IP Library › Granted Patent US 12,264,152
Granted Patent B2
US 12,264,152 · App. 18/097,782 · Granted Apr 1, 2025

Certain chemical compositions and methods of use thereof

Inventors: Andrei W. Konradi (Burlingame, CA); Chun-Hao Huang (San Francisco, CA); Ko-Chuan Lee (San Francisco, CA)
Assignee: Algen Biotechnologies, Inc.
C07D405/14
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Quick Facts
Patent No.
US 12,264,152
App. No.
18/097,782
Granted
Apr 1, 2025
Kind
B2
Abstract

The present disclosure provides CDK9 inhibitors. Also provided are methods of treating a disease or a disorder comprising administering to a subject in need of treatment one of the CDK9 inhibitors disclosed herein. In some embodiments, the disease or disorder to be treated is cancer. In some embodiments, the disease or disorder is liver cancer.

Claims (66)

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I-A):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is selected from C 3-6 cycloalkyl or C 6-10 aryl;

R 1 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, —CN, and NR 20 R 21 ,

R 2 is selected from halo, —CN, —OH, —OMe, —OEt, —NH 2 , —NHMe, —NMe 2 , Me, Et, n-Pr, i-Pr, —CF 3 , and cyclopropyl;

R 3 is selected from H, halo, —CN, —OR 18 , —SOR 15 , —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , —NR 19 SO 2 NR 16 R 17 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, —CN, and —NR 20 R 21 ;

R 4 is selected from C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl, —O(C 0-4 alkyl)C 3-6 cycloalkyl, —O(C 0-4 alkyl)(3- to 10-membered heterocycloalkyl), —O(C 0-4 alkyl)C 6-10 aryl, —O(C 0-4 alkyl)(6- to 10-membered heteroaryl), —O(C 0-4 alkyl)C(O)OR 18 , —O(C 0-4 alkyl)C(O)NR 19 SO 2 R 15 , —O(C 0-4 alkyl)SO 2 NR 19 C(O)R 18 , —O(C 3-6 cycloalkyl)C 3-6 cycloalkyl, —O(C 3-6 cycloalkyl)(3- to 10-membered heterocycloalkyl), —O(C 3-6 cycloalkyl)C 6-10 aryl, —O(C 3-6 cycloalkyl)(6- to 10-membered heteroaryl), —O(C 3-6 cycloalkyl)C(O)OR 18 , —(C 1-4 alkyl)C 3-6 cycloalkyl, —(C 1-4 alkyl)(3 to 10-membered heterocycloalkyl), —(C 1-4 alkyl)C 6-10 aryl, —(C 1-4 alkyl)(6- to 10-membered heteroaryl), and —(C 1-4 alkyl)C(O)OR 18 ; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, —OR 18 , —CN, —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —(C 1-4 alkyl)OC(O)(C 1-4 alkyl), —(C 1-4 alkyl)OC(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , and —NR 19 SO 2 NR 16 R 17 ; and

R 4 ′ and R 4 ″ are each independently selected from H, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl, —O(C 0-4 alkyl)C 3-6 cycloalkyl, —O(C 0-4 alkyl)(3- to 10-membered heterocycloalkyl), —O(C 0-4 alkyl)C 6-10 aryl, —O(C 0-4 alkyl)(6- to 10-membered heteroaryl), —O(C 0-4 alkyl)C(O)OR 18 , —O(C 0-4 alkyl)C(O)NR 19 SO 2 R 15 , —O(C 0-4 alkyl)SO 2 NR 19 C(O)R 18 , —O(C 3-6 cycloalkyl)C 3-6 cycloalkyl, —O(C 3-6 cycloalkyl)(3- to 10-membered heterocycloalkyl), —O(C 3-6 cycloalkyl)C 6-10 aryl, —O(C 3-6 cycloalkyl)(6- to 10-membered heteroaryl), —O(C 3-6 cycloalkyl)C(O)OR 18 , —(C 1-4 alkyl)C 3-6 cycloalkyl, —(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl), —(C 1-4 alkyl)C 6-10 aryl, and —(C 1-4 alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , —CN, —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —(C 1-4 alkyl)OC(O)(C 1-4 alkyl), —(C 1-4 alkyl)OC(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , and —NR 19 SO 2 NR 16 R 17 ; or

R 3 is H; and R 4 , R 4 ′, and R 4 ″ are taken together, along with the carbon atom to which they are attached, to form —C(O)R 18 or 6- to 10-membered heteroaryl;

R 5 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, —CN, and NR 20 R 21 ;

R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl, —(C 1-4 alkyl)C 3-6 cycloalkyl, —(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl), —(C 1-4 alkyl)C 6-10 aryl, and —(C 1-4 alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, —CN, and —NR 20 R 21 ;

R 8 and R 9 are both H;

each R 10 is independently selected from halo, —CN, —OR 18 , —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —NR 19 C(O)R 18 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents selected from oxo, halo, —OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, —CN, and —NR 20 R 21 ,

R 11 , R 12 , R 13 , and R 14 are each independently selected from H, halo, —CN, —OR 18 , —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —NR 19 C(O)R 18 , C 1-6 alkyl, and C 1-6 haloalkyl;

each R 15 is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl;

each R 16 and R 17 is independently selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl; or

an R 16 and an R 17 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl;

each R 18 is independently selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;

each R 19 is independently selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl; and

each R 20 and R 21 is independently selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl; or

an R 20 and an R 21 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycloalkyl; and

n is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein the compound of Formula (I-A) is a compound of Formula (I-B):

3. The method of claim 1 , wherein Ring A is C 3-6 cycloalkyl.

4. The method of claim 1 , wherein Ring A is selected from the group consisting of:

5. The method of claim 1 , wherein R 11 , R 12 , R 13 , and R 14 are each independently selected from H, halo, —CN, —OR 18 , and —NR 16 R 17 .

6. The method of claim 1 , wherein R 11 is chloro, and R 12 , R 13 , and R 14 are each H.

7. The method of claim 1 , wherein R 1 is H.

8. The method of claim 1 , wherein R 2 is Me and R 3 is H.

9. The method of claim 1 , wherein:

R 4 is selected from C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, 6- to 10-membered heteroaryl, —O(C 0-4 alkyl)C 3-6 cycloalkyl, —O(C 0-4 alkyl)(3- to 10-membered heterocycloalkyl), —O(C 0-4 alkyl)C 6-10 aryl, —O(C 0-4 alkyl)(6- to 10-membered heteroaryl), —O(C 0-4 alkyl)C(O)OR 18 , —O(C 0-4 alkyl)C(O)NR 19 SO 2 R 15 , —O(C 0-4 alkyl)SO 2 NR 19 C(O)R 18 , —O(C 3-6 cycloalkyl)C 3-6 cycloalkyl, —O(C 3-6 cycloalkyl)(3- to 10-membered heterocycloalkyl), —O(C 3-6 cycloalkyl)C 6-10 aryl, —O(C 3-6 cycloalkyl)(6- to 10-membered heteroaryl), —O(C 3-6 cycloalkyl)C(O)OR 18 , —(C 1-4 alkyl)C 3-6 cycloalkyl, —(C 1-4 alkyl)(3 to 10-membered heterocycloalkyl), —(C 1-4 alkyl)C 6-10 aryl, —(C 1-4 alkyl)(6- to 10-membered heteroaryl), and —(C 1-4 alkyl)C(O)OR 18 ; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, —OR 18 , —CN, —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)R 18 , —C(O)OR 18 , —(C 1-4 alkyl)OC(O)(C 1-4 alkyl), —(C 1-4 alkyl)OC(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , and —NR 19 SO 2 NR 16 R 17 , and

R 4 ′ and R 4 ″ are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more substituents selected from halo, —OR 18 , —CN, and —NR 16 R 17 , or

R 3 is H; and

R 4 , R 4 ′, and R 4 ″ are taken together, along with the carbon atom to which they are attached, to form —C(O)R 18 or 6- to 10-membered heteroaryl.

10. The method of claim 1 , wherein:

R 4 is selected from C 2-6 heteroalkyl, C 1-6 haloalkyl, 6- to 10-membered heteroaryl, —O(C 0-4 alkyl)(3- to 10-membered heterocycloalkyl), —O(C 0-4 alkyl)C 6-10 aryl, —O(C 0-4 alkyl)(6- to 10-membered heteroaryl), —O(C 0-4 alkyl)C(O)OR 18 , —O(C 0-4 alkyl)C(O)NR 19 SO 2 R 15 , —O(C 0-4 alkyl)SO 2 NR 19 C(O)R 18 , —O(C 3-6 cycloalkyl)(6- to 10-membered heteroaryl), —O(C 3-6 cycloalkyl)C(O)OR 18 , —(C 1-4 alkyl)(6- to 10-membered heteroaryl) and —(C 1-4 alkyl)C(O)OR 18 ; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, —OR 18 , —CN, —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)OR 18 , —(C 1-4 alkyl)OC(O)(C 1-4 alkyl), —(C 1-4 alkyl)OC(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , and —NR 19 SO 2 NR 16 R 17 , and

R 4 ′ and R 4 ′ are both H; or

R 3 is H; and

R 4 , R 4 ′, and R 4 ″ are taken together, along with the carbon atom to which they are attached, to form —C(O)R 18 or 6- to 10-membered heteroaryl.

11. The method of claim 1 , wherein:

R 4 is selected from C 2-6 heteroalkyl, —O(C 0-4 alkyl)(6- to 10-membered heteroaryl), —O(C 0-4 alkyl)C(O)OR 18 , —O(C 0-4 alkyl)C(O)NR 19 SO 2 R 15 , and —(C 1-4 alkyl)C(O)OR 18 ; wherein each alkyl, heteroalkyl, and heteroaryl is independently optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, —OR 18 , —CN, —NR 16 R 17 , —C(O)NR 16 R 17 , —SO 2 NR 16 R 17 , —C(O)OR 18 , —(C 1-4 alkyl)OC(O)(C 1-4 alkyl), —(C 1-4 alkyl)OC(O)OR 18 , —NR 19 C(O)R 18 , —NR 19 C(O)NR 16 R 17 , —NR 19 SO 2 R 15 , and —NR 19 SO 2 NR 16 R 17 ; and

R 4 ′ and R 4 ″ are both H.

12. The method of claim 11 , wherein R 4 is a 3- to 8-membered heteroalkyl comprising one or more O skeletal chain atom, wherein R 4 is connected through an O or a carbon in the heteroalkyl.

13. The method of claim 1 , wherein R 5 is H.

14. The method of claim 1 , wherein R 6 and R 7 are each independently selected from H and —(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, —OR 18 , —CN, and —NR 20 R 21 .

15. The method of claim 14 , wherein one of R 6 and R 7 is H and the other is

16. The method of claim 1 , wherein n is 0.

17. The method of claim 1 , wherein R 1 is H, R 2 is Me, R 3 is H, R 5 is H, R 8 and R 9 are both H, and one of R 6 and R 7 is H and the other is

18. The method of claim 17 , wherein R 11 is chloro, and R 12 , R 13 , and R 14 are each H.

19. The method of claim 1 , wherein the compound of Formula (I) is represented by Formula (I-C), Formula (I-D), Formula (I-E), or Formula (I-F):

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

21. The method of claim 1 , wherein the compound is selected from the group consisting of:

22. The method of claim 1 , wherein the compound is

23. The method of claim 1 , wherein the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, rectal cancer, cervical cancer, lung cancer, lymphoma, and liver cancer.

24. The method of claim 23 , wherein the cancer is selected from colon cancer, rectal cancer, and liver cancer.

25. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from:

wherein the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, rectal cancer, cervical cancer, lung cancer, lymphoma, and liver cancer.

26. The method of claim 25 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The method of claim 25 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

28. The method of claim 25 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

29. The method of claim 25 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2025
From: KONRADI, ANDREI W.; HUANG, CHUN-HAO; LEE, KO-CHUAN
To: ALGEN BIOTECHNOLOGIES, INC.
Reel/Frame 070111/0115 →
Continuity (4)
Continuation 17731943 · Apr 28, 2022
Continuation PCTUS2021032495 · May 14, 2021
Provisional Application 63025474 · May 15, 2020
Related Publication 20230295135A1 · Sep 21, 2023
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