Protein kinase modulators
The invention relates in part to molecules having certain biological activities that include, but are not limited to, inhibiting cell proliferation, modulating protein kinase activity and modulating polymerase activity. Molecules of the invention can modulate Pim kinase activity and/or FMS-like tyrosine kinase (Flt) activity. The invention also relates in part to methods for using such molecules.
1. A compound of Formula IA:
wherein:
Z 60 and Z 70 are independently N or CR 60 , provided at least one of them is N;
R 30 and each R 60 is independently H or an optionally substituted C1-C8 alkyl or C2-C8 heteroalkyl,
each R 40 is H or optionally substituted member selected from the group consisting of C 1 -C 6 alkyl, C2-C6 heteroalkyl, and C1-C6 acyl;
each R 50 is independently an optionally substituted member selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 heteroalkyl, C 3-8 carbocyclic ring, and C 3-8 heterocyclic ring optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring;
or R 50 can be a C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 heteroalkyl substituted with an optionally substituted C 3-8 carbocyclic ring or C 3-8 heterocyclic ring;
in each —NR 40 R 50 , R 40 and R 50 together with N may form an optionally substituted 3-8 membered ring, which may optionally contain an additional heteroatom selected from N, O and S as a ring member; and
each R 3P represents a polar substituent selected from the group consisting of tetrazole, triazole, imidazole, oxadiazole, oxothiadiazole, thiazole, aminothiazole, and hydroxythiazole;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Z 70 is N and Z 60 is CH.
3. The compound of claim 1 , wherein each R 60 and R 40 is H.
4. The compound of claim 1 , wherein R 3P is an optionally substituted imidazole or triazole ring.
5. The compound of claim 1 , wherein R 50 is unsubstituted phenyl or phenyl substituted with 1-3 substituents selected from halo, cyano, CF 3 , —OCF 3 , COOR 40 , and SO 2 NR 40 R 50 , and one or more of these substituents can be an optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl.
6. The compound of claim 1 , which is a compound of Formula IC:
or a pharmaceutically acceptable salt thereof,
wherein R 30 is as defined for claim 1 ,
and R 3P is an optionally substituted imidazole or triazole ring;
and each Φ independently represents an optionally substituted phenyl.
7. The compound of claim 6 , wherein Φ is unsubstituted phenyl or phenyl substituted with 1-3 substituents selected from halo, cyano, CF 3 , —OCF 3 , COOR 40 , and SO 2 NR 40 R 50 , and one or more of these substituents can be an optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl.
8. The compound of claim 1 , wherein R 50 is an optionally substituted C 3-8 carbocyclic or C 3-8 heterocyclic ring, each of which may be optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring.
9. The compound of claim 8 , wherein said optionally substituted C 3-8 carbocyclic or C 3-8 heterocyclic ring is an optionally substituted aromatic or heteroaromatic ring.
10. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.