Spiro ring-containing quinazoline compounds
The present invention relates to a spiro ring-containing quinazoline compound, a preparation method therefor, and use of the compound as a K-Ras G12C inhibitor in preparing antitumor medicaments.
1. A compound with a structure as shown in general formula (1), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:
wherein in formula (1):
R 1 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
R 2 is C1-C3 alkoxy, C1-C3 haloalkoxy or -NR a R b , wherein R a and R b are independently H, C1-C3 alkyl or C1-C3 haloalkyl, or R a and R b , together with a N atom, form a 4-7 membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted with 1-3 halogen atoms;
R 3 is
wherein R c is H or F; R d is H, F, Cl or Me; R e is H, F, Cl or Me; R f is F, NH 2 , Me or cyclopropyl; R x1 , R x2 , R x3 , R x4 , R x5 , R x6 and R x7 are independently H, F, Cl, OH, OMe, NH 2 , CF 3 , C1-C3 alkyl or C3-C6 cycloalkyl;
R 4 is H, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; and
when R 3 is
and R 4 is H, R 5 is:
wherein n 1 , n 2 , n 3 , m 1 , m 2 and m 3 are independently integers of 1 or 2; R g is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; R h is
when R 3 is
and R 4 is halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; or, when R 3 is
wherein n 1 , n 2 , n 3 , m 1 , m 2 and m 3 are independently integers of 1 or 2; R g is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3alkyl; R h is
R i is H, halogen, methyl or cyano.
2. The compound according to claim 1 , wherein in the general formula (1), R 1 is H, F, Cl, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
3. The compound according to claim 1 , wherein in the general formula (1), R 2 is CH 3 O—, CH 3 CH 2 O—, CF 3 CH 2 O—, CHF 2 CH 2 O—,
4. The compound according to claim 1 , wherein in the general formula (1), R 3 is
5. The compound according to claim 1 , wherein in the general formula (1), R 4 is H, F, CN, Me, CF 3 ,
6. The compound according to claim 1 , wherein in the general formula (1), when R 3 is
and R 4 is H, R 5 is:
7. The compound according to claim 1 , wherein in the general formula (1), when R 3 is
and R 4 is F, CN, Me, CF 3 ,
or, when R 3 is
8. The compound according to claim 1 , wherein in the general formula (1), R 5 is:
9. The compound, the optical isomers thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to claim 1 , wherein the compound has one of the following structures:
10. A compound with a structure as shown in general formula (2), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:
wherein in general formula (2):
R 1a is
R 2a is CH 3 O—, CH 3 CH 2 O—, CF 3 CH 2 O- or CHF 2 CH 2 O—;
R 3a is
wherein R c is H or F, R d is H, F, Cl or Me, R e is H, F, Cl or Me, and R f is F, NH 2 , Me or cyclopropyl;
R 4a is H or F; and
R 5a is: H,
wherein n 1 , n 2 , n 3 , m 1 , m 2 and m 3 are independently integers of 1 or 2; v is an integer of 1, 2 or 3; R g is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; R j is independently halogen, CN, SO 2 Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6cycloalkyl or
R k is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
R n is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl, two R n groups, together with one carbon atom, form a spiro ring, or two R n groups, together with different carbon atoms, form a bridged ring; R 1 and R m are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, or R 1 and R m , together with a N atom, form a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy or (halogenated C1-C3)alkoxy.
11. The compound according to claim 10 , wherein in the general formula (2),
R 3a is
12. The compound according to claim 10 , wherein in the general formula (2), R 5a is: H,
13. The compound, the optical isomers thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to claim 10 , wherein the compound has one of the following structures:
14. A compound with a structure as shown in general formula (3), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:
wherein, R 5b is:
wherein n 1 , n 2 , n 3 , m 1 , m 2 and m 3 are independently integers of 1 or 2; R g is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; R h is
R i is H, halogen, methyl or cyano; or
R 5b is: H,
wherein n 1 , n 2 , n 3 , m 1 , m 2 and m 3 are independently integers of 1 or 2; v is an integer of 1, 2 or 3; R g is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; R j is independently halogen, CN, SO 2 Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6cycloalkyl or
R k is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
R n is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl, two R n groups, together with one carbon atom, form a spiro ring, or two R n groups, together with different carbon atoms, form a bridged ring; R 1 and R m are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, or R 1 and R m , together with a N atom, form a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy or (halogenated C1-C3)alkoxy.
15. The compound according to claim 14 , wherein
R 5b is: H,
16. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formula (1), the optical isomers thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to claim 1 as active ingredients.
17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formula (2), the optical isomers thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to claim 10 as active ingredients.
18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formula (3), the optical isomers thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to claim 14 as active ingredients.