Pyrazole compounds and uses thereof
The present invention provides pyrazole derivatives, e.g., a compound of Formula (I), and their uses in methods of treating malignant disease and disorders and methods for treating inflammatory diseases and disorders.
1. A method of treating a malignant condition in a subject in need thereof, comprising administering to the subject a compound having Formula (I), or a stereoisomer or 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, —C(O)-(straight or branched C 1 -C 5 alkyl), phenyl, naphthyl, anthracenyl, and C 3 -C 7 heteroaryl, each optionally substituted by at least one of halide, hydroxyl, —C(O)OR 10 , —OC(O)R 10 , —R 13 OR 14′ , —OR 15′ , phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, —C(O)NR 11 R 12′ , and —NR 11 C(O)R 12′ ; 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 comprises at least one of N, O, NH, C═O, and SO 2 , and is optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, phenyl, naphthyl, anthracenyl, 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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, —C(O)OR 10 , —OC(O)R 10 , —C(O)NR 11 R 12′ , and —NR 11 C(O)R 12′ ; 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 comprises 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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, hydroxyl, and halide;
W, X, Y, and Z are each selected from CH, CR 5 , CR 5c , NH, N, and S; provided that at least one of W, X, Y and Z is selected from NH, N, and S; and provided that, when W is N and Z is N, then X is CR 5c ;
n is an integer of 0 or 1;
R 5 is OH, NH 2 , or halide; R 5c is OH or NH 2 ;
R 8 is 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 optionally substituted by at least one of straight or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, halide, hydroxyl, and C 1 -C 5 haloalkyl;
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 independently substituted by at least one of C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, halide, hydroxyl, and C 1 -C 5 haloalkyl;
each R 10 is independently straight or branched C 1 -C 8 alkyl;
each R 11 and R 12′ is independently H, or straight or branched C 1 -C 8 alkyl;
each R 13 is independently straight or branched C 1 -C 8 alkylene; and
each R 14′ and R 15′ is independently H, or straight or branched C 1 -C 8 alkyl;
wherein each heteroaryl independently comprises at least one heteroatom selected from N, O, and S and each heterocyclyl independently comprises at least one heteroatom selected from N, O, and S, and
wherein the malignant condition is selected from multiple myeloma, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), melanoma, breast cancer, diffuse large B cell lymphoma (DLBCL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), prostate cancer, colorectal cancer, and head and neck cancer.
2. The method 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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, hydroxyl, —C(O)OR 10 , —OC(O)R 10 , —R 13 OR 14′ , —OR 15′ , —C(O)NR 11 R 12′ , and —NR 11 C(O)R 12′ .
3. The method according to claim 1 , wherein R 4 is H.
4. The method according to claim 1 , wherein R 3 and R 4 are H.
5. The method according to claim 1 , wherein R 5 is halide.
6. The method according to claim 1 , wherein R 5 is NH 2 or OH.
7. The method according to claim 1 , wherein R 8 is selected from H, C 1 , and straight or branched C 1 -C 4 alkyl.
8. The method according to claim 1 , wherein R 8 is H.
9. The method according to claim 1 , wherein at least one of R 1 and R 2 is H.
10. The method according to claim 1 , wherein R 6 is 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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, halide, hydroxyl, and C 1 -C 5 haloalkyl.
11. The method 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.
12. The method 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.
13. The method according to claim 1 , 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, and CF 3 .
14. The method according to claim 1 , wherein R 7 is straight or branched C 1 -C 8 alkyl substituted by at least one C 3 -C 7 cycloalkyl.
15. The method according to claim 1 , wherein n is an integer of 1.
16. The method according to claim 1 , wherein n is an integer of 0.
17. The method according to claim 1 , wherein one of W, X, Y, and Z is N.
18. The method according to claim 1 , wherein two of W, X, Y, and Z are N.
19. The method according to claim 16 , wherein two of W, X, Y, and Z are independently selected from NH, N, and S.
20. The method according to claim 1 , selected from:
and stereoisomers and pharmaceutically acceptable salts thereof.
21. The method according to claim 1 , selected from:
and stereoisomers and pharmaceutically acceptable salts thereof.
22. The method according to claim 1 , wherein the malignant condition has WT p53.
23. The method according to claim 22 , wherein the WT p53 is a biomarker for the compound efficacy.
24. The method according to claim 1 , further comprising inducing a cancer immunotherapy response in the subject.