EGFR kinase inhibitor and preparation method and use thereof
The present invention provides an EGFR kinase inhibitor and a preparation method and use thereof. Specifically, the present invention provides a compound as shown in formula (I), the definition of each group therein being as described in the description. Said compound is an efficient EGFR inhibitor.
1. A compound of the following formula (I):
wherein:
X, Y are each independently selected from the group consisting of N, CH; with the proviso that X and Y are not CH at the same time;
R is selected from the group consisting of: unsubstituted 5-7 membered heterocycles, 5-7 membered heterocycles substituted by 1-5 substituents, C1-C6 alkyl-(unsubstituted 5-7 membered heterocycles), C1-C6 alkyl-(5-7 membered heterocycles substituted by 1-5 substituents), —NH-(unsubstituted 5-7 membered heterocycles), —NH-(5-7 membered heterocycles substituted by 1-5 substituents), —N(CH 3 )-(unsubstituted 5-7 membered heterocycles), —N(CH 3 )-(5-7 membered heterocycles substituted by 1-5 substituents), wherein the heterocycle contains at least one heteroatom selected from the group consisting of N, O and S; the substitution means one or more hydrogen atoms on the group are replaced by R 1 substituents;
wherein the R 1 is selected from the group consisting of: unsubstituted or halogenated C1-C6 alkyl, C3-C8 cycloalkyl, unsubstituted or halogenated C1-C6 alkoxy, C3-C8 cycloalkyloxy, —C(O)—R 2 , C2-C8 alkylacyl, C2-C8 alkoxyacyl, —S(O) 2 —R 2 , —SOR 2 ;
the R 2 is selected from the group consisting of unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8cycloalkoxy, —CH 2 —OAc, —NH 2 , —NH(C1-C6 alkyl), —N(C1-C6 alkyl) 2 .
2. The compound of claim 1 , wherein X is N, and Y is CH.
3. The compound of claim 1 , wherein the R is selected from the group; consisting of
wherein the R 1 is selected from the group consisting of: unsubstituted or halogenated C1-C6 alkyl, C3-C8 cycloalkyl, unsubstituted or halogenated C1-C6 alkoxy, C3-C8 cycloalkyloxy, —C(O)—R 2 , —Boc, —S(O) 2 —R 2 , —CH 2 —OAc;
the R 2 is selected from the group consisting of unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, —CH 2 —OAc, —NH 2 , —NH (C1-C6 alkyl), —N(C1-C6 alkyl) 2 .
4. The compound of claim herein the compound of formula (I) is selected from the following group:
5. The compound of claim 1 , wherein the compound of formula (I) is selected from the following group:
6. A preparation method of the compound of claim 1 , wherein comprising the following step:
in an inert solvent, reacting compound of formula II with compound of formula 7, thus obtaining compound of formula I′:
wherein R′ is selected from the group consisting of:
unsubstituted 5-7 membered heterocycles,
5-7 membered heterocycles substituted by 1-5 substituents,
C1-C6 alkyl-(unsubstituted 5-7 membered heterocycles),
C1-C6 alkyl-(5-7 membered heterocycles substituted by 1-5 substituents),
—NH-(unsubstituted 5-7 membered heterocycles),
—NH-(5-7 membered heterocycles substituted by 1-5 substituents),
—N(CH 3 )-(unsubstituted 5-7 membered heterocycles), and
—N(CH 3 )-(5-7 membered heterocycles substituted by 1-5 substituents),
wherein the heterocycle contains at least one heteroatom selected from the group consisting of N, O and S; the substitution means one or more hydrogen atoms on the group are replaced by R 1 substituents;
while the remaining groups are defined as in claim 1 .
7. The preparation method of claim 6 , wherein comprising the following step:
in an inert solvent, reacting compound of formula III with compound of formula 5, thus obtaining compound of formula II;
wherein, R′ is as defined in claim 6 , and
wherein:
X, Y are each independently selected from the group consisting of N, CH; with the provision that X and Y are not CH at the same time.
8. A pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of one or more of the compound of formula (I) of claim 1 , or pharmaceutically acceptable salts, tautomers, optical isomers, or pharmaceutically acceptable solvates, and optionally pharmaceutically acceptable carriers, excipients, adjuvants, accessories and/or diluents.
9. A compound of formula II:
wherein R′ is selected from the group consisting of:
unsubstituted 5-7 membered heterocycles,
5-7 membered heterocycles substituted by 1-5 substituents,
C1-C6 alkyl-(unsubstituted 5-7 membered heterocycles),
C1-C6 alkyl-(5-7 membered heterocycles substituted by 1-5 substituents),
—NH-(unsubstituted 5-7 membered heterocycles),
—NH-(5-7 membered heterocycles substituted by 1-5 substituents),
—N(CH 3 )-(unsubstituted 5-7 membered heterocycles), and
—N(CH 3 )-(5-7 membered heterocycles substituted by 1-5 substituents),
wherein the heterocycle contains at least one heteroatom selected from the group consisting of N, O and S; the substitution means one or more hydrogen atoms on the group are replaced by R 1 substituents, and
wherein X, Y are each independently selected from the group consisting of N, CH; with the provision that X and Y are not CH at the same time.