Azetidine derivative, preparation method therefor, and use thereof

Patent metadata

Field	Value
Publication number	US-10159662-B2
Application number	US-201615767508-A
Country	US
Kind code	B2
Filing date	Dec 8, 2016
Priority date	Dec 11, 2015
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The present invention relates to an azetidine derivative for use as a Janus kinase (JAK) inhibitor, a drug composition comprising same, a preparation method therefor, and a use thereof in the treatment of JAK-related diseases comprising, for example, inflammatory diseases, autoimmune diseases, and cancers.

First claim

What is claimed is:

1. A compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:

wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, C(O)R 10 , and S(O) 2 R 11 ;
R 2 and R 3 are each independently selected from the group consisting of H, CN, halogen, and C 1-6 alkyl;
R 4 and R 5 are each independently selected from group consisting of H, halogen, and CN;
X is CR 6 ;
Y is selected from the group consisting of N and CR 9 ;
Z is selected from the group consisting of N and CR 7 ;
W is selected from the group consisting of N and CR 8 ;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxyl, and C(O)NR 12 R 13 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 ;
R 12 and R 13 are each independently selected from the group consisting of H and C 1-6 alkyl;
wherein the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof, wherein the compound is a compound of Formula II:

3. The compound according to claim 2 , or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof, wherein the compound is a compound of Formula IV:

wherein:
R 1 is selected from the group consisting of C(O)R 10 and S(O) 2 R 11 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl.

4. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof, wherein the compound is a compound of Formula V:

5. The compound according to claim 4 , or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof, wherein the compound is a compound of Formula VI:

6. A compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof, wherein the compound is selected from the group consisting of:

7. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 and one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 7 , wherein the therapeutically effective amount is a range of about 0.01 mg to about 1000 mg.

9. The pharmaceutical composition according to claim 7 , further comprising one or more additional drugs.

10. The pharmaceutical composition according to claim 9 , wherein the additional drug(s) is one or more selected from the group consisting of efalizumab, mycophenolate sodium, etanercept, and methotrexate.

11. A method for the treatment of a JAK-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 1 , wherein the JAK-related disease is rheumatoid arthritis.

12. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 3 and one or more pharmaceutically acceptable carriers.

13. The pharmaceutical composition according to claim 12 , wherein the therapeutically effective amount is a range of about 0.01 mg to about 1000 mg.

14. The pharmaceutical composition according to claim 12 , further comprising one or more additional drugs.

15. The pharmaceutical composition according to claim 14 , wherein the additional drug(s) is one or more selected from the group consisting of efalizumab, mycophenolate sodium, etanercept, and methotrexate.

16. A method for the treatment of a JAK-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 3 , wherein the JAK-related disease is rheumatoid arthritis.

17. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 6 and one or more pharmaceutically acceptable carriers.

18. The pharmaceutical composition according to claim 17 , wherein the therapeutically effective amount is a range of about 0.01 mg to about 1000 mg.

19. The pharmaceutical composition according to claim 17 , further comprising one or more additional drugs.

20. The pharmaceutical composition according to claim 19 , wherein the additional drug(s) is one or more selected from the group consisting of efalizumab, mycophenolate sodium, etanercept, and methotrexate.

21. A method for the treatment of a JAK-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 6 , wherein the JAK-related disease is rheumatoid arthritis.

22. A method for the treatment of a JAK-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 7 , wherein the JAK-related disease is rheumatoid arthritis.

23. A method fo

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Xie Yinong
• You Zejin
• Deng Zhiwen
• Zhu Jun
• Wang Ao
• Feng Yan
• Long Dong
• Zeng Hong
• Song Hongmei
• Ye Qijun
• Qi Wei
• Su Donghai
• Wang Lichun
• Wang Jingyi

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title