SMAC mimetics used as IAP inhibitors and use thereof

Patent metadata

Field	Value
Publication number	US-11358950-B2
Application number	US-201816763746-A
Country	US
Kind code	B2
Filing date	Nov 13, 2018
Priority date	Nov 13, 2017
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Disclosed are a class of SMAC mimetics used as IAP inhibitors, and in particular disclosed are compounds as shown in formula (I), isomers thereof, and pharmaceutically acceptable salts thereof. The IAP inhibitors are drugs for treating cancers, in particular breast cancer.

First claim

What is claimed is:

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

wherein,
X 1 is C(R 5 ) or N;
X 2 is C(R 6 ), N, O, or S;
are each independently a single bond or a double bond;
L is a single bond or —O—;
R 1 is —C(═O)NH 2 , CN, C 1-5 alkyl, C 1-5 heteroalkyl, phenyl, 5-to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl; said C 1-5 alkyl, C 1-5 heteroalkyl, phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
R 2 is H, halogen, CN, COOH, —C(═O)NH 2 , C 1-4 alkyl, or C 1-4 heteroalkyl; said C 1-4 alkyl or C 1-4 heteroalkyl is optionally substituted with 1, 2 or 3 R;
R 3 and R 7 are each independently H, halogen or C 1-4 alkyl; said C 1-4 alkyl is optionally substituted with 1, 2 or 3 R;
R 4 is H, phenyl, or 5- to 6-membered heteroaryl;
R 5 is H or halogen;
R 6 is H, halogen, C 1-4 alkyl, C 1-4 heteroalkyl, CN, or COOH; said C 1-4 alkyl or C 1-4 heteroalkyl is optionally substituted with 1, 2 or 3 R;
R is 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, or NH 2 ; and
said 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 the group consisting of —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 compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of formula (I′):

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

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X 2 is C(R 6 ) or N.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is —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,

said 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,

is optionally substituted with 1, 2 or 3 R.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halogen, C 1-4 alkyl, or C 1-4 alkyl-O—; said C 1-4 alkyl or C 1-4 alkyl-O— is optionally substituted with 1, 2 or 3 halogens.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, Cl, Br, CF 3 , or OCF 3 .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 7 are each independently H, F, or Cl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is H or Cl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is H, Cl, or CH 3 .

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein a structural unit

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein a structural unit

is

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or (III):

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

15. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is a compound of formula (II′) or (III′):

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

16. A compound or a pharmaceutically acceptable salt thereof, which is

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, which is

18. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

19. A method for treating cancer, comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof;
wherein the cancer is breast cancer.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Chia Tai Tiangqing Pharmaceutical Group Co Ltd

Inventors

• Liu Yingchun
• Xu Zhaobing
• Hu Lihong
• Ding Charles Z
• Zhu Xingxun
• Hu Guoping
• Li Jian
• Chen Shuhui

Classifications

• C07K5/06026 Primary

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/05

  Dipeptides · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title