Combination of iap inhibitor and immune checkpoint inhibitor

Patent metadata

Field	Value
Publication number	US-2022175917-A1
Application number	US-202017436991-A
Country	US
Kind code	A1
Filing date	Mar 6, 2020
Priority date	Mar 7, 2019
Publication date	Jun 9, 2022
Grant date	—

Abstract

The present invention relates to a combination of a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof which are used as an IAP inhibitor, and an immune checkpoint inhibitor; and use of the combination in the preparation of a cancer treatment drug.

First claim

What is claimed is:

1 . A combination, comprising a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor,

wherein,
X 1 is selected from C(R 5 ) and N;
X 2 is selected from C(R 6 ), N, O, and S;
is selected from a single bond and a double bond;
L is selected from a single bond and —O—;
R 1 is selected from —C(═O)NH 2 , CN, C 1-5 alkyl, C 1-5 heteroalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl; the C 1-5 alkyl, C 1-5 heteroalkyl, phenyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
R 2 is selected from H, halogen, CN, COOH, —C(═O)NH 2 , C 1-4 alkyl, and C 1-4 heteroalkyl; the C 1-4 alkyl and C 1-4 heteroalkyl are optionally substituted with 1, 2 or 3 R;
R 3 and R 7 are each independently selected from H, halogen and C 1-4 alkyl; the C 1-4 alkyl is optionally substituted with 1, 2 or 3 R;
R 4 is selected from H, phenyl, and 5- to 6-membered heteroaryl;
R 5 is selected from H and halogen;
R 6 is selected from H, halogen, C 1-4 alkyl, C 1-4 heteroalkyl, CN, and COOH; the C 1-4 alkyl and C 1-4 heteroalkyl are optionally substituted with 1, 2 or 3 R;
R is selected from halogen, OH, CN, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , CH(CH 3 ) 2 , OCH 3 , OCF 3 , CHF 2 , CH 2 F, and NH 2 ; and
the C 1-4 heteroalkyl, C 1-5 heteroalkyl, 5- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl each contain 1, 2 or 3 heteroatoms or heteroatom radicals independently selected from —NH—, —O—, —S—, N, —C(═O)O—, —C(═O)—, —C(═O)NH—, —C(═S)—, —S(═O)—, —S(═O) 2 —, —C(═NH)—, —S(═O) 2 NH—, —S(═O)NH—, and —NHC(═O)NH—.

2 . The combination according to claim 1 , wherein the compound represented by formula (I), is selected from

wherein , X 1 , X 2 , L, R 1 , R 2 , R 3 , R 4 and R 7 are as defined in claim 1 .

3 . (canceled)

4 . The combination according to claim 1 , wherein X 2 is selected from C(H), C(Cl), C(CH 3 ), and N.

5 . The combination according to claim 1 , wherein R 1 is selected from —C(═O)NH 2 , CN, CH 3 , CH 3 CH 2 , C 1-5 alkyl-C(═O)—, C 1-4 alkyl-C(═O)—, C 1-5 alkyl-S(═O) 2 —, C 1-5 alkyl-N(H)C(═O)—, C 1-4 alkyl-N(H)C(═O)—, (C 1-2 alkyl) 2 -N—C(═O)—, phenyl,

the CH 3 , CH 3 CH 2 , C 1-5 alkyl-C(═O)—, C 1-4 alkyl-C(═O)—, C 1-5 alkyl-S(═O) 2 —, C 1-5 alkyl-N(H)C(═O)—, C 1-4 alkyl-N(H)C(═O)—, (C 1-2 alkyl) 2 -N—C(═O)—, phenyl,

are optionally substituted with 1, 2 or 3 R.

6 . The combination according to claim 5 , wherein R 1 is selected from

7 . (canceled)

8 . The combination according to claim 1 , wherein R 2 is selected from H, F, Cl, Br, CF 3 , and OCF 3 .

9 . The combination according to claim 1 , wherein R 3 and R 7 are each independently selected from H, F, and Cl.

10 . The combination according to claim 1 , wherein R 4 is selected from H and

11 . The combination according to claim 1 , wherein R 5 is selected from H and Cl.

12 . The combination according to claim 1 , wherein R 6 is selected from H, Cl, and CH 3 .

13 . The combination according to claim 1 , wherein a structural unit

is selected from

14 . The combination according to claim 1 , wherein a structural unit

is selected from

15 . (canceled)

16 . The combination according to claim 2 or 15 , wherein the compound represented by formula (1) is selected from

wherein R 2 , R 3 and R 7 are as defined in claim 2 .

17 . The combination according to claim 1 , wherein the compound represented by formula (I) is selected from

18 . The combination according to claim 17 , wherein the compound represented by formula (I) is selected from

19 . The combination according to claim 1 , wherein the immune checkpoint inhibitor is selected from an anti-PD-1 antibody, an anti-PDL1-antibody, and an anti-CTLA-4 antibody.

20 . A method for treating cancer, comprising administering an effect amount of the combination according to claim 1 to a subject in need thereof.

21 . A combined pharmaceutical composition, comprising the combination according to claim 1 and a pharmaceutically acceptable excipient.

22 . A kit, comprising the combined pharmaceutical composition according to claim 21 and instructions for use of a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor in the treatment of cancer.

23 . A method for treating cancer, comprising administering an effective amount of the combined pharmaceut

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Liu Yingchun
• Xu Zhaobing
• Han Shuhua
• Hu Lihong
• Ding Charles Z
• Xia Yuanfeng
• Tong Haijun
• He Lihua
• Tian Xin

Classifications

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title