Heterocyclic compounds as RET kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11548896-B2
Application number	US-202117165151-A
Country	US
Kind code	B2
Filing date	Feb 2, 2021
Priority date	Apr 15, 2016
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present invention relates to compounds of Formula I that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity: wherein HET, bonds a, b, c and d, X 1 , X 2 , X 3 , X 4 , R 2 , and R 3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.

First claim

The invention claimed is:

1. A compound of Formula Ig:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CH;
X 2 is CR k ;
R k is hydrogen or halo;
X 3 is N or CH;
R o is halo or (1-4C)alkyl;
R 1 is (1-4C)haloalkyl, (1-6C)alkyl, (3-10C)cycloalkyl, or 4-7 membered heterocyclyl, each of which is optionally substituted by one or more substituents independently selected from (1-4C)alkyl and C(O)OR c ;
each R c is independently (1-6C)alkyl;
R 2 is hydrogen or (1-4C)alkyl;
R y is hydrogen;
Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, phenyl, (3-8C)cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered-heterocyclyl,
wherein Q 3 is optionally substituted by one or more substituents independently selected from halo and OR z , or Q 3 is optionally substituted by a group of the formula -L 4 -L Q4 -Z 4 ;

each R z is independently hydrogen or (1-4C)alkyl;
L 4 is absent or (1-3C)alkylene;
L Q4 is absent or is O; and
Z 4 is hydrogen, (1-6C)alkyl, phenyl, or 5-6 membered heteroaryl,
wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, (1-4C)alkoxy, and halo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R k is hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R k is Cl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 3 is N.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 3 is CH.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R o is halo.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R o is chloro, bromo, or fluoro.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R o is chloro.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R o is (1-4C)alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is (1-6C)alkyl or (3-6C)cycloalkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 1 is (4-6C)alkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is tert-butyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (1-4C)alkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Q 3 is (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, or 5-6 membered heteroaryl,
wherein Q 3 is optionally substituted by one or more substituents independently selected from halo and OR z ; and

R z is hydrogen or (1-2C)alkyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Q 3 is (1-6C)alkyl, (1-6C)alkoxy, phenyl, (3-8C)cycloalkyl, or 5-6 membered heteroaryl,
wherein Q 3 is optionally substituted by a group of the formula -L 4 -L Q4 -Z 4 ;

L 4 is absent or (1-3C)alkylene;
L Q4 is absent or is O; and
Z 4 is hydrogen, (1-6C)alkyl, phenyl, or 5-6 membered heteroaryl,
wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl and halo.

17. A compound, or a pharmaceutically acceptable salt thereof, which is selected from:

18. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 17 , which is:

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

25. A pharmaceutical composition comprising the compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

26. A method for treatment of cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the subject.

27. The method according to claim 26 , wherein the cancer is leukemia, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, medullary thyroid cancer, or non-small cell lung cancer.

28. The method according to claim 26 , wherein the cancer comprises a RET mutation.

29. The method according to claim 28 , wherein the RET mutation is a RET fusion translocation, optionally wherein the RET fusion translocation is KIF5B-RET or CCDC6-RET.

30. The method according to claim 28 , wherein the RET mutation is a mutation at the RET gatekeeper residue V804, optionally wherein the mutation at the RET gatekeeper residue V804 is RET V804M .

Assignees

• Cancer Research Tech Ltd

Inventors

• Jordan Allan Michael
• Newton Rebecca
• Waszkowycz Bohdan
• Sutton Jonathan Mark
• Hynd George
• Paoletta Silvia
• Fordyce Euan Alexander Fraser

Classifications

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title