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CN-114644631-B - KRAS G12C protein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof

CN114644631BCN 114644631 BCN114644631 BCN 114644631BCN-114644631-B

Abstract

The invention discloses a KRAS G12C protein mutation inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof. And particularly discloses a compound shown in a formula I, a solvate, a prodrug, a metabolite or pharmaceutically acceptable salt thereof, wherein the compound has good KRAS G12C protein mutation inhibition activity and can be used for treating or preventing cancers.

Inventors

  • TANG GUOZHI
  • MA DAWEI
  • HUANG MENGWEI
  • LIU YONGFU
  • CHEN JUNLI
  • LI CHUNSHUI

Assignees

  • 上海维申医药有限公司

Dates

Publication Date
20260505
Application Date
20211215
Priority Date
20201217

Claims (20)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof: ring A is 6-10 membered alicyclic heterocyclic ring containing 2N atoms, wherein the alicyclic heterocyclic ring is a single ring, a bridged ring or a spiro ring; R 1 is-C (=o) -C (R a )＝C(R b )(R c )、-C(＝O)-C≡CR c 、-C(＝O)-C(＝O)-O-R d or-C (=o) -R d ; R a is hydrogen, halogen or C 1-6 alkyl; R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 "; Each R b-1 is independently halogen, C 1-6 alkoxy or-NR b-2 R b-3 ;R b-2 and R b-3 is independently hydrogen or C 1-6 alkyl; R d is C 1-6 alkyl; n is 0, 1, 2 or 3; Each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 "; Each R 4-1 is independently halogen, cyano, hydroxy, or C 1-6 alkoxy; r 2 is -OR 2-1 、-SR 2-2 、-C(＝O)R 2-3 、-S(＝O) 2 R 2-4 、-S(＝O)R 2-5 、-(CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ; R 1-1 、R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl; m is 0, when m is 0, R 2-6 is directly connected with a parent body through a single bond; r 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S substituted with one or more R e -1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a "heteroatom selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms," a "heteroatom selected from one or more of O and N substituted with one or more R e-3 , a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; R 2-6 is hydrogen, CN, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S substituted with one or more R e-1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a "heteroatom selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms," heteroatom selected from one or more of O and N substituted with one or more R e-3 , a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; R 2-7 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S, a "heteroatom substituted with one or more R e-1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a" heteroatom selected from one or more of O and N, a "heteroatom substituted with one or more R e-3 , a" 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; Each R e is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms, substituted with one or more R e-1 " heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms," heteroatom selected from one or more of O and N substituted with one or more R e-3 , "4-10 membered heterocycloalkyl having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; r e-1 、R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or NR e-5 R e-6 ;R e-5 and R e-6 are independently hydrogen or C 1-6 alkyl; Each R e-3 is independently halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e-7 , C 1-6 alkoxy, C 1-6 alkoxy substituted with one or more R e-8 or NR e-5 R e-6 ;R e-7 and R e-8 are independently halogen, hydroxy, cyano, C 1-6 alkoxy or NR e-9 R e-10 ,R e-9 and R e-10 are independently hydrogen or C 1-6 alkyl; R 3 is hydrogen or C 1-6 alkyl; X is O or CR 7 R 8 , Y is CR 7 R 8 , Z is a single bond, O or CR 7 R 8 , each R 7 and R 8 independently is H or C 1-6 alkyl; u, V, W and Q are independently CR 5 ; Each R 5 is independently H, halogen, hydroxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano, C 3-6 cycloalkyl, C 1-6 alkyl, or C 1-6 alkoxy; the carbon atom with "×" is chiral carbon atom, and is in S configuration, R configuration or their mixture.
  2. 2. The compound shown in the formula I or pharmaceutically acceptable salt thereof according to claim 1, wherein the ring A is a 6-10 membered alicyclic ring containing 2N atoms, wherein the alicyclic ring is a single ring, a bridged ring or a spiro ring; R 1 is-C (=o) -C (R a )＝C(R b )(R c )、-C(＝O)-C≡CR c 、-C(＝O)-C(＝O)-O-R d or-C (=o) -R d ; R a is hydrogen, halogen or C 1-6 alkyl; R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 "; Each R b-1 is independently halogen, C 1-6 alkoxy or-NR b-2 R b-3 ;R b-2 and R b-3 is independently hydrogen or C 1-6 alkyl; R d is C 1-6 alkyl; n is 0, 1, 2 or 3; Each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 "; Each R 4-1 is independently halogen, cyano, hydroxy, or C 1-6 alkoxy; r 2 is -OR 2-1 、-SR 2-2 、-C(＝O)R 2-3 、-S(＝O) 2 R 2-4 、-S(＝O)R 2-5 、-(CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ; R 1-1 、R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl; m is 0, when m is 0, R 2-6 is directly connected with a parent body through a single bond; r 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S substituted with one or more R e -1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a "heteroatom selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms," a "heteroatom selected from one or more of O and N substituted with one or more R e-3 , a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; R 2-6 is hydrogen, CN, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S substituted with one or more R e-1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a "heteroatom selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms," heteroatom selected from one or more of O and N substituted with one or more R e-3 , a 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; R 2-7 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group having 1-4 heteroatoms," heteroatom selected from one or more of N, O and S, a "heteroatom substituted with one or more R e-1 , a 5-12 membered heteroaryl group having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , a" heteroatom selected from one or more of O and N, a "heteroatom substituted with one or more R e-3 , a" 4-10 membered heterocycloalkyl group having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; Each R e is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms, substituted with one or more R e-1 " heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R e-2 , "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms," heteroatom selected from one or more of O and N substituted with one or more R e-3 , "4-10 membered heterocycloalkyl having 1-3 heteroatoms, C 3-10 cycloalkyl, or C 3-10 cycloalkyl substituted with one or more R e-4 ; r e-1 、R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or NR e-5 R e-6 ;R e-5 and R e-6 are independently hydrogen or C 1-6 alkyl; Each R e-3 is independently halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e-7 , C 1-6 alkoxy, C 1-6 alkoxy substituted with one or more R e-8 or NR e-5 R e-6 ;R e-7 and R e-8 are independently halogen, hydroxy, cyano, C 1-6 alkoxy or NR e-9 R e-10 ,R e-9 and R e-10 are independently hydrogen or C 1-6 alkyl; R 3 is hydrogen or C 1-6 alkyl; X is O or CH 2 , Y is CH 2 , Z is a single bond, O or CH 2 ; u, V, W and Q are independently CR 5 ; Each R 5 is independently H, halogen, hydroxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano, C 3-6 cycloalkyl, C 1-6 alkyl, or C 1-6 alkoxy; the carbon atom with "×" is chiral carbon atom, and is in S configuration, R configuration or their mixture.
  3. 3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, Ring A is Is that R 2-1 is C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e , "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" or "heteroatom substituted by one or more R e-1 is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" R 2-2 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e "; R 2-5 is C 1-6 alkyl substituted with one or more R e ; R 2-6 is hydrogen, hydroxy, halogen, one or more of "heteroatom selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more of "heteroatom selected from N, O and S substituted by one or more R e-1 , 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms" or "heteroatom selected from one or more of O and N substituted by one or more R e-3 , 4-10 membered heterocycloalkyl with 1-3 heteroatoms"; Each R e is independently "heteroatom selected from N, O and one or more of S, heteroatom 1-4 5-12 membered heteroaryl", substituted by one or more R e-1 "heteroatom selected from N, O and one or more of S, heteroatom 1-4 5-12 membered heteroaryl", "heteroatom selected from one or more of O and N, heteroatom 1-3 4-10 membered heterocycloalkyl" or "heteroatom substituted by one or more R e-3 " heteroatom selected from one or more of O and N, heteroatom 1-3 4-10 membered heterocycloalkyl "; R e-1 is independently C 1-6 alkyl; Each R e-3 is independently halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or NR e-5 R e-6 ; r e-5 and R e-6 are independently hydrogen or C 1-6 alkyl; R 3 is hydrogen or C 1-6 alkyl; X is O or CR 7 R 8 , Y is CR 7 R 8 , Z is a single bond, O or CR 7 R 8 ;R 7 and R 8 is H.
  4. 4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein when R a is halogen, the halogen is fluoro, chloro, bromo or iodo; And/or, when R a is C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when R b and R c are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl; and/or, when each R b-1 is independently halogen, the halogen is fluorine, chlorine, bromine, or iodine; and/or, when each R b-1 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy; And/or, when R b-2 and R b-3 are independently C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when R d is C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl; and/or, when each R 4-1 is independently halogen, the halogen is fluorine, chlorine, bromine, or iodine; And/or, when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy; And/or when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1 to 4 heteroatoms" or "heteroatom substituted with one or more R e-1 is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1 to 4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1 to 4 heteroatoms" is And/or when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1 to 3 heteroatoms" or "heteroatom substituted by one or more R e-3 is selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1 to 3 heteroatoms" said "heteroatom is selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1 to 3 heteroatoms" is And/or, when R 2-6 is halogen, the halogen is fluorine, chlorine, bromine or iodine; And/or, when R 2-6 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when R 2-6 is C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy; And/or when R 2-6 is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" or "heteroatom substituted by one or more R e-1 is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" is And/or, when R 2-6 is "a heteroatom selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms" or "a heteroatom substituted with one or more R e-3 is selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms" the "heteroatom is selected from one or more of O and N, a 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms" is And/or when each R e is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" or "heteroatom substituted by one or more R e-1 is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" is And/or, when each R e is independently "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1 to 3 heteroatoms" or "heteroatom substituted by one or more R e-3 is selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1 to 3 heteroatoms" is And/or, when R e-1 、R e-2 and R e-4 are independently C 1 -C 6 alkyl, C 1 -C 3 alkyl is said C 1 -C 6 alkyl; And/or, when R e-3 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine; And/or, when R e-3 is independently C 1 -C 6 alkyl or "C 1-6 alkyl substituted with one or more R e-7 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when R e-3 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy; And/or, when R e-5 and R e-6 are independently C 1 -C 6 alkyl, C 1 -C 3 alkyl is said C 1 -C 6 alkyl; And/or, when R 3 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when each R 5 is independently halogen, the halogen is fluorine, chlorine, bromine, or iodine; And/or, when each R 5 is independently C 1-6 alkyl substituted with one or more halo, the C 1-6 alkyl substituted with one or more halo is C 1-3 alkyl substituted with one or more halo; And/or, when each R 5 is independently C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl; And/or, when each R 5 is independently C 1-6 alkoxy substituted with one or more halo, the C 1-6 alkoxy substituted with one or more halo is C 1-3 alkoxy substituted with one or more halo; And/or, when each R 7 and R 8 is independently C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl.
  5. 5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, Is that And/or, when R a is halogen, the halogen is fluorine; and/or, when R a is C 1-6 alkyl, the C 1 -C 6 alkyl is methyl; And/or, when R b and R c are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", the C 1 -C 6 alkyl is methyl; And/or, when each R b-1 is independently halogen, the halogen is fluorine; And/or, when each R b-1 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy; and/or, when R b-2 and R b-3 are independently C 1-6 alkyl, the C 1 -C 6 alkyl is methyl; and/or, when R d is C 1-6 alkyl, the C 1 -C 6 alkyl is methyl; And/or, when each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ", the C 1 -C 6 alkyl is methyl; And/or, when each R 4-1 is independently halogen, the halogen is fluorine; And/or, when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ", the C 1 -C 6 alkyl is methyl; And/or, when R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy; And/or, when R 2-6 is halogen, the halogen is chlorine; And/or, when R 2-6 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ", the C 1 -C 6 alkyl is methyl; And/or, when R 2-6 is C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy; And/or, when R e-1 、R e-2 and R e-4 are independently C 1 -C 6 alkyl, methyl for the C 1 -C 6 alkyl; And/or, when R e-3 is independently halogen, the halogen is fluorine; And/or, when R e-3 is independently C 1 -C 6 alkyl or "C 1-6 alkyl substituted with one or more R e-7 ", the C 1 -C 6 alkyl is methyl; And/or, when R e-3 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy; And/or, when R e-5 and R e-6 are independently C 1 -C 6 alkyl, methyl or ethyl for the C 1 -C 6 alkyl; And/or, when R 3 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl; And/or, when each R 5 is independently halogen, the halogen is fluorine, chlorine or bromine; And/or, when each R 5 is independently C 1-6 alkyl substituted with one or more halogens, the C 1-6 alkyl substituted with one or more halogens is-CF 3 ; And/or, when each R 5 is independently C 1-6 alkyl, the C 1 -C 6 alkyl is methyl; And/or, when each R 5 is independently substituted with one or more halo-substituted C 1-6 alkoxy, said C 1-6 alkoxy substituted with one or more halo is-OCF 3 ; And/or, when each R 7 and R 8 is independently C 1-6 alkyl, the C 1 -C 6 alkyl is methyl.
  6. 6. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2 wherein ring a is a 6-10 membered alicyclic ring containing 2N atoms, said alicyclic ring being a single ring; And/or R 1 is-C (=o) -C (R a )＝C(R b )(R c )、-C(＝O)-C≡CCH 3 、-C(＝O)-C(＝O)-OCH 3 or-C (=o) -CH 3 ; R b and R c are hydrogen when R a is halogen or C 1-6 alkyl, and R a is hydrogen when R b or R c is C 1-6 alkyl or "C 1-6 alkyl substituted by one or more R b-1 "; And/or R a is hydrogen or halogen; And/or R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", and at least one of R b and R c is hydrogen; and/or, each R b-1 is independently halogen; And/or n is 0,1 or 2; and/or, each R 4 is independently methyl, cyano-substituted methyl, F-substituted methyl, or hydroxy-substituted methyl; And/or R 2-1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , or "heteroatom substituted with one or more R e-1 " is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms "; And/or R 2-2 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e "; And/or R 2-5 is C 1-6 alkyl substituted with one or more R e ; And/or R 2-6 is hydrogen, halogen, a "heteroatom substituted by one or more R e-3 is selected from one or more of O and N, a 4-10 membered heterocycloalkyl having 1-3 heteroatoms", "heteroatom is selected from one or more of N, O and S, a 5-12 membered heteroaryl having 1-4 heteroatoms", a "heteroatom substituted by one or more R e-1 is selected from one or more of N, O and S, a 5-12 membered heteroaryl having 1-4 heteroatoms" or a hydroxyl group; And/or each R e is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl group having 1 to 4 heteroatoms", one or more of N, O and S substituted with one or more R e-1 "heteroatom selected from one or more of O and N, 5-12 membered heteroaryl group having 1 to 4 heteroatoms", "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms" heteroatom selected from one or more of O and N substituted with one or more R e-3 ", 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms"; and/or R e-1 is independently C 1-6 alkyl; And/or each R e-3 is independently halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or NR e-5 R e-6 ; and/OR R 2 is-OR 2-1 、-SR 2-2 、-S(＝O)R 2-5 OR- (CR 1-1 R 1-2 ) m R 2-6 ; And/or X is O or CR 7 R 8 , Y is CR 7 R 8 , Z is a single bond, O or CR 7 R 8 ; And/or each R 5 is independently H, halogen, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano, C 3-6 cycloalkyl, C 1-6 alkyl, or C 1-6 alkoxy.
  7. 7. A compound of formula I as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R b and R c are independently hydrogen or "C 1-6 alkyl substituted by one or more halogens", and at least one of R b and R c is hydrogen; and/or n is 1 or 2; and/or, each R 4 is independently cyano-substituted methyl; And/or each R e-3 is independently halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or NR e-5 R e-6 ; And/or each R e is independently "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 heteroatoms" or "heteroatom substituted by one or more R e-3 is selected from one or more of O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms"; And/or X and Y are CH 2 , Z is a single bond, O or CH 2 ; And/or each R 5 is independently H, halogen or C 1-6 alkyl.
  8. 8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, Is that And/or R 1 is And/OR R 2 is-OR 2-1 OR- (CR 1-1 R 1-2 ) m R 2-6 ,R 2-1 is C 1-6 alkyl substituted by one OR more R e , each R e is independently one OR more of O and N substituted by one OR more R e-3 , 4-10 membered heterocycloalkyl having 1-3 heteroatoms, R e each R e-3 is independently halogen, C 1-6 alkyl OR C 1-6 alkoxy, m is 0, R 2-6 is one OR more of O and N substituted by one OR more R e-3 , 4-10 membered heterocycloalkyl having 1-3 heteroatoms, R 2-6 , each R e-3 is independently NR e-5 R e-6 .
  9. 9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, Is that And/or R 2 is hydrogen, hydroxy, chlorine, -OCH 3 、-SCH 3 、 And/or the number of the groups of groups, Is that
  10. 10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of formula I is any one of the following:
  11. 11. the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of formula I is any one of the following: the compound having a retention time of 1.21min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 1.99min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 0.93min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 1.43min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 1.24min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 2.56min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 1.01min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 2.17min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 4.74min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 5.44min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 4.08min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 4.22min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 1.42min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 2.71min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 1.11min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 2.21min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the retention time was 3.88min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; the compound having a retention time of 4.42min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 1.254min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 2.267min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 4.473min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 4.688min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 7.008min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 7.199min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 4.735min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 4.758min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 7.198min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 7.460min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 4.249min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 4.333min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; a compound having a retention time of 6.961min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 7.133min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 4.903min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 5.508min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; The compound having a retention time of 2.174min under the following conditions The stereoisomers of (a) are CHIRALART CELLULOSE SB,2cm x 25cm,5 μm chromatography column, (B) mobile phase (a) MtBE, (B) MEOH containing 0.5% by volume of 2mM NH 3 , (B) MEOH in dcm=1:1; The compound having a retention time of 2.950min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALART CELLULOSE SB,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; a compound having a retention time of 1.986min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALPAK IE,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; a compound having a retention time of 2.919min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALPAK IE,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; A compound having a retention time of 5.137min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 5.370min under the following conditions One stereoisomer of (a) is a chromatographic column of Dr. Main Reprosil Chiral-JM 250x 25mm,10 μm, a column temperature of room temperature, a mobile phase of CO 2 /MeOH=60/40; A compound having a retention time of 0.928min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALPAK IF,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; a compound having a retention time of 1.411min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALPAK IF,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; a compound having a retention time of 1.872min under the following conditions The stereoisomers of (3) are a chromatographic column CHIRALPAK IF,2cm x 25cm,5 μm, a mobile phase A, mtBE, a mobile phase B, meOH, DCM=1:1; the compound having a retention time of 2.467min under the following conditions The stereoisomers of (3) are a chromatographic column CHIRALPAK IF,2cm x 25cm,5 μm, a mobile phase A, mtBE, a mobile phase B, meOH, DCM=1:1; a compound having a retention time of 0.993min under the following conditions The stereoisomers of (A) are a chromatographic column CHIRALPAK IF,2cm multiplied by 25cm,5 μm, a mobile phase A is MtBE, a MEOH solution of 2mM NH 3 with the volume percentage of 0.5% in MtBE, and a mobile phase B is MeOH, DCM=1:1; a compound having a retention time of 2.596min under the following conditions The stereoisomers of (A) were found to be CHIRALPAK IF,2 cm. Times.25 cm,5 μm on a chromatographic column, and 0.5% by volume of 2mM NH 3 in the mobile phase A, mtBE, and MeOH in the mobile phase B, DCM=1:1.
  12. 12. The method for preparing a compound as defined in any one of claims 1 to 11, which is characterized by comprising the steps of: Carrying out substitution reaction on a compound shown in the formula K-X and a compound shown in the formula K-XIII to obtain a compound shown in the formula I; Wherein "", n, ring A, R 1 、R 2 、R 3 、R 4 , X, Y, Z, U, V, W, and Q are defined as defined in any one of claims 1 to 11, and L is halogen or hydroxy.
  13. 13. The method for preparing a compound of formula I according to claim 12, further comprising the steps of: deprotection reaction of a compound shown as a formula K-IX to obtain a compound shown as a formula K-X; The definitions of "#", n, ring A, R 2 、R 3 、R 4 , X, Y, Z, U, V, W and Q are as defined in any one of claims 1 to 10, and PG is an amino protecting group.
  14. 14. A compound of formula K-X: Wherein "#", n, ring A, R 2 、R 3 、R 4 , X, Y, Z, U, V, W, and Q are as defined in any one of claims 1 to 11.
  15. 15. The compound of formula K-X according to claim 14, wherein the compound of formula K-X is any one of the following:
  16. 16. a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, and a pharmaceutically acceptable adjuvant.
  17. 17. The use of a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, or a pharmaceutical composition as claimed in claim 16, in the manufacture of a medicament.
  18. 18. The use of claim 17, wherein the medicament is for the treatment of cancer.
  19. 19. The use of claim 18, wherein the cancer comprises lung cancer, colon cancer, pancreatic cancer, rectal cancer, lymphatic cancer, esophageal cancer, ovarian cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, cholangiocarcinoma, breast cancer, leukemia, and melanoma.
  20. 20. The use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 16, for the preparation of a KRAS G12C protein mutation inhibitor.

Description

KRAS G12C protein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof Technical Field The invention relates to a KRAS G12C protein mutation inhibitor, a preparation method, a pharmaceutical composition and application thereof. Background RAS (Rat sarcoma) proteins, including KRAS, HRAS and NRAS, are members of the small GTPase (GTPase) family. RAS proteins can bind to Guanosine Triphosphate (GTP) or Guanosine Dinucleotide Phosphate (GDP), and the transition between the two states is regulated by Guanosine Exchange Factors (GEFs) and GTP hydrolase activating proteins (GAPs). The RAS proteins are in an "inactive" state when bound to GDP and in an "active" state when bound to GTP. In the GTP-bound state, RAS proteins interact directly with a variety of downstream effector proteins and activate signaling pathways including mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinases (PI 3 ks), thereby regulating cell growth, cell movement or metabolism, and interactions between cells and their extracellular environment. Overactivating mutations of the RAS gene are the most common gene mutations in cancer, with some mutations carried in about 30% of human tumors. Of these KRAS is the most common mutated oncogene, accounting for 86% of all RAS mutations. Mutations in most RAS genes can reduce the binding of GAP to RAS proteins and thus affect the ability of GAP to catalyze GTP hydrolysis, intrinsic gtpase activity in RAS proteins, or both, resulting in an increase in GTP-bound RAS proteins, leaving RAS proteins in an "activated" state at all times. The activated RAS proteins continuously activate downstream signaling pathways, ultimately leading to continued growth and differentiation of cells, and thus to the development of tumors. RAS mutations are genetic drivers of a variety of cancer types including colorectal cancer (CRC), pancreatic Ductal Adenocarcinoma (PDAC), lung adenocarcinoma (LUAD; a subtype of non-small cell lung carcinoma (NSCLC)), melanoma, and certain hematological cancers. In KRAS mutant tumors, most oncogenic mutations occur within codon 12, accounting for 83%. The G12C mutation is a relatively common subtype in KRAS gene mutations. KRAS G12C mutations are common in lung adenocarcinoma and exist in other tumor types such as pancreatic and colorectal cancers. Despite a large number of drug discovery efforts, there is currently no drug on the market directed to KRAS G12C mutations. Mutations in KRAS G12C have been shown to be associated with poor prognosis of cancer. Thus, there is an important clinical need for the development of inhibitors of KRAS G12C mutations. Shokat and colleagues reported that covalent KRAS G12C inhibitors offer the possibility to treat KRAS G12C mutant tumors (Ostrem JM., et al nature,2013, 548-551). Although a series of patents have been published on KRASG12C inhibitors (WO 2014143659, WO2014152588, WO2015054572, WO2016049524, WO2017201161, WO2018119183, etc.), it is still important to find more potent KRAS inhibitors with better pharmacokinetic and pharmacodynamic properties. Disclosure of Invention Aiming at the defect that the existing KRAS G12C protein mutation inhibitor has a single structure, the invention provides a KRAS G12C protein mutation inhibitor, a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound shown in a formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof (referring to the compound shown in the formula I, the solvate thereof, the prodrug thereof or the metabolite thereof): ring A is a 4-12 membered alicyclic heterocyclic ring containing 2-4N atoms, wherein the alicyclic heterocyclic ring is a single ring, a bridged ring or a spiro ring; R 1 is-C (=o) -C (R a)＝C(Rb)(Rc)、-C(＝O)-C≡CRc、-C(＝O)-C(＝O)-O-Rd or-C (=o) -R d; R a is hydrogen, halogen or C 1-6 alkyl; R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1"; Each R b-1 is independently halogen, C 1-6 alkoxy or-NR b-2Rb-3;Rb-2 and R b-3 are independently hydrogen or C 1-6 alkyl, or R b-2、Rb-3 and the N to which they are attached together form "4-10 membered heterocycloalkyl having 1 or 2 heteroatoms N, or N and O"; R d is C 1-6 alkyl; n is 0, 1, 2 or 3; Each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1"; Each R 4-1 is independently halogen, cyano, hydroxy, or C 1-6 alkoxy; r 2 is -OR2-1、-SR2-2、-C(＝O)R2-3、-S(＝O)2R2-4、-S(＝O)R2-5、-(CR1-1R1-2)mR2-6 or NR 1-3R2-7; R 1-1、R1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl; m is 0, 1,2 or 3, when m is 0, R 2-6 is directly connected with the parent body through a single bond; R 2-1、R2-2、R2-3、R2-4 and R 2-5 are independently C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e, C 1-6 alkoxy, a "heteroatom selected from one or more of N, O and S, a 5-12 membered heteroaryl group hav