Pyrazole pyrimidine derivative and uses thereof
The present invention provides pyrazole pyrimidine derivatives which inhibit Casein kinase I (CKI) and/or Interleukin-1 receptor-associated kinase 1 (IRAKI) and methods of their manufacture, compositions comprising them and uses thereof in methods of treating malignant disease and disorders and methods for treating inflammatory diseases and disorders.
1. A compound of formula (I):
or a stereoisomer or pharmaceutically acceptable salt thereof; wherein:
R 1 and R 2 are each independently H; or straight or branched C 1 -C 8 alkyl, straight or branched C 1 -C 5 alkoxy, or straight or branched C 1 -C 5 acyl, each optionally substituted by at least one of halide or hydroxyl; or
R 3 and R 4 are each independently H; or straight or branched C 1 -C 8 alkyl, each optionally substituted by at least one of halide, hydroxyl, or C 1 -C 5 alkoxy R 5 and R 8 are each independently H or halide; or straight or branched C 1 -C 8 alkyl, straight or branched C 2 -C 8 alkenyl, or straight or branched C 2 -C 8 alkynyl each optionally substituted by at least one halide;
R 6 is straight or branched C 1 -C 8 alkyl, straight or branched C 2 -C 8 alkenyl, straight or branched C 2 -C 8 alkynyl, C 5 -C 10 cycloalkyl, or saturated or unsaturated 4-6 membered heterocyclyl, each optionally substituted by at least one of straight or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, halide, hydroxyl, or C 1 -C 5 haloalkyl; and
R 7 is straight or branched C 1 -C 8 alkyl, straight or branched C 2 -C 8 alkenyl, straight or branched C 2 -C 8 alkynyl, each substituted by at least one C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, halide, hydroxyl, or C 1 -C 5 haloalkyl.
2. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, or straight or branched C 1 -C 8 alkyl, each optionally substituted by at least one of halide or hydroxyl.
3. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, or C 1 -C 5 acyl, optionally substituted by at least one of halide or hydroxyl.
4. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is H.
5. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each H.
6. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is H, Cl, or straight or branched C 1 -C 4 alkyl.
7. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is H.
8. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 8 is H, Cl, or straight or branched C 1 -C 4 alkyl.
9. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 8 is H.
10. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one of R 5 or R 8 is H.
11. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is H.
12. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, or saturated or unsaturated 4-6 membered heterocyclyl; and R 7 is straight or branched C 1 -C 8 alkyl, substituted by at least one C 3 -C 7 cycloalkyl.
13. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is selected from a straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, and 4-6 membered saturated heterocyclyl.
14. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is a straight or branched C 1 -C 8 alkyl substituted by at least one of C 3 -C 7 cycloalkyl or hydroxyl.
15. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is straight or branched C 1 -C 8 alkyl, optionally substituted by at least one of straight or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, halide, hydroxyl, or CF 3 .
16. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is a straight or branched C 1 -C 8 alkyl substituted by at least one C 3 -C 7 cycloalkyl.
17. A compound selected from:
or a stereoisomer or pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according to claim 17 , or a stereoisomer or pharmaceutically acceptable salt thereof.
19. A method of treating a malignant condition in a subject in need thereof, comprising administering to the subject the compound according to claim 17 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the malignant condition is selected from hematological malignancies, multiple myeloma, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), melanoma, ER-negative breast cancer, diffuse large B cell lymphoma (DLBCL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), head and neck cancer, breast cancer, prostate cancer, and colorectal cancer.