Imidazopyrazine compounds, preparation methods and uses thereof
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.
1. A compound having a structure as represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof:
wherein,
A is selected from CH or N;
n is 0, 1, 2, or 3;
R 1 is selected from the following groups:
wherein R 3 and R 4 are each independently selected from H and C 1 -C 6 alkyl;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl substituted with C 1 -C 3 alkoxy, C 1 -C 4 alkyl substituted with amino, C 1 -C 4 alkyl substituted with C 1 -C 3 alkyl amino, C 1 -C 4 alkyl substituted with di(C 1 -C 3 alkyl) amino, and C 1 -C 4 alkyl substituted with heterocyclic group;
X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of C(R 2 ) and N;
R 2 is selected from the group consisting of H, halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogenated C 1 -C 6 alkyl;
W and Y are each independently selected from the group consisting of O, N(R 6 ), S and C 1 -C 6 alkylene, and at least one of W and Y is selected from C 1 -C 6 alkylene;
R 6 is selected from H or C 1 -C 6 alkyl; and
Ar is selected from phenyl or 5 to 6 membered heteroaryl, optionally, the phenyl or 5 to 6 membered heteroaryl is substituted with a group selected from the group consisting of halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogenated C 1 -C 6 alkyl.
2. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein X 1 , X 2 , X 3 and X 4 are each selected from C(R 2 ); or, one of X 1 , X 2 , X 3 and X 4 is N and the remaining are each selected from C(R 2 ).
3. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein the compound has a structure as represented by formula (II):
wherein X 5 , X 6 , X 7 , X 8 and X 9 are each independently selected from C(R 7 ) or N;
R 7 is selected from the group consisting of H, halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogenated C 1 -C 6 alkyl.
4. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein W is selected from O, N(R 6 ) or S, R 6 is selected from H or C 1 -C 6 alkyl; Y is selected from C 1 -C 6 alkylene.
5. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein n is 1 or 2;
a chiral carbon atom in
is of a sinister configuration.
6. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein R 1 is selected from the following groups:
7. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein R 1 is
R 3 is H;
R 4 is H;
preferably, R 5 is selected from the group consisting of H, C 1 -C 4 alkyl substituted with C 1 -C 3 alkoxy, C 1 -C 4 alkyl substituted with di(C 1 -C 3 alkyl) amino, and C 1 -C 4 alkyl substituted with 5 to 6 membered saturated nitrogen-contaning heterocyclic group.
8. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein R 1 is
R 5 is selected from the group consisting of H, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl.
9. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein,
A is CH;
X 1 , X 2 , X 3 and X 4 are each CH; or
X 1 is N, while X 2 , X 3 and X 4 are each CH; or
X 2 is N, while X 1 , X 3 and X 4 are each CH; or
X 3 is N, while X 1 , X 2 and X 4 are each CH; or
X 4 is N, while X 1 , X 2 and X 3 are each CH;
W is O, N(R 6 ) or S, wherein R 6 is selected from H or C 1 -C 3 alkyl;
Y is selected from C 1 -C 3 alkylene;
n is 1;
R 1 is selected from
wherein R 3 is H;
R 4 is H;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl substituted with C 1 -C 3 alkoxy, C 1 -C 4 alkyl substituted with C 1 -C 3 alkyl amino, C 1 -C 4 alkyl substituted with di(C 1 -C 3 alkyl) amino, and C 1 -C 4 alkyl substituted with 5 to 6 membered saturated nitrogen-contaning heterocyclic group;
Ar is selected from phenyl or 6 membered nitrogen-containing heteroaryl, optionally, the phenyl or 6 membered nitrogen-containing heteroaryl is substituted with a group selected from the group consisting of halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogenated C 1 -C 6 alkyl.
10. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein the compound has a structure as represented by formula (III):
wherein X 1 is CH or N;
W is selected from O, S and N(R 6 ), R 6 is selected from H or methyl;
Y is selected from the group consisting of methylene, 1,1-ethylidene and 1,2-ethylidene;
X 6 and X 7 are each independently selected from C(R 7 ), wherein R 7 is selected from the group consisting of H, F, trifluoromethyl and methoxyl;
X 9 is selected from CH or N;
R 1 is
wherein R 3 is H, R 4 is H, and R 5 is selected from the group consisting of H, methyl substituted with methoxyl, methyl substituted with dimethyl amino, and methyl substituted with piperidyl; or
R 1 is
wherein R 5 is selected from the group consisting of H, methyl, ethyl, isopropyl and cyclopropyl; or
R 1 is
wherein R 3 , R 4 and R 5 are each H.
11. The compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein the compound is selected from the group consisting of:
12. A pharmaceutical composition, comprising the compound of claim 1 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof.
13. A method for treating a disease in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 12 , wherein the disease is tumor, inflammation, or autoimmune disease, and the tumor, the inflammation, or the autoimmune disease is treated by inhibition of BTK.
14. The compound of claim 2 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein X 1 , X 2 , X 3 and X 4 are each CH; or, one of X 1 , X 2 , X 3 and X 4 is N and the remaining are each CH.
15. The compound of claim 3 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein X 5 , X 6 , X 7 , X 8 and X 9 are each selected from C(R 7 ); or, one of X 5 , X 6 , X 7 , X 8 and X 9 is N and the remaining are each selected from C(R 7 ).
16. The compound of claim 3 , the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein X 5 , X 6 , X 7 , X 8 and X 9 are each CH; or one of X 5 , X 6 , X 7 , X 8 and X 9 is C(R 7 ), the remaining are each CH, and R 7 is selected from the group consisting of halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkyl.
17. The method of claim 13 , wherein the disease is selected from the group consisting of B-cell Non-Hodgkin's lymphoma, primary macroglobulinemia, multiple myeloma, hairy cell leukemia, rheumatoid arthritis, lupus nephritis, and Sjogren's syndrome.
18. The method of claim 17 , wherein the B-cell Non-Hodgkin's lymphoma is selected from the group consisting of refractory mantle cell lymphoma, chronic lymphocytic leukemia, and diffuse large B cell lymphoma.
19. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition is a BTK inhibitor.