Pyrazole pyrimidine derivative and uses thereof

Patent metadata

Field	Value
Publication number	US-11925641-B2
Application number	US-202117215959-A
Country	US
Kind code	B2
Filing date	Mar 29, 2021
Priority date	Aug 4, 2015
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

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.

First claim

The invention claimed is:

1. A compound of formula (I):

or a stereoisomer or 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, or straight or branched C 1 -C 5 acyl, each optionally substituted by at least one of halide or hydroxyl; or
R 3 and R 4 are each independently H; or straight or branched C 1 -C 8 alkyl, each optionally substituted by at least one of halide, hydroxyl, or C 1 -C 5 alkoxy 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 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 optionally substituted by at least one of straight or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, halide, hydroxyl, or C 1 -C 5 haloalkyl; and
R 7 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, each substituted by at least one C 3 -C 7 cycloalkyl, 4-6 membered heterocyclyl, halide, hydroxyl, or C 1 -C 5 haloalkyl.

2. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, or straight or branched C 1 -C 8 alkyl, each optionally substituted by at least one of halide or hydroxyl.

3. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, or C 1 -C 5 acyl, optionally substituted by at least one of halide or hydroxyl.

4. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is H.

5. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each H.

6. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is H, Cl, or straight or branched C 1 -C 4 alkyl.

7. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is H.

8. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 8 is H, Cl, or straight or branched C 1 -C 4 alkyl.

9. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 8 is H.

10. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one of R 5 or R 8 is H.

11. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is H.

12. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, or saturated or unsaturated 4-6 membered heterocyclyl; and R 7 is straight or branched C 1 -C 8 alkyl, substituted by at least one C 3 -C 7 cycloalkyl.

13. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is selected from a straight or branched C 1 -C 8 alkyl, C 5 -C 10 cycloalkyl, and 4-6 membered saturated heterocyclyl.

14. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is a straight or branched C 1 -C 8 alkyl substituted by at least one of C 3 -C 7 cycloalkyl or hydroxyl.

15. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, 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, or CF 3 .

16. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is a straight or branched C 1 -C 8 alkyl substituted by at least one C 3 -C 7 cycloalkyl.

17. A compound selected from:

or a stereoisomer or pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 17 , or a stereoisomer or pharmaceutically acceptable salt thereof.

19. A method of treating a malignant condition in a subject in need thereof, comprising administering to the subject the compound according to claim 17 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the 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), head and neck cancer, breast cancer, prostate cancer, and colorectal cancer.

Assignees

• Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd

Inventors

• Ben-Neriah Yinon
• Brachya Guy
• Burstain Ido
• Minzel Waleed
• Snir-Alkalay Irit
• Vacca Joseph P
• Li Dansu

Classifications

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D403/04 Primary

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

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title