Substituted pyrazoles as inhibitors of fibroblast growth factor receptor

Patent metadata

Field	Value
Publication number	US-10214515-B2
Application number	US-201615741639-A
Country	US
Kind code	B2
Filing date	Aug 19, 2016
Priority date	Aug 20, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

An indole derivative as expressed by Formula (I), a preparation method thereof, a pharmaceutical salt, and use thereof as a therapeutic agent, especially as a FGFR inhibitor. Each substituent in Formula (I) has identical definition as specified in the specification.

First claim

The invention claimed is:

1. A compound represented by formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
wherein:
D is selected from N or CR 3 ;
each R 1 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR 4 R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —OC(O)R 6 , —C(O)OR 6 and —NR 4 C(O)R 5 , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR 4 R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —OC(O)R 6 , —C(O)OR 6 and —NR 4 C(O)R 5 ;
each R 2 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halogen, nitro, cyano, cycloalkyl, heterocyclyl, —NR 4 R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —OC(O)R 6 , —C(O)OR 6 and —NR 4 C(O)R 5 , wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR 4 R 5 , —C(O)NR 4 R 5 , —C(O)R 6 , —OC(O)R 6 , —C(O)OR 6 and —NR 4 C(O)R 5 ;
R 3 is selected from the group consisting of cycloalkyl, cyano, —NR 4 R 5 , —C(O)OR 6 , —OC(O)R 6 , —NR 4 C(O)R 5 and —C(O)NR 4 R 5 , wherein the cycloalkyl is optionally further substituted with one or more halogens;
R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, sodium, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 and —NR 7 C(O)R 8 ; or
R 4 and R 5 , together with the attached nitrogen atom, form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl contains one or more atoms selected from the group consisting of N, O and S(O) p , and the 4- to 8-membered heterocyclyl is further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 and —NR 7 C(O)R 8 ;
R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and carboxylate;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2 or 3; and
p is 0, 1 or 2.

2. The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of hydrogen and alkyl.

3. The compound according to claim 1 , wherein each R 1 is independently halogen.

4. The compound according to claim 3 , wherein each R 1 is independently selected from F, Cl or Br.

5. The compound according to claim 1 , wherein each R 1 is independently heteroaryl, wherein the heteroaryl is optionally further substituted by one or more alkyl substituents.

6. The compound according to claim 5 , wherein each R 1 is independently pyrazolyl.

7. The compound according to claim 5 , wherein the heteroaryl is optionally further substituted with one or more ethyl substituents.

8. The compound according to claim 1 , wherein each R 2 is independently selected from the group consisting of hydrogen and alkyl.

9. The compound according to claim 1 , wherein D is CR 3 .

10. The compound according to claim 9 , wherein:
each R 1 is independently hydrogen;
each R 2 is independently hydrogen; and
R 3 is cycloalkyl, wherein the cycloalkyl is optionally further substituted with one or more halogens.

11. The compound according to claim 10 , wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl and cyclopentyl.

12. The compound according to claim 10 , wherein R 3 is cyclopropyl.

13. The compound according to claim 9 , wherein:
each R 1 is independently selected from the group consisting of halogen, cyano, cycloalkyl, heterocyclyl and heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl and alkoxy;
each R 2 is independently hydrogen; and
R 3 is cycloalkyl, wherein the cycloalkyl is optionally further substituted with one or more halogens.

14. The compound according to claim 13 , wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl and cyclopentyl.

15. The compound according to claim 9 , wherein:
each R 1 is independently hydrogen;
each R 2 is independently hydrogen;
R 3 is —C(O)OR 6 ; and
R 6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and butyl.

16. The compound according to claim 15 , wherein R 6 is methyl or ethyl.

17. The compound according to claim 9 , wherein:
each R 1 is independently hydrogen;
each R 2 is independently hydrogen; and
R 3 is selected from the group consisting of —NR 4 R 5 , —C(O)OR 6 , —NR 4 C(O)R 5 and —C(O)NR 4 R 5 .

18. The compound according to claim 1 , wherein:
m is 0, 1 or 2; and
n is 0, 1 or 2.

19. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

20. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient, or a combination thereof.

21. A method for inhibiting fibroblast growth factor receptor in vitro, comprising contacting the receptor with the compound according to claim 1 , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

22. The method according to claim 21 , wherein the fibroblast growth factor receptor is selected from the group consisting of FGFR1, FGFR2 and FGFR3.

23. A method for inhibiting fibroblast growth factor receptor in vitro, comprising contacting the receptor with the pharmaceutical composition according to claim 20 .

24. A method for inhibiting fibroblast growth factor receptor activity in a patient, comprising administering to the patient an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, tautomer or stereoisomer.

25. The method according to claim 24 , wherein the patient has cancer.

26. The method according to claim 25 , wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, multiple myeloma, bladder cancer and liver

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Chen Lei
• Guan Dongliang
• Bai Hua
• Yan Xing
• Miao Shuai
• Zhu Songsong

Classifications

• C07D233/06

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms · CPC title

• C07D233/46

  with only hydrogen atoms attached to said nitrogen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D233/28

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title