阅读说明：本技术 Kras g12c抑制剂化合物及其用途 (KRAS G12C inhibitor compounds and uses thereof ) 是由 胡永韩 李昕 赵金凤 吴予川 刘霄 陈曦 于 2020-11-27 设计创作，主要内容包括：本发明提供了一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物：本发明提供的上述KRAS G12C抑制剂化合物对KRAS突变有较好的抑制作用,可以用于预防和/或治疗KRAS G12C介导的疾病。(The present invention provides a compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:)

A compound having the structure of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:

wherein the content of the first and second substances,

R ₁selected from unsubstituted or substituted by R₇Substituted C_6-10Aryl and 5-10 membered heteroaryl;

R ₂selected from unsubstituted or substituted by R₈Substituted C_6-10Aryl and 5-10 membered heteroaryl;

R ₃and R₄Each independently selected from hydrogen, deuterium, C_1-6Alkyl, or R₃And R₄Are linked to form an unsubstituted or optionally substituted 1-3 substituents selected from deuterium, halogen, hydroxy, C_1-63-7 membered cycloalkyl or 3-7 membered heterocycloalkyl substituted with a substituent of alkyl, or R₃And R₄Form ═ O, ═ S, ═ N-CN or ═ CH₂；

R ₅And R₆Each independently selected from hydrogen, deuterium and halogen;

each R₇And R₈Each independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C _3-6Cycloalkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -COOC_1-6Alkyl, said amino, alkyl, cycloalkyl, alkenyl and alkynyl groups being unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxy, amino, acetyl or deuterium atoms;

x is unsubstituted or substituted by R₉Substituted 4-9 membered heterocyclyl, each R₉Each independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy, said amino, alkyl being unsubstituted or substituted by substituents selected from 1 to 3 halogen, cyano, hydroxy, amino or deuterium atoms;

y isWherein R is₁₀、R ₁₁And R₁₂Each independently selected from hydrogen, deuterium, halogen, cyano, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-7 membered heterocyclyl, C_2-6Alkenyl radical, C_2-6Alkynyl, acetyl, propionyl, butyryl and-COOC_1-6Alkyl, said alkyl, cycloalkyl, alkenyl, alkynyl, acetyl, propionyl and butyryl being unsubstituted or substituted by 1 to 3 substituents selected from deuterium, halogen, cyano, hydroxy, amino, C_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Or 3-7 membered heterocyclyl; or said R is₁₀And R₁₂Are linked to each other to form a triple bond;

q is N or C-Q ', wherein Q' is selected from the group consisting of hydrogen, deuterium, cyano, halogen and C_1-6An alkyl group.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein Q is N.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₁Selected from unsubstituted or substituted by R₇Substituted C_6-10Aryl and 5-10 membered heteroaryl, said R₇At C_6-10Ortho-substitution of the atoms attached to the N atom in aryl and 5-to 10-membered heteroaryl groups.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₁Selected from unsubstituted or substituted by R₇Substituted C_6-10Aryl and 5-6 membered heteroaryl, said 5-6 membered heteroaryl comprising 1-3 heteroatoms or heteroatom groups selected from N, O, S (O)_mWherein m is an integer of 0 to 2.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₁Selected from unsubstituted or substituted by R₇Substituted C_6-10Aryl and 5-to 10-membered heteroaryl, said C_6-10Aryl is selected from phenyl, naphthyl, tetrahydronaphthyl and 2, 3-indanyl; the 5-to 10-membered heteroaryl group is selected from the group consisting of thienyl, pyridyl, pyridinyloxy, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl; preferably, said C_6-10Aryl being benzeneA group; the 5-10 membered heteroaryl is selected from pyridyl or pyrimidinyl.

The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein each R is₇Independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6A haloalkyl group.

The compound of claim 6, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein each R is₇Independently selected from hydrogen, deuterium, methyl, CH₂F、CHF ₂、CF ₃Ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The compound of claim 7, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₂Selected from unsubstituted or substituted by R₈Substituted C_6-10Aryl and 5-6 membered heteroaryl, said 5-6 membered heteroaryl comprising 1-3 heteroatoms or heteroatom groups selected from N, O, S (O)_rWherein r is an integer of 0 to 2.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₂Selected from unsubstituted or substituted by R₈Substituted C_6-10Aryl and 5-to 10-membered heteroaryl, said C_6-10Aryl is selected from phenyl, naphthyl, tetrahydronaphthyl and 2, 3-indanyl; the 5-10 membered heteroaryl group is selected from thienyl, pyridylPyridinyloxy, pyrimidyl, pyrazinyl, pyridazinyl, pyridonyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl.

The compound of claim 9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₂Selected from unsubstituted or substituted by R₈Substituted phenyl, imidazolyl, pyrrolyl, pyridinyloxy, pyridyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl and quinazolinyl.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein each R is₈Each independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C _1-6Alkoxy, said amino, alkyl being unsubstituted or substituted by 1 to 3 substituents selected from halogen, hydroxy, amino, acetyl or deuterium atoms.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein each R is₈Independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl and amino.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein，R ₃And R₄Independently selected from hydrogen, deuterium, C_1-6Alkyl, or R₃And R₄Are linked to form a cyclopropyl group, or R₃And R₄Form ═ O, ═ S, or ═ N-CN.

The compound of claim 13, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₃And R₄O is formed.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R is₅And R₆Each independently selected from hydrogen, deuterium, fluorine and chlorine.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein X is unsubstituted or substituted with R₉A substituted 4-9 membered heterocyclyl, and the atom to which the 4-9 membered heterocyclyl and Y are attached is N.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein X is unsubstituted or substituted with R₉Substituted 4-9 membered heterocyclic group, said 4-9 membered heterocyclic group comprises monocyclic ring, fused ring, bridged ring, spiro ring.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein X is unsubstituted or substituted with R₉A substituted 6-7 membered heterocyclyl, said 6-7 membered heterocyclyl containing no double bonds or 1 or 2 double bonds.

The compound of any one of claims 16-18, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein X is unsubstituted or substituted with R₉A substituted 6-7 membered heterocyclyl, said 6-7 membered heterocyclyl selected from

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein each R is₉Each independently selected from hydrogen, deuterium, methyl, ethyl, -CH₂OH、-CH ₂CN and-CH₂F。

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein X is the following group:

the compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein Y isWherein R is₁₀Selected from hydrogen, deuterium and fluorine, R₁₁Selected from hydrogen or deuterium; r ₁₂Selected from hydrogen, deuterium, acetyl, dimethylaminomethyl, piperidinyl or aminocyclopropyl, preferably, Y is selected from

The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof,

R ₁selected from unsubstituted or substituted by 1-3R₇Substituted C_6-10Aryl and 5-10 membered heteroaryl;

R ₂selected from unsubstituted or substituted by 1-3R₈Substituted C_6-10Aryl and 5-10 membered heteroaryl;

R ₃and R₄Each independently selected from hydrogen, deuterium and C_1-6Alkyl, or R₃And R₄Are linked to form a cyclopropyl group, or R₃And R₄To form ═ O;

R ₅and R₆Each independently selected from hydrogen, deuterium, and halogen;

each R₇Independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl radical, C_3-6A cycloalkyl group;

each R₈Independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C _1-6Alkoxy, the amino and the alkyl are unsubstituted or substituted by 1 to 3 groups selected from halogen, hydroxyl and aminoAcetyl or deuterium atom;

x is unsubstituted or substituted by 1 to 3R₉A substituted 6-7 membered heterocyclic ring, and the atom to which the 6-7 membered heterocyclic ring is attached to Y is N, each R₉Each independently selected from hydrogen, deuterium, methyl, ethyl, -CH₂OH、-CH ₂CN and-CH₂F；

Y isWherein R is₁₀Selected from hydrogen, deuterium and fluorine, R₁₁Selected from hydrogen or deuterium; r₁₂Selected from acetyl, dimethylaminomethyl, piperidinyl or aminocyclopropyl;

q is N or C-Q ', wherein Q' is selected from hydrogen, deuterium and cyano.

The compound of claim 23, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof,

R ₁selected from unsubstituted or substituted by 1-3R₇Substituted C_6-10Aryl and 5-10 membered heteroaryl; said C is_6-10Aryl is selected from phenyl, naphthyl, tetrahydronaphthyl and 2, 3-indanyl; the 5-to 10-membered heteroaryl group is selected from the group consisting of thienyl, pyridyl, pyridinyloxy, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl;

R ₂selected from unsubstituted or substituted by 1-3R₈Substituted C_6-10Aryl and 5-to 10-membered heteroaryl, said C_6-10Aryl is selected from phenyl, naphthyl, tetrahydronaphthyl and 2, 3-indanyl; the 5-to 10-membered heteroaryl group is selected from the group consisting of thienyl, pyridyl, pyridinyloxy, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl;

R ₃and R₄To form ═ O;

R ₅and R₆Each independently selected from hydrogen, deuterium, chlorine and fluorine;

each R₇Independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

each R₈Independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl and amino;

x is unsubstituted or substituted by 1-2R₉A substituted 6-7 membered heterocyclic ring, said 6-7 membered heterocyclic ring selected from Each R₉Independently selected from hydrogen, deuterium, methyl, ethyl, -CH₂CN、-CH ₂OH and-CH₂F；

Y isWherein R is₁₀Selected from hydrogen, deuterium and fluorine, R₁₁Selected from hydrogen or deuterium; r₁₂Selected from hydrogen, deuterium, acetyl, dimethylaminomethyl, piperidinyl or aminocyclopropyl;

q is N or C-Q ', wherein Q' is selected from hydrogen, deuterium and cyano.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula I has the structure of formula I-a, formula I-B, I-C, formula I-D, I-E, or formula I-F:

wherein R is₁₃And each R₁₅Each independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, amino, C_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C _1-6Alkoxy, said amino, alkyl being unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxy, amino, acetyl or deuterium atoms; n is an integer of 0 to 3; r₁₄Selected from hydrogen, deuterium, fluorine, hydroxyl and amino; w is selected from N, CH, CCH₃、CC ₂H ₅And CCH (CH)₃) ₂。

The compound of claim 25, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula I has a structure according to formula I-a or formula I-B, wherein n is 0 and R is₁₃And R₁₄One of which is hydrogen and the other is hydroxy or F, or R₁₃And R₁₄Simultaneously being hydroxy or F, or R₁₃And R₁₄One is hydroxy and the other is F; preferably, R₁₃And R₁₄Simultaneously being hydroxy or F, or R₁₃And R₁₄One is hydroxy and the other is F; more preferably, R₁₃And R₁₄One is hydroxy and the other is F.

A compound, or a pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, which compound is any one of:

a pharmaceutical composition comprising a compound of any one of claims 1-27, or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug, or isotopic label thereof.

Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer, tautomer, cis-trans-isomer, isotopic label or prodrug thereof, or a pharmaceutical composition of claim 28, in the manufacture of a medicament for the prevention and/or treatment of a KRAS G12C-mediated disease.

The use of claim 29, wherein the disease state comprises lung cancer, pancreatic ductal cancer, colon cancer, rectal cancer, appendiceal cancer, esophageal squamous cancer, head and neck squamous cancer, and breast cancer.