Nitrogen-containing heterocyclic ring compound, preparation method and application

Abstract

The invention discloses a nitrogen-containing heterocyclic ring compound as well as a preparation method and application thereof, and particularly relates to a nitrogen-containing heterocyclic ring compound as shown in a general formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers, tautomers, torsion isomers, solvates, polymorphic substances or prodrugs thereof, and a preparation method and pharmaceutical application thereof. Wherein the definition of each group is described in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a class of nitrogen-containing heterocyclic compounds, compounds capable of inhibiting the activity of Ras mutant proteins, and a preparation method and use thereof. Background Art

[0002] Ras was the first oncogene identified in human tumors, first discovered in two murine sarcoma viruses. The Ras gene family consists of three members: HRas, KRas, and NRas. KRas mutations are the most common in human tumors, accounting for approximately 85%. Previous studies have shown that KRas mutations cause cancer due to missense mutations at codon 12, which alter the structure of the KRas protein and maintain its activation. Ras' primary role in signaling is activating kinases that control gene transcription, thereby regulating cell differentiation and proliferation. It is closely associated with tumor cell survival, proliferation, migration, metastasis, and angiogenesis. KRas mutations are found at high rates in malignancies such as pancreatic cancer, colorectal cancer, ovarian cancer, and bile duct cancer. However, over three decades have passed since the KRas oncogene was first discovered, and while several generations of targeted drugs have been developed for common oncogenes such as EGFR and BCL, targeted drugs for KRas have remained elusive. For a long time, targeted drugs for KRas pathway mutant tumors have mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but with little success. In recent years, the development of inhibitors targeting specific KRas gene mutations has become a hot topic, although some inhibitors have gradually moved from preclinical incubation to clinical research, such as KRas G12C Inhibitors such as AMG510 and MRTX1257 have shown certain efficacy in early clinical trials. G12C The first clinical data of the inhibitor AMG510 was finally officially released at the American Society of Clinical Oncology in June 2019. In this clinical study, Amgen's drug AMG510 showed that it could prevent tumor growth in most patients with non-small cell lung cancer and colorectal cancer with KRas mutations.

[0003] However, current KRas inhibitors are limited to targeting KRas G12C Mutation patients, a large number of KRas G12C There has been no breakthrough in the development of drugs for mutation inhibitors other than KRas G12D 、KRas G12V 、KRas G13D Therefore, we should find and search for drugs with high specificity and excellent drugability targeting KRas G12CTargeted drugs for specific mutant genes other than KRas have become a hot topic in the industry. After long-term efforts, the inventors have discovered a class of KRas mutation inhibitors with new structures and mechanisms of action, especially for KRas G12D The mutation has better activity and drugability. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the KRas G12D The problem of lack of inhibitors is solved by providing a class of nitrogen-containing heterocyclic compounds, preparation methods and uses. The nitrogen-containing heterocyclic compounds provided by the present invention are a new class of KRas G12D Inhibitors show good inhibitory activity; they have good inhibitory activity against tumor cells and good drugability, especially improving the currently known KRas G12D Inhibitors have the disadvantage of low oral bioavailability and have broad prospects for drug development.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0006] The present invention provides 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.

[0007]

[0008] Wherein, R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, amino, hydroxyl, -SH, C 6-10 Aryl, 5-10 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 0 Replacement, R 0 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-8 Alkyl-SF5 is substituted by a substituent; the R 0 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0009] R 1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C3-6 Cycloalkyl, 3-8 membered heterocyclic group, amino, hydroxyl, -SH, C 6-10 Aryl, 5-10 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 11 Replacement, R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5 is substituted by a substituent; the R 11 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0010] R 2 Selected from the following substituted or unsubstituted groups: 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-, 5-16 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, the ring system includes spiro, bridged, fused or fused rings; the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 21 Replace, each R 21 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-OC(O)-NH2, -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 atoms or heteroatoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl group (preferably a 3-6 membered cycloalkyl group); 21 One or more hydrogen atoms (preferably 1, 2 or 3) on the group are independently optionally replaced by R 211 Replacement, R211 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 alkoxy;

[0011] R 4 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, 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-NH2, -C 0-6 Alkyl-(CO)-NH2, -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, amino, hydroxy, -SH; the "substituted" refers to one or more (1, 2, 3 or 4) R 41 Replacement, R 41 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 41 Optionally further represented by one or more (preferably 1, 2 or 3) R 411 Substituted, the R 411 independently selected from deuterium or halogen;

[0012] R 5a 、R 5b 、R 5c and R 5dEach is 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 heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R 51 Replacement, R 51 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 51 Optionally further represented by one or more (preferably 1, 2 or 3) R 511 Substituted, the R 511 independently selected from deuterium or halogen;

[0013] R 6a 、R 6b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl-C 1-6 Alkyl-, 3-12 membered heterocyclic-C 1-6 Alkyl-, C 1-8 Alkoxy, -C 1-8 Alkyl-OH, -C 1-8 Alkyl-SH, -C 1-8 Alkyl-NH2, -C 1-8 Alkyl-OC 1-6 Alkyl-, -C 0-6 Alkyl-(CO)-NH2, -C 0-6 Alkyl-(CO)-C 0-6 Alkyl, -C 0-6 Alkyl-(CO)-OC0-6 Alkyl, -C 0-6 Alkyl-P(O)(C 0-6 Alkyl)2, amino, hydroxyl, -SH, C 0-4 Alkyl-S(O)-, C 0-4 Alkyl-S(O)2-, C 0-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 Replacement, R 61 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 61 Optionally further represented by one or more (preferably 1, 2 or 3) R 611 Substituted, the R 611 independently selected from deuterium or halogen;

[0014] Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R Y1 Replacement, R Y1 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-, C1-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R Y1 Optionally further represented by one or more (preferably 1, 2 or 3) R Y11 Substituted, the R Y11 independently selected from deuterium or halogen;

[0015] L is independently selected from none, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, CR L1 R L2 , O, S, S(O), S(O)2 or NR L1 R L2 , where each R L1 and R L2 are independently selected from hydrogen, deuterium, substituted or unsubstituted hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, or R L1 and R L2 Together with the atoms directly connected thereto, they form a 3-6 membered cycloalkyl or heterocycloalkyl group; the "substituted" refers to one or more (1, 2, 3 or 4) R L11 Replacement, R L11 independently selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl;

[0016] Z and M are independently selected from N, CR Z1 ; Each R Z1 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the above "substituted" refers to one or more (1, 2 or 3) R Z11 Replacement, R Z11 independently selected from deuterium, halogen, cyano, nitro, azido, amino, hydroxyl, C1-4 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0017] Ar is selected from substituted or unsubstituted 5-12 membered aromatic rings or aromatic heterocycles, wherein "substituted" means that Ar is replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace;

[0018] Each R 3 Each is independently selected from cyano, amino, halogen, deuterium, substituted or unsubstituted groups: amino, hydroxyl, -SH, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, C 3-12 Cycloalkyl-C 1-6 Alkyl-, 3-12 membered heterocyclic-C 1-6 Alkyl-, C 1-8 Alkoxy, -C 1-8 Alkyl-OH, -C 1-8 Alkyl-NH2, -C 0-6 Alkyl-(CO)-NH2, -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 one or more (1, 2, 3 or 4) R 31 Replacement, R 31 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 1-4Alkoxy, C 1-4 Alkyl-CO-, C 1-4 Alkyl-S(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 31 Optionally further represented by one or more (preferably 1, 2 or 3) R 311 Substituted, the R 311 independently selected from deuterium, halogen or C 1-3 alkyl;

[0019] 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.

[0020] In certain preferred embodiments of the present invention, certain groups in the nitrogen-containing heterocyclic compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in certain embodiments of the present invention").

[0021] In certain embodiments of the present invention, R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, amino group, hydroxyl group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-6 Alkyl-(CO)-OC 1-6 Alkyl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 0 Replacement, R 0 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5; the R 0 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0022] In certain embodiments of the present invention, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and -(CO)-OC 1-6 alkyl;

[0023] In certain embodiments of the present invention, R 1is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, amino, hydroxyl, -SH, C 6-8 Aryl, 5-8 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 11 Replacement, R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5; the R 11 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0024] In certain embodiments of the present invention, R 1 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;

[0025] In certain embodiments of the present invention, R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5; the R 11 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0026] In certain embodiments of the present invention, Z is N, M is N;

[0027] In certain embodiments of the present invention, Z is CR Z1 , M is N;

[0028] In certain embodiments of the present invention, Z is N, M is CR Z1 ;

[0029] In certain embodiments of the present invention, Z is CR Z1 , M is CR Z1 ;

[0030] In certain embodiments of the present invention, each R Z1 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C 1-4 Alkyl, C 1-4 alkoxy;

[0031] In certain embodiments of the present invention, R Z11 independently selected from deuterium, halogen;

[0032] In certain embodiments of the present invention, Ar is selected from substituted or unsubstituted 6-10 membered aromatic rings, substituted or unsubstituted 6-10 membered aromatic heterocycles; the "substituted" refers to Ar being replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace;

[0033] In certain embodiments of the present invention, 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" refers to Ar being replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace;

[0034] In certain embodiments of the present invention, each R 3 independently selected from cyano, halogen, deuterium, substituted or unsubstituted amino, hydroxyl, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, -C 0-6 Alkyl-SF5, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocyclic-C 1-3 Alkyl-, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH2, -C 0-6 Alkyl-(CO)-NH2, -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 one or more (1, 2, 3 or 4) R 31 Substituted; the "substituted" refers to one or more (1, 2, 3 or 4) R 31 replace;

[0035] In certain embodiments of the present invention, R 3 independently selected from deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, -SH, C 1-4 Alkyl, C1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the "substituted" refers to one or more (1, 2, 3 or 4) R 31 replace;

[0036] In certain embodiments of the present invention, R 3 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;

[0037] In certain embodiments of the present invention, R 31 are 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 31 Optionally further represented by one or more (preferably 1, 2 or 3) R 311 Substituted, the R 311 independently selected from deuterium, halogen or C 1-3 alkyl;

[0038] In certain embodiments of the present invention, Ar is selected from the following structures:

[0039]

[0040] In certain embodiments of the present invention, R 2 Selected from the following substituted or unsubstituted groups: 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 1-3Alkyl-4-8 membered heterocycloalkyl-, 5-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, the ring system includes spiro, bridged, fused or fused ring; the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 21 replace.

[0041] In certain embodiments of the present invention, R 2 Selected from the following structures:

[0042]

[0043] Among them, R 7 and R 8 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or R 7 and R 8 The carbon atom directly linked to it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the "substituted" refers to one or more (1, 2 or 3) R 71 Replaced by R 71 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 heterocyclic group, said R 71 Optionally further substituted with one or more (1, 2 or 3) groups independently selected from deuterium or halogen;

[0044] 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;

[0045] R 9 independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6Alkyl-NH2, C 0-6 Alkyl-SH, -C 0-6 Alkyl-OC(O)-NH2, -C 0-6 Alkyl-OC(O)-(C 3-8 Heterocycloalkyl), -C 0-6 Alkyl-OC(O)-(C 3-8 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 Substituted, the R 91 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 alkoxy;

[0046] t is independently selected from 0, 1, 2 or 3;

[0047] r is independently selected from 0, 1, 2 or 3.

[0048] In certain embodiments of the present invention, Z is N, M is N, and R2 is where R 7 、R 8 、R 9 , t, r, and ring B are as defined elsewhere in the text;

[0049] In certain embodiments of the present invention, the nitrogen-containing heterocyclic compound represented by general formula (I) has a structure represented by formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6):

[0050]

[0051] Among them, Ar, R 1 、R 4 、R 5a 、R 5b 、R 5c 、R 5d 、R 6a 、R 6b 、R 7 、R 8 、R 9 , t, r, and Ring B are as defined elsewhere herein.

[0052] In certain embodiments of the present invention, Z is N, M is N, and R 1 F, R 4 is H, methyl, methoxy or ethoxy, Ar is When -LR 2 Not for

[0053] In certain embodiments of the present invention, Z is N, M is N, and Ar is And-LR 2 for When R 9 Not halogen.

[0054] In certain embodiments of the present invention, Z is N, M is N, and Ar is And R 2 for When R 9 independently selected from deuterium, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-NH2, C 0-6 Alkyl-SH, -C 0-6 Alkyl-OC(O)-NH2, -C 0-6 Alkyl-OC(O)-(C 3-8 Heterocycloalkyl), -C 0-6 Alkyl-OC(O)-(C 3-8 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 Substituted, the R 91 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy; R 7 、R 8 The definitions of , t are as defined elsewhere in the text.

[0055] In certain embodiments of the present invention, R 7 and R 8 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, or R 7 and R 8 The carbon atom directly linked to it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the "substituted" refers to one or more (1, 2 or 3) R71 replaced.

[0056] In certain embodiments of the present 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, cyclobutyloxy and azetidinyl, or R 7 and R 8 The carbon atoms to which they are directly attached form cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy and azetidinyl; the "substituted" refers to one or more (1, 2 or 3) R 71 replaced.

[0057] In certain embodiments of the invention, Ring B is a 6-8 membered heterocycloalkyl group.

[0058] In certain embodiments of the present invention, Ring B is selected from the following structures:

[0059]

[0060] In certain embodiments of the present invention, R 9 independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-4 Alkyl-NH2, C 0-4 Alkyl-SH, -C 0-4 Alkyl-OC(O)-NH2, -C 0-4 Alkyl-OC(O)-(C 3-6 Heterocycloalkyl), -C 0-4 Alkyl-OC(O)-(C 3-6 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 replace.

[0061] In certain embodiments of the present invention, R 9independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy, azetidinyl, =NH, =CH2, -CH2-OH, -CH2-NH2, -CH2-SH, -CH2-OC(O)-NH2, -CH2-OC(O)-(oxetanyl), -CH2-OC(O)-(cyclopropyl); the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 replace.

[0062] In certain embodiments of the present invention, R 2 Selected from the following structures:

[0063]

[0064] In certain embodiments of the present invention, Ar is selected from the following structures:

[0065]

[0066] In certain embodiments of the present invention, Ar is R2 is not

[0067] In certain embodiments of the present invention, Ar is R2 is not

[0068] In certain embodiments of the present invention, R 2 Selected from the following structures:

[0069]

[0070] In certain embodiments of the present invention, Z is N, M is N, and Ar is When R 2 for

[0071] In certain embodiments of the present invention, R 4 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: amino, hydroxyl, -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 3-6Cycloalkyl, 3-6 membered heterocyclic group; the "substituted" refers to one or more (1, 2 or 3) R 41 replace;

[0072] In certain embodiments of the present 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, isopropyloxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino and dimethylamino; the "substituted" refers to one or more (1, 2 or 3) R 41 replace;

[0073] In certain embodiments of the present invention, R 41 are 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-;

[0074] In certain embodiments of the present invention, R 5a 、R 5b 、R 5c and R 5d Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxyl, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R 51 replace;

[0075] In certain embodiments of the present invention, R 5a 、R 5b 、R 5c and R 5d Each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted following groups: methyl, ethyl, said "substituted" refers to one or more (1, 2, 3 or 4) R 51 replace;

[0076] In certain embodiments of the present invention, R 51 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 51 Optionally further represented by one or more (preferably 1, 2 or 3) R 511 Substituted, the R 511 independently selected from deuterium or halogen;

[0077] In certain embodiments of the present invention, R 6b independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocyclic-C 1-3 Alkyl-, C 1-4 Alkoxy, -C 1-4 Alkyl-OH, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OC 1-3 Alkyl, -C 0-4 Alkyl-(CO)-NH2, -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, hydroxyl, -SH, C 1-4 Alkyl-S(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 replace;

[0078] In certain embodiments of the present invention, R 6bindependently selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy and cyclobutyloxy, oxetanyl-CH2-, cyclopropyl-CH2-, pyrrolyl-CH2-, -(CO)-O-CH3, CH3-O-CH2-, CH3CH2-O-CH2-, CH3-SO2-CH2-, -CH2-NH2, -(CO)-CH3, -CO-NH2, -CH2-SH; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 replace;

[0079] In certain embodiments of the present invention, R 61 are independently selected from deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolane, azetidinyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy and cyclobutyloxy; said R 61 Optionally further represented by one or more (preferably 1, 2 or 3) R 611 Substituted, the R 611 are independently selected from deuterium or halogen.

[0080] In certain embodiments of the present invention, R 6b Independently selected from the following structures:

[0081]

[0082] In certain embodiments of the present invention, Z is N, M is N, and R 1 F, R 2 for where R 7 、R 8 、R 9 , t, r, and ring B are as defined elsewhere in the text;

[0083] In certain embodiments of the present invention, the nitrogen-containing heterocyclic compound represented by general formula (I) has a structure represented by formula (IV-1), (IIV-2), (IV-3) or (IV-4):

[0084]

[0085] Among them, Ar, R 1 、R 4 、R 6a 、R 6b 、R 7 、R 8 、R9 , t, r, and Ring B are as defined elsewhere herein.

[0086] In certain embodiments of the present invention, Ar is a substituted or unsubstituted 6-10 membered aromatic heterocycle; and Z is N.

[0087] In certain embodiments of the present invention, Ar is a substituted or unsubstituted 6-10 membered aromatic ring, R 2 for

[0088] where R 7 、R 8 、R 9 , t, r, and Ring B are as defined elsewhere herein.

[0089] In certain embodiments of the present invention, Ar is a substituted or unsubstituted 6-10 membered aromatic heterocycle, R 2 for where R 7 、R 8 、R 9 , t, r, and Ring B are as defined elsewhere herein.

[0090] In certain embodiments of the present invention, Ar, Z, M, L, Y, R, R 1 、R 2 、R 4 、R 5a 、R 5b 、R 5c 、R 5d 、R 6a 、R 6b Each group is independently a corresponding structure in the examples.

[0091] In certain embodiments of the present invention, the compound shown in formula (I) is not

[0092] In certain embodiments of the present invention, the compound represented by formula (I) has the following structure:

[0093]

[0094]

[0095]

[0096]

[0097] Thus, throughout this specification, those skilled in the art can select the groups and substituents thereof in the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof to provide a stable nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, including but not limited to the compounds described in the embodiments of the present invention.

[0098] The nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomeric form, solvate, polymorph, or prodrug thereof, can be synthesized by methods similar to those known in the chemical field, the steps and conditions of which can be referenced to the steps and conditions of similar reactions in the art, particularly according to the description herein. The starting materials are typically obtained from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtained through SciFinder, Reaxys online databases).

[0099] In the present invention, the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof, can also be prepared by preparing the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof, and using conventional methods in the art to obtain other nitrogen-containing heterocyclic compounds as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof through peripheral modification.

[0100] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in Formula I. The following reaction schemes and examples are provided to further illustrate the present invention.

[0101] The present invention also provides a method for preparing the nitrogen-containing heterocyclic biaryl compound as shown in Formula I, which comprises steps ac:

[0102] a) subjecting the compound of general formula (A) to a substitution reaction with a bridged ring compound under alkaline conditions to produce a compound of general formula (B);

[0103] b) Compound of formula (B) and R 2-LH undergoes a substitution reaction or a metal-catalyzed coupling reaction under alkaline conditions to generate a compound of formula (C);

[0104] c) reacting the compound of formula (C) with an arylboronic acid, arylboronic acid ester or an aryl metal reagent (R3-Ar-M) via a transition metal-catalyzed coupling reaction to produce a compound of formula (I).

[0105]

[0106] X is a halogen, LG and LG1 are leaving groups, and the definitions of the other groups are as described above;

[0107] Preferably, steps a), b) and c) are each carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0108] Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; 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 a combination thereof.

[0109] Preferably, the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanedichloropalladium, or a combination thereof; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tri-o-phenylmethylphosphine, or a combination thereof.

[0110] The necessary raw materials or reagents for preparing compounds of Formula I can be commercially available or prepared by synthetic methods known in the art. The methods described in the following experimental section can be used to prepare the compounds of the present invention in the form of free bases or acid salts thereof. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the pharmaceutical activities of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for an organic base and treating according to conventional methods to prepare pharmaceutically acceptable salts. Examples of salts include: salts 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, citric 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, mucofuric acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.

[0111] The nitrogen-containing heterocyclic compound shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph, or prodrug thereof may have one or more chiral carbon atoms, and thus can be separated to obtain optically pure isomers, such as pure enantiomers, racemates, or mixed isomers. Pure single isomers can be obtained by separation methods known in the art, such as chiral crystallization into salts, or separation using a chiral preparative column.

[0112] The chemicals used in the synthetic routes described in this patent include solvents, reagents, catalysts, and protecting and deprotecting groups. The above methods may also include additional steps before or after the steps specifically described herein to add or remove appropriate protecting groups to obtain the target compound. Furthermore, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

[0113] Another object of the present invention is to provide a drug and composition thereof for treating or preventing tumors. The technical solution for achieving the above object is as follows:

[0114] The present invention provides a pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic compound as shown in Formula I as described above, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and (one or more) pharmaceutically acceptable carriers (pharmaceutical excipients). For example, such a pharmaceutical composition may comprise one or more additional nitrogen-containing heterocyclic compounds as shown in 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 amount of the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof may be a therapeutically effective amount.

[0115] The present invention provides a pharmaceutical composition for treating tumors, which is composed of a nitrogen-containing heterocyclic compound represented by the above-mentioned general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof and a pharmaceutically acceptable carrier.

[0116] Another object of the present invention is to provide a use of the above-mentioned compound. The technical solution for achieving the above-mentioned object is as follows:

[0117] The present invention also provides a use of the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof in the preparation of a Ras mutant protein inhibitor; in the application, the Ras mutant protein may be KRAS G12D The Ras mutant protein inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of Ras mutant protein.

[0118] The present invention also provides a nitrogen-containing heterocyclic compound as shown in Formula I, or its pharmaceutically acceptable salt, or its enantiomer, diastereomer, tautomer, torsomeric form, solvate, polymorph or prodrug for use in preparing a drug; the drug can be a drug for treating a disease related to the activity or expression of a Ras mutant protein; or the drug can be a drug for treating tumors. The Ras mutant protein can be KRas G12DThe tumors can be 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, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, etc.

[0119] Another aspect of the present invention relates to a method for preventing and / or treating diseases related to the activity or expression of Ras mutant proteins, which comprises administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof.

[0120] Another aspect of the present invention relates to a method for preventing and / or treating tumors, comprising administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof.

[0121] Another aspect of the present invention relates to a drug for preventing and / or treating diseases related to the activity or expression of Ras mutant proteins, or tumors, which comprises the nitrogen-containing heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof.

[0122] The nitrogen-containing heterocyclic compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomeric form, solvate, polymorph, or prodrug thereof is used to prepare a drug for treating a disease associated with the activity or expression of a Ras mutant protein, in particular a drug for treating a tumor. The tumor can be 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, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, etc.

[0123] The pharmaceutical excipients may be those widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers, or may provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0124] Examples of pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, 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-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed 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 saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0125] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0126] The pharmaceutical dosage form of the compound of the present invention can be provided in the form of a quick release, controlled release, sustained release or targeted drug release system. For example, conventional dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized preparations. Depending on the route of administration used, special devices may be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms are often composed of drugs, excipients and container / sealing systems. One or more excipients (also known as inactive ingredients) can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and a method for obtaining a desired drug release profile can be provided. Therefore, the type of excipient added to the drug can be determined based on various factors, such as the physical and chemical properties, route of administration and preparation steps of the drug.

[0127] The pharmaceutical dosage forms of the compounds of the present invention can be prepared by any method well known in the art, such as by conventional mixing, sieving, dissolving, melting, granulating, making dragees, tableting, suspending, extruding, spray drying, grinding, emulsifying, (nano / micron) encapsulation, coating or lyophilization processes. As mentioned above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of the active molecules into preparations for pharmaceutical use.

[0128] The pharmaceutical composition of the present invention can be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and comprises a therapeutically effective amount of a compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined above and below and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated, and the mode of administration. For enteral administration, such as oral administration, the compounds of the present invention can be formulated into a wide variety of dosage forms.

[0129] The pharmaceutical compositions and dosage forms may contain one or more compounds of the present invention, their stereoisomers, or one or more pharmaceutically acceptable salts thereof as active ingredients. Pharmaceutically acceptable carriers may be solid or liquid. Solid formulations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may also be one or more substances that act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is typically a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding properties in appropriate proportions and compacted into the desired shape and size. 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 compound may include an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without a carrier, is surrounded by a carrier associated therewith.

[0130] Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations that are intended to be converted into liquid form preparations shortly before use. Emulsions can be prepared in solutions, such as propylene glycol aqueous solutions, or can contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing fine particles of the active ingredient in water with a binder such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other commonly used suspending agents. Solid form preparations include solutions, suspensions, and emulsions and can contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0131] Exemplary compositions 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.

[0132] The compounds of the present invention may also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.

[0133] Thus, for parenteral administration, the pharmaceutical compositions of the present invention may be in the form of sterile injectable or infusible injection preparations, for example, as sterile aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable or infusible preparations may also be sterile injectable or infusible solutions or suspensions in a nontoxic, 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 commonly used as solvents or suspending media. Any bland, non-volatile oil may be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives may be used to prepare injections, as may natural, pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated forms. The invention also can comprise the oil solution of parenteral administration or suspension.These oil solutions or suspensions also can contain long-chain alcohol diluent or dispersant.The solution that is used for parenteral administration can also comprise suitable stabilizing agent, can comprise buffer substance if desired.Suitable stabilizing agent comprises antioxidant, for example sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and its salt and EDTA sodium salt separately or in combination.Parenteral solution can also comprise preservative, as benzalkonium chloride, p-hydroxybenzoic acid or propyl parahydroxybenzoate and chlorobutanol.

[0134] For inhaled or nasal administration, suitable pharmaceutical formulations include particles, aerosols, powders, mists or droplets, for example, having an average size of about 10 microns in diameter or less. For example, compositions for inhalation can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other solubilizing or dispersing agents known in the art.

[0135] The pharmaceutical composition of the present invention can also be administered topically to the skin or mucous membranes. For topical application, the pharmaceutical composition can be, for example, a lotion, a gel, a paste, a tincture, a transdermal patch, a gel for transmucosal delivery.

[0136] The pharmaceutical composition can be prepared in a suitable ointment formulation comprising an active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or emulsion comprising an 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 composition of the present invention can also be topically applied to the lower intestinal tract via a rectal suppository formulation or a suitable enema formulation.

[0137] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one.

[0138] the term

[0139] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0140] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0141] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0142] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0143] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0144] Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example: C1-6 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 shorthand notation does not include carbon that may be present in substituents of the group being described. The total number of carbon atoms in the shorthand notation does not include carbon that may be present in substituents of the group being described.

[0145] Certain chemical groups defined herein are preceded by a simplified notation to indicate 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 refers to a heterocycloalkyl group, as defined below, having a total of 3 to 8 (3, 4, 5, 6, 7, or 8) carbon atoms and heteroatoms; C5-10 heteroaryl, C5-C10 heteroaryl, or 5-10 membered heteroaryl refers to a heteroaryl group, 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 notation does not include the carbon atoms and heteroatoms that may be present in substituents of the group.

[0146] As used herein, numerical ranges defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., represent integers within the range, such as 1-6, which represents 1, 2, 3, 4, 5, 6.

[0147] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0148] In some specific structures, when an alkyl group is clearly indicated as a linking group, the alkyl group represents a linked alkylene group, for example, the C1-C6 alkyl in the group "halo-C1-C6 alkyl" should be understood as a C1-C6 alkylene (e.g., methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, neopentylene or 1,1-dimethylpropylene, etc.).

[0149] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0150] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0151] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable.

[0152] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Furthermore, when a group is substituted with one or more of the substituents, the substituents are independent of each other, i.e., the one or more substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at every substitutable position of the substituted group. When more than one position in a given structure is substitutable by one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0153] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently; "C 1-4The term "alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl), and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0154] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an -OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted by a hydroxy (-OH) group; "carbonyl" refers to a -C(=O)- group; "nitro" refers to a -NO2; "cyano" refers to -CN; "amino" refers to -NH2; "substituted amino" refers to an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, Alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" refers to -COOH; "acyl" refers to a -C(=O)H group; "sulfone" refers to a -S(=O)2- group; "sulfoxide" refers to a -S(=O)- group; "sulfonyl" refers to a -S(=O)2H group; "urea" refers to -NH-C(=O)-NH2; "sulfonylurea" refers to a -S(=O)2-NH-C(=O)-NH2 group; "alkoxy" refers to an alkyl-O- group as defined below.

[0155] In this application, the term "alkyl" as a group or part of another group (for example, as used in groups such as halogen-substituted alkyl) means a straight or branched hydrocarbon chain group consisting only of 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 connected to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl.

[0156] As used herein, the term "alkylene" refers to a saturated, branched, straight-chain or cyclic hydrocarbon radical of the stated number of carbon atoms (typically 1 to 6 carbon atoms) and having two monovalent radical centers derived from the same or two different carbon atoms of a parent alkane by removing two hydrogen atoms. Typical alkylene groups include, but are not limited to, methylene (-CH2-), ethylene {including 1,2-ethylene (-CH2CH2-), 2,2-dimethylene (-CH(CH3)-)}, propylene {including 2-methylpropylene (-CH(CH3)CH2-), isopropylene (-C(CH3)2-), 1,3-propylene (-CH2CH2CH2-)}, butylene {including 1,4-butylene (-CH2CH2CH2CH2-)}.

[0157] In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting only of carbon atoms 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 connected 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-enyl, pent-1,4-dienyl, etc. "Alkenyl" refers to a straight or branched olefin chain group.

[0158] In the present application, the term "alkynyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting only of 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 connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc. "Alkynyl" refers to a straight or branched alkyne chain group.

[0159] In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be connected to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specified in the specification, the carbon atoms in the cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindanyl, 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-benzocyclohepten-6-yl, 5,6,7,8,9,10-hexahydro-benzo Cyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0160] In the present application, the term "heterocyclyl" as a group or part of another 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 otherwise specified in this specification, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the heteroatoms in the heterocyclyl group can be optionally oxidized, that is, the heteroatoms can be in different oxidation states; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. The heterocyclyl group can be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl group containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic 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, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0161] In the present application, the term "heterocycloalkyl" as a group or part of another group means a stable 3- to 20-membered saturated cyclic group consisting of 2-14 carbon atoms and 1-6 heteroatoms selected from nitrogen, phosphorus, oxygen, silicon, boron, selenium and sulfur. Unless otherwise specified in the specification, the heterocycloalkyl group can be either monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or higher ring system, which can include fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). The bicyclic ring system of the heterocycloalkyl group can include one or more heteroatoms in one or both rings; and is saturated. For the purposes of the present invention, the heterocycloalkyl group is preferably a stable 4- to 12-membered saturated monocyclic, bicyclic, bridged or spirocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, selenium, boron, phosphorus, silicon and sulfur, more preferably a stable 4- to 12-membered saturated monocyclic, bicyclic, bridged or spirocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, selenium, boron, phosphorus, silicon and sulfur, more preferably a stable 4- to 12-membered saturated monocyclic, bicyclic, bridged or spirocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, selenium, boron, phosphorus, silicon and sulfur. A stable 4- to 7-membered saturated monocyclic, bicyclic, bridged, or spirocyclic group containing 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 heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 7; more particularly, the heterocycloalkyl group may contain 3, 4, or 5 carbon atoms and one or two of the above heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 6 ("4- to 6-membered heterocycloalkyl"). The heteroatoms in the heterocyclyl group may optionally be oxidized, i.e., the heteroatoms may be in different oxidation states; the nitrogen atom may optionally be quaternized.

[0162] In this application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or higher ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like.

[0163] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0164] In the present application, the term "heteroaryl" as a group or part of another group means a 5- to 16-membered conjugated ring system radical having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, sulfur and selenium in the ring. Unless otherwise specified in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The heteroatoms in the heteroaryl group can be optionally oxidized, that is, the heteroatoms can be optionally in different oxidation states; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0165] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0166] It should be understood that the singular forms used in the present invention, such as "a", include plural references unless otherwise specified. In addition, the term "comprising" is an open limitation rather than a closed limitation, that is, it includes the content specified in the present invention, but does not exclude other aspects of the content.

[0167] Unless otherwise stated, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0168] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques for analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light-emitting device performance testing.

[0169] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0170] Those skilled in the art will understand that according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0171] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. 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.

[0172] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0173] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0174] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0175] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0176] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to 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 present invention may be prepared using 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.

[0177] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography.

[0178] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0179] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-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, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0180] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness 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, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural 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 etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0181] "Polymorphs" refers to different solid crystalline phases of certain compounds of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to encompass various crystalline forms and mixtures thereof.

[0182] Typically, 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 the compounds of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, may only retain adventitious water or a mixture of water and a portion of an adventitious solvent. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

[0183] The present invention also includes prodrugs of the above-mentioned compounds. In this application, the term "prodrug" means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. When administered to an individual in need, the prodrug may not be active, but is converted into the active compound of the present invention in vivo. The prodrug is typically rapidly converted in vivo to produce the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrug compounds typically provide advantages of solubility, tissue compatibility, or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.

[0184] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0185] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0186] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0187] The "tumors" and "diseases related to abnormal cell proliferation" mentioned in the present invention include but are not limited to leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, 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, kidney cancer, oral cancer and other diseases.

[0188] As used herein, the terms "prophylactic," "prevention," and "preventing" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

[0189] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0190] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0191] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0192] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0193] (iv) Alleviate the symptoms of the disease or condition.

[0194] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0195] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal 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.

[0196] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0197] Those skilled in the art will also appreciate that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl, and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino, and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein "R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0198] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group can also be a polymer resin.

[0199] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0200] The reagents and raw materials used in the present invention are commercially available.

[0201] The positive progress of the present invention is to provide a nitrogen-containing heterocyclic compound that can be used as a KRAS G12D Inhibitors can be used to prepare anti-tumor drugs to prevent and / or treat tumors. DETAILED DESCRIPTION

[0202] After long and in-depth research, the inventors prepared a class of novel nitrogen-containing heterocyclic compounds with the structure shown in Formula I and found that they have good inhibitory effects on KRas G12D The compound has an inhibitory activity on KRas protein at a relatively low concentration (as low as less than 10 nM). G12D The related cell proliferation and downstream signaling pERK inhibitory activity is quite excellent (IC 50 Even less than 10nM), so it can be used to treat KRas G12D Related diseases such as tumors caused by mutations or abnormal expression levels. Based on the above findings, the inventors have completed the present invention.

[0203] The present invention is further illustrated by way of examples, but the invention is not limited to the scope of these examples. Experimental procedures in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to the product specifications. Experimental procedures in the following examples, where specific conditions are not specified, were generally performed according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.

[0204] Preparation of intermediates Intermediate A1: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0205]

[0206] Step 1: Mix 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.5 g, 5.62 mmol) and urea (2.7 g, 44.9 mmol) and heat to 200°C for 4 hours. Cool to room temperature, then add water (50 mL), heat to 100°C, stir for another hour, and filter while hot. The solid is slurried with ethyl acetate (50 mL), and the filtered solid is dried to obtain a reddish-brown intermediate product (1.3 g). LC-MS [MH] - :m / z 292.9. 1 H NMR (400MHz, DMSO-d6): δ11.50-11.3(dt,2H),7.83(s,1H).

[0207] Step 2: The above intermediate compound (413 mg, 1.41 mmol) was suspended in phosphorus oxychloride (POCl3) (20 mL), three drops of N,N-dimethylaniline were added, and the mixture was heated under reflux overnight. The mixture was then dried by rotary evaporation. The residual liquid was dissolved in dichloromethane (DCM) (10 mL) and added dropwise to a saturated aqueous sodium bicarbonate (NaHCO3) solution, maintaining the pH at 7-8. The mixture was 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 obtain intermediate A1 (219 mg) as a yellow solid. LC-MS [M+H] + :m / z328.8 / 330.8. 1 H NMR (400MHz, DMSO-d6): δ8.05 (s, 1H).

[0208] Preparation of intermediate A2: 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-cyano

[0209]

[0210] Step 1: Dissolve methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (710 mg, 2.51 mmol) and cyanoacetic acid (213 mg, 2.51 mmol) in acetonitrile (10 mL), add pyridine (1.98 g, 25.1 mmol), cool to about 5°C, add phosphorus oxychloride (1.17 g, 7.53 mmol) dropwise, stir at room temperature for 2 hours, pour into water, adjust the pH to about 5, filter, and dry to obtain a yellow solid intermediate product (510 mg). LC-MS [MH] - :m / z 349.1.

[0211] Step 2: Add the above intermediate compound (100 mg, 0.29 mmol) to a freshly prepared solution of sodium ethoxide (20 mg, 0.86 mmol) in ethanol (2 mL), heat under reflux overnight, spin dry, add water, and adjust the pH to about 4 with hydrochloric acid. Solid precipitates, filter the crude solid, and dry to obtain a light yellow intermediate product (45 mg). LC-MS [M+H] + :m / z 316.9 / 318.9.

[0212] Step 3: Suspend the above intermediate compound (370 mg, 1.16 mmol) in phosphorus oxychloride (POCl3) (10 mL), add one drop of N,N-dimethylformamide (DMF), heat under reflux overnight, spin dry, and dissolve the residue in dichloromethane (DCM) (10 mL). Add dropwise to a saturated aqueous sodium bicarbonate solution (NaHCO3) while maintaining the pH at an alkaline level, and extract three times with DCM (30 mL). The combined organic phases were dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure to yield intermediate A2 (298 mg) as a yellow solid. LC-MS [M+H]+: m / z 352.8 / 354.8. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H).

[0213] Intermediate A3: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0214]

[0215] Step 1: Dissolve methyl 4-amino-6-chloro-5-fluoronicotinate (500 mg, 2.45 mmol) and cyanoacetic acid (208 mg, 2.45 mmol) in acetonitrile (10 mL), add pyridine (19.4 g, 24.5 mmol), cool to about 5°C, add phosphorus oxychloride (1.12 g, 7.35 mmol) dropwise, stir at room temperature for 2 hours, pour into water, adjust the pH to about 6, solid precipitates, filter the crude solid product, and dry to obtain a yellow intermediate product (530 mg). LC-MS [M+H] + :m / z 272.1.

[0216] Step 2: Under ice-cooling, add NaH (60%, 200 mg, 5.0 mmol) to a solution of the above intermediate compound (500 mg, 1.84 mmol) in DMF (10 mL). The reaction is allowed to warm to room temperature and stirred overnight. Water is added to quench the reaction. The pH is adjusted to approximately 4 with 4M aqueous hydrochloric acid. Solids precipitate. The crude solid product is filtered and dried to obtain a yellow intermediate product (200 mg). LC-MS [M+H] + :m / z240.

[0217] Step 3: The above intermediate compound (150 mg, 0.63 mmol) was suspended in POCl3 (10 mL), one drop of DMF was added, and the mixture was heated under reflux overnight. After the reaction was detected to be complete, the reaction solution was spin-dried, the residual solution was dissolved in DCM (10 mL), and added dropwise to a saturated aqueous NaHCO3 solution, maintaining the pH at 7-8, and extracted three times with DCM (20 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a yellow solid intermediate A3 (219 mg). LC-MS [M+H] + :m / z 276.1. 1 H NMR (400MHz, DMSO-d6): δ8.55 (s, 1H).

[0218] Intermediate A4: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0219]

[0220] Step 1: Dissolve 2-chloro-3-fluoroisonicotinic acid (18 g, 103 mmol) in a mixture of toluene (55 mL) and tert-butanol (55 mL). Add triethylamine (28.5 mL, 205 mmol), diphenylphosphoryl azide (DPPA) (23 mL, 107 mmol), and Boc anhydride (2.2 mL, 10.2 mmol), respectively. Stir the reaction mixture under a nitrogen atmosphere for 30 minutes, then heat to 80°C and react for 8 hours. After completion of the reaction, cool to room temperature, dilute with water, extract with ethyl acetate (200 mL), wash with saturated sodium bicarbonate solution and purified water, and dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify by column chromatography to obtain the title compound (10 g, light yellow powder). ESI (M+H): 247.

[0221] Step 2: Dissolve the solid obtained in the previous step (6 g) in tetrahydrofuran (50 mL), cool to -78°C, and add n-butyllithium solution (24 mL, 60 mmol) dropwise under nitrogen. After the addition is complete, warm the reaction solution to -20°C and continue the reaction for 1 hour. Then, add tert-butyl isocyanate (29 mL, 48 mmol) dropwise to the reaction solution. After the addition is complete, warm the reaction solution to room temperature and continue stirring for 1 hour, then heat to 70°C and react overnight. The reaction solution is slowly poured into saturated sodium bicarbonate solution (60 mL), extracted with ethyl acetate, and the organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (4 g, yellow solid).

[0222] Step 3: The solid obtained in the previous step (2.4 g, 8.8 mmol) was slowly added to phosphorus oxychloride (30 mL) in portions. N,N-diisopropylethylamine (4.4 mL) was slowly added dropwise under ice-cold water. After the addition was complete, the temperature was raised to 110°C and the reaction was allowed to proceed overnight. After evaporating most of the phosphorus oxychloride under reduced pressure, the residue was poured into cooled saturated aqueous sodium bicarbonate solution (60 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried in petroleum ether and filtered to obtain 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.5 g). 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H).

[0223] Intermediate A5: 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyridin[4,3-d]pyrimidin-4(3H)-one

[0224]

[0225] Step 1: Dissolve 4-amino-2,6-dichloro-5-fluoronicotinic acid (15 g, 66.7 mmol) in thionyl chloride (50 mL). Stir the reaction mixture at 60°C until the reaction is complete. Concentrate the reaction mixture under reduced pressure to remove the solvent to obtain the title compound, which is used directly in the next step without purification.

[0226] Step 2: Dissolve the compound obtained in the previous step in 80 mL of anhydrous acetone. Slowly add dropwise a solution of 15 g of ammonium thiocyanate dissolved in 80 mL of anhydrous acetone. After the addition is complete, the reaction mixture is reacted at 50°C for approximately 1 hour. Pour the reaction mixture into 400 mL of water and stir for 10 minutes. The precipitated solid is filtered, washed with water, and dried to obtain the desired product (15 g, yellow solid).

[0227] Step 3: Dissolve the solid obtained in methanol (120 mL), and add iodomethane (12.7 g, 894 mmol) and 1 M aqueous sodium hydroxide solution (100 mL) sequentially. The mixture is reacted at room temperature for 3 hours, then poured into 400 mL of water. The pH is adjusted to ~6 with dilute hydrochloric acid to precipitate a solid, which is filtered. The filter cake is washed with water and dried to obtain the title compound (15 g, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ13.31 (s, 1H), 2.59 (s, 3H).

[0228] Step 4: After adding methanol (2 mL) and anhydrous tetrahydrofuran (100 mL) to a 250 mL reaction flask, the mixture was cooled in an ice-water bath and then slowly added in portions with sodium hydride (2.9 g). After stirring for 10 minutes, the solid obtained in the previous step (4 g) was added in portions. The mixture was naturally warmed to room temperature and stirred for 15 minutes, indicating that the reaction was complete. After cooling the reaction solution in an ice-water bath, a saturated aqueous ammonium chloride solution (100 mL) was slowly added dropwise to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain the target compound (4 g). LC-MS [M+H] + :m / z 276.0.

[0229] Intermediate A6: 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-deuterium-4-ol

[0230]

[0231] Step 1: Dissolve 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (2.8 g, 10 mmol) in anhydrous DMF (30 mL), then add cesium carbonate powder (3.9 g, 12 mmol). Cool in an ice-water bath and add methoxymethyl chloride (960 mg, 12 mmol) dropwise to the reaction mixture. After the addition is complete, continue stirring at room temperature for 3 hours. After quenching the reaction mixture with water, extract with ethyl acetate (100 mL x 3), separate the organic phase, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography to obtain the title compound (2.2 g, yellow solid). LC-MS [M+H] + :m / z 324.2 / 326.2.

[0232] Step 2: Dissolve the compound obtained in the previous step (2.0g, 6.2mmol) in anhydrous tetrahydrofuran solution (200mL), cool to -20 degrees Celsius, and slowly add 1M isopropylmagnesium bromide in tetrahydrofuran solution (75mL, 7.5mmol). After the addition is complete, the reaction mixture is stirred for 2 hours at -20 degrees Celsius. Then, heavy water (0.5g) is slowly added to the reaction solution. After the addition is complete, the reaction mixture is warmed to room temperature and stirred for 16 hours. After the reaction is complete, the reaction mixture is extracted with ethyl acetate (300mLx2), the separated organic phase is concentrated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography to obtain the target compound (0.97g, yellow solid). LC-MS[M+H] + :m / z 291.0.

[0233] Step 3: Dissolve the compound obtained in the previous step (0.9 g, 3.1 mmol) in dichloromethane (30 mL) and add trifluoroacetic acid (30 mL) under ice-water cooling. The reaction mixture is stirred at room temperature for 6 hours. After the reaction is complete as determined by LC-MS, saturated sodium carbonate solution is added dropwise under ice-water cooling to quench the reaction. The mixture is extracted twice with ethyl acetate (100 mL), and the combined organic phases are concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography to obtain the title compound (0.46 g, yellow solid). LC-MS [M+H] + :m / z247.1.

[0234] Intermediate A7: 7-chloro-8-fluoro-5-(methoxy-d3)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0235]

[0236] Intermediate A7 was prepared by referring to step 4 of intermediate A5. LC-MS [M+H] + :m / z 279.2.

[0237] Intermediate B1: 1-((1-(hydroxymethyl)cyclopropyl)methyl)-4-methyl-1,4-azophosphorane-4-oxide

[0238]

[0239] Step 1: Under nitrogen, cool a solution of methylphosphoryl dichloride (3.97 g, 30.1 mmol) in tetrahydrofuran (50 mL) to -78°C, then slowly add vinylmagnesium bromide (2 M, 35 mL, 70 mmol). Continue stirring at this temperature for one hour, then add ethanol (10 mL), and heat and stir overnight. The reaction mixture is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (eluent: dichloromethane / ethanol = 30 / 1) to afford the intermediate compound (3.1 g) as a white oil. 1 H NMR (400 MHz, DMSO-d6): δ

[0240] 6.07-6.38(m,6H),1.61(d,J=7.2Hz,3H).

[0241] Step 2: Under nitrogen, benzylamine (733 mg, 6.85 mmol) was added to a solution of the intermediate compound (0.8 g, 6.85 mmol) in ethanol (30 mL). The reaction mixture was heated to 100°C overnight. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane / ethanol = 25 / 1) to obtain the intermediate compound (750 mg) as a white oil. LC-MS [M+H] +:m / z 224.1. 1 H 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).

[0242] Step 3: Under nitrogen, add 1-chloroethyl chloroformate (572 mg, 4.03 mmol) to a solution of the intermediate compound (750 mg, 3.36 mmol) in dichloroethane (10 mL). Heat the reaction mixture to 100°C and stir overnight. Concentrate the reaction mixture under reduced pressure, dry the crude product, and slurry it with petroleum ether. The filtered solid is dried to yield 4-methyl-1,4-azophosphorane 4-oxide hydrochloride (380 mg). LC-MS [M+H] + :m / z 134.1.

[0243] Step 4: Under nitrogen protection, imidazole (7.5g, 110.2mmol) and tert-butyldiphenylsilyl chloride (13.8g, 50.1mmol) were added to cyclohexane-1,1-dimethanol (5.11g, 50.1mmol) in dichloroethane (50mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction solution was washed twice with saturated brine (30mL), 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain a white solid intermediate product (12.6g). LC-MS [M+H] + :m / z 341.2.

[0244] Step 5: Under nitrogen protection, to a dichloromethane solution (30 mL) of the above intermediate (3 g, 8.8 mmol) was 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. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution. 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 obtain a crude oily intermediate product (2.6 g). LC-MS [M+H] + :m / z 419.2.

[0245] Step 6: Under nitrogen protection, to a solution of the above intermediate (910 mg, 2.2 mmol) in N,N-dimethylformamide (10 mL), 4-methyl-1,4-azophosphane 4-oxide hydrochloride (380 mg, 2.2 mmol) and potassium carbonate (695 mg, 5.0 mmol) were added. The reaction mixture was stirred at 50 degrees overnight. After adding water (50 mL) to the reaction solution, it was extracted twice with ethyl acetate (50 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to obtain a white solid intermediate (150 mg). LC-MS [M+H] + :m / z 456.2.

[0246] Step 7: To a methanol solution (10 mL) of the above intermediate (150 mg, 0.33 mmol), add ammonium fluoride (40 mg, 1.1 mmol). The reaction mixture was stirred at 60°C for 3 hours. TLC confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain a white solid (43 mg). LC-MS [M+H] + :m / z 218.2. 1 H 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).

[0247] Intermediate B2: (1-(selenomorpholinomethyl)cyclopropyl)methanol

[0248]

[0249] Step 1: At -10°C under nitrogen, slowly add sodium borohydride (1.9 g, 50.3 mmol) to a suspension of selenium powder (3.95 g, 49.4 mmol) in anhydrous ethanol (30 mL). After the reaction mixture becomes clear, add sodium hydroxide (2.1 g, 52.5 mmol) in portions and continue stirring for 30 minutes. Slowly add a solution of bis(2-chloroethyl)amine (7.08 g, 50.2 mmol) in ethanol (5 mL) to the reaction mixture, and heat the reaction mixture under reflux for 6 hours. After cooling to room temperature, filter the reaction mixture and distill under reduced pressure to remove the low-boiling point solvent to obtain the crude intermediate compound (2.5 g) as a colorless oil. LC-MS [M+H] +:m / z 151.1.

[0250] Step 2: Under nitrogen, to a dichloromethane solution of the above intermediate (2.5 g, 16.5 mmol) was added 1-(chlorocarbonyl)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 mixture was concentrated under reduced pressure, and the 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.

[0251] Step 3: Under nitrogen protection, a tetrahydrofuran solution (50 mL) of the above intermediate (3.6 g, 12.4 mmol) was cooled to -70 degrees Celsius, and lithium aluminum hydride (1.41 g, 37.3 mmol) was added to the reaction solution in batches. The reaction mixture was stirred at this temperature for 30 minutes, then slowly warmed to room temperature and stirred overnight. LC-MS detection showed that the reaction was essentially complete. After cooling the reaction solution to zero degrees Celsius, ethyl acetate (20 mL) was added to the reaction solution, slowly warmed to room temperature and continued stirring for half an hour. Water (1.4 g) was then slowly added to the reaction solution, followed by sodium hydroxide (0.14 g) and water (4.2 g). The reaction mixture was stirred for several minutes and then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to obtain a colorless oily compound (2.1 g, colorless oil). LC-MS [M+H] + :m / z 236.0. 1 H NMR (400MHz, DMSO): δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.5 7(m,2H),2.32(s,2H),1.53-1.44(m,4H),0.48-0.43(m,2H),0.28-0.24(m,2H).

[0252] Intermediate B3: 4-((1-(hydroxymethyl)cyclopropyl)methyl)-1-(methylimino)-1λ 6 -Thiomorpholine-1-oxide

[0253]

[0254] Step 1: Under nitrogen protection, to a solution of tert-butyl 1-iminothiomorpholine-4-carboxylate-1-oxide (3.7 g, 15.8 mmol) in tetrahydrofuran (50 mL) was added potassium carbonate (4.45 g, 32.2 mmol) and iodomethane (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 resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid intermediate compound (3.1 g). LC-MS [M+H] + :m / z 249.1.

[0255] Step 2: 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 mixture was concentrated under reduced pressure to obtain a crude white solid compound (2.3 g). LC-MS [M+H] + :m / z 149.0.

[0256] Step 3: Referring to the sixth step of the preparation method of intermediate B1, the above intermediate was used instead of 4-methyl-1,4-azophosphoranil 4-oxide hydrochloride to synthesize a white solid compound (1.6 g). LC-MS [M+H] + :m / z 471.1.

[0257] Step 4: Referring to the seventh step of the preparation method of intermediate B1, the above intermediate was used to remove the protecting group to obtain a white solid compound (450 mg). LC-MS [M+H] + :m / z 471.1. 1 H NMR (400MHz, DMSO): δ4.43(br.s,1H),3.36(s,2H),2.93-2.83(m,2H),2.65-2.5 5(m,5H),2.36(s,2H),1.81-1.67(m,4H),0.43-0.40(m,2H),0.23-0.21(m,2H).

[0258] Intermediate B4: N-4-((1-(hydroxymethyl)cyclopropyl)methyl)-1-oxide-1λ 6 -thiomorpholin-1-ylidene)aminonitrile

[0259]

[0260] Step 1: To a solution of benzyl thiomorpholine-4-carboxylate (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 mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to afford the intermediate compound (1.1 g) as a yellow solid. LC-MS [M+H] + :m / z278.1.

[0261] Step 2: To a solution (10 mL) of the intermediate compound (1.1 g, 4.0 mmol) in ethanol, add m-chloroperbenzoic 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 adding 50 mL of water to the reaction solution, the reaction solution 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain a white solid compound (470 mg). LC-MS [M+H] + :m / z 294.0.

[0262] Step 3: To a solution of the intermediate compound (470 mg, 1.6 mmol) in ethanol (5 mL) was added 5% palladium on carbon (55 mg, 0.5 mmol). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere (1 atm). The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a white solid compound (120 mg). LC-MS [M+H] + :m / z 160.0.

[0263] Step 4: Referring to the sixth step preparation method of intermediate B1, the above intermediate was used instead of 4-methyl-1,4-azaphosphane 4-oxide hydrochloride to synthesize a white solid compound (150 mg). LC-MS [M+H] + :m / z 482.2.

[0264] Step 5: Referring to the seventh step of the preparation method of intermediate B1, the above intermediate was used to remove the protecting group to obtain a white solid compound (40 mg). 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),2.68-2.5 5(m,2H),2.32(s,2H),1.83-1.65(m,4H),0.45-0.40(m,2H),0.26-0.22(m,2H).

[0265] Intermediate B5: (1-(4,4-dimethyl-1,4-azasilan-1-yl)methyl)cyclopropyl)methanol

[0266]

[0267] Refer to the synthesis method of intermediate B2 to obtain a colorless oily compound. LC-MS [M+H] + :m / z 214.2. 1 HNMR (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).

[0268] Referring to the synthetic routes and methods similar to those of B1-B5 above, the following intermediates were prepared;

[0269]

[0270] Example Preparation

[0271] Example 1: 7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)quinoline-3-cyano

[0272]

[0273] Step 1: Dissolve 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-cyano (298 mg, 0.84 mmol) in dichloromethane (DCM) (15 mL), then add 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) and stir at room temperature overnight. The reaction mixture was dried and the residue was purified by flash column chromatography to obtain a yellow solid product (265 mg). ESI-MS m / z: 573.1 / 575.1 [M+H] + .

[0274] Step 2: Sodium hydride (NaH) (20 mg, 0.50 mmol) was dissolved in tetrahydrofuran (THF) (10 mL), cooled to zero degrees Celsius, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (80 mg, 0.50 mmol) was added. After stirring for half an hour, the solid from the previous step (238 mg, 0.417 mmol) was added. The mixture was stirred at room temperature for 2 hours, and quenched with saturated aqueous ammonium chloride (NH4Cl) (50 mL). The mixture was then extracted three times with ethyl acetate (50 mL). The combined organic phases were dried, and the residue after concentration under reduced pressure was purified by silica gel column chromatography (eluent: DCM / MeOH = 30:1 volume ratio) to obtain a yellow solid product (260 mg). LC-MS [M+H] + :m / z 696.0 / 698.1.

[0275] Step 3: To a solution of the above solid (111 mg, 0.16 mmol) in 1,4-dioxane / water (12 mL / 4 mL) was added 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide borate (51 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol), and sodium carbonate powder (Na2CO3) (56 mg, 0.53 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under argon. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to yield the product as a yellow solid (95 mg). LC-MS m / z: 808.3 [M+H] + .

[0276] Step 4: Trifluoroacetic acid (3 mL) was added to a solution of the solid obtained in the previous step (89 mg, 0.11 mmol) in dichloromethane (DCM) (6 mL) under ice cooling. The reaction mixture was warmed to room temperature and stirred for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative purification (chiral column: Unichiral CMD-5H, 20 mm ID x 250 mm L; mobile phase (volume ratio): 60% n-hexane / 40% ethanol / 0.1% diethylamine; flow rate: 25 mL / min) to afford 1-a (23 mg, light yellow solid, retention time 6.59 min) and 1-b (21 mg, light yellow solid, retention time 11.26 min).

[0277] Compound 1-a: 1 H-NMR (400MHz, DMSO-d6): δ8.23(s,1H),8.11(s,1H),7.85(s,1H),7.26(dd,J=8.4,5.2 Hz,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] + .

[0278] Compound 1-b: 1 H-NMR (400MHz, DMSO-d6): δ8.21(s,1H),8.10(s,1H),7.84(s,1H),7.26(dd,J=8.4,5.2H z,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] + .

[0279] Example 2: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-cyanoacetate

[0280]

[0281] Step 1: Dissolve 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) in DCM (200 mL). Then add tert-butyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.86 g, 27.6 mmol) and stir at room temperature for 2 hours. After the reaction is complete, add 100 mL of water and 500 mL of DCM and continue stirring for 10 minutes. Let stand and separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by flash chromatography (mobile phase: 0-40% by volume ethyl acetate / petroleum ether) to obtain the title compound (9.8 g, off-white solid). LC-MS: [M+H] + =549.2 / 551.1.

[0282] Step 2: The solid obtained in the previous step (5 g, 9.1 mmol) was dissolved in anhydrous DMF (50 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (2.8 g, 18.2 mmol) and cesium carbonate (8.9 g, 27.3 mmol) were added sequentially. Under nitrogen protection, the reaction solution was reacted at 140°C for 2 hours, the reaction was stopped, and the reaction was cooled to room temperature. 300 mL of water was added to dilute the reaction solution, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain the target compound (pale yellow solid, 2.4 g). LC-MS: [M+H] + =672.1 / 674.1.

[0283] Step 3: Under nitrogen, the yellow solid compound from the previous step (2.28 g, 3.4 mmol) was dissolved in 50 mL of anhydrous toluene. 2-Amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (1.5 g, 4.7 mmol), Pd(DPEPhos)Cl2 (720 mg, 1 mmol), and anhydrous cesium carbonate (2.73 g, 8.4 mmol) were added sequentially. Under nitrogen, the reaction mixture was incubated at 105°C for 6 hours, then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 1:2) to yield the title compound (yellow solid, 920 mg). LC-MS: [M+H]+ = 784.1.

[0284] Step 4: Under ice-cooling, the yellow solid from the previous step (783 mg, 1 mmol) was dissolved in 30 mL of a mixture of trifluoroacetic acid (TFA) and dichloromethane (v / v, 1 / 1). Under nitrogen, the reaction mixture was allowed to react at room temperature for 1 hour. The reaction was terminated by slowly adding saturated sodium bicarbonate solution dropwise to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by preparative separation (chiral column: Unichiral CMD-5H, 20 mm ID x 250 mmL; mobile phase (volume ratio): 60% n-hexane / 40% ethanol / 0.1% diethylamine; flow rate: 25 mL / min) to afford the target compounds 2-a (76 mg, light yellow solid, 7.15 min) and 2-b (81 mg, light yellow solid, 10.83 min).

[0285] 2-a: 1 H-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),3.6 7-3.51(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.

[0286] 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),2.86-2.7 8(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.

[0287] Example 3: 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-cyano

[0288]

[0289] Step 1: Dissolve 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) in anhydrous dichloromethane (10 mL). Slowly add DIEA (0.72 mL, 4.35 mmol) dropwise under nitrogen in an ice-water bath. Continue the reaction for 1 hour. The reaction mixture is diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phase is washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is isolated by flash silica gel column chromatography to yield the title compound (320 mg, light yellow solid). ESI-MS: 472.1 [M+1]. + .

[0290] Step 2: The solid obtained in the previous step (300 mg, 0.64 mmol) and ((2R7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a-ylmethanol (102 mg, 0.64 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL). The mixture was cooled in an ice-water bath and sodium tert-butoxide (150 mg, 1.56 mmol) was slowly added under nitrogen. The reaction mixture was maintained at 0°C for 1 hour. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the title compound (152 mg, light yellow solid). ESI-MS: 595.1 [M+1].

[0291] Step 3: The above solid (95 mg, 0.16 mmol) was dissolved in 1,4-dioxane / water (12 mL / 4 mL) at room temperature. 2-Amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (51 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol), and sodium carbonate powder (Na2CO3) (56 mg, 0.53 mmol) were added sequentially under nitrogen. The reaction mixture was stirred at 100°C overnight under nitrogen. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to yield the title compound (yellow solid, 95 mg). LC-MS m / z: 751.3 [M+H] + .

[0292] Step 4: Dissolve the solid obtained in the previous step (82 mg, 0.11 mmol) in dichloromethane (DCM) (6 mL) under ice-cooling. Add trifluoroacetic acid (3 mL) dropwise under ice-cooling. After the addition is complete, warm the reaction mixture to room temperature and stir for 4 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by HPLC to yield the title compound (pale yellow solid, 47 mg). 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).

[0293] The same method as in Example 3 was used to prepare and synthesize the following compounds:

[0294]

[0295]

[0296] Example 14: 7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,6-naphthyridine-3-cyano

[0297]

[0298] Step 1: Dissolve 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-cyanide (215 mg, 0.79 mmol) in anhydrous dichloromethane (10 mL). Slowly add DIEA (0.72 mL, 4.35 mmol) dropwise under nitrogen in an ice-water bath. Continue the reaction for 1 hour. The reaction mixture is diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phase is washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is isolated by flash silica gel column chromatography to yield the title compound (176 mg, light yellow solid). ESI-MS: 496.1 [M+1]. + .

[0299] Step 2: The solid obtained in the previous step (150 mg, 0.32 mmol) and ((2R7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a-ylmethanol (50 mg, 0.32 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL). The mixture was 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°C for 1 hour. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the title compound (72 mg, light yellow solid). ESI-MS: 619.2 [M+1].

[0300] Step 3: The above solid (62 mg, 0.1 mmol) was dissolved in 1,4-dioxane / water (12 mL / 4 mL) at room temperature. 2-Amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (51 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol), and sodium carbonate powder (Na2CO3) (56 mg, 0.53 mmol) were added sequentially under nitrogen. The reaction mixture was stirred at 100°C overnight under nitrogen. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to yield the title compound (yellow solid, 50 mg). LC-MS m / z: 775.3 [M+H] + .

[0301] Step 4: Dissolve the solid obtained in the previous step (46 mg, 0.06 mmol) in dichloromethane (DCM) (6 mL) under ice-cooling. Add trifluoroacetic acid (3 mL) dropwise under ice-cooling. After the addition is complete, warm the reaction mixture to room temperature and stir for 4 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by HPLC to yield the title compound (pale yellow solid, 27 mg). 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).

[0302] Example 15: 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-5-methoxy-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-cyano

[0303]

[0304] Step 1: 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 tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-ate (590 mg, 2.3 mmol) in DMF (6 mL) was added DBU (1.5 mL) and PyBOP (1.6 g, 3.1 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 30 minutes. After LC-MS indicated completion of the reaction, saturated brine (30 mL) and ethyl acetate (EA) (30 mL) were added to the reaction mixture. The organic phase was separated, washed three times with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0%-15%) to obtain the title compound (420 mg, yellow solid). ESIMS m / z: 514.3 [M+H].

[0305] Step 2: The solid obtained in the previous step (260 mg, 0.5 mmol) was dissolved in DCM (5 mL). mCPBA (198 mg, 1.2 mmol) was added portionwise under ice-water cooling, and the mixture was stirred at room temperature overnight. After the reaction was complete, DCM (20 mL) and saturated NaHCO₃ solution (20 mL) were added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted with DCM (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 0%-30%) to obtain the title compound (148 mg). ESI-MS m / z: 546.1 [M+H].

[0306] Step 3: The solid obtained in the previous step (140 mg, 0.26 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (62 mg, 0.39 mmol) were dissolved in anhydrous THF (10 mL). The mixture was cooled in an ice-water bath. Under nitrogen, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.31 mL, 0.31 mmol) was added. After stirring for 1 hour, saturated brine was slowly added dropwise to the reaction mixture to quench the reaction. Ethyl acetate (50 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the title compound (84 mg, yellow solid). ESI-MS m / z: 625.2 [M+H].

[0307] Step 4: To a 50 mL sealed tube, the above solid (80 mg, 0.13 mmol), 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (50 mg, 0.16 mmol), K2CO3 powder (54 mg, 0.39 mmol), Pd(dppf)Cl2.DCM (15 mg, 0.02 mmol), and 10 mL of dioxane / 3 mL of water were added. The atmosphere was purged with nitrogen for 10 minutes and the mixture was sealed and reacted at 130°C for 60 minutes. After completion of the reaction, the mixture was cooled to room temperature and EA (20 mL x 3) was added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA / PE = 0%-30%) to obtain the title compound (40 mg, yellow solid). ESI-MS m / z:781.2[M+H].

[0308] Step 5: The solid obtained in the previous step (39 mg, 0.05 mmol) was dissolved in dichloromethane (DCM) (6 mL). Trifluoroacetic acid (3 mL) was added dropwise under ice-cooling. After the addition was complete, the reaction solution 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 obtain the title compound (pale yellow solid, 17 mg). ESI-MS m / z: 681.2 [M+H]. 1 H-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).

[0309] The same method as in Example 15 was used to prepare and synthesize the following compounds:

[0310]

[0311]

[0312] Example 24: 2-amino-4-(6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-cyano

[0313]

[0314] Step 1: To a solution of 7-bromo-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (722 mg, 2.2 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-ate (590 mg, 2.3 mmol) in DMF (6 mL) was added DBU (1.5 mL) and PyBOP (1.6 g, 3.1 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 30 minutes. After LC-MS indicated completion of the reaction, saturated brine (30 mL) and ethyl acetate (EA) (30 mL) were added to the reaction mixture. The organic phase was separated, washed three times with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0%-15%) to obtain the title compound (448 mg, yellow solid). ESIMS m / z: 567.3 / 569.2 [M+H].

[0315] Step 2: The solid obtained in the previous step (362 mg, 0.64 mmol) and ((2R7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a-ylmethanol (102 mg, 0.64 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL). The mixture was cooled in an ice-water bath. Under nitrogen, sodium tert-butoxide (150 mg, 1.56 mmol) was slowly added. The reaction was maintained at 0°C for 1 hour. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the title compound (238 mg, light yellow solid). ESIMS: 690.1 / 692.1 [M+1].

[0316] Step 3: Under nitrogen, the yellow solid compound from the previous step (234 mg, 0.34 mmol) was dissolved in 20 mL of anhydrous toluene. 2-Amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (150 mg, 0.47 mmol), Pd(DPEPhos)Cl2 (72 mg, 0.1 mmol), and anhydrous cesium carbonate (273 mg, 0.84 mmol) were added sequentially. Under nitrogen, the reaction mixture was incubated at 105°C for 6 hours, then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 1:2) to yield the title compound (a yellow solid, 164 mg). LC-MS: [M+H] + =802.1.

[0317] Step 4: Under ice-cooling, the yellow solid from the previous step (80 mg, 0.1 mmol) was dissolved in 10 mL of a mixture of trifluoroacetic acid (TFA) and dichloromethane (v / v, 1 / 1). Under nitrogen, the reaction mixture was allowed to react at room temperature for 1 hour. The reaction was terminated by slowly adding saturated sodium bicarbonate solution dropwise to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by preparative separation (chiral column: Unichiral CMD-5H, 20 mm ID x 250 mmL; mobile phase (volume ratio): 60% n-hexane / 40% ethanol / 0.1% diethylamine; flow rate: 25 mL / min) to afford the target compounds 24-a (16 mg, light yellow solid, 8.11 min) and 24-b (21 mg, light yellow solid, 11.96 min).

[0318] 24-a:LC-MS:[M+H] + =702.1. 1 H-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).

[0319] 24-b:LC-MS:[M+H] + =702.1. 1 H-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).

[0320] Example 25: 2-amino-4-(6-chloro-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-cyano

[0321]

[0322] Step 1: Dissolve 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) in 20 mL of anhydrous THF in a 100 mL reaction flask. Add potassium tert-butoxide powder (340 mg, 3.64 mmol) and stir at room temperature for 30 minutes. Under ice-water cooling, slowly add (1-(morpholinomethyl)cyclopropyl)methanol (350 mg, 2.0 mmol) dissolved in 10 mL of anhydrous THF dropwise. Stirring is continued for approximately 1 hour until the reaction is complete. Pour the reaction mixture into 100 mL of ice water, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The residue is purified by column chromatography (petroleum ether:ethyl acetate, volume ratio, 1:1) to yield the title compound (pale yellow solid, 916 mg). LC-MS: [M+H] + =684.1.

[0323] Step 2: Under nitrogen, the solid obtained in the previous step (512 mg, 0.75 mmol), 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-cyanide (324 mg, 1.02 mmol), Pd(DPEPhos)Cl2 (22 mg, 0.03 mmol), cesium carbonate (438 mg, 1.35 mmol), and toluene (15 mL) were placed in a reaction flask and purged with nitrogen for 10 minutes. Under nitrogen, the reaction mixture was incubated at 105°C overnight. After completion of the reaction, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate, volume ratio 1:2) to yield the title compound (yellow solid, 450 mg). LC-MS: [M+H]+ = 796.2.

[0324] Step 3: Under ice cooling, the solid obtained in the previous step (100 mg, 0.125 mmol) was dissolved in 10 mL of a mixture of trifluoroacetic acid and dichloromethane (v / v, 1 / 1). Under nitrogen, the reaction solution was stirred for approximately 2 hours. Upon completion, the reaction was stopped and saturated sodium bicarbonate solution was slowly added dropwise to the system, adjusting the pH to approximately 8. The mixture was extracted three times with ethyl acetate (50 mL x 3) and concentrated under reduced pressure. The residue was separated by column chromatography to yield the title compound (yellow solid, 45 mg). LC-MS: [M+H]+ = 696.2. The above solid was purified by preparative chromatography (chiral column: Unichiral CMD-5H, 20 mm ID x 250 mm L; 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).

[0325] 25-a:LC-MS:[M+H] + =696.1. 1 H-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,2 H),2.17-1.96(m,4H),1.87-1.74(m,4H),1.69-1.62(m,2H),1.37-1.39(m,2H).

[0326] 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,2 H),2.17-1.96(m,4H),1.87-1.74(m,4H),1.69-1.62(m.2H),1.35-1.38(m,2H).

[0327] Example 26: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(selenomorpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0328]

[0329] Step 1: Sodium methanethiolate (1.22 g, 17.37 mmol) was added to a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[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 16 hours. LC-MS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (200 mL) and saturated brine (200 mL). The organic phase was extracted and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, volume ratio 10:1 to 2:1) to yield the title compound (6.3 g, yellow solid). LC-MS (ESI) m / z: 440.1 (M+H) + .

[0330] Step 2: The compound obtained in the previous step (1.3 g, 2.96 mmol) was dissolved in 1,4-dioxane (16 mL), and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.97 g, 3.84 mmol), Pd catalyst (cas: 1651823-59-4) (215.6 mg) was added. , 0.296 mmol) and potassium phosphate tribasic (1.9 g, 8.88 mmol) in water (4 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction was monitored for completion by LC-MS. The reaction solution was extracted with ethyl acetate (200 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio 3:1) to obtain the title compound (1.5 g, white solid). LC-MS (ESI) m / z: 790.4 (M+H) + .

[0331] Step 3: Under ice-water cooling, the compound obtained in the previous step (1.4 g) was dissolved in dichloromethane (50 mL), and 3-chloroperoxybenzoic acid (424 mg, 2.09 mmol) was added. The mixture was stirred at 0°C for 3 hours. The reaction was monitored for completion by LC-MS. The reaction solution was quenched with aqueous sodium thiosulfate solution and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA volume ratio 3:1) to obtain the title compound (1.1 g, yellow solid). LC-MS (ESI) m / z: 806.2 (M+H) + .

[0332] Step 4: Under ice-water cooling, lithium bis(trimethylsilyl)amide (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-(selenomorpholinomethyl)cyclopropyl)methanol (0.2 g, 0.853 mmol) in tetrahydrofuran (20 mL). The reaction mixture was allowed to react at 0°C for 2 hours. LC-MS confirmed the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (100 mL), and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate, volume ratio 1:1) to yield the title compound (0.2 g, pale yellow solid). LC-MS (ESI) m / z: 977.2 (M+H). + .

[0333] Step 5: Cesium fluoride (0.3 g, 2.02 mmol) was added to a solution of the compound obtained in the previous step (197 mg, 0.202 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was allowed to react overnight at room temperature. LC-MS confirmed the reaction was complete. The mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was isolated and purified by column chromatography (petroleum ether / ethyl acetate, volume ratio 2:1) to obtain the title compound (140 mg, light yellow solid). LC-MS (ESI) m / z: 821.1 (M+H) + .

[0334] Step 6: Dissolve the compound obtained in the previous step (140 mg, 0.171 mmol) in acetonitrile (4 mL). Add a 4M HCl / dioxane solution of hydrogen chloride (2 mL, 8 mmol) dropwise at room temperature. Continue the reaction at room temperature for 1 hour. LC-MS analysis confirmed the reaction was complete. The product was concentrated at low temperature to remove a large amount of low-boiling substances. The residue was then directly purified by preparative chromatography (0.1% NH3.H2O) to yield the title compound (41 mg, light yellow solid). LC-MS (ESI) m / z: 677.5 (M+H) + . 1 H 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).

[0335] The same method as Example 26 was used to prepare and synthesize the following example compounds:

[0336]

[0337]

[0338]

[0339] Example 43: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(selenomorpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0340]

[0341] Step 1: At -40 degrees, 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-(selenomorpholinomethyl)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) and N,N-diisopropylethylamine (2.1 g, 16.08 mmol) in dichloromethane (50 mL), and the reaction mixture was reacted at -40 degrees for 2 hours. LC-MS analysis showed the reaction was complete. The product was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 1:1) to obtain the target compound (1.2 g, yellow solid). LC-MS (ESI) m / z: 1109.1 [M+H] + .

[0342] Step 2: Under nitrogen, tris(dibenzylideneacetone)dipalladium (100 mg, 0.14 mmol) was added to a mixture of the compound obtained in the previous step (1.1 g, 1.0 mmol), benzophenone imine (496 mg, 2.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (158 mg, 0.27 mmol), cesium carbonate (1.3 g, 4.11 mmol), and toluene (15 mL). The reaction mixture was allowed to react at 100°C for 16 hours. LC-MS indicated completion of the reaction. The mixture was then 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 concentrated under reduced pressure. The residue was isolated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1, volume ratio) to obtain the title compound (550 mg, yellow solid). LC-MS (ESI) m / z: 1140.1 [M+H] + .

[0343] Step 3: Dissolve the compound obtained in the previous step (100 mg, 0.088 mmol) in dichloromethane (10 mL). Add a 4 M hydrogen chloride / dioxane solution (5 mL) to the reaction mixture at room temperature. Stir the reaction mixture at room temperature for 2 hours. LC-MS analysis indicates the reaction is complete. Remove low-boiling substances under reduced pressure and slurry with diethyl ether to obtain the title compound (50 mg, gray solid). LC-MS (ESI) m / z: 876.1 [M+H] + .

[0344] Step 4: The compound obtained in the previous step (50 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (59 mg, 0.43 mmol) and cesium fluoride (13 mg, 0.26 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, ethyl acetate and water were added to the reaction mixture for extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then slurried with diethyl ether to obtain the target compound (5 mg, white solid). LC-MS (ESI) m / z: 719.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (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 compounds were prepared and synthesized using the same method as in Example 43:

[0345]

[0346]

[0347] Example 62: 6-(8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(selenomorpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0348]

[0349] Step 1: 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. The mixture was stirred at 120°C under nitrogen for 5 hours. LC-MS analysis indicated the reaction was complete. Ethyl acetate and saturated brine were added to the reaction solution. The organic phase was separated, dried, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio 4:1) to obtain the title compound (white solid, 1.8 g). LCMS (ESI) m / z: 456.2 [M+H] + .

[0350] Step 2: methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (565 mg, 0.776 mmol) was added to a solution of the compound obtained in the previous 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 room temperature under nitrogen atmosphere at 110°C for 16 hours. LC-MS analysis indicated the reaction was complete. The reaction solution was filtered through celite, and the solvent was removed under reduced pressure. The product was extracted with ethyl acetate and saturated brine. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio 50:1) to afford the title compound as a pale yellow solid, 1.2 g. LCMS (ESI) m / z: 768.1 [M+H] + . 1 H 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).

[0351] Step 3: Add p-toluenesulfonic acid (23 mg, 0.133 mmol) to a solution of the compound obtained in the previous step (1.2 g, 1.66 mmol) in N,N-dimethylformamide (15 mL). Add N-iodosuccinimide (1.12 g, 4.97 mmol) with stirring, and continue stirring at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1) to obtain the title compound (pale yellow solid, 1.1 g). LCMS (ESI) m / z: 894.2 [M+H] + .

[0352] Step 4: Add cuprous iodide (491 mg, 2.58 mmol) to a solution of the compound obtained in the previous 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 under nitrogen at 90°C for 3 hours. LC-MS analysis indicated the reaction was complete. The reaction solution was filtered through celite, concentrated under reduced pressure, extracted with ethyl acetate, and 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 yield the title compound (pale yellow solid, 280 mg). LCMS (ESI) m / z: 836.3 [M+H] + .

[0353] Step 5: Dissolve the compound obtained in the previous step (284 mg, 0.34 mmol) and (1-(selenomorpholinomethyl)cyclopropyl)methanol (165 mg, 0.68 mmol) in anhydrous tetrahydrofuran (5 mL). Slowly add sodium hydride (41 mg, 2.04 mmol) while cooling in an ice bath. Stir and continue the reaction at 0°C for 2 hours. LC-MS analysis indicates the reaction is complete. The reaction solution is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase is concentrated and the concentrate is purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio = 3:1) to obtain the title compound (pale yellow solid, 205 mg). LCMS (ESI) m / z: 1051.4 [M+H] + .

[0354] Step 6: Trifluoroacetic acid (2 mL) was added dropwise to a solution of the compound obtained in the previous step (201 mg, 0.2 mmol) in dichloromethane (5 mL) at room temperature. The reaction was continued at 50°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The product was concentrated under reduced pressure at low temperature to remove low-boiling substances. The residue was further purified by preparative chromatography (0.1% NH3·H2O) to yield the title compound (white solid, 38 mg). LCMS (ESI) m / z: 711.2 [M+H] + . 1 H-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).

[0355] The same method as Example 62 was used to prepare and synthesize the following example compounds:

[0356]

[0357]

[0358] The following compounds were obtained by similar operations to Example 3 using intermediates A4-A7, B5-B10 and other commercially available raw materials:

[0359]

[0360]

[0361] Example 89: 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(selenomorpholinomethyl)cyclopropyl)methoxy)-1,6-naphthyridine-3-cyano

[0362] The compound of Example 89 (12 mg, white solid) was prepared 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).

[0363] Test Example 1: Cell proliferation inhibition experiment

[0364] Testing method: 1) Expression of KRAS G12D 1) AGS cells (ATCC) were cultured in DMEM supplemented with 10% fetal bovine serum, 10mM HEPES, and penicillin / streptomycin, seeded at a density of 40,000 cells / well in a 96-well plate, and allowed to adhere for 12-14 hours. 2) After the cells adhered, the test compound was added to the 96-well plate at final concentrations of 10,000, 2,000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, and 0 nM (all with a final DMSO concentration of 0.5%). After incubation at 37°C for 96 hours, 50 μL of Cel-titer GLO working solution was added to each well, mixed by vortexing, and incubated at room temperature for 10 minutes. 3) Luminescence values ​​were read on a multi-function microplate reader and converted to percentage inhibition. The percentage of cell proliferation inhibition was calculated according to the following formula: Inhibition percentage = (maximum value - measured value) / (maximum value - blank) x 100 ("maximum value" is from the 0.5% DMSO control well, "blank" is from the blank control well, and "measured value" is from the Example compound-treated well). 4) Curve fitting was performed using GraphPad Prism software to obtain the IC 50 Value. (A represents IC 50 <10nM, B represents 10nM≤IC 50 <100nM, C represents 100nM≤IC 50 <1000nM, D represents IC 50 ≥1000nM)

[0365]

[0366]

[0367] The results showed that the compounds of the present invention have an inhibitory effect on KRASG12D The mutant AGS cells have a strong proliferation inhibitory effect. Under the same test conditions, the cell proliferation inhibitory activity of most of the example compounds is comparable to that of the positive compound MRTX1133 (IC 50 The inhibitory activity of most of the compounds in the examples was IC 50 The inhibitory activity of some examples is even close to 1 nM, such as Examples 3, 8, 15, 22, 27, 32, 39, 45, 58, 60 and 71;

[0368] Test Example 2: Compounds for KRas G12D Effect of ERK-mediated phosphorylation capacity

[0369] Testing method: 1) Expression of KRAS G12D AGS cells (ATCC) were cultured in DMEM supplemented with 10% fetal bovine serum, 10 mM HEPES, and penicillin / streptomycin, seeded at a density of 40,000 cells / well in 96-well plates, and allowed to adhere for 12-14 hours. 2) A solution of the example compound was added at a final concentration of 0.5% DMSO. After 3 hours, the medium was removed, 150 μL of 4.0% formaldehyde was added, and the plate was incubated at room temperature for 20 minutes. 3) The plate was washed with PBS and permeabilized with 150 μL of ice-cold methanol for 10 minutes. 4) Nonspecific antibody binding to the plate was blocked using 100 μL of blocking buffer at room temperature for 1 hour. ERK phosphorylation was detected using a p-ERK-specific antibody, with GAPDH as an internal standard. Primary antibody information and experimental conditions are 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. Incubate with antibodies for 2 hours at room temperature, then wash with PBS + 0.05% Tween 20. Secondary antibodies used to visualize the primary antibodies are as follows: anti-rabbit-680 diluted 1:1000 in blocking buffer + 0.05% Tween 20, and anti-mouse-800 diluted 1:1000 in blocking buffer + 0.05% Tween 20, and incubate for 1 hour at room temperature. 5) Wash the plate with PBS + 0.05% Tween 20, add 100 μL of PBS to each well, and read the plate. 6) The phosphorylated ERK (Thr202 / Tyr204) signal in each well was normalized with the GAPDH signal and calculated as the percentage of the DMSO control value. IC was calculated by four-parameter dose-response curve fitting. 50 value.

[0370] Results: Most of the compounds provided in the present invention have a significant inhibitory effect on the phosphorylated ERK level in AGS cells, and the inhibitory activity IC 50 Less than 500 nM, some of the example compounds are less than 100 nM, such as 3, 4, 15, 19, 22, 26, 27, 32, 37, 62, 65, 71, etc.

[0371] Test Example 3: Test of the Inhibitory Activity of Example Compounds on BaF3-KRAS-G12D Cell Proliferation

[0372] This experiment uses the CellTiter-Glo (CTG) kit provided by Promega, which is a homogenized cell viability assay that measures the cell viability of cultured cells by quantifying ATP. 1. Experimental reagents and 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. Experimental instruments and equipment: CO2 incubator (Thermo Scientific, Model 3100 Series), microscope (OLYMPUS, CKX41SF), multifunctional microplate reader (BMG, Plus) in a biosafety cabinet (Thermo, Model 1300 Series A2). 3. Cell proliferation assay: All cell lines were cultured in complete medium at 37°C, 5% CO2. Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed by trypan blue exclusion to ensure viability was above 90%. Cell density was adjusted with complete medium and then seeded into 96-well cell culture plates, with 90 μL per well for a total of 3,000 cells. The cells in the 96-well plates were incubated at 37°C, 5% CO2. A 10x drug solution was prepared, and 10 μL of each serially diluted compound was transferred to the corresponding experimental wells of the 96-well plate. Compounds were tested starting at a 10 μM concentration and then diluted 3-fold over nine concentrations, with triplicate wells for each drug concentration. The cells in the drug-treated 96-well plate were incubated at 37°C, 5% CO2 for 72 hours before CTG analysis. The CTG reagent was thawed and the plate was equilibrated to room temperature for 30 minutes. Add an equal volume of CTG solution to each well. Shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the cold light signal. Use Luminescence Read Mode to read the cold light value (Luminescence) and collect data. 4. Data analysis: Use GraphPad Prism 7.0 software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-effect curve, and thus calculate the IC50 value. Cell viability (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%.

[0373] Results: Most of the compounds provided in the present invention have a significant inhibitory effect on the proliferation of BaF3-KRAS-G12D cells. The inhibitory activity IC 50 The activity of the compounds in the examples is less than 500 nM, and most of the compounds in the examples are less than 100 nM, and some of the compounds in the examples are even less than 10 nM or even close to 1 nM, which is significantly better than the activity of the positive compound MRTX1133 (IC 50 About 10 nM), such as Examples 3, 4, 15, 19, 22, 26, 27, 32, 37, 62, 65, 71, etc.

[0374] Test Example 4: Pharmacokinetics of Compounds in Mice

[0375] Test Methods: 1) Weigh the compound and add it to a 20% HP-B-CD solution in 50 mM pH 4.7 Acetate buffer, shake well, and sonicate to obtain a clear solution. Three ICR male mice were fasted overnight and administered via tail vein injection at a dose of 2 mg / kg. 2) Weigh the compound and add it to a 0.5% CMC + 1% Tween 80 solution, shake well, and sonicate to obtain a suspension. Three ICR male mice were fasted overnight and administered orally via gavage at a dose of 10 mg / kg. 3) Sample Collection: Blood was collected retro-orbitally and anticoagulated with sodium heparin. After collection, the blood was placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). 40 μL of plasma sample was added to 160 μL of cold acetonitrile containing an internal standard, vortexed for 1 minute, and centrifuged at 18,000 rpm for 10 minutes. The supernatant was transferred to a 96-well plate and 5 μL was injected for analysis. 4) Drug concentration was analyzed by LC-MS / MS and pharmacokinetic parameters were calculated using Phoenix WinNolin software.

[0376] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

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, in, R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, amino, hydroxyl, -SH, C 6-10 Aryl, 5-10 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 0 Replacement, R 0 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-8 Alkyl-SF5 is substituted by a substituent; the R 0 optionally further substituted with one or more groups independently selected from deuterium or halogen; R 1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, amino, hydroxyl, -SH, C 6-10 Aryl, 5-10 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 11 Replacement, R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5 is substituted by a substituent; the R 11 optionally further substituted with one or more groups independently selected from deuterium or halogen; R 2 Selected from the following substituted or unsubstituted groups: 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, fused or fused ring; the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 21 Replace, each R 21 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-OC(O)-NH2, -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 atoms or heteroatoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl group (preferably a 3-6 membered cycloalkyl group); 21 One or more hydrogen atoms (preferably 1, 2 or 3) on the group are independently optionally replaced by R 211 Replacement, R 211 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 alkoxy; R 4 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, 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-NH2, -C 0-6 Alkyl-(CO)-NH2, -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, amino, hydroxy, -SH; the "substituted" refers to one or more (1, 2, 3 or 4) R 41 Replacement, R 41 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 41 Optionally further represented by one or more (preferably 1, 2 or 3) R 411 Substituted, the R 411 independently selected from deuterium or halogen; R 5a 、R 5b 、R 5c and R 5d Each is 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 heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R 51 Replacement, R 51 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 51 Optionally further represented by one or more (preferably 1, 2 or 3) R 511 Substituted, the R 511 independently selected from deuterium or halogen; R 6a 、R 6b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl-C 1-6 Alkyl-, 3-12 membered heterocyclic-C 1-6 Alkyl-, C 1-8 Alkoxy, -C 1-8 Alkyl-OH, -C 1-8 Alkyl-SH, -C 1-8 Alkyl-NH2, -C 1-8 Alkyl-OC 1-6 Alkyl-, -C 0-6 Alkyl-(CO)-NH2, -C 0-6 Alkyl-(CO)-C 0-6 Alkyl, -C 0-6 Alkyl-(CO)-OC 0-6 Alkyl, -C 0-6 Alkyl-P(O)(C 0-6 Alkyl)2, amino, hydroxyl, -SH, C 0-4 Alkyl-S(O)-, C 0-4 Alkyl-S(O)2-, C 0-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 Replacement, R 61 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 61 Optionally further represented by one or more (preferably 1, 2 or 3) R 611 Substituted, the R 611 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 groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R Y1 Replacement, R Y1 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R Y1 Optionally further represented by one or more (preferably 1, 2 or 3) R Y11 Substituted, the R Y11 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 R L2 , O, S, S(O), S(O)2 or NR L1 R L2 , where each R L1 and R L2 are independently selected from hydrogen, deuterium, substituted or unsubstituted hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, or R L1 and R L2 Together with the atoms directly connected thereto, they form a 3-6 membered cycloalkyl or heterocycloalkyl group; the "substituted" refers to one or more (1, 2, 3 or 4) R L11 Replacement, R L11 independently selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl; Z and M are independently selected from N, CR Z1 ; Each R Z1 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the above "substituted" refers to one or more (1, 2 or 3) R Z11 Replacement, R Z11 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 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 replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace; Each R 3 Each is independently selected from cyano, amino, halogen, deuterium, substituted or unsubstituted groups: amino, hydroxyl, -SH, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, C 3-12 Cycloalkyl-C 1-6 Alkyl-, 3-12 membered heterocyclic-C 1-6 Alkyl-, C 1-8 Alkoxy, -C 1-8 Alkyl-OH, -C 1-8 Alkyl-NH2, -C 0-6 Alkyl-(CO)-NH2, -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 one or more (1, 2, 3 or 4) R 31 Replacement, R 31 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 31 Optionally further represented by one or more (preferably 1, 2 or 3) R 311 Substituted, the R 311 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 represented by the 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 meets one or more of the following conditions: (1) R is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, amino group, hydroxyl group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-6 Alkyl-(CO)-OC 1-6 Alkyl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 0 replace; (2)R 0 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5; the R 0 optionally further substituted with one or more groups independently selected from deuterium or halogen; (3)R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, amino, hydroxyl, -SH, C 6-8 Aryl, 5-8 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 11 replace; (4)R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5; the R 11 optionally further substituted with 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 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C 1-4 Alkyl, C 1-4 alkoxy; (7)R Z11 independently selected from deuterium, 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 term "substituted" means that Ar is replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace; (9) Each R 3 independently selected from cyano, halogen, deuterium, substituted or unsubstituted amino, hydroxyl, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, -C 0-6 Alkyl-SF5, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocyclic-C 1-3 Alkyl-, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH2, -C 0-6 Alkyl-(CO)-NH2, -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 one or more (1, 2, 3 or 4) R 31 Substituted; the "substituted" refers to one or more (1, 2, 3 or 4) R 31 replace; (10)R 2 Selected from the following substituted or unsubstituted groups: 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, the ring system includes spiro, bridged, fused or fused rings; the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 21 replace; (11) Each R 21 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, =CH2, -C 0-3 Alkyl-OH, -C 0-4 Alkyl-OC(O)-NH2, -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 atoms or heteroatoms to which they are connected, they form a 3-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl group; said R 21 One or more hydrogen atoms (preferably 1, 2 or 3) on the group are independently optionally replaced by R 211 Replacement, R 211 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 alkoxy; (12)R 4 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: amino, hydroxyl, -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 heterocyclic group; the "substituted" refers to one or more (1, 2 or 3) R 41 replace; (13)R 41 are 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; (14)R 5a 、R 5b 、R 5c and R 5d Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxyl, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R 51 replace; (15)R 51 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 51 Optionally further represented by one or more (preferably 1, 2 or 3) R 511 Substituted, the R 511 independently selected from deuterium or halogen; (16)R 6b independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocyclic-C 1-3 Alkyl-, C 1-4 Alkoxy, -C 1-4 Alkyl-OH, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OC 1-3 Alkyl, -C 0-4 Alkyl-(CO)-NH2, -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, hydroxyl, -SH, C 0-4 Alkyl-S(O)-, C 0-4 Alkyl-S(O)2-, C 0-4 Alkyl-S-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 replace; (17)R 61 are independently selected from deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolane, azetidinyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy and cyclobutyloxy; said R 61 Optionally further represented by one or more (preferably 1, 2 or 3) R 611 Substituted, the R 611 are 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 meets 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)R 1 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 replaced by one or more (preferably 1, 2, 3, 4 or 5) R 3 replace; (4)R 3 independently selected from deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the "substituted" refers to one or more (1, 2, 3 or 4) R 31 replace; (5)R 2 Selected from the following structures: Among them, R 7 and R 8 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or R 7 and R 8 The carbon atom directly linked to it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the "substituted" refers to one or more (1, 2 or 3) R 71 Replaced by R 71 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 heterocyclic group, said R 71 Optionally 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 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 independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-NH2, C 0-6 Alkyl-SH, -C 0-6 Alkyl-OC(O)-NH2, -C 0-6 Alkyl-OC(O)-(C 3-8 Heterocycloalkyl), -C 0-6 Alkyl-OC(O)-(C 3-8 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 Substituted, the R 91 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 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: 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 "substituted" refers to one or more (1, 2 or 3) R 41 replace; (9)R 5a 、R 5b 、R 5c and R 5d Each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted following groups: methyl, ethyl, said "substituted" refers to one or more (1, 2, 3 or 4) R 51 replace; (10)R 6b independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy and cyclobutyloxy, oxetanyl-CH2-, cyclopropyl-CH2-, pyrrolyl-CH2-, -(CO)-O-CH3, CH3-O-CH2-, CH3CH2-O-CH2-, CH3-SO2-CH2-, -CH2-NH2, -(CO)-CH3, -CO-NH2, -CH2-SH; the "substituted" refers to one or more (1, 2, 3 or 4) R 61 replace.

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 meets one or more of the following conditions: (1)R 3 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 are 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-, NH2-S(O)-, NH2-S(O)2-, NH2-S-; the R 31 Optionally further represented by one or more (preferably 1, 2 or 3) R 311 Substituted, the R 311 independently selected from deuterium, halogen or C 1-3 alkyl; (3)R 7 and R 8 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, or R 7 and R 8 The carbon atom directly linked to it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the "substituted" refers to one or more (1, 2 or 3) R 71 replaced by; (6) Ring B is a 5-8 membered heterocycloalkyl group; (7)R 9 independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-4 Alkyl-NH2, C 0-4 Alkyl-SH, -C 0-4 Alkyl-OC(O)-NH2, -C 0-4 Alkyl-OC(O)-(C 3-6 Heterocycloalkyl), -C 0-4 Alkyl-OC(O)-(C 3-6 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 replace.

5. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, characterized in that: It meets 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, isopropoxy, cyclopropyloxy, cyclobutyloxy and azetidinyl, or R 7 and R 8 The carbon atoms directly connected thereto form cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy and azetidinyl; the "substituted" refers to one or more (1, 2 or 3) R 71 replaced by; (2) Ring B is selected from the following structures: (3)R 9 independently selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, cyclobutyloxy, azetidinyl, =NH, =CH2, -CH2-OH, -CH2-NH2, -CH2-SH, -CH2-OC(O)-NH2, -CH2-OC(O)-(oxetanyl), -CH2-OC(O)-(cyclopropyl); the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 replace; (4) Ar is selected from the following structures: (5)R 2 Selected from the following structures: (6)R 6b 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 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 meets one or more of the following conditions: (1) Z is N, M is N, R 2 for where 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 for When R 7 、R 8 、R 9 , t, are as defined in claim 3, and wherein R 9 Not halogen; (3) Z is N, M is N, Ar is And R 2 for When R 9 independently selected from deuterium, cyano, nitro, azido, substituted or unsubstituted groups: 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, =CH2, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-NH2, C 0-6 Alkyl-SH, -C 0-6 Alkyl-OC(O)-NH2, -C 0-6 Alkyl-OC(O)-(C 3-8 Heterocycloalkyl), -C 0-6 Alkyl-OC(O)-(C 3-8 cycloalkyl), the "substituted" refers to one or more (preferably 1, 2, 3 or 4) R 91 Substituted, the R 91 independently selected from deuterium, halogen, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy; R 7 、R 8 , t is defined 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 meets one or more of the following conditions: (1) Z is N, M is N, R 1 F, R 4 is H, methyl, methoxy or ethoxy, Ar is When -LR 2 Not for (2) Z is N, M is N, Ar is When R 2 for (3) Z is N, M is N, R 1 F, R 2 for where 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 for where 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 for where 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, torsomer, 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 a 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, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, and pancreatic cancer.

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