CN114630832A - Pyrimido-cyclic derivative and application thereof in medicine - Google Patents

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 eutectic crystal or a pharmaceutically acceptable salt thereof. The invention also relates to an intermediate of the compound, a preparation method of the compound and application of the compound in preparing a medicament for preventing or treating diseases related to KRAS G12C activity or expression quantity.

Description

Pyrimido-cyclic derivative and application thereof in medicine Technical Field

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

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 an inhibitor of KRAS G12C protein.

In particular, the present invention provides compounds capable of inhibiting KRAS G12C protein or a stereoisomer, deutero, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof. The invention also provides an intermediate and a preparation method of the compound, and application of the compound or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a cocrystal or a pharmaceutically acceptable salt of the compound in preparation of a medicine for preventing or 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 eutectic crystal or a pharmaceutically acceptable salt thereof, wherein

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

-S(＝O) ₂-C(R ^1a)＝C(R ^1b) ₂Or

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

In some embodiments, R¹Is selected from

In some embodiments, R^1aEach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^1aSelected from H, F or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^1aSelected from H, F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, 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、-(CH ₂) _p-N(C _1-4Alkyl radical)₂、-(CH ₂) _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 being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R^1bEach independently selected from H, C_1-4Alkyl or- (CH)₂) _p-3 to 6 membered heterocycle, said alkyl or heterocycle being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Carbocyclic ring orSubstituted with a substituent of a 3-to 6-membered heterocyclic ring containing 1 to 4 (e.g., 1,2, 3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R^1bEach independently selected from H, methyl, ethyl, propyl, isopropyl, -CH₂-4-membered nitrogen-containing heterocycle, -CH₂-5-membered nitrogen-containing heterocycle, -CH₂-6-membered, 4-membered, 5-membered or 6-membered nitrogen-containing heterocycle, said methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycle being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

in some embodiments, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^1aWith any one of R^1bForm C_5-10A carbocyclic ring or a 5 to 12 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^1dEach independently selected from H or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

in some embodiments, ring a is selected from a4 to 12 membered nitrogen containing heterocycle selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) R^aSubstitution;

in some embodiments, ring a is selected from a4 to 9 membered nitrogen containing heterocycle selected from one of the following saturated or partially saturated structures: monocyclic, fused, bridged or spiro ring, said nitrogen-containing heterocycle being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) R^aSubstituted by a substituent;

in some embodiments, R^aEach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, ring a is selected from unsubstituted or substituted

When substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) R^aSubstituted by a substituent;

in some embodiments, ring a is selected from one of the following substituted or unsubstituted groups:

when substituted, is optionally substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, cyano, OH, CF₃Methyl, ethyl, propyl, isopropyl or CH₂CN;

in some embodiments, ring a is selected from

In some embodiments, ring a is selected from

In some embodiments, R^aEach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, Q, M forms C with the atom directly attached to both_3-12A carbocycle or 3-to 12-membered heterocycle which is monocyclic, bicyclic or spirocyclic, optionally further substituted by 0 to 5 (e.g. 0, 1,2, 3,4 or 5) R²(ii) substituted, said heterocyclic ring containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, Q, M forms with the atom directly attached to both

Ring B is selected from a non-aromatic 4-to 7-membered heterocyclic ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N, X₁Selected from N, ring C and ring D together form C_6-12A carbocyclic fused ring or a 5 to 12 membered heterocyclic fused ring, said heterocyclic fused ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N, m1 is selected from 0, 1,2, 3 or 4, m2, m3 are each independently selected from 0, 1,2, 3 or 4, and m2+ m3 ≦ 5;

in some embodiments, Q, M forms with the atom directly attached to both

Ring B is selected from azetidine, cyclopentane, piperidine or imidazolidine, and ring D is selected from a benzene ring, pyridine, pyridazine or pyrimidine; ring C is selected from C_4-6A carbocycle, a 4-to 6-membered heterocycle containing 1 to 3 (e.g., 1,2, or 3) heteroatoms selected from O, S, N;

in some embodiments, Q, M forms with the atom directly attached to both

Ring B is selected from piperidine;

in some embodiments, Q, M forms with the atom directly attached to both

In some embodiments, Q, M forms with the atom directly attached to both

Is selected from

In some embodiments of the present invention, the substrate is,

is selected from

In some embodiments, Q, M forms with the atom directly attached to both

G _1-G ₂Is selected from-CH₂CH ₂-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH ₃)-、-N(CH ₃) -C (═ O) -or-NH-C (═ O) -, m2 is selected from 0, 1,2 or 3;

in some embodiments, Q, M forms with the atom directly attached to both

R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents, m2 is selected from 0, 1,2 or 3;

in some embodiments, R²Each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8 membered heterocycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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;

in some embodiments, R²Each independently selected from R^2a、R ^2b、R ^2c、R ^2d；

In some embodiments, R^2aSelected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8 membered heteroCycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^2aSelected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-4Alkyl, -C (═ O) -phenyl, -C (═ O) -5 to 6 membered heteroaryl, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^2aSelected from H or one of the following substituted or unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl, when substituted, are optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, cyano, CF, Br, I, OH₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

in some embodiments, R^2aSelected from H or substituted orOne of the following unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, are optionally selected from H, F, Cl, Br, I, OH, cyano, CF or 4, optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl or ethyl;

in some embodiments, R^2aSelected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 3 to6-membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^2aSelected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、NH ₂Methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl;

in some embodiments, R^2bEach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃COOH or C_1-6Alkyl optionally further substituted by 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl or C_1-6Substituted by a substituent of alkoxy;

in some embodiments, R^2bEach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, optionally substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^2bEach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, optionally substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

in some embodiments, R^2c、R ^2dEach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、COOH、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-4Alkyl radical, C_1-4Alkoxy 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 (e.g. 0, 1,2, 3 or4) are selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、--C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF, Cl, Br, n₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxyOptionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 41, 2,3 or 4 heteroatoms selected from O, S, N;

in some embodiments, R^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl being optionally further substituted by 0 to 4 (e.g. methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl0.1, 2,3 or 4) are selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents;

in some embodiments, R^2dEach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、C _1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂Or C_1-6Alkyl is substituted by a substituent;

in some embodiments, R^2dEach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

in some embodiments, R^2dEach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

in some embodiments, R^2A、R ^2BOr R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

in some embodiments, X₃Selected from the group consisting of a bond, O, -OCH₂-、-CH ₂O-, S or NR^x；

In some embodiments, X₃Selected from a bond or O;

in some embodiments, R^xSelected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0, 1,2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy; 0 to 4 (e.g. 0, 1,2, 3 or 4)

In some embodiments, R³Selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _{1- 6}Alkyl radical, C_1-6Alkoxy, N (R)^3a) ₂、-(CH ₂) _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、-(CH ₂) _q-N(R ^3a)-C(＝O)R ^3b、-(CH ₂) _q-3 to 12 membered heterocycle or- (CH)₂) _q-C _3-10Carbocyclic ring of said CH₂Optionally further substituted by 0 to 4 (e.g. alkyl, alkoxy, carbocycle or heterocycle)0.1, 2,3 or 4) are selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 heterocycle containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R³Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃) ₂、-N(CH ₂CH ₃) ₂、-(CH ₂) _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-pyrimidine, - (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-pyridineAzole, - (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 ^3bOptionally substituted, by 0, 1,2, 3 or 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N or a 3 to 12 membered heterocycle;

in some embodiments, R³Selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, - (CH)₂) _q-tetrahydropyrrole, - (CH)₂) _qAzetidine, -N (CH)₃) ₂or-N (CH)₂CH ₃) ₂Optionally substituted, by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

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

in some embodiments, R^3aSelected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Alkoxy substituents;

in some embodiments, two R are^3aAnd the nitrogen atom directly linked to both form a 4-to 8-membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring being optionally further substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

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

in some embodiments, R^3bSelected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azetidine or oxetane being optionally further selected from 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Alkoxy substituents;

in some embodiments, R³Is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

In some embodiments, X₃-R ³Is selected from

In some casesIn the embodiment, R⁴Each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or C_1-6Alkyl optionally further substituted by 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R⁴Each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or a methyl group;

in some embodiments, n, p, q are each independently selected from 0, 1,2, 3 or 4;

in some embodiments, n is selected from 0;

in some embodiments, m2 is selected from 0, 1,2, or 3.

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

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

-S(＝O) ₂-C(R ^1a)＝C(R ^1b) ₂Or

R ^1aEach independently selected from H, F, Cl, Br, I, cyano, CF₃、C _1-4Alkyl radical, C_1-4Alkoxy or-NHC (═ O) R^1dSaid alkyl or alkoxy being optionally further substituted by 0 to4 (e.g. 0, 1,2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-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、-(CH ₂) _p-N(C _1-4Alkyl radical)₂、-(CH ₂) _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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N;

alternatively, R^1aWith any one of R^1bForm C_5-10A carbocyclic ring or a 5 to 12 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^1deach independently selected from H or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-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 4-12 membered nitrogen-containing heterocyclic rings selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) R^aSubstitution;

R ^aeach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

q, M together with the atom to which they are directly attached form C_3-12A carbocycle or a 3-to 12-membered heterocycle which is monocyclic, fused or spirocyclic, optionally further substituted with 0 to 5R²(ii) substituted, said heterocyclic ring containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ²each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8 membered heterocycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5-to 10-membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C(ii) said heterocycloalkyl or heteroaryl group contains 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2A、R ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

X ₃selected from the group consisting of a bond, O, -OCH₂-、-CH ₂O-, S or NR^x；

R ^xSelected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

R ³selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-6Alkyl radical, C_1-6Alkoxy, N (R)^3a) ₂、-(CH ₂) _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、-(CH ₂) _q-N(R ^3a)-C(＝O)R ^3b、-(CH ₂) _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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N or a 3 to 12 membered heterocycle;

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

alternatively, two R^3aAnd the nitrogen atom directly attached to both form a 4-to 8-membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

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

R ⁴each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or C_1-6Alkyl optionally further substituted by 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

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

As a second embodiment of the present invention, a compound of the following general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Ring B is selected from a non-aromatic 4-to 7-membered heterocyclic ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N;

X ₁is selected from N;

R ^2aselected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8-membered heterocycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Substituted by substituents of aryl or 5-to 10-membered heteroaryl, said heteroarylCycloalkyl or heteroaryl contains 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2beach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃COOH or C_1-6Alkyl optionally further substituted by 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl or C_1-6Substituted by a substituent of alkoxy;

ring C and ring D together form C_6-12A carbocyclic fused ring or a 5 to 12 membered heterocyclic fused ring containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2c、R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、COOH、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6A cycloalkyl group, a,3 to 6 membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2A、R ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

m1 is selected from 0, 1,2, 3 or 4;

m2 and m3 are respectively and independently selected from 0, 1,2, 3 or 4, and m2+ m3 is less than or equal to 5;

the remaining groups are as defined for the first embodiment.

As a third embodiment of the present invention, the above compound of formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radicalOr C_1-4Substituted by a substituent of alkoxy;

ring a is selected from a 4-to 9-membered nitrogen-containing heterocycle selected from one of the following saturated or partially saturated structures: monocyclic, fused, bridged or spiro ring, said nitrogen-containing heterocycle being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) R^aSubstituted by a substituent;

R ^aeach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

the remaining groups are as defined for the second embodiment.

As a fourth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Ring A is selected from unsubstituted or substituted

When substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) R^aSubstituted by a substituent;

R ^aeach independently selected from H, oxo, F, Cl, Br, I, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxyFurther substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

the remaining groups are defined as in the third embodiment.

As a fifth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, cocrystal or pharmaceutically acceptable salt thereof, wherein

Ring B is selected from azetidine, aziridine or piperidine;

or ring B is selected from imidazolidine;

R ^2aselected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-4Alkyl, -C (═ O) -phenyl, -C (═ O) -5 to 6 membered heteroaryl, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

ring D is selected from a benzene ring, pyridine, pyridazine or pyrimidine;

ring C is selected from C_4-6A carbocyclic ring;

or ring C is selected from a4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-4Alkyl radical, C_1-4Alkoxy 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2A、R ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl,the heterocycloalkyl group contains 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、C _1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂Or C_1-6Alkyl is substituted by a substituent;

the remaining groups are as defined for any of the second, third or fourth embodiments.

As a sixth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, cocrystal or pharmaceutically acceptable salt thereof, wherein

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

R ^1aSelected from H, F or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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, C_1-4Alkyl or- (CH)₂) _p-3 to 6 membered heterocycle, said alkyl or heterocycle being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Carbocyclic or 3 to 6 membered heterocyclic ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N;

the remaining groups are as defined for any of the second, third, fourth or fifth embodiments.

As a seventh embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

R ^1aSelected from H, F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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, isopropyl, -CH₂-4-membered nitrogen-containing heterocycle, -CH₂-5-membered nitrogen-containing heterocycle, -CH₂-6-membered, 4-membered, 5-membered or 6-membered nitrogen-containing heterocycle, said methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycle being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

X ₃selected from a bond or O;

R ^2aselected from H or one of the following substituted or unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl, when substituted, are optionally selected from 0 to 4 (e.g. 0, 1,2, 3 or 4) H, F, Cl, Br, I, OH, cyano, CF, Br₃、- C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

R ^2beach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, optionally substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

ring C and ring D together form a fused ring selected from

Or ring C and ring D together form a fused ring selected from

R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、--C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF, Cl, Br, n₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Substituted with an alkoxy substituent;

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R ³selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃) ₂、-N(CH ₂CH ₃) ₂、-(CH ₂) _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 ^3bOptionally substituted, by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N, or a 3 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 (e.g. 0, 1,2, 3 or 4) groups 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 selected from 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Alkoxy substituents;

R ⁴each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or a methyl group;

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

the remaining groups are as defined for any of the second, third, fourth, fifth or sixth embodiments.

As an eighth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a cocrystal or a pharmaceutically acceptable salt thereof, wherein

R ¹Is selected from

Ring a is selected from one of the following substituted or unsubstituted groups:

when substituted, are optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, cyano, OH, CF₃Methyl, ethyl, propyl, isopropyl or CH₂CN;

ring B is selected from piperidine;

or alternatively

Is selected from

R ^2aSelected from H or one of the following substituted or unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, are optionally selected from H, F, Cl, Br, I, OH, cyano, CF or 4, optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl or ethyl;

R ^2beach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, optionally substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF, and mixtures thereof₃、COOH、NH ₂Methyl or ethyl;

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

R ³selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, - (CH)₂) _q-tetrahydropyrrole, - (CH)₂) _qAzetidine, -N (CH)₃) ₂or-N (CH)₂CH ₃) ₂Optionally substituted, by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

the remaining groups are as defined for any of the second, third, fourth, fifth, sixth or seventh embodiments.

As a ninth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, cocrystal or pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

X ₃Selected from O or a bond;

R ³is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

n is selected from 0;

the remaining groups are as defined for any of the second, third, fourth, fifth, sixth, seventh or eighth embodiments.

As a tenth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deutero, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

X ₃-R ³Is selected from

n is selected from 0;

the remaining groups are as defined for any of the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments.

As an eleventh embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deutero, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Is selected from

Is selected from

R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

n is selected from 0;

m2 is selected from 0, 1,2 or 3;

the remaining groups are as defined for any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments.

As a twelfth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, cocrystal or pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

X ₃Selected from O or a bond;

R ³is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

n is selected from 0;

the remaining groups are as defined for the eleventh embodiment.

As a thirteenth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

X ₃-R ³Is selected from

The remaining groups are as defined in the twelfth embodiment.

As a fourteenth embodiment of the present invention, a compound of the following general formula (Ia-1) or (Ib-1) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

G _1-G ₂Is selected from-CH₂CH ₂-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH ₃)-、-N(CH ₃) -C (═ O) -or-NH-C (═ O) -;

R ^2aselected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_{3- 6}Cycloalkyl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

m2 is selected from 0, 1,2 or 3;

the remaining groups are as defined for any of the second, third, fourth, fifth, sixth, seventh or eighth embodiments.

As a fifteenth embodiment of the present invention, the compound of the above general formula (Ia-1) or (Ib-1) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

R ¹Is selected from

R ^2aSelected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、NH ₂Methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl;

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyanogenRadical, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents;

ring A is selected from

X ₃-R ³Is selected from

n is selected from 0.

As a sixteenth embodiment of the present invention, the compounds of the following general formulae (Ic-1) and (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

Each group is defined as any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments of the invention.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuteron, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

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

R ^1aSelected from H, F or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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 optionally further substituted by 0 to 4 (e.g. alkyl)0.1, 2,3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

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

R ^1aSelected from H, F or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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, C_1-4Alkyl or- (CH)₂) _p-3 to 6 membered heterocycle, said alkyl or heterocycle being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Carbocyclic or 3 to 6 membered heterocyclic ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt, (Ic-1) or (Ic-2) or co-crystal thereof,

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

R ^1aSelected from H, F or C_1-4Alkyl optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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, C_1-4Alkyl or- (CH)₂) _p-a 4 to 6 membered nitrogen containing heterocycle, said alkyl or nitrogen containing heterocycle optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Carbocyclic or 3 to 6 membered heterocyclic ring containing 1 to 4 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or a stereoisomer, deuteron, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

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

R ^1aSelected from H, F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups 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 selected from 0 to 4 (e.g. 0, 1,2, 3 or 4) H, F, Cl, Br, I, oxo, OH, cyanogenBasic, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

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

R ^1aSelected from H, F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

R ^1beach independently selected from H, methyl, ethyl, propyl, isopropyl, -CH₂-4-membered nitrogen-containing heterocycle, -CH₂-5-membered nitrogen-containing heterocycle, -CH₂-6-membered, 4-membered, 5-membered or 6-membered nitrogen-containing heterocycle, said methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycle being optionally further substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Alkoxy groups.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ¹is selected from

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

ring a is selected from one of the following substituted or unsubstituted groups:

when substituted, is optionally substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, cyano, OH, CF₃Methyl, ethyl, propyl, isopropyl or CH₂CN.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

ring a is selected from one of the following substituted or unsubstituted groups:

when substituted, is optionally substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) groups selected from H, F, Cl, Br, I, oxo, cyano, OH, CF₃Methyl, ethyl, propyl, isopropyl or CH₂CN.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

ring a is selected from one of the following unsubstituted or substituted structures:

when substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4) R^aTaking substitution;

R ^aeach independently selected 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Alkoxy groups.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

ring A is selected from

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ³selected from one of the following substituted or unsubstituted groups: H. methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃) ₂、-N(CH ₂CH ₃) ₂、-(CH ₂) _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 ^3bOptionally substituted, by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N, or a 3 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 (e.g. 0, 1,2, 3 or 4) groups 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 selected from 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, cyano, OH, CF₃、C _1-4Alkyl or C_1-4Alkoxy substituents.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuteron, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, R³Selected from one of the following substituted or unsubstituted groups: H. methyl, ethyl, - (CH)₂) _q-tetrahydropyrrole, - (CH)₂) _qAzetidine, -N (CH)₃) ₂or-N (CH)₂CH ₃) ₂Optionally substituted, by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ³is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

Some embodiments of the invention relate to a compound of formula (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, X₃-R ³Is selected from

Some embodiments of the invention relate to a compound of formula (Ia) or a stereoisomer, deuteron, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, ring B being selected from azetidine, azetidine or piperidine.

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

ring B is selected from imidazolidine.

Some embodiments of the invention relate to a compound of formula (Ia) or (Ia-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

R ^2aselected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-4Alkyl, -C (═ O) -3 to 8 membered heterocycloalkyl, -C (═ O) -phenyl, -C (═ O) -5 to 6 membered heteroaryl, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C _1-6Alkyl radical, C_2-6Alkynyl, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said heterocycloalkyl orHeteroaryl contains 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;

R ^2A、R ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、 COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (Ia) or (Ia-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

R ^2aselected from one of the following substituted or unsubstituted groups: H. -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、--C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cycloButyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl, when substituted, optionally substituted with 0 to 4 (e.g., 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4And a substituent of the alkynyl group.

Some embodiments of the invention relate to a compound of formula (Ia) or (Ia-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

R ^2aselected from one of the following substituted or unsubstituted groups: H. -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, are optionally selected from H, F, Cl with 0 to 4 (e.g. 0, 1,2, 3 or 4) sBr, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl or ethyl.

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

is selected from

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

is selected from

R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

m2 is selected from 0, 1,2 or 3.

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

R ^2beach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, optionally substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl.

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

ring D is selected from a benzene ring, pyridine, pyridazine or pyrimidine;

ring C is selected from C_4-6A carbocyclic ring or a4 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N.

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

ring C and ring D together form a fused ring selected from

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

ring C and ring D together form a fused ring selected from

Some embodiments of the invention relate to a compound of formula (Ib) or (Ib-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-4Alkyl radical, C_1-4Alkoxy 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (Ib) or (Ib-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-4Alkyl radical, C_1-4Alkoxy 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the invention relate to a compound of formula (Ib) or (Ib-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) substituents selected from H, F, C (═ O) NH-phenyl, C (═ O) -phenyl, methyl, ethyl, methoxy, ethoxy or phenyl,Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Substituted with an alkoxy substituent;

some embodiments of the invention relate to a compound of formula (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、C _1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂Or C_1-6Alkyl substituents.

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

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

Some embodiments of the invention relate to a compound of formula (Ib) or (Ib-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF, Cl, Br, n₃、COOH、NH ₂Methyl or ethyl;

some embodiments of the invention relate to a compound of formula (Ib) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl.

Some embodiments of the present invention relate to a compound of formula (Ib-1) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, G_1-G ₂Is selected from-CH₂CH ₂-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH ₃)-、-N(CH ₃) -C (═ O) -or-NH-C (═ O) -.

Some embodiments of the present invention relate to compounds of formula (Ia-1) or a stereoisomer, deutero, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

R ^2aselected from H, C_1-6Alkyl 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, 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 (e.g., 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the present invention relate to compounds of formula (Ia-1) or a stereoisomer, deutero, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

R ^2aselected from one of the following substituted or unsubstituted groups: H. methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, optionally substituted with 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl.

Some embodiments of the present invention relate to a compound of formula (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_{3- 6}Cycloalkyl, 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 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C _2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 (e.g. 1,2, 3 or 4) heteroatoms selected from O, S, N.

Some embodiments of the present invention relate to a compound of formula (Ib-1), (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof,

R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2, 3 or 4) groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents.

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

ring A is selected from

Ring B is piperidine; n is 0; m1 is 0;

R ¹is selected from

R ^2aSelected from one of the following substituted or unsubstituted groups: -C (═ O) -C_1-4Alkyl, phenyl, naphthyl, pyridyl, when substituted, optionally substituted with 0 to 4 (e.g., 0, 1,2, 3, or 4)) Selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl or-C (═ O) NH-phenyl;

R ³is selected from

X ₃Is a bond or O.

Some embodiments of the present invention relate to compounds of formula (Ia) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

Ring B is selected from azetidine or aziridine;

n is 0; m1 is 0, 1 or 2;

R ¹is selected from

R ^2aSelected from substituted or unsubstituted phenyl or naphthyl, which when substituted is optionally substituted with 0 to 4 (e.g., 0, 1,2, 3 or 4) groups selected from F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy and ethoxy;

R ^2bis oxo;

R ³is selected from

X ₃Is O.

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

ring A is selected from

Ring C and ring D together form a fused ring selected from

n is 0; m2 is 1; m3 is 0;

R ¹is selected from

R ^2cEach independently selected from F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy or ethoxy;

R ³is selected from

X ₃Is O.

Some embodiments of the present invention relate to compounds of formula (Ia-1) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

n is 0;

R ^2ais H or phenyl, said phenyl being optionally substituted by 1,2, 3 or 4 substituents selected from F, Cl, Br, I, OH, cyano, CF₃、NH ₂Methyl, ethyl, methoxy and ethoxy substituentSubstitution;

R ³is selected from

X ₃Is O.

Some embodiments of the present invention relate to a compound of formula (Ic-1) or a stereoisomer, deuteron, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

R ¹Is selected from

R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃-C (═ O) NH-phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Substituted with an alkoxy substituent; m2 is selected from 0, 1,2 or 3;

R ³is selected from

X ₃Is O.

Some embodiments of the present invention relate to a compound of formula (Ib-1) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

n is 0; m2 is 0;

R ³is selected from

X ₃Is O;

G ₁-G ₂is NH-C (═ O) -or-C (═ O) -NH.

Some embodiments of the present invention relate to compounds of formula (Ic-2) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

m2 is 0;

R ³is selected from

X ₃Is O.

Some embodiments of the present invention relate to compounds of formula (Ia-1) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

n is 0; r^2aIs phenyl;

R ³is selected from

X ₃Is O.

Some embodiments of the present invention relate to a compound of formula (Ib-1) or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

n is 0; m2 is 0;

R ³is selected from

X ₃Is O;

G ₁-G ₂is NH-C (═ O) -.

Some embodiments of the present invention relate to compounds of formula (Ic-1) or (Ic-2) or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein,

ring A is selected from

m2 is 0;

R ³is selected from

X ₃Is O.

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

The invention relates to an application of a compound or a stereoisomer, a deutero-isomer, a solvate, a prodrug, a metabolite, a eutectic crystal or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating diseases related to KRAS G12C activity or expression amount, preferably an application in preparing a tumor medicament. The tumor is preferably selected from hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, non-small cell lung cancer or small cell lung cancer.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from compounds described in the commercial chemicals and/or chemical literature. "commercial chemicals" are obtained from regular commercial sources, and suppliers include: tatan science and technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical engineering, Shaoshao chemical technology, Nanjing Yashi, Yaogongkang and Bailingwei science and technology.

References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley-Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.

Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.

R ¹、R ^2a、R ^2b、R ^2c、R ^2d、R ³、R ⁴Ring A, ring B, ring C, ring D, X₁、X ₃Or m1, m2, m3, n are as defined above for the compounds of the general formulae (Ia) and (Ib);

R ⁵is selected from C_1-6An alkyl group;

R ⁶selected from a leaving group, preferably F, Cl, Br, I, triflate, mesylate, p-toluenesulfonate or benzenesulfonate; PG and R⁷Selected from amino protecting groups;

the first synthesis method comprises the following steps:

reacting the compound of the general formula (Ia-1) with a compound containing double leaving groups under the action of alkali to obtain a compound of a general formula (Ia-2);

after the carbonyl group and the ethylene glycol protecting group are removed from the compound of the general formula (Ia-2), the compound of the general formula (Ia-3) is obtained;

reacting the compound of the general formula (Ia-3) with a carbonic diester-based compound under the action of alkali to obtain a compound of a general formula (Ia-4);

reacting the compound of the general formula (Ia-4) with S-methylisothiourea sulfate under the action of alkali, or reacting the compound of the general formula (Ia-4) with thiourea and then reacting with a methylating agent under the action of alkali to obtain a compound of a general formula (Ia-5);

reacting the compound of the general formula (Ia-5) with trifluoromethanesulfonic anhydride under the action of a base, or carrying out chlorination reaction on the compound of the general formula (Ib-5) to obtain a compound of the general formula (Ia-6);

carrying out substitution reaction on the compound with the general formula (Ia-6) to obtain a compound with a general formula (Ia-7);

carrying out oxidation reaction on the compound of the general formula (Ia-7) to obtain a compound of a general formula (Ia-8);

carrying out substitution reaction on the compound with the general formula (Ia-8) to obtain a compound with a general formula (Ia-9);

the compound of the general formula (Ia-9) is separated from R⁷Then obtaining the compound with the general formula (Ia-10);

the compound of the general formula (Ia-10) is prepared by coupling, substituting or condensing a compound of the general formula (Ib-11);

removing the amino protecting group from the compound of the general formula (Ia-11) to obtain a compound of a general formula (Ib-12);

the compound of the general formula (Ib-10) is subjected to substitution reaction or condensation reaction to obtain the compound of the general formula (Ia).

And a second synthesis method comprises the following steps:

reacting the compound with the general formula (Ib-a) with a compound containing double leaving groups under the action of alkali to obtain a compound with a general formula (Ib-2);

the compound of the general formula (Ib-2) is subjected to carbonyl and ethylene glycol protecting group removal to obtain a compound of the general formula (Ib-3);

reacting the compound of the general formula (Ib-3) with a carbonic diester-based compound under the action of alkali to obtain a compound of a general formula (Ib-4);

reacting the compound of the general formula (Ib-4) with S-methylisothiourea sulfate under the action of alkali, or reacting the compound of the general formula (Ib-4) with thiourea and then reacting with a methylating agent under the action of alkali to obtain a compound of the general formula (Ib-5);

reacting the compound of the general formula (Ib-5) with trifluoromethanesulfonic anhydride under the action of a base, or performing chlorination reaction on the compound of the general formula (Ib-5) to obtain a compound of the general formula (Ib-6);

obtaining a compound with a general formula (Ib-7) by a substitution reaction of the compound with the general formula (Ib-6);

the compound of the general formula (Ib-7) is oxidized to obtain a compound of the general formula (Ib-8);

carrying out substitution reaction on the compound with the general formula (Ib-8) to obtain a compound with a general formula (Ib-9);

removing the amino protecting group from the compound of the general formula (Ib-9) to obtain a compound of the general formula (Ib-10);

the compound with the general formula (Ib-10) is subjected to substitution reaction or condensation reaction to obtain the compound with the general formula (Ib).

The third synthesis method comprises the following steps:

carrying out Danheiser-Stork reaction on the compound with the general formula (Ib-1a) to obtain a compound with a general formula (Ib-1 b);

removing methyl from the compound with the general formula (Ib-1b) under the catalysis of acid to obtain a compound with the general formula (Ib-1 c);

the compound of the general formula (Ib-1c) is catalyzed by organic amine to obtain a compound of the general formula (Ib-1 d);

introducing a leaving group such as OTf, halogen and the like into the compound of the general formula (Ib-1d) under the action of alkali to obtain a compound of the general formula (Ib-1 e);

hydrogenating the compound with the general formula (Ib-1e) under the action of a metal catalyst to obtain a compound with the general formula (Ib-1 f);

the synthesis method comprises the following steps:

carrying out substitution reaction on the compound with the general formula (Ib-1g) to obtain a compound with a general formula (Ib-1 h);

hydrogenating the compound with the general formula (Ib-1h) under the action of a metal catalyst to obtain a compound with the general formula (Ib-1 i);

the compound of the general formula (Ib-1i) is catalyzed by acid to obtain a compound of the general formula (Ib-1 f);

the synthesis method comprises the following steps:

reacting the compound of the general formula (Ib-1f) with a carbonic diester-based compound or a cyano carbonate-based compound under the action of alkali to obtain a compound of the general formula (Ib-1 j);

reacting the compound of the general formula (Ib-1j) with ammonia to obtain a compound of the general formula (Ib-1 k);

reacting the compound with the general formula (Ib-1k) with benzoyl isothiocyanate to obtain a compound with the general formula (Ib-1 l);

the compound of the general formula (Ib-1l) is subjected to ring closing under the alkaline condition to obtain a compound of the general formula (Ib-1 m); or reacting the compound with the general formula (Ib-1j) with thiourea to obtain a compound with the general formula (Ib-1 m);

reacting the compound with the general formula (Ib-1m) with a methylating agent under the action of alkalinity to obtain a compound with the general formula (Ib-1 n); or reacting the compound with the general formula (Ib-1j) with S-methylisothiourea sulfate under the action of alkali to obtain a compound with a general formula (Ib-1 n);

reacting the compound of the general formula (Ib-1n) with trifluoromethanesulfonic anhydride under the action of a base, or carrying out chlorination reaction on the compound of the general formula (Ib-1n) to obtain a compound of the general formula (Ib-1 o);

obtaining a compound with a general formula (Ib-1p) by a substitution reaction of the compound with the general formula (Ib-1 o);

oxidizing the compound of the general formula (Ib-1p) to obtain a compound of the general formula (Ib-1q) (q is 1 or 2);

carrying out substitution reaction on the compound with the general formula (Ib-1q) to obtain a compound with a general formula (Ib-1 r);

removing the amino protecting group from the compound of the general formula (Ib-1r) to obtain a compound of the general formula (Ib-1 s);

the compound with the general formula (Ib-1s) is subjected to substitution reaction or condensation reaction to obtain the compound with the general formula (Ib-1).

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, S 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; 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, alkyl appearing herein, the definition of which is consistent with the present definition.

"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 radical, typically of 3 to 10 carbon atoms, non-limiting examples of which include 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" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple 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, with examples of alkynyl including, but not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-butynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, 1, 3-butadiynyl, 1, 3-pentadiynyl, 1, 4-hexadiynyl and the like; the alkynyl 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 a 3 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 containing 1 to 3 heteroatoms selected from N, O or S, which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system, preferably a 3-to 8-membered heterocyclic group, optionally substituted N, S in the ring of the heterocyclic group being oxidizable 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.

"spiro" refers to a 5 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 contain 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-(CH ₂) _m-C(＝O)-Ra、-(CH ₂) _m-C(＝O)-NRbRc、-(CH ₂) _mS(＝O)nRa、-(CH ₂) _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, carbonylAn ester group, a bridged ring group, a spiro ring group or a fused ring group. 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-(CH ₂) _m-C(＝O)-Ra、-(CH ₂) _m-C(＝O)-NRbRc、-(CH ₂) _mS(＝O)nRa、-(CH ₂) _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 group. 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 a polycyclic group in which any two rings share 2 atoms not directly attached, may contain 0 or more double bonds, and may be substituted or unsubstituted, and any ring in the bridged 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, still further preferably 5 to 10. Non-limiting examples include

And adamantane. 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-(CH ₂) _m-C(＝O)-Ra、-(CH ₂) _m-C(＝O)-NRbRc、-(CH ₂) _mS(＝O)nRa、-(CH ₂) _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 independent of each otherSelected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or fused ring. The definition of bridged ring, as found herein, is consistent with this definition.

"Heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system, as found herein, which is defined consistent with this 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, 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-(CH ₂) _m-C(＝O)-Ra、-(CH ₂) _m-C(＝O)-NRbRc、-(CH ₂) _mS(＝O)nRa、-(CH ₂) _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, carbonylAn ester group, a bridged ring group, a spiro ring group or a fused ring group. 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 a 5 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, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂) _m-C(＝O)-Ra、-O-(CH ₂) _m-C(＝O)-Ra、-(CH ₂) _m-C(＝O)-NRbRc、-(CH ₂) _mS(＝O)nRa、-(CH ₂) _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, and cyclicAlkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heteroaryl, as used herein, is defined in accordance with the present definition.

"contains 1 to 4 heteroatoms selected from O, S, N" means containing 1,2, 3 or 4 heteroatoms selected from O, S, N. Herein, "said heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N" means that all heterocyclic rings in the paragraph in which the expression is located each independently contain 1,2, 3 or 4 heteroatoms selected from O, S, N.

"substituted with 0 to X substituents" means substituted with 0, 1,2, 3 … X substituents, X is selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1,2, 3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1,2, 3,4, or 5 substituents. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1,2, 3 or 4 substituents selected from H or F.

The ring of X-Y element (X is selected from the integer less than or equal to Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes the ring of X +1, X +2, X +3, X +4 …. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring. "4-to 9-membered nitrogen-containing heterocycle" refers to a4-, 5-, 6-, 7-, 8-, or 9-membered nitrogen-containing heterocycle.

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 of the compounds of the present invention or stereoisomers, deuterons, solvates, prodrugs, metabolites, co-crystals, or pharmaceutically acceptable salts thereof, and other chemical components, wherein "other chemical components" refers to a pharmaceutically acceptable carrier. 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.

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 can be 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;

boc: a tert-butoxycarbonyl group; ts: a p-toluenesulfonyl group; cbz: a benzyloxycarbonyl group; TMS: trimethylsilyl;

example 1

2- [ (S) -1-acryloyl-4- [2'- [ [ (S) -1-methylpyrrolidin-2-yl ] methoxy ] -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin-4' -yl ] piperazin-2-yl ] acetonitrile; 2,2, 2-trifluoroacetate salt (compound 1);

2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.

the first step is as follows: 1, 3-dihydrodispiro [ indene-2, 3' -cyclohexane-1 ',2 "- [1,3] dioxolane ] -4' -one (1 a);

1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2”-[1,3]dioxolan]-4'-one.

1, 4-cyclohexanedione monoethylene ketal (8g, 51.3mmol) was dissolved in dry tert-butanol (130mL) under nitrogen and potassium tert-butoxide solid (12.8g, 113.7mmol) was added. After stirring at room temperature for 30min, 1, 2-bis (bromomethyl) benzene (13.5g, 51.2mmol) was added and the reaction was allowed to stand at room temperature overnight. After TLC monitoring the reaction was complete, the reaction was quenched by addition of 100mL ice water, extracted three times with 100mL dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the desired product 1a was obtained as a colorless viscous liquid (3g, yield: 22.7%).

MS m/z(ESI):259.3[M+H] ⁺

The second step is that: 1, 3-dihydrodispiro [ indene-2, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] (1 b);

1,3-dihydrodispiro[indene-2,1'-cyclohexane-3',2”-[1,3]dioxolane].

dissolving the compound 1a (1g, 3.87mmol) in 10mL of diethylene glycol, adding 2mL of hydrazine hydrate, heating the system to 80 ℃ for reaction for 1h, and then heating the system to 200 ℃ by using microwaves for reaction for 30 min. TLC monitored the reaction was complete, diluted with 15mL water, extracted three times with 20mL dichloromethane, combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the objective product 1b was obtained as a colorless viscous liquid (0.7g, yield: 77%).

MS m/z(ESI):245.3[M+H] ⁺

The third step: 1',3' -dihydrospiro [ cyclohexane-1, 2' -indene ] -3-one (1 c);

1',3'-dihydrospiro[cyclohexane-1,2'-inden]-3-one.

compound 1b (2.5g, 10.23mmol) was dissolved in 10mL of tetrahydrofuran solution, 20mL of 6N hydrochloric acid was added dropwise at room temperature, and after completion of the addition, reaction was carried out at room temperature for 4 hours. TLC monitored the reaction completion, added 15mL water dilution, 20mL dichloromethane extraction three times, combined organic phase, dried with anhydrous sodium sulfate, vacuum concentration. After column chromatography, the objective product 1c was obtained as a white solid (1.8g, yield: 87.8%).

MS m/z(ESI):201.3[M+H] ⁺

The fourth step: 3-oxo-1 ',3' -dihydrospiro [ cyclohexane-1, 2' -indene ] -4-carboxylic acid methyl ester (1 d);

methyl 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate.

sodium hydride (0.4g, 10.0mmol) was suspended in 15mL of dry tetrahydrofuran, under nitrogen, dimethyl carbonate (2.1mL, 25.0mmol) was added and, after addition, the system was heated to 80 ℃ and stirred for 30 min. Then, a tetrahydrofuran solution (8mL) of Compound 1c (1.0g, 5.0mmol) was added dropwise thereto, and the reaction was continued for 2 hours while maintaining 80 ℃. After the reaction was monitored by TLC, it was cooled to room temperature, filtered through celite, the filtrate was diluted with 20mL of ice water, extracted three times with 30mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the objective product 1d was obtained as a white solid (0.8g, yield: 62%).

MS m/z(ESI):259.1[M+H] ⁺

The fifth step: 2'- (methylthio) -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin ] -4' -ol (1 e);

2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-ol.

compound 1d (0.2g, 0.78mmoL) was dissolved in 1mL of tetrahydrofuran, S-methylisothiourea sulfate (335mg, 1.17mmoL) was added, and an aqueous solution (2mL) of potassium hydroxide (359mg, 6.4mmoL) was dropped at room temperature. After the addition, the reaction was kept at room temperature overnight. After the reaction was completed, 10mL of water was added for dilution, the pH was adjusted to about 9 to 10 with 1N hydrochloric acid, and then extracted three times with 20mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the objective product 1e was obtained as a white solid (34mg, yield: 14.6%).

Ms m/z(ESI):299.4[M+H] ⁺

And a sixth step: 2'- (methylthio) -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazoline ] -4' -trifluoromethanesulfonate (1 f);

2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate

compound 1e (34mg, 0.114mmol) was dissolved in 5mL of dichloromethane, N-diisopropylethylamine (0.08mL, 0.456mmol) was added, trifluoromethanesulfonic anhydride (64.3mg, 0.228mmol) was added under ice-bath, and the mixture was stirred for 1h under ice-bath. After the reaction was completed, 15mL of dichloromethane was added for dilution, the reaction mixture was washed with 10mL of water, then 10mL of saturated aqueous sodium bicarbonate was used for washing, the organic layer was dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. After column chromatography, the objective product 1f was obtained as a white solid (30mg, yield: 61%).

MS m/z(ESI):431.5[M+H] ⁺

The seventh step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylthio) -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (1 g);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

compound 1f (30mg, 0.07mmol) was dissolved in 3mL of N, N-dimethylacetamide, and (S) -2- (piperazin-2-yl) acetonitrile (9.6mg, 0.08mmol) and diisopropylethylamine (54mg, 0.42mmol) were added and stirred at room temperature for 3 h. After the reaction was monitored by TLC to completion, di-tert-butyl dicarbonate (46mg, 0.21mmol) was added to the system, and after the addition was completed, the reaction was allowed to stand at room temperature overnight. After diluting with 20mL of ethyl acetate, the organic phase was washed three times with 10mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, 1g of the objective product was obtained as a white solid (40mg, yield: 100%).

MS m/z(ESI):506.7[M+H] ⁺

Eighth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylsulfonyl) -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (1H);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

compound 1g (40mg, 0.079mmol) was dissolved in 2mL of tetrahydrofuran, and m-chloroperoxybenzoic acid (27mg, 0.16mmol) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. 5mL of saturated aqueous sodium thiosulfate solution was added, the mixture was stirred for 20min, 15mL of ethyl acetate was added for extraction, and the organic layer was washed with 10mL of saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to give the target compound as a crude product for 1h, 48mg of a yellow solid, which was used directly in the next step.

MS m/z(ESI):538.7[M+H] ⁺

The ninth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (1 i);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

dissolve compound 1h crude (48mg, 0.089mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (22mg, 0.19mmol) in 2mL toluene, add sodium tert-butoxide (14mg, 0.14mmol) under ice bath, and stir for 1h under ice bath. The reaction was quenched with 5mL of water, extracted three times with 10mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography gave the desired product 1i as a white solid (46mg, yield: 95%).

MS m/z(ESI):573.6[M+H] ⁺

The tenth step: 2- ((S) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl ] methoxy)) 1,3,5',8 '-tetrahydro-6' H-spiro [2,7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (1 j);

2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

compound 1i (46mg, 0.08mmol) was dissolved in 3mL of dichloromethane, 0.5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, 5mL of water was added for dilution, followed by extraction three times with 10mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the objective compound 1j as a yellow solid, 40mg, which was used directly in the next step.

MS m/z(ESI):473.6[M+H] ⁺

The eleventh step: 2- [ (S) -1-acryloyl-4- [2'- [ [ (S) -1-methylpyrrolidin-2-yl ] methoxy ] -1,3,5',8 '-tetrahydro-6' H-spiro [ indene-2, 7 '-quinazolin-4' -yl ] piperazin-2-yl ] acetonitrile; 2,2, 2-trifluoroacetate salt (compound 1);

2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.

crude compound 1j (46mg, 0.097mmol) was dissolved in 5mL of dichloromethane, triethylamine (49mg, 0.49mmol) was added, acryloyl chloride (8mg, 0.092mmol) was counted under ice bath, and stirred for 30min under ice bath. The reaction was quenched by the addition of 5mL of ice water, followed by extraction three times with 10mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared with liquid phase acidity (mobile phase system: acetonitrile/0.1% TFA water) to give the title compound 1 as a white solid (23mg, yield: 45%).

¹H NMR(400MHz,CD ₃OD)δ7.21–7.08(m,4H),6.90–6.70(m,1H),6.29(d,1H),5.84(d,1H),4.69(dd,1H),4.60(d,1H),4.41(d,1H),4.20–4.03(m,1H),3.96–3.83(m,1H),3.78–3.41(m,4H),3.26–3.14(m,1H),3.06–2.93(m,6H),2.89–2.81(m,3H),2.80(d,1H),2.75(s,2H),2.44–2.32(m,1H),2.22–1.97(m,4H),1.94–1.85(m,2H),1.35–1.25(m,2H).

Ms m/z(ESI):527.6[M+H] ⁺

Example 2

2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2 '-oxo-spiro [6, 8-dihydro-5H-quinazolin-7, 3' -indolin ] -4-yl ] piperazin-2-yl ] acetonitrile; 2,2, 2-trifluoroacetic acid (Compound 2);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid

the first step is as follows: 3- (2-aminophenyl) cyclohex-2-en-1-one (2a)

3-(2-aminophenyl)cyclohex-2-en-1-one

2-iodoaniline (44g,200.9mmol), tris (o-methylphenyl) phosphorus (6.11g,20.09mmol), palladium acetate (2.26g,10.04mmol), cyclohexenone (21.24g,221.0mmol) and triethylamine (40.66g,401.8mmol) were dissolved in 1220mL of acetonitrile and heated to 85 ℃ under nitrogen atmosphere for reflux reaction for 40 hours. After TLC monitoring reaction is completed, the reaction liquid is cooled to room temperature, reduced pressure concentration is carried out to remove acetonitrile, 800mL ethyl acetate is added for dilution, 300mL water washing is added, stirring and standing are carried out for demixing, water phase is extracted by 400mL x 2 of ethyl acetate, organic phase is combined, 500mL saturated saline solution is used for washing, anhydrous sodium sulfate is used for drying, filtration and reduced pressure concentration are carried out to obtain crude product, and the crude product is purified by column chromatography to obtain target product 2a and tawny solid (11.2g, yield: 29.8%).

MS m/z(ESI):188.1[M+H] ⁺

The second step is that: spiro [ cyclohexane-3, 3 '-indoline ] -1,2' -dione (2b)

spiro[cyclohexane-3,3'-indoline]-1,2'-dione

Triphosgene (9.51g,32.0mmol) was dissolved in dichloromethane (200mL) in a 500mL single neck round bottom flask, compound 2a (3g,16.0mmol) was dissolved in dichloromethane (100mL) and added dropwise to the reaction, after which a solution of triethylamine (9.73g,96.1mmol) diluted with dichloromethane (100mL) was added dropwise to the reaction and stirred at room temperature for 3 hours. The dichloromethane is removed by concentration under reduced pressure, the residue is stirred for 10 minutes with 200mL of diethyl ether, filtered off with suction and the filter cake is washed with 100mL of diethyl ether. The residue obtained after concentrating the filtrate under reduced pressure was dissolved in a 1L capacity three-necked round-bottomed flask with 100mL of tetrahydrofuran, and t-butanol (1.19g,16.0mmol) was added thereto, followed by stirring for ten minutes while cooling to-78 ℃ under nitrogen atmosphere. A mixed solution of anhydrous lithium chloride (5.43g,128.2mmol) and samarium diiodide-tetrahydrofuran solution (40mmol,400mL,0.1M) was stirred at room temperature for 10 minutes and then added dropwise to the reaction, and the reaction was stirred at-78 ℃ for half an hour. TLC showed complete consumption of starting material, quenched by addition of 200mL saturated aqueous ammonium chloride, warmed to room temperature, extracted by addition of ethyl acetate (3 × 300mL), combined organic phases washed with saturated brine, dried organic phase over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography to give 2b as a brown solid (2.34g, yield: 67.8%).

MS m/z(ESI):216.2[M+H] ⁺

The third step: 2,2 '-Dioxaspiro [ cyclohexane-4, 3' -indoline ] -1-carboxylic acid ethyl ester (2c)

ethyl 2,2'-dioxospiro[cyclohexane-4,3'-indoline]-1-carboxylate

Compound 2b (2.34g,10.9mmol) was dissolved in tetrahydrofuran (200mL) in a 500mL three-necked round bottom flask, cooled to-78 ℃ under nitrogen, LiHMDS (22mL, 1M in THF) was measured and added dropwise to the reaction flask, stirred for ten minutes, 3mL of tetrahydrofuran diluted ethyl cyanoformate (1.4g,14.1mmol) was slowly added dropwise to the reaction, reacted at-78 ℃ for half an hour and then warmed to room temperature for 2 hours. The reaction was quenched by addition of 50mL of saturated aqueous ammonium chloride, 100mL of water was added, ethyl acetate (3X 80mL) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 2c as a pale yellow solid (1.22g, yield: 38.4%).

MS m/z(ESI):288.2[M+H] ⁺

The fourth step: 4-hydroxy-2-sulfanyl-spiro [6, 8-dihydro-5H-quinazoline-7, 3 '-indolin ] -2' -one (2 d);

4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one

compound 2c (1.22g,4.25mmol) was dissolved in methanol (25mL) in a single neck round bottom flask and sodium methoxide (1.38g,25.48mmol) and thiourea (970mg,12.74mmol) were weighed in turn and added to the reaction flask. Heating to 60 ℃ for 5 hours, LC-MS shows complete consumption of the raw materials. Most of the methanol was concentrated under reduced pressure, the residue was dissolved in 35mL of water, 25mL of methyl t-butyl ether was added for washing, 2N diluted hydrochloric acid was added to the aqueous phase to adjust the pH to 3-4, a large amount of solid was precipitated, suction filtration was performed, and the filter cake was washed with water. The filter cake was slurried with 8mL of ethanol overnight, filtered under suction, and the filter cake was dried to give a white solid (0.358g, yield: 28.2%) in 2 days.

MS m/z(ESI):298.1[M-H] ^-

The fifth step: 4-hydroxy-2-methylsulfanyl-spiro [6, 8-dihydro-5H-quinazoline-7, 3 '-indolin ] -2' -one (2 e);

4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one.

compound 2d (0.1g,0.334mmol) was dissolved in methanol (15mL) in a single neck round bottom flask, potassium carbonate (0.185g,1.34mmol) was added and stirred for half an hour, iodomethane (0.05g,0.334mmol) was added and stirred for 1 hour, LC-MS showed no complete consumption of starting material, and continued addition of iodomethane (0.05g,0.334mmol) and stirring for 1 hour, LC-MS showed almost complete consumption of starting material. The mixture was concentrated under reduced pressure to remove methanol, dissolved in 20mL of water, adjusted in pH 3-4 with 2N dilute hydrochloric acid, to precipitate a white solid, extracted with 3 × 80mL of a mixed solvent (dichloromethane/methanol (v/v) ═ 10/1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2e as a yellowish white solid (120mg, yield: 100%).

Ms m/z(ESI):314.1[M+H] ⁺

And a sixth step: (2-methylsulfanyl-2 '-O-spiro [6, 8-dihydro-5H-quinazoline-7, 3' -indolin ] -4-yl) trifluoromethanesulfonate (2 f);

(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoromethanesulfonate

dissolving the compound 2e (0.12g,0.383mmol) in dichloromethane (20mL) in a single-neck round-bottom flask, adding triethylamine (0.117g,1.15mmol), cooling with an ice-water bath under a nitrogen atmosphere, reducing the internal temperature to 5-10 ℃, adding trifluoromethanesulfonic anhydride (0.162g, 0.574mmol) diluted with 2mL dichloromethane into the reaction, reacting for ten minutes, monitoring by TLC that the raw material is not completely consumed, supplementing trifluoromethanesulfonic anhydride (0.05g,0.191mmol), continuing the reaction for ten minutes, and monitoring by TLC that the raw material is completely consumed. After quenching with 20mL of a saturated aqueous solution of sodium bicarbonate, the mixture was stirred and allowed to stand for separation, the aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed with 30mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2f, a tan solid (170mg, yield: 100%). The crude product was used directly in the next step.

MS m/z(ESI):446.1[M+H] ⁺

The seventh step: (2S) -2- (cyanomethyl) -4- (2-methylsulfanyl-2 '-oxospiro [6, 8-dihydro-5H-quinazoline-7, 3' -indolin ] -4-yl) piperazine-1-carboxylic acid tert-butyl ester (2 g);

tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

compound 2f (0.17g,0.383mmol) was dissolved in N, N-dimethylacetamide (15mL) in a single neck round bottom flask, N-diisopropylethylamine (0.21g,1.62mmol) and (S) -2- (piperazin-2-yl) acetonitrile hydrochloride (0.152g,0.81mmol) were added and the reaction was allowed to proceed for half an hour at room temperature with TLC monitoring for complete consumption of starting material, di-tert-butyl carbonate (240mg,1.08mmol) was added and stirred at room temperature for 16 h. Adding 45mL of water for quenching, adding dichloromethane (30mL x 4) for extraction, combining organic phases, washing the organic phases with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain 2g of brown solid (0.13g, yield: 65%)

MS m/z(ESI):521.3[M+H] ⁺

Eighth step: (2S) -2- (cyanomethyl) -4- (2-methylsulfinyl-2 '-oxopiroyl [6, 8-dihydro-5H-quinazoline-7, 3' -indolin ] -4-yl) piperazine-1-carboxylic acid tert-butyl ester (2H);

tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

compound 2g (0.13g,0.250mmol) was dissolved in 20mL tetrahydrofuran in a single neck round bottom flask, m-chloroperoxybenzoic acid (87mg,0.499mmol) was weighed into the reaction flask, stirred at room temperature for 1 hour and sampled TLC showed complete consumption of starting material. And can be processed later. The reaction was quenched by the addition of 20mL of saturated aqueous sodium thiosulfate, stirred for half an hour, extracted with ethyl acetate (20mL x 3), the organic phases combined, washed with saturated aqueous sodium bicarbonate (30mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude 2f as a pale yellow solid (0.134g, yield: 100%) which was used directly in the next step.

MS m/z(ESI):537.3[M+H] ⁺

The ninth step: (2S) -2- (cyanomethyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2 '-oxospiro [6, 8-dihydro-5H-quinazoline-7, 3' -indolin ] -4-yl ] piperazine-1-carboxylic acid tert-butyl ester (2 i);

tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]piperazine-1-carboxylate

compound 2h (0.134g, 0.250mmoL) was dissolved in dry tetrahydrofuran (15mL) in a single-neck round-bottom flask, N-methyl-L-prolinol (87mg,0.749mmoL) was added, the temperature was lowered with ice-water bath under nitrogen atmosphere, the inner temperature was lowered to 5-10 ℃, sodium tert-butoxide (48mg,0.499mmoL) was added, the reaction was carried out for ten minutes at this temperature, and TLC showed complete consumption of the starting material. Quenched with 10mL of saturated aqueous sodium bicarbonate solution, quenched with 20mL of a mixed solvent of x 3 (dichloromethane/methanol (v/v) ═ 10/1), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, and purified by column chromatography on crude silica gel to give 2h as a pale yellow solid (108mg, yield: 73.6%).

MS m/z(ESI):588.3[M+H] ⁺

The tenth step: 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2 '-oxo-spiro [6, 8-dihydro-5H-quinazoline-7, 3' -indolin ] -4-yl ] piperazin-2-yl ] acetonitrile (2 i);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile

compound 2h (0.108g,0.184mmol) was dissolved in dichloromethane (5mL) in a single neck round bottom flask, 2.5mL trifluoroacetic acid was added, stirred at room temperature for one hour, sampled, TLC and LC-MS. MS showed product formation and TLC showed complete consumption of starting material. Concentration under reduced pressure gave a crude product of 2i as a yellow solid (89mg, yield: 99%) which was used directly in the next step.

MS m/z(ESI):488.3[M+H] ⁺

The eleventh step: 2- [ ((2S) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2 '-oxo-spiro [6, 8-dihydro-5H-quinazolin-7, 3' -indolin ] -4-yl ] piperazin-2-yl ] acetonitrile; 2,2, 2-trifluoroacetic acid (Compound 2);

2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid

compound 2i (0.089g,0.182mmol) was dissolved in 30mL of dichloromethane in a single-neck round-bottom flask, N-diisopropylethylamine (0.2g,1.46mmol) was added, the temperature was lowered with an ice-water bath under a nitrogen atmosphere to 5-10 ℃ the internal temperature, 2mL of dichlormethane-diluted acryloyl chloride (0.016g,0.182mmol) was injected into the reaction, the reaction was continued at this temperature for 10 minutes, and TLC monitored the completion of the starting material reaction. Quench with 15mL saturated aqueous sodium bicarbonate, stir and stand for stratification, extract with dichloromethane (20mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to give the crude product, which is sent to the preparative liquid phase (acidic preparative, mobile phase system: acetonitrile/0.1% TFA water) to give the title compound 2 as a white solid (25mg, yield: 26%).

¹H NMR(400MHz,CD ₃OD)δ7.27(t,1H),7.22–7.13(m,1H),7.07–6.94(m,2H),6.90–6.70(m,1H),6.30(d,1H),5.84(d,1H),5.10–4.78(m,2H),4.73–4.62(m,1H),4.60–4.46(m,1H),4.40–4.04(m,2H),4.01–3.35(m,5H),3.30-3.19(m,1H),3.17–2.84(m,9H),2.49–2.34(m,1H),2.28–1.85(m,5H).

Ms m/z(ESI):542.3[M-CF ₃COOH+H] ⁺

Example 3

2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline ] -7,4' -pyrrolidine ] -4-yl ] -1-prop-2-enoyl-piperazin-2-yl ] acetonitrile (compound 3);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

the first step is as follows: 3- [ tert-butyl (dimethyl) silyl ] oxycyclohexanol (3 a);

3-[tert-butyl(dimethyl)silyl]oxycyclohexanol.

the compound 1, 3-cyclohexanediol (5g,43.04mmol) was dissolved in 30mL of N, N-dimethylformamide, and imidazole (4.40g,64.50mmol) and t-butyldimethylchlorosilane (6.49g,43.04mmol) were added in this order and stirred at room temperature for 4 h. 50mL of methyl t-butyl ether and 50mL of water were added to the reaction mixture, followed by extraction, separation, washing of the organic layer with a saturated saline solution (40 mL. times.3), concentration of the organic layer under reduced pressure, and purification by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v): 1/10-1/3) to obtain Compound 3a as a pale yellow oil (4g, yield: 40%).

Ms m/z(ESI):231.3[M+H] ⁺

The second step is that: 3- [ tert-butyl (dimethyl) silyl ] oxycyclohexanone (3 b);

3-[tert-butyl(dimethyl)silyl]oxycyclohexanone.

compound 3a (2.7g,11.74mmol) was dissolved in 20mL of dichloromethane, dessimutan oxidant (5g,11.79mmol) was added, and the reaction was stirred at room temperature for 1h. After 20mL of saturated sodium thiosulfate and 20mL of saturated aqueous sodium bicarbonate solution were added and stirred at room temperature for 20min, the organic layer was separated and concentrated under reduced pressure, and then purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/10-1/3) to give compound 3b as a pale yellow oil (2g, yield: 75%).

¹HNMR(400MHz,CDCl ₃)δ4.21-4.10(m,1H),2.56-2.48(m,1H),2.42-2.34(m,1H),2.34-2.22(m,2H),2.12-2.00(m,1H),1.93-1.85(m,1H),1.78-1.62(m,2H),0.87(s,9H),0.05(s,6H).

Ms m/z(ESI):229.3[M+H] ⁺

The third step: ethyl 2- [3- [3- [ tert-butyl (dimethyl) silyl ] oxycyclohexylidene ] acetate (3 c);

ethyl 2-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene]acetate.

sodium hydride (2.05g,85.38mmol) was added to 100mL of tetrahydrofuran, triethyl phosphonoacetate (21.69g,96.76mmol) was slowly added dropwise over ice, and after stirring for 30min, 3b (13g,56.92mmol) was added and stirred for 30min over ice. After addition of 30mL of a saturated aqueous ammonium chloride solution and 100mL of water, quenching was performed, 100mL of methyl t-butyl ether was added, extraction was performed, and the organic layer was washed with 100mL of saturated brine, dried under reduced pressure, and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v): 1/20-1/6) to obtain compound 3c as a pale yellow oil (13g, yield: 76%).

Ms m/z(ESI):299.3[M+H] ⁺

The fourth step: ethyl 2- [ 3-hydroxy-1- (nitromethyl) cyclohexyl ] acetate (3 d);

ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate.

compound 3c (0.5g,1.7mmol) was dissolved in 10mL of tetrahydrofuran, nitromethane (0.31g,5.0mmol) and tetrabutylammonium fluoride (1.1g,4.2mmol) were added in this order, and the mixture was stirred at elevated temperature under reflux overnight. After 20mL of water and 20mL of methyl t-butyl ether were added for extraction, and the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/10-1/2) to give compound 3d as a pale yellow oil (0.35g, yield: 85%).

Ms m/z(ESI):246.3[M+H] ⁺

The fifth step: 7-hydroxy-2-azaspiro [4.5] decan-3-one (3 e);

7-hydroxy-2-azaspiro[4.5]decan-3-one.

compound 3d (0.35g,1.4mmol) was dissolved in 10mL of methanol, Raney nickel (0.1g,. ltoreq.50 μm, dispersed in water) and potassium carbonate (19mg,0.14mmol) were added, and the mixture was stirred under hydrogen (1atm) overnight. Filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v) ═ 100/1-10/1) to give compound 3e as a white solid (0.16g, yield: 66%).

¹H NMR(400MHz,CD ₃OD)δ3.68-3.58(m,1H),3.21-3.14(m,2H),2.26-2.13(m,2H),1.94-1.84(m,2H),1.78-1.68(m,1H),1.65-1.56(m,1H),1.48-1.20(m,4H).

Ms m/z(ESI):170.2[M+H] ⁺

And a sixth step: 7- [ tert-butyl (dimethyl) silyl ] oxy-2-azaspiro [4.5] decan-3-one (3 f);

7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decan-3-one.

compound 3e (0.16g,0.95mmol) was dissolved in 10mL of dichloromethane, imidazole (0.13g,1.90mmol) and tert-butyldimethylsilyl chloride (0.17g,1.10mmol) were added in that order, and the mixture was stirred at room temperature for 3 hours. The organic layer was washed with 10mL of an aqueous solution, and the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v): 1/5-1/0) to give compound 3f as a white solid (0.17g, yield: 63%).

Ms m/z(ESI):284.3[M+H] ⁺

The seventh step: 7- [ tert-butyl (dimethyl) silyl ] oxy-2-phenyl-2-azaspiro [4.5] decan-3-one (3 g);

7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decan-3-one.

compound 3f (0.13g,0.46mmol) and iodobenzene (0.14g,0.69mmol) were dissolved in 10mL of toluene, cesium carbonate (0.30g,0.92mmol), trans 1, 2-cyclohexanediamine (5.2mg,0.046mmol) and cuprous iodide (4.4mg,0.023mmol) were added sequentially, and the mixture was heated to 110 ℃ under nitrogen and stirred overnight. After cooling to room temperature, 10mL of ethyl acetate and 20mL of aqueous ammonia were added for extraction, and the organic layer was dried over anhydrous sodium sulfate, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/20-1/5) to give compound 3g as a white solid (0.1g, yield: 61%).

¹HNMR(400MHz,CDCl ₃)δ7.59(d,2H),7.38-7.32(m,2H),7.16-7.10(m,1H),3.93-3.85(m,1H),3.83-3.64(m,2H),2.51-2.36(m,2H),1.82-1.74(m,2H),1.70-1.40(m,6H),0.90(s,9H),0.06(d,6H).

Ms m/z(ESI):360.3[M+H] ⁺

The eighth step: 7-hydroxy-2-phenyl-2-azaspiro [4.5] decan-3-one (3 h);

7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one.

compound 3g (1g,2.78mmol) was dissolved in 10mL of tetrahydrofuran, tetrabutylammonium fluoride (1.45g,5.56mmol) was added, and the mixture was stirred at 60 ℃ for 2 hours. 20mL of water and 20mL of ethyl acetate were added for extraction, and the organic layer was concentrated under reduced pressure and used in the next step.

Ms m/z(ESI):246.2[M+H] ⁺

The ninth step: 2-phenyl-2-azaspiro [4.5] decane-3, 7-dione (3 i);

2-phenyl-2-azaspiro[4.5]decane-3,7-dione.

compound 3h (0.7g,2.85mmol) was dissolved in 20mL of dichloromethane, dessimutan oxidant (1.21g,2.85mmol) was added and the reaction stirred at room temperature for 1h. After 20mL of saturated sodium thiosulfate and 20mL of saturated aqueous sodium bicarbonate solution were added, the mixture was stirred at room temperature for 20min, and the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/10-1/1) to give compound 3i as a white solid (0.6g, yield: 86%).

Ms m/z(ESI):244.2[M+H] ⁺

The tenth step: 3, 7-dioxo-2-phenyl-2-azaspiro [4.5] decane-8-carboxylic acid ethyl ester (3 k);

ethyl 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylate.

compound 3i (0.4g,1.64mmol), ethyl (2,3,4,5, 6-pentafluorophenyl) carbonate (3j, synthetic reference Org.Lett.2013,15,2,370-373) (0.42g,1.64mmol), diisopropylethylamine (0.64g,4.95mmol) and 4-dimethylaminopyridine (0.06g,0.493mmol) were mixed in a 50mL single-necked flask, 20mL of dichloromethane were added, magnesium bromide diethyl ether complex (1.06g,4.11mmol) was added under nitrogen, and the mixture was stirred at room temperature for 3h under nitrogen. After extraction with 20mL of a 5% aqueous hydrochloric acid solution and 20mL of a dichloromethane solution, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/5-1/1) to give compound 3k as a pale yellow oil (0.4g, yield: 77%).

Ms m/z(ESI):316.2[M+H] ⁺

The eleventh step: 2-methylsulfanyl-1 ' -phenyl-spiro [3,5,6, 8-tetrahydroquinazoline-7, 4' -pyrrolidine ] -2', 4-dione (3 l);

2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4-dione.

compound 3k (0.36g,1.14mmol) and S-methylisothiouronium sulfate (0.32g,1.71mmol) were dissolved in 5mL acetonitrile, 5mL water and potassium carbonate (0.32g,2.30mmol) were added, and the mixture was stirred at 60 ℃ for 3 h. The pH was adjusted to 5 to 6 with 0.5N dilute hydrochloric acid, the mixture was filtered, and the filter cake was washed with 20mL of a 50% acetonitrile aqueous solution and 20mL of water in this order. After drying the filter cake under reduced pressure, 3l of the compound was obtained as a white solid (0.18g, yield: 46%) and used directly in the next step.

Ms m/z(ESI):342.2[M+H] ⁺

The twelfth step: (2-methylsulfanyl-2 ' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline-7, 4' -pyrrolidin ] -4-yl) trifluoromethanesulfonate (3 m);

(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)trifluoromethanesulfonate.

compound 3l (0.17g,0.50mmol) was dissolved in 10mL of dichloromethane, triethylamine (0.10g,1.0mmol) was added, trifluoromethanesulfonic anhydride (0.21g,0.75mmol) was added under ice bath, and the mixture was 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, and then the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/20-1/5) to give compound 3m as a yellow solid (0.17g, yield: 72%).

Ms m/z(ESI):474.1[M+H] ⁺

The thirteenth step: tert-butyl (2S) -2- (cyanomethyl) -4- (2-methylsulfanyl-2 ' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline-7, 4' -pyrrolidin ] -4-yl) piperazine-1-carboxylate (3 n);

tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

compound 3m (0.17g,0.36mmol) was dissolved in 10mL of N, N-dimethylformamide, diisopropylethylamine (0.28g,2.17mmol) and 2- [ (2S) -piperazin-2-yl ] acetonitrile dihydrochloride (0.071g,0.36mmol) were added, and after stirring at room temperature for 1h, di-tert-butyl dicarbonate (0.24g,1.10mmol) was added and stirring was continued for 5 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 (mobile phase: ethyl acetate/petroleum ether (v/v) ═ 1/10-1/2) to give compound 3n as a white solid (0.14g, yield: 71%).

Ms m/z(ESI):549.3[M+H] ⁺

The fourteenth step is that: tert-butyl (2S) -2- (cyanomethyl) -4- (2-methylsulfinyl-2 ' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline-7, 4' -pyrrolidin ] -4-yl) piperazine-1-carboxylate (3 o);

tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

compound 3n (0.13g,0.24mmol) was dissolved in 10mL tetrahydrofuran, m-chloroperoxybenzoic acid (0.082g,0.47mmol) was added, and the mixture was stirred at room temperature for 2 h. 10mL of saturated aqueous sodium thiosulfate solution 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 saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to give compound 3o, which was used directly in the next step.

Ms m/z(ESI):565.3[M+H] ⁺

The fifteenth step: tert-butyl (2S) -2- (cyanomethyl) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline-7, 4' -pyrrolidin ] -4-yl ] piperazine-1-carboxylate (3 p);

tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate.

compound 3o (0.15g,0.27mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (0.092g,0.80mmol) were dissolved in 10mL tetrahydrofuran, sodium tert-butoxide (0.051g,0.53mmol) was added under ice bath, and stirred for 1h under ice bath. The reaction was quenched with 10mL of water, extracted with 20mL of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v) ═ 50/1-10/1) to give compound 3p as a white solid (0.11g, yield: 67%).

Ms m/z(ESI):616.3[M+H] ⁺

Sixteenth, step: 2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline ] -7,4' -pyrrolidin ] -4-yl ] piperazin-2-yl ] acetonitrile; 2,2, 2-trifluoroacetate salt (3 q);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.

compound 3p (0.11g,0.18mmol) was dissolved in 4mL of dichloromethane, 4mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give compound 3q, which was used directly in the next step.

Ms m/z(ESI):516.4[M+H] ⁺

Seventeenth step: 2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -2' -oxo-1 ' -phenyl-spiro [6, 8-dihydro-5H-quinazoline ] -7,4' -pyrrolidine ] -4-yl ] -1-prop-2-enoyl-piperazin-2-yl ] acetonitrile (compound 3);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

compound 3p (0.13g,0.17mmol) was dissolved in 5mL of dichloromethane, triethylamine (0.053g,0.52mmol) was added, acryloyl chloride (16mg,0.17mmol) was added under ice bath, and stirring was performed for 30min under ice bath. After quenching with 10mL of a saturated aqueous solution of sodium hydrogencarbonate, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v) ═ 30/1-8/1) to give compound 3 as a white solid (0.06g, yield: 60%).

¹H NMR(400MHz,CDCl ₃)δ7.59(t,2H),7.40-7.32(m,2H),7.19-7.10(m,1H),6.65-6.50(m,1H),6.43-6.33(m,1H),5.86-5.77(m,1H),5.16-4.33(m,2H),4.25-3.94(m,3H),3.93-3.45(m,4H),3.42-3.26(m,1H),3.24-3.11(m,1H),3.11-2.98(m,1H),2.98-2.87(m,2H),2.85-2.59(m,6H),2.58-2.45(m,4H),2.41-2.29(m,1H),2.13-1.93(m,2H),1.92-1.70(m,4H).

Ms m/z(ESI):570.4[M+H] ⁺

Example 4

2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methyleneoxy ] heterocycle [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -1-propyl-2-enoyl-piperazin-2-yl ] acetonitrile (compound 4);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

the first step is as follows: 2- (3, 5-dimethoxyphenyl) ethan-1-ol (4 a);

2-(3,5-dimethoxyphenyl)ethan-1-ol.

a solution of (3, 5-dimethoxyphenyl) acetic acid (1.07g, 5.48mmol) in THF (10mL) was added dropwise to a suspension of lithium aluminum hydride (312mg, 8.22mmol) in THF (35mL) at room temperature. The reaction was maintained at room temperature for one hour, after the starting materials had reacted completely, the reaction was cooled to 0 ℃ and the excess lithium aluminum hydride was quenched by the slow addition of 1mL of water. The mixture was then poured into 1N aqueous HCl solution, extracted 3 times with ethyl acetate (50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a colorless liquid crude product (4a) which was used directly in the next step (0.9g, yield: 90%).

The second step is that: 1- (2-bromoethyl) -3, 5-dimethoxybenzene (4 b);

1-(2-bromoethyl)-3,5-dimethoxybenzene.

compound 4a was dissolved in dichloromethane (11mL) and CBr was added₄(2.00g, 6.03 mmol). The system was then cooled to 0 ℃ and Ph was added slowly₃P (1.58g, 6.03 mmol). The system was allowed to spontaneously warm to room temperature and stirred for 30 minutes, after the reaction of the starting materials was completed, the solution was poured into 20mL of water, extracted 3 times with 50mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated mixture was placed at-20 ℃ to precipitate a white solid, the mixture was dissolved in a mixed solvent (cold n-hexane: ether: 7:1), and then filtered, the cake was further washed twice with a mixed solvent (cold n-hexane: ether: 7:1), the filtrate was spin-dried, and column chromatography was performed to obtain compound 4b (1.18g, yield: 88%) as a clear oily substance.

MS m/z(ESI):245.1[M+H] ⁺

The third step: 3- (3, 5-dimethoxyphenethyl) cyclohex-2-en-1-one (4 c);

3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one.

magnesium turnings (228mg, 8.65mmol) were placed in a 50mL three-necked flask under dry nitrogen and a solution of about 1/4 of Compound 4b (424mg, 1.73mmol) in THF (0.5mL) was slowly added dropwise. One iodine pellet was added and the flask was heated to remove the color of the iodine, and the addition of the THF solution of compound 4b was continued slowly to keep the reaction system slightly boiling. After the dropwise addition, the system was allowed to continue the reaction at room temperature for 1 hour. And added dropwise to a solution of 3-ethoxy-2-cyclohexenone (107mg, 0.763mmol) in THF (1.5mL) at 0 ℃. The system was stirred at room temperature for 2h and the reaction was quenched by addition of 1N aqueous HCl (10mL) at 0 ℃. After stirring at room temperature for a further 30 minutes, the mixture was extracted with EA (20 mL. times.3). The combined extracts were dried and concentrated under reduced pressure. Purification by column chromatography (EtOAc/hexane, 1: 4) gave compound 4c (89mg, yield: 45%) as a colorless oil.

MS m/z(ESI):261.1[M+H] ⁺

The fourth step: 3- (3, 5-dihydroxyphenethyl) cyclohex-2-en-1-one (4 d);

3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one.

4c (2.5g, 9.6mmol) was dissolved in DCM (100mL) and cooled to-78 ℃. Then BBr is slowly dripped₃(1N CH)₂Cl ₂Solution, 24mL, 24 mmol). After the dropwise addition, the system was automatically warmed to room temperature for 6 h. After the reaction was completed, ice water was added to quench the reaction at-78 ℃ and EA (100mL) was used for 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography gave 4d as a white solid (1.3g, yield: 58%).

MS m/z(ESI):233.1[M+H] ⁺

The fifth step: 5', 7' -dihydroxy-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indenyl ] -3-one (4 e);

5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.

to a stirred solution of 4d (19.4mg, 83.5. mu. mol) in benzene (0.8mL) was added the catalyst catPara-bromophenol (14.4mg, 83.5. mu. mol), and H (A: B ═ 1:1,24.4mg, 83.5. mu. mol)₂O (1.5. mu.L, 83. mu. mol). After stirring at 65 ℃ for 10h, the mixture was quenched with 1N aqueous HCl (3mL) and extracted with EtOAc (5 mL. times.3). The combined extracts were dried and concentrated under reduced pressure. Purification by column chromatography gave 4e as a white solid (15mg, yield: 77%).

MS m/z(ESI):233.1[M+H] ⁺

And a sixth step: 3-oxo-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -5', 7' -diyl bis (trifluoromethanesulfonate) (4 f);

3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diyl bis(trifluoromethanesulfonate).

compound 4e (0.35g, 1.51mmol) was dissolved in 15mL of dichloromethane, N-diisopropylethylamine (1.5mL, 9.05mmol) was added, trifluoromethanesulfonic anhydride (0.76mL, 4.53mmol) was added under ice-bath, and the mixture was stirred for 1h under ice-bath. After the reaction was completed, 15mL of dichloromethane was added for dilution, 5mL of water was added for washing and quenching the reaction, 10mL of saturated aqueous sodium bicarbonate solution was used for washing the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and the concentration under reduced pressure was carried out. After column chromatography, the objective product 4f was obtained as a colorless liquid (0.37g, yield: 50%).

MS m/z(ESI):497.0[M+H] ⁺

The seventh step: 2', 3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one (4 g);

(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.

4f (0.1g, 0.2mmol) was dissolved in DMF (5mL) and Pd (OAc) was added successively under ice bath₂(4.4mg,0.02 mmol), dppe (1, 2-bis (diphenylphosphine)) Ethane, cas 1663-45-2, 16.4mg, 0.04mmol), Et₃N (110. mu.L, 0.8mmol) and formic acid (30. mu.L, 0.8 mmol). Replacing gas with nitrogen for three times, heating to 60 ℃, stirring for 1 hour, and then using saturated NH₄Aqueous Cl (30mL) was quenched and extracted with EtOAc (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography gave 4g (22mg, yield: 55%) of a white solid.

MS m/z(ESI):201.3[M+H] ⁺

Eighth step: 3-oxo-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester (4 h);

methyl-3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

sodium hydride (0.1g, 4.0mmol) was suspended in 10mL dry tetrahydrofuran, under nitrogen, dimethyl carbonate (0.9g, 10.0mmol) was added and after addition, the system was heated to 80 ℃ and stirred for 30 min. Then, a solution of 4g (0.4g, 2.0mmol) of the compound in tetrahydrofuran (8mL) was added dropwise thereto, and the reaction was continued for 2 hours while maintaining 80 ℃. After the reaction was monitored by TLC, it was cooled to room temperature, filtered through celite, the filtrate was diluted with 20mL of ice water, extracted three times with 30mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the product was obtained as a viscous liquid (0.4g, yield: 80%) for 4 h.

MS m/z(ESI):259.1[M+H] ⁺

The ninth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (4 i);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

compound 4h (0.4g, 2.0mmol) was dissolved in 1mL tetrahydrofuran, S-methylisothiouronium sulfate (858mg, 3.0mmol) was added, and then an aqueous solution (5mL) of potassium hydroxide (897mg, 16mmol) was dropped at room temperature. After the addition, the reaction was kept at room temperature overnight. After the reaction was completed, 10mL of water was added for dilution, the pH was adjusted to about 9 to 10 with 1N hydrochloric acid, and then extracted three times with 20mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography gave the desired product 4i as a white solid (0.1g, yield: 20%).

Ms m/z(ESI):299.4[M+H] ⁺

The tenth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -trifluoromethanesulfonate (4 j);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

compound 4i (100mg, 0.3mmol) was dissolved in 5mL of dichloromethane, N-diisopropylethylamine (0.5g, 1.2mmol) was added, trifluoromethanesulfonic anhydride (169.2mg, 0.6mmol) was added under ice-bath, and the mixture was stirred for 1h under ice-bath. After the reaction was completed, 15mL of dichloromethane was added for dilution, 5mL of water was added for washing and quenching the reaction, 10mL of saturated aqueous sodium bicarbonate solution was used for washing the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and the concentration under reduced pressure was carried out. After column chromatography, the product 4j was obtained as a white solid (80mg, yield: 61%).

MS m/z(ESI):431.5[M+H] ⁺

The eleventh step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 k);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 4j (80mg, 0.18mmol) was dissolved in 3mL of N, N-dimethylacetamide, and (S) -2- (piperazin-2-yl) acetonitrile (40mg, 0.2mmol) and diisopropylethylamine (139mg, 1.08mmol) were added and stirred at room temperature for 1h. After the reaction was monitored by TLC to completion, di-tert-butyl dicarbonate (118mg, 0.54mmol) was added to the system, and after the addition was completed, the reaction was allowed to stand at room temperature overnight. After diluting with 20mL of ethyl acetate, the organic phase was washed three times with 10mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the product was obtained as 4k as a white solid (90mg, yield: 100%).

MS m/z(ESI):506.7[M+H] ⁺

The twelfth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylsulfonyl) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 l);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 4k (90mg, 0.178mmol) was dissolved in 2mL of tetrahydrofuran, and m-chloroperoxybenzoic acid (61mg, 0.356mmol) was added at room temperature, followed by stirring at room temperature for 2 h. 5mL of saturated aqueous sodium thiosulfate solution was added, stirring was carried out for 20min, 15mL of ethyl acetate was added for extraction, the organic layer was washed 3 times with 10mL of saturated aqueous sodium bicarbonate solution, the organic phase was dried and concentrated under reduced pressure to give 4l of crude compound as a yellow solid 90mg, which was used directly in the next step.

MS m/z(ESI):538.7[M+H] ⁺

The thirteenth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 m);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

4l of crude compound (90mg, 0.167mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (38mg, 0.335mmol) were dissolved in 2mL of toluene, and sodium tert-butoxide (14mg, 0.14mmol) was added under ice bath and stirred for 1h under ice bath. The reaction was quenched with 5mL of water, extracted three times with 10mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the product was obtained as a white solid (78mg, yield: 80%).

MS m/z(ESI):573.6[M+H] ⁺

The fourteenth step is that: 2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methyleneoxy ] heterocycle [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -piperazin-2-yl ] acetonitrile (4 n);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

compound 4m (78mg, 0.136mmol) was dissolved in 3mL of dichloromethane, 0.5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, 5mL of water was added for dilution, saturated sodium bicarbonate was added dropwise to adjust the pH to alkaline, then extracted three times with 10mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 4n as a yellow solid 63mg, which was used directly in the next step.

MS m/z(ESI):473.6[M+H] ⁺

The fifteenth step:

2- [ (2S) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methyleneoxy ] heterocycle [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -1-propyl-2-enoyl-piperazin-2-yl ] acetonitrile (Compound 4)

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Crude compound 4n (63mg, 0.133mmol) was dissolved in 5mL of dichloromethane, triethylamine (40mg, 0.4mmol) was added, acryloyl chloride (12mg, 0.13mmol) was added under ice-bath, and stirred for 30min under ice-bath. The reaction was quenched by the addition of 5mL of ice water, followed by extraction three times with 10mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC to give Compound 4(8mg, yield: 10%). Chiral HPLC integral area_{T 8.2min}Integral area_{T 11.6min}(63:37)

Ms m/z(ESI):527.6[M+H] ⁺

Chiral HPLC analytical method:

the sample was dissolved in n-hexane/isopropanol (90:10),

the instrument comprises the following steps: shimadzu LC-20 AT; chiral column: CHIRALPAK AD-H, 4.6X 250mm,5 μm

Mobile phase: n-hexane (containing 0.1% diethylamine) -isopropanol (80: 20); flow rate: 1mL/min

Column temperature: 35 ℃; detection wavelength: 210 nm; sample introduction amount: 20 μ L

Examples 4-1 and 4-2:

2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile-isomer 4-1 and isomer 4-2

2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile–isomer 4-1and isomer 4-2.

The first step is as follows: 3-oxo-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid ethyl ester (4 o);

ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

4g of the compound (0.37g, 1.84mmol, see synthesis route intermediate 4g of compound 4) was suspended in 30mL of dry tetrahydrofuran under nitrogen protection at-78 deg.C, a tetrahydrofuran solution of LiHMDS (2.77mL,1mol/L, 2.77mmol) was slowly added dropwise, the reaction mixture was stirred at-78 deg.C for 30min, a tetrahydrofuran solution (8mL) of ethyl cyanoformate (0.3g, 2.77mmol) was slowly added dropwise to the reaction mixture, and the reaction mixture was slowly warmed to room temperature after completion of the addition and reacted for 4 h. TLC monitored the reaction completion, cooled to 0 deg.C and quenched by the addition of 100mL ice water. Ethyl acetate 100mL was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 4o, a yellow viscous liquid (0.54g crude). The reaction mixture was used in the next reaction without further purification.

MS m/z(ESI):273.1[M+H] ⁺

The second step is that: 3-amino-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (4 p);

ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

the crude compound 4o was dissolved in 20mL ethanol, ammonium acetate (0.7g, 9.2mmol) was added to react at room temperature for 12h, after TLC monitoring the reaction was complete, the solvent was dried under reduced pressure, diluted with 100mL ethyl acetate, then washed three times with 10mL water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 4p as a yellow viscous liquid (0.49g crude) which was used in the next reaction without purification.

MS m/z(ESI):272.2[M+H] ⁺

The third step: 3- (3-benzoylthioureido) -2', 3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (4 q);

ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

the crude compound 4p was dissolved in 50mL of acetone, added sodium benzoyl isothiocyanate hydride (0.37mL, 2.76mmol), and heated to 80 ℃ under nitrogen for 1h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. Column chromatography (PE: EA ═ 3:1) gave the desired product 4q as a yellow viscous liquid (0.43g, three step yield: 53%).

MS m/z(ESI):435.2[M+H] ⁺

The fourth step: 2 '-mercapto-2, 3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (4 r);

2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

compound 4q (0.43g, 0.99mmol) was dissolved in 15mL of ethanol, potassium hydroxide (0.17g, 3.0mmol) was added, and the system was heated to 80 ℃ and stirred for 1h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent to about 2 mL. 1N diluted hydrochloric acid was added dropwise until no white solid precipitated (pH 2), and the mixture was filtered, and the filter cake was washed twice with water to collect the filter cake to obtain the objective product 4r as a white solid (0.28g, yield: 99%).

MS m/z(ESI):285.4[M+H] ⁺

The fifth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (4 i);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

compound 4r (0.28g, 0.99mmoL) was dissolved in an aqueous solution of potassium hydroxide (0.17g, 3.0mmoL), and 2mL of methanol was added to dissolve insoluble matter. Methyl iodide (184mg, 1.3mmoL) was added dropwise at room temperature, and the reaction was continued at room temperature for 2 hours. After completion of the reaction monitored by TLC, 1N diluted hydrochloric acid was added dropwise until no more white solid precipitated (pH 2), filtered, and the filter cake was washed twice with water to collect the filter cake to obtain the target product 4i as a white solid (0.2g, yield: 68%).

Ms m/z(ESI):299.4[M+H] ⁺

And a sixth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -trifluoromethanesulfonate (4 j);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

compound 4i (200mg, 0.67mmol) was dissolved in 5mL dichloromethane, N-diisopropylethylamine (1.0g, 1.2mmol) was added, trifluoromethanesulfonic anhydride (378mg, 1.35mmol) was added under ice bath, and the mixture was stirred for 1h under ice bath. After the reaction was completed, 30mL of dichloromethane was added for dilution, 5mL of water was added for washing and quenching the reaction, 10mL of saturated aqueous sodium bicarbonate solution was used for washing the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and the concentration was performed under reduced pressure. After column chromatography, the objective product 4j was obtained as a white solid (256mg, yield: 89%).

MS m/z(ESI):431.5[M+H] ⁺

The seventh step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 k);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 4j (256mg, 0.6mmol) was dissolved in 3mL of N, N-dimethylacetamide, and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (202mg, 0.9mmol) and diisopropylethylamine (0.4mL, 2.4mmol) were added and stirred at room temperature for 12 h. TLC monitored the reaction completion, diluted with 50mL ethyl acetate, washed the organic phase three times with 10mL water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the objective product 4k was obtained as a white solid (330mg, yield: 99%).

MS m/z(ESI):506.7[M+H] ⁺

Eighth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylsulfonyl) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 l);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 4k (330mg, 0.65mmol) was dissolved in 15mL tetrahydrofuran, and m-chloroperoxybenzoic acid (449mg, 2.6mmol) was added at room temperature and stirred at room temperature for 2 h. 10mL of saturated aqueous sodium thiosulfate solution was added, the mixture was stirred for 20min, 50mL of ethyl acetate was added for extraction, the organic layer was washed with 10mL of saturated aqueous sodium bicarbonate solution for 3 times, the organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to obtain 4l of the objective product as a white solid (300mg, yield: 93%).

MS m/z(ESI):538.7[M+H] ⁺

The ninth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (4 m);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 4l (300mg, 0.56mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (128mg, 1.1mmol) were dissolved in 10mL of toluene, and sodium tert-butoxide (81mg, 0.84mmol) was added under ice bath and stirred for 1h under ice bath. The reaction was quenched with 5mL of water, extracted three times with 50mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography gave the desired product 4m as a white solid (292mg, yield: 91%).

MS m/z(ESI):573.6[M+H] ⁺

The tenth step: 2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (compound 4 n);

2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

compound 4m (292mg, 0.51mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is finished, adding 5mL of water for dilution, dropwise adding saturated sodium bicarbonate to adjust the pH value to be alkaline, then extracting with 30mL of dichloromethane for three times, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of the target compound 4n, wherein the yellow solid is 350mg and is directly used in the next step.

MS m/z(ESI):473.6[M+H] ⁺

The eleventh step: 2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile-isomer 4-1 and isomer 4-2

2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile–isomer 4-1and isomer 4-2.

The crude compound 4n (350mg) was dissolved in 20mL of dichloromethane, triethylamine (258mg, 2.55mmol) was added, acryloyl chloride (46mg, 0.51mmol) was added dropwise in ice bath, and the mixture was stirred for 30min in ice bath. The reaction was quenched by the addition of 5mL of ice water, then extracted three times with 30mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 4(216mg, yield: 81%, chiral HPLC integrated area) was obtained_{T 8.2min}: integral area_{T 11.6min}65: 35 analytical methods refer to example 4). Compound 4 was isolated and purified by SFC preparative separation to give 4-1(60mg, SFC preparative retention time 4.5 min; chiral HPLC retention time 8.2min) and 4-2(31mg, SFC preparative retention time 3.9 min; chiral HPLC retention time 11.6min).

SFC preparation separation conditions: instrument MG II preparatory SFC

Column ChiralCel OJ, 250X 30mm I.D.,5 μm mobile phase, A is CO₂B is ethanol (containing 0.1% ammonia), and 30% B is eluted. The flow rate is 60 mL/min; the column temperature is 38 ℃; the detection wavelength is 220nm, components with the same retention time are merged after preparation and separation,concentrating under reduced pressure to obtain compounds 4-1 and 4-2.

Compound 4-1:

LCMS:m/z(ESI):527.3[M+H] ⁺

¹H NMR(400MHz,CD ₃COOD)δ7.30–7.11(m,4H),6.91–6.67(m,1H),6.37(d,1H),5.87(d,1H),5.16–5.02(m,1H),4.97–4.80(m,2H),4.72–4.57(m,1H),4.56–4.43(m,1H),4.24–4.07(m,1H),4.06–3.53(m,5H),3.51–3.16(m,2H),3.13–2.77(m,10H),2.48–2.34(m,1H),2.26–2.05(m,6H),1.91–1.79(m,1H).

compound 4-2:

LCMS:m/z(ESI):527.3[M+H] ⁺

¹H NMR(400MHz,CD ₃OD)δ7.27–7.19(m,1H),7.19–7.08(m,2H),7.08–7.01(m,1H),6.94–6.72(m,1H),6.28(d,1H),5.82(d,1H),5.15–5.00(m,1H),4.63–4.46(m,1H),4.43–4.28(m,2H),4.18–3.92(m,3H),3.68–3.49(m,1H),3.26–3.19(m,1H),3.16–2.73(m,9H),2.72–2.60(m,1H),2.54(s,3H),2.47–2.37(m,1H),2.17–1.94(m,4H),1.89–1.66(m,4H).

2', 3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one (intermediate 1)

The first step is as follows: 2-bromo-1-cyclopropene-1-one (intermediate 1B)

2-bromo-1-cyclopropylethan-1-one

Dissolving raw material methyl cyclopropanone (8.4g,0.1mol) in 60mL of methanol, stirring and dissolving at 0 ℃, slowly dropwise adding bromine (5.0mL, 90mmol) into the system, and after the dropwise adding of the bromine is finished, continuously stirring at the temperature until the reaction system becomes colorless and transparent. After completion of the reaction, triethylamine was added to the reaction solution until the pH of the system was neutral, and the reaction solution methanol was distilled off under reduced pressure to obtain a mixture of triethylamine hydrobromide solid and an oily product, which was washed with petroleum ether and filtered, and the liquid portion was rotary evaporated to dryness to obtain a colorless oily product (intermediate 1B) (16.0g, yield 97%).

The second step is that: 1, 5-Dibromopentane-2-one (intermediate 1C)

1,5-dibromopentan-2-one

Substrate intermediate 1B (16.0g,98mmol) was added to 50mL of aqueous hydrobromic acid (v/v ═ 48%) and the reaction was stirred at 50 ℃ for 2 hours, after completion of the reaction, 200mL of petroleum ether was added to the reaction mixture, and an appropriate amount of ice was added thereto until a white solid precipitated, followed by filtration and drying to give the product (intermediate 1C) (18g, 75%) as a white solid.

The third step: 2- (bromomethyl) -2- (3-bromopropyl) -1, 3-dioxacycloalkane (intermediate 1D)

2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxolane

Substrate intermediate 1C (14.0g,57.6mmol) and ethylene glycol (21.4g,0.35mol) and p-toluenesulfonic acid (1.1g,5.8mmol) were added to 150mL of toluene, and the system was heated at 120 ℃ under reflux to dehydrate. The reaction was completed until no more water was added to the trap and the toluene was clear, cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on silica gel to give intermediate 1D as a yellow oil (11.7g, 70% yield).

¹H NMR(400MHz,CDCl ₃)δ4.09–4.04(m,2H),4.03–3.98(m,2H),3.43(t,2H),3.37(s,2H),2.02–1.96(m,4H).

The fourth step: bis-spiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxacycloalkane ] (intermediate 1E)

dispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]

Indene (4.87g,42.0mmol) was added to 80mL of THF, the mixture was stirred at 0 ℃ to dissolve, LiHMDS (42mL,42.0mmol,1M in hexane) was slowly added dropwise to the system, and after the addition was complete, the reaction was allowed to stand at this temperature and stirred for a further 30 min. The reaction solution was slowly added dropwise to a solution of intermediate 1D (10.0g,35.0mmol) in THF (80mL) at 0 ℃ with a transfer needle, and after completion of the addition, the reaction was stirred at 0 ℃ for 1 hour. LiHMDS (42mL,42.0mmol,1M in hexane) was slowly added dropwise to the system, and after the addition was complete, the reaction temperature was slowly raised to room temperature and stirred overnight. After the reaction, the reaction mixture was cooled to 0 ℃ and NH was added to the reaction mixture₄Quenched with saturated aqueous Cl, extracted with ethyl acetate, dried organic phase filtered and spun dry directly, and chromatographed on silica gel to give intermediate 1E as a white solid (4.1g, 48% yield).

The fifth step: 2, 3-dihydrobis-spiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxacycloalkane ] (intermediate 1F)

2,3-dihydrodispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]

Intermediate 1E (4.0g,16.5mmol) was dissolved in 50mL of methanol and 400mg Pd/C (10%_wt) The reaction was protected with a hydrogen balloon and stirred at room temperature for 3 hours. The reaction was terminated, and the reaction mixture was filtered through celite, and the filtrate was dried by spin-drying and then separated by silica gel chromatography to obtain intermediate 1F (3.7g, 92% yield) as a colorless oily product.

And a sixth step: 2', 3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one (intermediate 1)

2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one

Intermediate 1F (3.7g,15.1mmol) was dissolved in 10mL of THF, 6N methanol hydrochloride solution (20mL) was added to the system, and the reaction was left to stir at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with 50mL of water and ethyl acetate (50 mL. times.3) and saturated NaHCO₃The aqueous solution was washed, the organic phase was dried, filtered and directly spin-dried, and separated by silica gel chromatography to give intermediate 1(2.8g, 94% yield) as a white solid.

LCMS:m/z(ESI):201.2[M+H] ⁺

¹H NMR(400MHz,CDCl ₃)δ7.24–7.02(m,4H),2.96–2.76(m,2H),2.55–2.24(m,4H),2.11–1.64(m,4H).

Example 5

2- [ (2S) -4- [2- [ [ ((2S,4R) -4-fluoro-1-methyl-pyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -1-prop-2-enoyl-piperazin-2-yl ] acetonitrile (compound 5);

2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

the first step is as follows: 3-oxo-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid ethyl ester (5 b);

ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

suspending the intermediate 1(8.0g, 40mmol) in 150mL of dry tetrahydrofuran, reducing the temperature to-78 ℃ under the protection of nitrogen, slowly adding a tetrahydrofuran solution of LiHMDS (60mL,1mol/L, 60mmol) dropwise, and after the addition is finished, keeping the system at-78 ℃ and stirring for 30 min. Ethyl cyanoformate (5.9g, 60mmol) in tetrahydrofuran (20mL) was then added dropwise, and the system allowed to spontaneously warm to room temperature for reaction. After the completion of the reaction monitored by TLC, it was cooled to 0 ℃ and quenched by the addition of 100mL ice water. It was then extracted three times with 150mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 5b as a yellow viscous liquid (11.5g of crude product) which was used in the next reaction without purification.

MS m/z(ESI):273.1[M+H] ⁺

The second step is that: 3-amino-2 ',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (5 c);

ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

the crude compound 5b was dissolved in 200mL ethanol, ammonium acetate (23.1g, 300mmol) was added and reacted for 12h at room temperature, after TLC monitoring the reaction was complete, the solvent was dried under reduced pressure, diluted with 100mL ethyl acetate and then washed three times with 30mL water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 5c as a yellow viscous liquid (10.7g crude) which was used in the next reaction without purification.

MS m/z(ESI):272.2[M+H] ⁺

The third step: 3- (3-benzoylthioureido) -2', 3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (5 d);

ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

the crude compound 5c was dissolved in 100mL of acetone, benzoyl isothiocyanate (12.1mL, 90mmol) was added, and the mixture was heated to 80 ℃ under nitrogen for 1h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. Column chromatography (PE: EA ═ 3:1) gave the desired product 5d as a yellow viscous liquid (12g, three step yield: 69%).

MS m/z(ESI):435.2[M+H] ⁺

The fourth step: 2 '-mercapto-2, 3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (5 e);

2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

compound 5d (12g, 27.6mmol) was dissolved in 150mL of ethanol, potassium hydroxide (4.6g, 82.8mmol) was added, and the system was heated to 80 ℃ and stirred for 1h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent to about 20 mL. 1N aqueous HCl was added dropwise until no more white solid precipitated (pH 2), filtered, and the cake was washed twice with water to collect the cake to give the desired product 5e as a white solid (6.0g, yield: 70.5%).

MS m/z(ESI):285.4[M+H] ⁺

The fifth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (5 f);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

compound 5e (6.0g, 21.1mmoL) was dissolved in a solution of potassium hydroxide (3.6g, 63.4mmoL) in water (100mL), and 2mL of methanol was added to dissolve insoluble matter. Methyl iodide (3.9g, 27.4mmoL) was added dropwise at room temperature, and the reaction was maintained at room temperature for 2 hours. After completion of the reaction monitored by TLC, 1N HCl was added dropwise until no more white solid precipitated (pH 2), filtered, the cake was washed twice with water, and the cake was collected to give the desired product 5f as a white solid (4.1g, yield: 65%).

MS m/z(ESI):299.4[M+H] ⁺

And a sixth step: 2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -trifluoromethanesulfonate (5 g);

2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

compound 5f (1.7g, 5.7mmol) was dissolved in 300mL of dichloromethane, N-diisopropylethylamine (4.4g, 34.2mmol) was added, trifluoromethanesulfonic anhydride (4.83g, 17.1mmol) was added under ice-bath, and the mixture was stirred for 1h under ice-bath. After the reaction was completed, 30mL of water was added to wash and quench the reaction, 20mL of saturated aqueous sodium bicarbonate solution was used to wash the reaction solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, 5g of the objective product was obtained as a white solid (2.42g, yield: 99%).

MS m/z(ESI):431.5[M+H] ⁺

The seventh step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylthio) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (5H);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 5g (2.42g, 5.6mmol) was dissolved in 30mL of N, N-dimethylacetamide, and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.9g, 8.4mmol) and diisopropylethylamine (3.67mL, 22.4mmol) were added and stirred at room temperature for 12 h. TLC monitored the reaction completion, diluted with 150mL ethyl acetate, washed the organic phase three times with 30mL water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the desired product was obtained as a white solid for 5h (2.73g, yield: 96%).

MS m/z(ESI):506.7[M+H] ⁺

Eighth step: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (methylsulfonyl) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (5 i);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 5h (2.73g, 5.4mmol) was dissolved in 100mL tetrahydrofuran, m-chloroperoxybenzoic acid (2.8g, 16.2mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. 20mL of a saturated aqueous solution of sodium thiosulfate was added, the mixture was stirred for 20min, most of the solvent was removed under reduced pressure, 100mL of ethyl acetate was added for dilution, the organic layer was washed with 30mL of a saturated aqueous solution of sodium hydrogencarbonate 3 times, the organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to obtain the objective product 5i as a white solid (2.54g, yield: 87%).

MS m/z(ESI):538.7[M+H] ⁺

The ninth step: (2S) -2- (cyanomethyl) -4- [2- [ [ ((2S,4R) -4-fluoro-1-methyl-pyrrolidinyl-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazoline-7, 1' -indan ] -4-yl ] piperazine-1-carboxylic acid tert-butyl ester (5 j);

tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazine-1-carboxylate.

compound 5i (950mg, 1.77mmol) and (1-methyl-4-fluoropyrrolidin-2-yl) methanol (471mg, 3.54mmol) were dissolved in 40mL of toluene, and sodium tert-butoxide (255mg, 2.66mmol) was added under ice bath and stirred for 1h under ice bath. The reaction was quenched with 15mL of water, extracted three times with 100mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the objective product 5j was obtained as a white solid (1.0g, yield: 96%).

MS m/z(ESI):591.3[M+H] ⁺

The tenth step: 2- [ (2S) -4- [2- [ [ ((2S,4R) -4-fluoro-1-methyl-pyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] piperazin-2-yl ] acetonitrile (5 k);

2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

compound 5j (1.0g, 1.7mmol) was dissolved in 20mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is finished, the solvent is dried by spinning under reduced pressure, then 100mL of dichloromethane is added for dilution, saturated sodium bicarbonate is added dropwise to adjust the pH value to be alkaline, then 100mL of dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, reduced pressure concentration is carried out, and the crude product of the target compound 5k and 1.2g of yellow solid are obtained and directly used in the next step.

MS m/z(ESI):491.3[M+H] ⁺

The eleventh step: 2- [ (2S) -4- [2- [ [ ((2S,4R) -4-fluoro-1-methyl-pyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -1-prop-2-enoyl-piperazin-2-yl ] acetonitrile (compound 5);

2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

crude compound 5k (0.6g, 1.23mmol) was dissolved in 50mL of dichloromethane, triethylamine (0.85mL, 6.1mmol) was added, acryloyl chloride (111mg, 1.23mmol) was added under ice bath, and the mixture was stirred for 30min under ice bath. The reaction was quenched by the addition of 5mL of ice water, then extracted three times with 50mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography gave the title compound 5 as a white solid (254mg, two-step yield: 55%). The compound 5 is separated and purified by SFC preparation to obtain an isomer 5-1(95mg, SFC preparation retention time is 1.23 min; chiral HPLC retention time is 12.78min) and an isomer 5-2(100mg, SFC preparation retention time is 1.47min, chiral HPLC retention time is 18.30min).

Chiral HPLC analytical method:

the sample was dissolved in n-hexane/isopropanol (90:10),

the instrument comprises the following steps: shimadzu LC-20 AT; chiral column: CHIRALPAK AD-H, 4.6X 250mm,5 μm

Mobile phase: n-hexane (containing 0.1% diethylamine) -isopropanol (80: 20); flow rate: 1mL/min

Column temperature: 35 ℃; detection wavelength: 210 nm; sample introduction amount: 50 μ L

SFC preparation separation conditions: the instrument is MG II preparative SFC column, ChiralPak AD, 250X 30mm I.D.,10 μm

Mobile phase A is CO₂B is ethanol (containing 0.1% ammonia), and 30% B is eluted.

The flow rate is 70 mL/min; the column temperature is 38 ℃; detection wavelength of 220nm

After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain the compounds 5-1 and 5-2.

Isomer 5-1

¹H NMR(400MHz,CD ₃OD)δ7.30–7.03(m,4H),6.93–6.71(m,1H),6.27(d,1H),5.82(d,1H),5.26–4.99(m,2H),4.43–4.30(m,2H),4.21–3.96(m,3H),3.76–3.58(m,1H),3.57–3.42(m,2H),3.42–3.36(m,1H),3.18–3.03(m,2H),3.02–2.90(m,3H),2.90–2.77(m,3H),2.77–2.48(m,5H),2.33–2.18(m,1H),2.13–1.86(m,4H),1.85–1.75(m,1H).

¹⁹F NMR(376MHz,CD ₃OD)δ-169.68.

Ms m/z(ESI):545.3[M+H] ⁺

Isomer 5-2

¹H NMR(400MHz,CD ₃OD)δ7.26–7.19(m,1H),7.19–7.09(m,2H),7.09–7.02(m,1H),6.94–6.72(m,1H),6.28(d,1H),5.82(d,1H),5.28–5.00(m,2H),4.44–4.31(m,2H),4.21–3.93(m,3H),3.67–3.43(m,2H),3.28–3.20(m,1H),3.19–3.08(m,2H),3.07–2.86(m,4H),2.85–2.62(m,5H),2.55(s,3H),2.35–2.21(m,1H),2.10–1.88(m,4H),1.82–1.72(m,1H).

¹⁹F NMR(376MHz,CD ₃OD)δ-169.73.

Ms m/z(ESI):545.3[M+H] ⁺

Example 6

2- [ (2S) -4- [2- [ [ ((2S,4R) -4-fluoro-1-methyl-pyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl ] acetonitrile (compound 6);

2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

crude compound 5k (0.6g, 1.23mmol) and 2-fluoroacrylic acid (166mg, 1.85mmol) were dissolved in 30ml of N, N-dimethylformamide, diisopropylethylamine (793mg, 6.15mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N' was added at room temperature; tetramethylurea hexafluorophosphate (701mg, 1.85mmol), reaction for 3 h. After the reaction of the raw materials is completed, 100mL of ethyl acetate is added to dilute the reaction, then the organic phase is washed with 30mL of water for three times, dried by anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography gave the title compound 6 as a white solid (334mg, yield: two steps 70%). The compound 6 is separated and purified by SFC preparation to obtain an isomer 6-1(100mg, SFC preparation retention time is 1.07 min; chiral HPLC retention time is 11.46min) and an isomer 6-2(150mg, SFC preparation retention time is 1.29min, chiral HPLC retention time is 19.75min).

Chiral HPLC analytical method:

the sample was dissolved in n-hexane/isopropanol (90:10),

the instrument comprises the following steps: shimadzu LC-20 AT; chiral column: CHIRALPAK AD-H, 4.6X 250mm,5 μm

Mobile phase: n-hexane (containing 0.1% diethylamine) -isopropanol (80: 20); flow rate: 1mL/min

Column temperature: 35 ℃; detection wavelength: 210 nm; sample injection amount: 50 μ L

SFC preparation separation conditions: the instrument is MG II preparative SFC column, ChiralPak AD, 250X 30mm I.D.,10 μm

Mobile phase A is CO₂B is ethanol (containing 0.1% ammonia), and 30% B is eluted.

The flow rate is 70 mL/min; the column temperature is 38 ℃; detection wavelength of 220nm

After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain the compounds 6-1 and 6-2.

Isomer 6-1

¹H NMR(400MHz,CD ₃OD)δ7.06–7.02(m,4H),5.42–5.04(m,3H),5.02–4.85(m,1H),4.44–4.30(m,2H),4.20–3.98(m,3H),3.75–3.57(m,1H),3.56–3.42(m,1H),3.42–3.34(m,1H),3.17–2.76(m,9H),2.76–2.64(m,2H),2.52(s,3H),2.33–2.18(m,1H),2.12–1.85(m,4H),1.85–1.74(m,1H).

¹⁹F NMR(376MHz,CD ₃OD)δ-105.10,-169.66.

Ms m/z(ESI):563.3[M+H] ⁺

Isomer 6-2

¹H NMR(400MHz,CD ₃OD)δ7.26–7.20(m,1H),7.19–7.09(m,2H),7.09–7.02(m,1H),5.42–5.05(m,3H),4.99–4.84(m,1H),4.43–4.31(m,2H),4.22–3.93(m,3H),3.63–3.42(m,2H),3.28–3.11(m,3H),3.10–3.01(m,2H),3.01–2.85(m,2H),2.85–2.72(m,3H),2.71–2.57(m,2H),2.53(s,3H),2.34–2.16(m,1H),2.11–1.85(m,4H),1.85–1.71(m,1H).

¹⁹F NMR(376MHz,CD ₃OD)δ-105.06,-169.64.

Ms m/z(ESI):563.3[M+H] ⁺

Example 7

2- [ (2S) -1- (2-fluoroprop-2-enoyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] piperazin-2-yl ] acetonitrile (compound 7);

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

the first step is as follows: (S) -tert-butyl 2- (cyanomethyl) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (7 a);

tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

compound 5i (1.6g, 3.0mmol) and (1-methylpyrrolidin-2-yl) methanol (686mg, 6.0mmol) were dissolved in 60mL of toluene, sodium tert-butoxide (432mg, 4.5mmol) was added under ice bath, and stirred for 1h under ice bath. The reaction was quenched with 20mL of water, extracted three times with 1000mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the objective product 7a was obtained as a white solid (1.54g, yield: 90%).

MS m/z(ESI):573.6[M+H] ⁺

The second step is that: 2- ((S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (7 b);

2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

compound 7a (1.54g, 2.7mmol) was dissolved in 25mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is finished, the solvent is dried by spinning under reduced pressure, then 100mL of dichloromethane is added for dilution, saturated sodium bicarbonate is added dropwise to adjust the pH value to be alkaline, then 100mL of dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, reduced pressure concentration is carried out, and a crude product of the target compound 7b is obtained, wherein the yellow solid is 1.5g, and the crude product is directly used in the next step.

MS m/z(ESI):473.6[M+H] ⁺

The third step: 2- [ (2S) -1- (2-fluoroprop-2-enoyl) -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] spiro [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] piperazin-2-yl ] acetonitrile (compound 7);

2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

crude compound 7b (0.46g, 0.97mmol) and 2-fluoroacrylic acid (132mg, 1.46mmol) were dissolved in 30mL of N, N-dimethylformamide, diisopropylethylamine (626mg, 4.85mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N' was added at room temperature; tetramethylurea hexafluorophosphate (555mg, 1.46mmol), reaction for 3 h. After the reaction of the raw materials is completed, 100mL of ethyl acetate is added to dilute the reaction, then the organic phase is washed with 30mL of water for three times, dried by anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography gave the title compound 7 as a white solid (330mg, two-step yield: 72%). The compound 7 is separated and purified by SFC preparation to obtain isomer 7-1(95mg, SFC preparation retention time of 1.07 min; chiral HPLC retention time of 7.69min) and isomer 7-2(60mg, SFC preparation retention time of 1.26min, chiral HPLC retention time of 13.65min).

Chiral HPLC analytical method:

the sample was dissolved in n-hexane/isopropanol (90:10),

the instrument comprises the following steps: shimadzu LC-20 AT; chiral column: CHIRALPAK AD-H, 4.6X 250mm,5 μm

Mobile phase: n-hexane (containing 0.1% diethylamine) -isopropanol (80: 20); flow rate: 1mL/min

Column temperature: 35 ℃; detection wavelength: 210 nm; sample introduction amount: 50 μ L

SFC preparation separation conditions:

instrument MG II preparative SFC column, ChiralPak AD, 250X 30mm I.D.,10 μm; mobile phase A is CO₂B is ethanol (containing 0.1% ammonia), and 30% B is eluted.

The flow rate is 70 mL/min; the column temperature is 38 ℃; detection wavelength of 220nm

After separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain the compounds 7-1 and 7-2.

Isomer 7-1

¹H NMR(400MHz,CD ₃OD)δ7.26–7.06(m,4H),5.41–5.22(m,2H),5.02–4.84(m,1H),4.43–4.25(m,2H),4.21–3.99(m,3H),3.75–3.52(m,1H),3.44–3.33(m,1H),3.17–3.00(m,3H),2.99–2.90(m,3H),2.89–2.65(m,5H),2.51(s,3H),2.37(dd,1H),2.16–1.96(m,4H),1.88–1.76(m,3H),1.76–1.64(m,1H).

¹⁹F NMR(376MHz,CD ₃OD)δ-105.11.

Ms m/z(ESI):545.3[M+H] ⁺

Isomer 7-2

¹H NMR(400MHz,CD ₃OD)δ7.26–7.19(m,1H),7.19–7.08(m,2H),7.09–7.01(m,1H),5.42–5.19(m,2H),5.01–4.84(m,1H),4.42–4.25(m,2H),4.23–3.91(m,3H),3.67–3.38(m,1H),3.27–3.01(m,5H),3.01–2.85(m,2H),2.85–2.60(m,5H),2.50(s,3H),2.36(dd,1H),2.15–1.94(m,4H),1.89–1.64(m,4H).

¹⁹F NMR(376MHz,CD ₃OD)δ-105.06.

Ms m/z(ESI):545.3[M+H] ⁺

Example 8

2- [ ((2S) -1- [ (E) -4- (dimethylamino) but-2-enoyl ] -4- [2- [ [ ((2S) -1-methylpyrrolidin-2-yl ] methoxy ] spiro ] [6, 8-dihydro-5H-quinazolin-7, 1' -indan ] -4-yl ] piperazin-2-yl ] acetonitrile (compound 8);

2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

the crude compound 7b (0.4g, 0.85mmol) and trans-4-dimethylaminocrotonate (211mg, 1.28mmol) were dissolved in 30mL of N, N-dimethylformamide, diisopropylethylamine (548mg, 4.25mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N' was added at room temperature; tetramethylurea hexafluorophosphate (486mg, 1.28mmol), reaction for 3 h. After the reaction of the raw materials is completed, 100mL of ethyl acetate is added to dilute the reaction, then the organic phase is washed with 30mL of water for three times, dried by anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography gave the title compound 8 as a white solid (100mg, yield: 23%). The compound 8 is separated and purified by SFC preparation to obtain an isomer 8-1(36mg, SFC preparation retention time is 5.57 min; chiral HPLC retention time is 11.6min) and an isomer 8-2(25mg, SFC preparation retention time is 6.08min, chiral HPLC retention time is 14.9min).

Chiral HPLC analytical method:

the sample was dissolved in n-hexane/isopropanol (90:10),

the instrument comprises the following steps: shimadzu LC-20 AT; chiral column: CHIRALPAK AD-H, 4.6X 250mm,5 μm

Mobile phase: n-hexane (containing 0.1% diethylamine) -ethanol (80: 20); flow rate: 1mL/min

Column temperature: 35 ℃; detection wavelength: 210 nm; sample introduction amount: 50 μ L

SFC preparation separation conditions: MG II preparatory SFC; column ChiralCel OD, 250X 30mm I.D.,5 μm

Mobile phase A is CO₂B is ethanol (containing 0.1% ammonia), and 30% B is eluted.

The flow rate is 70 mL/min; the column temperature is 38 ℃; detection wavelength of 220nm

After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain the compounds 8-1 and 8-2.

Isomer 8-1

¹H NMR(400MHz,CD ₃OD)δ7.26–7.19(m,1H),7.19–7.05(m,3H),6.91–6.59(m,2H),5.12–4.97(m,1H),4.60–4.46(m,1H),4.43–4.28(m,2H),4.19–3.99(m,3H),3.76–3.60(m,1H),3.44–3.35(m,1H),3.23–3.16(m,2H),3.16–3.06(m,2H),3.00–2.76(m,7H),2.76–2.67(m,1H),2.53(s,3H),2.48–2.34(m,1H),2.30(s,6H),2.16–1.97(m,4H),1.90–1.65(m,4H).

Ms m/z(ESI):584.3[M+H] ⁺

Isomer 8-2

¹H NMR(400MHz,CD ₃OD)δ7.27–7.19(m,1H),7.19–7.08(m,2H),7.08–7.01(m,1H),6.89–6.79(m,1H),6.79–6.58(m,1H),5.16–4.98(m,1H),4.61–4.45(m,1H),4.42–4.26(m,2H),4.19–3.92(m,3H),3.66–3.50(m,1H),3.26–3.06(m,5H),3.06–2.86(m,4H),2.85–2.74(m,3H),2.71–2.61(m,1H),2.51(s,3H),2.42–2.33(m,1H),2.29(s,6H),2.15–1.95(m,4H),1.87–1.65(m,4H).

Ms m/z(ESI):584.3[M+H] ⁺

Example 9:

optically pure isomers of 2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Compound 9-1 and Compound 9-2)

2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile；isomer 9-1 and isomer 9-2

The first step is as follows: spiro [ cyclohexane-1, 1' -indene ] -3-one (9F)

spiro[cyclohexane-1,1'-inden]-3-one

Intermediate 1E (3.0g,12.4mmol) was dissolved in THF (10.0mL), 6N hydrochloric acid (20.0mL) was added to the system, and the reaction was allowed to stir at room temperature for 1h. After the reaction is finished, the reaction liquid is directly dried by spinning, extracted by ethyl acetate and saturated NaHCO₃The aqueous solution was washed, the organic phase was dried, filtered and directly spin-dried, and separated by silica gel chromatography to give the product 9F as an oil-free product (2.5g, 98% yield).

The second step is that: 3-Hydroxyspirocyclo [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (9G)

ethyl 3-hydroxyspiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

Dissolving spiro [ cyclohexane-1, 1' -indene ] -3-ketone (9F) (2.3g,11.6mmol) in THF (80.0mL), stirring and cooling at-70 ℃, slowly adding LiHMDS (14mL,14.0mmol) dropwise to the system, keeping the reaction at the temperature, continuing stirring for 1h, slowly adding ethyl cyanoformate (1.38g,14.0mmol) dropwise to the reaction, after the dropwise addition is finished, slowly heating the reaction to room temperature, and then stirring for 30m in. After the reaction is finished, cooling the reaction solution to 0 ℃, quenching the reaction solution by using a saturated ammonium chloride aqueous solution, extracting by using ethyl acetate, drying and filtering the organic phase, directly spin-drying, and separating by using a silica gel chromatographic column to obtain a product 9G which is free of oil substances (2.3G, the yield is 73%).

The third step: 3-Aminospiro [1,1' -indene ] -3-ene-4-carboxylic acid ethyl ester (9H)

ethyl 3-aminospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

Ethyl 3-hydroxyspiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylate (9G) (2.3G,8.4mmol) and ammonium acetate (2.2G,29mmol) were dissolved in ethanol (80.0mL) and stirred at 90 ℃ under reflux for 2 hours. After the reaction was completed, the reaction solution was directly spin-dried, and the product 9H was isolated by silica gel chromatography without oil (2.15g, 95% yield).

The fourth step: 3- (3-benzoylthioureido) spiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylic acid ethyl ester (9I)

ethyl 3-(3-benzoylthioureido)spiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

3-amino spiro [1,1' -indene ] -3-ene-4-carboxylic acid ethyl ester (9H) (2.1g,8.0mmol) and benzoyl isothiocyanate (1.9g,12.0mmol) are added into acetone (50.0mL) and stirred uniformly, then the mixture is placed at 60 ℃ and stirred and refluxed for 1H, after the reaction is finished, the reaction liquid is cooled to room temperature, reduced pressure rotary evaporation is directly carried out on the reaction liquid, and the product 9I is obtained after purification by a silica gel column and is white solid (2.8g, the yield is 81%).

The fifth step: 2 '-mercapto-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -ol (9J)

2'-mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

Ethyl 3- (3-benzoylthioureido) spiro [ cyclohexane-1, 1' -indene ] -3-ene-4-carboxylate (9I) (2.8g,6.5mmol) and KOH (1.1g,19.5mmol) were dissolved in ethanol (50.0mL) and stirred at 90 ℃ under reflux for 30 min. After the reaction is finished, cooling the reaction liquid to room temperature, neutralizing the reaction liquid with 2N hydrochloric acid until a large amount of white solid is separated out, filtering the solid to obtain a filter cake, and drying the filter cake under reduced pressure to obtain a product 9J. White solid (1.3g, 74% yield).

And a sixth step: 2'- (methylthio) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -ol (9K)

2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

2' -mercapto-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -ol (9J) (1.3g,4.6mmol) and KOH (1.0g,18mmol) were dissolved in THF (10mL) -H₂O (40.0mL) was added to the mixed solvent at room temperature, followed by stirring, and then placed in an ice bath, and MeI (930mg,6.4mmol) was added dropwise to the reaction mixture, and after the addition was completed, stirring was continued at that temperature for 1 hour. After the reaction is finished, the reaction is proceededThe solution was neutralized with 2N hydrochloric acid to pH 7, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, spun dried and purified by silica gel column to give product 9K as a white solid (1.3g, 95% yield).

The seventh step: 2'- (methylthio) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -trifluoromethylsulfonate (9L)

2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate

2' - (methylthio) -5', 8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -ol (9K) (1.3g,4.5mmol) and DIPEA (1.5g,11.6mmol) were dissolved in DCM (50.0mL), stirred at-20 ℃ for 10min, and Tf was slowly added dropwise to the reaction₂O (1.9g,6.7mmol), and the reaction was stirred at this temperature for a further 10 min. After the reaction was complete, the reaction was quenched with aqueous sodium bicarbonate, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, spun dried and purified on a silica gel column to give the product 9L as a colorless oil (1.7g, 88% yield).

Eighth step: optically pure isomers of tert-butyl (2S) -2- (cyanomethyl) -4- (2'- (methanethiol) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazine-1-carboxylate (9M-1 and 9M-2)

tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9M-1 and isomer 9M-2

2'- (methylthio) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -trifluoromethylsulfonate (9L) (1.7g,4.0mmol), DIPEA (1.3g,10.0mmol), and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.1g,4.8mmol) were dissolved in DMA (20.0mL) and stirred at room temperature for 1H. After the reaction was completed, the reaction mixture was directly spin-dried and purified by a silica gel column to obtain tert-butyl (2S) -2- (cyanomethyl) -4- (2'- (methanethiol) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (9M racemate) as a white solid (1.7g, yield 88%).

9M racemate was resolved by hand (Preparative separation method: Instrument: MG II Preparative SFC (SFC-14), Column: Chiralcel OJ, 250X 30mm I.D.,5 μ M, Mobile phase: A for CO₂and B for Ethanol, Gradient: B40%, Flow rate:50mL/min, Back pressure:100bar, Column temperature:38 ℃, wavelet: 220nm, Cycle time: -4.2 min) to obtain optically pure isomer 9M-1(860mg) and isomer 9M-2(820 mg).

The ninth step: one of the optically pure isomers of tert-butyl (2S) -2- (cyanomethyl) -4- (2'- (methylsulfinyl) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (9N-1)

tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9N-1

9M-1(150mg,0.3mmol) was dissolved in DCM (6.0mL), stirred at 0 ℃ for 10min, M-chloroperoxybenzoic acid (62mg,0.36mmol) was added to the system, and the reaction was stirred at room temperature for 1h. After the reaction is finished, adding sodium thiosulfate aqueous solution into the reaction solution to quench the reaction, extracting with DCM, drying the organic phase with anhydrous sodium sulfate, spin-drying, and purifying with a silica gel column to obtain the product 9N-1. White solid (140mg, 90% yield).

The tenth step: one of the optically pure isomers of tert-butyl (2S) -2- (cyanomethyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate (9O-1)

tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9O-1

Substrate 9N-1(140mg,0.27mmol) and N-methyl-L-prolinol (46mg,0.4mmol) were dissolved in toluene (6.0mL), and after stirring at 0 ℃ for 10min, sodium tert-butoxide (39mg,0.4mmol) was further added to the system, and stirring at that temperature was continued for 30 min. After the reaction is finished, adding an ammonium chloride aqueous solution into the reaction solution for quenching, extracting with DCM, drying an organic phase with anhydrous sodium sulfate, filtering, spin-drying, and purifying by a silica gel column to obtain a product 9O-1. White solid (140mg, 91% yield).

The eleventh step: one of the optically pure isomers of 2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (9P-1)

2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile；isomer 9P-1

Substrate 9O-1(140mg,0.24mmol) was dissolved in DCM (6.0mL), and trifluoroacetic acid (1.0mL) was slowly added dropwise and stirred at room temperature for 30 min. After the reaction was completed, the reaction was quenched with aqueous sodium carbonate and extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to give the product 9P-1. White solid (120mg, 106% yield).

The twelfth step: optically pure isomers of 2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Compound 9-1 and Compound 9-2)

2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

Substrate 9P-1(70mg,0.15mmol) and triethylamine (46mg,0.45mmol) were dissolved in DCM (10.0mL), stirred at 0 deg.C for 10min, and acryloyl chloride (20mg,0.23mmol) was slowly added dropwise, stirred at that temperature for 30 min. After the reaction, the reaction was quenched with aqueous sodium carbonate and extracted with DCM, the organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried and purified by HPLC (preparation conditions: instrument and preparative column: preparation of liquid phase using WATERS 2767, preparative column with column number Xbridge C18,5 μm, inner diameter × length 19mm × 250 mm. mobile phase system: acetonitrile/(water containing 0.05% trifluoroacetic acid), gradient elution: acetonitrile content 30% to 75%, elution time 15 min.) to give compound 9-1. White solid (33mg, 42% yield).

LCMS m/z＝525.3[M+1] ⁺

¹H NMR(400MHz,CD ₃OD)δ7.34(d,1H),7.29(d,1H),7.25(dt,1H),7.17(dt,1H),6.84(s,1H),6.80(d,1H),6.58(d,1H),6.28(d,1H),5.83(d,1H),5.10(s,1H),4.70–4.36(m,3H),4.23(d,1H),4.19–4.09(s,1H),4.06(d,1H),3.58(s,1H),3.37–3.31(m,1H),3.27–3.12(m,3H),3.09–3.01(m,2H),2.94(t,2H),2.72(s,3H),2.68(t,2H),2.25–2.15(m,1H),2.04–1.93(m,2H),1.93–1.89(m,1H),1.88–1.80(m,1H),1.80–1.71(m,1H).

9M-2(150mg,0.3mmol) was subjected to the same synthetic route as that for 9M-1 to compound 9-1 to give compound 9-2. White solid (28 mg).

LCMS m/z＝525.3[M+1] ⁺

¹H NMR(400MHz,CD ₃OD)δ7.33(t,2H),7.24(dt,1H),7.19(dt,1H),6.81(d,2H),6.69(d,1H),6.28(d,1H),5.83(d,1H),5.05(s,1H),4.50–4.38(m,2H),4.16(d,2H),4.09(s,1H),3.72(s,1H),3.47(s,1H),3.29–3.24(m,1H),3.21–3.05(m,3H),3.02–2.86(m,4H),2.67(s, 3H),2.65–2.60(t,1H),2.54(d,1H),2.24–2.04(m,2H),1.96–1.93(m,1H),1.92–1.88(m,1H),1.85–1.75(m,1H),1.70–1.61(m,1H).

Example 10

1- (7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 10)

1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

First step tert-butyl 7- (2'- (methylthio) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2,7 diazaspiro [3.5] nonane-2-carboxylate (10a)

tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To compound 5f (2.1g,7.04mmol) were added 15mL of DMF followed by diisopropylethylamine (2.73g,21.12mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (4.4g,8.45mmol) was added with stirring. After the addition, 2-tert-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane (1.91g,8.45mmol) was added to the reaction mixture after the reaction mixture was clarified, and the mixture was stirred at 80 ℃ for 2 hours. Diluting with 50mL of ethyl acetate, washing the organic phase three times with 30mL of water, drying the organic phase over anhydrous sodium sulfate, and concentrating under reduced pressure. Silica gel column chromatography gave the desired product tert-butyl 7- (2'- (methylthio) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2,7 diazaspiro [3.5] nonane-2-carboxylate (10a) as a white solid (2.7g, yield: 75%).

LCMS m/z＝507.2[M+H] ⁺.

The second step is that: tert-butyl 7- (2'- (methylsulfonyl) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2,7 diazaspiro [3.5] nonane-2-carboxylate (10b)

tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Compound 10a (2.7g, 5.33mmol) was dissolved in 20mL of toluene, and m-chloroperoxybenzoic acid (1.84g, 10.66mmol) was added under ice-bath, and the mixture was stirred at room temperature for 1 hour. 20mL of saturated aqueous sodium thiosulfate solution was added, stirring was carried out for 40min, 50mL of ethyl acetate was added, the mixture was washed 3 times with 30mL of saturated aqueous sodium bicarbonate solution, the organic phase was dried and concentrated under reduced pressure to give the crude target product tert-butyl 7- (2'- (methylsulfonyl) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -2,7 diazaspiro [3.5] nonane-2-carboxylate (10b) (2.9g) which was used directly in the next step.

LCMS m/z＝539.2[M+H] ⁺

The third step: tert-butyl 7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (10c)

tert-butyl 7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Compound 10b (2.7g) and ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (2.67g, 20.04mmol) were dissolved in 20mL of toluene, and sodium tert-butoxide (1.44g, 15.03mmol) was added under ice bath, followed by stirring for 1h under ice bath. The reaction mixture was quenched with 15mL of water, extracted with 20mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography gave the desired product tert-butyl 7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (10c) as a white solid (2.0g, two step yield: 67%).

LCMS m/z＝592.3[M+H] ⁺

The fourth step: 2'- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2- (yl) methoxy) -4' - (2, 7-diazaspiro [3.5] nonyl-7-yl) -2,3,6',8' -tetrahydro-5 'H-spiro [ indene-1, 7' -quinazoline ] (10d)

2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]

Substrate 10d (2g,3.38mmol) was dissolved in DCM (10mL) and trifluoroacetic acid (5mL) was slowly added dropwise and stirred at room temperature for 30 min. After the reaction was complete, concentrated under reduced pressure, the residue was basified with 10mL of saturated aqueous sodium bicarbonate solution and extracted with DCM (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 2'- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2- (yl) methoxy) -4' - (2, 7-diazaspiro [3.5] nonyl-7-yl) -2,3,6',8' -tetrahydro-5 'H-spiro [ indene-1, 7' -quinazoline ] (10d) (2g) which was used directly in the next step.

The fifth step: 1- (7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 10)

1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

Substrate 9d (800mg,1.63mmol) and diisopropylethylamine (0.63g,4.89mmol) were dissolved in DCM (10.0mL), stirred at 0 deg.C for 10min, and acryloyl chloride (150mg,1.63mmol) was slowly added dropwise, stirred at that temperature for 30 min. After the reaction was completed, the reaction was quenched with 20mL of an aqueous sodium bicarbonate solution and extracted with 20mL of DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1- (7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 10) as a white solid (450mg, two-step yield: 61%).

LCMS m/z＝546.2[M+H] ⁺

Example 11

2-fluoro-1- (7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indole-1, 7 '-quinazolin-4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 11)

2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

The first step is as follows: 2-fluoro-1- (7- (2'- (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indole-1, 7 '-quinazolin-4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 11)

2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

Compound 10d (0.65g, 1.32mmol) and 2-fluoroacrylic acid (140mg, 1.58mmol) were dissolved in 10mL of N, N-dimethylformamide, diisopropylethylamine (510mg, 3.96mmol) was added, and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (0.82g, 1.58mmol) was added at room temperature and reacted for 1H. 20mL of water was added to precipitate a large amount of solid, which was filtered, the filter cake was dried under reduced pressure, and purified by silica gel column chromatography to give 2-fluoro-1- (7- (2'- (((((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2,3,6',8 '-tetrahydro-5' H-spiro [ indole-1, 7 '-quinazolin-4' -yl) -2, 7-diazaspiro [3.5] nonyl-2-yl) prop-2-en-1-one (Compound 11) as a white solid (200mg, two-step yield: 32%).

LCMS m/z＝564.3[M+H] ⁺

By taking the corresponding starting materials/intermediates and taking the procedure of example 3, the compounds 12, 13, 14, 15, 16, 17, 18 of the following table a were prepared.

By taking the corresponding starting materials/intermediates and preparing the compounds by reference to the procedure of example 1, compounds 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 of the following table a are obtained.

By referring to the procedures of examples 4 to 11, the corresponding starting materials/intermediates were selected to prepare compounds 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126 as shown in table a below.

TABLE A Structure of Compounds 12-126

Biological test example

Method 1 NCI-H358 cells (human non-small cell lung carcinoma cells) were purchased from ATCC and 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 for 2 minutes with a microplate shaker, left at room temperature for 10 minutes, and then measured for fluorescence signal values with an Envision2104 plate reader.

The cell viability was calculated by the formula (1). Wherein V_sampleReading for the drug treatment group, V_{vehicle control}Mean values for the solvent control group. Application of GraphPad Prism 5.0 software, sigmoidal dose-survival curves using a non-linear regression model and calculating IC₅₀The value is obtained. 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% formula (1)

1-V _sample/V _{vehicle control}x 100% formula (2)

Method 2 NCI-H358 cells were purchased from ATCC in RPMI1640+ 10% FBS at 37 ℃ in 5% CO₂Culturing in an incubator. On the first day, NCI-H358 cells in the exponential growth phase were collected and viable cell counts were performed using an automated cell analyzer (countstar). The cell suspension was conditioned with medium and plated in 96 well cell culture plates, 1500 cells per well. The following day, the medium was aspirated and 90 μ L of fresh medium and 10 μ L of different concentrations of compound were added to each well, with a final DMSO concentration of 0.1%. At 37 ℃ with 5% CO₂Incubate for 72 hours. After 72 hours of drug treatment, 50. mu.L 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, left at room temperature for 10 minutes, and then the fluorescence signal value was measured by a microplate reader (PHERAStar FSX).

Formula V for cell viability_sample/V _{vehicle control}x 100% calculation. Wherein V_sampleReading for the drug treatment group, V_{vehicle control}Mean values for the solvent control group. Using origen9.2 software, a non-linear regression model was used to plot a sigmoidal dose-survival curve and calculate IC₅₀The value is obtained.

TABLE 1 IC for inhibition of NCI-H358 cell proliferation₅₀Value of

Serial number	Test method	Compound numbering	IC 50(μM)
1	Method 1	Compound 1	0.279
2	Method 2	Compound 4	0.035
3	Method 2	Compound 4-1	0.024
4	Method 2	Compound 4-2	1.231
5	Method 2	Compound 5	0.117
6	Method 2	Compound 5-1	0.044
7	Method 2	Compound 5-2	0.968
8	Method 2	Compound 6-1	0.467
9	Method 2	Compound 6-2	4.244
10	Method 2	Compound 7-1	1.133
11	Method 2	Compound 8-1	0.375
12	Method 2	Compound 8-2	4.702
13	Method 2	Compound 9-1	0.605
14	Method 2	Compound 9-2	0.055

And (4) conclusion: the compounds of the embodiment of the invention have good effect of inhibiting NCI-H358 cell proliferation, and the IC of the compounds 1, 4-1, 4-2, 5-1, 5-2, 6-1, 6-2, 7-1, 8-2, 9-1, 9-2 and 10₅₀IC of Compound 10 less than 5. mu.M₅₀Less than 3. mu.M. Specific IC of a part of the Compound₅₀The values are shown in Table 1.

Test example 2: KRAS G12C kinase inhibitory activity assay

KRAS G12C (Sino, Cat. No. 12259-H07E2) was prepared as a 2.5 Xkinase solution, and a 2 Xsolution was prepared as a substrate and antibody mixture (c-RAF: Pharmaron; SOS 1: Pharmaron; GTP: Sigma, Cat. No. G8877-25 MG; MAb Anti 6HIS-d 2: Cisbio, Cat. No. 61 HISDLB; MAb Anti GST-Eu: Cisbio, Cat. No. 61 TKGSLB). mu.L of compounds at different concentrations were added to 384-well plates, 4. mu.L of 2.5 Xkinase solution was added, and incubation was carried out at room temperature for 60 minutes. After adding 5. mu.L of a 2X mixture of substrate and antibody, and incubating at room temperature for 120 minutes, the excitation light was set at 320nM and the emission light at 615nM and 665nM using a BioTek (Synergy 4) microplate reader, and the fluorescence signals at 615nM (Eu) and 665nM (d2) were read. The Ratio per well was calculated as (665/615) × 10000. IC calculation Using Prism GraphPad 7.0 software₅₀The value is obtained. The inhibition rate is calculated by formula 1, wherein

Average of 10 positive control well ratios (10 μ M AMG510),

average of 10 negative control well ratios (0.5% DMSO).

TABLE 2 IC for inhibition of KRAC G12C kinase₅₀Value of

Serial number	Compound numbering	IC 50(μM)
1	Compound 4-1	0.041
2	Compound 5-1	0.008
3	Compound 6-1	0.050
4	Compound 8-1	0.027
5	Compound 9-2	0.010

And (4) conclusion: the compound of the embodiment of the invention has good effect of inhibiting the activity of KRAC G12C kinase.

Test example 3: human liver microparticle CYP enzyme inhibition assay

The incubation system was 200. mu.L. Taking 20 mu L of substrate solution in a sample hole, taking 20 mu L of blank phosphate buffer solution in a blank control hole, then adding 2 mu L of working solution of the compound to be detected with serial concentration and a positive control into the corresponding sample hole, and adding 2 mu L of blank solvent for replacement in the negative control hole and the blank control hole; adding 158 mu L of human liver microsome working solution into all sample wells, pre-incubating in 37 ℃ water bath for 10min, adding 20 mu L of NADPH regeneration system to start reaction, continuing incubating in 37 ℃ water bath for 10min, adding 400 mu L of acetonitrile ice solution containing 200ng/mL tolbutamide and labetalol to stop reaction and precipitate protein, centrifuging the sample at 4000rpm and 4 ℃ for 20min, taking 200 mu L of supernatant, adding 100 mu L of ultrapure water, mixing uniformly in vortex for 10min, and performing LC-MS/MS sample injection analysis.

TABLE 3 inhibition of human liver particulate CYP enzyme IC₅₀Value of

J.Med.chem.2020,63,13, 6679-

And (4) conclusion: the compounds of the embodiment of the invention have no obvious Inhibition (IC) on the main metabolic enzyme subtype of human liver microparticles₅₀Greater than 10 μ M) and significantly reduced inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3a4-M subtype metabolizing enzymes as compared to MRTX 849.

Test example 4: hERG inhibition assay

Extracellular fluid formulation (mM): 140NaCl,5KCl,1CaCl₂,1.25MgCl ₂10HEPES and 10Glucose, adjusted to pH 7.4 with NaOH. Intracellular fluid formulation (mM): 140KCl,1MgCl2,1CaCl2,10EGTA and 10HEPES, pH adjusted to 7.2 with KOH.

CHO cells stably expressing hERG were cultured in 35mm diameter cell culture dishes at 37 ℃ with 5% CO₂The culture box of (1) is used for culturing according to the proportion of every 48 hoursSubculturing is carried out according to the proportion of 1:5, and the formula of a culture medium is as follows: 90% F12(Invitrogen), 10% fetal bovine serum (Gibco), 100. mu.g/mL G418(Invitrogen) and 100. mu.g/mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture fluid was aspirated, and after rinsing with extracellular fluid, 0.25% Trypsin-EDTA (Invitrogen) solution was added and digested at room temperature for 3-5 minutes. The digestion solution was aspirated, resuspended in extracellular fluid and the cells transferred to a petri dish for electrophysiological recording.

On the day of testing, compound DMSO stock was diluted with 100% DMSO, i.e., 10 μ L of compound stock was added to 20 μ L of DMSO, and 3-fold dilutions were serially released to intermediate concentrations. Then 10 μ L of the intermediate compound concentration was added to 4990 μ L of extracellular fluid, and 500-fold dilution was performed to obtain the final concentration to be tested: the highest concentration tested was 40. mu.M, 40, 13.33, 4.44, 1.48, 0.49, 0.16. mu.M at one time. Positive control compound cisapride preparation: mu.L of the stock solution of cisapride DMSO at 150. mu.M was added to 4990. mu.L of the extracellular fluid and diluted 500-fold to give the final concentration to be tested, 300 nM. The final concentration of DMSO in the test does not exceed 0.2%, the concentration of DMSO on hERG potassium channel has no effect.

Stably expressing hERG potassium channel CHO (Chinese Hamster ovary) cells, at room temperature using the whole cell patch clamp technology record hERG potassium channel current. The data analysis was performed using pClamp 10, GraphPad Prism 5 and Excel software. The degree of inhibition of hERG potassium current (-50mV induced hERG tail current peak) by different compound concentrations was calculated using the following equation:

Inhibition％＝[1–(I/Iο)]×100％

wherein, Inhibition% represents the percentage of Inhibition of the compound on the hERG potassium current, and I omicron represent the amplitude of the hERG potassium current after and before dosing respectively.

Compound IC₅₀Calculated using GraphPad Prism 5 software by equation fitting:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

wherein X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage under the corresponding concentration, and Bottom and Top are respectively the minimum and maximum inhibition percentages.

Table 4 compounds on hERG potassium channel current inhibition of IC₅₀Value of

Compound numbering	IC 50(μM)
Compound 4-1	4.51
MRTX849	1.60

And (4) conclusion: compared with MRTX849, the compound of the embodiment of the invention has obviously reduced hERG potassium channel current inhibition effect.

Claims (21)

1. A compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

   

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

   

   -S(＝O) ₂-C(R ^1a)＝C(R ^1b) ₂Or

   

   R ^1aEach independently selected 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、NH ₂、-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、-(CH ₂) _p-N(C _1-4Alkyl radical)₂、-(CH ₂) _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、NH ₂、-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;

   alternatively, R^1aWith any one of R^1bForm C_5-10Carbocyclic ring or 5 toA 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、NH ₂、-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、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

   ring A is selected from 4-12 membered nitrogen containing heterocyclic ring selected from one of saturated or partially saturated group: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4R^aSubstitution;

   R ^aeach independently selected 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、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   q, M together with the atom to which they are directly attached form C_3-12A carbocycle or a 3-to 12-membered heterocycle which is monocyclic, fused or spirocyclic, optionally further having 0 to 5R²(ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

   R ²are independently selected fromFrom H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8 membered heterocycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5-to 10-membered heteroaryl, 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, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2CSaid heterocycloalkyl or heteroaryl having 1 to 4 heteroatoms selected from O, S, N;

   R ^2A、R ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C _3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

   X ₃selected from the group consisting of a bond, O, -OCH₂-、-CH ₂O-, S or NR^x；

   R ^xSelected 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、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   R ³selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-6Alkyl radical, C_1-6Alkoxy, N (R)^3a) ₂、-(CH ₂) _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、-(CH ₂) _q-N(R ^3a)-C(＝O)R ^3b、-(CH ₂) _q-3 to 12 membered heterocycle or- (CH)₂) _q-C _3-10Carbon 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、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl, -C_{1- 4}alkylene-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 a 3 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、NH ₂、-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^3aAnd the nitrogen atom directly connected with the two are combined to form a 4-to 8-membered nitrogen-containing heterocyclic ring, and the nitrogen-containing heterocyclic ring is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、-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_1-6Alkyl 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、NH ₂、-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 ⁴each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   n, p, q are each independently selected from 0, 1,2, 3 or 4.
2. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (Ia) or (Ib),

   

   r in the general formulae (Ia) and (Ib)¹、R ⁴、R ³、X ₃Ring a and n are as defined in claim 1;

   ring B is selected from a non-aromatic 4-to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

   X ₁is selected from N;

   R ^2aselected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -3 to 8 membered heterocycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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 the group consisting of H, F, Cl,Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 ^2beach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃COOH or C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl or C_1-6Substituted with a substituent of alkoxy;

   ring C and ring D together form C_6-12A carbocyclic fused ring or a 5 to 12 membered heterocyclic fused ring, said heterocyclic fused ring containing 1 to 4 heteroatoms selected from O, S, N;

   R ^2c、R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、COOH、-C(＝O)-C _1-6Alkyl, -C (═ O) -C_3-6Cycloalkyl, -C (═ O) -C_6-10Aryl, -C (═ O) -5 to 10 membered heteroaryl, 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, cyclicThe alkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

   m1 is selected from 0, 1,2, 3 or 4;

   m2 and m3 are respectively and independently selected from 0, 1,2, 3 or 4, and m2+ m3 is less than or equal to 5.
3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein

   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、NH ₂、-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 9-membered nitrogen-containing heterocycle selected from one of the following saturated or partially saturated structures: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle being optionally further substituted by 0 to 4R^aSubstituted by a substituent;

   R ^aeach independently selected 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、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.
4. The compound of claim 3, or a stereoisomer, deuteride, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

   ring A is selected from unsubstituted or substituted

   

   

   

   When being substitutedOptionally further substituted with 0 to 4R^aSubstituted by a substituent;

   R ^aeach independently selected 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、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.
5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

   ring B is selected from azetidine, aziridine or piperidine;

   or ring B is selected from imidazolidine;

   R ^2aselected from H, COOH, -C (═ O) NR^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C(＝O)-C _1-4Alkyl, -C (═ O) -phenyl, -C (═ O) -5 to 6 membered heteroaryl, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 substituents selected from O, SA heteroatom of N;

   ring D is selected from a benzene ring, pyridine, pyridazine or pyrimidine;

   ring C is selected from C_4-6A carbocyclic ring;

   or ring C is selected from a4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;

   R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-4Alkyl radical, C_1-4Alkoxy 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, oxo, OH, cyano, CF₃、COOH、NH ₂、-C(＝O)NR ^2AR ^2B、-NR ^2AC(＝O)R ^2C、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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 ^2Bor R^2CEach independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_{6- 10}Aryl or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

   R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、C _1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂Or C_1-6Alkyl substituents.
6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein

   R ¹Is 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 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, C_1-4Alkyl or- (CH)₂) _p-3 to 6 membered heterocycle, said alkyl or heterocycle optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Carbocyclic or 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N.
7. The compound of claim 6, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein

   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, isopropyl, -CH₂-4-membered nitrogen-containing heterocycle, -CH₂-5-membered nitrogen-containing heterocycle, -CH₂-6-membered, 4-membered, 5-membered or 6-membered nitrogen-containing heterocycle, said methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycle being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   X ₃selected from a bond or O;

   R ^2aselected from H or one of the following substituted or unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl-C (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzpyrazolyl or pyridyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_2-4Substituted by a substituent of alkynyl;

   R ^2beach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   ring C and ring D together form a fused ring selected from

   

   Or a ring C and a ring D together form a fused ring selected from

   

   

   R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、--C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy, or ethoxy, said methyl, ethyl, methoxy, ethoxy, or phenyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF, and mixtures thereof₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy substituents;

   R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   R ³selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N (CH)₃) ₂、-N(CH ₂CH ₃) ₂、-(CH ₂) _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、NH ₂、-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 a 3 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;

   R ⁴each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Or a methyl group;

   q is selected from 0, 1,2, 3 or 4.
8. The compound of claim 7, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein

   R ¹Is selected from

   

   

   Ring a is selected from one of the following substituted or unsubstituted groups:

   

   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 CH ₂CN;

   ring B is selected from piperidine;

   or

   

   Is selected from

   

   

   R ^2aSelected from H or one of the following substituted or unsubstituted groups: -C (═ O) NH₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂、-C(＝O)-CH ₃、-C(＝O)-CH ₂CH ₃、-C(＝O)-CH ₂CH ₂CH ₃、-C(＝O)-CH(CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, -C (═ O) -pyridine, -C (═ O) -thiophene, -C (═ O) -furan, -C (═ O) -pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl or pyridyl, when substituted, are optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF, Br, and optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, I, and optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, and substituted aryl₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl or ethyl;

   R ^2beach independently selected from H, F, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

   R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、-C(＝O)NH ₂、-NHC(＝O)H、-C(＝O)NH-CH ₃、-NHC(＝O)-CH ₃、-C(＝O)NH-CH ₂CH ₃、-NHC(＝O)CH ₂CH ₃、-C(＝O)N(CH ₃) ₂、-C(＝O)N(CH ₂CH ₃) ₂-C (═ O) NH-phenyl, -NHC (═ O) -phenyl, methyl, ethyl, methoxy, or ethoxy, said methyl, ethyl, methoxy, ethoxy, or phenyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF, and mixtures thereof₃、COOH、NH ₂Methyl or ethyl;

   R ^2deach independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃Methyl or ethyl, said methyl or ethyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

   R ³selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, - (CH)₂) _q-tetrahydropyrrole, - (CH)₂) _qAzetidine, -N (CH)₃) ₂or-N (CH)₂CH ₃) ₂When being substitutedOptionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-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.
9. The compound of claim 8, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein

   Ring A is selected from

   

   

   X ₃Selected from O or a bond;

   R ³is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

   

   

   n is selected from 0.
10. The compound of claim 9, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    ring A is selected from

    

    X ₃-R ³Is selected from

    

    n is selected from 0.
11. The compound of claim 8, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    

    is selected from

    

    

    

    Is selected from

    

    

    R ^2cEach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂Methyl or ethyl;

    n is selected from 0;

    m2 is selected from 0, 1,2 or 3.
12. The compound of claim 11, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    ring A is selected from

    

    

    X ₃Selected from O or a bond;

    R ³is selected from-CH₂N(CH ₃) ₂、-CH ₂N(CH ₂CH ₃) ₂、-N(CH ₂CH ₃) ₂、-N(CH ₃) ₂、

    

    

    n is selected from 0.
13. The compound of claim 12, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    ring A is selected from

    

    X ₃-R ³Is selected from

    

    
14. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, which is selected from compounds represented by general formula (Ia-1) or (Ib-1),

    

    G _1-G ₂is selected from-CH₂CH ₂-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH ₃)-、-N(CH ₃) -C (═ O) -or-NH-C (═ O) -;

    R ^2aselected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 8-membered heterocycloalkyl, C_6-10Aryl or 5-to 10-membered heteroaryl, saidThe alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, 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 ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_{3- 6}Cycloalkyl, 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, oxo, OH, cyano, CF₃、COOH、NH ₂、-NH(C _1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C _1-6Alkyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl radical, 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;

    m2 is selected from 0, 1,2 or 3.
15. The compound of claim 14, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    R ¹is selected from

    

    

    R ^2aSelected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、NH ₂Methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or phenyl;

    R ^2ceach independently selected from H, F, Cl, Br, I, OH, cyano, CF₃Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF₃、COOH、NH ₂、C _1-4Alkyl radical, C_1-4Substituted with an alkoxy substituent;

    ring A is selected from

    

    

    X ₃-R ³Is selected from

    

    

    n is selected from 0.
16. The compound of claim 15, which is selected from the group consisting of compounds represented by general formulae (Ic-1) and (Ic-2), or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof,

    
17. the compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

    

    

    

    

    

    

    

    

    

    

    

    

    

    

    
18. a pharmaceutical composition comprising a compound of any one of claims 1-17, or a stereoisomer, deuterode, solvate, prodrug, metabolite, co-crystal, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. Use of a compound according to any one of claims 1-17, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a co-crystal, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with activity or expression of KRAS G12C.
20. The use according to claim 19, wherein the disease is selected from the group consisting of tumors.
21. The use of claim 20, wherein the tumor is selected from the group consisting of hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, non-small cell lung cancer, and small cell lung cancer.