New macrocyclic compound

Abstract

The present application relates to a broad-spectrum RAS inhibitor having a macrocyclic structure as represented by formula (I). Specifically, the present invention relates to a compound as represented by formula (I), a preparation method therefor, and a pharmaceutical composition thereof, and further relates to the use of the compound and pharmaceutical composition thereof in the preparation of a drug for treating KRAS protein-related diseases, for example, for treating cancer.

Claims

Compound of formula (I) or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, in X is CH or N. Y is -C(O)-R6, -C(S)-R6, -S(O)(R6)(=NR9), -S(O)(R6), -S(O2)(R6), -P(O)(R7)(R8), -C(O)-C 1-4 Alkyl-NR 10 -S(O)(R6)(=NR9), or -C(O)-C 1-4 Alkyl-N=S(O)(R6)(R6), R7 and R8 are each independently C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution, R9 is C 1-6 Alkyl groups, optionally substituted with halogens, -CN, -NH2, or -OH, R 10 For H or C 1-6 Alkyl groups, optionally substituted with halogens, -CN, -NH2, or -OH, R6 is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl groups are optionally oxidized, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally halogenated, -CN, -NH2, -OH, or -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 alkyl), or R 11 replace, R 11 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-12 membered heteroaryl, -C(O)-R 12 -C(O)-OR 13 -OC(O)-R 12 -C(O)-NR 13 R 14 -NR 13 -C(O)-R 12 -S(O)-R 12 -S(O2)-R 12 -S(O2)-NR 13 R 14 , or -NR 13 -S(O2)R 12 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally converted by halogen, -CN, -NH2, -OH, or -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, L is -(L1) p -(L3) m -(L2) q -, m is 0 or 1, p is 0 or 1, q is 0 or 1 L1 and L2 are each independently C 1-4 Alkylene, wherein the alkylene is optionally coated with a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered cycloalkyl group, or 3-8 membered heterocyclic group substitution. L3 is a 3-8 membered cycloalkylene group, a 3-8 membered heterocyclic group, a 6-10 membered aryl group, or a 5-12 membered heterocyclic group, wherein the cycloalkylene group, heterocyclic group, aryl group, or heterocyclic group is optionally coated with a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution, Ring A is a 5-8 membered heterocycle, wherein the heterocycle is optionally divided by C. 1-3 Alkyl or halogen substitution, Ring B is a 3-6 membered cycloalkylene, a 3-6 membered heterocycloalkylene, a phenylene, or a 5-12 membered heteroaryl, wherein the cycloalkylene, heterocycloalkylene, phenylene, or heteroaryl group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C≡CC 1-6 Alkyl group, -C≡C-(CH2) 0-4 -(3-8 membered cycloalkyl), -C≡C-(CH2) 0-4 -(3-8-membered heterocyclic group), -(6-10-membered arylene group)-(CH2) 0-4 -(3-8 membered cycloalkyl), -(6-10 membered arylene)-(CH2) 0-4 -(3-8 membered heterocyclic group), -(5-12 membered heteroaryl group)-(CH2) 0-4 -(3-8 membered cycloalkyl), or -(5-12 membered heteroaryl)-(CH2) 0-4 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl and heterocyclic group is optionally replaced by (=O), halogen, -CN, -NH2, -OH, (optionally replaced by halogen, -CN, -NH2, -OH, -OC) 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 alkyl) substituted C 1-6 alkyl), -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), -C(O)-R 12 -C(O)-OR 13 -OC(O)-R 12 -C(O)-NR 13 R 14 -NR 13 -C(O)-R 12 -S(O)-R 12 -S(O2)-R 12 -S(O2)-NR 13 R 14 -NR 13 -S(O2)R 12 Or R 20 Substitution, and the S in the heterocyclic group is optionally oxidized to R 20 It is a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R 21 replace, R 21 -(CH2) 0-4 -(3-8 membered cycloalkyl), -(CH2) 0-4 -(3-8 membered heterocyclic group), -(CH2) 0-4 -(6-10 aryl), or -(CH2) 0-4 -(5-12-membered heteroaryl), wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic substituted, R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl groups are optionally oxidized, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally oxidized by halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R 13 and R 14 Each independently is H or C 1-6 Alkyl groups, optionally substituted with halogens, -CN, -NH2, or -OH, R2 represents H, deuterium, halogens, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution, R3 represents H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution, n can be 0, 1, 2, or 3. According to claim 1, the compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, wherein R 21 It is a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group. According to claim 2, the compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, wherein R 20 It is a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution. The compound according to claim 3, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein each of R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C≡C-(CH2) 0-4 -(3-8 membered cycloalkyl), -C≡C-(CH2) 0-4 -(3-8-membered heterocyclic group), -(6-10-membered arylene group)-(CH2) 0-4 -(3-8 membered cycloalkyl), or -(5-12 membered heteroaryl)-(CH2) 0-4 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl and heterocyclic group are optionally replaced by halogen, -CN, -NH2, -OH, (C group optionally replaced by halogen, -CN, -NH2, or -OH) 1-6 alkyl), -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R 20 Substitution, and the S in the heterocyclic group is optionally oxidized to R 20 As defined in claim 3. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein each of R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C≡C-(CH2) 0-4 -(3-8 membered cycloalkyl), -C≡C-(CH2) 0-4 -(3-8-membered heterocyclic group), -(6-10-membered arylene group)-(CH2) 0-4 -(3-8 membered cycloalkyl), or -(5-12 membered heteroaryl)-(CH2) 0-4 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by halogen, -CN, -NH2, -OH, -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R 20 Substitution, and the S in the heterocyclic group is optionally oxidized to R 20 It is a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution. The compound according to claim 5, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein each of R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C≡C-(CH2) 0-4 -(3-8 membered cycloalkyl), or -C≡C-(CH2) 0-4 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by halogen, -CN, -NH2, -OH, -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R 20 Substitution, and the S in the heterocyclic group is optionally oxidized to R 20 As defined in claim 5. According to claim 6, the compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, wherein L1 and L2 are each independently C 1-4 Alkylene, wherein the alkylene is optionally coated with a halogen, -CN, -NH2, -OH, or C 1-6 Alkyl substitution The compound according to claim 7, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein each of R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, or R 20 replace, R 20 It is a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally converted by halogen, -CN, -NH2, -OH, -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution. The compound according to claim 8 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein ring A is tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexyl, 5,6-diazaspiro[2.5]octyl, 3,4-diazabicyclo[4.2.0]octyl, or 2,3-diazabicyclo[3.1.1]heptyl. R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein Y is -C(O)-R6 or -S(O2)(R6), R6 is C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally converted by halogen, -CN, -NH2, -OH, (=O), or -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 alkyl), or R 11 replace, R 11 C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C(O)-R 12 -C(O)-OR 13 -OC(O)-R 12 -C(O)-NR 13 R 14 -NR 13 -C(O)-R 12 -S(O2)-R 12 -S(O2)-NR 13 R 14 , or -NR 13 -S(O2)R 12 The alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by halogen, -CN, -NH2, -OH, or -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R 12 C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally converted by halogen, -CN, -NH2, -OH, (=O), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R 13 and R 14 Each independently is H or C 1-6 Alkyl groups, optionally substituted with halogens, -CN, -NH2, or -OH, m+p+q = 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein L3 is a 3-8 membered cycloalkylene group or a 3-8 membered heterocyclic group, wherein the cycloalkylene group or heterocyclic group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution. According to claim 1, the compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, wherein ring A is... or, The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein the B ring is a phenylene or a 5-6-membered heteroaryl group, wherein the phenylene and heteroaryl group are optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R2 is H or a halogen, and R3 is H or C. 1-6 Alkyl group, n is 0. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, has the structure shown in formula (II). in R6 is a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, wherein the cycloalkyl group or heterocyclic group is optionally replaced by (=O), halogen, -CN, -NH2, -OH, or -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), or C 1-6 Alkyl substitution, L is -(L1) p -(L3) m -(L2) q -, m is 0 or 1, p is 0 or 1, q is 0 or 1, and m + p + q = 1, 2, or 3. L1 and L2 are each independently C 1-4 Alkylene, wherein the alkylene is optionally coated with a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered cycloalkyl group, or 3-8 membered heterocyclic group substitution. L3 is a 3-8 membered cycloalkylene group, a 3-8 membered heterocyclic group, a 6-10 membered aryl group, or a 5-12 membered heterocyclic group, wherein the cycloalkylene group, heterocyclic group, aryl group, or heterocyclic group is optionally coated with a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl substitution, Ring A is a 5-8 membered heterocycle, wherein the heterocycle is optionally divided by C. 1-3 Alkyl or halogen substitution, Ring B is a 3-6 membered cycloalkylene, a 3-6 membered heterocycloalkylene, a phenylene, or a 5-12 membered heteroaryl, wherein the cycloalkylene, heterocycloalkylene, phenylene, or heteroaryl group is optionally converted by a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R1 is independently C 1-6 Alkyl, -OC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, -C≡CC 1-6 Alkyl group, -C≡C-(CH2) 0-4 -(3-8 membered cycloalkyl), -C≡C-(CH2) 0-4 -(3-8-membered heterocyclic group), -(6-10-membered arylene group)-(CH2) 0-4 -(3-8 membered cycloalkyl), -(6-10 membered arylene)-(CH2) 0-4 -(3-8 membered heterocyclic group), -(5-12 membered heteroaryl group)-(CH2) 0-4 -(3-8 membered cycloalkyl), or -(5-12 membered heteroaryl)-(CH2) 0-4 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl and heterocyclic group is optionally replaced by (=O), halogen, -CN, -NH2, -OH, (optionally replaced by halogen, -CN, -NH2, -OH, -OC) 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 alkyl) substituted C 1-6 alkyl), -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), -C(O)-R 12 -C(O)-OR 13 -OC(O)-R 12 -C(O)-NR 13 R 14 -NR 13 -C(O)-R 12 -S(O)-R 12 -S(O2)-R 12 -S(O2)-NR 13 R 14 -NR 13 -S(O2)R 12 Or R 20 Substitution, and the S in the heterocyclic group is optionally oxidized to R 20 It is a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R 21 replace, R 21 -(CH2) 0-4 -(3-8 membered cycloalkyl), -(CH2) 0-4 -(3-8 membered heterocyclic group), -(CH2) 0-4 -(6-10 aryl), or -(CH2) 0-4 -(5-12-membered heteroaryl), wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally converted by halogen, -CN, -NH2, -OH, or -(CH2). 1-6 -NH2、-(CH2) 1-6 -OH, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic substituted, R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl groups are optionally oxidized, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally oxidized by halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R 13 and R 14 Each independently is H or C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with halogen, -CN, -NH2, or -OH. The compound of claim 15 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R6 is a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally converted by a halogen or C 1-6 Alkyl substitution, L is C 1-8 Alkylene Ring B is a 5-6 membered heteroaryl group, wherein the heteroaryl group is optionally coated with a halogen or C. 1-6 Alkyl substitution, R 12 C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally replaced by (=O), halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C) 1-6 Alkyl)(C 1-6 Alkyl) substitution, R 13 and R 14 Each independently is H or C 1-6 alkyl. The following compounds, or their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, A pharmaceutical composition comprising a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier. Use of the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the pharmaceutical composition of claim 18 in the preparation of a medicament for treating diseases related to the KRAS protein. According to the use of claim 19, the disease associated with the KRAS protein is lung cancer, colorectal cancer, pancreatic cancer, melanoma, leukemia, multiple myeloma, malignant lymphoma, bladder cancer, thyroid cancer, or head and neck cancer.

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