Pyrazole compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11072599-B2
Application number	US-201816482199-A
Country	US
Kind code	B2
Filing date	Jan 30, 2018
Priority date	Feb 1, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

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.

First claim

The invention claimed is:

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, o

Assignees

• Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd
• Biotheryx Inc

Inventors

• Li Dansu
• Snir-Alkalay Irit
• VACCA Joseph
• Ben-Neriah Yinon
• Venkatachalam Avanthika

Classifications

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title