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 method of inhibiting Casein kinase I in a subject, comprising administering to the subject a compound having formula (I), or a stereoisomer or a 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, straight or branched C 1 -C 5 acyl, C 5 -C 15 aryl, or C 3 -C 7 heteroaryl, each of which is optionally substituted by at least one of halide, hydroxyl, an ester, an ether, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, and an amide; or
R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered saturated, unsaturated, or aromatic ring that optionally includes at least one of N, O, NH, C═N, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 8 alkyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, halide, and cyano;
R 3 and R 4 are each independently H, or straight or branched C 1 -C 8 alkyl optionally substituted by at least one of halide, hydroxyl, C 1 -C 5 alkoxy, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, an ester, and an amide; or
R 1 or R 2 together with R 3 and the carbon and nitrogen atoms they are each connected to form a 4-7 membered saturated, unsaturated, or aromatic ring that optionally includes at least one of N, NH, O, C═N, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, and halide;
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 of which is 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 of which is optionally substituted by at least one of straight or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, halide, hydroxyl, and C 1 -C 5 alkyl halide; and
R 7 is 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 of which is substituted by at least one C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, halide, hydroxyl, and C 1 -C 5 alkyl halide.
2. The method of claim 1 , wherein R 1 is H; or straight or branched C 1 -C 8 alkyl, C 5 -C 15 aryl, or C 3 -C 7 heteroaryl, each of which is optionally substituted by at least one of halide, hydroxyl, an ester, an ether, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, and an amide.
3. The method of claim 1 , wherein R 1 is H.
4. The method of claim 1 , wherein R 2 is H; or straight or branched C 1 -C 8 alkyl, C 5 -C 15 aryl, or C 3 -C 7 heteroaryl, each of which is optionally substituted by at least one of halide, hydroxyl, an ester, an ether, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, and an amide.
5. The method of claim 1 , wherein R 2 is H.
6. The method of claim 1 , wherein R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered saturated, unsaturated, or aromatic ring that optionally includes at least one of N, O, NH, C═N, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, halide, and cyano.
7. The method of claim 1 , wherein R 1 together with R 3 and the carbon and nitrogen atoms they are each connected to form a 4-7 membered saturated, unsaturated, or aromatic ring that optionally includes at least one of N, NH, 0, C═N, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, and halide.
8. The method of claim 1 , wherein R 3 is H, or straight or branched C 1 -C 8 alkyl optionally substituted by at least one of halide, hydroxyl, C 1 -C 5 alkoxy, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, an ester, and an amide.
9. The method of claim 1 , wherein R 3 is H.
10. The method of claim 1 , wherein R 4 is H, or straight or branched C 1 -C 8 alkyl optionally substituted by at least one of halide, hydroxyl, C 1 -C 5 alkoxy, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, an ester, and an amide.
11. The method of claim 1 , wherein R 4 is H.
12. The method of claim 1 , wherein R 5 is selected from H, Cl, and straight or branched C 1 -C 4 alkyl.
13. The method of claim 1 , wherein R 5 is H.
14. The method of claim 1 , wherein R 6 is straight or branched C 1 -C 8 alkyl, or saturated, unsaturated, or aromatic 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, halide, hydroxyl, and CF 3 .
15. The method of claim 1 , wherein R 6 is straight or branched C 1 -C 8 alkyl.
16. The method of claim 1 , wherein R 6 is methyl.
17. The method of claim 1 , wherein R 7 is straight or branched C 1 -C 8 alkyl substituted by at least one of C 3 -C 7 cycloalkyl and hydroxyl.
18. The method of claim 1 , wherein R 8 is selected from H, Cl, and straight or branched C 1 -C 4 alkyl.
19. The method of claim 1 , wherein R 8 is H.
20. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.