Macrocyclic fused pyrazoles as Mcl-1 inhibitors

Patent metadata

Field	Value
Publication number	US-12319703-B2
Application number	US-202017048688-A
Country	US
Kind code	B2
Filing date	Jan 22, 2020
Priority date	Jan 23, 2019
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

Provided are compounds represented by Formula IA: (IA), and the pharmaceutically acceptable salts and solvates thereof, wherein R, R 1a , R 1b , L 1 , L 2 , L 3 , X, A, B and C are as defined as set forth in the specification. Also provided compounds of Formula IA for use to treat a condition or disorder responsive to Mcl-1 inhibition such as cancer.

First claim

What is claimed is:

1. A compound of Formula III:

wherein:
R is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 —, and —N(R 3 )—;
R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, hydroxyalkyl, —C(═O)R 4 , and —S(═O) 2 R 5 ;
R 4 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C 6 -C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C 6 -C 10 aryl)C 1 -C 4 alkyl;
R 5 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C 6 -C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C 6 -C 10 aryl)C 1 -C 4 alkyl;
{circle around (A)} is selected from the group consisting of:

R 2a , R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each independently selected from the group consisting of hydrogen, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
{circle around (B)} is selected from the group consisting of arylenyl and heteroarylenyl;
wherein:
m is 0, 1, or 2;
n is or 1;
with the proviso that when m is 0, Z is —CR 13a R 13b —;
Z is selected from the group consisting of —CR 13a R 13b —, —O—, —S—, S(═O)—, S(═O) 2 —, and —N(R 10 )—;
R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, —C(═O) 2 R 11 , and —S(═O) 2 R 12 ;
R 11 is selected from the group consisting of C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl, and optionally substituted 5- to 10-membered heteroaryl;
R 12 is selected from the group consisting of C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl, and optionally substituted 5- to 10-membered heteroaryl; and
R 13a and R 13b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of Formula III-S or III-R:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein Z is —O— or —CH 2 —, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein {circle around (A)} is A-1, wherein:
R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl; and
R 2d is hydrogen,
or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein {circle around (A)} is A-2, wherein the 1-position of A-2 is attached to the oxygen atom and the 3-position of A-2 is attached to the sulfur atom, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein:
R 6a , R 6b , R 6c , R 6d and R 6e are each independently selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl; and
R 6f is hydrogen,
or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein:
{circle around (B)} is selected from the group consisting of:

R 8a , R 8b , R 8c , and R 8d are each independently selected from the group consisting of hydrogen, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl; and
R 9a , R 9b , R 9c , and R 9d are each independently selected from the group consisting of hydrogen, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl,
or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein R 8a , R 8b , R 8c , and R 8d are each independently selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10 , wherein R 9a , R 9b , R 9c , and R 9d are each independently selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein:
{circle around (B)} is selected from the group consisting of:

Z 1 is selected from the group consisting of —O—, —S—, and —N(R 7a )—;
R 7a is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
Z 2 is selected from the group consisting of —C(R 7b )═ and —N═;
R 7b is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
Z 3 is selected from the group consisting of —O—, —S—, and —N(R 7c )—;
R 7c is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
R 7d is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
Z 4 is selected from the group consisting of —O—, —S—, and —N(R 7e )—;
R 7e is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
R 7f is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
Y is selected from the group consisting of —C(R 10a )═ and —N═;
Y 1 is selected from the group consisting of —C(R 10b )═ and —N═;
Y 2 is selected from the group consisting of —C(R 10c )═ and —N═;
Y 3 is selected from the group consisting of —C(R 10d )═ and —N═;
with proviso that at least one of Y, Y 1 , Y 2 , and Y 3 is —N═;
R 10a , R 10b , R 10c , and R 10d are each independently selected from the group consisting of hydrogen, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
Y 4 is selected from the group c

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Univ Michigan Regents
• Ascentage Pharma Group Corp Ltd
• Univ Michigan

Inventors

• Tang Guozhi
• Li Dongbo
• Li Liugen
• Zha Xianchan
• Chen Wenming
• Wang Shaomeng
• Yang Chao-Yie

Classifications

• C07D497/22

  in which the condensed system contains four or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/04

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

• C07D513/04

  Ortho-condensed systems · CPC title