Nitrogen-containing heterocyclic compounds, processes for their preparation and their use in medicine

Abstract

Disclosed are nitrogen-containing heterocyclic compounds, a preparation method therefor, and medical applications thereof. Specifically, disclosed are nitrogen-containing heterocyclic compounds represented by general formula (I), a preparation method therefor, pharmaceutical compositions containing the compounds, and uses of the compounds as therapeutic agents, particularly as FGFR2 inhibitors and in the preparation of drugs for treating and / or preventing tumors.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: X is selected from -NR 5 -; Y 1 Y 2 and Y 3 Each independently for CR 4 ; Z 1 Selected from nitrogen atoms; Z 2 For carbon atoms, Z 3 For NR 0 And Z 4 It consists of carbon atoms; Ring A is selected from 6- to 10-membered aryl and 5- to 10-membered heteroaryl; Ring B is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 0 Selected from hydrogen atoms, C 1-6 Alkyl groups, 3- to 12-membered cycloalkyl groups, and 3- to 12-membered heterocyclic groups; Each R 1 The same or different, and each independently is -L 2 -R 2 ; L 1 Selected from -O- and -C(O)-; L 2 Selected from chemical bonds, -NR 5a -C(O)- and -C(O)-NR 5a -; R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, , 3 to 12-membered cycloalkyl groups and 3 to 12-membered heterocyclic groups; R 11 R 12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, -C(O)NR 6 R 7 -C(O)R 10 -C(O)OR 10 -C(O)-N(R) 5b )-OR 10 , cyano, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, -NR 8 R 9 hydroxyl group, C 1-6 The substituent is one or more of the following: hydroxyalkyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Each R 3 The same or different, and each independently selected from C 1-6 Alkyl, halogen, cyano, oxo, -NR 6 R 7 -C(O)NR 6 R 7 -C(O)R 10 -C(O)OR 10 -OC(O)R 10 -OR 10 -S(O) p R 10 -S(O) p NR 6 R 7 , 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, -NR 8 R 9 hydroxyl group, C 1-6 The substituent is one or more of the following: hydroxyalkyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R 4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, cyano, -NR 6 R 7 -C(O)NR 6 R 7 -C(O)R 10 -C(O)OR 10 -OC(O)R 10 -OR 10 -S(O) p R 10 -S(O) p NR 6 R 7 , 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, -NR 8 R 9 hydroxyl group, C 1-6 The substituent is one or more of the following: hydroxyalkyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R 5 R 5a and R 5b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; R 6 R 7 R 8 and R 9 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 hydroxyalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; R 10 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 hydroxyalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; p is 0, 1, or 2; m is 1 or 2; s is 0, 1, 2, 3, 4, or 5; and t can be 0, 1, 2, 3, 4 or 5.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-membered heteroaryl group.

3. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is the compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: Each R 1a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy and cyano groups; s1 can be 0, 1, 2, 3 or 4.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a hydrogen atom.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 For chemical bonds or -NR 5a -C(O)-.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 For -NR 5a -C(O)-.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IIIN) or a pharmaceutically acceptable salt thereof is: in: Each R 1a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy and cyano groups; R 4a and R 4b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, halogen, cyano, -NR 6 R 7 -C(O)NR 6 R 7 -C(O)R 10 -C(O)OR 10 and -OR 10 The C mentioned therein 1-6 Alkyl groups are optionally selected from halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, -NR 8 R 9 hydroxyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; s1 can be 0, 1, 2, 3 or 4; m is 1 or 2.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidinyl.

10. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl.

11. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

12. The compound of general formula (I) according to claim 1, 3 or 8, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl.

13. The compound of formula (I) according to claim 1, 3 or 8, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 3- to 6-membered heterocyclic groups, phenyl groups and 5- or 6-membered heteroaryl groups.

14. The compound of general formula (I) according to claim 1, 3 or 8, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyridinyl, pyrimidinyl and tetrahydropyrroleyl.

15. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, and .

16. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from and .

17. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 11 R 12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

18. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, cyano groups, oxo groups, and -NR 6 R 7 And t is 0, 1 or 2.

19. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R 3 The same or different, and each independently selected from C 1-6 alkyl.

20. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 0 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

21. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 0 C 1-6 alkyl.

22. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y 1 For CR 4 And R 4 It can be a hydrogen atom or a halogen.

23. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L 1 It is -C(O)-.

24. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L 1 It is -O-.

25. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein each R 1a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

26. The compound of formula (I) according to claim 3 or 8, or a pharmaceutically acceptable salt thereof, wherein each R 1a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Alkyl group.

27. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, cyano groups and -NR 6 R 7 .

28. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b It is a hydrogen atom.

29. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

30. A compound of general formula (Ia) or a salt thereof, in: W is a halogen; Rings B, X, Z 1 To Z 4 L 1 Y 1 To Y 3 R 3 m and t are as defined in claim 1.

31. The compound or a salt thereof according to claim 30, wherein W is iodine.

32. A compound or a salt thereof, selected from: , , , , , , , , , , , , and .

33. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: A compound of general formula (Ia) or a salt thereof undergoes a coupling reaction with a compound of general formula (X) to give a compound of general formula (I) or a pharmaceutically usable salt thereof; in: W is a halogen; L is or R is a hydrogen atom or C 1-6 alkyl; Ring A, Ring B, X, Z 1 To Z 4 L 1 Y 1 To Y 3 R 1 R 3 m, s, and t are as defined in claim 1.

34. The method of claim 33, wherein W is iodine.

35. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, and one or more pharmaceutically acceptable carriers, diluents or excipients.

36. Use of the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 35 in the preparation of a medicament for inhibiting FGFR2.

37. Use of the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 35 in the preparation of a medicament for the treatment and / or prevention of gastric cancer.

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