IP Library › Granted Patent US 7,250,435

Granted Patent B2

US 7,250,435 · App. 11/064,758 · Granted Jul 31, 2007

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

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Quick Facts

Patent No.: US 7,250,435
App. No.: 11/064,758
Granted: Jul 31, 2007
Kind: B2

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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.

Claims (85)

1. A compound according to formula (I):

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 —NHR 4 ;

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 , and C 3-10 carbocycle substituted with 0-5 R a ;

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 , and C 3-10 carbocycle substituted with 0-5 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 , and 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 , and C 3-10 carbocycle substituted with 0-5 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 , and SO 2 R 3b ;

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 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 , and C 3-10 carbocycle substituted with 0-5 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 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 3 b , NHC(O)NR 3 R 3 b , NHC(S)NR 3 R 3 b , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , and SO 2 NR 3 R 3 b , SO 2 R 3b ;

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 , and C 3-10 carbocycle substituted with 0-5 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 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 , and C 3-6 carbocycle substituted with 0-5 R a ;

provided that if R 3 is phenyl, it is substituted with 1-5 R a ;

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 , and C 3-10 carbocycle substituted with 0-5 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 , and SO 2 R 3b ;

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 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 , and C 3-10 carbocycle substituted with 0-5 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 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 , and SO 2 R 3b ;

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;

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 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 , and C 3-6 carbocycle substituted with 0-5 R a ;

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 , C 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 C 3-10 carbocycle substituted with 0-5 R a ;

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 , and C 3-10 carbocycle substituted with 0-5 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 , and SO 2 R 3b ;

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 , C 2 R 3 , CONR 3 R 3a , NHC(O)NR 3 R 3a , SO 2 NR 3 R 3a , SO 2 R 3b , and C 3-10 carbocycle substituted with 0-5 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 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 , and SO 2 R 3b ;

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;

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 2 is selected from the group: H, C 1-5 alkyl substituted with 0-3 R c , —(CF 2 ) m CF 3 , and C 3-6 carbocycle substituted with 0-5 R a ;

provided that if R 3 is phenyl, it is substituted with 1-5 R a ;

provided that at least one R 3 present and that this R 3 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 , and C 3-10 carbocycle substituted with 0-5 R 6 ;

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 , and C 3-10 carbocycle substituted with 0-5 R a ;

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 , and SO 2 R 3b ;

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;

m is selected from 0, 1, 2, and 3.

5. A compound according to claim 1 , wherein the compound is selected from:

3-(4-methoxyphenyl)-5-(2-phenethylacetylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; and

3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .