Trifluoromethyl-substituted sulfonamide as BCL-2-selective inhibitor

Patent metadata

Field	Value
Publication number	US-12371431-B2
Application number	US-201917289406-A
Country	US
Kind code	B2
Filing date	Oct 29, 2019
Priority date	Oct 29, 2018
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

Disclosed is a trifluoromethyl-substituted sulfonamide BCL-2-selective inhibitor, in particular disclosed are a compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition thereof. Also disclosed are the uses of said compound and of a pharmaceutical composition comprising same for treating anti-apoptotic BCL-2-related diseases, such as cancer.

First claim

The invention claimed is:

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein,
R 1 is chlorine;
R 2 is —(CH 2 ) n —R 3 , wherein n is 1;
R 3 is a 6 membered heterocycloalkyl, and the heteroatom in the 6 membered heterocycloalkyl is selected from the group consisting of N and O, and the number of the heteroatom is 1 or 2, wherein the 6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, —COR a , —SO 2 R b , —COOC 1-6 alkyl, and C 1-6 alkyl optionally substituted with halogen; and
R a or R b is each independently selected from the group consisting of H, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with halogen, —CN, —N(C 1-6 alkyl) 2 , —NHC 1-6 alkyl or —OC 1-6 alkyl,

wherein the heteroatom in the 3-6 membered heterocycloalkyl is selected from the group consisting of N and O, and the number of the heteroatom is 1 or 2;
wherein the structural fragment

is

2. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is a 6-membered heterocycloalkyl, and wherein the 6-membered heterocycloalkyl is optionally substituted with one or two groups at ring N atom.

3. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is 6-membered heterocycloalkyl, and wherein the 6-membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, —COR a , —SO 2 R b , —COOC 1-4 alkyl, and C 1-6 alkyl optionally substituted with halogen.

4. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R a or R b is each independently selected from the group consisting of H, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl and C 1-4 alkyl, and wherein the C 1-4 alkyl is optionally substituted with halogen, —CN, —N(C 1-4 alkyl) 2 , —NHC 1-4 alkyl or —OC 1-4 alkyl.

5. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein R a or R b is each independently selected from C 1-4 alkyl optionally substituted with —OC 1-4 alkyl.

6. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is a 6-membered heterocycloalkyl, and wherein the 6-membered heterocycloalkyl is optionally substituted with —C(O)H, —COCH 3 , —COCH(CH 3 ) 2 , —COC(CH 3 ) 3 , —COCF 3 , —COCH 2 CN, —COCH 2 OCH 3 , —COCH 2 N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —SO 2 CF 3 , —SO 2 C 2 F 5 , methyl, ethyl, —CF 3 , —CH 2 CH 2 F, —C 2 F 5 , tetrahydropyran, monooxacyclobutane, —SO 2 -cyclopropane, —CO-cyclopropane, —CO-monooxacyclobutane, —SO 2 -monooxacyclobutane, —SO 2 -cyclobutane, —COOCH 2 CH 3 or —COOCH 3 .

7. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is selected from the group consisting of

8. A pharmaceutical composition comprising the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 .

9. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein R a or R b is each independently selected from the group consisting of H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, —CH 2 OCH 3 , —CH 2 CN and —CH 2 N(CH 3 ) 2 , cyclopropyl, cyclobutyl and monooxacyclobutyl.

10. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9 , wherein R a or R b is each independently selected from the group consisting of methyl, isopropyl, and —CH 2 OCH 3 .

11. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 2 , wherein R 3 is a 6-membered heterocycloalkyl, and wherein the 6-membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of —COR a , —SO 2 R b , and C 1-6 alkyl optionally substituted with halogen.

12. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 6 , wherein R 3 is selected from the group consisting of tetrahydropyran, piperidine, morpholine and dioxane, and wherein the tetrahydropyran, piperidine, morpholine or dioxane is optionally substituted with —COCH 3 , —COCH(CH 3 ) 2 , —COCH 2 OCH 3 , —SO 2 CH 3 , methyl, ethyl, —CH 2 CH 2 F, —COOCH 2 CH 3 or —COOCH 3 .

13. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 6 , wherein R 3 is selected from the group consisting of

14. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is selected from the group consisting of tetrahydropyran and dioxane.

15. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , selected from a compound of the following formulas:

or a compound of the following formula:

wherein R is independently selected from the group consisting of:

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. The compound of formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , selected from a compound of the following formulas:

or a compound of t

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Liu Fei
• Feng Weiwei
• Wang Bin
• Xu Hongjiang
• Wang Jinan
• Zhang Xiquan
• Wang Shanchun
• Liu Yanlong
• Zhang Jianqing
• Yao Yiyan
• Tang Xujing
• Shi Wei
• Zhang Hongying
• Li Yang
• Tang Song
• Zhu Yizhong
• Liu Limin
• Gu Hongmei
• Yang Ling

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title