IMIDAZOPYRAZINE COMPOUNDS, PREPARATION METHODS AND USES THEREOF

• US 20190367524A1
• Filed: 01/15/2018
• Published: 12/05/2019
• Est. Priority Date: 01/16/2017
• Status: Active Grant

• Current Assignee: Dongguan Zhenxing Beite Medical Technology Co., Ltd.
• Original Assignee: Dongguan Zhenxing Beite Medical Technology Co., Ltd.
• Inventors: CAI, Xiong, ZHONG, Xianbin, YE, Chunqiang, HE, Qijie, QIN, Shifeng, QIAN, Changgeng
• Granted Patent: US 10,919,899 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Disclosed are an imidazopyrazine compound, a preparation method therefor and use thereof. Specifically, disclosed are a compound having a structure as represented by formula (I), a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof, and use of the compound, the pharmaceutically acceptable salt, the stereoisomer or the prodrug thereof in the preparation of a medicament. The medicament is used for preventing and/or treating diseases and/or conditions related to Bruton'"'"'s tyrosine kinase overactivity in a subject. Further disclosed is use of the compound, the pharmaceutically acceptable salt, the stereoisomer or the prodrug thereof in the preparation of a formulation. The formulation is used for reducing or inhibiting the activity of the Bruton'"'"'s tyrosine kinase in cells.

Claims

1. A compound having a structure as represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug thereof:

2. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein X₁, X₂, X₃ and X₄ are each selected from C(R₂);

or, one of X₁, X₂, X₃ and X₄ is N and the remaining are each selected from C(R₂).

3. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein the compound has a structure as represented by formula (II):

4. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein W is selected from O, N(R₆) or S, R₆ is selected from H or C₁-C₆ alkyl;

Y is selected from C₁-C₆ alkylene.

5. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein n is 1 or 2;

a chiral carbon atom in

6. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein R₁ is selected from the following groups:

7. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein R₁ is

8. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein R₁ is

9. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein,

A is CH;

X₁, X₂, X₃ and X₄ are each CH;

or

X₁ is N, while X₂, X₃ and X₄ are each CH;

or

X₂ is N, while X₁, X₃ and X₄ are each CH;

or

X₃ is N, while X₁, X₂ and X₄ are each CH;

or

X₄ is N, while X₁, X₂ and X₃ are each CH;

W is O, N(R₆) or S, wherein R₆ is selected from H or C₁-C₃ alkyl;

Y is selected from C₁-C₃ alkylene;

n is 1;

R₁ is selected from

10. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein the compound has a structure as represented by formula (III):

11. The compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein the compound is selected from:

12. A pharmaceutical composition, comprising the compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the prodrug thereof.

13. Use of the compound of claim 1, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the prodrug thereof in the preparation of a drug, wherein the drug is used for preventing and/or treating a disease and/or a condition of a subject associated with overactivity of Bruton'"'"'s tyrosine kinase.

16. The compound of claim 2, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein X₁, X₂, X₃ and X₄ are each CH;

or, one of X₁, X₂, X₃ and X₄ is N and the remaining are each CH.

17. The compound of claim 3, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein X₅, X₆, X₇, X₈ and X₉ are each selected from C(R₇);

or, one of X₅, X₆, X₇, X₈ and X₉ is N and the remaining are each selected from C(R₇).

18. The compound of claim 3, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, or the prodrug thereof, wherein X₅, X₆, X₇, X₈ and X₉ are each CH;

or one of X₅, X₆, X₇, X₈ and X₉ is C(R₇), the remaining are each CH, and R₇ is selected from the group consisting of halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy and halogenated C₁-C₆ alkyl.

19. The use of claim 13, wherein the disease and/or the condition associated with overactivity of Bruton'"'"'s tyrosine kinase is selected from the group consisting of tumor, inflammation and autoimmune disease.

20. The use of claim 19, wherein the tumor is selected from the group consisting of lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia, lung cancer, breast cancer, prostate cancer, stomach cancer, liver cancer, pancreatic cancer, ovarian cancer and colon cancer;

the inflammation or the autoimmune disease is selected from the group consisting of rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren'"'"'s syndrome and underlying disease asthma.

14. (canceled)

15. (canceled)