CN112778284B

CN112778284B - Pyrimido-cyclic derivative and application thereof in medicine

Info

Publication number: CN112778284B
Application number: CN202011151946.XA
Authority: CN
Inventors: 张晨; 王健民; 钱国飞; 叶飞; 李瑶; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2019-11-01
Filing date: 2020-10-26
Publication date: 2022-04-05
Anticipated expiration: 2040-10-26
Also published as: CN112778284A

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of medicines for treating diseases related to KRas-G12C activity or expression quantity.

Description

Pyrimido-cyclic derivative and application thereof in medicine

Technical Field

Background

RAS protein is expressed by RAS gene (Rat Sarcoma viral oncogene), is intracellular guanine nucleotide binding protein, and belongs to gtpase (weak hydrolytic activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. The RAS protein in the activated state signals through interaction with various downstream effectors, and has effects on growth, differentiation, cytoskeleton, protein transport and secretion, etc. of cells. Activation of RAS signaling is regulated by guanine nucleotide exchange factors (GEF, which can lead to GDP-GTP exchange) or gtpase activating proteins (GAP, which can lead to the transition of RAS proteins from an active state to an inactive state), and resistance of mutant RAS proteins to GAP can lead to the RAS proteins being in a sustained active state, causing uncontrolled growth of cells and ultimately developing cancerous tissues (Molecular Cancer,2018,17: 33).

RAS gene mutations are a common type of gene mutation in cancer patients (nat. rev. drug discov.2014,13,828-. The KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation among RAS mutations, accounting for 86% of all RAS mutations. The most common way to activate the KRAS gene is by point mutation, with 95% of KRAS mutations occurring primarily at codon 12 and codon 13 of exon 2, and the common forms of mutation being KRAS G12C (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%).

KRAS mutein inhibitors have received much attention since the discovery of KRAS muteins in cancer and the observation that inhibition of these muteins can inhibit tumor proliferation. KRAS has long been recognized as an "unforgeable target": RAS has a high affinity for GTP/GDP (picomolar), and the entire protein also lacks the other "ligand binding pocket" (clin. cancer res.2015,21, 1810-. In the KRAS G12C mutein, a "binding pocket II" (Nature.2013,503,548-551) was identified to appear in the immediate vicinity of the GTP/GDP-RAS binding pocket and to act as a binding site for KRAS G12C mutein inhibitors.

Disclosure of Invention

The invention aims to provide a compound capable of inhibiting KRAS G12C protein or a stereoisomer, a deuteroide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to KRAS-G12C activity or expression.

The invention provides a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

R^1aSelected from H, F, Cl, Br, I, cyano, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy or-NHC (═ O) R^1dSaid alkyl or alkoxy is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^1bor R^1cEach independently selected from H, F, Cl, Br, I, cyano, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) N (R)^1d)₂、-(CH₂)_p-N(C_1-4Alkyl radical)₂、-(CH₂)_pNHC(＝O)-C_1-4Alkyl, - (CH)₂)_p-C_3-10Carbocyclic ring or- (CH)₂)_p-3 to 12 membered heterocycle, said alkyl, alkoxy, heterocycle or carbocycle optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-10Carbocyclic ringOr a 5-to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

alternatively, R^1aWith any one of R^1bForm C_5-10A carbocyclic ring or a5 to 12 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-N(C_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-10Carbocyclyl or 5-to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^1deach independently selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

ring A is selected from a 4-to 12-membered nitrogen-containing heterocycle selected from a saturated or partially saturated monocyclic, fused, bridged or spiro ring, said nitrogen-containing heterocycle optionally further substituted with 0 to 4R^aSubstituted by a substituent;

R^aselected from H, oxo, F, Cl, Br, I, cyano, C_1-6Alkyl or C_1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

ring B is selected from C_6-10An aromatic ring or a5 to 10 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S, N;

R²each independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C_1-6Alkylene-hydroxy, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R^2a、R^2beach independently selected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

X₁、X₂any one of which is selected from a bond or C (R)^x)₂And the other is selected from O, -C (═ O) -, S, NR^xOr C (R)^x)₂；

X₃Selected from the group consisting of a bond, O, -OCH₂-、-CH₂O-, S or NR^x；

R^xEach independently selected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R³selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, N (R)^3a)₂、-(CH₂)_q-C(＝O)C_1-6Alkyl, - (CH)₂)_q-C (═ O) -3 to 12 membered heterocycle, - (CH)₂)_q-C(＝O)-C_3-10Carbocyclic ring, - (CH)₂)_q-C(＝O)-N(R^3a)₂、-(CH₂)_q-N(R^3a)-C(＝O)R^3b、-(CH₂)_q-3 to 12 membered heterocycle or- (CH)₂)_q-C_3-10Carbocyclic ring of said CH₂Alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, -C_1-4alkylene-OH, - (CH)₂)_q-C_3-10Carbocyclic ring, - (CH)₂)_q-3 to 12 membered heterocycle, C_3-6Cycloalkyl radical, C_1-4Alkoxy, -N (C)_1-4Alkyl) C (═ O) -3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from O, S, N or a3 to 12 membered heterocycle;

R^3aeach independently selected from H, C_1-4Alkyl, -C_1-4Alkyl-3 to 12 membered heterocycle, said alkyl or heterocycle optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

alternatively, two R^3aTogether with the nitrogen atom to which they are directly attached form a 4-to 8-membered nitrogen-containing heterocycle optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

R^3bselected from H, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3 to 12 membered heterocycle, said alkyl, cycloalkylOr the heterocyclic ring is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

n, p, q are each independently selected from 0, 1, 2, 3 or 4.

Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

R¹Is selected from-C (═ O) -C (R)^1a)＝C(R^1b)₂；

R^1aSelected from H, F or C_1-4Alkyl, preferably H, F, methyl, ethyl, propyl or isopropyl, optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^1beach independently selected from H or C_1-4Alkyl, preferably H, methyl, ethyl, propyl or isopropyl, said alkyl, methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

R¹Is selected from

Ring B is selected from a benzene ring or a 5-to 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S, N.

Ring B is selected from phenyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl or pyrimidinyl.

Ring A is selected from a 4-to 9-membered nitrogen-containing heterocycle selected from a saturated or partially saturated monocyclic, fused, bridged or spiro ring, said nitrogen-containing heterocycle optionally further substituted with 0 to 4R^aSubstituted by a substituent;

R^aselected from H, oxo, F, Cl, Br, I, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

Ring A is selected from unsubstituted or substituted

When substituted, is optionally further substituted with 0 to 4R^aSubstituted by a substituent;

R²Each independently selected from substituted or unsubstituted H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, benzimidazolyl, benzopyrolyl, benzopyrazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinolinyl, pyridine [3,2-d ]]Pyrimidine or pyridine [4,3-d ]]Pyrimidines, when substituted, are optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

R^2a、R^2beach independently selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

R²Each independently selected from substituted or unsubstituted H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, benzimidazolyl, benzopyrolyl or benzopyrazolyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

R^2a、R^2beach independently selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, when substituted, optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy.

R²Each independently selected from substituted or unsubstituted H, isopropyl, cyclopropyl, phenyl, naphthyl, pyridinyl, benzimidazolyl, benzopyrolyl or benzopyrazolyl, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、-NHC(＝O)H、-NHC(＝O)CH₃、NHC(＝O)CH₂CH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Methyl, ethyl, propyl, isopropyl, acetyleneSubstituted with a substituent selected from the group consisting of phenyl, pyridyl, propargyl, methoxy, ethoxy and propoxy.

R³Selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃)₂、-N(CH₂CH₃)₂、-(CH₂)_q-cyclopropane, - (CH)₂)_q-cyclobutane, - (CH)₂)_q-cyclopentane, - (CH)₂)_q-cyclohexane, - (CH)₂)_q-azetidine, - (CH)₂)_q-oxetane, - (CH)₂)_q-tetrahydrothiophene, - (CH)₂)_q-tetrahydrofuran, - (CH)₂)_q-tetrahydropyrrole, - (CH)₂)_q-phenyl, - (CH)₂)_q-naphthyl, - (CH)₂)_q-Pyridine, - (CH)₂)_q-pyrimidines, - (CH)₂)_q-pyrazine, - (CH)₂)_q-thiophene, - (CH)₂)_q-furan, - (CH)₂)_q-pyrrole, - (CH)₂)_q-imidazole, - (CH)₂)_q-imidazole, - (CH)₂)_q-pyrazole, - (CH)₂)_q-triazole, - (CH)₂)_qTetrazole, - (CH)₂)_q-piperidine, - (CH)₂)_q-morpholine, - (CH)₂)_q-tetrahydropyran, - (CH)₂)_q-pyrrolidinediamine, - (CH)₂)_q-1, 3-oxazepan, - (CH)₂)_q-2-oxa-5-azabicyclo [2.2.1]Heptane, - (CH)₂)_q-piperazine or- (CH)₂)_q-N(R^3a)-C(＝O)R^3bWhen substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, -C_1-4alkylene-OH, - (CH)₂)_q-C_3-6Carbocyclic ring, - (CH)₂)_q-3 to 6 membered heterocycle, C_3-6Cycloalkyl radical, C_1-4Alkoxy, -N (C)_1-4Alkyl) C (═ O) -3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from O, S, N or a3 to 12 membered heterocycle;

R^3aselected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Alkoxy substituents;

R^3bselected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azetidine or oxetane being optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Alkoxy substituents;

q is selected from 0, 1, 2, 3 or 4.

R³Selected from substituted or unsubstituted H, methyl, ethyl, - (CH)₂)_q-tetrahydropyrrole, - (CH)₂)_qAzetidine, -N (CH)₃)₂or-N (CH)₂CH₃)₂When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, -C_1-4alkylene-OH, - (CH)₂)q-C_3-6Carbocyclic ring, - (CH)₂) q-3 to 6 membered heterocycle, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

q is selected from 0, 1, 2, 3 or 4.

Ring A is selected from

R³Is selected from-CH₂N(CH₃)₂、-CH₂N(CH₂CH₃)₂、-N(CH₂CH₃)₂、-N(CH₃)₂、

As a first embodiment of the present invention, the compound of the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein

R¹Is selected from-C (═ O) -C (R)^1a)＝C(R^1b)₂、

-S(＝O)₂-C(R^1a)＝C(R^1b)₂Or

R^1bor R^1cEach independently selected from H, F, Cl, Br, I, cyano, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) N (R)^1d)₂、-(CH₂)_p-N(C_1-4Alkyl radical)₂、-(CH₂)_pNHC(＝O)-C_1-4Alkyl, - (CH)₂)_p-C_3-10Carbocyclic ring or- (CH)₂)_p-3 to 12 membered heterocycle, said alkyl, alkoxy, heterocycle or carbocycle optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-10Carbocyclic or 5 to 12 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R³selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, N (R)^3a)₂、-(CH₂)_q-C(＝O)C_1-6Alkyl, - (CH)₂)_q-C (═ O) -3 to 12 membered heterocycle, - (CH)₂)_q-C(＝O)-C_3-10Carbocyclic ring, - (CH)₂)_q-C(＝O)-N(R^3a)₂、-(CH₂)_q-N(R^3a)-C(＝O)R^3b、-(CH₂)_q-3 to 12 membered heterocycle or- (CH)₂)_q-C_3-10Carbocyclic ring of said CH₂Alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, -C_1-4alkylene-OH, - (CH)₂)_q-C_3-10Carbocyclic ring, - (CH)₂)_q-3 to 12 membered heterocycle, C_3-6Cycloalkyl radical, C_1-4Alkoxy, -N (C)_1-4Alkyl) C (═ O) -3 to 12 membered heterocycle or 3 to 12 membered heterocycleRing substituents, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

R^3bselected from H, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3 to 12 membered heterocycle, said alkyl, cycloalkyl or heterocycle being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

n, p, q are each independently selected from 0, 1, 2, 3 or 4.

As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R^1cselected from H, F, Cl, Br, I, cyano, CF₃、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^aselected from H, oxo, F, Cl, Br, I, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

the remaining groups are defined as in the first embodiment.

As a third embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

ring A is selected from unsubstituted or substituted

the remaining groups are defined as in the second embodiment.

As a fourth embodiment of the present invention, there is provided a compound represented by the general formula (I) above or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

ring B is selected from a benzene ring or a 5-to 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S, N;

R²each independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C_1-6Alkylene-hydroxy, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, phenyl or 5-to 6-membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

the remaining groups are defined as in the third embodiment.

As a fifth embodiment of the present invention, there is provided a compound represented by the general formula (I) above or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R¹is selected from-C (═ O) -C (R)^1a)＝C(R^1b)₂；

R^1aSelected from H, F or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4Selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^1beach independently selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

the remaining groups are defined as in the fourth embodiment.

As a sixth embodiment of the present invention, there is provided a compound represented by the general formula (I) above or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R^1aselected from H, F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^1beach independently selected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

ring B is selected from phenyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl or pyrimidinyl;

R^xeach independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, Cl, and cyclohexyl,Cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

X₃selected from a bond or O;

R²each independently selected from substituted or unsubstituted H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, benzimidazolyl, benzopyrolyl, benzopyrazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinolinyl, pyridine [3,2-d ]]Pyrimidine or pyridine [4,3-d ]]Pyrimidines, when substituted, are optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、-NR^2aC(＝O)R^2b、-C(＝O)NR^2aR^2b、C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

R^2a、R^2beach independently selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R³selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃)₂、-N(CH₂CH₃)₂、-(CH₂)_q-cyclopropane, - (CH)₂)_q-cyclobutane, - (CH)₂)_q-cyclopentane, - (CH)₂)_q-cyclohexane, - (CH)₂)_q-azetidine, - (CH)₂)_q-oxetane, - (CH)₂)_q-tetrahydrothiophene、-(CH₂)_q-tetrahydrofuran, - (CH)₂)_q-tetrahydropyrrole, - (CH)₂)_q-phenyl, - (CH)₂)_q-naphthyl, - (CH)₂)_q-Pyridine, - (CH)₂)_q-pyrimidines, - (CH)₂)_q-pyrazine, - (CH)₂)_q-thiophene, - (CH)₂)_q-furan, - (CH)₂)_q-pyrrole, - (CH)₂)_q-imidazole, - (CH)₂)_q-imidazole, - (CH)₂)_q-pyrazole, - (CH)₂)_q-triazole, - (CH)₂)_qTetrazole, - (CH)₂)_q-piperidine, - (CH)₂)_q-morpholine, - (CH)₂)_q-tetrahydropyran, - (CH)₂)_q-pyrrolidinediamine, - (CH)₂)_q-1, 3-oxazepan, - (CH)₂)_q-2-oxa-5-azabicyclo [2.2.1]Heptane, - (CH)₂)_q-piperazine or- (CH)₂)_q-N(R^3a)-C(＝O)R^3bWhen substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, -C_1-4alkylene-OH, - (CH)₂)_q-C_3-6Carbocyclic ring, - (CH)₂)_q-3 to 6 membered heterocycle, C_3-6Cycloalkyl radical, C_1-4Alkoxy, -N (C)_1-4Alkyl) C (═ O) -3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from O, S, N or a3 to 12 membered heterocycle;

R^3bselected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azetidineThe cyclobutane or oxetane is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C_1-4Alkyl or C_1-4Alkoxy substituents;

q is selected from 0, 1, 2, 3 or 4;

the remaining groups are defined as in the fifth embodiment.

As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R¹is selected from

Ring A is selected from substituted or unsubstituted

When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, cyano, OH, CF₃Methyl, ethyl, propyl, isopropyl or CH₂CN;

ring B is selected from phenyl, pyridyl, thiazolyl, oxazolyl or imidazolyl;

R^2a、R^2beach independently selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which, when substituted,optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

the remaining groups are defined as in the sixth embodiment.

As an eighth embodiment of the present invention, the compound of the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R²each independently selected from substituted or unsubstituted H, isopropyl, cyclopropyl, phenyl, naphthyl, pyridinyl, benzimidazolyl, benzopyrolyl or benzopyrazolyl, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, OH, CF₃、-NHC(＝O)CH₃、NHC(＝O)CH₂CH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, or propoxy; ring A is selected from

X₁、X₂Any one of which is selected from a bond or C (R)^x)₂And the other is selected from O or C (R)^x)₂；

R^xEach independently selected from H, methyl or ethyl;

X₃selected from O or a bond;

The remaining groups are defined as in the seventh embodiment.

Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

the invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to an application of the compound or the stereoisomer, the deutero-derivative, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof in preparing a medicament for treating diseases related to the activity or the expression quantity of KRas-G12C, preferably an application in preparing a medicament for treating tumors, wherein the tumors are preferably hematological cancers, pancreatic cancers, MYH-related polyposis, colorectal cancers, non-small cell lung cancers or small cell lung cancers.

The first synthesis method comprises the following steps:

PG is selected from amino protecting groups;

R⁴is selected from C_1-6An alkyl group;

R⁵selected from a leaving group, preferably F, Cl, Br, I, triflate, mesylate, p-toluenesulfonate or benzenesulfonate;

R²、R³ring A, ring B, X₁、X₂、X₃Or n is as defined above for compounds of formula (I);

reacting the compound of the general formula (A1) with a carbonic diester-based compound under the action of a base to obtain a compound of the general formula (A2);

reacting the compound with the general formula (A2) with S-methylisothiourea sulfate under the action of alkali, or reacting the compound with the general formula (A2) with thiourea and then reacting with a methylating reagent under the action of alkali to obtain a compound with the general formula (A3);

reacting the compound of the general formula (A3) with trifluoromethanesulfonic anhydride under the action of a base, or carrying out chlorination reaction on the compound of the general formula (A3) to obtain a compound of the general formula (A4);

carrying out substitution reaction on the compound of the general formula (A4) to obtain a compound of the general formula (A5); carrying out oxidation reaction on the compound of the general formula (A5) to obtain a compound of a general formula (A6);

carrying out substitution reaction on the compound of the general formula (A6) to obtain a compound of the general formula (A7);

removing the amino protecting group from the compound of the general formula (A7) to obtain a compound of the general formula (A8);

the compound of the general formula (A8) is subjected to substitution reaction or condensation reaction to obtain the compound of the general formula (I).

And a second synthesis method comprises the following steps:

PG is selected from amino protecting groups;

R⁴is selected from C_1-6An alkyl group;

X₄selected from a leaving group, preferably F, Cl, Br, I, triflate, mesylate, p-toluenesulfonate or benzenesulfonate;

reacting the compound of the general formula (B1) with a carbonic diester-based compound under the action of a base to obtain a compound of the general formula (B2);

reacting the compound with the general formula (B2) with S-methylisothiourea sulfate under the action of alkali, or reacting the compound with the general formula (B2) with thiourea and then reacting with a methylating reagent under the action of alkali to obtain a compound with the general formula (B3);

reacting the compound with the general formula (B3) with trifluoromethanesulfonic anhydride under the action of a base, or carrying out chlorination reaction on the compound with the general formula (B3) to obtain a compound with the general formula (B4);

carrying out substitution reaction on the compound of the general formula (B4) to obtain a compound of a general formula (B5);

carrying out oxidation reaction on the compound of the general formula (B5) to obtain a compound of a general formula (B6);

carrying out substitution reaction on the compound of the general formula (B6) to obtain a compound of a general formula (B7);

carrying out a coupling reaction or a substitution reaction on the compound of the general formula (B7) to obtain a compound of the general formula (B8);

removing the amino protecting group from the compound of the general formula (B8) to obtain a compound of the general formula (B9);

the compound of the general formula (B9) is subjected to substitution reaction or condensation reaction to obtain the compound of the general formula (I).

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof(ii) a The alkyl group may be optionally further substituted with 0 to 6 groups selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, carboxy, or carboxylate, wherein alkyl is as defined herein.

"alkylene" refers to a straight and branched chain divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like; the alkylene group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkylene groups, as used herein, are defined in accordance with the present definition.

"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically of 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Cycloalkyl as found herein, is as defined above.

"alkynyl" means a straight and branched chain monovalent unsaturated hydrocarbon radical having at least 1, and typically 1, 2 or 3 carbon double bonds, and a backbone containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, and mixtures thereof, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; the alkyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkynyl groups are presented herein, and their definitions are consistent with this definition.

"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkoxy group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkoxy groups, as used herein, are defined in accordance with the present definition.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the aromatic or non-aromatic ring being optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, or naphthalene ring. The carbocycle may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Carbocyclic or carbocyclic groups, as used herein, are defined in accordance with the present definition.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and contain 1 to 3 heteroatoms selected from N, O or S, preferably a3 to 8 membered heterocyclyl, the optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom to which the heterocyclic group may be attached a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuryl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydropyridinyl, chromanyl, azabicyclo [3.2.1] octanyl, Azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptanyl. The heterocyclic group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Heterocyclyl groups, as found herein, are defined in accordance with this definition.

"Spirocyclic" refers to a5 to 20 membered polycyclic group sharing one carbon atom (referred to as spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may containThere are 0 to 5 heteroatoms selected from N, O or S (═ O) n. Preferably 6 to 14, more preferably 6 to 12, more preferably 6 to 10, non-limiting examples of which include:

when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-Ra、-O-(CH₂)_m-C(＝O)-Ra、-(CH₂)_m-C(＝O)-NRbRc、-(CH₂)_mS(＝O)nRa、-(CH₂)_m-alkenyl-Ra, ORd or- (CH)₂)_m-alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRc, wherein Rb and Rc are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally Rb and Rc may form a five or six membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused. Spiro rings appear herein, and their definition is consistent with this definition.

"fused ring" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms selected from N, S (═ O) n or O. Preferably 5 to 20, more preferably 5 to 14, more preferably 5 to 12, and even more preferably 5 to 10 yuan. Non-limiting examples include:

when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-Ra、-O-(CH₂)_m-C(＝O)-Ra、-(CH₂)_m-C(＝O)-NRbRc、-(CH₂)_mS(＝O)nRa、-(CH₂)_m-alkenyl-Ra, ORd or- (CH)₂)_m-alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRc, wherein Rb and Rc are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally Rb and Rc may form a five or six membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused. The definition of fused rings appearing herein is consistent with this definition.

"bridged ring" means any two polycyclic group of carbon atoms not directly linked, which may contain 0 or more double bonds and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 heteroatoms or groups selected from N, S (═ O) n or O (where n is 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include

And adamantane. When substituted, the substituents may beIs 1 to 5 substituents selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged cyclic, spiro cyclic, fused cyclic, hydroxyalkyl, (-) O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)₂)_m-C(＝O)-Ra、-O-(CH₂)_m-C(＝O)-Ra、-(CH₂)_m-C(＝O)-NRbRc、-(CH₂)_mS(＝O)nRa、-(CH₂)_m-alkenyl-Ra, ORd or- (CH)₂)_m-alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRc, wherein Rb and Rc are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally Rb and Rc may form a five or six membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused. The definition of bridged ring, as found herein, is consistent with this definition.

"Heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, heterocyclyl groups appearing herein, the definition of which is consistent with the present definition.

"fused ring" means a "fused ring" containing a heteroatom. The definition of fused ring appearing herein is consistent with this definition.

"Heterospirocyclic" refers to "spirocyclic" rings containing heteroatoms. The definition of the heterospirocyclic ring as presented herein is consistent with this definition.

"heterobridged ring" refers to a "bridged ring" containing a heteroatom. Heterobridged rings, as used herein, are defined in accordance with the present definition.

"aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single ring or fused rings, typically 6 to 10 carbon atoms, and which may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, arylHeteroaryl, heterocyclyl, bridged cyclic, spiro cyclic, fused cyclic, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)₂)_m-C(＝O)-Ra、-O-(CH₂)_m-C(＝O)-Ra、-(CH₂)_m-C(＝O)-NRbRc、-(CH₂)_mS(＝O)nRa、-(CH₂)_m-alkenyl-Ra, ORd or- (CH)₂)_m-alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRc, wherein Rb and Rc are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally Rb and Rc may form a five or six membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused. Aryl or aromatic rings are present herein, and the definition is consistent with the present definition.

"heteroaryl" refers to a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S (═ O) n, preferably a5 to 10 membered heteroaromatic ring, more preferably 5 to 6 membered aromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine, thiomorpholine, 1, 3-dithiane, benzopyrazoles, perindopyridinyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together to the parent structure is a heteroaryl ring, non-limiting examples of which include

When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, alkoxy, haloalkyl, thiol, heteroaryl, aryl, heteroaryl, aryl, heteroaryl, or heteroaryl, or heteroaryl,Carboxylic acid, formic ester, - (CH)₂)_m-C(＝O)-Ra、-O-(CH₂)_m-C(＝O)-Ra、-(CH₂)_m-C(＝O)-NRbRc、-(CH₂)_mS(＝O)nRa、-(CH₂)_m-alkenyl-Ra, ORd or- (CH)₂)_m-alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRc, wherein Rb and Rc are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally Rb and Rc may form a five or six membered cycloalkyl or heterocyclyl. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused. Heteroaryl, as used herein, is defined in accordance with the present definition.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and an internal standard of Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);

the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;

the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier;

the known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical industry, Shaoshanghi chemical technology, and Bailingwei technology;

boc: a tert-butoxycarbonyl group;

ts: a p-toluenesulfonyl group;

cbz: a benzyloxycarbonyl group;

TMS: trimethylsilyl;

example 1:

2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate salt (Compound 1)

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；trifluoroacetic acid.

The first step is as follows: 1-Oxetanochyl-2-carboxylic acid methyl ester (1A)

methyl 1-oxotetralin-2-carboxylate

Tetrahydronaphthalen-1-one (7g, 47.88mmol) was dissolved in 25mL of toluene, dimethyl carbonate (25mL) and 0.1mL of methanol were added, sodium hydride (2.30g, 95.70mmol) was slowly added at room temperature, and after the addition was completed, the mixture was heated to 90 ℃ and stirred for 2 hours. After cooling to room temperature, 20mL of a saturated aqueous ammonium chloride solution was added to quench the reaction, 20mL of ethyl acetate was added to conduct extraction, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the objective compound methyl 1-oxotetrao-methyl-2-carboxylate (1A) as a brown solid (10g, yield: 100%).

The second step is that: 2-thio-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (1B)

2-thioxo-5,6-dihydro-1H-benzo[h]quinazolin-4-one

After mixing the compound methyl 1-oxytetramethyl-2-carboxylate (1A) (2g, 9.79mmol) and thiourea (2.2g, 29.4mmol), it was heated to 190 ℃ under nitrogen atmosphere, stirred for 2h and cooled to room temperature. 40mL of a 1N aqueous solution of sodium hydroxide and 40mL of a methyl tert-butyl ether solution were added, and the mixture was stirred until the solid was completely dissolved, the organic phase was discarded, the aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid, a large amount of solid was precipitated, and the cake was filtered and dried under reduced pressure to give the target compound, 2-thio-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (1B), as a yellow solid (0.5g, yield: 22%).

The third step: 2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (1C)

2-methylsulfanyl-5,6-dihydro-3H-benzo[h]quinazolin-4-one

To sodium hydroxide (0.17g, 4.34mmol) was added 20mL of water, and after stirring to dissolve the solution, 2-thioxo-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (1B) (0.5g, 2.17mmol) and iodomethane (0.46g, 3.26mmol) were added in that order, and the mixture was stirred at room temperature for 5H. 20mL of methyl tert-butyl ether was added thereto, the mixture was stirred for 2min, the organic layer was discarded, the aqueous layer was adjusted to pH 4-5 with concentrated hydrochloric acid, a large amount of solid was precipitated, filtered, and the cake was dried under reduced pressure to give the desired compound, 2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (1C), as a yellow solid (0.4g, yield: 75%).

Ms m/z(ESI):245.1[M+1]⁺

The fourth step: (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (1D)

(2-methylsulfanyl-5,6-dihydrobenzo[h]quinazolin-4-yl)trifluoromethanesulfonate

The compound 2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (1C) (0.21g, 0.86mmol) was dissolved in 10mL of dichloromethane, triethylamine (0.26g, 2.58mmol) was added, trifluoromethanesulfonic anhydride (0.36g, 1.29mmol) was added under ice bath, and the mixture was stirred for 1H under ice-water bath. The reaction mixture was washed with 10mL of water, then with 10mL of saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure to give the compound (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (1D) as a yellow solid (0.33g, yield: 100%) which was used in the next step.

Ms m/z(ESI):377.1[M+1]⁺

The fifth step: (2S) -2- (cyanomethyl) -4- (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylic acid benzyl ester (1E)

benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6-dihydrobenzo[h]quinazolin-4-yl)piperazine-1-carboxylate

The compound (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (1D) (0.33g, 0.88mmol) was dissolved in 10mL of N, N-dimethylacetamide, and benzyl (2S) -2- (cyanomethyl) piperazine-1-carboxylate (0.27g, 1.1mmol) and diisopropylethylamine (0.34g, 2.6mmol) were added, and the mixture was stirred at room temperature for 3 h. After extraction with 20mL of water and 20mL of ethyl acetate, and concentration of the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/10-1/2) to give benzyl (2S) -2- (cyanomethyl) -4- (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylate (1E) as a pale yellow solid (0.34g, yield: 80%).

Ms m/z(ESI):486.2[M+1]⁺

And a sixth step: benzyl (2S) -2- (cyanomethyl) -4- (2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylate (1F)

benzyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-5,6-dihydrobenzo[h]quinazolin-4-yl)piperazine-1-carboxylate

The compound benzyl (2S) -2- (cyanomethyl) -4- (2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylate (1E) (0.34g, 0.70mmol) was dissolved in 10mL tetrahydrofuran, and m-chloroperoxybenzoic acid (0.18g, 1.05mmol) was added and stirred at room temperature for 2 h. 10mL of a saturated aqueous solution of sodium thiosulfate was added, the mixture was stirred for 20min, 20mL of ethyl acetate was added for extraction, and the organic layer was washed with 10mL of a saturated aqueous solution of sodium hydrogencarbonate, and concentrated under reduced pressure to give benzyl (2S) -2- (cyanomethyl) -4- (2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylate (1F), which was a target compound, as a yellow solid (0.35g, yield: 100%) which was used directly in the next step.

Ms m/z(ESI):502.2[M+1]⁺

The seventh step: benzyl (2S) -2- (cyanomethyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazine-1-carboxylate (1G)

benzyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazine-1-carboxylate

The compound benzyl (2S) -2- (cyanomethyl) -4- (2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) piperazine-1-carboxylate (1F) (0.18g, 0.36mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (0.083g, 0.72mmol) were dissolved in 10mL of toluene, and sodium tert-butoxide (0.05g, 0.53mmol) was added under ice bath and stirred under ice bath for 1 h. The reaction was quenched with 10mL of water, extracted with 10mL of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1-10/1.) to give the desired compound benzyl (2S) -2- (cyanomethyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazine-1-carboxylate (1G) as a pale yellow solid (0.17G, yield: 85%).

Ms m/z(ESI):553.3[M+1]⁺

Eighth step: 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile (1H)

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazin-2-yl]acetonitrile

Dissolving the compound (2S) -2- (cyanomethyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazine-1-carboxylate (1G) (0.16G, 0.29mmol) in 5mL of ethyl acetate, adding 5mL of methanol, adding 200mg of palladium on carbon (wt% ═ 10%), stirring under 1atm of hydrogen for 2H, filtering, removing the solvent under reduced pressure to give the objective compound 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile (1H), a yellow solid (0.10g, yield: 83%) was used directly in the next step.

Ms m/z(ESI):419.3[M+1]⁺

The ninth step: 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate salt (Compound 1)

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；trifluoroacetic acid

Dissolving the compound 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile (1H) (0.10g, 0.24mmol) in 5mL of dichloromethane, adding triethylamine (73mg, 0.72mmol), adding acryloyl chloride (20mg, 0.22mmol) in ice bath, stirring for 30min in ice bath, adding 10mL of saturated aqueous sodium bicarbonate solution, quenching, concentrating the organic layer under reduced pressure, preparing liquid chromatography (instrument and preparative column: preparing liquid phase using Glison GX-281, model number of preparative column is Sunfire C18, 5 μm, inner diameter ═ 30mm ═ 150 mm; preparation method: dissolving the crude product with N, N-dimethylformamide, filtering with 0.45 μm filter membrane to obtain sample solution; mobile phase system: acetonitrile/0.1% TFA water) to give 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile, trifluoroacetate (Compound 1) as a white solid (45mg, yield: 32%).

¹H NMR(400MHz,D₂O)δ7.86(d,1H),7.67-7.58(m,1H),7.56-7.44(m,2H),6.98-6.72(m,1H),6.41-6.23(m,1H),6.06-5.90(m,1H),5.25-5.10(m,1H),4.98-4.93(m,1H),4.92-4.80(m,1H),4.52(d,1H),4.36-4.12(m,2H),4.10-3.96(m,1H),3.90-3.79(m,1H),3.78-3.40(m,3H),3.38-3.24(m,1H),3.12(s,3H),3.10-2.98(m,2H),2.98-2.82(m,4H),2.56-2.43(m,1H),2.35-2.25(m,1H),2.24-2.04(m,2H).

Ms m/z(ESI):473.3[M+1]⁺

Example 2:

2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate (Compound 2)

2-[(2S)-4-[9-cyclopropyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；trifluoroacetic acid

The first step is as follows: 7-bromo-1-oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2A)

methyl 7-bromo-1-oxo-tetralin-2-carboxylate

7-bromo-3, 4-dihydro-2H-1-naphthalenone (5g, 22.2mmol) was dissolved in 15mL of toluene, dimethyl carbonate (15mL) and 0.1mL of methanol were added, sodium hydride (1.07g, 44.4mmol) was slowly added at room temperature, and after the addition was completed, the mixture was heated to 90 ℃ and stirred for 2H. After cooling to room temperature, 20mL of a saturated aqueous ammonium chloride solution was added to quench the reaction, and 20mL of ethyl acetate was added to conduct extraction, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, the objective compound methyl 7-bromo-1-oxotetrahydronaphthalene-2-carboxylate (2A) was obtained as a brown solid (6.4g, yield: 100%).

The second step is that: 9-bromo-2-thioxo-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (2B)

9-bromo-2-thioxo-5,6-dihydro-1H-benzo[h]quinazolin-4-one

After mixing the compound methyl 7-bromo-1-oxotetrahydronaphthalene-2-carboxylate (2A) (4g, 14.1mmol) and thiourea (3.23g, 42.4mmol), it was heated to 190 ℃ under nitrogen, stirred for 2h, and cooled to room temperature. 80mL of a 1N aqueous solution of sodium hydroxide and 80mL of a methyl tert-butyl ether solution were added, and the mixture was stirred until the solid was completely dissolved, the organic phase was discarded, the aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid, a large amount of solid was precipitated, and the cake was filtered and dried under reduced pressure to give the target compound, 9-bromo-2-thio-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (2B), as a yellow solid (1.3g, yield: 30%).

The third step: 9-bromo-2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (2C)

9-bromo-2-methylsulfanyl-5,6-dihydro-3H-benzo[h]quinazolin-4-one

To sodium hydroxide (0.34g, 8.41mmol) was added 20mL of water, and after stirring to dissolve the solution, 9-bromo-2-thioxo-5, 6-dihydro-1H-benzo [ H ] quinazolin-4-one (2B) (1.30g, 4.20mmol) and iodomethane (0.90g, 6.31mmol) were added in that order and stirred at room temperature for 0.5H. 20mL of methyl tert-butyl ether was added thereto, the mixture was stirred for 2min, the organic layer was discarded, the aqueous layer was adjusted to pH 4-5 with concentrated hydrochloric acid, a large amount of solid was precipitated, filtered, and the cake was dried under reduced pressure to give the target compound, 9-bromo-2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (2C), as a yellow solid (1.2g, yield: 88%).

Ms m/z(ESI):323.0[M+1]⁺

The fourth step: (9-bromo-2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (2D)

(9-bromo-2-methylsulfanyl-5,6-dihydrobenzo[h]quinazolin-4-yl)trifluoromethanesulfonate

The compound 9-bromo-2-methylsulfanyl-5, 6-dihydro-3H-benzo [ H ] quinazolin-4-one (2C) (0.6g, 1.9mmol) was dissolved in 10mL of dichloromethane, triethylamine (0.56g, 5.6mmol) was added, trifluoromethanesulfonic anhydride (0.79g, 2.8mmol) was added under ice bath, and stirred for 1H under ice bath. The reaction mixture was washed with 10mL of water, then with 10mL of saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure to give compound (9-bromo-2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (2D) which was used directly in the next step as a yellow solid (0.75g, yield: 89%).

The fifth step: (2S) -4- (9-bromo-2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (2E)

tert-butyl(2S)-4-(9-bromo-2-methylsulfanyl-5,6-dihydrobenzo[h]quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

The compound (9-bromo-2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) trifluoromethanesulfonate (2D) (0.75g, 1.6mmol) was dissolved in 10mL of N, N-dimethylacetamide, 2- [ ((2S) -piperazin-2-yl ] acetonitrile dihydrochloride (0.33g, 1.6mmol) and diisopropylethylamine (1.3g, 9.9mmol) were added thereto, stirring was performed at room temperature for 1 hour, di-tert-butyl dicarbonate (0.72g, 3.3mmol) was added thereto, 20mL of water and 20mL of ethyl acetate were added thereto and extraction was performed, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/10-1/2) to give the objective compound (2S) -4- (9-bromo-2-methylsulfanyl-5, tert-butyl 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2E), light yellow solid (0.72g, yield: 82%).

Ms m/z(ESI):530.2[M+1]⁺

And a sixth step: (2S) -4- (9-bromo-2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (2F)

tert-butyl(2S)-4-(9-bromo-2-methylsulfinyl-5,6-dihydrobenzo[h]quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

The compound tert-butyl (2E) (0.72g, 1.3mmol) 4- (9-bromo-2-methylsulfanyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate was dissolved in 10mL tetrahydrofuran, and m-chloroperoxybenzoic acid (0.33g, 1.9mmol) was added and stirred at room temperature for 2 h. 10mL of a saturated aqueous solution of sodium thiosulfate was added, the mixture was stirred for 20min, 20mL of ethyl acetate was added for extraction, and the organic layer was washed with 10mL of a saturated aqueous solution of sodium hydrogencarbonate and concentrated under reduced pressure to give the objective compound tert-butyl (2S) -4- (9-bromo-2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2F) which was used directly in the next step as a yellow solid (0.72g, yield: 97%).

The seventh step: tert-butyl (2S) -4- [ 9-bromo-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -2- (cyanomethyl) piperazine-1-carboxylate (2G)

tert-butyl(2S)-4-[9-bromo-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate.

The compound (2S) -tert-butyl 4- (9-bromo-2-methylsulfinyl-5, 6-dihydrobenzo [ h ] quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2F) (0.72g, 1.2mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (0.29g, 2.5mmol) were dissolved in 10mL of toluene, and sodium tert-butoxide (0.18g, 1.9mmol) was added under ice bath and stirred under ice bath for 1 h. The reaction was quenched with 10mL of water, extracted with 10mL of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1-10/1.) to give the objective compound tert-butyl (2S) -4- [ 9-bromo-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -2- (cyanomethyl) piperazine-1-carboxylate (2G) as a pale yellow solid (0.60G, yield: 77%).

Ms m/z(ESI):597.2[M+1]⁺

Eighth step: tert-butyl (2S) -2- (cyanomethyl) -4- [ 9-cyclopropyl-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazine-1-carboxylate (2H)

tert-butyl(2S)-2-(cyanomethyl)-4-[9-cyclopropyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazine-1-carboxylate

Dissolving the compound tert-butyl (2S) -4- [ 9-bromo-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -2- (cyanomethyl) piperazine-1-carboxylic acid ester (2G) (0.13G, 0.22mmol) and cyclopropylboronic acid (37mg, 0.44mmol) in a mixture of 4mL of toluene and 1mL of water, adding potassium phosphate, adding bis (triphenyl phosphonium) palladium dichloride (15mg, 0.02mmol) under nitrogen protection, heating to 110 ℃, stirring for 2h, cooling to room temperature, adding 10mL of water and 10mL of ethyl acetate, extracting the organic layer under reduced pressure, concentrating the residue under reduced pressure using a silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1-10/1.) to obtain the target compound tert-butyl (2S) -2- (cyanomethyl) -4- [ 9-cyclopropyl-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazine-1-carboxylate (2H), light yellow solid (80mg, yield: 66%).

Ms m/z(ESI):559.3[M+1]⁺

The ninth step: 2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (2I)

2-[(2S)-4-[9-cyclopropyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazin-2-yl]acetonitrile；trifluoroacetic acid

The compound tert-butyl (2S) -2- (cyanomethyl) -4- [ 9-cyclopropyl-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazine-1-carboxylate (2H) (80mg, 0.14mmol) was dissolved in 2mL of dichloromethane, 2mL of trifluoroacetic acid was added, stirring at room temperature for 2H, solvent was removed under reduced pressure to give 2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ H ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (2I), used directly in the next step as a yellow solid (90mg, yield: 100%).

Ms m/z(ESI):459.4[M+1]⁺

The tenth step: 2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate (Compound 2)

The compound 2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (2I) (0.080g, 0.14mmol) was dissolved in 5mL dichloromethane, triethylamine (42mg, 0.42mmol) was added, acryloyl chloride (13mg, 0.14mmol) was added under ice bath, stirred for 30min under ice bath, 10mL saturated aqueous sodium bicarbonate was added and quenched, the organic layer was concentrated under reduced pressure, a liquid chromatograph was prepared (instrument and preparative column: liquid phase was prepared using Glison GX-281, model number Sunfire C18, 5 μm, internal diameter: 30mm length: 150 mm; crude product was prepared using N, dissolving N-dimethylformamide, and filtering with 0.45 μm filter membrane to obtain sample solution; mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- [ ((2S) -4- [ 9-cyclopropyl-2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate salt (Compound 2), white solid (28mg, yield: 32%).

¹H NMR(400MHz,D₂O)δ7.51(s,1H),7.36-7.20(m,2H),6.95-6.68(m,1H),6.36-6.19(m,1H),6.01-5.85(m,1H),5.16-5.07(m,1H),4.99-4.80(m,2H),4.56-4.39(m,1H),4.27-4.08(m,2H),4.05-3.93(m,1H),3.86-3.74(m,1H),3.70-3.45(m,2H),3.43-3.17(m,2H),3.08(s,3H),3.03-2.90(m,2H),2.86-2.68(m,4H),2.53-2.37(m,1H),2.33-2.19(m,1H),2.18-1.91(m,3H),1.07-0.98(m,2H),0.78-0.68(m,2H).

Ms m/z(ESI):513.3[M+1]⁺

Example 3:

2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile, trifluoroacetate (Compound 3)

2-[(2S)-4-[9-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；trifluoroacetic acid；

The first step is as follows:

tert-butyl (2S) -2- (cyanomethyl) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazine-1-carboxylate (3A)

tert-butyl(2S)-2-(cyanomethyl)-4-[9-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazine-1-carboxylate

The compound tert-butyl (2S) -4- [ 9-bromo-2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -2- (cyanomethyl) piperazine-1-carboxylate (2G) (0.15G, 0.25mmol) and (2-fluoro-6-hydroxy-phenyl) boronic acid (78mg, 0.50mmol) were dissolved in a mixture of 4mL1, 4-dioxane and 1mL water, potassium acetate (74mg, 0.75mmol) was added, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (10mg, 0.025mmol) was added under nitrogen, the mixture was warmed to 100 ℃ and stirred for 5h, cooled to room temperature, 10mL water and 10mL ethyl acetate were added and extracted, after the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1-10/1.) to give the objective compound tert-butyl (2S) -2- (cyanomethyl) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazine-1-carboxylate (3A) as a yellow solid (80mg, yield: 51%).

Ms m/z(ESI):629.3[M+1]⁺

The second step is that: 2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (3B)

2-[(2S)-4-[9-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid

The compound tert-butyl (2S) -2- (cyanomethyl) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] piperazine-1-carboxylate (3A) (80mg, 0.13mmol) was dissolved in 2mL of dichloromethane, 2mL of trifluoroacetic acid was added and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give 2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (3B), which was used directly in the next step as a yellow solid (100mg, yield: 100%).

The third step: 2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile, trifluoroacetate (Compound 3)

2-[(2S)-4-[9-(2-fluoro-6-hydroxy-phenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；trifluoroacetic acid

2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] ] quinazolin-4-yl ] piperazin-2-yl ] acetonitrile, trifluoroacetate (3B) (0.10g, 0.13mmol) was dissolved in 5mL of dichloromethane, triethylamine (42mg, 0.42mmol) was added, acryloyl chloride (12mg, 0.13mmol) was added under ice bath, stirring was carried out for 30min under ice bath, 10mL of saturated aqueous sodium bicarbonate was added and quenched, the organic layer was concentrated under reduced pressure, a liquid chromatograph was prepared (instrument and preparative column: preparation of liquid phase using Glison GX-281, preparative column type Sunfire C18, 5 μm, internal diameter: 30mm x 150mm, preparative method: crude product was treated with N, dissolving N-dimethylformamide, and filtering with 0.45 μm filter membrane to obtain sample solution; mobile phase system: acetonitrile/0.1% TFA water) to obtain target 2- [ (2S) -4- [9- (2-fluoro-6-hydroxy-phenyl) -2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -5, 6-dihydrobenzo [ h ] quinazolin-4-yl ] -1-prop-2-enoylpiperazin-2-yl ] acetonitrile; trifluoroacetate salt (compound 3), white solid (20mg, yield: 22%).

¹H NMR(400MHz,D₂O)δ7.86(s,1H),7.35-7.00(m,3H),6.91-6.80(m,1H),6.79-6.47(m,2H),6.31-6.08(m,1H),5.97-5.76(m,1H),4.99-4.87(m,1H),4.76-4.45(m,3H),4.34-3.55(m,5H),3.44-3.11(m,3H),3.10-2.65(m,7H),2.63-2.22(m,3H),2.20-2.08(m,1H),2.07-1.95(m,1H),1.94-1.78(m,1H).

Ms m/z(ESI):583.3[M+1]⁺

Biological test example

NCI-H358 cells were purchased from ATCC, cultured in RPMI1640, 10% FBS, 37 ℃, 5% CO 2. On the first day, NCI-H358 cells in exponential growth phase were collected and viable cells were counted using a Vi-Cell XR Cell counter (Beckman Coulter, TACEL 0030). The cell suspension was adjusted to 5000/90. mu.L with the medium. Add 90. mu.L of cell suspension to each well in 96-well cell culture plates. The next day, the compounds were incubated. Test compounds were initially at 10 μ M, 3-fold diluted, 9 concentrations, with a final DMSO concentration of 0.1% per well. At 37 ℃ with 5% CO₂Incubate for 72 hours. After 72 hours of drug treatment, 50. mu.L (1/2 culture volume) of CTG solution (promega, G7572) which had been previously thawed and equilibrated to room temperature was added to each well, mixed by a microplate shaker for 2 minutes, allowed to stand at room temperature for 10 minutes, and then measured for the fluorescence signal value by an Envision2104 plate reader.

The cell viability was calculated by the formula (1). Wherein V_sampleReading for the drug treatment group, V_vehicle _controlMean values for the solvent control group. Sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 5.0 software and IC50 values were calculated. Maximum inhibition of cells (Max inh.%) maximum inhibition of cells by compound at a certain concentration was calculated using formula (2)

V_sample/V_{vehicle control}x 100% equation 1

1-V_sample/V_{vehicle control}x 100% equation 2

TABLE 1 inhibition of NCI-H358 cell proliferation

The compound of the embodiment of the invention has an IC50 of less than 10 mu M on NCI-H358 cell proliferation, and Max inh (%) reaches more than 90% at a concentration of 10 uM.

Claims

1. A compound of the general formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein

R¹Is selected from-C (═ O) -C (R)^1a)＝C(R^1b)₂；

R^1aIs selected from H;

R^1bis selected from H;

ring A is selected from

Ring B is selected from phenyl;

R²each independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, said alkyl, alkoxy or phenyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH;

X₁、X₂any one of which is selected from C (R)^x)₂；

X₃Selected from O and-OCH₂-, S or NR^x；

R^xEach independently selected from H;

R³is selected from

Optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、NH₂、C_1-4Alkyl, -C_1-4alkylene-OH, C_1-4Substituted by a substituent of alkoxy;

n is independently selected from 0, 1, 2, 3 or 4.

2. A compound of general formula (I) according to claim 1 or a stereoisomer, pharmaceutically acceptable salt thereof, wherein

X₃Is selected from O;

R²each independently selected from substituted orUnsubstituted H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, phenyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH;

R³is selected from

Optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、C_1-4Alkyl, -C_1-4alkylene-OH.

3. A compound of general formula (I) according to claim 2 or a stereoisomer pharmaceutically acceptable salt thereof, wherein

R¹Is selected from

R²Each independently selected from substituted or unsubstituted H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, isopropyl, phenyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH.

4. A compound of general formula (I) according to claim 3 or a stereoisomer pharmaceutically acceptable salt thereof, wherein

R²Each independently selected from substituted or unsubstituted H, phenyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R³is selected from

5. The compound of formula (I) according to claim 1, or a stereoisomer pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

6. a pharmaceutical composition for treating non-small cell lung cancer, comprising a compound of any one of claims 1-5, or a stereoisomer, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.