Tricyclic compounds acting on crbn proteins

Patent metadata

Field	Value
Publication number	US-2022119376-A1
Application number	US-201917273997-A
Country	US
Kind code	A1
Filing date	Sep 9, 2019
Priority date	Sep 7, 2018
Publication date	Apr 21, 2022
Grant date	—

Abstract

The present invention discloses a series of tricyclic compounds and use thereof in preparing a medicament for treating a disease related to CRBN protein. Specifically, the present invention discloses a derivative compound of formula (I) or a pharmaceutically acceptable salt thereof.

First claim

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

wherein,
n is selected from the group consisting of 0, 1, 2 and 3;
each R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl,

—S(═O) 2 NH 2 , —NHS(═O) 2 —C 1-6 alkyl, —N[S(═O) 2 —C 1-6 alkyl] 2 , —N[C(═O)—C 1-6 alkyl] 2 , —NHC(═O)—C 1-6 alkyl and —C(═O)NH 2 , wherein the OH, NH 2 , C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl,

—S(═O) 2 NH 2 , —NHS(═O) 2 —C 1-6 alkyl, —N[S(═O) 2 —C 1-6 alkyl] 2 , —N[C(═O)—C 1-6 alkyl] 2 , —NHC(═O)—C 1-6 alkyl and —C(═O)NH 2 are optionally substituted with 1, 2 or 3 R a ;
ring A is selected from the group consisting of 5-6 membered heteroaryl, phenyl, C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkenyl;
ring B is selected from the group consisting of 5-6 membered heteroaryl and phenyl;
each R a is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylamino, —C(═O)NH—C 1-10 alkyl, —NHC(═O)—C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylamino and 4-10 membered heterocycloalkyl substituted with one carbonyl, wherein the OH, NH 2 , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylamino, —C(═O)NH—C 1-10 alkyl, —NHC(═O)—C 1-10 alkyl, —COOC 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, 4-10 membered heterocycloalkyl and 4-10 membered heterocycloalkylamino are optionally substituted with 1, 2 or 3 R;
each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl, —C(═O)—C 1-3 alkyl, —C(═O)O—C 1-6 alkyl, —S(═O) 2 —C 1-3 alkyl,

the 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylamino, 4-7 membered heterocycloalkenyl and 4-10 membered heterocycloalkyl substituted with one carbonyl each contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of —NH—, —O—, —S— and N.

2 . (canceled)

3 . The compound according to claim 1 , wherein ring A is selected from the group consisting of 5-6 membered heteroaryl, phenyl and 4-7 membered heterocycloalkenyl; or each R a is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, —C(═O)NH—C 1-6 alkyl, —NHC(═O)—C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylamino, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylamino and 4-10 membered heterocycloalkyl substituted with one carbonyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, —C(═O)NH—C 1-6 alkyl, —NHC(═O)—C 1-6 alkyl, —COOC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylamino, 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkylamino are optionally substituted with 1, 2 or 3 R.

4 . The compound according to claim 1 , wherein each R a is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , —CH 2 —, —CH 2 CH 2 —,

wherein the —CH 2 —, —CH 2 CH 2 —,

are optionally substituted with 1, 2 or 3 R.

5 . The compound according to claim 1 , wherein each R a is independently selected from the group consisting of F, Cl, Br, I, Me, OH, NH 2 ,

—C(═O)NHCH 3 , —NHC(═O)CH 3 , —CH 2 COOt-Bu,

6 . The compound according to claim 1 , wherein each R is independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, —C(═O)—C 1-3 alkyl, C 3-5 cycloalkyl, —C(═O)O—C 1-4 alkyl, —S(═O) 2 —C 1-3 alkyl,

7 . The compound according to claim 1 , wherein each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , —CH 2 —, —CH 2 CH 2 —,

8 . The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 3-5 cycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 2-4 alkenyl,

—S(═O) 2 NH 2 , —S(═O) 2 NH—C 1-3 alkyl, —NHS(═O) 2 —C 1-3 alkyl, —N[S(═O) 2 —C 1-3 alkyl] 2 , —N[C(═O)—C 1-3 alkyl] 2 , —NHC(═O)—C 1-3 alkyl, —C(═O)NH 2 and —C(═O)NH—C 1-3 alkyl, wherein the C 1-3 alkyl, C 3-5 cycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 2-4 alkenyl,

—S(═O) 2 NH 2 , —S(═O) 2 NH—C 1-3 alkyl, —NHS(═O) 2 —C 1-3 alkyl, —N[S(═O) 2 —C 1-3 alkyl] 2 , —N[C(═O)—C 1-3 alkyl] 2 , —NHC(═O)—C 1-3 alkyl, —C(═O)NH 2 and —C(═O)NH—C 1-3 alkyl are optionally substituted with 1, 2 or 3 R a .

9 . The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and —C(═O)NH 2 , wherein the C 1-3 alkyl, C 1-3 alkoxy and —C(═O)NH 2 are optionally substituted with 1, 2 or 3 R a .

10 . The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a .

11 . The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me,

—S(═O) 2 NH 2 ,

—NHCH 3 and —C(═O)NH 2 , wherein the Me,

—S(═O) 2 NH 2 ,

—NHCH 3 and —C(═O)NH 2 are optionally substituted with 1, 2 or 3 R a .

12 . The compound according to claim 1 , wherein ring A is selected from the group consisting of 5-6 membered heteroaryl, phenyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkenyl.

13 . The compound according to claim 1 , wherein ring A is selected from the group consisting of phenyl, 1,3-dioxolanyl, morpholinyl, oxazolyl, cyclobutyl, oxapanyl, thiazolyl, tetrahydrothiazolyl, furanyl, 1,4-oxazep

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Medshine Discovery Inc

Inventors

• Lei Maoyi
• Luo Yunfu
• Xu Yu
• Zhang Guoli
• Yu Zhijuan
• Li Jian
• Chen Shuhui

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/04

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/02

  specific for leukemia · CPC title