Search

CN-116829557-B - Pentaheterocycle compound, preparation method and application thereof

CN116829557BCN 116829557 BCN116829557 BCN 116829557BCN-116829557-B

Abstract

The application discloses a penta-heterocyclic compound, a preparation method and application thereof. The application discloses a compound shown in a formula I, pharmaceutically acceptable salt or solvate thereof, a composition containing the compound and a pharmaceutical application of the compound in preparing medicines for treating diseases or disorders related to the action mechanism of KRAS G12C mutant proteins. The penta-heterocyclic compound has the activity of inhibiting the proliferation of Ba/F3KRAS-G12C cells, NCI-H358 cells and MIA PaCa-2 cells expressing KRAS G12C muteins, and has good inhibition effect on the growth of subcutaneous transplantation tumor of a cell line NCI-H358 nude mouse.

Inventors

  • LUO HUIBING
  • JIANG JIAJUN

Assignees

  • 上海艾力斯医药科技股份有限公司

Dates

Publication Date
20260512
Application Date
20220129
Priority Date
20210201

Claims (20)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof; , X is O, SO or SO 2 ; y is CH or absent; Z is O; x 1 is CR 7 or N; Y 1 is CR 7 or N; A is ; Each R 1 is independently C 1-6 alkyl; R 2 and R 3 are each independently C 1-6 alkyl, H, deuterium, C 1-6 alkyl substituted with one or more deuterium, -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxy groups or 3-12 membered heterocycloalkyl, wherein said 3-12 membered heterocycloalkyl is optionally substituted with 1-3 substituents each independently selected from C 1-6 alkyl, said substituents being the same or different when the substituents are 2 or 3; Each of R 11 and R 12 is independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, or R 11 、R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl; R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1-5 substituents selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogen, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl and C 2-6 alkynyl, said substituents being the same or different when the substituents are 2-5, wherein said C 1-6 alkyl, C 1-6 alkoxy or C 2-6 alkenyl is optionally substituted with-CN or C 2-6 alkynyl; each R 5 is independently H, deuterium, or halogen; Each R 6 is independently H, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuterium; each R 7 is independently halogen; R 7A is H; n is 0 or 1; the hetero atoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2, 3 or 4; When the belt is " When the carbon atom of the "is a chiral carbon atom, it is in the R configuration, S configuration or a mixture thereof.
  2. 2. The compound of claim 1, wherein R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-5 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 1-6 alkoxy, or C 2-6 alkenyl is optionally substituted with-CN or C 2-6 alkynyl; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl is optionally substituted with 1-5 substituents selected from-NR 11 R 12 , said R 11 is H; And/or R 12 is H when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1-5 substituents selected from-NR 11 R 12 .
  3. 3. The compound of claim 1, wherein R 2 or R 3 is each independently H, C 1-6 alkyl, deuterium, C 1-6 alkyl substituted with one or more deuterium, -C 1-6 alkylene-NR 11 R 12 , 3-12 membered heterocycloalkyl substituted with 2 or 3C 1-6 alkyl, or C 1-6 alkyl substituted with one or more hydroxy.
  4. 4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: X 1 is CR 7 ; And/or Y 1 is CR 7 ; And/or Y is CH; and/or, each R 5 is independently H or halogen; and/or, each R 6 is independently H or C 1-6 alkyl substituted with one or more halogens; And/or R 1 is methyl; And/or R 2 or R 3 are each independently H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , 3-12 membered heterocycloalkyl substituted by 1-3C 1-6 alkyl or C 1-6 alkyl substituted by one or more hydroxy; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 , each R 11 or R 12 is each independently H, methyl, CD 3 , or R 11 、R 12 together with the attached atoms form ; And/or R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally being substituted with 1-5 substituents selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, amino, -OH and halogen, wherein said C 1-6 alkyl is optionally substituted with-CN or C 2-6 alkynyl.
  5. 5. The compound of formula I or a pharmaceutically acceptable salt thereof, as claimed in claim 4, wherein R 2 or R 3 are each independently H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , 3-12 membered heterocycloalkyl substituted by 2 or 3C 1-6 alkyl groups, or C 1-6 alkyl substituted by one or more hydroxy groups.
  6. 6. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is O; and/or R 5 is H or fluoro; And/or R 6 is H or monofluoromethyl; And/or R 2 or R 3 are each independently H, C 1-6 alkyl, 3-12 membered heterocycloalkyl substituted with 1-3C 1-6 alkyl or-C 1-6 alkylene-NR 11 R 12 ; And/or R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally being substituted with 1-5 groups selected from amino, hydroxy, fluoro, chloro, methyl, difluoromethyl, 、 Ethyl, trifluoromethyl, 、 And substituent substitution of methoxy.
  7. 7. The compound of claim 6, wherein R 2 or R 3 are each independently H, C 1-6 alkyl, 3-12 membered heterocycloalkyl substituted with 2 or 3C 1-6 alkyl or-C 1-6 alkylene-NR 11 R 12 .
  8. 8. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: When X 1 is CR 7 , said R 7 is chloro or fluoro; And/or, when Y 1 is CR 7 , said R 7 is chloro or fluoro; and/or R 2 or R 3 are each independently H, methyl, 、 、 、 、 、 、 Or (b) ; And/or R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1-5 substituents selected from amino, hydroxy, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl and methoxy.
  9. 9. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: When X 1 is CR 7 , R 7 is chlorine; And/or, when Y 1 is CR 7 , said R 7 is fluorine; And/or R 4 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  10. 10. The compound of claim 1, wherein R 2 is H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxy groups, or 3-12 membered heterocycloalkyl, wherein said 3-12 membered heterocycloalkyl is optionally substituted with 1,2 or 3C 1-6 alkyl, and when the substituents are 2 or 3, the substituents are the same or different; And/or R 3 is H, deuterium, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 or 3-12 membered heterocycloalkyl substituted by 1-3C 1-6 alkyl; And/or R 4 is 10 membered aryl or 9-10 membered heteroaryl, said aryl or heteroaryl optionally being substituted with 1, 2,3, 4 or 5 substituents selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogen, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl and C 2-6 alkynyl, said substituents being the same or different when the substituents are 2-5, wherein said C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are optionally substituted with-CN or C 2-6 alkynyl.
  11. 11. The compound of claim 10, wherein R 3 is H, deuterium, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , or 3-12 membered heterocycloalkyl substituted with 2 or 3C 1-6 alkyl.
  12. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, as defined in formula I, wherein: When R 1 is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when R 2 or R 3 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; and/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 , said C 1-6 alkylene is methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert-butylene; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said plurality is two or three; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when R 11 or R 12 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And/or, when R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said plurality is two or three; And/or, when R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; and/or, when R 11 、R 12 together with the attached atom form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is tetrahydropyrrole; And/or, when R 2 or R 3 are each independently C 1-6 alkyl substituted with one or more hydroxy groups, the plurality is two or three; And/or, when R 2 or R 3 are each independently C 1-6 alkyl substituted with one or more hydroxy groups, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when R 2 or R 3 are each independently a 3-12 membered heterocycloalkyl, said 3-12 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl; And/or, when each R 2 or R 3 is independently a 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is substituted with C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when each R 2 or R 3 is independently a 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is substituted with C 1-6 alkyl, said 3-12 membered heterocycloalkyl is 3-6 membered heterocycloalkyl; And/or, when R 4 is a 6-10 membered aryl group, the 6-10 membered aryl group is phenyl or naphthyl; and/or, when R 4 is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is pyridinyl, pyrazolyl, benzothiazolyl, indazolyl, benzoxazolyl, indolyl, benzimidazolyl, benzofuranyl, or quinolinyl; And/or, when R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkoxy, said C 1-6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl substituted with one or more halogens, the halogen is fluorine, chlorine, bromine or iodine; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl substituted with a plurality of halogens, the plurality is two or three; And/or, when R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl substituted with one or more halogens, the C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; and/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl being substituted with a substituent selected from-NR 11 R 12 , said R 11 and R 12 are H; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from halogen, the halogen is fluorine, chlorine, bromine or iodine; And/or, when R 4 is 6-10 membered aryl or 5-10 membered heteroaryl, aryl or heteroaryl is substituted with a substituent selected from C 2-6 alkenyl, said C 2-6 alkenyl is ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-isobutenyl or 2-isobutenyl; and/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 2-6 alkynyl, said C 2-6 alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl; And/or, when R 4 is 6-10 membered aryl or 5-10 membered heteroaryl, aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkoxy or C 2-6 alkenyl is substituted with-CN or C 2-6 alkynyl, said C 2-6 alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl; And/or, when R 5 is halogen, said halogen is fluorine, chlorine, bromine or iodine; And/or, when R 6 is C 1-6 alkyl substituted with a plurality of halogens, the plurality is two or three; And/or, when R 6 is C 1-6 alkyl substituted with one or more halogens, the halogen is fluorine, chlorine, bromine or iodine; And/or, when R 6 is C 1-6 alkyl substituted with one or more halogens, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; and/or, when R 7 is halogen, the halogen is fluorine, chlorine, bromine or iodine.
  13. 13. A compound of formula I according to claim 12, or a pharmaceutically acceptable salt thereof, wherein: when R 4 is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is pyridinyl, pyrazolyl, benzothiazolyl, indazolyl, benzoxazolyl, indolyl, benzimidazolyl or quinolinyl.
  14. 14. A compound of formula I according to claim 12, or a pharmaceutically acceptable salt thereof, wherein: When R 1 is C 1-6 alkyl, said C 1-6 alkyl is methyl; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 , said C 1-6 alkylene is methylene; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said C 1-6 alkyl is methyl; and/or, when R 2 or R 3 are each independently C 1-6 alkyl substituted with one or more hydroxy groups, said C 1-6 alkyl is methyl; And/or, when R 11 or R 12 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl; And/or, when R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said C 1-6 alkyl is methyl; and/or, when R 11 、R 12 together with the attached atom form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is ; And/or, when R 2 or R 3 are each independently C 1-6 alkyl substituted with a hydroxy group, said C 1-6 alkyl substituted with a hydroxy group is ; And/or, when R 2 or R 3 are each independently 3-12 membered heterocycloalkyl, said 3-12 membered heterocycloalkyl is tetrahydropyrrole; And/or, when R 2 or R 3 are each independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl is substituted by C 1-6 alkyl, said C 1-6 alkyl is methyl; And/or, when each R 2 or R 3 is independently a 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is substituted with C 1-6 alkyl, said 3-12 membered heterocycloalkyl is tetrahydropyrrole; and/or, when R 4 is a 6-10 membered aryl group, the 6-10 membered aryl group is phenyl or ; And/or, when R 4 is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 、 、 、 、 、 、 、 、 、 、 、 Or (b) ; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl, said C 1-6 alkyl is methyl or ethyl; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkoxy, said C 1-6 alkoxy is methoxy; and/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl being substituted with a substituent selected from C 1-6 alkyl substituted with one or more halogens, said halogen is fluorine; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl substituted with one or more halogens, said C 1-6 alkyl is methyl; and/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from halogen, said halogen is fluorine or chlorine; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 2-6 alkenyl, said C 2-6 alkenyl is vinyl; And/or, when R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, the aryl or heteroaryl being substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkoxy or C 2-6 alkenyl being substituted with-CN or C 2-6 alkynyl, said C 2-6 alkynyl being ethynyl; And/or, when R 5 is halogen, said halogen is fluorine; And/or, when R 6 is C 1-6 alkyl substituted with one or more halogens, said halogen is fluorine; And/or, when R 6 is C 1-6 alkyl substituted with one or more halogens, said C 1-6 alkyl is methyl; And/or, when R 7 is halogen, the halogen is fluorine or chlorine.
  15. 15. A compound of formula I according to claim 14, or a pharmaceutically acceptable salt thereof, wherein: When R 4 is 6-10 membered aryl, the 6-10 membered aryl is phenyl; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 or R 12 are each independently C 1-6 alkyl substituted with a plurality of deuterium, said C 1-6 alkyl substituted with a plurality of deuterium is CD 3 ; And/or, when R 11 or R 12 are each independently C 1-6 alkyl substituted with a plurality of deuterium, said C 1-6 alkyl substituted with a plurality of deuterium is CD ３ ; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 , said-C 1-6 alkylene-NR 11 R 12 is 、 、 Or (b) ; And/or, when R 2 or R 3 are each independently a 3-12 membered heterocycloalkyl, said 3-12 membered heterocycloalkyl is ; And/or when R 2 or R 3 are each independently 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is substituted by C 1-6 alkyl, said 3-12 membered heterocycloalkyl is ; And/or, when R 4 is a 6-10 membered aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl substituted with multiple halogens, C 1-6 alkyl substituted with multiple halogens is difluoromethyl or trifluoromethyl; and/or, when R 6 is C 1-6 alkyl substituted with a halogen, said C 1-6 alkyl substituted with a halogen is a fluoromethyl group.
  16. 16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 15, wherein when R 2 or R 3 are each independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl is substituted with C 1-6 alkyl, said 3-12 membered heterocycloalkyl substituted with C 1-6 alkyl is 、 Or (b) 。
  17. 17. The compound of any one of claims 1 to 11, wherein when R 1 is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R 2 or R 3 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 , said C 1-6 alkylene is methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene; and/or, when R 11 or R 12 are each independently C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R 11 or R 12 are each independently C 1-6 alkyl substituted with one or more deuterium, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R 11 、R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is monocyclic, bicyclic or tricyclic; And/or, when R 11 、R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is 4-6 membered heterocycloalkyl; And/or, when R 11 、R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl, the heteroatom in said 3-7 membered heterocycloalkyl is N; and/or, when R 11 、R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl, the number of heteroatoms in said 3-7 membered heterocycloalkyl is 1 or 2; And/or, when each R 2 or R 3 is independently-C 1-6 alkylene-NR 11 R 12 ,R 11 、R 12 together with the attached atoms forms a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is monocyclic, bicyclic or tricyclic; And/or, when R 2 or R 3 are each independently-C 1-6 alkylene-NR 11 R 12 ,R 11 、R 12 , together with the attached atoms, form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl; And/or, when each R 2 or R 3 is independently-C 1-6 alkylene-NR 11 R 12 ,R 11 、R 12 , together with the attached atoms, forms a 3-7 membered heterocycloalkyl, the heteroatom in said 3-7 membered heterocycloalkyl is N; And/or when each R 2 or R 3 is independently-C 1-6 alkylene-NR 11 R 12 ,R 11 、R 12 , together with the attached atoms, forming a 3-7 membered heterocycloalkyl, the number of heteroatoms in said 3-7 membered heterocycloalkyl is 1 or 2; And/or, when R 2 or R 3 are each independently C 1-6 alkyl substituted with one or more hydroxy groups, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when each R 2 or R 3 is independently a 3-12 membered heterocycloalkyl, said 3-12 membered heterocycloalkyl is monocyclic, bicyclic or tricyclic; And/or, when R 2 or R 3 are each independently 3-12 membered heterocycloalkyl, the heteroatom in said 3-12 membered heterocycloalkyl is N; And/or, when each of R 2 or R 3 is independently a 3-12 membered heterocycloalkyl, the number of heteroatoms in the 3-12 membered heterocycloalkyl is 1 or 2; And/or, when each R 2 or R 3 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl is substituted with C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R 4 is a 6-10 membered aryl group, the 6-10 membered aryl group is phenyl, Or (b) ; And/or, when R 4 is a 6-10 membered aryl, said 6-10 membered aryl is not fused to cycloalkyl or heterocyclyl; and/or, when R 4 is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is monocyclic or bicyclic; And/or, when R 4 is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is not fused to cycloalkyl or heterocyclyl; And/or, when R 4 is a 5-10 membered heteroaryl, the number of heteroatoms in the 5-10 membered heteroaryl is 1 or 2; And/or, when R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkyl, said C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R 4 is a 6-10 membered aryl or a 5-10 membered heteroaryl, the aryl or heteroaryl is substituted with a substituent selected from C 1-6 alkoxy, said C 1-6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; And/or, when R 7 in X 1 is halogen, said halogen is fluorine, chlorine, bromine or iodine; And/or, when R 7 in Y 1 is halogen, said halogen is fluorine, chlorine, bromine or iodine.
  18. 18. The compound of any one of claims 1 to 11, wherein when R 11 、R 12 and the attached atom together form a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is a spiro or bridged ring; And/or, when each R 2 or R 3 is independently-C 1-6 alkylene-NR 11 R 12 ,R 11 、R 12 together with the attached atoms forms a 3-7 membered heterocycloalkyl, said 3-7 membered heterocycloalkyl is spiro or bridged; And/or, when R 2 or R 3 are each independently a 3-12 membered heterocycloalkyl, said 3-12 membered heterocycloalkyl is a spiro ring or a bridged ring.
  19. 19. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: r 4 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  20. 20. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, as defined in formula I, wherein: in R 2 and R 3 , the 3-12 membered heterocycloalkyl is a single ring, a double ring or a triple ring; and/or, in R 4 , the 6-10 membered aryl is monocyclic or bicyclic; and/or, in R 4 , the 6-10 membered aryl is not fused to cycloalkyl or heterocyclyl; and/or, in R 4 , the 5-10 membered heteroaryl is monocyclic or bicyclic; And/or, in R 4 , the 5-10 membered heteroaryl is not fused to cycloalkyl or heterocyclyl; and/or, all atoms except the specifically identified isotope atom are atoms of the element in natural abundance, i.e., the mixed atoms of the isotopes in natural abundance.

Description

Pentaheterocycle compound, preparation method and application thereof The present application claims priority from China patent application 202110138250.1 with the application date 2021/2/1. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention relates to a penta-heterocyclic compound, a preparation method and application thereof. Background The RAS protein is a Guanine Trinucleotide Phosphate (GTP) binding protein with molecular weight of 21kDa, which is positioned on cell membrane and consists of 188 or 189 amino acids. The active state of RAS proteins has an effect on cell growth, differentiation, cytoskeleton, protein trafficking and secretion, etc., and its activity is regulated by binding to GTP or Guanine Dinucleotide Phosphate (GDP). When RAS protein is combined with GDP, it is in "deactivated" state, and when it is stimulated by upstream specific cell growth factor, guanine nucleotide exchange factor (GEF) catalyzes RAS protein to release GDP, and is combined with GTP, it is in "activated" state. RAS proteins that bind to GTP activate downstream proteins, activating downstream signaling pathways. RAS proteins themselves have weak gtpase activity, capable of hydrolyzing GTP to GDP, thereby effecting conversion from an activated state to an inactivated state. During this hydrolysis, there is also a need for the involvement of the GTPase Activating Protein (GAP), which interacts with the RAS protein and greatly promotes its ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own gtpase activity or its ability to interact with GAP or hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state, which continues to signal downstream protein growth, resulting in continued growth and differentiation of cells, ultimately possibly leading to cancer. About 30% of human tumors carry some mutated RAS genes. Among RAS family members, oncogenic mutations are most commonly found in the V-Ki-RAS2 Kirsten rat sarcoma virus oncogene homolog (KRAS) (85%), while neuroblastoma RAS virus oncogene homolog (NRAS) (12%) and the V-Ha-RAS murine Harvey sarcoma virus oncogene Homolog (HRAS) (3%) are less common. For KRAS mutations, the most common mutations occur at residues 12 glycine (G12), 13 glycine (G13) and 61 glutamine (Q61), with the G12 mutation accounting for 83%. The G12C mutation is one of the most common KRAS mutations, specifically the mutation of glycine (glycine) to cysteine (cysteine) at KRAS position 12, which is present in about 14% of non-small cell lung cancers (NSCLC), in 4% of colorectal cancers, and in 2% of pancreatic cancers. Other common KRAS mutations include G12D, G V, which are expressed at high levels in colorectal and pancreatic cancers. In 2013, the literature reported for the first time the feasibility of using small molecules to covalently bind KRAS G12C mutants (Nature, 2013,503 (7477):548-551). In recent years ARAXES PHARMA filed several patents for KRAS G12C inhibitors, such as WO2014152588A1, WO2015054572A1, WO2018064510A1, etc., patent WO2018217651A1 filed AMGEN discloses a series of KRAS G12C inhibitors, such as AMG510, the structure of which is shown below, month 2021, AMG510 being FDA approved for the treatment of non-small cell lung cancer patients suffering from KRAS G12C mutations, who have received at least one prior systemic treatment, and patent WO2019099524A1 filed concurrently with MIRATI THERAPEUTICS INC and aray bipararma discloses a series of compounds which irreversibly inhibit the activity of KRAS G12C, such as MRTX849, the structure of which is shown below, currently in clinical stage III. Despite advances in this area, there is a continuing need to develop potent, stable, safe small molecule KRAS G12C inhibitors for the treatment of diseases mediated by KRAS G12C mutations, such as cancer. Disclosure of Invention The application aims to solve the technical problem of single structure of KRAS G12C inhibitor in the prior art, and provides a penta-heterocyclic compound, a preparation method and application thereof. The penta-heterocyclic compound has the activity of inhibiting the proliferation of Ba/F3 KRAS-G12C cells, NCI-H358 cells and MIA PaCa-2 cells expressing KRAS G12C muteins, and has good inhibition effect on the growth of subcutaneous transplantation tumor of a cell line NCI-H358 nude mouse. The invention solves the technical problems through the following technical proposal. The invention provides a compound shown as a formula I, pharmaceutically acceptable salt or solvate thereof; X is O, S, SO, SO 2 or NR 8; y is CH or absent; z is O or absent; X 1 is CH, CR 7 or N; y 1 is CH, CR 7 or N; A is Or-SO 2-(CH2)qNR11R12; Each R 1 is independently deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, C 1-6 alkyl substituted with one or more deuteriu