , NR 5 C(O)OR 5 , NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5 R a , NHC(S) NR 5 R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 1-4  alkyl, phenyl, benzyl, C 1-4  alkyl substituted with 1-3 R c , C 5-10  alkyl substituted with C 2-10  alkenyl optionally substituted with 0-3 R 6 , C 2-10  alkynyl substituted with 0-3 R 6 , —(CF 2 ) m CF 3 , C 3-10  carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 6 ; and  
 provided that if R 3  is phenyl, it is substituted with 1-5 R a ;  
 R 3a  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
 R 3b  is selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
 R 5  is independently selected from the group: H, C 1-4  alkyl, phenyl and benzyl;  
 R 5a  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
 R 5b  is independently selected from the group: H, C 1-4  alkyl, phenyl, and benzyl;  
 R 6  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(O)OR, NR 5 C(O)R 5 , ═O, OR 5 , COR 5 , CO 2 R 5 , CONR 5 R 5a , NHC(O)NR 5R 5a , NHC(S)NR R 5a , SO 2 NR 5 R 5a , SO 2 R 5b , C 3-10  carbocycle substituted with 0-5 R 5 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 5 ;  
 R a  is independently at each occurrence selected from the group: H, halo, C 1-4  alkyl, NR 3 R 3a , and R 3 ;  
 R c  is independently at each occurrence selected from the group: halo, —CN, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, NR 3 R 3a , NR 5 NR 5 R 5a , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , ═O, OR 3 , COR 3 , CO 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , NHC(S)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , C 3-10  carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3 ;  
 R d  is independently at each occurrence selected from the group: OR 3 , COR 3 , and NR 3 R 3a ; and  
 m is selected from 0, 1, 2, and 3.  
 
     
     
         11 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 8 .  
     
     
         12 . A method of treating cancer and proliferative diseases comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of  claim 8 , or a pharmaceutically acceptable salt or prodrug form thereof.