Pyrazolopyrimidines and related heterocycles as kinase inhibitors
The invention provides compounds of general formula (I) that inhibit selected kinases (Pim and/or CK2 kinases) and compositions containing such compounds. These compounds and compositions are useful for treating proliferative disorders such as cancer, as well as other kinase-associated conditions including inflammation, pain, and certain infections and immunological disorders.
1. A compound of Formula (I):
wherein the bicyclic ring system containing Z 1 -Z 4 is aromatic;
Z 1 and Z 3 are N; Z 2 is C; and Z 4 is CR 5 ;
where R 5 can be H or R 1 ;
R 1 is H, halo, CN, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
R 2 is H, halo, CN, or optionally substituted C1-C4 alkyl;
R 3 and R 4 are independently selected from H and optionally substituted C1-C10 alkyl;
X is NR 6 , O, or S, where R 6 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl;
Y is O or S or NR 10 ;
R 10 is selected from H, CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 alkoxy, or —NR 7 R 8 , where R 7 and R 8 are independently selected from H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl,
or R 7 and R 8 taken together with the N of —NR 7 R 8 can form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
W is optionally substituted aryl, optionally substituted heteroaryl, —OR 7 , —NR 7 R 8 , or optionally substituted heterocyclyl,
wherein n is 0, 1 or 2,
each R 7 and R 8 are each independently selected from H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
wherein R 7 and R 8 in NR 7 R 8 can be taken together along with N to form a 5-8 membered ring that can be optionally substituted, and can optionally contain an additional heteroatom selected from N, O and S as a ring member;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X is NR 6 or S.
3. The compound of claim 1 , wherein R 2 is H, Me.
4. The compound of claim 1 , wherein R 3 and R 4 are both H.
5. The compound of claim 1 , wherein R 1 is H, Me, halo, OMe, or CF 3 .
6. The compound of claim 1 , wherein Y is O.
7. The compound of claim 1 , wherein Y is S.
8. The compound of claim 1 , wherein W is —NH-A, wherein A is optionally substituted phenyl.
9. The compound of claim 1 , wherein W is optionally substituted aryl or optionally substituted heteroaryl.
10. The compound of claim 9 , wherein W is optionally substituted phenyl or optionally substituted thienyl.
11. The compound of claim 1 , which is a compound of Formula Ia or Formula Ib:
wherein R 1 , R 3 , R 4 , R 9 , R 10 , X, and Y are as defined in claim 1 ,
and Ar is optionally substituted phenyl or optionally substituted thienyl.
12. The compound of claim 1 , which is selected from the group consisting of
13. A pharmaceutical composition comprising the compound of claim 1 , admixed with a pharmaceutically acceptable excipient.