Iminosulfanone compound as bromodomain protein inhibitor and pharmaceutical composition and medical use thereof

Patent metadata

Field	Value
Publication number	US-12030880-B2
Application number	US-201917262053-A
Country	US
Kind code	B2
Filing date	Jul 25, 2019
Priority date	Jul 25, 2018
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

The present invention relates to a iminosulfanone compound represented by formula (I) as a bromodomain protein inhibitor and a pharmaceutically acceptable salt thereof and to a preparation method, pharmaceutical composition, and medical use thereof.

First claim

What is claimed is:

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

wherein,
R 1 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 acyl, the C 1 -C 3 alkyl or C 1 -C 3 acyl is optionally substituted with one or more halogens;
Y is selected from the group consisting of O, S, and NR Y , the R Y is selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 acyl, the C 1 -C 3 alkyl or C 1 -C 3 acyl is optionally substituted with one or more halogens;
X 1 is selected from the group consisting of N and CR X1 , the R X1 is selected from the group consisting of H, C 1 -C 6 alkyl, halogen, and C 1 -C 6 haloalkyl;
X 2 is selected from the group consisting of N and CR X2 , and X 3 is selected from the group consisting of N and CR X3 , the R X2 and R X3 are each independently selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OR a , —C(O)NR b R c , —C(O)R d , —S(O) 2 R e , and —S(O) 2 NR b R c , the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more halogen, hydroxyl, amino, nitro, or cyano;
Z 1 is N, Z 2 is selected from the group consisting of N and CR Z2 , and Z 3 is selected from the group consisting of N and CR Z3 , the R Z2 , and R Z3 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, and nitro, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more halogens, hydroxyl, amino, nitro, or cyano; or
Z 1 is selected from the group consisting of N and CR Z1 , Z 2 is N, and Z 3 is selected from the group consisting of N and CR Z3 , the R Z1 and R Z3 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, and nitro, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more halogens, hydroxyl, amino, nitro, or cyano; or
Z 1 is selected from the group consisting of N and CR Z1 , Z 2 is selected from the group consisting of N and CR Z2 , and Z 3 is N, the R Z1 and R Z2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, and nitro, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more halogens, hydroxyl, amino, nitro, or cyano;
R 2 and R 3 are each independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, and (C 1 -C 6 alkyl) 2 amino, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or (C 1 -C 6 alkyl) 2 amino is optionally substituted with one or more halogens, hydroxyl, amino, nitro, or cyano; or
R 2 and R 3 are connected and form a 3-8 membered heterocycloalkyl together with an adjacent S atom, the 3-8 membered heterocycloalkyl optionally contains 1-3 heteroatoms selected from the group consisting of N, O, and S, in addition to the S atom to which R 2 and R 3 are both connected; and the ring carbon atoms of the 3-8 membered heterocycloalkyl are optionally substituted with one or more halogens, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or (C 1 -C 6 alkyl) 2 amino, or substituted with one or more oxo;
L is selected from the group consisting of a single bond, —O—, —NH—, —(C 1 -C 3 alkyl)-O—, —(C 1 -C 3 alkyl)-NH—, and —C 1 -C 3 alkyl-; and
R 4 is selected from the group consisting of C 6 -C 10 aryl, C 3 -C 10 cycloalkenyl, C 3 -C 10 cycloalkyl, 3-10 membered heteroaryl, 3-10 membered heterocycloalkenyl, and 3-10 membered heterocycloalkyl, the 3-10 membered heteroaryl, 3-10 membered heterocycloalkenyl, or 3-10 membered heterocycloalkyl each independently contains 1-3 heteroatoms selected from the group consisting of N, O, and S; and R 4 is optionally substituted with one or more halogens, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, (C 1 -C 6 alkyl) 2 amino, —C(O)OR a , —C(O)NR b R c , —C(O)R d , —S(O) 2 R e , —NHS(O) 2 R e , or —S(O) 2 NR b R c , or substituted with one or more oxo;
the R a , R b , R c , R d , and R e are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.

2. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of H and C 1 -C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with one or more F, Cl, or Br.

3. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein Y is NR Y , the R Y is selected from the group consisting of H and C 1 -C 3 alkyl, the C 1 -C 3 alkyl is optionally substituted with one or more F, Cl, or Br.

4. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is CR X1 , the R X1 is selected from the group consisting of H, C 1 -C 4 alkyl, F, Cl, Br, and C 1 -C 4 alkyl substituted with F, Cl, or Br.

5. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 2 is CR X2 , the R X2 is selected from the group consisting of H, —C(O)OR a , and —C(O)NR b R c .

6. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 3 is CR X3 , the R 13 is selected from the group consisting of H and C 1 -C 4 alkyl, the C 1 -C 4 alkyl is optionally substituted with one or more F, Cl, Br, hydroxyl, amino, nitro, or cyano.

7. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the R Z1 is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, cyano, and nitro, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is optionally substituted with one or more halogen, hydroxyl, amino, nitro, or cyano.

8. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the R Z2 is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, cyano, and nitro, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is optionally substituted with one or more F, Cl, Br, hydroxyl, amino, nitro, or cyano.

9. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the R Z3 is selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, cyano, and nitro, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is optionally substituted with one or more F, Cl, Br, hydroxyl, amino, nitro, or cyano.

10. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, and (C 1 -C 4 alkyl) 2 amino, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, or (C 1 -C 4 alkyl) 2 amino is optionally substituted with one or more F, Cl, Br, hydroxyl, amino, nitro, or cyano; or R 2 an

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Shouyao Holdings Beijing Co Ltd
• Lianyungang Runzhong Pharmaceutical Co Ltd

Inventors

• Li Jijun
• Zhu Yan
• Wang Yeliu
• Shang Xianxing
• Wang Huting
• He Weinan
• Yan Qin
• Sun Yinghui
• Zhang Kai
• Lu Chang
• Xu Hongjiang
• Tian Xin
• Yang Ling

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title