Serine/threonine kinase inhibitors
Compounds having the formula I wherein A, Z, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R a , R b and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
1. A compound according to formula I
wherein:
A is A-1 or A-2;
Z is N or CR 2 ;
R 1a and R 1b are (i) each independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-3 alkoxy-C 1-6 alkyl, or, (ii) R 1a and R 1b together are (CH 2 ) 2-5 ;
R 2 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;
R a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy-C 1-6 alkyl, C 4-7 cycloalkyl, pyrrolidinyl, piperidinyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R b is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl;
R c and R d are independently (i) hydrogen or C 1-6 alkyl or (ii) R c and R d together with the nitrogen to which they are attached are a pyrrolidine and piperidine ring;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen, C 1-6 acyl or C 1-3 haloalkanoyl;
R 4 is independently in each occurrence hydroxy, thiol, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, halogen, C 1-6 alkoxycarbonyl, carboxyl, C 1-6 alkylthio, C 1-6 hydroxyalkyl, nitro, amino, C 1-3 alkylamino, C 1-3 dialkylamino, amino-C 1-3 alkyl, C 1-3 alkylamino-C 1-3 alkyl, C 1-3 dialkylamino C 1-3 alkyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkylaminosulfonyl, arylaminosulfonyl, C 1-6 alkylsulfonylamido, arylsulfonylamido, carbamoyl, C 1-3 alkylcarbamoyl and C 1-3 dialkylcarbamoyl, arylcarbamoyl, C 1-6 alkylcarbonylamino, arylcarbonylamino;
n is zero, one, two or three;
R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy-C 1-6 alkyl, cyano or OR 9 ;
R 6 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 hydroxyalkyl or C 1-3 alkoxy-C 1-6 alkyl;
R 7 is selected from the group consisting of (i) C 1-10 alkyl, (ii) C 1-10 haloalkyl, (iii) optionally substituted C 3-7 cycloalkyl (iv) C 3-7 cycloalkyl-C 1-6 alkyl, (v))R 9 O[C(R 10 ) 2 ] 0-6 , (vi) C 3-7 heterocyclyl and (vii) C 3-7 heterocyclyl-C 1-6 alkyl (viii) C 1-6 cyanoalkyl;
R 9 is independently in each occurrence C 1-10 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, phenyl-C 1-6 alkyl, pyridinyl-C 1-6 alkyl, pyridinyl or phenyl;
R 10 is independently in each occurrence hydrogen or C 1-6 alkyl;
said cycloalkyl in each occurrence is independently optionally substituted with C 1-6 alkyl, halogen or optionally substituted phenyl;
said phenyl in each occurrence is independently optionally substituted with C 1-6 alkyl, halogen or C 1-6 alkoxy;
said heterocyclyl is independently substituted with halogen or C 1-6 alkyl; or,
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein A is A2, Z is CR 2 and, R 2 and R b are hydrogen.
3. The compound according to claim 2 wherein A is optionally substituted indol-5-yl (A2a):
4. The compound according to claim 3 wherein:
R a is independently hydrogen, C 1-6 alkyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R 1a is hydrogen or C 1-6 alkyl;
R 1b is hydrogen;
R 5 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is hydrogen or halogen;
R 7 is optionally substituted C 3-7 cycloalkyl, C 3-7 heterocyclyl or C 1-6 haloalkyl.
5. The compound according to claim 4 wherein R 7 is optionally substituted C 3-7 cycloalkyl, C 1-6 haloalkyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl or tetrahydropyranyl.
6. The compound according to claim 5 wherein R 1a is C 1-6 alkyl, R 1b is hydrogen and the configuration of the carbon atom to which they both are attached is (S).
7. The compound according to claim 2 wherein A is optionally substituted indol-4-yl (A2b):
8. The compound according to claim 7 wherein:
R a is independently hydrogen, C 1-6 alkyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R 1a is hydrogen or C 1-6 alkyl;
R 1b is hydrogen;
R 5 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is hydrogen or halogen;
R 7 is optionally substituted C 3-7 cycloalkyl, C 3-7 heterocyclyl or C 1-6 haloalkyl.
9. The compound according to claim 8 wherein R 7 is optionally substituted C 3-7 cycloalkyl, C 1-6 haloalkyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl or tetrahydropyranyl.
10. The compound according to claim 8 wherein R 1a is C 1-6 alkyl, R 1b is hydrogen and the configuration of the carbon atom to which they both are attached is (S).
11. The compound according to claim 1 wherein A is A-1 and R 2 is hydrogen.
12. The compound according to claim 11 wherein A is optionally substituted benzimidazol-5-yl (A1a):
13. The compound according to claim 12 wherein:
R a is independently hydrogen, C 1-6 alkyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R 1a is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl;
R 1b is hydrogen;
R 5 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is hydrogen or halogen;
R 7 is optionally substituted C 3-7 cycloalkyl, C 3-7 heterocyclyl or C 1-6 haloalkyl.
14. The compound according to claim 13 wherein R 7 is optionally substituted C 3-7 cycloalkyl, C 1-6 haloalkyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl or tetrahydropyranyl.
15. The compound according to claim 14 wherein R 1a is C 1-6 alkyl, R 1b is hydrogen and the configuration of the carbon atom to which they both are attached is (S).
16. The compound according to claim 11 wherein A is optionally substituted benzimidazol-4-yl (A1b):
17. The compound according to claim 16 wherein:
R a is independently hydrogen, C 1-6 alkyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R 1a is hydrogen or C 1-6 alkyl;
R 1b is hydrogen;
R 5 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is hydrogen or halogen;
R 7 is optionally substituted C 3-7 cycloalkyl, C 3-7 heterocyclyl or C 1-6 haloalkyl.
18. The compound according to claim 17 wherein R 7 is optionally substituted C 3-7 cycloalkyl, C 1-6 haloalkyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl or tetrahydropyranyl.
19. The compound according to claim 18 wherein R 1a is C 1-6 alkyl, R 1b is hydrogen and the configuration of the carbon atom to which they both are attached is (S).
20. The compound according to claim 1 wherein A is A2, Z is N, R b is hydrogen and R 3 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
21. The compound according to claim 20 wherein:
R a is independently hydrogen, C 1-6 alkyl or R c R d N[C(R 10 ) 2 ] 2-6 ;
R 1a is hydrogen or C 1-6 alkyl;
R 1b is hydrogen;
R 5 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is hydrogen or halogen;
R 7 is optionally substituted C 3-7 cycloalkyl, C 3-7 heterocyclyl or C 1-6 haloalkyl.
22. The compound according to claim 1 which compound is any one or more compounds selected from the group consisting of compounds I-1 to I-117 of TABLE I or compounds II-1 to II-113 of TABLE II.
23. A composition comprising a compound according to any of claim 1 and at least one pharmaceutically acceptable carrier, excipient or diluent.