Pyrazole compounds and uses thereof
The present invention provides pyrazole derivatives of Formula (I), and in particular N1-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl) pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as casein kinase 1 (CK1) and/or interleukin 1 receptor associated kinase 1 (IRAKI) inhibitors for treating cancer, inflammatory and immune related disorders.
1. A compound of 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, —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 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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, hydroxyl, and halide;
W, X, Y, and Z are each independently 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 selected from OH, NH 2 , and halide; R 5 , 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.
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, phenyl, naphthyl, anthracenyl, C 3 -C 7 heteroaryl, hydroxyl, an ester, an ether, and an amide.
3. The compound according to claim 1 , wherein R 4 is H.
4. The compound according to claim 1 , wherein R 3 and R 4 are each H.
5. The compound according to claim 1 , wherein R 5 is halide.
6. The compound according to claim 1 , wherein R 5 is NH 2 .
7. The compound according to claim 1 , wherein R 5 is OH.
8. The compound according to claim 1 , wherein R 8 is selected from H, Cl, and straight or branched C 1 -C 4 alkyl.
9. The compound according to claim 1 , wherein R 8 is H.
10. The compound according to claim 1 , wherein at least one of R 1 and R 2 is H.
11. 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 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.
12. 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.
13. 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.
14. The compound according to claim 1 , wherein R 6 is straight or branched C 1 -C 8 alkyl, l 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 compound 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.
16. The compound according to claim 1 , wherein n is an integer of 1.
17. The compound according to claim 1 , wherein n is an integer of 0.
18. The compound according to claim 1 , wherein one of W, X, Y, and Z is N.
19. The compound according to claim 1 , wherein two of W, X, Y, and Z is N.
20. The compound according to claim 17 , wherein two of W, X, Y, and Z are each independently selected from NH, N, and S.
21. The compound according to claim 1 , selected from:
and stereoisomers and pharmaceutically acceptable salts thereof.
22. A compound selected from:
23. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1 ; and a pharmaceutically acceptable excipient.
24. A compound of Formula (IA):
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, —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, 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 independently selected from CH, CR 5 , NH, N, and S; provided that at least one of W, X, Y and Z is selected from NH, N and S; provided that, when W is N and Z is N, then R 8 is other than H;
n is an integer of 0 or 1;
R 5 is selected from OH, NH 2 , and halide;
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.
25. A compound selected from:
(1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine;
(1r,4r)-N 1 -(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine;
(1r,4r)-N 1 -(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)cyclohexane-1,4-diamine;
N 4 -((1r,4r)-4-aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;
2-(((1r,4r)-4-aminocyclohexyl)amino)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol;
N 2 -((1r,4r)-4-aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine; and
(1r,4r)-N 1 -(5-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)cyclohexane-1,4-diamine;
and stereoisomers and pharmaceutically acceptable salts thereof.