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 having formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R 2 are each independently selected from H; and 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, and 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 5 alkyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, halide, and cyano;
R 3 and R 4 are each independently selected from H, and 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 selected from H and halide; and straight or branched C 1 -C 8 alkyl, straight or branched C 2 -C 8 alkenyl, and straight or branched C 2 -C 8 alkynyl, each optionally substituted by at least one halide;
R 6 is selected from 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, and 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, and hydroxyl; and
R 7 is selected from straight or branched C 1 -C 8 alkyl, straight or branched C 2 -C 8 alkenyl, and straight or branched C 2 -C 8 alkynyl, each of which is substituted by at least one of C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, halide, and hydroxyl.
2. The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from H and straight or branched C 1 -C 8 alkyl optionally substituted by at least one of halide, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, hydroxyl, an ester, an ether, and an amide.
3. The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from H and straight or branched C 1 -C 5 alkoxy optionally substituted by at least one of halide, hydroxyl, an ester, and an amide.
4. The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from H and C 1 -C 5 acyl optionally substituted by at least one of halide, hydroxyl, an ester, an ether, and an amide.
5. The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from H and C 5 -C 15 aryl optionally substituted by at least one of halide, hydroxyl, an ester, an ether, and an amide.
6. The compound according to claim 1 , wherein R 4 is H.
7. The compound according to claim 1 , wherein R 3 and R 4 are each H.
8. The compound according to claim 1 , wherein R 5 is selected from H, Cl, and straight or branched C 1 -C 4 alkyl.
9. The compound according to claim 1 , wherein R 5 is H.
10. The compound according to claim 1 , wherein R 8 is selected from H, Cl, and straight or branched C 1 -C 4 alkyl.
11. The compound according to claim 1 , wherein R 8 is H.
12. The compound according to claim 1 , wherein one of R 5 and R 8 is H.
13. The compound according to claim 1 , wherein at least one of R 1 and R 2 is H.
14. The compound according to claim 1 , wherein R 6 selected from straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, and saturated or unsaturated 4-6 membered heterocyclyl; and R 7 is selected from straight or branched C 1 -C 8 alkyl substituted by at least one of C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, C 5 -C 15 aryl, C 3 -C 7 heteroaryl, halide, and hydroxyl.
15. The compound according to claim 1 , wherein R 6 is selected from straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, and 4-6 membered saturated heterocyclyl.
16. The compound according to 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.
17. The compound according to claim 1 , wherein R 6 is selected from straight or branched C 1 -C 8 alkyl, and saturated , unsaturated, or aromatic 4-6 membered heterocyclyle, each of which is 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 .
18. The compound according to claim 1 , wherein R 7 is a straight or branched C 1 -C 8 alkyl substituted by at least one C 3 -C 7 cycloalkyl.
19. The compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered saturated ring optionally including at least one of N, O, NH, C═N, C═O, and SO 2 ; and optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide, and cyano.
20. The compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered saturated ring.
21. The compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered saturated ring including at least one of N and O.
22. The compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom they are connected to form a 4-7 membered aromatic ring optionally including at least one of N and O.
23. The compound according to claim 1 , wherein R 3 and R 4 are each H.
24. The compound according to claim 1 , wherein R 1 or R 2 together with R 3 and the carbon and nitrogen atoms they are connected to form a 4-7 membered saturated ring that optionally includes at least one of N, NH, O, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, and halide.
25. The compound according to claim 1 , wherein R 1 or R 2 together with R 3 and the carbon and nitrogen atoms they are connected to form a 4-7 membered saturated ring that includes at least one of NH, O, and C═O.
26. The compound according to claim 1 , selected from:
and pharmaceutically acceptable salts thereof.
27. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
28. A method of treating cancer in a subject in need thereof, comprising administering to said subject a compound according to claim 1 or a pharmaceutically acceptable salt thereof; wherein the cancer is leukemia, multiple myeloma, malignant melanoma, breast cancer, prostate cancer, or colorectal cancer.
29. The method according claim 28 , wherein said cancer has WT p53.
30. A method of treating a malignant condition in a subject in need thereof, comprising administering to said subject a compound according to claim 1 or a pharmaceutically acceptable salt thereof; wherein said 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), and head and neck cancer.
31. The method according to claim 28 , further comprising inducing a cancer immunotherapy response in said subject.
32. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 32 , wherein the compound is
or a p-toluensulfonate salt thereof.
34. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34 , wherein the compound is
or a p-toluensulfonate salt thereof.
36. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 36 , wherein the compound is
or a p-toluensulfonate salt thereof.
38. The method according claim 30 , wherein the malignant condition is myelodysplastic syndrome (MDS).
39. The method according claim 30 , wherein the malignant condition is acute myeloid leukemia (AML).