CN120590414A

CN120590414A - Nitrogen-containing heterocyclic compounds, preparation methods and uses

Info

Publication number: CN120590414A
Application number: CN202510223508.6A
Authority: CN
Inventors: 万惠新; 查传涛
Original assignee: Shanghai Lingda Biomedical Co ltd
Current assignee: Shanghai Lingda Biomedical Co ltd
Priority date: 2024-03-04
Filing date: 2025-02-27
Publication date: 2025-09-05

Abstract

The invention discloses a nitrogen-containing heterocyclic compound, a preparation method and application thereof, in particular to a nitrogen-containing heterocyclic compound shown in a general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method thereof and application thereof in pharmacy, wherein the definition of each group is as described in the specification.

Description

Nitrogen-containing heterocyclic compound, preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a nitrogen-containing heterocyclic compound, a compound for inhibiting activity of Ras mutein, a preparation method and application thereof.

Background

Ras is the first oncogene identified in human tumors, and was first discovered in two murine sarcoma viruses. The Ras gene family has three members, HRas, KRas, NRas, respectively. In human tumors, KRas mutations are most common, accounting for about 85%. Previous studies have shown that KRas mutations are oncogenic because of missense mutations at codon 12, altering the structure of the KRas protein and allowing it to remain active. Ras plays a major role in signaling pathway in activating kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and is intimately involved in tumor cell survival, proliferation, migration, metastasis, and angiogenesis. It is counted that a high proportion of KRas mutations occur in malignant tumors such as pancreatic cancer, colorectal cancer, ovarian cancer, cholangiocarcinoma and the like. However, targeting drugs for common proto-oncogenes such as EGFR, BCL, etc. have been developed for several generations since the first discovery of KRas oncogenes, but targeting drugs for KRas have not been successfully developed all the time. Targeting drugs against KRas pathway mutant tumors have been mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but have had little effect. In recent years, inhibitors against KRas specific gene mutations have been developed as hot spots, although some inhibitors have gradually moved from preclinical hatching to clinical studies, such as KRas ^G12C inhibitor AMG510, MRTX1257, etc., and have shown some efficacy in early clinical trials. The first clinical data of the global first-line KRas ^G12C inhibitor AMG510 was formally published by the american clinical oncology institute held at month 6 of 2019, in which the drug AMG510 was shown to be able to prevent tumor growth in most non-small cell lung and colorectal cancer patients with KRas mutations.

However, the KRAS inhibitor is limited to KRAS ^G12C mutant patients, and the research and development of a large number of mutant inhibitor drugs except KRAS ^G12C have not been broken through, such as high-frequency KRAS ^G12D、KRas^G12V、KRas^G13D and other mutations. Therefore, finding and searching for a targeted drug with high specificity and excellent pharmaceutical properties for a specific mutant gene other than KRas ^G12C is a great hotspot in the industry. Through the long-term efforts of the inventor, a KRAS mutation inhibitor with novel structure and action mechanism is discovered, and particularly has better activity and drug-forming property on KRAS ^G12D mutation.

Disclosure of Invention

The invention aims to solve the technical problem of lack of KRAS ^G12D inhibitors in the prior art and provides a nitrogen-containing heterocyclic compound, a preparation method and application thereof. The nitrogen-containing heterocyclic compound provided by the invention is a brand-new KRAS ^G12D inhibitor, shows good inhibition activity, has good inhibition activity on tumor cells and good drug-forming property, particularly improves the defect of low oral bioavailability of the currently known KRAS ^G12D inhibitor, and has wide drug development prospect.

The invention solves the technical problems by the following technical proposal:

The invention provides a nitrogen-containing heterocyclic compound shown in a general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

Wherein R is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, amino, hydroxy, -SH, C _6-10 aryl, 5-10 membered heteroaryl, said "substituted" meaning substituted with one or more (preferably 1,2 or 3) R ⁰ groups, R ⁰ being independently selected from the group consisting of deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -C _0-8 alkyl-SF ₅ groups, said R ⁰ optionally being further substituted with one or more groups independently selected from deuterium or halogen;

R ¹ is selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, amino, hydroxy, -SH, C _6-10 aryl, 5-10 membered heteroaryl, said "substituted" meaning substituted with one or more (preferably 1,2 or 3) R ¹¹ groups, R ¹¹ is independently selected from the group consisting of deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -C _0-4 alkyl-SF ₅ groups, said R ¹¹ is optionally further substituted with one or more groups independently selected from the group consisting of deuterium or halogen;

r ² is selected from the group consisting of substituted or unsubstituted C _1-6 alkyl, 3-12 membered heterocycloalkyl-C _1-6 alkyl- (preferably 4-8 membered heterocycloalkyl-C _1-3 alkyl-) 3-6 membered cycloalkyl-C _1-6 alkyl-, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, C _1-6 alkyl-3-12 membered cycloalkyl-, or C _1-6 alkyl-3-12 membered heterocycloalkyl-, A 5-16 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system comprising a spiro, bridged, fused or fused ring, said "substituted" meaning substituted with one or more (preferably 1, 2, 3 or 4) R ²¹, each R ²¹ being independently selected from deuterium, halogen, cyano, nitro, azido, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-to 6-membered cycloalkyl, 4-to 8-membered heterocyclyl, 6-to 10-membered aryl, 5-to 10-membered heteroaryl, =NH, =CH ₂、-C_0-6 alkyl-OH, -C _0-6 alkyl-O-C (O) -NH ₂、-C_0-6 alkyl-O-C (O) - (C _3-8 heterocycloalkyl), -C _0-6 alkyl-O-C (O) - (C _3-8 cycloalkyl), or two R ²¹ together with the carbon atom or heteroatom to which they are attached form a 3-8 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl (preferably forming a 3-6 membered cycloalkyl), one or more hydrogens on the R ²¹ group (preferably 1, 2 or 3) are independently optionally substituted with R ²¹¹, R ²¹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy;

R ⁴ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅、C_3-18 cycloalkyl-C _1-6 alkyl- 3-18 membered heterocyclyl-C _1-6 alkyl-, -C _1-8 alkyl-OH, -C _1-8 alkyl-NH ₂、-C_0-6 alkyl- (CO) -NH ₂、-C_0-6 alkyl- (CO) -C _1-6 alkyl, -C _0-6 alkyl- (CO) -O-C _1-6 alkyl, -C _0-6 alkyl-P (O) (C _1-6 alkyl) ₂, Amino, hydroxy, -SH, said "substituted" meaning substituted with one or more (1, 2, 3 or 4) R ⁴¹, R ⁴¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ⁴¹ optionally being further substituted with one or more (preferably 1), 2 or 3) R ⁴¹¹ substitutions, said R ⁴¹¹ being independently selected from deuterium or halogen;

R ^5a、R^5b、R^5c and R ^5d are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxy, -SH, C _1-6 alkyl, C _1-6 alkoxy, c _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C _6-10 aryl, A 5-to 10-membered heteroaryl group, said "substituted" meaning substituted with one or more (1, 2, 3 or 4) R ⁵¹, R ⁵¹ is independently selected from deuterium, halogen, cyano, amino, 3-to 6-membered cycloalkyl, 4-to 8-membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ⁵¹ optionally being further substituted with one or more (preferably 1), 2 or 3) R ⁵¹¹ substitutions, said R ⁵¹¹ being independently selected from deuterium or halogen;

R ^6a、R^6b is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-12 cycloalkyl-C _1-6 alkyl-, 3-12 membered heterocyclyl-C _1-6 alkyl-, C _1-8 alkoxy, -C _1-8 alkyl-OH, -C _1-8 alkyl-SH, -C _1-8 alkyl-NH ₂、-C_1-8 alkyl-O-C _1-6 alkyl-, -C _0-6 alkyl- (CO) -NH ₂、-C_0-6 alkyl- (CO) -C _0-6 alkyl, -C _0-6 alkyl- (CO) -O-C _0-6 alkyl, -C _0-6 alkyl-P (O) (C _0-6 alkyl) ₂, Amino, hydroxy, -SH, C _0-4 alkyl-S (O) -, C _0-4 alkyl-S (O) ₂-、C_0-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, where "substituted" means substituted with one or more groups (1), 2.3 or 4) R ⁶¹ are substituted and R ⁶¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, 3-6 membered cycloalkyl-C _1-4 alkyl-, 4-8 membered heterocycloalkyl-C _1-4 alkyl- C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO- C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ⁶¹ optionally being further substituted with one or more (preferably 1), 2 or 3) R ⁶¹¹ substitutions, said R ⁶¹¹ being independently selected from deuterium or halogen;

Y is independently selected from N or CR ^Y,R^Y is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, c _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, said "substituted" meaning substituted with one or more (1, 2, 3 or 4) R ^Y1, R ^Y1 being independently selected from deuterium, Halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ^Y1 optionally being further substituted with one or more (preferably 1), 2 or 3) R ^Y11 substitutions, said R ^Y11 being independently selected from deuterium or halogen;

L is independently selected from none, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, CR ^L1R^L2、O、S、S(O)、S(O)₂, or NR ^L1R^L2, wherein each R ^L1 and R ^L2 is independently selected from hydrogen, Deuterium, substituted or unsubstituted hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, c _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, or R ^L1 and R ^L2 together with the atoms to which they are directly attached form a 3-6 membered cycloalkyl or heterocycloalkyl, where "substituted" means substituted with one or more (1, 2.3 or 4) R ^L11 are substituted, R ^L11 is independently selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, halo-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, a C _6-8 aryl, a 5-8 membered heteroaryl;

Z, M are each independently selected from N, CR ^Z1, each R ^Z1 is each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, where "substituted" means substituted with one or more (1, 2 or 3) R ^Z11, R ^Z11 is independently selected from deuterium, halogen, cyano, nitro, azido, amino, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _0-4 alkyl-CO-, C _0-4 alkyl-CO-NH-, C _1-4 alkyl-C (O) O-, C _0-4 alkyl-S (O) -, C _0-4 alkyl-S (O) ₂-、C_0-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂-S-、C_3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

ar is selected from a substituted or unsubstituted 5-12 membered aromatic or heteroaromatic ring, said "substituted" meaning Ar is substituted with one or more (preferably 1, 2, 3, 4 or 5) R ³;

Each R ³ is independently selected from the group consisting of cyano, amino, halogen, deuterium, substituted or unsubstituted amino, hydroxy, -SH, C _1-8 alkyl, C _1-8 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl, -C _0-8 alkyl-SF ₅、C_3-12 cycloalkyl-C _1-6 alkyl- 3-12 membered heterocyclyl-C _1-6 alkyl-, C _1-8 alkoxy, -C _1-8 alkyl-OH, -C _1-8 alkyl-NH ₂、-C_0-6 alkyl- (CO) -NH ₂、-C_0-6 alkyl- (CO) -C _1-6 alkyl, -C _0-6 alkyl- (CO) -O-C _1-6 alkyl, -C _0-6 alkyl-P (O) (C _1-6 alkyl) ₂, said "substituted" meaning substituted with one or more (1), 2.3 or 4) R ³¹ are substituted, R ³¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ³¹ being optionally further substituted with one or more (preferably 1,2 or 3) R ³¹¹, said R ³¹¹ being independently selected from deuterium, halogen or C _1-3 alkyl;

the hetero atoms are independently selected from N, O, P, S, se, si and different oxidation states thereof, and the number of the hetero atoms is 1,2 or 3.

In certain preferred embodiments of the present invention, certain groups of the nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, are defined as follows, and the non-mentioned groups are as described in any one of the embodiments of the present invention (abbreviated as "in certain embodiments of the present invention").

In certain embodiments of the invention, R is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxy, C _6-8 aryl, 5-8 membered heteroaryl, -C _0-6 alkyl- (CO) -O-C _1-6 alkyl, said "substituted" meaning substituted with one or more (preferably 1, 2 or 3) R ⁰ groups, R ⁰ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -C _0-4 alkyl-SF ₅, said R ⁰ optionally being further substituted with one or more groups independently selected from deuterium or halogen;

In certain embodiments of the invention, R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and- (CO) -O-C _1-6 alkyl;

In certain embodiments of the invention, R ¹ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxy, -SH, C _6-8 aryl, 5-8 membered heteroaryl, said "substituted" meaning substituted with one or more (preferably 1, 2, or 3) R ¹¹, R ¹¹ is independently selected from the group consisting of deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -C _0-4 alkyl-SF ₅, said R ¹¹ is optionally further substituted with one or more groups independently selected from the group consisting of deuterium or halogen;

In certain embodiments of the invention, R ¹ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutoxy, methylthio, and ethylthio;

In certain embodiments of the invention, R ¹¹ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -C _0-4 alkyl-SF ₅, said R ¹¹ being optionally further substituted with one or more groups independently selected from deuterium or halogen;

in certain aspects of the invention, Z is N and M is N;

In certain aspects of the invention, Z is CR ^Z1 and M is N;

in certain aspects of the invention, Z is N and M is CR ^Z1;

In certain aspects of the invention, Z is CR ^Z1 and M is CR ^Z1;

In certain embodiments of the invention, each R ^Z1 is independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy;

In certain embodiments of the invention, R ^Z11 is independently selected from deuterium, halogen;

In certain embodiments of the invention Ar is selected from a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 6-10 membered aromatic heterocyclic ring, wherein "substituted" means that Ar is substituted with one or more (preferably 1, 2, 3, 4 or 5) R ³;

in certain embodiments of the invention, ar is selected from the group consisting of a benzene ring, pyridine ring, naphthalene ring, benzothiazole ring, benzothiophene ring, indazole ring, indole ring, azaindole ring, benzimidazole ring, which "substituted" means that Ar is substituted with one or more (preferably 1, 2, 3, 4, or 5) R ³;

In certain embodiments of the invention, each R ³ is independently selected from cyano, halogen, deuterium, substituted or unsubstituted amino, hydroxy, -SH, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, -C _0-6 alkyl-SF ₅、C_3-6 cycloalkyl-C _1-3 alkyl- 3-6 membered heterocyclyl-C _1-3 alkyl-, C _1-6 alkoxy, -C _1-6 alkyl-OH, -C _1-6 alkyl-NH ₂、-C_0-6 alkyl- (CO) -NH ₂、-C_0-4 alkyl- (CO) -C _1-3 alkyl, -C _0-4 alkyl- (CO) -O-C _1-3 alkyl, -C _0-4 alkyl-P (O) (C _1-3 alkyl) ₂, said "substituted" meaning substituted with one or more (1), 2. 3 or 4) R ³¹ are substituted, said "substituted" meaning substituted with one or more (1, 2, 3 or 4) R ³¹;

In certain embodiments of the invention, R ³ is independently selected from deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, where "substituted" means substituted with one or more (1, 2,3, or 4) R ³¹;

in certain embodiments of the invention, R ³ is independently selected from deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, ethynyl, oxetanyl, azetidinyl, hydroxy, amino, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio;

In certain embodiments of the invention, R ³¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C _6-9 aryl, 5-9 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ³¹ being optionally further substituted with one or more (preferably 1,2 or 3) R ³¹¹, said R ³¹¹ being independently selected from deuterium, halogen or C _1-3 alkyl;

in certain embodiments of the invention, ar is selected from the following structures:

In certain embodiments of the invention R ² is selected from the group consisting of substituted or unsubstituted C _1-4 alkyl, 4-9 membered heterocycloalkyl-C _1-3 alkyl-, 3-6 membered cycloalkyl-C _1-3 alkyl-, 3-6 membered cycloalkyl, 4-9 membered heterocycloalkyl, 5-9 membered aryl or heteroaryl, C _1-4 alkyl-3-6 membered cycloalkyl-, or C _1-3 alkyl-4-8 membered heterocycloalkyl-, 5-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring systems including spiro, bridged, fused or fused rings, where "substituted" means substituted with one or more (preferably 1,2, 3 or 4) R ²¹.

In certain embodiments of the invention, R ² is selected from the following structures:

Wherein R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, or R ⁷ and R ⁸ form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are directly attached, said "substituted" meaning substituted with one or more (1, 2 or 3) R ⁷¹ groups, R ⁷¹ is independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, said R ⁷¹ optionally being further substituted with one or more (1, 2 or 3) groups independently selected from deuterium or halogen;

Ring B is a 5-10 membered heterocycloalkyl (preferably a 5-8 membered heterocycloalkyl) having 1,2 or 3 heteroatoms independently selected from N, O, P, S, si, se heteroatoms and their different oxidation states;

R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂、-C_0-6 alkyl-OH, -C _0-6 alkyl-NH ₂、C_0-6 alkyl-SH, -C _0-6 alkyl-O-C (O) -NH ₂、-C_0-6 alkyl-O-C (O) - (C _3-8 heterocycloalkyl), -C _0-6 alkyl-O-C (O) - (C _3-8 cycloalkyl), said "substituted" meaning substituted by one or more (preferably 1, 2, 3 or 4) R ⁹¹, said R ⁹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy;

t is independently selected from 0, 1,2 or 3;

r is independently selected from 0, 1,2 or 3.

In certain embodiments of the invention, Z is N, M is N, R2 is Wherein R ⁷、R⁸、R⁹, t, R, and ring B are defined elsewhere herein;

In some embodiments of the present invention, the nitrogen-containing heterocyclic compound of formula (I) has a structure as shown in formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6):

Wherein ,Ar、R¹、R⁴、R^5a、R^5b、R^5c、R^5d、R^6a、R^6b、R⁷、R⁸、R⁹、t、r、 ring B is defined as elsewhere herein.

In certain embodiments of the invention, Z is N, M is N, R ¹ is F, R ⁴ is H, methyl, methoxy or ethoxy, ar isWhen-L-R ² is not

In certain embodiments of the invention, Z is N, M is N, ar isAnd-L-R ² isIn this case, R ⁹ is not halogen.

In certain embodiments of the invention, Z is N, M is N, ar isAnd R ² isWherein R ⁹ is independently selected from deuterium, cyano, nitro, azido, substituted or unsubstituted C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂、-C_0-6 alkyl-OH, -C _0-6 alkyl-NH ₂、C_0-6 alkyl-SH, -C _0-6 alkyl-O-C (O) -NH ₂、-C_0-6 alkyl-O-C (O) - (C _3-8 heterocycloalkyl), -C _0-6 alkyl-O-C (O) - (C _3-8 cycloalkyl), said "substituted" meaning substituted by one or more (preferably 1, 2, 3, or 4) R ⁹¹ substitutions, said R ⁹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, R ⁷、R⁸, the definition of t is as defined elsewhere herein.

In certain embodiments of the invention, R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, or R ⁷ and R ⁸ form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are directly attached, where "substituted" means substituted with one or more (1, 2 or 3) R ⁷¹.

In certain embodiments of the invention, R ⁷ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutoxy and azetidinyl, or R ⁷ and R ⁸ together with the carbon atom to which they are directly attached form cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutoxy and azetidinyl, where "substituted" means substituted with one or more (1, 2 or 3) R ⁷¹.

In certain embodiments of the invention, ring B is a 6-8 membered heterocycloalkyl.

In certain embodiments of the invention, ring B is selected from the following structures:

In certain embodiments of the invention, R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-9 membered aryl, 5-9 membered heteroaryl, =NH, =CH ₂、-C_0-6 alkyl-OH, -C _0-4 alkyl-NH ₂、C_0-4 alkyl-SH, -C _0-4 alkyl-O-C (O) -NH ₂、-C_0-4 alkyl-O-C (O) - (C _3-6 heterocycloalkyl), -C _0-4 alkyl-O-C (O) - (C _3-6 cycloalkyl), the "substituted" meaning substituted with one or more (preferably 1,2, 3 or 4) R ⁹¹.

In certain embodiments of the invention, R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutoxy, azetidinyl 、＝NH、＝CH₂、-CH₂-OH、-CH₂-NH₂、-CH₂-SH、-CH₂-O-C(O)-NH₂、-CH₂-O-C(O)-( oxetanyl), -CH ₂ -O-C (O) - (cyclopropyl), where "substituted" means substituted with one or more (preferably 1,2, 3 or 4) R ⁹¹.

in certain embodiments of the invention, ar is R2 is not

In certain embodiments of the invention, ar isR2 is not

In certain embodiments of the invention, Z is N, M is N, ar is When R ² is

In certain embodiments of the invention, R ⁴ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, (C _1-4 alkyl) NH-, (C _1-4 alkyl) ₂NH-、C_2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, where "substituted" means substituted with one or more (1, 2 or 3) R ⁴¹;

In certain embodiments of the invention, R ⁴ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino, where "substituted" means substituted with one or more (1, 2, or 3) R ⁴¹;

in certain embodiments of the invention, R ⁴¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C _6-9 aryl, 5-9 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-;

In certain embodiments of the invention, R ^5a、R^5b、R^5c and R ^5d are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, where "substituted" means substituted with one or more (1, 2, 3, or 4) R ⁵¹;

In certain embodiments of the invention, R ^5a、R^5b、R^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, said "substituted" meaning substituted with one or more (1, 2,3 or 4) R ⁵¹;

In certain embodiments of the invention, R ⁵¹ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said R ⁵¹ being optionally further substituted with one or more (preferably 1,2 or 3) R ⁵¹¹, said R ⁵¹¹ being independently selected from deuterium or halogen;

in certain embodiments of the invention, R ^6b is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, C _3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocyclyl-C _1-3 alkyl-, C _1-4 alkoxy, -C _1-4 alkyl-OH, -C _1-4 alkyl-NH ₂、-C_1-4 alkyl-O-C _1-3 alkyl, -C _0-4 alkyl- (CO) -NH ₂、-C_0-4 alkyl- (CO) -C _1-3 alkyl, -C _0-4 alkyl- (CO) -O-C _1-3 alkyl, -C _0-4 alkyl-P (O) (C _1-3 alkyl) ₂, amino, hydroxy, -SH, C _1-4 alkyl-S (O) -, C _1-4 alkyl-S (O) ₂-、C_1-4 alkyl-S-, NH ₂-S(O)-、NH₂-S(O)₂-、NH₂ -S-, said "substituted" meaning substituted with one or more (1, 2,3 or 4) R ⁶¹;

In certain embodiments of the invention, R ^6b is independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclobutoxy, oxetanyl-CH ₂ -, cyclopropyl-CH ₂ -, pyrrolyl -CH₂-、-(CO)-O-CH₃、CH₃-O-CH₂-、CH₃CH₂-O-CH₂-、CH₃-SO₂-CH₂-、-CH₂-NH₂、-(CO)-CH₃、-CO-NH₂、-CH₂-SH; said "substituted" meaning substituted with one or more (1, 2,3 or 4) R ⁶¹;

In certain embodiments of the invention, R ⁶¹ is independently selected from deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, methoxyl, ethoxyl, propoxyl, isopropoxy, cyclopropyloxy and cyclobutoxy, said R ⁶¹ is optionally further substituted with one or more (preferably 1,2 or 3) R ⁶¹¹, said R ⁶¹¹ is independently selected from deuterium or halogen.

In certain embodiments of the invention, R ^6b is independently selected from the following structures:

In certain embodiments of the invention, Z is N, M is N, R ¹ is F, R ² is Wherein R ⁷、R⁸、R⁹, t, R, and ring B are defined elsewhere herein;

in some embodiments of the present invention, the nitrogen-containing heterocyclic compound of formula (I) has a structure represented by formula (IV-1), (IIV-2), (IV-3) or (IV-4):

Wherein Ar, R ¹、R⁴、R^6a、R^6b、R⁷、R⁸、R⁹, t, R, and ring B are as defined elsewhere herein.

In certain embodiments of the invention, ar is a substituted or unsubstituted 6-10 membered aromatic heterocycle, and Z is N.

In certain embodiments of the invention, ar is a substituted or unsubstituted 6-10 membered aromatic ring, R ² is

Wherein R ⁷、R⁸、R⁹, t, R, and ring B are defined elsewhere herein.

In certain embodiments of the invention, ar is a substituted or unsubstituted 6-10 membered aromatic heterocycle, R ² is Wherein R ⁷、R⁸、R⁹, t, R, and ring B are defined elsewhere herein.

In certain embodiments of the invention, Ar、Z、M、L、Y、R、R¹、R²、R⁴、R^5a、R^5b、R^5c、R^5d、R^6a、R^6b groups in the compounds of formula (I) are independently of the corresponding structures in the examples.

In certain embodiments of the invention, the compound of formula (I) is other than

In certain embodiments of the invention, the compounds of formula (I) have the following structure,

Thus, throughout this specification, one skilled in the art may select the groups and substituents thereof in the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, to provide a stable nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, including but not limited to the compounds described in the examples of the invention.

The nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, according to the invention, may be synthesized by methods that include methods similar to those known in the chemical arts, the steps and conditions of which may be referred to in the art as procedures and conditions of similar reactions, particularly in light of the description herein. The starting materials are typically from commercial sources, such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SCIFINDER, REAXYS on-line databases).

In the invention, the nitrogen-containing heterocyclic compound shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can also be prepared into the nitrogen-containing heterocyclic compound shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and other nitrogen-containing heterocyclic compounds shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can be obtained by peripheral modification by adopting a conventional method in the art.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

The invention also provides a preparation method of the nitrogen-containing heterocyclic biaryl compound shown in the formula I, which comprises the following steps:

a) Carrying out substitution reaction on a compound of the general formula (A) and a bridged ring compound under alkaline conditions to generate a compound of the general formula (B);

b) Carrying out substitution reaction or metal catalytic coupling reaction on the compound of the general formula (B) and R ² -L-H under alkaline conditions to generate a compound of the general formula (C);

c) The compound of the general formula (C) and arylboric acid or arylboric acid ester or arylmetal reagent (R3-Ar-M) are subjected to a transition metal catalytic coupling reaction to generate the compound of the general formula (I).

X is halogen, LG and LG1 are leaving groups, and the definition of each other is as described above;

Preferably, each of said steps a), b), c) is performed in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof, and the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.

Preferably, the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd ₂(dba)₃), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃)₄), palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, bis (triphenylphosphine) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof, and the catalyst ligand is selected from the group consisting of tri-t-butylphosphine, tri-t-butyltetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.

The necessary starting materials or reagents for preparing the compounds of formula I are commercially available or may be prepared by synthetic methods known in the art. The compounds of the invention may be prepared as free bases or as salts thereof with acids, as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and has all of the pharmaceutical activity of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for the organic base, and processing according to conventional methods. Examples of salt formation include salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, euryalonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, or trimethylacetic acid.

The nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, may have one or more chiral carbon atoms, and thus may be isolated as optically pure isomers, e.g., pure enantiomers, or racemates, or mixed isomers. Pure single isomers may be obtained by separation methods in the art, such as chiral crystallization to form salts, or chiral preparative column separation.

Chemicals used in the synthetic routes described in this patent include solvents, reagents, catalysts and protecting groups, deprotecting groups. The above-described methods may additionally include steps prior to or subsequent to the steps specifically described herein, and suitable protecting groups may be added or removed to provide the subject compounds. In addition, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

It is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:

The invention provides a pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic compound shown as the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and (one or more) pharmaceutically acceptable carrier (pharmaceutical auxiliary materials). For example, such pharmaceutical compositions may comprise one or more additional nitrogen-containing heterocyclic compounds of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof. In the pharmaceutical composition, the nitrogen-containing heterocyclic compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can be used in an amount which is effective for treatment.

The invention provides a pharmaceutical composition for treating tumors, which consists of a nitrogenous heterocyclic compound shown in the general formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof and a pharmaceutically acceptable carrier.

It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:

The invention also provides an application of the nitrogenous heterocyclic compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof in preparing Ras mutein inhibitor, wherein in the application, the Ras mutein can be KRAS ^G12D, the Ras mutein inhibitor can be used in a mammalian organism, can also be used in vitro, mainly used for experimental purposes, for example, can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to a conventional method in the field for providing rapid detection for the inhibition effect of Ras mutein.

The invention also provides an application of the nitrogen-containing heterocyclic compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof in preparing medicines, wherein the medicines can be medicines for treating diseases related to activity or expression quantity of Ras muteins, or the medicines can be medicines for treating tumors. The Ras mutein may be KRAS ^G12D. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

Another aspect of the invention relates to a method for preventing and/or treating a disease associated with activity or expression of a Ras mutein, comprising administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

Another aspect of the present invention relates to a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

Another aspect of the invention relates to a medicament for preventing and/or treating a disease or tumor associated with activity or expression of a Ras mutein, which comprises the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

The nitrogen-containing heterocyclic compound shown in the general formula (I), or pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof are used for preparing medicaments for treating diseases related to activity or expression quantity of Ras mutant protein, in particular to medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can include one or more of binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, binders, disintegrants, lubricants, anti-adherent agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch, celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, gum powders, malt, gelatin, talc, adjuvants such as cocoa butter and suppository waxes, oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycol compounds such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic salts, ringer's solution, ethanol, phosphate buffer solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coating materials, sweeteners, flavoring agents and fragrances, preservatives and antioxidants.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical dosage forms of the compounds of the present invention may be provided in the form of immediate release, controlled release, sustained release or target drug release systems. For example, common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special bottles (SPECIAL FLASK). Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps.

Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any of the methods well known in the art, for example by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano/micro) encapsulating, packaging, or lyophilizing processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.

The pharmaceutical compositions of the invention may be administered topically or systemically, e.g. for enteral, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprise a therapeutically effective amount of a compound according to the invention, a stereoisomer or a pharmaceutically acceptable salt thereof as active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. A therapeutically effective amount of the active ingredient is defined as above and below and depending on the species, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal, for enteral administration, such as oral administration, the compounds of the invention can be formulated in a wide variety of dosage forms.

The pharmaceutical compositions and dosage forms may comprise one or more compounds of the present invention, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof, as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms of preparation include powders, tablets, pills, troches, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Formulations of the active compounds may include an encapsulating material as a carrier providing a capsule in which the active ingredient with or without the carrier is surrounded by a carrier to which it is bound.

Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to liquid form preparations shortly before use. The emulsion may be prepared in solution, for example in an aqueous propylene glycol solution, or may contain an emulsifier such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose and other commonly used suspending agents. Solid form preparations include solutions, suspensions and emulsions which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures, but melt and/or dissolve in the rectal cavity to release the drug.

The compounds of the invention may also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intra-arterial, intra-osseous, intramuscular, intra-cerebral, extra-cerebral, intra-synovial, intra-sternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the invention may be in the form of sterile injectable or infusible preparations, e.g., as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable or infusible formulation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1, 3-butanediol. Other examples of acceptable vehicles and solvents that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant. Solutions for parenteral use may also include suitable stabilizers and, if desired, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and salts thereof and sodium EDTA alone or in combination. The parenteral solution may also contain preservatives such as benzalkonium chloride, parahydroxybenzoic acid or propyl parahydroxybenzoate and chlorobutanol.

For inhalation or nasal administration, suitable pharmaceutical formulation chamber particles, aerosols, powders, mists or droplets, for example, have an average size of about 10 microns or less in diameter. For example, compositions for inhalation may be prepared in saline as solutions, using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbon and/or other solubilizing or dispersing agents known in the art.

The pharmaceutical compositions of the present invention may also be administered topically to the skin or mucosa. For topical application, the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.

The pharmaceutical compositions may be formulated in a suitable ointment comprising the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Or the pharmaceutical compositions may be formulated as suitable lotions or emulsions comprising the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be administered topically to the lower intestinal tract in rectal suppository formulations or in suitable enema formulations.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.

Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods, unless specifically defined, terms used herein in analytical chemistry, organic synthetic chemistry, and related descriptions of drugs and pharmaceutical chemistry are known in the art, the above techniques and methods may be generally performed according to a number of general and more specific references cited and discussed in the present specification, according to conventional methods well known in the art in this specification, groups and substituents thereof may be selected by one of ordinary skill in the art to provide stable moieties and compounds in this specification.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -.

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl or C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 (1, 2, 3, 4, 5 or 6) carbon atoms, C2-C6 alkenyl refers to an alkenyl group as defined below having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms, C2-C6 alkynyl refers to an alkynyl group as defined below having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms, C3-C8 cycloalkyl or 3-8 membered cycloalkyl refers to a cycloalkyl group as defined below having a total of 3 to 8 (1, 2, 3, 4, 5, 6, 7 or 8) carbon atoms, C6-C10 aryl or 6-10 membered aryl refers to an aryl group as defined below having a total of 6 to 10 (6, 7, 8, 9 or 10) carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

Certain chemical groups defined herein are preceded by a simplified symbol to represent the total number of carbon atoms and heteroatoms present in the group. For example, C3-8 heterocycloalkyl, C3-C8 heterocycloalkyl or 3-8 membered heterocycloalkyl means a heterocycloalkyl as defined below having a total of 3 to 8 (3, 4, 5,6, 7 or 8) carbon atoms and heteroatoms, and C5-10 heteroaryl, C5-C10 heteroaryl or 5-10 membered heteroaryl means a heteroaryl as defined below having a total of 5 to 10 (5, 6, 7, 8, 9 or 10) carbon atoms and heteroatoms. The total number of carbon atoms and heteroatoms in the simplified symbol excludes carbon atoms and heteroatoms that may be present in substituents of the group.

In this context, a numerical range defined in a substituent such as 0 to 4, 1-4, 1 to 3, etc. means an integer within the range, such as 1-6 being 1, 2, 3, 4, 5, 6.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the C ₁-C₆ alkyl in the group "halo-C ₁-C₆ alkyl" is understood to be C ₁-C₆ alkylene (e.g., methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, 2-methylbutylene, 1-ethylpropylene, 1, 2-dimethylpropylene, neopentylene, or 1, 1-dimethylpropylene, etc.).

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C ₁～C₆ alkyl" or "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl, and "C _1-4 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl (i.e., propyl, including n-propyl and isopropyl), C ₄ alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine, "hydroxy" means an-OH group, "hydroxyalkyl" means an alkyl group as defined below substituted by a hydroxy (-OH), "carbonyl" means a-C (=o) -group, "nitro" means-NO ₂, "cyano" means-CN ", amino" means-NH ₂, "substituted amino" means an amino group substituted by one or two of an alkyl, alkylcarbonyl, aralkyl, heteroaralkyl group, e.g., a mono-alkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino group, "carboxy" means-COOH ", an" acyl "means a-C (=o) H group, a" sulfonyl "means-S (=o) ₂ -group, a" sulfoxide "means-S (=o) -group, a" sulfonyl "means-S (=o) ₂ H group, a-C (=o) ₂ H group, a-NH-C (=o) means-NH-24, a" means-C (=o) H group, a "C (=o) H-group, a" means-C (=o) H group, a "C (=o) ₂ -group, a" means-C (=o) H group, a "C (=o) means" C (=o) H.

In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and linked to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.

The term "alkylene" as used herein refers to a saturated, branched or straight chain or cyclic hydrocarbon group of the number of carbon atoms (typically 1-6 carbon atoms) and having two monovalent radical centers derived from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene { including 1, 2-ethylene (-CH ₂CH₂ -), 2-dimethylene (-CH (CH ₃) -) }, propylene { including 2-methylpropylene (-CH (CH ₃)CH₂ -), isopropylene (-C (CH ₃)₂ -)), 1, 3-propylene (-CH ₂CH₂CH₂ -) }, butylene { including 1, 4-butylene (-CH ₂CH₂CH₂CH₂ -) }.

In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like. "alkenyl" refers to a straight or branched olefin chain group.

In the present application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like. "alkynyl" refers to a straight or branched alkyne chain group.

In the present application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.

In the present application, the term "heterocyclyl" as part of a group or other group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, sulfur and selenium. Unless specifically indicated otherwise in the present specification, a heterocyclyl may be a monocyclic, bicyclic, tricyclic or more cyclic ring system which may include fused, bridged or spiro ring systems, a heteroatom in a heterocyclyl may optionally be oxidized, i.e., the heteroatom may be in its different oxidation states, a nitrogen atom may optionally be quaternized, and a heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In the present application, the term "heterocycloalkyl" means a stable 3-to 20-membered saturated cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, silicon, boron, selenium and sulfur as part of a group or other groups. Unless specifically indicated otherwise in the present specification, a heterocycloalkyl group may be either a monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or more ring system, which may include fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). A heterocycloalkyl bicyclic ring system may include one or more heteroatoms in one or both rings; for the purposes of the present application, heterocycloalkyl is preferably a stable 4-to 12-membered saturated monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, selenium, boron, phosphorus, silicon and sulfur, more preferably a stable 4-to 7-membered saturated monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, in particular, the 4-to 7-membered heterocycloalkyl group may contain 3,4, 5 or 6 carbon atoms and one or two of the above mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not more than 7, more in particular the heterocycloalkyl group may contain 3,4 or 5 carbon atoms and one or two of the above mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not more than 6 ("4-6 membered heterocycloalkyl"), the heteroatoms in the heterocyclyl group may optionally be oxidized, i.e. the heteroatoms may be in their different oxidized states, and the nitrogen atom may optionally be quaternized with ammonium.

In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, sulfur and selenium within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The heteroatoms in the heteroaryl groups may optionally be oxidized, i.e., the heteroatoms may optionally be in different oxidation states, and the nitrogen atoms may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is an open-ended limitation and does not exclude other aspects, i.e. it includes the content indicated by the invention.

Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.

The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.

In addition, unless explicitly stated otherwise, the description used in this invention ". In the broad sense, it is to be understood that each individual described is independent of the others and may be independently the same or different. In more detail, the description "..independently" may mean that specific options expressed between the same symbols in different groups do not affect each other, or that specific options expressed between the same symbols in the same groups do not affect each other.

Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedMeaning that the corresponding group is linked to other fragments, groups in the compound through this site.

In the present application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

"Stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like, organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

"Polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.

In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Or the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted into the biologically active compound of the present application under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the application. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present application. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present application, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The "tumor", "cell proliferation abnormality related disease", and the like of the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e. causing regression of the state of the disease or condition, or

(Iv) Alleviating symptoms caused by the disease or condition.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.

It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include-C (O) -R "(wherein" R "is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group may also be a polymeric resin.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects of providing a nitrogenous heterocyclic compound which can be used as a KRAS ^G12D inhibitor and can be used for preparing anti-tumor medicines and preventing and/or treating tumors.

Detailed Description

The inventor has prepared a class of nitrogen-containing heterocyclic compounds with novel structure shown in formula I through long-term and intensive research, and found that the compounds have better KRAS ^G12D protein inhibition activity, and the compounds have quite excellent inhibition activity (IC ₅₀ is even less than 10 nM) on cell proliferation and downstream signal pERK related to KRAS ^G12D under lower concentration (which can be lower than 10 nM), so that the compounds can be used for treating related diseases caused by KRAS ^G12D mutation or abnormal expression quantity, such as tumors. Based on the above findings, the inventors have completed the present invention.

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

Preparation of intermediate A1:7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

Step one 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.5 g,5.62 mmol) and urea (2.7 g,44.9 mmol) were mixed and heated to 200 ℃ and reacted for 4 hours. Cooled to room temperature, then water (50 mL) was added, heated to 100 ℃ and stirred for an additional hour, filtered while hot. The solid was slurried with ethyl acetate (50 mL), and the filtered solid was dried to afford a reddish brown intermediate product (1.3g).LC-MS[M-H]^-:m/z 292.9.¹H NMR(400MHz,DMSO-d₆):δ11.50-11.3(dt,2H),7.83(s,1H).

Step two, the above intermediate compound (413 mg,1.41 mmol) was suspended in phosphorus oxychloride (POCl ₃) (20 mL), three drops of N, N-dimethylaniline were added, heated under reflux overnight, dried by spinning, the residue was dissolved in dichloromethane DCM (10 mL) and added dropwise to saturated aqueous sodium bicarbonate (NaHCO ₃) and the pH was kept at 7-8, and extracted three times with DCM (30 mL). The combined organic phases were dried over anhydrous magnesium sulfate (MgSO ₄), filtered and concentrated under reduced pressure to give intermediate A1 (219 mg) as a yellow solid. LC-MS [ M+H ] ⁺:m/z328.8/330.8.¹H NMR(400MHz,DMSO-d₆): delta 8.05 (s, 1H).

Preparation of intermediate A2 7-bromo-2, 4, 6-trichloro-8-fluoroquinoline-3-cyano

Step one methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (710 mg,2.51 mmol) and cyanoacetic acid (213 mg,2.51 mmol) were dissolved in acetonitrile (10 mL), pyridine (1.98 g,25.1 mmol) was added, cooled to about 5 ℃, phosphorus oxychloride (1.17 g,7.53 mmol) was added dropwise and stirred at room temperature for 2 hours, poured into water, pH was adjusted to about 5, filtered and dried to give a yellow solid intermediate product (510 mg). LC-MS [ M-H ] ^-:m/z 349.1.

Step two, the intermediate compound (100 mg,0.29 mmol) is added into the existing ethanol (2 mL) solution of sodium ethoxide (20 mg,0.86 mmol), heated and refluxed overnight, dried by spin, added with water, and adjusted to pH about 4 by hydrochloric acid, and solid is separated out, the crude solid product is filtered, and dried to obtain a pale yellow intermediate product (45 mg). LC-MS [ M+H ] ⁺:m/z 316.9/318.9.

Step three the above intermediate compound (370 mg,1.16 mmol) was suspended in phosphorus oxychloride POCl ₃ (10 mL), one drop of N, N-dimethylformamide DMF was added, heated under reflux overnight, dried by spinning, the residue was dissolved in dichloromethane DCM (10 mL) and added dropwise to saturated aqueous sodium bicarbonate NaHCO ₃ and the pH was kept basic, and extracted three times with DCM (30 mL). The combined organic phases were dried over anhydrous magnesium sulfate, mgSO4, filtered and concentrated under reduced pressure to give intermediate A2 (298 mg) as a yellow solid. LC-MS [ M+H ] +: M/z352.8/354.8.1H NMR (400 MHz, DMSO-d 6): delta 8.43 (s, 1H).

Intermediate A3:7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

Step one methyl 4-amino-6-chloro-5-fluoronicotinate (500 mg,2.45 mmol) and cyanoacetic acid (208 mg,2.45 mmol) were dissolved in acetonitrile (10 mL), pyridine (19.4 g,24.5 mmol) was added, cooled to about 5 ℃, phosphorus oxychloride (1.12 g,7.35 mmol) was added dropwise and stirred at room temperature for 2 hours, poured into water, after pH was adjusted to about 6, a solid was precipitated, the solid crude product was filtered, and dried to give a yellow intermediate product (530 mg). LC-MS [ M+H ] ⁺:m/z 272.1.

Step two, naH (60%, 200mg,5.0 mmol) was added to a DMF (10 mL) solution of the above intermediate compound (500 mg,1.84 mmol) under ice-bath cooling, the reaction was warmed to room temperature and stirred overnight, water was added to quench, pH was adjusted to around 4 with 4M aqueous hydrochloric acid, solid precipitated, the crude solid product was filtered, and dried to give a yellow intermediate product (200 mg). LC-MS [ M+H ] ⁺:m/z 240.

Step three, the intermediate compound (150 mg,0.63 mmol) was suspended in POCl ₃ (10 mL), one drop of DMF was added, and the mixture was heated to reflux overnight. After completion of the assay, the reaction was dried by spinning, the residue was dissolved in DCM (10 mL) and added dropwise to saturated aqueous NaHCO ₃ and the pH was kept at 7-8 and extracted three times with DCM (20 mL). The combined organic phases were dried over MgSO ₄, filtered and concentrated under reduced pressure to give intermediate A3 (219 mg) as a yellow solid. LC-MS [ M+H ] ⁺:m/z 276.1.¹H NMR(400MHz,DMSO-d₆): delta 8.55 (s, 1H).

Intermediate A4, 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine

Step one 2-chloro-3-fluoroisonicotinic acid (18 g,103 mmol) was dissolved in a mixed solution of toluene (55 mL) and t-butanol (55 mL), triethylamine (28.5 mL,205 mmol) and diphenyl azide phosphate DPPA (23 mL,107 mmol) were added respectively, boc anhydride (2.2 mL,10.2 mmol) and the reaction mixture was stirred under nitrogen atmosphere for 30 minutes and then heated to 80℃for reaction for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate solution and purified water, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound (10 g, pale yellow powder), ESI (M+H): 247.

And step two, dissolving the solid (6 g) obtained in the step two in tetrahydrofuran (50 mL), cooling to-78 ℃, dropwise adding n-butyllithium solution (24 mL,60 mmol) under the protection of nitrogen, heating the reaction solution to-20 ℃ after the dropwise adding is completed, dropwise adding tert-butyl isocyanate (29 mL,48 mmol) into the reaction solution after the continuous reaction is carried out for 1 hour, heating the reaction solution to room temperature after the dropwise adding is completed, continuously stirring for 1 hour, and then heating to 70 ℃ for reaction overnight. The reaction solution was slowly poured into saturated sodium bicarbonate solution (60 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure by filtration, and purified by column-free chromatography to give the objective compound (4 g, yellow solid).

Step three, slowly adding phosphorus oxychloride (30 mL) into the solid (2.4 g,8.8 mmol) obtained in the step three in batches, slowly dropwise adding N, N-diisopropylethylamine (4.4 mL) under ice water cooling, and heating to 110 ℃ after dropwise adding, and reacting overnight. After most of phosphorus oxychloride was evaporated under reduced pressure, the residue was poured into a cooled saturated aqueous sodium bicarbonate solution (60 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure by filtration, and the residue was slurried in petroleum ether and filtered to give 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine (1.5 g). ¹H NMR(400MHz,DMSO-d₆ ) Delta 8.95 (s, 1H).

Intermediate A5:7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyridine [4,3-d ] pyrimidin-4 (3H) -one

Step one 4-amino-2, 6-dichloro-5-fluoronicotinic acid (15 g,66.7 mmol) was dissolved in thionyl chloride (50 mL) and the reaction solution stirred at 60℃until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the solvent to obtain the objective compound, which was used in the next reaction without purification.

Step two, the compound obtained in the step two is dissolved in anhydrous acetone (80 mL), 15g of ammonium thiocyanate solution dissolved in 80mL of anhydrous acetone is slowly added dropwise, and the reaction solution is reacted for about 1 hour at 50 ℃ after the dropwise addition. The reaction solution was poured into 400mL of water, stirred for 10 minutes, solid was precipitated, filtered, and the cake was washed with water and dried to give the objective product (15 g, yellow solid).

Step three, the solid obtained in the previous step was dissolved in methanol (120 mL), and methyl iodide (12.7 g,894 mmol) and 1M aqueous sodium hydroxide solution (100 mL) were added in this order. The mixture was reacted at room temperature for 3 hours, and then poured into 400mL of water, pH was adjusted to 6 with dilute hydrochloric acid to precipitate a solid, the solid was filtered, and the cake was washed with water and dried to give the objective compound (15 g, yellow solid). ¹H NMR(400MHz,DMSO-d₆ ) Delta 13.31 (s, 1H), 2.59 (s, 3H).

And step four, respectively adding methanol (2 mL) and anhydrous tetrahydrofuran (100 mL) into a 250mL reaction bottle, cooling by an ice water bath, slowly adding sodium hydride (2.9 g) in batches, continuously stirring for 10 minutes, adding the solid (4 g) obtained in the step three in batches, naturally heating to room temperature, and stirring for 15 minutes to show that the reaction is completed. The reaction solution was cooled in an ice-water bath, and then was slowly added dropwise to a saturated aqueous ammonium chloride solution (100 mL) to quench the reaction, followed by extraction with ethyl acetate three times, drying of the organic phase, and concentration under reduced pressure to give the objective compound (4 g). LC-MS [ M+H ] ⁺:m/z 276.0.

Intermediate A6:7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-5-deuterium-4-ol

Step one methoxy methyl chloride (960 mg,12 mmol) was added dropwise to the reaction mixture after dissolving 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-ol (2.8 g,10 mmol) in anhydrous DMF (30 mL) followed by cesium carbonate powder (3.9 g,12 mmol) cooled in an ice-water bath. After the completion of the dropwise addition, the reaction was continued at room temperature for 3 hours with stirring. After the reaction mixture was quenched with water, ethyl acetate (100 ml x 3) was extracted, the separated organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the objective compound (2.2 g, yellow solid). LC-MS [ M+H ] ⁺:m/z 324.2/326.2.

Step two, the compound (2.0 g,6.2 mmol) obtained in the previous step is dissolved in anhydrous tetrahydrofuran solution (200 mL), cooled to minus 20 ℃, 1M isopropyl magnesium bromide tetrahydrofuran solution (75 mL,7.5 mmol) is slowly added dropwise, and the reaction mixture is stirred for 2 hours at minus 20 ℃. Heavy water (0.5 g) was then slowly added to the reaction solution. After the completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (300 ml x 2), the separated organic phase was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to give the objective compound (0.97 g, yellow solid). LC-MS [ M+H ] ⁺:m/z 291.0.

Step three, the compound (0.9 g,3.1 mmol) obtained in the previous step was dissolved in dichloromethane (30 mL), trifluoroacetic acid (30 mL) was added under ice-water bath cooling, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the LC-MS detection reaction, the mixture was quenched by dropwise addition of saturated sodium carbonate solution under ice water cooling, extracted twice with ethyl acetate (100 mL), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the objective compound (0.46 g, yellow solid). LC-MS [ M+H ] ⁺:m/z 247.1.

Intermediate A7:7-chloro-8-fluoro-5- (methoxy-d 3) -2- (methylthio) pyrido [4,3-d ] pyrimidin-4-ol

The intermediate A7, LC-MS [ M+H ] ⁺:m/z 279.2, is prepared and synthesized in reference to step four of the intermediate A5.

Intermediate B1- ((1- (hydroxymethyl) cyclopropyl) methyl) -4-methyl-1, 4-azaphospha-hex-4-oxide

Step one A solution of methylphosphoryl dichloride (3.97 g,30.1 mmol) in tetrahydrofuran (50 mL) was cooled to-78℃under nitrogen and then vinyl magnesium bromide (2M, 35mL,70 mmol) was slowly added. After continuing the stirring reaction at this temperature for one hour, ethanol (10 mL) was added, followed by warming and stirring overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethanol=30/1) to obtain an intermediate compound (3.1 g) as a white oil. ¹H NMR(400MHz,DMSO-d₆ ) Delta. Of

6.07-6.38(m,6H),1.61(d,J=7.2Hz,3H)。

Step two to an ethanol solution (30 mL) of the intermediate compound (0.8 g,6.85 mmol) under nitrogen was added benzylamine (733 mg,6.85 mmol). The reaction mixture was heated to 100 degrees and reacted overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethanol=25/1) to give intermediate compound as a white oil (750mg).LC-MS[M+H]⁺:m/z 224.1.¹H NMR(400MHz,CDCl₃):δ7.26-7.38(m,5H),3.71-3.73(m,2H),2.96-3.01(m,2H),2.63-2.65(m,2H),1.86-1.99(m,4H),1.39(d,J＝7.2Hz,3H).

Step three to the intermediate compound (750 mg,3.36 mmol) in dichloroethane (10 mL) was added 1-chloroethyl chloroformate (578mg, 4.03 mmol) under nitrogen. The reaction mixture was heated to 100 degrees and stirred overnight. The reaction mixture was concentrated under reduced pressure, the crude product was dried and slurried with petroleum ether, and the filtered solid was dried to give 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride (380 mg). LC-MS [ M+H ] ⁺:m/z 134.1.

Step four imidazole (7.5 g,110.2 mmol) and tert-butyldiphenylsilicon chloride (13.8 g,50.1 mmol) were added to ethylene dichloride (50 mL) of cyclohexane-1, 1-dimethanol (5.11 g,50.1 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed twice with saturated brine (30 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtered organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10:1) to give the intermediate product (12.6 g) as a white solid. LC-MS [ M+H ] ⁺:m/z 341.2.

To a dichloromethane solution (30 mL) of the above intermediate (3 g,8.8 mmol) under nitrogen protection were added methylsulfonyl chloride (1.04 g,9.1 mmol) and triethylamine (1.87 g,18.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate (20 mL). The separated organic phase was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The filtered organic phase was concentrated under reduced pressure to give the crude oily intermediate product (2.6 g). LC-MS [ M+H ] ⁺:m/z 419.2.

Step six to a solution of the intermediate (910 mg,2.2 mmol) in N, N-dimethylformamide (10 mL) under nitrogen was added 4-methyl-1, 4-azaphospha-hex-4-oxide hydrochloride (380 mg,2.2 mmol) and potassium carbonate (695 mg,5.0 mmol). The reaction mixture was stirred at 50 degrees overnight. After adding water (50 mL) to the reaction solution, extraction was performed twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8:1) to give intermediate (150 mg) as a white solid. LC-MS [ M+H ] ⁺:m/z 456.2.

Step seven to a solution of the above intermediate (150 mg,0.33 mmol) in methanol (10 mL) was added ammonium fluoride (40 mg,1.1 mmol). The reaction mixture was stirred at 60 degrees for 3 hours. TLC detection reaction was complete. Concentrating the reaction solution under reduced pressure, and purifying the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain white solid (43mg).LC-MS[M+H]⁺:m/z 218.2.¹H NMR(400MHz,DMSO):δ4.40(br.s,1H),3.30(s,2H),2.93-2.83(m,2H),2.59-2.55(m,2H),2.36(s,2H),1.81-1.67(m,4H),1.42-1.38(m,3H),0.43-0.40(m,2H),0.23-0.21(m,2H).

Intermediate B2 (1- (selenomorphlmethyl) cyclopropyl) methanol

Step one sodium borohydride (1.9 g,50.3 mmoL) was slowly added to an anhydrous ethanol suspension (30 mL) of selenium powder (3.95 g,49.4 mmoL) at-10℃under nitrogen. After the reaction mixture became clear, sodium hydroxide (2.1 g,52.5 mmol) was added in portions to the reaction solution, and stirring was continued for 30 minutes. A solution of bis (2-chloroethyl) amine (7.08 g,50.2 mmol) in ethanol (5 mL) was slowly added to the reaction mixture, and the mixture was heated under reflux for 6 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, distilled under reduced pressure, and the low-boiling point solvent was removed to obtain a crude intermediate compound (2.5 g) as a colorless oil. LC-MS [ M+H ] ⁺:m/z 151.1.

Step two to a dichloromethane solution of the above intermediate (2.5 g,16.5 mmol) under nitrogen protection were added 1- (chloroformyl) cyclopropane-1-ethyl carbonate (2.90 g,16.5 mmol) and triethylamine (3.34 g,33.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:4) to obtain a colorless oily compound (3.6 g). LC-MS [ M+H ] ⁺:m/z 292.0.

Step three, after the intermediate (3.6 g,12.4 mmol) in tetrahydrofuran (50 mL) was cooled to-70℃under nitrogen protection, lithium aluminum hydride (1.41 g,37.3 mmol) was added to the reaction mixture in portions. After stirring the reaction mixture at this temperature for 30 minutes, it was slowly warmed to room temperature and stirred overnight. The LC-MS detection reaction was substantially complete. After the reaction solution was cooled to zero, ethyl acetate (20 mL) was added to the reaction solution, and the mixture was slowly warmed to room temperature and stirred for half an hour. Then, water (1.4 g) was slowly added to the reaction solution, sodium hydroxide (0.14 g) and water (4.2 g) were further added, the reaction mixture was stirred for several minutes, then, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:2) to give a colorless oily compound (2.1 g, colorless oily substance) ).LC-MS[M+H]⁺:m/z 236.0.¹H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),1.53-1.44(m,4H),0.48-0.43(m,2H),0.28-0.24(m,2H).

Intermediate B3:4- ((1- (hydroxymethyl) cyclopropyl) methyl) -1- (methylimino) -1λ ⁶ -thiomorpholine-1-oxide

Step one to a solution of tert-butyl 1-iminothiomorpholine-4-carboxylate (3.7 g,15.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was added potassium carbonate (4.45 g,32.2 mmol) and methyl iodide (2.27 g,16.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain an intermediate compound (3.1 g) as a white solid. LC-MS [ M+H ] ⁺:m/z 249.1.

Step two to a solution of the above intermediate (3.1 g,12.5 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2 mL,26.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude white solid compound (2.3 g). LC-MS [ M+H ] ⁺:m/z 149.0.

Step three referring to the sixth preparation of intermediate B1, the above intermediate was used in place of 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride to synthesize a white solid compound (1.6 g). LC-MS [ M+H ] ⁺:m/z 471.1.

Step four, referring to a seventh preparation method of the intermediate B1, removing the protecting group by using the intermediate to obtain a white solid compound (450mg).LC-MS[M+H]⁺:m/z 471.1.¹H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.36(s,2H),2.93-2.83(m,2H),2.65-2.55(m,5H),2.36(s,2H),1.81-1.67(m,4H),0.43-0.40(m,2H),0.23-0.21(m,2H).

Intermediate B4N-4- ((1- (hydroxymethyl) cyclopropyl) methyl) -1-oxide-1 lambda ⁶ -thiomorpholin-1-ylidene) aminonitrile

Step one to a solution of thiomorpholine-4-carboxylic acid benzyl ester (3.6 g,14.8 mmol), cyanamide (0.59 g,15.5 mmol) and potassium tert-butoxide (1.8 g,16.0 mmol) in ethanol (20 mL) was added N-bromosuccinimide (2.85 g,16.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain a yellow solid intermediate compound (1.1 g). LC-MS [ M+H ] ⁺:m/z 278.1.

Step two to an ethanol solution (10 mL) of the above intermediate compound (1.1 g,4.0 mmol) were added m-chloroperoxybenzoic acid (1.40 g,8.1 mmol) and potassium carbonate (1.17 g,8.5 mmol). The reaction mixture was stirred at room temperature overnight. After 50mL of water was added to the reaction mixture, the reaction mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure and the resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give the compound as a white solid (470 mg). LC-MS [ M+H ] ⁺:m/z 294.0.

Step three to an ethanol solution (5 mL) of the above intermediate compound (470 mg,1.6 mmol) was added 5% palladium on carbon (55 mg,0.5 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a white solid compound (120 mg). LC-MS [ M+H ] ⁺:m/z 160.0.

Step four referring to the sixth preparation of intermediate B1, the above intermediate was used in place of 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride to synthesize a white solid compound (150 mg). LC-MS [ M+H ] ⁺:m/z 482.2.

Step five, referring to a seventh preparation method of the intermediate B1, removing the protecting group by using the intermediate to obtain a white solid compound (40mg).LC-MS[M+H]⁺:m/z 244.0.¹H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.37(s,2H),2.93-2.83(m,2H),2.68-2.55(m,2H),2.32(s,2H),1.83-1.65(m,4H),0.45-0.40(m,2H),0.26-0.22(m,2H).

Intermediate B5 (1- (4, 4-dimethyl-1, 4-azasilan-1-yl) methyl) cyclopropyl) methanol

Reference to the synthesis of intermediate B2, the colorless oily compound is prepared .LC-MS[M+H]⁺:m/z 214.2.¹H NMR(400MHz,DMSO-d6):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),0.75-0.65(m,4H),0.47-0.41(m,2H),0.29-0.23(m,2H),0.19-0.16(s,6H).

Referring to the synthetic routes and methods analogous to B1-B5 above, the following intermediates were prepared;

Example preparation

EXAMPLE 1 7- (2-amino-3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) quinolin-3-cyanogen

In the first step, 7-bromo-2, 4, 6-trichloro-8-fluoroquinoline-3-cyano (298 mg,0.84 mmol) was dissolved in dichloromethane DCM (15 mL), after which tert-butyl-1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (215 mg,0.84 mmol) and triethylamine TEA (0.5 mL,4.20 mmol) were added and stirred at room temperature overnight. The reaction solution was dried by spinning, and the residue was purified by flash column chromatography to give a yellow solid product (265 mg). ESI-MS m/z 573.1/575.1[ M+H ] ⁺.

In a second step sodium hydride NaH (20 mg,0.50 mmol) was dissolved in tetrahydrofuran THF (10 mL), cooled to zero, ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methanol (80 mg,0.50 mmol) was added, after half an hour of stirring, the last solid (238 mg,0.417 mmol) was added, stirred at room temperature for 2H, saturated ammonium chloride NH ₄ Cl aqueous solution (50 mL) was added to quench, then extracted three times with ethyl acetate (50 mL), the combined organic phases dried and the concentrated residue under reduced pressure was purified by silica gel column chromatography (eluent DCM/MeOH=30:1 volume ratio mixture) to give the yellow solid product (260 mg). LC-MS [ M+H ] ⁺:m/z 696.0/698.1.

In a third step, a solution of the above solid (111 mg,0.16 mmol) in 1, 4-dioxane/water (12 mL/4 mL) was added to the borate 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ b ] thiophene-3-cyanogen (51 mg,0.16 mmol), tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol) and sodium carbonate powder (Na ₂CO₃) (56 mg,0.53 mmol) at room temperature and the reaction mixture was stirred overnight at 100℃under argon. After completion of the reaction, ethyl acetate was extracted, and the organic phase was washed with saturated brine, dried over anhydrous Na ₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give a yellow solid product (95 mg). LC-MS m/z 808.3[ M+H ] ⁺.

In the fourth step, trifluoroacetic acid (3 mL) was added to a solution of the solid (89 mg,0.11 mmol) obtained in the previous step in Dichloromethane (DCM) (6 mL) under ice-bath cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative (chiral column: unichiral CMD-5H,20mm I.D.x 250mmL; mobile phase (volume ratio): 60% n-hexane/40% ethanol/0.1% diethylamine; flow rate: 25 mL/min) to give 1-a (23 mg, pale yellow solid, retention time 6.59 min) and 1-b (21 mg, pale yellow solid, retention time 11.26 min).

Compounds of formula (I) 1-a:¹H-NMR(400MHz,DMSO-d6):δ8.23(s,1H),8.11(s,1H),7.85(s,1H),7.26(dd,J＝8.4,5.2Hz,1H),7.15(dd,J＝9.6,8.4Hz,1H),5.40-5.18(m,1H),4.60-4.29(m,3H),4.18-3.91(m,3H),3.67-3.51(m,2H),3.48-3.35(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),2.86-2.78(m,1H),2.17-1.96(m,3H),1.87-1.74(m,4H),1.69-1.62(m.2H),1.37-1.39(m,1H).LC-MS m/z:708.1[M+H]⁺.

Compounds of formula (I) 1-b:¹H-NMR(400MHz,DMSO-d6):δ8.21(s,1H),8.10(s,1H),7.84(s,1H),7.26(dd,J＝8.4,5.2Hz,1H),7.18-7.12(m,1H),5.43-5.16(m,1H),4.61-4.27(m,2H),4.19-3.83(m,3H),3.66-3.53(m,2H),3.48-3.34(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),3.01(s,1H),2.86-2.75(m,1H),2.15-1.93(m,3H),1.83-1.76(m,4H),1.67-1.61(m.2H),1.36-1.33(m,1H).LC-MS m/z:708.1[M+H]⁺.

EXAMPLE 2-amino-4- (6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) quinazolin-7-yl) -7-fluorobenzo [ b ] thiophene-3-cyanogen

In the first step, 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (9.0 g,27.4 mmol) and N, N-diisopropylethylamine DIPEA (7.10 g,55.2 mmol) were dissolved in DCM (200 mL) and tert-butyl-3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (5.86 g,27.6 mmol) was added and stirred at room temperature for 2 hours. After the completion of the reaction, 100mL of water and 500mL of DCM were added to the reaction mixture and stirring was continued for 10 minutes, the organic phase was separated by standing, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration and the residue was separated by flash chromatography (mobile phase 0-40% by volume of ethyl acetate/petroleum ether) to give the title compound (9.8 g, off-white solid). LC-MS: [ M+H ] ⁺ = 549.2/551.1.

In the second step, the solid (5 g,9.1 mmol) obtained in the previous step was dissolved in anhydrous DMF (50 mL), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methanol (2.8 g,18.2 mmol) and cesium carbonate (8.9 g,27.3 mmol) were added sequentially, then the reaction solution was reacted under nitrogen protection for 2 hours at 140℃and cooled to room temperature. To the reaction solution was added 300mL of water for dilution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give the title compound (pale yellow solid, 2.4 g). LC-MS, [ m+h ] ⁺ = 672.1/674.1.

In a third step, the yellow solid compound (2.28 g,3.4 mmol) from the previous step was dissolved in 50mL of anhydrous toluene under nitrogen, and 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ b ] thiophene-3-cyanogen (1.5 g,4.7 mmol), pd (DPEPhos) Cl ₂ (720 mg,1 mmol) and anhydrous cesium carbonate (2.73 g,8.4 mmol) were added sequentially. The reaction mixture was reacted at 105℃for 6 hours under nitrogen protection, the reaction was stopped, cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate=1:2) to give the title compound (yellow solid, 920 mg). LC-MS: [ m+h ] += 784.1.

In the fourth step, the yellow solid from the previous step (783 mg,1 mmol) was dissolved in 30mL of a mixed solution of trifluoroacetic acid TFA and dichloromethane (v/v, 1/1) under ice-bath. Under the protection of nitrogen, the reaction liquid is reacted for 1 hour at room temperature, the reaction is stopped, saturated sodium bicarbonate solution is slowly added into the system in a dropwise manner, the pH value is regulated to about 8, the ethyl acetate is used for extraction, and the concentration is reduced in pressure. The residue was isolated and purified by preparative separation (chiral column: unichiral CMD-5H,20mm I.D.x 250mmL; mobile phase (volume ratio): 60% n-hexane/40% ethanol/0.1% diethylamine; flow rate: 25 mL/min) to give the title compound 2-a (76 mg, pale yellow solid, 7.15 min) and 2-b (81 mg, pale yellow solid, 10.83 min).

2-a:¹H-NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.11(s,1H),7.85(s,1H),7.33-7.27(m,1H),7.17-7.11(m,1H),5.40-5.18(m,1H),4.60-4.29(m,3H),4.18-3.91(m,3H),3.67-3.51(m,2H),3.48-3.35(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),2.86-2.78(m,1H),2.17-1.96(m,3H),1.87-1.74(m,4H),1.69-1.62(m.2H),1.37-1.39(m,1H).LC-MS:[M+H]⁺＝684.1.

2-b:¹H-NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.09(s,2H),7.86(s,1H),7.32-7.28(m,1H),7.18-7.11(m,1H),5.41-5.16(m,1H),4.61-4.27(m,2H),4.19-3.83(m,3H),3.66-3.53(m,2H),3.48-3.35(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),3.01(s,1H),2.86-2.78(m,1H),2.17-1.96(m,3H),1.87-1.74(m,4H),1.69-1.62(m.2H),1.37-1.39(m,1H).LC-MS:[M+H]⁺＝684.1.

EXAMPLE 3 2-amino-7-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) benzo [ b ] thiophene-3-cyanogen

In the first step, tert-butyl-1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (223 mg,0.87 mmol) and 2,4, 7-trichloro-8-fluoropyrido [4,3d ] pyrimidine (218 mg,0.87 mmol) were dissolved in anhydrous dichloromethane (10 mL), DIEA (0.72 mL,4.35 mmol) was slowly added under the protection of ice-water bath cooling nitrogen, and the reaction was continued for 1 hour after the addition. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL x 2), the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by flash silica gel column chromatography to give the title compound (320 mg, pale yellow solid). ESI-MS 472.1[ M+1] ⁺.

In a second step, the solid obtained in the previous step (300 mg,0.64 mmol) and ((2R 7 aS) -2-fluorotetrahydro-1H-pyrrolizidin-7 a-yl methanol (102 mg,0.64 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL), cooled in an ice-water bath, sodium tert-butoxide (150 mg,1.56 mmol) was slowly added under nitrogen protection, the reaction was maintained at 0℃for 1 hour, the reaction solution was diluted with water (20 mL), ethyl acetate (20 mL. Times.2) was extracted, the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was isolated by flash column chromatography on silica gel to give the title compound (152 mg, pale yellow solid). ESI-MS:595.1[ M+1].

The third step was dissolving the above solid (95 mg,0.16 mmol) in 1, 4-dioxane/water (12 mL/4 mL) at room temperature, adding 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ b ] thiophene-3-cyanogen (51 mg,0.16 mmol), tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol) and sodium carbonate powder (Na ₂CO₃) (56 mg,0.53 mmol) in sequence under nitrogen protection and stirring the reaction mixture at 100℃overnight under nitrogen protection. After completion of the reaction, ethyl acetate was extracted, and the organic phase was washed with saturated brine, dried over anhydrous Na ₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give the title compound (yellow solid, 95 mg). LC-MS m/z 751.3[ M+H ] ⁺.

In the fourth step, the solid (82 mg,0.11 mmol) obtained in the previous step was dissolved in Dichloromethane (DCM) (6 mL) under ice-bath cooling, trifluoroacetic acid (3 mL) was added dropwise under ice-bath cooling, and the reaction mixture was warmed to room temperature after the dropwise addition and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (pale yellow solid) ,47mg).LC-MS m/z:651.1[M+H]⁺.¹H-NMR(400MHz,DMSO-d6):δ9.07(s,1H),8.08(s,2H),7.41(dd,J＝8.4,5.2Hz,1H),7.14(dd,J＝9.6,8.4Hz,1H),5.41-5.16(m,1H),4.61-4.27(m,2H),4.19-3.83(m,3H),3.66-3.53(m,2H),3.48-3.35(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),3.01(s,1H),2.86-2.78(m,1H),2.17-1.96(m,3H),1.87-1.74(m,4H),1.69-1.62(m,2H),1.37-1.39(m,1H).

The following example compounds were prepared and synthesized in the same manner as in example 3:

EXAMPLE 14 7- (2-amino-3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1, 6-naphthyridine-3-cyanogen

In the first step, tert-butyl-1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (223 mg,0.87 mmol) and 2,4, 7-trichloro-8-fluoro-1, 6 naphthyridine-3-cyanogen (215 mg,0.79 mmol) were dissolved in anhydrous dichloromethane (10 mL), DIEA (0.72 mL,4.35 mmol) was slowly added under the protection of ice-water bath cooling nitrogen, and the reaction was continued for 1 hour after the addition. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL x 2), the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by flash silica gel column chromatography to give the title compound (176 mg, pale yellow solid). ESI-MS 496.1[ M+1] ⁺.

In a second step, the solid obtained in the previous step (150 mg,0.32 mmol) and ((2R 7 aS) -2-fluorotetrahydro-1H-pyrrolizidin-7 a-yl methanol (50 mg,0.32 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL), cooled in an ice-water bath, sodium tert-butoxide (75 mg,0.78 mmol) was slowly added under nitrogen protection, the reaction was maintained at 0℃for 1 hour, the reaction solution was diluted with water (20 mL), ethyl acetate (20 mL. Times.2) was extracted, the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was isolated by flash column chromatography on silica gel to give the title compound (72 mg, pale yellow solid). ESI-MS: 619.2M+1 ].

The third step was dissolving the above solid (62 mg,0.1 mmol) in 1, 4-dioxane/water (12 mL/4 mL) at room temperature, adding 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ b ] thiophene-3-cyanogen (51 mg,0.16 mmol), tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol) and sodium carbonate powder (Na ₂CO₃) (56 mg,0.53 mmol) in sequence under nitrogen protection and stirring the reaction mixture at 100℃overnight under nitrogen protection. After completion of the reaction, ethyl acetate was extracted, and the organic phase was washed with saturated brine, dried over anhydrous Na ₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give the title compound (yellow solid, 50 mg). LC-MS m/z 775.3[ M+H ] ⁺.

In the fourth step, the solid (46 mg,0.06 mmol) obtained in the previous step was dissolved in Dichloromethane (DCM) (6 mL) under ice-bath cooling, trifluoroacetic acid (3 mL) was added dropwise under ice-bath cooling, and the reaction mixture was warmed to room temperature after the dropwise addition and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (pale yellow solid) ,27mg).LC-MS m/z:675.1[M+H]⁺.¹H-NMR(400MHz,DMSO-d6):δ9.07(s,1H),8.11(s,2H),7.41(dd,J＝8.4,5.2Hz,1H),7.16(dd,J＝9.6,8.4Hz,1H),5.41-5.26(m,1H),4.63-4.37(m,2H),4.29-3.91(m,3H),3.76-3.65(m,2H),3.52-3.41(m,4H),3.42(s,3H),3.15(d,J＝7.2Hz,2H),3.08(s,1H),2.96-2.87(m,1H),2.29-2.16(m,3H),1.91-1.74(m,4H),1.71-1.62(m,2H),1.41-1.38(m,1H).

EXAMPLE 15 2-amino-7-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -5-methoxy-4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) benzo [ b ] thiophene-3-cyanogen

The first step was to a solution of 7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one (600 mg,2.2 mmol) and t-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (560 mg,2.3 mmol) in DMF (6 mL) at room temperature was added DBU (1.5 mL) and PyBOP (1.6 g,3.1 mmol) in sequence and the reaction was stirred at room temperature for 30 min. LC-MS showed that saturated brine (30 mL) and ethyl acetate EA (30 mL) were added to the reaction solution after completion of the reaction, and an organic phase was separated, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA/pe=0% -15%) to give the objective compound (420 mg, yellow solid). ESIMS m/z 514.3[ M+H ].

In a second step, the solid from the previous step (260 mg,0.5 mmol) was dissolved in DCM (5 mL), and mCPBA (198 mg,1.2 mmol) was added in portions with ice-water bath cooling and stirred overnight at room temperature. After completion of the reaction, DCM (20 mL) and saturated NaHCO3 solution (20 mL) were added to the reaction solution, the organic phase was separated, the aqueous phase was extracted with DCM (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (EA/pe=0% -30%) to give the objective compound (148 mg). ESI-MS m/z 546.1[ M+H ].

And thirdly, dissolving the solid (140 mg,0.26 mmol) obtained in the last step and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methanol (62 mg,0.39 mmol) in anhydrous THF (10 mL), cooling by an ice water bath, adding 1M tetrahydrofuran solution (0.31 mL,0.31 mmol) of lithium bis (trimethylsilyl) amide into the solution under the protection of nitrogen, stirring for 1 hour, slowly dripping saturated salt water to quench the reaction solution, adding ethyl acetate (50 mL) to extract a liquid, drying the organic phase by anhydrous sodium sulfate, and separating and purifying by column chromatography to obtain the target compound (84 mg, yellow solid). ESI-MS m/z 625.2[ M+H ].

In a fourth step, the above solid (80 mg,0.13 mmol), 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ b ] thiophene-3-cyanogen (50 mg,0.16 mmol), K ₂CO₃ powder (54 mg,0.39 mmol), pd (dppf) Cl ₂. DCM (15 mg,0.02 mmol) and 10mL Dioxane/3mL water were added separately to a 50mL lock tube, and after 10min of nitrogen substitution, the reaction was carried out at 130℃for 60 min in the lock tube. After the reaction was completed, cooled to room temperature, EA (20 ml x 3) was added to the reaction solution, the separated solution was extracted, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the concentrate was purified by column chromatography (EA/pe=0% -30%) to give the objective compound (40 mg, yellow solid). ESI-MS m/z 781.2[ M+H ].

Fifth step solid (39 mg,0.05 mmol) obtained in the previous step was dissolved in Dichloromethane (DCM) (6 mL), trifluoroacetic acid (3 mL) was added dropwise under ice-bath cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (pale yellow solid) ,17mg).ESI-MS m/z:681.2[M+H].¹H-NMR(400MHz,DMSO-d6)δ8.14(s.2H),7.31-7.22(m,1H),7.19-7.14(m,1H),5.36-5.20(m,1H),4.20(d,J＝16.4Hz,1H),4.14(d,J＝10.4Hz,1H),3.99(dd,J＝2.4,10.2Hz,1H),3.89(s,3H),3.52(s,2H),3.34(s,3H),3.08(d,J＝6.8Hz,3H),3.01(s,1H),2.86-2.79(m,1H),2.51(s,2H),2.13-1.96(m,4H),1.87-1.63(m,7H),1.47-1.35(m.2H).

The following example compounds were prepared and synthesized using the same procedure as in example 15:

EXAMPLE 24 2-amino-4- (6-chloro-5, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a (5H) -yl) methoxy) -4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) quinazolin-7-yl) -7-fluorobenzo [ b ] thiophene-3-cyanogen

The first step was to a solution of 7-bromo-2, 6-dichloro-5, 8-difluoroquinazolin-4 (3H) -one (720 mg,2.2 mmol) and (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-acid tert-butyl ester (560 mg,2.3 mmol) in DMF (6 mL) at room temperature was added DBU (1.5 mL) and PyBOP (1.6 g,3.1 mmol) in this order and the reaction was stirred at room temperature for 30 minutes. LC-MS showed that saturated brine (30 mL) and ethyl acetate EA (30 mL) were added to the reaction solution after completion of the reaction, and an organic phase was separated, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA/pe=0% -15%) to give the objective compound (448 mg, yellow solid). ESIMS m/z 567.3/569.2[ M+H ].

In a second step, the solid obtained in the previous step (362 mg,0.64 mmol) and ((2R 7 aS) -2-fluorotetrahydro-1H-pyrrolizidine-7 a-yl methanol (102 mg,0.64 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL), cooled in an ice-water bath, sodium tert-butoxide (150 mg,1.56 mmol) was slowly added under nitrogen protection, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was isolated by flash column chromatography on silica gel to give the target compound (238 mg, pale yellow solid) ESIMS:690.1/692.1[ M+1].

In a third step, the yellow solid compound (234 mg,0.34 mmol) from the previous step was dissolved in 20mL of anhydrous toluene under nitrogen, and 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ b ] thiophene-3-cyanogen (150 mg,0.47 mmol), pd (DPEPhos) Cl ₂ (72 mg,0.1 mmol) and anhydrous cesium carbonate (2793 mg,0.84 mmol) were added sequentially. The reaction mixture was reacted at 105℃for 6 hours under nitrogen protection, the reaction was stopped, cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate=1:2) to give the title compound (yellow solid, 164 mg). LC-MS, [ m+h ] ⁺ =802.1.

In the fourth step, the yellow solid from the previous step (80 mg,0.1 mmol) was dissolved in 10mL of a mixed solution of TFA and dichloromethane (v/v, 1/1) under ice-bath. Under the protection of nitrogen, the reaction liquid is reacted for 1 hour at room temperature, the reaction is stopped, saturated sodium bicarbonate solution is slowly added into the system in a dropwise manner, the pH value is regulated to about 8, the ethyl acetate is used for extraction, and the concentration is reduced in pressure. The residue was purified by preparative separation (chiral column: unichiral CMD-5H,20mm I.D.x 250mmL; mobile phase (volume ratio): 60% n-hexane/40% ethanol/0.1% diethylamine; flow rate: 25 mL/min) to give the title compound 24-a (16 mg, pale yellow solid, 8.11 min) and 24-b (21 mg, pale yellow solid, 11.96 min).

24-a:LC-MS:[M+H]⁺＝702.1.¹H-NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.85(s,1H),7.33-7.27(m,1H),7.17-7.11(m,1H),5.51-5.38(m,1H),4.68-4.55(m,3H),4.38-3.99(m,3H),3.87-3.61(m,2H),3.52-3.43(m,4H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),2.86-2.78(m,1H),2.26-1.96(m,3H),1.92-1.74(m,6H),1.67-1.59(m,1H).

24-b:LC-MS:[M+H]⁺＝702.1.¹H-NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.88(s,1H),7.35-7.32(m,1H),7.18-7.12(m,1H),5.41-5.26(m,1H),4.63-4.57(m,2H),4.39-4.21(m,3H),3.96-3.83(m,2H),3.68-3.55(m,4H),3.35(s,3H),3.11(d,J＝7.2Hz,2H),3.06(s,1H),2.88-2.81(m,1H),2.27-2.06(m,3H),1.97-1.83(m,4H),1.69-1.48(m,3H).

EXAMPLE 25 2-amino-4- (6-chloro-8-fluoro-4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy) quinazolin-7-yl) -7-fluorobenzo [ b ] thiophene-3-cyano

In the first step, tert-butyl-3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.3 g,2.42 mmol) was dissolved in 20mL of anhydrous THF and placed in a 100mL reaction flask, followed by addition of potassium tert-butoxide powder (340 mg,3.64 mmol) and stirring at room temperature for 30 minutes. A solution of (1- (morpholinomethyl) cyclopropyl) methanol (350 mg,2.0 mmol) in 10mL anhydrous THF was slowly added dropwise with cooling in an ice-water bath and stirring was continued for about 1 hour until the reaction was complete. The reaction solution was poured into 100mL of ice water, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate volume ratio 1:1) to give the title compound (pale yellow solid, 916 mg). LC-MS, [ m+h ] ⁺ = 684.1.

Second step solid (512 mg,0.75 mmol) obtained in the previous step, 2-amino-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) benzo [ b ] thiophene-3-cyanogen (324 mg,1.02 mmol), pd (DPEPhos) Cl ₂ (22 mg,0.03 mmol), cesium carbonate (438 mg,1.35 mmol) and toluene (15 mL) were placed in a reaction flask under nitrogen atmosphere, and nitrogen was replaced for 10 minutes. The reaction mixture was reacted overnight at 105℃under nitrogen protection, cooled to room temperature after the reaction was completed, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate volume ratio 1:2) to give the title compound (yellow solid, 450 mg). LC-MS: [ m+h ] +=796.2.

In the third step, the solid (100 mg,0.125 mmol) obtained in the previous step was dissolved in 10mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-bath cooling. The reaction solution was stirred under nitrogen protection for about 2 hours, after the reaction was completed, the reaction was stopped, a saturated sodium bicarbonate solution was slowly added dropwise to the system, the pH was adjusted to about 8, extraction was performed three times with ethyl acetate (50 ml x 3), and concentration was performed under reduced pressure. The residue was separated by column chromatography to give the target compound (yellow solid, 45 mg). LC-MS: [ m+h ] += 696.2. The above solid was purified by preparation (chiral column: unichiral CMD-5H,20mm I.D.x 250mmL; mobile phase (volume ratio): 60% n-hexane/40% ethanol/0.1% diethylamine; flow rate: 25 mL/min) to give the target compound 25-a (16 mg, yellow solid, 5.98 min) and the target compound 25-b (12 mg, yellow solid, 10.36 min).

25-a:LC-MS:[M+H]⁺＝696.1.¹H-NMR(400MHz,DMSO-d6)δ8.15(s,2H),7.86(s,1H),7.32-7.26(m,1H),7.19-7.13(m,1H),5.35-5.18(m,1H),4.60-4.29(m,2H),4.18-3.91(m,4H),3.67-3.51(m,2H),3.48-3.35(m,3H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),2.86-2.78(m,2H),2.17-1.96(m,4H),1.87-1.74(m,4H),1.69-1.62(m,2H),1.37-1.39(m,2H).

25-b:LC-MS:[M+H]⁺＝696.1.¹H-NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.86(s,1H),7.32-7.28(m,1H),7.18-7.11(m,1H),5.35-5.16(m,1H),4.61-4.27(m,2H),4.19-3.83(m,4H),3.66-3.53(m,2H),3.48-3.35(m,3H),3.32(s,3H),3.07(d,J＝7.2Hz,2H),2.86-2.78(m,2H),2.17-1.96(m,4H),1.87-1.74(m,4H),1.69-1.62(m.2H),1.35-1.38(m,2H).

EXAMPLE 26 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((1- (selenomorphine methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

In the first step, sodium methyl mercaptide (1.22 g,17.37 mmol) was added to a solution of tert-butyl (1R, 5S) -3- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (6.2 g,14.48 mmol) in tetrahydrofuran (80 mL) at room temperature. The reaction mixture was stirred at room temperature for a further 16 hours. LC-MS showed the reaction was complete, the reaction was diluted with ethyl acetate (200 mL) and saturated brine (200 mL), extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 10:1 to 2:1) to give the title compound (6.3 g, yellow solid). LC-MS (ESI) M/z 440.1 (M+H) ⁺.

In a second step, the compound (1.3 g,2.96 mmol) obtained in the above step was dissolved in 1, 4-dioxane (16 mL), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (1.97 g,3.84 mmol), pd catalyst (cas: 1651823-4) (215.6 mg, 0.96 mmol) and tripotassium phosphate (1.9 g,8.88 mmol) were added, the reaction mixture was stirred at 100℃for 16 hours, the completion of the reaction was monitored by LC-MS, the reaction solution was extracted with ethyl acetate (200 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio 3:1) to give the title compound (1.5 g, white solid). LC-MS (ESI) M/z 790.4 (M+H) ⁺.

In the third step, the compound (1.4 g) obtained in the above step was dissolved in methylene chloride (50 mL) with cooling in an ice-water bath, and 3-chloroperoxybenzoic acid (424 mg,2.09 mmol) was added, and the mixture was stirred at 0℃for 3 hours. The completion of the reaction was monitored by LC-MS, the reaction mixture was quenched by adding an aqueous solution of sodium thiosulfate, extracted with methylene chloride (100 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: EA volume ratio 3:1) to give the objective compound (1.1 g, yellow solid). LC-MS (ESI) M/z 806.2 (M+H) ⁺.

In the fourth step, lithium bistrimethylsilylamino (1.7 mL,1.7 mmol) was added to a solution of the compound obtained in the previous step (0.34 g,0.422 mmol) and 1- (selenomorphine methyl) cyclopropyl) methanol (0.2 g,0.853 mmol) in tetrahydrofuran (20 mL) under ice-water bath cooling, and the reaction mixture was reacted at 0℃for 2 hours. LC-MS detection of completion of the reaction, quenching the reaction solution with saturated aqueous ammonium chloride, extracting with ethyl acetate (100 mL), washing with saturated saline, drying and concentrating the organic phase with anhydrous sodium sulfate, and then column chromatography (petroleum ether/ethyl acetate volume ratio 1:1) to obtain the target compound (0.2 g, pale yellow solid). LC-MS (ESI) M/z 977.2 (M+H) ⁺.

In a fifth step, cesium fluoride (0.3 g,2.02 mmol) was added to a solution of the compound (197mg, 0.202 mmol) obtained in the above step in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted overnight at room temperature. LC-MS detection of the completion of the reaction, extraction with ethyl acetate (100 mL), washing of the organic phase with saturated brine, drying, concentration under reduced pressure, and separation and purification of the residue by column chromatography (petroleum ether/ethyl acetate volume ratio 2:1) gave the title compound (140 mg, pale yellow solid). LC-MS (ESI) M/z 821.1 (M+H) ⁺.

Sixth step Compound (140 mg,0.171 mmol) obtained in the previous step was dissolved in acetonitrile (4 mL), and a dioxane solution of hydrogen chloride (4M HCl/dioxane (2 mL,8 mmol) was added dropwise at room temperature, and the reaction was continued at room temperature for 1 hour after the addition. LC-MS detection of completion of the reaction, low-temperature concentration to remove a large amount of low-boiling substances, and direct purification of the residue by preparative chromatography (0.1% NH ₃.H₂ O) to give the target compound (41 mg, pale yellow solid) ).LC-MS(ESI)m/z:677.5(M+H)⁺.¹H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.03(s,1H),7.97(dd,J＝9.0,6.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),4.48(d,J＝11.2Hz,1H),4.26(dd,J＝19.2,11.2Hz,3H),3.92(s,1H),3.63(d,J＝12.0Hz,1H),3.54(s,3H),2.81(d,J＝3.6Hz,4H),2.60(d,J＝2.8Hz,4H),2.37-2.28(m,2H),1.66-1.53(m,4H),0.64-0.53(m,2H),0.38-0.31(m,2H).

The following example compounds were prepared and synthesized using the same procedure as in example 26:

EXAMPLE 43 5-Ethynyl-6-fluoro-4- (8-fluoro-4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- (selenomorphine methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-amine

In the first step, trifluoromethanesulfonic anhydride (2.3 g,8.04 mmol) was added to a solution of tert-butyl-3- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((1- (selenomorphyrinomethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (2.7 g,2.68 mmol) in dichloromethane (50 mL) and the reaction mixture was reacted at-40℃for 2 hours. LC-MS detection showed that the reaction was complete, extraction with ethyl acetate, washing with saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure and separating and purifying the residue by column chromatography (petroleum ether: ethyl acetate volume ratio=1:1) to give the title compound (1.2 g, yellow solid). LC-MS (ESI) m/z 1109.1[ M+H ] ⁺.

In the second step, tris (dibenzylideneacetone) dipalladium (100 mg,0.14 mmol) was added to a mixture of the compound (1.1 g,1.0 mmol), benzophenone imine (496 mg,2.7 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (158 mg,0.27 mmol), cesium carbonate (1.3 g,4.11 mmol) and toluene (15 mL) obtained in the previous step under nitrogen atmosphere. The reaction mixture was reacted at 100℃for 16 hours, and LC-MS showed that the reaction was completed, filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate volume ratio=10:1) to give the objective compound (550 mg, yellow solid). LC-MS (ESI) m/z 1140.1[ M+H ] ⁺.

In the third step, the compound (100 mg,0.088 mmol) obtained in the above step was dissolved in methylene chloride (10 mL), and a hydrogen chloride/dioxane solution (4M, 5 mL) was added to the reaction solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and LC-MS detection showed that the reaction was completed, and after removing low boiling substances under reduced pressure, it was slurried with diethyl ether to obtain the objective compound (50 mg, gray solid). LC-MS (ESI) m/z 876.1[ M+H ] ⁺.

In a fourth step, the compound (50 mg,0.06 mmol) obtained in the previous step was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (59 mg,0.43 mmol) and cesium fluoride (13 mg,0.26 mmol) were sequentially added at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ethyl acetate and water were added to the reaction mixture, extraction was performed, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with diethyl ether to obtain the objective compound (5 mg, white solid ).LC-MS(ESI)m/z:719.2[M+H]⁺.¹H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.27(s,1H),7.87–7.67(m,1H),7.35-7.34(m,1H),7.04-7.01(m,1H),5.63(bs,2H),4.50-4.48(m,1H),4.27-4.23(m,4H),3.84(s,1H),3.66-3.51(m,7H),2.81-2.78(m,4H),2.59-2.38(m,6H),1.67(s,4H),0.68-0.64(m,2H),0.45-0.41(m,2H)., the following example compound was synthesized by the same procedure as in example 43:

EXAMPLE 62 6- (8-fluoro-4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- (selenomorphine methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

In the first step, potassium fluoride (4.6 g,7.1 mmol) was added to a solution of tert-butyl-3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (3.5 g,7.6 mmol) in dimethyl sulfoxide (50 mL) at room temperature, and the reaction was stirred at 120℃for 5 hours under nitrogen. LC-MS detection shows that the reaction is completed, ethyl acetate and saturated saline are added into the reaction liquid, an organic phase is separated, dried, filtered and concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio is 4:1) to obtain a target compound (white solid, 1.8 g). LCMS (ESI) m/z 456.2[ M+H ] ⁺.

In the second step, N-butylbis (1-adamantyl) phosphine methanesulfonate [ 2-amino-1, 1' -biphenyl-2-yl) palladium (II) (560 mg,0.776 mmol) was added to a solution of the compound obtained in the above step (1.8 g,3.88 mmol) and N, N-bis (4-methoxybenzyl) -4-methyl-6- (tributyltin) pyridin-2-amine (4.95 g,7.77 mmol) in N, N-dimethylacetamide (20 mL) at 110℃under nitrogen atmosphere for 16 hours. LC-MS detection shows that the reaction is completed, the reaction solution is filtered by diatomite, most of the solvent is removed under reduced pressure, then the solution is extracted by ethyl acetate and saturated saline, the organic phase is concentrated, and the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio is 50:1) to obtain the target compound (light yellow solid) ,1.2g).LCMS(ESI)m/z:768.1[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ9.25(s,1H),7.31(s,1H),7.23(d,J＝8.4Hz,4H),6.84(d,J＝8.4Hz,4H),6.52(s,1H),4.90-4.85(m,4H),4.62-4.59(m,1H),4.51-4.33(m,2H),3.78-3.55(m,7H),3.41(s,3H),3.32(s,3H),2.33(s,3H),2.06-1.98(m,2H),1.75-1.70(m,2H),1.53(s,9H).

In the third step, p-toluenesulfonic acid (23 mg,0.133 mmol) was added to a solution of the compound (1.2 g,1.66 mmol) obtained in the above step in N, N-dimethylformamide (15 mL), N-iodosuccinimide (1.12 g,4.97 mmol) was added with stirring, and the reaction was continued at room temperature with stirring for 2 hours. After the completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate volume ratio=3:1) to give the objective compound (pale yellow solid, 1.1 g). LCMS (ESI) m/z 894.2[ M+H ] ⁺.

Fourth step copper iodide (491 mg,2.58 mmol) was added to a solution of the compound obtained in the above step (1.1 g,1.29 mmol) and methyl-2, 2-difluoro-2- (fluorosulfonyl) ester (2.49 g,12.9 mmol) in N, N-dimethylformamide (20 mL) at room temperature, and reacted at 90℃under nitrogen atmosphere for 3 hours. LC-MS detection showed the reaction was complete, the reaction was filtered over celite, concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated brine, the organic phase was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=3:1) to give the title compound (pale yellow solid, 280 mg). LCMS (ESI) m/z 836.3[ M+H ] ⁺.

Fifth step Compound (284 mg,0.34 mmol) obtained in the previous step and (1- (selenomorphenylmethyl) cyclopropyl) methanol (165 mg,0.68 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and sodium hydride (41 mg,2.04 mmol) was slowly added under ice-bath cooling. The reaction was continued to stir at 0 ℃ for 2 hours after the addition, and LC-MS detection showed the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase was concentrated, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=3:1) to give the objective compound (pale yellow solid, 205 mg). LCMS (ESI) m/z 1051.4[ M+H ] ⁺.

In the sixth step, trifluoroacetic acid (2 mL) was added to a solution of the compound (201 mg,0.2 mmol) obtained in the above step in methylene chloride (5 mL) at room temperature, and the mixture was reacted at 50℃for 16 hours after the completion of the dropwise addition. LC-MS monitoring shows that the reaction is completed, low boiling point substances are removed by concentrating under reduced pressure at low temperature, and the residue is further purified by preparative chromatography (0.1% NH ₃·H₂ O) to obtain the target compound (white solid) ,38mg).LCMS(ESI)m/z:711.2[M+H]⁺.¹H-NMR(400MHz,DMSO-d6)δ9.00(s,1H),6.79(s,2H),6.49(s,1H),4.90-4.85(m,4H),4.62-4.59(m,1H),3.78-3.55(m,3H),3.41(s,3H),3.32(s,3H),2.84–2.76(m,4H),2.61–2.56(m,3H),2.36-2.33(m,4H),2.06-1.98(m,2H),1.73-1.62(m,4H),0.64(t,J＝4.8Hz,2H),0.41(t,J＝4.8Hz,2H).

The following example compounds were synthesized using the same procedure as in example 62:

The following example compounds were obtained in analogy to example 3 starting from intermediates A4-A7, B5-B10 and other commercially available starting materials:

EXAMPLE 89 7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-4- (1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- (selenomorphine methyl) cyclopropyl) methoxy) -1, 6-naphthyridine-3-cyanogen

Synthesis of example 89 (12 mg, white solid) was obtained by the same method as in example 14 ).LC-MS(ESI)m/z:745.1(M+H)⁺.¹H-NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.20(s,1H),8.08-7.92(m,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.4Hz,1H),7.19(d,J＝2.3Hz,1H),4.53-4.39(m,4H),4.11-3.87(m,5H),3.24-3.06(m,4H),2.85-2.71(m,5H),2.65-2.52(m,4H),2.42-2.46(m,2H),1.72-1.82(m,4H),0.77-0.54(s,4H).

Test example 1 cell proliferation inhibition experiment

Test method 1) AGS cells (ATCC) expressing KRAS ^G12D were cultured in DMEM medium containing 10% fetal bovine serum, 10mM HEPES and penicillin/streptomycin, seeded in 96-well plates at a density of 40,000 cells/well and attached for 12-14 hours. 2) After the cells are attached, the compound to be tested is added into a 96-well plate according to the final concentration of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025 and 0nM (the final concentration of DMSO is 0.5 percent), and after the culture is carried out for 96 hours at 37 ℃, 50uL Cel-titer GLO working solution is added into each well, and after shaking and mixing, the mixture is incubated for 10 minutes at room temperature. 3) And reading Luminescence values of the luminescences in the multifunctional enzyme-labeled instrument, and calculating and converting the Luminescence value data into inhibition percentages. And the percent inhibition of cell proliferation was calculated according to the following formula = (max-measured)/(max-Blank) x100, ("max" from 0.5% dmso control well, "Blank" from Blank control well, "measured" from example compound treated well). 4) Curve fitting was performed using GraphPadPrism software and IC ₅₀ values were obtained. (A represents IC ₅₀ <10nM, B represents 10 nM≤IC ₅₀ <100nM, C represents 100 nM≤IC ₅₀ <1000nM, D represents IC ₅₀. Gtoreq.1000 nM)

The results show that the compounds of the series of examples of the invention have a strong proliferation inhibition effect on KRAS ^G12D mutated AGS cells. Under the same test conditions, the cell proliferation inhibition activity of most of the example compounds is equivalent to that of the positive compound MRTX1133 (IC ₅₀ is 15 nM), and the cell proliferation inhibition activity of some of the example compounds is obviously improved compared with that of the positive compound. Most of the compounds of the examples have an inhibitory activity IC ₅₀ of about 10nM, as in examples 3, 8, 15, 22, 27, 32, 39, 45, 58, 60 and 71, etc., and some of the examples have an inhibitory activity even approaching 1nM, as in examples 3, 8, 15, 22, 27, 39, 45, 58 and 71, etc.;

test example 2 test of the Effect of Compounds on KRAS ^G12D -mediated ERK phosphorylation Capacity

Test method 1) AGS cells (ATCC) expressing KRAS ^G12D were cultured in DMEM medium containing 10% fetal bovine serum, 10mM HEPES and penicillin/streptomycin, seeded in 96-well plates at a density of 40,000 cells/well and attached for 12-14 hours. 2) After 3 hours, the medium was removed, 150. Mu.L of 4.0% formaldehyde was added, and the plate was incubated at room temperature for 20 minutes. 3) The plates were washed with PBS and infiltrated with 150. Mu.L ice-cold methanol for 10 min. 4) Binding of non-specific antibodies to the plates was blocked with 100 μl of blocking buffer for 1 hour at room temperature. Phosphorylation of ERK was detected using p-ERK specific antibodies, GAPDH as an internal standard. One antibody information and experimental conditions were as follows, p-ERK (Cell signaling) diluted 1:500 in blocking buffer+ 0.05%tween 20;GAPDH diluted 1:500 in blocking buffer+0.05% tween 20. The antibody was incubated for 2h at room temperature, PBS+0.05% Tween20, and the plate was washed. The secondary antibodies used to display primary antibodies were added as anti-rabbit-680 to be diluted 1:1000 in blocking buffer+0.05% tween20, anti-mouse-800 to be diluted 1:1000 in blocking buffer+0.05% tween20 and incubated for 1 hour at room temperature. 5) Plates were washed with PBS +0.05% tween20, 100 μl PBS was added to each well and the plates were read. 6) The phosphorylated ERK (Thr 202/Tyr 204) signal was normalized to GAPDH signal for each well and the percentage of DMSO control value was calculated. IC ₅₀ values were calculated by four parameter dose-response curve fitting.

As a result, most of the compounds of the examples provided herein have significant inhibitory effect on the phosphorylated ERK levels of AGS cells, most of the examples have inhibitory activity IC ₅₀ of less than 500nM, and some of the compounds of the examples have inhibitory activity IC of less than 100nM, such as 3,4, 15, 19, 22, 26, 27, 32, 37, 62, 65, 71, etc.

Test example 3 test of the inhibitory Activity of example Compounds against BaF3-KRAS-G12D cell proliferation

The test adopts CellTiter-Glo (CTG) kit provided by Promega company, which is a method for detecting cell viability by a homogenization method, and the cell viability of the cultured cells is determined by quantifying ATP. 1. Experimental reagent consumables ：RPMI1640(Hyclone,SH30809.01),Fetal Bovine Serum(FBS,Gibco,10099-141),Phosphate Buffered Saline(PBS,Solarbio,P1020-500),Celltiter Glo assay kit(Promega,G7573),Blank 96-cell culture plate(Thermo,165305).2、 laboratory instruments and equipment, CO2 incubator (Thermo Scientific, model 3100 Series), microscope (OLYMPUS, CKX41 SF), multifunctional enzyme-labeled instrument (BMG,Plus), biosafety cabinet (Thermo, model 1300series A2). 3. Cell proliferation experiments all cell lines were grown in complete medium at 37℃under 5% CO 2. Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. The cell density was adjusted using complete medium and then seeded into 96 well cell culture plates with 90 μl total of 3000 cells per well. Cells in 96-well plates were incubated at 37 ℃ under 5% co 2. A 10-fold drug solution was prepared and then transferred from 10 μl of each serial diluted compound to the corresponding experimental well of a 96-well cell plate, the initial concentration of compound test 10um, 3-fold dilution, 9 concentrations, three multiplex wells were set for each drug concentration. Cells in the dosed 96-well plates were incubated at 37 ℃ under 5% co2 for a further 72 hours before CTG analysis. The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes. An equal volume of CTG solution was added to each well. Cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal. Using Luminescence Read Mode, read Luminescence (Luminescence) and collect data. 4. Analysis of data were analyzed using GRAPHPAD PRISM 7.0.0 software, and non-linear S-curve regression was used to fit the data to yield a dose-response curve, and IC50 values were calculated therefrom. Cell viability (%) = (Lum _{Drug to be tested}-Lum_{Culture broth control})/(Lum_{Cell control}-Lum_{Culture broth control}) ×100%.

As a result, most of the example compounds provided by the invention have obvious inhibition effect on BaF3-KRAS-G12D cell proliferation, most of the example compounds have inhibition activity IC ₅₀ of less than 500nM, most of the example compounds have inhibition activity IC ₅₀ of less than 100nM, some of the example compounds have activity of even less than 10nM and even close to 1nM, and the activity of the example compounds is obviously superior to that of positive compound MRTX1133 (IC ₅₀ is about 10 nM), such as examples 3,4, 15, 19, 22, 26, 27, 32, 37, 62, 65, 71 and the like.

Test example 4 pharmacokinetic experiments of Compounds in mice

The test method comprises 1) weighing the compounds, respectively adding into 50mM pH 4.7Acetate bufer% HP-B-CD solvent, shaking, and ultrasonic treating to obtain clear solution. 3 mice (ICR mice, male) were administered by tail vein injection after one night with a dose of 2mg/kg. 2) Weighing the compounds, respectively adding the compounds into a solvent of 0.5% CMC+1% Tween80, shaking uniformly, and performing ultrasonic treatment to obtain a suspension. 3 mice (ICR mice, male) were orally administered by gavage after one night with a dose of 10mg/kg. 3) Sample collection, blood was taken via the orbit, heparin sodium was anticoagulated, placed on ice after collection, and plasma was centrifuged within 1 hour (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ℃). A40 uL sample of plasma was taken, 160uL cold acetonitrile containing an internal standard was added, vortexed for 1 minute, and centrifuged at 18000 rpm for 10 minutes. The supernatant was transferred to a 96-well plate and 5uL of sample was taken for analysis. 4) Drug concentrations were analyzed by LC-MS/MS method and drug substitution parameters were calculated using Phoenix WinNolin software.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A nitrogen-containing heterocyclic compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof,

wherein R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, amino, hydroxy, -SH, C _6-10 aryl, 5-10 membered heteroaryl, and the “substituted” refers to substitution by one or more (preferably 1, 2 or 3) R ⁰ , R ⁰ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, ＝O, ＝S, -C _0-8 alkyl-SF ₅ substituents; the R ⁰ is optionally further substituted by one or more groups independently selected from deuterium or halogen;

R ¹ is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, amino, hydroxy, -SH, C _6-10 aryl, 5-10 membered heteroaryl, wherein the "substituted" refers to substitution by one or more (preferably 1, 2 or 3) R ¹¹ , R ¹¹ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, =O, =S, -Co _0-4 alkyl-SF ₅ substituents; said R ¹¹ is optionally further substituted by one or more groups independently selected from deuterium or halogen;

R ² is selected from the following groups substituted or unsubstituted: C _1-6 alkyl, 3-12 membered heterocycloalkyl-C _1-6 alkyl-, 3-6 membered cycloalkyl-C _1-6 alkyl-, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, C _1-6 alkyl-3-12 membered cycloalkyl-, or C _1-6 alkyl-3-12 membered heterocycloalkyl-, 5-16 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, the ring system includes spiro, bridged ring, fused ring or fused ring; the "substituted" refers to being substituted by one or more (preferably 1, 2, 3 or 4) R ²¹ , each R ²¹ is independently selected from deuterium, halogen, cyano, nitro, azido, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂ , -C _0-6 alkyl-OH, -C _0-6 alkyl-OC(O)-NH ₂ , -C _0-6 alkyl-OC(O)-(C _3-8 heterocycloalkyl), -C _0-6 alkyl-OC(O)-(C _3-8 cycloalkyl), or two R ²¹ together with the carbon atom or heteroatom to which they are attached form a 3-8 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl (preferably a 3-6 membered cycloalkyl); one or more hydrogen atoms (preferably 1, 2 or 3) on the R ²¹ group are independently optionally substituted by R ²¹¹ , and R ²¹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy;

^R4 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted _C1-6 alkyl, _C1-6 alkoxy, C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , C3-18 cycloalkyl- _C1-6 alkyl-, _3-18 membered heterocyclyl- _C1-6 alkyl-, _-C1-8 alkyl-OH, _{-C1-8 alkyl-NH2, -C0-6} _alkyl- (CO) _-NH2 , _-C0-6 alkyl-(CO)-C1-6 _alkyl , _-C0-6 alkyl-(CO) _-OC1-6 _alkyl , _-C0-6 _alkyl -P(O)( _C1-6 alkyl) ₂ , amino, hydroxy, -SH; the "substituted" refers to being substituted by one or more (1, 2, 3 or 4) R ⁴¹ , R ⁴¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; the R ⁴¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ⁴¹¹ , the R ⁴¹¹ is independently selected from deuterium or halogen;

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxyl, -SH, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; the “substituted” refers to substitution by one or more (1, 2, 3 or 4) R ⁵¹ , R ⁵¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; said R ⁵¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ⁵¹¹ , said R ⁵¹¹ being independently selected from deuterium or halogen;

R ^6a , R ^6b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, _5-10 membered heteroaryl, C _3-12 cycloalkyl-C _1-6 alkyl-, 3-12 membered heterocyclyl-C _1-6 alkyl-, C _1-8 alkoxy, -C _1-8 alkyl-OH, -C _{1-8 alkyl-SH, -C 1-8} _alkyl -NH ₂ , -C _1-8 alkyl-OC _1-6 alkyl-, -C _0-6 alkyl-(CO)-NH ₂ , -C _0-6 alkyl-(CO)-C _0-6 alkyl, -C _0-6 alkyl-(CO)-OC _6- alkyl-C _1-4 alkyl-, C _6-10 aryl, _5-10 _membered heteroaryl _, C _1-4 ^alkyl , _C _1-4 alkoxy, ^C _1-4 _alkyl _- _CO- _, _C _1-4 _alkyl _... _{C 1-4} alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; said R ⁶¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ⁶¹¹ , said R ⁶¹¹ being independently selected from deuterium or halogen;

Y is independently selected from N or CR ^Y , ^RY is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; the "substituted" refers to substitution by one or more (1, 2, 3 or 4) ^RY1 , ^RY1 is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; said ^RY1 is optionally further substituted by one or more (preferably 1, 2 or 3) ^RY11 , said ^RY11 being independently selected from deuterium or halogen;

L is independently selected from none, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, CR ^L1 ^RL2 , O, S, S(O), S(O) ₂ or NR ^L1 ^RL2 , wherein each ^RL1 and ^RL2 are independently selected from hydrogen, deuterium, substituted or unsubstituted hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, or, ^RL1 and ^RL2 together with the atoms to which they are directly attached form a 3-6 membered cycloalkyl or heterocycloalkyl; the "substituted" refers to substitution by one or more (1, 2, 3 or 4) ^RL11 , ^RL11 being independently selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 -membered alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _6-8 aryl, 5-8-membered heteroaryl;

Z, M are independently selected from N, CR ^Z1 ; each R ^Z1 is independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted following groups: C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, the above-mentioned "substituted" refers to substitution by one or more (1, 2 or 3) R ^Z11 , R ^Z11 is independently selected from deuterium, halogen, cyano, nitro, azido, amino, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _{0-4 alkyl-CO-, C 0-4} _alkyl -CO-NH-, C _1-4 alkyl-C(O)O-, C _0-4 alkyl-S(O)-, C _0-4 alkyl-S(O) ₂ -, C _0-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

Ar is selected from substituted or unsubstituted 5-12 membered aromatic rings or aromatic heterocycles, wherein "substituted" means that Ar is substituted by one or more (preferably 1, 2, 3, 4 or 5) R ³ ;

Each R ³ is independently selected from cyano, amino, halogen, deuterium, substituted or unsubstituted amino, hydroxy, -SH, C _1-8 alkyl, C _1-8 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ , C _3-12 cycloalkyl-C _1-6 alkyl-, 3-12 membered heterocyclyl-C _1-6 alkyl-, C _1-8 alkoxy, -C _1-8 alkyl-OH, -C _1-8 alkyl-NH ₂ , -C _0-6 alkyl-(CO)-NH ₂ , -C _0-6 alkyl-(CO)-C _1-6 alkyl, -C _0-6 alkyl-(CO)-OC _1-6 alkyl, -C _0-6 alkyl-P(O)(C _1-6 alkyl) ₂ ; the “substituted” refers to being substituted by one or more (1, 2, 3 or 4) R ³¹ , R ³¹ being independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; the R ³¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ³¹¹ , the R ³¹¹ being independently selected from deuterium, halogen or C _1-3 alkyl;

The heteroatoms are independently selected from N, O, P, S, Se, Si and different oxidation states thereof, and the number of heteroatoms is 1, 2 or 3.

2. The nitrogen-containing heterocyclic compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxy, C _6-8 aryl, 5-8 membered heteroaryl, -C _0-6 alkyl-(CO)-OC _1-6 alkyl, wherein "substituted" refers to substitution by one or more (preferably 1, 2 or 3) R ⁰ ;

(2) R ⁰ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, ＝O, ＝S, -C _0-4 alkyl-SF ₅ ; said R ⁰ is optionally further substituted by one or more groups independently selected from deuterium or halogen;

(3) R ¹ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxy, -SH, C _6-8 aryl, 5-8 membered heteroaryl, wherein the "substituted" refers to substitution by one or more (preferably 1, 2 or 3) R ¹¹ ;

(4) R ¹¹ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, ═O, ═S, or —C _0-4 alkyl-SF ₅ ; said R ¹¹ is optionally further substituted by one or more groups independently selected from deuterium or halogen;

(5) Z is N, M is N; Z is CR ^Z1 , M is N; Z is N, M is CR ^Z1 ; or Z is CR ^Z1 , M is CR ^Z1 ;

(6) Each R ^Z1 is independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy;

(7) R ^Z11 is independently selected from deuterium and halogen;

(8) Ar is selected from a substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 6-10 membered aromatic heterocycle; the "substituted" means that Ar is substituted by one or more (preferably 1, 2, 3, 4 or 5) R ³ ;

(9) Each R ³ is independently selected from cyano, halogen, deuterium, substituted or unsubstituted amino, hydroxy, -SH, C _1-6 alkyl, C _1-6 alkoxy, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, -C _0-6 alkyl-SF ₅ , C _3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocyclyl-C _1-3 alkyl-, C _1-6 alkoxy, -C _1-6 alkyl-OH, -C _1-6 alkyl-NH ₂ , -C _0-6 alkyl-(CO)-NH ₂ , -C _0-4 alkyl-(CO)-C _1-3 alkyl, -C _0-4 alkyl-(CO)-OC _1-3 alkyl, -C _0-4 alkyl-P(O)(C _1-3 alkyl) ₂ ; the "substituted" refers to being substituted by one or more (1, 2, 3 or 4) R ³¹ ; the "substituted" refers to being substituted by one or more (1, 2, 3 or 4) R ³¹ ;

(10) R ² is selected from the following groups, which are substituted or unsubstituted: C _1-4 alkyl, 4-9 membered heterocycloalkyl-C _1-3 alkyl-, 3-6 membered cycloalkyl-C _1-3 alkyl-, 3-6 membered cycloalkyl, 4-9 membered heterocycloalkyl, 5-9 membered aryl or heteroaryl, C _1-4 alkyl-3-6 membered cycloalkyl-, or C _1-3 alkyl-4-8 membered heterocycloalkyl-, 5-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, wherein the ring system includes spirocyclic, bridged, fused or fused rings; the term "substituted" refers to substitution by one or more (preferably 1, 2, 3 or 4) R ²¹ ;

(11) Each R ²¹ is independently selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂ , -C _0-3 alkyl-OH, -C _0-4 alkyl-OC(O)-NH ₂ , -C _0-4 alkyl-OC(O)-(C _3-8 heterocycloalkyl), -C _0-4 alkyl-OC(O)-(C _3-6 cycloalkyl), or two R ²¹ together with the carbon atom or heteroatom to which they are attached form a 3-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl; one or more hydrogen atoms (preferably 1, 2 or 3) on the R ²¹ group are independently optionally substituted by R ²¹¹ , R ²¹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy;

(12) R ⁴ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, (C _1-4 alkyl) NH-, (C _1-4 alkyl) ₂ NH-, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl; the "substituted" refers to substitution by one or more (1, 2 or 3) R ⁴¹ ;

(13) R ⁴¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C _6-9 aryl, 5-9 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-;

(14) R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl; the term "substituted" refers to substitution by one or more (1, 2, 3 or 4) R ⁵¹ ;

(15) R ⁵¹ is independently selected from deuterium, halogen, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; said R ⁵¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ⁵¹¹ , said R ⁵¹¹ being independently selected from deuterium or halogen;

(16) R ^6b is independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-9 aryl, 5-9 membered heteroaryl, C 3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocyclyl-C _1-3 alkyl-, C _{1-4 alkoxy, -C 1-4} _alkyl -OH, -C _1-4 alkyl-NH ₂ , -C _1-4 alkyl-OC _1-3 alkyl, -C _0-4 alkyl-(CO)-NH ₂ , -C _0-4 alkyl-(CO) _{-C 1-3 alkyl, -C 0-4 alkyl-(CO)-OC 1-3} _alkyl _, _-C _0-4 alkyl-P(O)(C _1-3 alkyl) ₂ , amino, hydroxy, -SH, C _0-4 alkyl-S(O)-, C _0-4 alkyl-S(O) ₂ -, C _0-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; the "substituted" refers to being substituted by one or more (1, 2, 3 or 4) R ⁶¹ ;

(17) R ⁶¹ is independently selected from deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolane, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclobutyloxy; said R ⁶¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ⁶¹¹ , said R ⁶¹¹ being independently selected from deuterium or halogen.

3. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and -(CO)-OC _1-6 alkyl;

(2) ^R1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio and ethylthio;

(3) Ar is selected from the following substituted or unsubstituted groups: benzene ring, pyridine ring, naphthalene ring, benzothiazole ring, benzothiophene ring, indazole ring, indole ring, azaindole ring, benzimidazole ring; the "substituted" means that Ar is substituted by one or more (preferably 1, 2, 3, 4 or 5) R ³ ;

(4) R ³ is independently selected from deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C 2-4 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl; the "substituted" refers to substitution by one or more (1, 2, 3 or 4) R ³¹ ;

(5) R ² is selected from the following structures:

wherein R ⁷ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: amino, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, or R ⁷ and R ⁸ together with the carbon atom to which they are directly linked form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein “substituted” refers to being substituted by one or more (1, 2 or 3) R ⁷¹ , R ⁷¹ being independently selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, wherein R ⁷¹ is optionally further substituted by one or more (1, 2 or 3) groups independently selected from deuterium or halogen;

Ring B is a 5-10 membered heterocycloalkyl group (preferably a 5-8 membered heterocycloalkyl group), wherein the heteroatoms in the heterocycloalkyl group are 1, 2 or 3 heteroatoms independently selected from N, O, P, S, Si, Se and different oxidation states thereof;

R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 alkyl, C 1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, _3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂ , -Co _0-6 alkyl-OH, -Co 0-6 alkyl-NH ₂ , Co _0-6 alkyl-SH, -Co _0-6 alkyl-OC(O)-NH ₂ , -Co _0-6 alkyl-OC(O)-(C _3-8 heterocycloalkyl), -Co _0-6 alkyl-OC(O)-(C _3-8 cycloalkyl), wherein the “substituted” refers to being substituted by one or more (preferably 1, 2, 3 or 4) R ⁹¹ _, wherein the R ⁹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy;

t is independently selected from 0, 1, 2 or 3;

r is independently selected from 0, 1, 2 or 3;

(8) R ⁴ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxy, -SH, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxy, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino and dimethylamino; the term "substituted" refers to substitution by one or more (1, 2 or 3) R ⁴¹ ;

(9) R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, wherein “substituted” means substituted by one or more (1, 2, 3 or 4) R ⁵¹ ;

(10) R ^6b is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy and cyclobutyloxy, oxetanyl-CH _{2 -, cyclopropyl-CH 2} -, pyrrolyl-CH 2 -, -(CO)-O-CH ₃ , CH 3 -O-CH ₂ -, CH 3 CH ₂ _-O -CH ₂ -, CH ₃ _-SO 2 -CH ₂ -, -CH ₂ _-NH ₂ , -(CO) _{-CH 3} _, -CO-NH ₂ , -CH ₂ -SH; the "substituted" refers to substitution by one or more ₍ 1, 2, 3 or 4) R ⁶¹ .

4. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) R ³ is independently selected from deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, ethynyl, oxetanyl, azetidinyl, hydroxy, amino, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, and ethylthio;

(2) R ³¹ is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C _6-9 aryl, 5-9 membered heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-CO-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) ₂ -, C _1-4 alkyl-S-, NH ₂ -S(O)-, NH ₂ -S(O) ₂ -, NH ₂ -S-; said R ³¹ is optionally further substituted by one or more (preferably 1, 2 or 3) R ³¹¹ , said R ³¹¹ being independently selected from deuterium, halogen or C _1-3 alkyl;

(3) ^R7 and ^R8 are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C6-9 aryl, 5-9 membered heteroaryl, or ^R7 and ^R8 together with the carbon atom to which they are directly linked form a substituted or unsubstituted _C3-6 cycloalkyl or 3-6 membered heterocyclyl; the term "substituted" refers to substitution by one or more (1, 2 or 3) ^R71 ;

(6) Ring B is a 5-8 membered heterocycloalkyl group;

(7) R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy, C 2-4 alkenyl, C _2-4 alkynyl, _3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-9 membered aryl, 5-9 membered heteroaryl, =NH, =CH ₂ , -C _0-6 alkyl-OH, -C 0-4 alkyl-NH ₂ , C _0-4 alkyl-SH, -C _0-4 alkyl-OC(O)-NH ₂ , -C _0-4 alkyl _- OC(O)-(C _3-6 heterocycloalkyl), -C _0-4 alkyl-OC(O)-(C _3-6 cycloalkyl), wherein "substituted" refers to substitution by one or more (preferably 1, 2, 3 or 4) R ⁹¹ .

5. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) R ⁷ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy and azetidinyl, or R ⁷ and R ⁸ together with the carbon atom to which they are directly attached form cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy and azetidinyl; the term "substituted" refers to substitution by one or more (1, 2 or 3) R ⁷¹ ;

(2) Ring B is selected from the following structures:

(3) R ⁹ is independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy, azetidinyl, =NH, =CH ₂ , -CH ₂ -OH, -CH ₂ -NH ₂ , -CH 2 -SH, -CH ₂ -OC(O)-NH ₂ , -CH ₂ -OC(O)-(oxetanyl ₎ , -CH ₂ -OC(O)-(cyclopropyl); the "substituted" refers to substitution by one or more (preferably 1, 2, 3 or 4) R ⁹¹ ;

(4) Ar is selected from the following structures:

(5) R ² is selected from the following structures:

(6) R ^6b is independently selected from the following structures:

(7) Ar is selected from the following structures:

(8)Ar is R2 is not

(9)Ar is R2 is not

(10) R ² is selected from the following structures:

6. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) Z is N, M is N, R ² is wherein R ⁷ , R ⁸ , R ⁹ , r, t, and Ring B are as defined in claim 3;

(2) Z is N, M is N, Ar is And -LR ² is When R ⁷ , R ⁸ , R ⁹ , t, are as defined in claim 3 , and wherein R ⁹ is not halogen;

(3) Z is N, M is N, Ar is And ^R2 is wherein R ⁹ is independently selected from deuterium, cyano, nitro, azido, substituted or unsubstituted C _1-8 alkyl, C 1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, _3-6 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, =NH, =CH ₂ , -Co _0-6 alkyl-OH, -Co 0-6 alkyl-NH ₂ , Co _0-6 alkyl-SH, -Co _0-6 alkyl-OC(O)-NH ₂ , _{-Co 0-6} _alkyl -OC(O)-(C _3-8 heterocycloalkyl), -Co _0-6 alkyl-OC(O)-(C _3-8 cycloalkyl), the “substituted” refers to being substituted by one or more (preferably 1, 2, 3 or 4) R ⁹¹ , the R ⁹¹ is independently selected from deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy; R ⁷ , R ⁸ , and t are as defined in claim 3.

7. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that it satisfies one or more of the following conditions:

(1) Z is N, M is N, R ¹ is F, R ⁴ is H, methyl, methoxy or ethoxy, Ar is When -LR ² is not (2) Z is N, M is N, Ar is When ^R2 is

(3) Z is N, M is N, ^R1 is F, ^R2 is wherein R ⁷ , R ⁸ , R ⁹ , r, t, and Ring B are as defined in claim 3;

(4) Ar is a substituted or unsubstituted 6-10 membered aromatic ring, R ² is wherein R ⁷ , R ⁸ , R ⁹ , r, t, and Ring B are as defined in claim 3;

(5) Ar is a substituted or unsubstituted 6-10 membered aromatic heterocycle, R ² is wherein R ⁷ , R ⁸ , R ⁹ , r, t and ring B are as defined in claim 3.

8. The compound according to any one of claims 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, characterized in that the compound has the following structure and is not

9. A pharmaceutical composition comprising an effective amount of the nitrogen-containing heterocyclic compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of the nitrogen-containing heterocyclic compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition according to claim 9 in the preparation of a Ras mutant protein inhibitor or drug; the Ras mutant protein may be KRAS ^G12D ; the drug may be a drug for treating a disease associated with the activity or expression of the Ras mutant protein; or the drug may be a drug for treating a tumor; the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, and pancreatic cancer.