US 12,319,703 B2
Macrocyclic fused pyrazoles as Mcl-1 inhibitors
Guozhi Tang, Suzhou (CN); Dongbo Li, Suzhou (CN); Liugen Li, Suzhou (CN); Xianchan Zha, Suzhou (CN); Wenming Chen, Suzhou (CN); Shaomeng Wang, Superior Township, MI (US); and Chao-Yie Yang, Ann Arbor, MI (US)
Assigned to ASCENTAGE PHARMA (SUZHOU) CO., LTD., Suzhou (CN); REGENTS OF THE UNIVERSITY OF MICHIGAN, Ann Arbor, MI (US); and ASCENTAGE PHARMA GROUP CORP LIMITED, Hong Kong (CN)
Appl. No. 17/048,688
Filed by ASCENTAGE PHARMA (SUZHOU) CO., LTD., Suzhou (CN); THE REGENTS OF THE UNIVERSITY OF MICHIGAN, Ann Arbor, MI (US); and ASCENTAGE PHARMA GROUP CORP LIMITED, Hong Kong (CN)
PCT Filed Jan. 22, 2020, PCT No. PCT/CN2020/073742
§ 371(c)(1), (2) Date Oct. 19, 2020,
PCT Pub. No. WO2020/151738, PCT Pub. Date Jul. 30, 2020.
Claims priority of application No. PCT/CN2019/072801 (WO), filed on Jan. 23, 2019.
Prior Publication US 2022/0396587 A1, Dec. 15, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 515/22 (2006.01); A61P 35/00 (2006.01); C07D 497/22 (2006.01)
CPC C07D 515/22 (2013.01) [A61P 35/00 (2018.01); C07D 497/22 (2013.01)] 20 Claims
 
1. A compound of Formula III:

OG Complex Work Unit Chemistry
wherein:
R is selected from the group consisting of hydrogen and C1-C6 alkyl;
X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R3)—;
R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, hydroxyalkyl, —C(═O)R4, and —S(═O)2R5;
R4 is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
R5 is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
A is selected from the group consisting of:

OG Complex Work Unit Chemistry
R2a, R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, halo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;
R6a, R6b, R6c, R6d, R6e, and R6f are each independently selected from the group consisting of hydrogen, halo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;
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 —CR13aR13b—;
Z is selected from the group consisting of —CR13aR13b—, —O—, —S—, S(═O)—, S(═O)2—, and —N(R10)—;
R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, —C(═O)2R11, and —S(═O)2R12;
R11 is selected from the group consisting of C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl;
R12 is selected from the group consisting of C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl; and
R13a and R13b are independently selected from the group consisting of hydrogen and C1-C4 alkyl,
or a pharmaceutically acceptable salt thereof.