Fused ring compound and use thereof in KRAS inhibitor

Abstract

A fused ring compound, a pharmaceutical composition comprising same, and the use thereof. The compound has a structure as represented by formula (I), or is a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a metabolite, a metabolic precursor, an isotope-substituted form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof. The compound can be used for treating one or more cancers caused by KRAS mutation.

Description

A fused ring compound and its application in KRAS inhibitors Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a fused ring compound, a pharmaceutical composition containing the same, and applications thereof. Background Art

[0002] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family, along with two other genes: HRAS and NRAS. These genes share up to 85% homology. KRAS is essentially a monomeric G protein located on both sides of the cell membrane and possesses GTPase activity. The encoded protein consists of 188-189 amino acids with a molecular weight of 21 kDa. KRAS plays a crucial role in regulating signaling pathways in processes such as tumor cell growth and angiogenesis. Normally, it controls pathways that regulate cell growth; when abnormal, it leads to continued cell growth and prevents cell self-destruction. When the KRAS gene mutates, it becomes permanently activated, continuously stimulating cell growth, disrupting intracellular signaling, and causing uncontrolled cell proliferation, leading to cancer.

[0003] KRAS is the most common cancer mutation gene in humans. Approximately 30% of all cancers are associated with the activation of KRAS mutations, including 95% of pancreatic ductal adenocarcinomas (PDAC), 45% of colon and rectal cancers (CRC), and 35% of non-small cell lung cancers (NSCLC). Due to protein structure issues, KRAS was once considered an "undruggable" target in the field of oncology drug development. However, as research deepened, researchers discovered that some specific mutant KRAS proteins form a site that can interact with drugs. After binding to small molecule drugs, they can lock KRAS in the inactive KRAS protein-GDP state, inhibiting the activation of the KRAS pathway and thus initiating anti-tumor effects. In recent years, several KRAS G12C drug candidates have entered the clinic, with Amgen's AMG 510 and Mirati Therapeutics' MRTX 849 making the most progress. The former has been approved by the FDA for marketing. However, the inhibition of these drugs requires an active cysteine ​​residue, making them unsuitable for treating non-G12C mutants (such as G12D, G12V, G12R, G12S, G12A, G13D, etc.), which constitute the majority of KRAS alterations in cancer. Therefore, efforts to find therapeutic options that can inhibit various KRAS mutants continue.

[0004] Currently, there are numerous patents reporting on pan-KRAS inhibitor compounds, such as those publicly reported by KUMQUAT BIOSCOENCES INC. and China Jiakos Pharmaceuticals (WO2022173870) and (WO2023020519), respectively. However, many of the reported pan-KRAS inhibitors suffer from low exposure and low bioavailability. Therefore, the search and development of new and highly effective pan-KRAS inhibitors is of great clinical significance.

[0005] Summary of the Invention

[0006] In view of this, the present application provides a fused ring compound, a pharmaceutical composition comprising the same, and applications thereof. The provided compound can be used to treat one or more cancers caused by KRAS mutations, has good pharmacokinetic properties, can be used to prepare drugs for preventing and / or treating diseases mediated by various KRAS mutants, and has good application prospects.

[0007] The present invention provides a compound as shown in Formula I, its tautomers, meso-racemates, racemates, enantiomers, diastereomers or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals:

[0008] A1 is selected from C or N;

[0009] A2 is selected from S, N or C; A3 is selected from N, O or C; and A2 and A3 are not C at the same time;

[0010] Z, at each occurrence, is independently selected from H or deuterium;

[0011] Ra is selected from H, halogen, C(CH3)=CH- or -CH=CH2, -CF=CH2, -CN, OH, NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aroyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclopentenyl, cyclohexyl, cycloheptyl, methyl, ethyl, propyl, butyl, pentyl, vinyl, propenyl, allyl, butenyl, butylene, pentadienyl, dipentenyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy;

[0012] n1 is an integer selected from 0 to 3, such as 0, 1, 2 or 3;

[0013] Ra2 is selected from -CN, H or none;

[0014] Rb1, Rb2, Rb3 are selected from the group consisting of none, hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, and phosphate, wherein the substituents are independently selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, and phosphate;

[0015] n2 is an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0016] Ring A is a substituted or unsubstituted 4- to 12-membered heterocyclic ring, wherein the heteroatom is N and / or O; and Not the following structure: Among them, Rb 31 , Rb 32 are independently selected from -H, C 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted heteroalkyl, -CO(C 0-10 substituted or unsubstituted alkyl), -(CH2)n 21 CO(C 0-10 Substituted or unsubstituted alkyl), -COO(C 0-10 substituted or unsubstituted alkyl), -COO-(CH2)n 22 -OCO(C 0-10 Substituted or unsubstituted alkyl), -COO-CH(CH3)-OCO(C 0-10 substituted or unsubstituted alkyl), the substituent being selected from deuterium, halogen, hydroxyl, cyano, amino, ester, and amide; n 21 、n 22 are independently selected from integers from 0 to 5, such as 0, 1, 2, 3, 4 or 5; X 3’ is C, N or O;

[0017] Ring B is a substituted or unsubstituted 4- to 12-membered heterocyclic ring, wherein the heteroatom is N;

[0018] Ring C is a substituted or unsubstituted 4- to 12-membered carbocyclic or heterocyclic ring, wherein the heteroatom is N and / or O;

[0019] The ring A, ring B, and ring C are independently selected from a monocyclic ring, a fused ring, a bridged ring, and a spirocyclic ring, and the substituents are selected from -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester group, amide group, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid group, and phosphate group.

[0020] In the present invention, It refers to Ring A; It is Ring B; It refers to ring C.

[0021] Furthermore, ring A is selected from one of the following substituted or unsubstituted structures, in which case n2 is 0:

[0022] X1, X2 are independently selected from N or C; X3 is selected from N, O or C; and only one of X1, X2, and X3 is C; Rb4 and Rb5 are independently selected from each occurrence, H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxyl, cyano, -C(=O)NRb 41 Rb 42 、-(CH2)m 121 C(=O)NRb 41 Rb 42 、-(CH2)m 121 NRb 41 Rb 42 、-NRb 41 Rb 42 、-C(=O)Rb 41 、-C(=O)ORb 41 ; Rb 41 , Rb 42 Each of the substituents is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, and phosphate; m 11 An integer selected from 0 to 3, such as 0, 1, 2 or 3; m 12 、m 13 、m 121 are independently selected from integers from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0023] X4, X5 are independently selected from N, O or C; Rb6, at each occurrence, is independently selected from none, H, deuterium, halogen, hydroxyl, cyano, amino, alkoxyl, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 14 An integer selected from 0 to 3, such as 0, 1, 2 or 3; m 15 an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0024] X6 is selected from N or O; X7 is selected from N, O or C; Rb7 is independently selected at each occurrence from none, H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxy, cyano, carbonyl, -C(=O)NRb 41 Rb 42 、-(CH2)m 121 C(=O)NRb 41 Rb 42 、-(CH2)m 121 NRb 41 Rb 42 、-NRb 41 Rb 42 、-C(=O)Rb 41 、-C(=O)ORb 41 ; Rb 41 , Rb 42 Each of the substituents is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, and phosphate; m 16 An integer selected from 0 to 6; m 17 an integer selected from 0 to 3, such as 0, 1, 2 or 3;

[0025] X8 is selected from N, O or C; Rb8 is independently selected at each occurrence from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 18 an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0026] X9, X 10 Rb9 is independently selected from N or O; each occurrence of Rb9 is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 19 an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0027] X 11 Selected from N, O or C; Rb 20 Each occurrence is independently selected from H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 21 An integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6; m 20 、m 22 an integer selected from 0 to 3, such as 0, 1, 2 or 3;

[0028] X 12 、X 13 、X 14 are independently selected from N or O; Rb 21 Each occurrence is independently selected from H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 23 An integer selected from 1 to 3, such as 1, 2 or 3; m 24 an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0029] Rb 22Each occurrence is independently selected from H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidino, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 25 an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0030] m 26 、m 27 an integer selected from 0 to 3, such as 0, 1, 2 or 3;

[0031] X 15 、X 16 are independently selected from O, -NH;

[0032] X 17 Selected from O or N; Rb 10 , Rb 11 Independently selected from -OH, -CH3, H.

[0033] Furthermore, ring B is selected from substituted or unsubstituted structures:

[0034] in,

[0035] X1 and X2 are independently selected from hydrogen, deuterium, and halogen; Y is selected from hydrogen or deuterium;

[0036] Rd1 is ring C.

[0037] Further, ring C is selected from one of the following:

[0038] Re1, Re2, Re3, at each occurrence, are independently selected from -H, -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonic acid, phosphate;

[0039] n3 is independently selected from an integer from 0 to 5 at each occurrence, such as 0, 1, 2, 3, 4 or 5; n4 is independently selected from 0 or 1 at each occurrence;

[0040] Or, when n3 is greater than or equal to 2, two adjacent Re1, Re2 or Re3 may also form a 4- to 7-membered ring with the atoms connected therebetween;

[0041] A4 to A8 are independently selected from heteroatoms or C, and are not all C. The number of heteroatoms in A4 to A8 is 1, 2 or 3, and the heteroatoms are selected from N and / or O;

[0042] A9~A 14 are independently selected from heteroatoms or C, and not all are C, A9 to A 14 The number of heteroatoms in is 1 or 2, and the heteroatoms are selected from N and / or O.

[0043] Further, each occurrence of Re1, Re2, and Re3 is independently selected from -H, -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, phosphate, monomethyl phosphate, dimethyl phosphate, C 1-5 Straight-chain or branched alkyl, C 1-5 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 alkyl), -OCON(C 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 Aryl, five-membered heteroaryl, six-membered heteroaryl;

[0044] Or when n3 is greater than or equal to 2, two adjacent Re1, Re2 or Re3 can also form a saturated or unsaturated C 3-8 Cycloalkyl, saturated or unsaturated C 3-8 Heterocycloalkyl, saturated or unsaturated cyclic lactone, C 5-6 Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl, amide substitution.

[0045] Further, ring C is selected from:

[0046] Each occurrence of Re1 is independently selected from -H, -OH, -F, -Cl, -CN, -CF3, -C2F5, -OCF3, monomethylphosphoryl, dimethylphosphoryl, C 1-5 Straight-chain or branched alkyl, C 1-5 Alkoxy, C 3-10 Cycloalkyl, C3-10 Heterocycloalkyl, -S(C 0-10 alkyl), -OCON(C 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 Aryl, five-membered heteroaryl, six-membered heteroaryl;

[0047] Or when n3 is greater than or equal to 2, two adjacent Re1s form a saturated or unsaturated C 3-8 Cycloalkyl, saturated or unsaturated C 3-8 Heterocycloalkyl, five-membered ring lactone, C 5-6 Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl, amide substitution.

[0048] Furthermore, n3 is selected from 1, 2, 3, 4 or 5.

[0049] Furthermore, n3 is selected from 1, 2 or 3.

[0050] Furthermore, Re1 is not H at the same time.

[0051] Furthermore, each occurrence of Re1 is independently selected from halogen, -CF3, -C2F5, -OCF3, -OCHF2, and -OCH2F.

[0052] Furthermore, each occurrence of Re1 is independently selected from H or halogen.

[0053] Furthermore, Selected from

[0054] In the present invention, when Re1 is selected from halogen, F, Cl, etc. may be preferably selected.

[0055] Furthermore, when n3 is greater than or equal to 2, two adjacent Re1s can also form one of the following structures with their connected benzene rings:

[0056] wherein K2, K3, K4 are fused with a benzene ring to form a saturated or unsaturated five-membered ring; K2, K3, K4 are independently selected from C, N, O, S; K5, K6, K7 are independently selected from C, N, O, S; K8 is independently selected from C, N, O, S; R 50 、R 51 、R 52 、R 53 Independently selected from -H, -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, m6, m7, m8, m9 are selected from integers of 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6.

[0057] Furthermore,

[0058] Selected from

[0059] Selected from

[0060] When ring B is selected from the following structures: Ring C is selected from: When, Formula I presents the following structure:

[0061] Furthermore, In the example, X1, X2, and X3 are selected from one of the following combinations:

[0062] (1) X1 and X3 are N, and X2 is C;

[0063] (2) X1 is N, X2 is N, and X3 is O;

[0064] (3) X1 and X2 are N, and X3 is C.

[0065] Furthermore, m 11 Choose 1 or 2.

[0066] Furthermore, In the example, X4 and X5 are selected from one of the following combinations:

[0067] (1) X4 is O, X5 is C;

[0068] (2) X4 and X5 are C;

[0069] (3) X4 is N, X5 is C;

[0070] (4) X4 is O, and X5 is N.

[0071] Furthermore, m 14 Selected from 0, 1 or 2.

[0072] Furthermore, m 14 Select 1 or 2, m 15 Choose 1 or 2.

[0073] Preferably, m 14 is selected from 2, and X4 is O, X5 is C. On this basis, The structure is as follows:

[0074] Furthermore, m 15 Select from 2.

[0075] Furthermore, The structure is as follows:

[0076] Further, each occurrence of Rb6 is independently selected from hydroxyl, substituted or unsubstituted C 1-3 Alkyl; the substituents are independently selected from halogen and hydroxyl.

[0077] Preferably, The two Rb6s in are different.

[0078] Furthermore, In, X 15 、X 16 are independently selected from O and -NH, and are different.

[0079] Furthermore, In, X 17 Selected from O; Rb 10 , Rb 11 Choose from one of the following combinations:

[0080] (1)Rb 10 , Rb 11 are independently selected from -OH and -CH3, and the two are different;

[0081] (2)Rb 10 , Rb 11 Selected from H.

[0082] Furthermore, A1 is selected from C.

[0083] Furthermore, Rb1 is selected from halogen, substituted or unsubstituted alkyl or cycloalkyl, -CN, phosphoryl, and the substituents are independently selected from deuterium and halogen; Rb2 is selected from halogen.

[0084] Furthermore, Rb1 is selected from Cl, Br, and I; and Rb2 is selected from F.

[0085] Furthermore, A2 is selected from S; A3 is selected from C.

[0086] Further, Ra1 is selected from H and halogen; further, Ra1 is selected from H, F, Cl, and Br.

[0087] Furthermore, n1 is selected from 1 or 2.

[0088] Further, Ra2 is selected from -CN.

[0089] Further, Formula I is selected from one of the following:

[0090] The present invention also provides a pharmaceutical composition, the active compound of the pharmaceutical composition includes one or more selected from the aforementioned compounds, their tautomers, mesomers, racemates, enantiomers, diastereomers or their mixtures, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals.

[0091] The present invention also provides the use of the above-mentioned compounds, their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms (such as hydrogen atoms replaced by deuterium atoms), pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals in the preparation of KRAS inhibitor drugs.

[0092] The present application provides a pharmaceutical composition, the active compound of the pharmaceutical composition includes one or more selected from the above-mentioned compounds, their tautomers, mesomers, racemates, enantiomers, diastereomers or their mixtures, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals.

[0093] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from one or more of a carrier, a diluent or an excipient. In addition, the present application has no particular restrictions on the formulation type of the pharmaceutical composition.

[0094] The present application also provides the use of the above-mentioned compounds, their tautomers, meso-racemates, racemates, enantiomers, diastereomers or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms (such as hydrogen atoms replaced by deuterium atoms), pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals in the preparation of KRAS inhibitor drugs.

[0095] Preferably, the above-mentioned compound, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal is used in the preparation of KRAS mutation inhibitor drugs.

[0096] The present application also provides the use of the above-mentioned compound, its tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or cocrystals in the preparation of medicaments for treating, alleviating, or preventing diseases or conditions associated with Noonan syndrome, leopard syndrome, leukemia, neuroblastoma, lymphoma, melanoma, esophageal cancer, head and neck cancer, breast cancer, lung cancer, bone cancer, biliary tract cancer, glioma, nasopharyngeal cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, bladder cancer, prostate cancer, testicular cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, ovarian cancer, rectal cancer, and colon cancer.

[0097] The present application also provides a method for inhibiting KRAS, which comprises administering to a patient a certain effective dose of the above-mentioned compound, its tautomer, meso-racemate, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form (such as hydrogen atom replaced by deuterium atom), pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal.

[0098] The present application also provides a method for inhibiting various KRAS mutations, which comprises administering to a patient a certain effective dose of the above-mentioned compound, its tautomer, meso-racemate, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form (such as hydrogen atom replaced by deuterium atom), pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal.

[0099] The present application also provides a method for treating, alleviating, or preventing a disease, comprising administering to a patient an effective dose of the aforementioned compound, its tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms (e.g., hydrogen atoms substituted with deuterium atoms), pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or cocrystals; the diseases include, but are not limited to, Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, lymphoma, melanoma, esophageal cancer, head and neck cancer, breast cancer, lung cancer, bone cancer, biliary tract cancer, glioma, nasopharyngeal cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, bladder cancer, prostate cancer, testicular cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, ovarian cancer, and rectal and colon cancer-related diseases or conditions.

[0100] In order to more clearly describe the content of this application, the terms involved are defined as follows:

[0101] As used herein, "pharmaceutically acceptable" is intended to include any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0102] The pharmaceutically acceptable excipients described in this application are a general term for all additional materials in a drug other than the main drug. Excipients should have the following properties: (1) be non-toxic to the human body and have almost no side effects; (2) be chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) have no incompatibility with the main drug and do not affect the efficacy and quality inspection of the main drug; (4) do not interact with the packaging materials. Excipients in this application include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc. Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.), gelatin slurry, syrup, starch slurry or polyvinyl pyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowdered silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, etc. , pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinyl pyrrolidone or microcrystalline cellulose, etc.; wetting agents include sodium lauryl sulfate, water or alcohol, etc.; antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutyl benzoic acid, etc.; antibacterial agents include 0.5% phenol, 0.3% cresol, 0.5% trichlorobutanol, etc.; regulators include hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate and buffers (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; emulsifiers include polysorbate 80, sorbitan oleate, poloxamer F-68, lecithin, soy lecithin, etc.; solubilizers include Tween-80, bile, glycerol, etc.

[0103] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present application. Representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0105] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0107] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0108] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0109] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0110] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0111] The compounds of the present application can also be used in injectable preparations. The injectable preparations are selected from liquid injections (water injections), sterile powders for injection (powder injections), or injectable tablets (referring to molded or machine-pressed tablets made using aseptic techniques, dissolved in water for injection upon use, and intended for subcutaneous or intramuscular injection).

[0112] The powder for injection contains, in addition to the above-mentioned compound, at least an excipient. The excipient referred to in this application is an ingredient intentionally added to a drug that should not have pharmacological properties in the amount used. However, the excipient may aid in drug processing, solubility or dissolution, delivery via targeted routes of administration, or stability.

[0113] Refers to single or double bonds, satisfying all valence states.

[0114] The ring structure contains When , it represents that the ring structure is a conjugated system.

[0115] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0116] The term "membered" refers to the number of skeletal atoms constituting the ring.

[0117] The term "one key" in this application means that there is only one connecting key, which can also be understood as "none".

[0118] "Alkyl" refers to an aliphatic hydrocarbon group, including saturated hydrocarbon groups. The alkyl portion can be either straight-chain or branched. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0119] As used herein, C1-Cn includes C1-C2, C1-C3, ..., C1-Cn, where n is an integer greater than one. The prefix of a substituent indicates the minimum and maximum number of carbon atoms in the substituent. For example, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group containing one to six carbon atoms. As used herein, "C0-substituted or unsubstituted alkyl" or "C0-alkyl" refers to H.

[0120] Furthermore, the alkyl group as described above is selected from C 0-10 Furthermore, C 0-10 Alkyl is selected from C 1-10 Furthermore, C 1-10 The alkyl group can be selected from C 1-9 Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 of alkyl.

[0121] Furthermore, the alkyl group is preferably C 1-3 alkyl.

[0122] Furthermore, the alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl.

[0123] Furthermore, the substituted alkyl group is selected from -CF3, -C2F5.

[0124] "Heteroalkyl" refers to an alkyl group containing heteroatoms, including but not limited to O, S, N, P, Si, etc. Heteroalkyl includes alkoxy groups, such as methoxy (CH3O-), ethoxy (C2H5O-), propoxy (C3H7O-), etc.

[0125] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group can be straight-chain or branched.

[0126] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched.

[0127] "Amide" is a chemical structure having the formula -C(O)NHR or -NHC(O)R, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0128] "Sulfonyl" is a chemical structure having the formula -S(=O)2R, including sulfonamide, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, etc.;

[0129] "Phosphoryl" is a chemical structure having the formula -P(=O)RR', wherein R and R' can be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, amino, etc.; wherein alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

[0130] "Ester" refers to a chemical structure having the formula -COOR, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0131] "Acyl" refers to a chemical structure having the formula -C(O)R, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0132] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl or cycloalkyl group), a heterocyclic ring (e.g., a heteroaryl or heterocycloalkyl group), an aromatic group (e.g., an aryl or heteroaryl group), or a non-aromatic group (e.g., a cycloalkyl or heterocycloalkyl group). As used herein, the "ring" may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spirocyclic ring, or a bridged ring.

[0133] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent. Cycloalkyl is generally selected from C 1-10 of a cycloalkyl group.

[0134] Typical cycloalkyl groups include, but are not limited to:

[0135] Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0136] "Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the ring backbone. Heterocycloalkyl groups are generally selected from C 1-10 of a cycloalkyl group.

[0137] Typical heterocycloalkyl groups include, but are not limited to:

[0138] "Aryl" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.

[0139] Typical heteroaryl groups include, but are not limited to:

[0140] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0141] "Deuterium" refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the element symbol is generally D or 2 H.

[0142] The alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, borate ester, guanidine, acylguanidine, aryl, heteroaryl, imino and the like described herein may be unsubstituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, borate ester, guanidine, acylguanidine, aryl, heteroaryl, imino; or may be substituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, borate ester, guanidine, acylguanidine, aryl, heteroaryl, imino.

[0143] As used herein, “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently selected from the group consisting of alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylthio, aryloxy, O=, guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0144] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base suitable for pharmaceutical use. The acids and bases described above are broadly defined as Lewis acids and bases. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0145] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0146] "KRAS inhibitor" refers to a drug that inhibits KRAS activity.

[0147] Compared with the prior art, the present application is described in detail as follows:

[0148] The present application provides a novel class of compounds targeting pan-KRAS, which have unexpectedly excellent activity and pharmacokinetic properties.

[0149] The compounds of the present application, their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals can be used to prepare drugs for treating, alleviating or preventing diseases or conditions related to Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer and colon cancer, and have great development value.

[0150] The compounds provided herein can be used to treat one or more cancers caused by KRAS mutations.

[0151] The compound provided in the present application can effectively block KRAS activity and has a good oral exposure.

[0152] The synthetic method of the present application is simple to operate and has a high yield. DETAILED DESCRIPTION

[0153] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention is further described in detail below with reference to specific embodiments.

[0154] In the present invention, the structure of the compound is determined by mass spectrometry (MS) and / or nuclear magnetic resonance ( 1 The chemical abbreviations have the following meanings:

[0155] DMF: N,N-dimethylformamide

[0156] THF: Tetrahydrofuran

[0157] DIPEA: N,N-diisopropylethylamine

[0158] PE: Petroleum ether

[0159] EA: ethyl acetate

[0160] DCM: dichloromethane

[0161] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea

[0162] HBTU: Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0163] DMSO: dimethyl sulfoxide

[0164] BOP-Cl: Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride

[0165] (BOC)2O:Di-tert-butyl dicarbonate

[0166] SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride

[0167] NCS: N-chlorosuccinimide

[0168] NBS: N-bromosuccinimide

[0169] NIS: N-iodosuccinimide

[0170] LHMDS: lithium bis(trimethylsilyl)amide

[0171] TBAF: Tetrabutylammonium fluoride

[0172] TMSCF3: (trifluoromethyl)trimethylsilane

[0173] CS2CO3: Cesium carbonate

[0174] NMP: N-methylpyrrolidone

[0175] NMO: N-methylmorpholine oxide

[0176] K2OsO4: Potassium osmate

[0177] Pd / C: Palladium on carbon

[0178] SFC: Supercritical Fluid Chromatography

[0179] Synthesis of intermediates

[0180] Preparation of Intermediate 1: 7-Bromo-2,6-dichloro-8-fluoroquinazoline-4-ol

[0181] Step 1: Synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzene-1-carboxamide

[0182] To a reaction flask, 2-amino-4-bromo-5-chloro-3-fluorobenzene-1-carboxylic acid (76.0 g, 284.6 mmol), ammonium chloride (91.2 g, 1704.7 mmol), and DMF (800 mL) were added. DIPEA (365.6 g, 2834.1 mmol) and HATU (212.8 g, 560.0 mmol) were then added sequentially. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 3 L of water, whereupon a large amount of brown solid precipitated. After stirring for 0.5 hours, the mixture was filtered, the filter cake rinsed with a small amount of water, and then dried to yield 42.5 g of the desired product. Total yield: 56.1%.

[0183] LC / MS: m / z = 267.0 [M+H] + .

[0184] Step 2: Synthesis of 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol

[0185] 2-Amino-4-bromo-5-chloro-3-fluorobenzene-1-carboxamide (23.2 g, 87.2 mmol) was dissolved in 1,4-dioxane (200 mL). After nitrogen substitution, a solution of thiophosgene (30.0 g, 260.9 mmol) in 1,4-dioxane (50 mL) was added dropwise at room temperature. After addition, the mixture was stirred at room temperature for 1 hour, then heated to 100°C and stirred for 1 hour. The reaction mixture was concentrated to dryness and slurried with a mixture of PE / EA = 3 / 1 (150 mL) for 1 hour. After filtration and drying, 23.0 g of an off-white solid was obtained with a yield of 85.2%.

[0186] LC / MS: m / z=311.1[M+H] + .

[0187] Preparation of Intermediate 2: 2-Methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate

[0188] Step 1: Synthesis of (6-bromo-2,3-difluorophenyl)methanol

[0189] Dissolve 6-bromo-2,3-difluorobenzene-1-carbaldehyde (100.0 g, 450 mmol) in ethanol (1 L). Add sodium borohydride (18.0 g, 480 mmol) in portions at 0°C and stir at room temperature for 0.5 hours. Pour the reaction system into water (3 L) and extract with dichloromethane. Backwash the organic phase once with saturated brine, dry, and spin-dry to obtain 100.9 g of a white solid, which was used directly in the next step.

[0190] LC / MS: m / z = 223.1 [M+H] + .

[0191] Step 2: Synthesis of (4-bromo-1,2-difluorophenyl-3-yl)methyl methanesulfonate

[0192] Dissolve (6-bromo-2,3-difluorophenyl)methanol (product from the previous step) and triethylamine (91.6 g, 900 mmol) in dichloromethane (1 L). Add methanesulfonyl chloride (57.0 g, 500 mmol) dropwise at 0°C. Stir at 0°C for 1 hour. Pour the reaction system into water (3 L) and extract with dichloromethane. Backwash the organic phase once with saturated brine, dry, and spin-dry to obtain 119.7 g of an off-white solid. The two-step yield is 87.5%.

[0193] Step 3: Synthesis of (6-bromo-2,3-difluorophenyl)acetonitrile

[0194] Methanesulfonic acid (4-bromo-1,2-difluorophenyl-3-yl)methyl ester (119.7 g, 397.7 mmol) and trimethylsilyl cyanide (78.9 g, 795.3 mmol) were dissolved in acetonitrile (1 L). A solution of tetrabutylammonium fluoride trihydrate (250.9 g, 795.3 mmol) in tetrahydrofuran (500 mL) was added dropwise under an ice bath. After the addition, the mixture was stirred at room temperature for 1 hour. The reaction system was poured into saturated brine (3 L) and extracted with ethyl acetate. The organic phase was backwashed once with saturated brine, dried, and spin-dried to give 89.0 g of a yellow solid (96.0% yield).

[0195] LC / MS: m / z = 231.2 [M+H] + .

[0196] Step 4: Synthesis of ethyl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate

[0197] Dissolve (6-bromo-2,3-difluorophenyl)acetonitrile (89.0 g, 380 mmol) in 900 mL of DMF. Add potassium tert-butoxide (64.4 g, 580 mmol) in portions at 0°C. Stir at 0°C for 20 minutes, then add ethyl isothiocyanate (75.4 g, 580 mmol) dropwise. Stir at room temperature for 1 hour, then at 100°C for 0.5 hour. After cooling to room temperature, pour into 3 L of water. A large amount of solid precipitates, which is filtered, and the filter cake is rinsed with a small amount of water and dried to obtain the crude product, which is used directly in the next step.

[0198] LC / MS: m / z=343.1[M+H] + .

[0199] Step 5: Synthesis of 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile

[0200] Ethyl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate (product from the previous step) was dissolved in DMSO (680 mL) and a solution of sodium hydroxide (112.0 g, 2800 mmol) in water (400 mL) was added. The mixture was reacted at 100°C overnight. After cooling to room temperature, the reaction solution was poured into water (1 L) and slurried for 1 hour. The filter cake was filtered and rinsed once with a small amount of water and dried to obtain 88.0 g of a yellow solid. The two-step yield was 84.6%.

[0201] LC / MS: m / z = 271.1 [M+H] + .

[0202] Step 6: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate

[0203] Dissolve 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile (88.0 g, 320 mmol) and 4-dimethylaminopyridine (4.0 g, 30 mmol) in THF / DMF (450 mL / 450 mL) and add (Boc)2O (99 g, 450 mmol). Stir the reaction system overnight at room temperature. Pour the reaction solution into water (2 L) and extract with ethyl acetate. Add activated carbon (360 g) and silica gel (50 g) to the organic phase and stir overnight. Filter with suction, dry the filtrate, and spin dry to obtain 86.0 g of a yellow solid (yield: 72.0%).

[0204] LC / MS: m / z=371.1[M+H] + .

[0205] Step 7: Synthesis of 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate

[0206] To a reaction flask were added 2-methylpropan-2-yl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate (24.0 g, 64.7 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (43.9 g, 194.1 mmol), potassium acetate (19.0 g, 194.1 mmol), and dioxane (450 mL). After nitrogen was replaced, Pd(dppf)Cl2 (2.3 g, 3.2 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into water (1.5 L). The product was extracted with ethyl acetate. The organic phase was dried and spin-dried, and then purified by silica gel column chromatography (PE / EA=50 / 1) to obtain 11.8 g of a white solid. The yield was 45.5%.

[0207] LC / MS: m / z=405.2[M+H] + .

[0208] Preparation of Intermediate 3: 2-Methylpropan-2-yl {[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylate

[0209] Step 1: Synthesis of (2,6-dibromophenyl)methanol

[0210] Dissolve 2,6-dibromobenzene-1-carboxaldehyde (25.0 g, 94.7 mmol) in ethanol (250 mL). Add sodium borohydride (3.8 g, 100.0 mmol) at 0°C and stir at room temperature for 0.5 hour. Pour the reaction system into water (1 L) and extract with dichloromethane. Backwash the organic phase once with saturated brine, dry, and spin-dry to obtain 25.0 g of a white solid (yield: 99.3%).

[0211] LC / MS: m / z=265.0[M+H] + .

[0212] Step 2: Synthesis of (1,3-dibromobenz-2-yl)methyl methanesulfonate

[0213] Dissolve (2,6-dibromophenyl)methanol (15.0 g, 56.4 mmol) and triethylamine (11.4 g, 112.8 mmol) in dichloromethane (150 mL). Add methanesulfonyl chloride (7.1 g, 62.1 mmol) dropwise at 0°C. Stir at 0°C for 1 hour. Pour the reaction system into water (500 mL) and extract with dichloromethane. Backwash the organic phase once with saturated brine, dry, and spin-dry to obtain 16.6 g of an off-white solid (yield: 85.6%).

[0214] Step 3: Synthesis of (2,6-dibromophenyl)acetonitrile

[0215] Methanesulfonic acid (1,3-dibromophenyl-2-yl)methyl ester (16.6 g, 48.3 mmol) and trimethylsilyl cyanide (9.6 g, 96.5 mmol) were dissolved in acetonitrile (170 mL). A solution of tetrabutylammonium fluoride trihydrate (30.4 g, 96.5 mmol) in tetrahydrofuran (90 mL) was added dropwise under an ice bath. After the addition, the mixture was stirred at room temperature for 1 hour. The reaction system was poured into saturated brine (500 mL) and extracted with ethyl acetate. The organic phase was backwashed once with saturated brine, dried, and then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 11.9 g of an off-white solid (yield: 89.4%).

[0216] LC / MS: m / z = 273.1 [M+H] + .

[0217] Step 4: Synthesis of ethyl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate

[0218] (2,6-Dibromophenyl)acetonitrile (11.9 g, 43.2 mmol) was dissolved in DMF (120 mL). After nitrogen displacement, NaH (60%, 1.7 g, 43.1 mmol) was added at 0°C. After stirring at 0°C for 20 minutes, ethyl isothiocyanatoformate (6.2 g, 47.4 mmol) was added dropwise at 0°C. After the addition, the mixture was stirred at room temperature for 20 minutes. Copper iodide (822 mg, 4.3 mmol) and L-proline (994 mg, 8.6 mmol) were added, and the mixture was stirred at 60°C overnight. After cooling the reaction mixture to room temperature, it was poured into water (300 mL) containing 2.0% ethylenediaminetetraacetic acid and stirred overnight. The mixture was filtered, and the filter cake was rinsed three times with small amounts of water and then dried to obtain 11.8 g of a light yellow solid (yield: 84.0%).

[0219] LC / MS: m / z=325.1[M+H] + .

[0220] Step 5: Synthesis of 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile

[0221] Dissolve ethyl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate (11.8 g, 36.2 mmol) in DMSO (55 mL) and add a solution of sodium hydroxide (10.1 g, 253.6 mmol) in water (36 mL). The mixture is reacted at 110°C overnight. After cooling to room temperature, the reaction solution is poured into ice water (300 mL) and blended for 1 hour. Filter the mixture with suction, rinse the filter cake once with a small amount of water, and dry it to obtain 9.0 g of a light yellow solid, which is used directly in the next reaction.

[0222] LC / MS: m / z=253.1[M+H] + .

[0223] Step 6: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate

[0224] Dissolve 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile (crude product from the previous step) and 4-dimethylaminopyridine (442 mg, 3.6 mmol) in THF / DMF (50 mL / 50 mL), and add (Boc)2O (10.3 g, 47.1 mmol). Stir the reaction system overnight at room temperature. Pour the reaction solution into water (300 mL), extract with ethyl acetate, and the organic phase is dried and spin-dried. Purify by silica gel column chromatography (PE / EA = 10 / 1) to obtain 10.5 g of a light yellow solid. The two-step yield is 82.4%.

[0225] LC / MS: m / z=353.0[M+H] + .

[0226] Step 7: Synthesis of 2-methylpropan-2-yl {[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylate

[0227] To a reaction flask, 2-methylpropane-2-[(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate (10.5 g, 29.8 mmol), bis(pinacolato) borate (15.1 g, 59.7 mmol), potassium acetate (8.8 g, 89.6 mmol), and dioxane (100 mL) were added. After nitrogen was replaced, Pd(dppf)Cl2 (1.1 g, 1.5 mmol) was added. The reaction mixture was heated to 90°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (300 mL). The mixture was extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain 5.2 g of an off-white solid in a yield of 43.9%.

[0228] LC / MS: m / z = 401.2 [M+H] + .

[0229] Preparation of Intermediate 4: [3-(3,4,5-Trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate)

[0230] Step 1: Synthesis of methyl 2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate

[0231] Magnesium turnings (4.8 g, 200 mmol) were weighed into reaction flask A. 3,4,5-trifluorobromobenzene (1 g, 4.8 mmol), iodine (0.2 g), and tetrahydrofuran (5 mL) were added. After heating to initiate the reaction, a solution of 3,4,5-trifluorobromobenzene (20.0 g, 95.2 mmol) in tetrahydrofuran (150 mL) was added dropwise, maintaining the reaction system at reflux. Reflux was continued for 0.5 hours after the addition was complete. To another reaction flask B, 1-(tert-butyl)-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate (24.3 g, 100 mmol) and tetrahydrofuran (250 mL) were added. The reaction mixture was cooled to -70°C in a dry ice-ethanol bath under nitrogen. The p-methoxyphenylmagnesium bromide solution in reaction flask A was added portionwise to reaction flask B. The reaction was continued at this temperature for 3 hours. Saturated ammonium chloride solution (500 mL) was added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried and spin-dried, and then purified by column chromatography (PE / EA=1 / 1) to obtain 26.4 g of the target product in a yield of 70.0%.

[0232] LC / MS: m / z=376.1[M+H] + .

[0233] Step 2: Synthesis of methyl 5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

[0234] To a reaction flask, add methyl 2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate (26.4 g, 70.4 mmol). HCl / MeOH (4 M, 200 mL) was added at room temperature and stirred overnight. The reaction system was directly spin-dried, and saturated aqueous sodium bicarbonate (100 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was dried and spin-dried to obtain 17.0 g of the product (94.0% yield).

[0235] LC / MS: m / z = 258.1 [M+H] + .

[0236] Step 3: Synthesis of methyl 2-(3-chloropropyl)-5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

[0237] Methyl 5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (17.0 g, 66.1 mmol) and 1-bromo-3-chloropropane (20.6 g, 132.3 mmol) were dissolved in a mixture of DMF (100 mL) and THF (200 mL). Sodium hydride (60%, 4.0 g, 99.2 mmol) was added portionwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction system was poured into saturated aqueous ammonium chloride (1 L), extracted with ethyl acetate, and the organic phase was dried and spin-dried. The crude product was purified by column chromatography (PE / EA = 8 / 1) to obtain 16.6 g of an off-white solid (yield: 75.5%).

[0238] LC / MS: m / z=334.1[M+H] + .

[0239] Step 4: Synthesis of methyl 3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (Trans racemate)

[0240] Methyl 2-(3-chloropropyl)-5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (16.6 g, 49.8 mmol) was dissolved in methanol (200 mL). Acetic acid (2 mL) was added, and NaBH3CN (6.3 g, 100.3 mmol) was added portionwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction system was concentrated to dryness, and water (200 mL) was added. The mixture was adjusted to a weak base with sodium carbonate, extracted with ethyl acetate, and the organic phase was dried and spin-dried. The crude product was purified by column chromatography (PE / EA = 5 / 1) to afford 6.3 g of the cis-product as a light yellow oil (Sic racemate). Further elution with (PE / EA = 2 / 1) afforded 5.0 g of the trans-product (Trans racemate) as an off-white solid, with an overall yield of 75.8%.

[0241] LC / MS: m / z=300.2[M+H] + .

[0242] Step 5: Synthesis of [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate)

[0243] Methyl 3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (Trans racemate) (5.0 g, 16.7 mmol) was dissolved in tetrahydrofuran (50 mL). Lithium aluminum hydride (1.14 g, 30 mmol) was added at 0°C and stirred for 1 hour. Water (200 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 4.1 g of the desired product in a yield of 91%.

[0244] LC / MS: m / z = 272.2 [M+H] + .

[0245] Preparation of Intermediate 5: [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2)

[0246] Step 1: Synthesis of (2S)-2-phenylpropionic acid-[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl ester (TLC spot 2)

[0247] To a reaction flask were added [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (1.0 g, 3.7 mmol), (S)-2-phenylpropionic acid (554 mg, 3.7 mmol), 4-dimethylaminopyridine (24 mg, 0.2 mmol), and dichloromethane (10 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.0 g, 5.2 mmol) was added portionwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by column chromatography (DCM / MeOH = 50 / 1) to obtain 560 mg of the upper spot (TLC spot 1) as a pale yellow solid, and 570 mg of the lower spot (TLC spot 2) as a pale yellow solid. Total yield: 75.8%.

[0248] LC / MS: m / z = 404.2 [M+H] +.

[0249] Step 2: Synthesis of [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2)

[0250] (2S)-2-phenylpropanoic acid [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl ester (TLC spot 2, 570 mg, 1.4 mmol, product from the previous step) was dissolved in MeOH / H₂O (5 mL / 0.5 mL). NaOH (80 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction system was poured into water (20 mL) and extracted with ethyl acetate. The organic phase was backwashed once with 1 M aqueous NaOH, dried, and spin-dried to give 380 mg of the desired product (Trans isomer 2) in a 99% yield.

[0251] LC / MS: m / z = 272.2 [M+H] +.

[0252] Preparation of Intermediate 6: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyanothieno[2,3-c]pyridin-2-yl)amino]methane

[0253] Step 1: Synthesis of 3,5-dibromo-4-(bromomethyl)pyridine

[0254] Dissolve 3,5-dibromo-4-methylpyridine (10.0 g, 40 mmol) in acetonitrile (100 mL). Add NBS (8.5 g, 48 mmol) in portions at room temperature, then heat to 80°C for 3 hours. Pour the reaction system into water (300 mL) and extract with ethyl acetate. The organic phase is backwashed once with saturated brine, dried, and spin-dried to obtain 18.9 g of a black oil, which is used directly in the next step.

[0255] LC / MS: m / z = 325.9 [MH] - .

[0256] Step 2: Synthesis of 3,5-dibromo-4-(cyanomethyl)pyridine

[0257] Dissolve 3,5-dibromo-4-(bromomethyl)pyridine in acetonitrile (100 mL). Add trimethylsilyl cyanide (5.9 g, 60 mmol) at 0°C. Then, add tetrabutylammonium fluoride in tetrahydrofuran (60 mL, 60 mmol) dropwise at 0°C. After completion of the addition, react at room temperature for 3 hours. Pour the reaction system into water (300 mL) and extract with ethyl acetate. The organic phase is dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 6 / 1) to yield 6.9 g of a yellow solid. The total yield for the two steps is 62.7%.

[0258] LC / MS: m / z = 272.8 [MH] - .

[0259] Step 3: Synthesis of ethyl [(4-bromo-3-cyanothieno[2,3-c]pyridin-2-yl)amino]methane

[0260] 3,5-Dibromo-4-(cyanomethyl)pyridine (5.0 g, 18.3 mmol) was dissolved in DMF (50 mL). Sodium hydride (730 mg, 20.1 mmol) was added at 0°C and stirred at 0°C for 0.5 hours. Ethyl isothiocyanatoformate (2.6 g, 20.1 mmol) was then added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour. Cuprous iodide (347 mg, 1.8 mmol) and L-proline (210 mg, 1.8 mmol) were then added, and the mixture was heated to 65°C and reacted for 16 hours. Aqueous ammonia (150 mL) was added dropwise to the reaction system, causing a large amount of solid to precipitate. The mixture was stirred at room temperature for 6 hours, filtered, and the filter cake was rinsed with a small amount of water and dried to obtain 3.2 g of a green solid (yield: 53.9%).

[0261] LC / MS: m / z = 323.9 [MH] - .

[0262] Step 4: Synthesis of 2-amino-4-bromothieno[2,3-c]pyridine-3-carbonitrile

[0263] Ethyl [(4-bromo-3-cyanothieno[2,3-c]pyridin-2-yl)amino]methane (3.2 g, 10 mmol) was dissolved in DMSO (15 mL). Aqueous sodium hydroxide (5.0 mol / L, 15 mL) was added and heated to 60°C for 3 hours. After the reaction solution was cooled to room temperature, water (90 mL) was added dropwise. A large amount of solid precipitated and was filtered. The filter cake was rinsed with a small amount of water and dried to obtain 2.2 g of a green solid (yield: 88.3%).

[0264] LC / MS: m / z = 251.9 [MH] - .

[0265] Step 5: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyanothieno[2,3-c]pyridin-2-yl)amino]methane

[0266] 2-Amino-4-bromothieno[2,3-c]pyridine-3-carbonitrile (2.2 g, 9 mmol) was dissolved in DMF (11 mL) and tetrahydrofuran (11 mL). Di-tert-butyl dicarbonate (3.0 g, 14 mmol) was added and allowed to react at room temperature for 3 hours. The reaction system was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 664 mg of a yellow solid, with a yield of 21.6%.

[0267] LC / MS: m / z = 351.9 [MH] - .

[0268] Example 1

[0269] 2-Methylpropane-2-yl ({4-[6-chloro-4-(6-{[(2,2-dimethyl-1,3-dioxolan-4-yl)carbonyl]amino}-1,4-oxazepan-4-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methane)

[0270] Step 1: Synthesis of 2-methylpropan-2-yl 6-(benzylamino)-1,4-oxazepane-4-carboxylate

[0271] 2-Methylpropane-2-yl 6-oxyylidene-1,4-oxazepane-4-carboxylate (1.0 g, 4.69 mmol), benzylamine (502 mg, 4.69 mmol), and 4A molecular sieves (100 mg) were dissolved in DCM (15 mL) and stirred at room temperature for 2 hours. Sodium acetate borohydride (2.0 g, 9.38 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (50 mL), filtered, and the filtrate was collected and extracted three times with DCM. The organic phase was dried and spin-dried to dryness, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 1.0 g of a colorless oil, with a yield of 58.8%.

[0272] LC / MS: m / z=367.2[M+H] + .

[0273] Step 2: Synthesis of 2-methylpropan-2-yl 6-amino-1,4-oxazepane-4-carboxylate

[0274] To a reaction flask, 2-methylpropane-2-yl 6-(benzylamino)-1,4-oxazepane-4-carboxylate (1.0 g, 2.73 mmol) was dissolved in methanol (10 mL). After replacing the hydrogen atmosphere, Pd / C (500 mg) was added. The reaction was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction system was filtered through a pad of celite, and the filtrate was collected and dried to give 782 mg of a colorless oil, which was used directly in the next step.

[0275] LC / MS: m / z = 217.2 [M+H] + .

[0276] Step 3: Synthesis of 2-methylpropan-2-yl 6-{[(2,2-dimethyl-1,3-dioxolan-4-yl)carbonyl]amino}-1,4-oxazepane-4-carboxylate

[0277] Ethyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (200 mg, 1.25 mmol) and 2-methylprop-2-yl 6-amino-1,4-oxazepane-4-carboxylate (430 mg, crude) were dissolved in tetrahydrofuran (5 mL). The system was cooled to 0°C and LHMDS (1.9 mL, 2 M) was slowly added. After completion, the temperature was slowly raised to room temperature and stirred for 16 hours. The reaction solution was added to saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The organic phase was dried and spin-dried, and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 110 mg of a white oil, with a two-step yield of 21.3%.

[0278] LC / MS: m / z=345.2[M+H] + .

[0279] Step 4: Synthesis of 2,3-dihydroxy-N-(1,4-oxazepan-6-yl)propionamide hydrochloride

[0280] 6-{[(2,2-dimethyl-1,3-dioxolane-4-yl)carbonyl]amino}-1,4-oxazepane-4-carboxylic acid-2-methylprop-2-yl ester (210 mg, 0.21 mmol) was weighed and dissolved in DCM (3 mL). Dioxane hydrochloride (1 mL) was added and the system was stirred at room temperature for 2 hours, dried by rotation, and used directly in the next step.

[0281] LC / MS: m / z=245.1[M+H] + .

[0282] Step 5: Synthesis of N-[4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxamide

[0283] To a reaction flask were added 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (200 mg, 0.65 mmol), 2,3-dihydroxy-N-(1,4-oxazepan-6-yl)propionamide hydrochloride (182 mg, 0.65 mmol), DIPEA (168 mg, 1.30 mmol), and dichloromethane (6 mL). After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (249 mg, 0.98 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain 150 mg of a yellow solid, with a yield of 43.4%.

[0284] LC / MS: m / z=537.0[M+H] + .

[0285] Step 6: Synthesis of N-{4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-1,4-oxazepan-6-yl}-2,2-dimethyl-1,3-dioxolane-4-carboxamide (Trans racemate)

[0286] To the reaction flask were added N-[4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxamide (150 mg, 0.28 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (76 mg, 0.28 mmol) and DMF / THF (2 mL / 2 mL), and then CS2CO3 (183 mg, 0.56 mmol) and DABCO (31 mg, 0.28 mmol). The mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain 74 mg of a yellow solid. Yield: 34.3%.

[0287] LC / MS: m / z=772.1[M+H] + .

[0288] Step 7: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-4-(6-{[(2,2-dimethyl-1,3-dioxolan-4-yl)carbonyl]amino}-1,4-oxazepan-4-yl)-8-fluoro-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0289] N-{4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-4-yl]-1,4-oxazepan-6-yl}-2,2-dimethyl-1,3-dioxolane-4-carboxamide (Trans racemate) (74 mg, 0.1 mmol), 2-methylpropane-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (40 mg, 0.1 mmol), CS2CO3 (49 mg, 0.15 mmol) and toluene (2 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (7 mg, 0.01 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (10 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 18 mg of a yellow solid, yield: 19.1%.

[0290] LC / MS: m / z = 984.3 [M+H] + .

[0291] Step 8: Synthesis of N-{4-[7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulene-3a-yl]methyl}oxy)quinazolin-4-yl]-1,4-oxazepan-6-yl}-2,3-dihydroxypropionamide (Trans racemate)

[0292] To the reaction flask was added 2-methylpropan-2-yl ({4-[6-chloro-4-(6-{[(2,2-dimethyl-1,3-dioxolan-4-yl)carbonyl]amino}-1,4-oxazepan-4-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate) (18 mg) dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The product was dried by spin drying, added to saturated aqueous NaHCO 3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to give 7 mg of the desired product in a yield of 45.5%.

[0293] LC / MS: m / z=844.2[M+H] + .

[0294] Example 2

[0295] 2-Amino-4-{6-chloro-8-fluoro-4-[6-hydroxy-6-(hydroxymethyl)-1,4-oxazepan-4-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0296] Step 1: Synthesis of 2-methylprop-2-yl 6-methylidene-1,4-oxazepane-4-carboxylate

[0297] NaH (141 mg, 3.5 mmol, 60%) was dissolved in DMF (3 mL). The system was cooled to 0°C and then slowly added with 3-chloro-2-(chloromethyl)prop-1-ene (200 mg, 1.6 mmol). After 10 minutes, 2-methylprop-2-yl[(2-hydroxyethyl)amino]methane was added (258 mg, 1.6 mmol). The temperature was raised to room temperature and the reaction was stirred for 2.5 hours. The reaction solution was added to water (20 mL) and extracted three times with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 170 mg of a yellow oil, with a yield of 64.2%.

[0298] LC / MS: m / z=214.1[M+H] + .

[0299] Step 2: Synthesis of 2-methylpropan-2-yl 6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

[0300] To the reaction flask were added 2-methylprop-2-yl 6-methylidene-1,4-oxazepane-4-carboxylate (2.6 g, 12.2 mmol), NMO (1.4 g, 12.2 mmol), K2OsO4 (747 mg, 2.44 mmol), and THF / H2O (26 mL / 3.3 mL). The system was reacted at room temperature for 2 hours, then added to H2O, extracted three times with ethyl acetate, the organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA = 1 / 1) to give 780 mg of a brown oil, with a yield of 26.0%.

[0301] LC / MS: m / z=248.1[M+H] + .

[0302] Step 3: Synthesis of (6-methyl-1,4-oxazepan-6-yl)methanol hydrochloride

[0303] 2-Methylpropane-2-yl 6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (200 mg, 0.81 mmol) was dissolved in a hydrochloric acid / methanol solution (4 M, 4 mL). The mixture was stirred at room temperature for 2 hours, and the mixture was dried by rotary evaporation. The crude product was used directly in the next reaction.

[0304] LC / MS: m / z=148.1[M+H] + .

[0305] Step 4: Synthesis of 7-bromo-2,6-dichloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-fluoro-3,4-dihydroquinazolin-4-one

[0306] 7-Bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (2.0 g, 6.4 mmol) was weighed and dissolved in DCM (30 mL), and DIEA (2.0 g, 16 mmol) was added. After completion, SEM-Cl (1.38 g, 8.3 mmol) and TBAI (230 mg, 0.64 mmol) were added under stirring. The system was stirred at room temperature for 2 hours, and water (150 mL) was added. The product was extracted with DCM, and the organic phase was dried and spin-dried. It was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 1.89 g of a light yellow solid in a yield of 95.9%.

[0307] LC / MS: m / z=310.0[M+H] + .

[0308] Step 5: Synthesis of 7-bromo-6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-3,4-dihydroquinazolin-4-one (Trans racemate)

[0309] [3-(3,4,5-Trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (1.65 g, 6.0 mmol) was dissolved in THF. When the temperature dropped to 0°C, NaH (480 mg, 12.0 mmol) was slowly added. The system was reacted at this temperature for 0.5 hour. A solution of 7-bromo-2,6-dichloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-fluoro-3,4-dihydroquinazolin-4-one (1.89 g, 6.0 mmol) in THF (15 mL) was then added. The system was stirred at room temperature for 4 hours. Water (150 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA = 4 / 1) to give 2.2 g of a white solid compound in a yield of 67.4%.

[0310] LC / MS: m / z=545.2[M+H] + .

[0311] Step 6: Synthesis of 2-methylpropan-2-yl({4-[6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-4-oxylidene-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0312] 7-Bromo-6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-3,4-dihydroquinazolin-4-one (Trans racemate) (2.2 g, 4.0 mmol), 2-methylpropane-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (1.61 g, 4.0 mmol), cesium carbonate (2.6 g, 8.0 mmol) and toluene (25 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (286 mg, 0.1 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate, and the organic phase was dried and spin-dried, and then purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 1.5 g of a yellow solid with a yield of 49.6%.

[0313] LC / MS: m / z=757.2[M+H] + .

[0314] Step 7: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-hydroxy-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0315] Trans racemate (1.0 g, 1.3 mmol) was dissolved in DCM (10 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 2 h, dried by evaporation, and the crude product was used directly in the next reaction.

[0316] LC / MS: m / z=658.2[M+H] + .

[0317] Step 8: Synthesis of 2-amino-4-{6-chloro-8-fluoro-4-[6-hydroxy-6-(hydroxymethyl)-1,4-oxazepan-4-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0318] To a reaction flask were added 2-amino-4-[6-chloro-8-fluoro-4-hydroxy-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate) (50 mg, crude), (6-methyl-1,4-oxazepan-6-yl)methanol hydrochloride (14 mg, crude), DIPEA (0.1 mL) and dichloromethane (2 mL). After nitrogen replacement, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (20 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain 4 mg of the target compound in a yield of 7.7%.

[0319] LC / MS: m / z = 787.2 [M+H] + .

[0320] Example 3

[0321] 2-Amino-4-[6-chloro-8-fluoro-4-(3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0322] Step 1: Synthesis of 2-methylprop-2-yl 4-methylideneazepane-1-carboxylate

[0323] Methyltriphenylphosphonium bromide (1.67 g, 4.6 mmol) was weighed and dissolved in THF (15 mL), and the nitrogen was replaced 3 times. The reaction system was cooled to -30-35 ° C, and n-butyl lithium (2.7 mL, 6.9 mmol) was slowly added dropwise and kept at -30-35 ° C. After the addition was completed, the reaction was continued for 1 hour. 4-Oxylideneazepane-1-carboxylic acid-2-methylprop-2-yl ester (1.0 g, 4.6 mmol) was dissolved in THF (7 mL) and added dropwise. The above reaction system was added and the temperature was maintained at -10°C to -20°C. After the addition, the reaction was allowed to react at 0°C to -10°C for 1 hour. The reaction was then allowed to warm to room temperature and stirred for 16 hours. The reaction system was poured into a saturated aqueous solution of NH4Cl and a small amount of solid NaCl was added. The upper organic phase was collected and dried. The residue was dissolved in EA and water was added. The EA phase was collected and purified by column chromatography (PE / EA = 6 / 1) to obtain 560 mg of the target product in a yield of 56.0%.

[0324] LC / MS: m / z = 212.2 [M+H] + .

[0325] Step 2: Synthesis of 2-methylprop-2-yl 3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-8-carboxylate

[0326] Acetaldehyde oxime (185 mg, 3.1 mmol) was weighed and dissolved in DCM / DMF (5 mL / 5 mL). NCS (412 mg, 3.1 mmol) was added and allowed to react at room temperature for 1 hour. 2-Methylpropane-2-yl 4-methylideneazepane-1-carboxylate (450 mg, 2.1 mmol) and TEA (636 mg, 6.3 mmol) were added to the reaction system and stirred at room temperature for 16 hours. DCM and water were added to the reaction mixture, and the DCM phase was separated and separated. The organic phase was washed with saturated brine, dried, spin-dried, and purified by column chromatography (PE / EA = 3 / 1) to obtain 300 mg of the desired product in a yield of 53.3%.

[0327] LC / MS: m / z=269.2[M+H] + .

[0328] Step 3: Synthesis of 3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene hydrochloride

[0329] 2-Methylprop-2-yl 3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-8-carboxylate (300 mg, 0.99 mmol) was dissolved in dioxane (2 mL). HCl / dioxane (4 M, 5 mL) was then added and stirred at room temperature for 16 hours. The reaction mixture was directly spin-dried to obtain 140 mg of the desired product in an 84.3% yield.

[0330] LC / MS: m / z = 169.2 [M+H] + .

[0331] Step 4: Synthesis of 7-bromo-2,6-dichloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-fluoro-3,4-dihydroquinazolin-4-one

[0332] 7-Bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (2.0 g, 6.4 mmol) was weighed and dissolved in DCM (30 mL), and DIEA (2.0 g, 16 mmol) was added. After completion, SEM-Cl (1.38 g, 8.3 mmol) and TBAI (230 mg, 0.64 mmol) were added under stirring. The system was stirred at room temperature for 2 hours. Water was added and extracted with DCM (150 mL). The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain 1.89 g of a light yellow solid in a yield of 95.9%.

[0333] LC / MS: m / z=310.2[M+H] + .

[0334] Step 5: Synthesis of 7-bromo-6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-3,4-dihydroquinazolin-4-one (Trans racemate)

[0335] [3-(3,4,5-Trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (1.65 g, 6.0 mmol) was weighed and dissolved in THF. When the temperature dropped to 0°C, NaH (480 mg, 12.0 mmol) was slowly added. The system was reacted at this temperature for 0.5 hour. Then, a solution of 7-bromo-2,6-dichloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-fluoro-3,4-dihydroquinazolin-4-one (1.89 g, 6.0 mmol) in THF (15 mL) was added. The system was stirred and reacted at room temperature for 4 hours. Water (150 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA=4 / 1) to give 2.2 g of a white solid compound in a yield of 67.4%.

[0336] LC / MS: m / z=545.2[M+H] + .

[0337] Step 6: Synthesis of 2-methylpropan-2-yl({4-[6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-4-oxylidene-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0338] 7-Bromo-6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-3,4-dihydroquinazolin-4-one (Trans racemate) (2.2 g, 4.0 mmol), 2-methylpropane-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (1.61 g, 4.0 mmol), Cs2CO3 (2.6 g, 8.0 mmol) and toluene (25 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (286 mg, 0.1 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (200 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 1.5 g of a yellow solid with a yield of 49.6%.

[0339] LC / MS: m / z=757.2[M+H] + .

[0340] Step 7: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-hydroxy-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0341] 2-Methylpropane-2-yl({4-[6-chloro-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-fluoro-4-oxyylidene-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methane (Trans racemate) (1.0 g, 1.3 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (3 mL) was added. The system was stirred at room temperature for 2 hours, dried by spin drying, and the crude product was used directly in the next reaction.

[0342] LC / MS: m / z=658.2[M+H] + .

[0343] Step 8: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0344] To a reaction flask were added 2-amino-4-[6-chloro-8-fluoro-4-hydroxy-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate) (10 mg, 0.015 mmol), 3-methyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene hydrochloride (6 mg, 0.03 mmol), DIPEA (6 mg, 0.045 mmol) and dichloromethane (1.5 mL). After nitrogen replacement, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (6 mg, 0.02 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by pre-TLC (DCM / MeOH=15 / 1) to obtain 1 mg of a light yellow solid, with a yield of 8.3%.

[0345] LC / MS: m / z=808.2[M+H] + .

[0346] Example 4

[0347] 8-[7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxamide (Trans racemate)

[0348] Step 1: Synthesis of 2-methylprop-2-yl 4-methylideneazepane-1-carboxylate

[0349] Methyltriphenylphosphonium bromide (1.670 g, 4.6 mmol) was weighed and dissolved in THF (15 mL). The atmosphere was replaced with nitrogen three times. The reaction system was cooled to -30-35°C. N-butyllithium (2.7 mL, 6.9 mmol) was slowly added dropwise and maintained at -30-35°C. After the addition was complete, the reaction was allowed to proceed for 1 hour. 2-Methylpropane-2-oxyylideneazepane-1-carboxylate (1.002 g, 4.6 mmol) was dissolved in THF (7 mL). The above reaction system was added dropwise, maintaining the temperature at -10°C to -20°C. After the addition, the reaction was allowed to react at 0°C to -10°C for 1 hour. The reaction was then allowed to warm to room temperature and stirred for 16 hours. The reaction system was poured into a saturated aqueous solution of NH4Cl, and a small amount of solid NaCl was added. The upper organic phase was collected and dried. The residue was dissolved in ethyl acetate and water was added. The organic phase was collected and purified by column chromatography (PE / EA = 6 / 1) to obtain 560 mg of the target product in a yield of 56%.

[0350] LC / MS: m / z = 212.2 [M+H] + .

[0351] Step 2: Synthesis of ethyl 8-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxylate

[0352] 2-Methylprop-2-yl 4-methylideneazepane-1-carboxylate (290 mg, 1.3 mmol) was dissolved in a DCM / H2O (5 mL / 5 mL) mixed solvent, and then ethyl chlorooxime acetate (249 mg, 1.3 mmol) was added. The reaction was stirred at room temperature for 16 hours. DCM and water were added to the reaction, the DCM phase was collected and the organic phase was washed with saturated brine, then dried and spin-dried. The residue was purified by pre-TLC (PE / EA=3 / 1) to give 140 mg of the target product in a yield of 31%.

[0353] LC / MS: m / z=327.2[M+H] + .

[0354] Step 3: Synthesis of 8-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxylic acid

[0355] Ethyl 8-{[(2-methylprop-2-yl)oxy]carbonyl}-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxylate (140 mg, 0.4 mmol) was dissolved in ethanol / H2O (3 mL / 0.3 mL), and then solid NaOH (34 mg, 0.8 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was spin-dried, water was added, and the pH was adjusted to 3-4 with aqueous hydrochloric acid (2 M). EA was added for extraction and the layers were separated. The EA phase was collected, dried over sodium sulfate, and spin-dried to give 90 mg of the desired product in a yield of 70%.

[0356] LC / MS: m / z = 299.2 [M+H] + .

[0357] Step 4: Synthesis of 2-methylpropan-2-yl 3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-8-carboxylate

[0358] 8-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxylic acid (90 mg, 0.3 mmol) was dissolved in THF (2 mL), followed by the addition of DIEA (116 mg, 0.9 mmol) and HBTU (148 mg, 0.45 mmol). The mixture was stirred at room temperature for 10 minutes, and then a solution of dimethylamine (2 M in THF) (0.22 mL, 0.45 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. Water and EA were added to the reaction system, and the layers were separated. The EA phase was collected, dried over sodium sulfate, and then spin-dried. The resulting mixture was purified by Pre-TLC (PE / EA = 2 / 1) to give 42 mg of the desired product in a yield of 42%.

[0359] LC / MS: m / z=326.2[M+H] + .

[0360] Step 5: Synthesis of N,N-dimethyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxamide hydrochloride

[0361] 2-Methylprop-2-yl 3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-8-carboxylate (40 mg, 0.12 mmol) was dissolved in dioxane (0.5 mL). HCl / dioxane (4 M, 2 mL) was then added, and the reaction was stirred at room temperature for 16 hours. The reaction system was directly spin-dried to obtain 25 mg of the desired product in a yield of 78.1%.

[0362] LC / MS: m / z = 226.2 [M+H] + .

[0363] Step 6: Synthesis of 2-methylpropan-2-yl {[3-cyano-4-(2,6-dichloro-4-{3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl}-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}methane

[0364] 2-Methylpropane-2-yl {[3-cyano-4-(2,6-dichloro-8-fluoro-4-hydroxyquinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}methane ester (48 mg, 0.09 mmol) was dissolved in DCM (2 mL), and DIEA (34 mg, 0.27 mmol) and N,N-dimethyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-yl) were added. -formamide hydrochloride (25 mg, 0.09 mmol), and finally bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (45 mg, 0.18 mmol) were added, and the reaction was stirred at room temperature for 4 hours; DCM and water were added to the reaction system, and the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by Pre-TLC (PE / EA=2 / 1) to obtain 35 mg of the target product, with a yield of 54.6%.

[0365] LC / MS: m / z=730.2[M+H] + .

[0366] Step 7: Synthesis of 2-methylpropan-2-yl {[4-(6-chloro-4-{3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl}-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl]amino}methanoate (Trans racemate)

[0367] 2-Methylpropane-2-yl {[3-cyano-4-(2,6-dichloro-4-{3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl}-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}methane (35 mg, 0.05 mmol) was dissolved in DMF / THF (2 mL / 2 mL), and Cs2CO3 (49 mg, 0.15 mmol), DABCO (28 mg, 0.025 mmol) and [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (20 mg, 0.075 mmol) were added, and the mixture was stirred at 60°C for 16 hours. The reaction solution was added to water (20 mL), extracted three times with ethyl acetate, and the organic phase was dried and spin-dried. It was purified by pre-TLC (DCM / MeOH=20 / 1) to obtain 11 mg of light yellow solid, with a yield of 23.4%.

[0368] LC / MS: m / z = 965.2 [M+H] + .

[0369] Step 8: Synthesis of 8-[7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-2,8-diaza-1-oxaspiro[4.6]undec-2-ene-3-carboxamide (Trans racemate)

[0370] Weigh out 2-methylpropan-2-yl {[4-(6-chloro-4-{3-[(dimethylamino)carbonyl]-2,8-diaza-1-oxaspiro[4.6]undec-2-en-8-yl}-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl]amino}methanoate (Trans racemate) (11 mg, 0.01 mmol) was dissolved in DCM / TFA (1.2 mL / 0.4 mL), stirred at room temperature for 30 minutes, dried by rotation, added to a saturated aqueous NaHCO3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by pre-TLC (DCM / MeOH = 10 / 1) gave 1 mg of the target product in a yield of 11.8%.

[0371] LC / MS: m / z=865.2[M+H] + .

[0372] Example 5

[0373] 2-Methylpropane-2-[(4-{6-chloro-8-fluoro-4-[4-hydroxy-4-(trifluoromethyl)azepan-1-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]methane

[0374] Step 1: Synthesis of 2-methylpropan-2-yl 4-hydroxy-4-(trifluoromethyl)azepane-1-carboxylate

[0375] Weigh 2-methylpropane-2-yl 4-oxoazepane-1-carboxylate (1.0 g, 4.69 mmol) and dissolve it in THF (10 mL). After cooling to 0°C, add TMSCF3 (1.0 g, 7.0 mmol) and TBAF (2 mL, 1 M in THF). Stir the mixture at room temperature for 3 hours. The reaction mixture is added to water (100 mL) and extracted three times with ethyl acetate. The organic phase is dried and spin-dried to obtain 1.5 g (crude product), which is used directly in the next step.

[0376] LC / MS: m / z=284.1[M+H] + .

[0377] Step 2: Synthesis of 6-(trifluoromethyl)-1,4-oxazepan-6-ol hydrochloride

[0378] 2-Methylpropane-2-yl 4-hydroxy-4-(trifluoromethyl)azepane-1-carboxylate (1.5 g, crude product) was dissolved in hydrochloric acid / dioxane (4 M, 20 mL) and stirred at room temperature for 2 hours. The mixture was dried by vortexing and used directly in the next reaction.

[0379] LC / MS: m / z=184.1[M+H] + .

[0380] Step 3: Synthesis of 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-4-(trifluoromethyl)azepan-4-ol

[0381] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (200 mg, 0.65 mmol), 6-(trifluoromethyl)-1,4-oxazepan-6-ol hydrochloride (142 mg, 0.65 mmol), DIPEA (170 mg, 1.30 mmol), and dichloromethane (10 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (249 mg, 0.98 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (100 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 142 mg of a light yellow solid, with a yield of 46.3%.

[0382] LC / MS: m / z=476.0[M+H] + .

[0383] Step 4: Synthesis of 1-[7-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-4-(trifluoromethyl)azepan-4-ol (Trans racemate) 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-4-(trifluoromethyl)azepan-4-ol (142 mg, 0.30 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) were added to the reaction flask. Racemate (81 mg, 0.30 mmol) was added to DMF / THF (2 mL / 2 mL), followed by CS2CO3 (196 mg, 0.6 mmol) and DABCO (34 mg, 0.30 mmol). The mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (20 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain 82 mg of a yellow solid, with a yield of 38.7%.

[0384] LC / MS: m / z=711.1[M+H] + .

[0385] Step 5: Synthesis of 2-methylpropan-2-yl [(4-{6-chloro-8-fluoro-4-[4-hydroxy-4-(trifluoromethyl)azepan-1-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]methane ester (Trans racemate)

[0386] To the reaction flask was added 1-[7-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-4-(trifluoromethyl)azepan-4-ol (Trans racemate) (82 mg, 0.12 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (48 mg, 0.12 mmol), CS2CO3 (59 mg, 0.18 mmol) and toluene (2 mL). After replacing the atmosphere with nitrogen, Pd(DPEPhos)Cl2 (8.4 mg, 0.012 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 23 mg of a yellow solid, a yield of 21.7%.

[0387] LC / MS: m / z = 923.2 [M+H] + .

[0388] Step 6: Synthesis of 2-amino-4-{6-chloro-8-fluoro-4-[4-hydroxy-4-(trifluoromethyl)azepan-1-yl]-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl}-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0389] To a reaction flask, add 2-methylpropan-2-yl [(4-{6-chloro-8-fluoro-4-[4-hydroxy-4-(trifluoromethyl)azepan-1-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]methane (Trans racemate) (23 mg, 0.025 mmol) dissolved in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 30 minutes. The mixture is then spin-dried and added to a saturated aqueous NaHCO solution (10 mL). The mixture is extracted with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 9 mg of the desired product in a yield of 43.9%.

[0390] LC / MS: m / z=823.2[M+H]+ .

[0391] 1 H NMR(400MHz,d6-DMSO)δ1.27-1.49(2H,m),1.53-1.64(3H,m),1.72-2.34(11H,m),3.14-3.29(1H,m),3.58-3.88(2 H,m),4.01-4.28(4H,m),6.04(1H,brs),7.12-7.31(3H,m),7.79(1H,d,J=8.0Hz),7.83(1H,s),7.96-8.01(1H,m).

[0392] Example 6

[0393] 2-Amino-4-[6-chloro-8-fluoro-4-(4-hydroxy-4-methylazepan-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0394] Step 1: Synthesis of 2-methylpropan-2-yl 4-hydroxy-4-methylazepane-1-carboxylate

[0395] 2-Methylpropane-2-oxyylideneazepane-1-carboxylate (1.0 g, 4.69 mmol) was dissolved in THF (10 mL). The mixture was cooled to 0°C and then methylmagnesium bromide (3.1 mL, 3 M in THF) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was added to saturated aqueous ammonium chloride (50 mL) and extracted three times with ethyl acetate. The organic phase was dried and spin-dried, and purified by Prep-TLC (PE / EA = 4 / 1) to obtain 1.3 g of a colorless oil (yield: 31.0%).

[0396] LC / MS: m / z = 230.2 [M+H] + .

[0397] Step 2: Synthesis of 4-methylazepan-4-ol hydrochloride

[0398] 2-Methylpropane-2-yl 4-hydroxy-4-(methyl)azepane-1-carboxylate (1.3 g, 5.67 mmol) was dissolved in hydrochloric acid / dioxane (4 M, 10 mL) and stirred at room temperature for 2 hours. The mixture was dried and the crude product was used directly in the next reaction.

[0399] LC / MS: m / z = 130.1 [M+H] +.

[0400] Step 3: Synthesis of 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-4-methylazepan-4-ol

[0401] To a reaction flask were added 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (50 mg, 0.32 mmol), 4-methylazacycloheptan-4-ol hydrochloride (53 mg, 0.32 mmol), DIPEA (124 mg, 0.96 mmol), and dichloromethane (3 mL). After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 23 mg of a light yellow solid, with a yield of 33.8%.

[0402] LC / MS: m / z = 422.0 [M+H] + .

[0403] Step 4: Synthesis of 1-[7-bromo-6-chloro-8-fluoro-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulene-3a-yl]methyl}oxy)quinazolin-4-yl]-4-methylazepan-4-ol (Trans racemate)

[0404] To a reaction flask, 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-4-methylazepan-4-ol (23 mg, 0.055 mmol) and [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (trans racemate) (14 mg, 0.055 mmol) were added to DMF / THF (2 mL / 2 mL). CS2CO3 (27 mg, 0.083 mmol) and DABCO (6 mg, 0.055 mmol) were then added. The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain 15 mg of a yellow solid, with a yield of 41.9%.

[0405] LC / MS: m / z=657.1[M+H] + .

[0406] Step 5: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(4-hydroxy-4-methylazepan-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0407] To the reaction flask were added 1-[7-bromo-6-chloro-8-fluoro-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-4-yl]-4-methylazepan-4-ol (Trans racemate) (15 mg, 0.023 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (9 mg, 0.023 mmol), CS2CO3 (11 mg, 0.035 mmol) and toluene (2 mL). After replacing the atmosphere with nitrogen, Pd(DPEPhos)Cl2 (1.6 mg, 0.0023 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 6 mg of a yellow solid (yield: 30.3%).

[0408] LC / MS: m / z=869.3[M+H] + .

[0409] Step 6: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(4-hydroxy-4-methylazepan-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0410] To a reaction flask, 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(4-hydroxy-4-methylazepan-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methane (Trans racemate) (6 mg, 0.007 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 30 minutes. The mixture was spin-dried and added to a saturated aqueous NaHCO solution (10 mL). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 2 mg of the desired product in a yield of 37.7%.

[0411] LC / MS: m / z=769.2[M+H] + .

[0412] 1 H NMR(400MHz,d6-DMSO)δ1.56-1.71(4H,m),1.78-1.91(4H,m),1.92-2.02(4H,m),2.06-2.27(5H,m),3.54-3.65(1H,m),3.73-3.92(2 H,m),4.10-4.26(2H,m),4.41-4.43(1H,m),5.31-5.33(1H,m),7.12-7.33(3H,m),7.48-7.65(2H,m),7.97(0.6H,s),8.12(1.4H,s).

[0413] Example 7

[0414] 2-Amino-4-{6-chloro-8-fluoro-4-[(1S)-6-oxyylidene-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-11-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-7-yl}-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0415] Step 1: Synthesis of (1S)-11-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-6-one

[0416] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (60 mg, 0.19 mmol), cytisine (36 mg, 0.19 mmol), DIPEA (49 mg, 0.38 mmol), and dichloromethane (3 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (74 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 36 mg of a light yellow solid, with a yield of 38.7%.

[0417] LC / MS: m / z=483.0[M+H] + .

[0418] Step 2: Synthesis of (1S)-11-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-6-one (Trans racemate)

[0419] To the reaction flask were added (1S)-11-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-6-one (36 mg, 0.075 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate) (20 mg, 0.075 mmol), DMF / THF (2 mL / 2 mL), and then CS2CO3 (36 mg, 0.11 mmol) and DABCO (8.4 mg, 0.075 mmol). The mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 22 mg of a light yellow solid. Yield: 41.0%.

[0420] LC / MS: m / z=718.1[M+H] + .

[0421] Step 3: Synthesis of 2-methylpropan-2-yl [(4-{6-chloro-8-fluoro-4-[(1S,9R)-6-oxylidene-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-11-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]methane ester (Trans racemate)

[0422] (1S)-11-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-4-yl]-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-diene-6-one (Trans racemate) (22 mg, 0.03 mmol), 2-methylpropane-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (12 mg, 0.03 mmol), CS2CO3 (15 mg, 0.045 mmol) and toluene (2 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (2.1 mg, 0.003 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (20 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 14 mg of a yellow solid, yield: 49.1%.

[0423] LC / MS: m / z = 930.2 [M+H] + .

[0424] Step 4: Synthesis of 2-amino-4-{6-chloro-8-fluoro-4-[(1S)-6-oxylidene-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-11-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-7-yl}-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0425] To the reaction flask was added 2-methylpropan-2-yl [(4-{6-chloro-8-fluoro-4-[(1S,9R)-6-oxylidene-7,11-diazatricyclo[7.3.1.02,7]trideca-2(3),4-dien-11-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]methane (Trans racemate) (14 mg, 0.015 mmol) dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 30 minutes. The product was dried by spin drying, added to saturated aqueous NaHCO 3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to give 4 mg of the desired product in a yield of 32.0%.

[0426] LC / MS: m / z=830.2[M+H] + .

[0427] 1 H NMR (400MHz, d6-DMSO) δ1.64-2.19(6H,m),2.31-2.40(1H,m),2.63-2.70(2H,m),3.43-3.55(2H,m),3.59-3.82(2H,m),3.93-4. 60(6H,m),4.65-4.98(1H,m),6.23(1H,d,J=8.0Hz),6.29-6.44(1H,m),7.14-7.42(5H,m),7.55-7.68(1H,m),8.07-8.19(2H,m).

[0428] Example 8

[0429] 4-[4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0430] Step 1: Synthesis of 4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-7-bromo-2,6-dichloro-8-fluoroquinazoline

[0431] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (100 mg, 0.32 mmol), hexahydro-1H-furo[3,4-c]pyrrole (36 mg, 0.32 mmol), DIPEA (83 mg, 0.64 mmol), and dichloromethane (4 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 97 mg of a light yellow solid, with a yield of 74.3%.

[0432] LC / MS: m / z=406.0[M+H] + .

[0433] Step 2: Synthesis of 4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate)

[0434] To the reaction flask were added 4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-7-bromo-2,6-dichloro-8-fluoroquinazoline (97 mg, 0.24 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (65 mg, 0.24 mmol), and DMF / THF (2 mL / 2 mL) were added, followed by CS2CO3 (117 mg, 0.36 mmol) and DABCO (27 mg, 0.24 mmol), and the mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain 56 mg of a yellow solid, with a yield of 36.6%.

[0435] LC / MS: m / z=641.1[M+H] + .

[0436] Step 3: Synthesis of 2-methylpropan-2-yl({4-[4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0437] 4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate) (56 mg, 0.09 mmol), 2-methylpropane-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (36 mg, 0.09 mmol), CS2CO3 (46 mg, 0.14 mmol) and toluene (2 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (6.3 mg, 0.009 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (20 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 36 mg of a yellow solid with a yield of 48.3%.

[0438] LC / MS: m / z=853.2[M+H] + .

[0439] Step 4: Synthesis of 4-[4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0440] To the reaction flask was added 2-methylpropan-2-yl ({4-[4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate) (36 mg, 0.04 mmol) dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. The product was dried by spin drying, added to saturated aqueous NaHCO 3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to give 13 mg of the desired product in a yield of 40.9%.

[0441] LC / MS: m / z=753.2[M+H] + .

[0442] 1 H NMR(400MHz,d6-DMSO)δ1.64-1.69(2H,m),1.77-1.96(3H,m),2.04-2.24(3H,m),2.30-2.40(2H,m),2.98-3.17(3H,m),3.51 -3.97(6H,m),4.06-4.29(4H,m),7.13-7.37(3H,m),8.11(1H,s),8.16(1H,s),7.70-7.77(1H,m),7.95(1H,s),8.17(2H,s).

[0443] Example 9

[0444] 2-Amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0445] Step 1: Synthesis of 2-methylpropan-2-yl 6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate

[0446] 2-Methylpropane-2-yl 6-oxyylidene-1,4-oxazepane-4-carboxylate (1.0 g, 4.65 mmol) was dissolved in THF (10 mL). The mixture was cooled to 0°C and then methylmagnesium bromide (3.1 mL, 3 M) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was added to saturated ammonium chloride solution (100 mL) and extracted three times with ethyl acetate. The organic phase was dried and spin-dried. Purification by Prep-TLC (PE / EA = 3 / 1) afforded 0.7 g of a yellow oil, yielding 65.4%.

[0447] LC / MS: m / z = 232.2 [M+H] + .

[0448] Step 2: Synthesis of 6-methyl-1,4-oxazepan-6-ol hydrochloride

[0449] 2-Methylpropane-2-yl 6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (0.7 g, 3.03 mmol) was dissolved in 4M hydrochloric acid / dioxane (8 mL). The mixture was stirred at room temperature for 2 hours. The mixture was then dried and the crude product was used directly in the next reaction.

[0450] LC / MS: m / z=132.1[M+H] + .

[0451] Step 3: Synthesis of 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0452] To a reaction flask were added 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (100 mg, 0.32 mmol), 6-methyl-1,4-oxazepan-6-ol hydrochloride (53 mg, 0.32 mmol), DIPEA (124 mg, 0.96 mmol), and dichloromethane (5 mL). After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain 46 mg of a light yellow solid, with a yield of 33.8%.

[0453] LC / MS: m / z=424.0[M+H] + .

[0454] Step 4: Synthesis of 4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-6-methyl-1,4-oxazepan-6-ol (Trans isomer 2)

[0455] To a reaction flask were added 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (46 mg, 0.11 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans isomer 2) (30 mg, 0.11 mmol), and then DMF / THF (2 mL / 2 mL). CS2CO3 (55 mg, 0.17 mmol) and DABCO (12 mg, 0.11 mmol) were added. The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain 22 mg of a light yellow solid, a yield of 30.7%.

[0456] LC / MS: m / z=659.1[M+H] + .

[0457] Step 5: Synthesis of 2-methylpropan-2-yl({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0458] Add 4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-4-yl]-6-methyl-1,4-oxazepan-6-ol (Trans isomer 2) (22 mg, 0.033 mmol), {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylic acid-2-methylpropane-2-yl ester (13 mg, 0.033 mmol), CS2CO3 (15 mg, 0.045 mmol) and toluene (2 mL), after replacing nitrogen, Pd(DPEPhos)Cl2 (2.3 mg, 0.0033 mmol) was added. The reaction mixture was heated to 100 ° C. and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (20 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 12 mg of yellow solid, yield: 41.4%.

[0459] LC / MS: m / z = 871.2 [M+H] + .

[0460] Step 6: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0461] To the reaction flask was added 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2) (12 mg, 0.014 mmol) dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. The product was dried by spin drying, added to saturated aqueous NaHCO 3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to give 7 mg of the desired product in a yield of 66.0%.

[0462] LC / MS: m / z=771.2[M+H] + .

[0463] 1 H NMR(400MHz,d6-DMSO)δ1.52-1.70(3H,m),1.87-1.94(2H,m),1.97-2.02(2H,m),2.07-2.19(3H,m),2.30-2.38(1H,m),3.69-3.72(2H,m ),3.77-3.83(1H,m),3.90-4.03(3H,m),4.07-4.31(5H,m),5.28-5.41(2H,m),7.13-7.38(4H,m),8.11(2H,brs),8.55(1H,d,J=24.0Hz).

[0464] Step 7: Resolution of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0465] Separation method: Instrument: Waters SFC-80; Column: Chiralcel AD-3 (4.6*100 mm); Mobile phase: A (supercritical CO2), B (isopropanol, 0.2% 7M ammonia in isopropanol); Gradient: B% = 50%, Flow rate: 1.5 mL / min; Wavelength: 215 nm; Pressure: 2000 psi. Retention time of the first eluent, Rt = 1.446 min; retention time of the second eluent, Rt = 1.446 min; retention time of the third eluent, Rt = 2.247 min; retention time of the fourth eluent, Rt = 2.659 min.

[0466] The first eluting substance (retention time Rt=1.446 min) was defined as the compound of Example 10:

[0467] LC / MS: m / z=771.2[M+H] + .

[0468] The second eluting product (retention time Rt=1.446 min) was defined as the compound of Example 11:

[0469] LC / MS: m / z=771.2[M+H] + .

[0470] The third eluting product (retention time Rt=2.247 min) was defined as the compound of Example 12:

[0471] LC / MS: m / z=771.2[M+H] + .

[0472] 1 H NMR(400MHz,d6-DMSO)δ1.13(s,3H),8.50(s,1H),1.53-1.64(m,3H),1.84-1.86( m,2H),1.95-1.99(m,1H),2.06-2.11(m,2H),2.18-2.24(m,1H),2.35-2.50(m,1H ),3.55(s,2H),3.63-3.68(m,1H),3.88-3.98(m,3H),4.08-4.24(m,5H),5.27(s, 1H),7.16(dd,J=4.0Hz,8.0Hz,1H),7.25-7.32(m,3H),8.10(s,2H),8.51(s,1H).

[0473] The fourth eluting product (retention time Rt=2.659 min) was defined as the compound of Example 13:

[0474] LC / MS: m / z=771.2[M+H] + .

[0475] Example 14

[0476] 8-[7-(2-amino-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-8-aza-1-oxaspiro[4.5]decan-3-ol (Trans racemate)

[0477] Step 1: Synthesis of 8-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-8-aza-1-oxaspiro[4.5]decan-3-ol

[0478] 7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (100 mg, 0.32 mmol), 8-aza-1-oxaspiro[4.5]decan-3-ol (50 mg, 0.32 mmol), DIPEA (83 mg, 0.64 mmol), and dichloromethane (5 mL) were added to a reaction flask. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 70 mg of a white solid, with a yield of 53.6%.

[0479] LC / MS: m / z=406.1[M+H] + .

[0480] Step 2: Synthesis of 8-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-8-aza-1-oxaspiro[4.5]decan-3-ol (Trans racemate)

[0481] To the reaction flask were added 4-(3,3a,4,5,6,6a-hexahydro-1H-furo[4,3-c]pyrrol-5-yl)-7-bromo-2,6-dichloro-8-fluoroquinazoline (70 mg, 0.17 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (46 mg, 0.17 mmol), and DMF / THF (2 mL / 2 mL) were added. CS2CO3 (85 mg, 0.26 mmol) and DABCO (19 mg, 0.17 mmol) were added, and the mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain 33 mg of a yellow solid, with a yield of 28.0%.

[0482] LC / MS: m / z=685.1[M+H] + .

[0483] Step 3: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(3-hydroxy-8-aza-1-oxaspiro[4.5]dec-8-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0484] 8-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-8-aza-1-oxaspiro[4.5]decan-3-ol (Trans racemate) (33 mg, 0.048 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (19 mg, 0.048 mmol), CS2CO3 (23 mg, 0.072 mmol) and toluene (2 mL), after nitrogen replacement, Pd(DPEPhos)Cl2 (3.4 mg, 0.0048 mmol) was added. The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen protection. The reaction system was cooled to room temperature and poured into water (20 mL), extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 16 mg of a yellow solid, with a yield of 37.2%.

[0485] LC / MS: m / z=897.2[M+H] + .

[0486] Step 4: Synthesis of 8-[7-(2-amino-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-8-aza-1-oxaspiro[4.5]decan-3-ol (Trans racemate)

[0487] To a reaction flask, 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(3-hydroxy-8-aza-1-oxaspiro[4.5]dec-8-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophen-2-yl}amino)methane (trans racemate) (16 mg, 0.018 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 30 minutes. The mixture was then dried and added to a saturated aqueous NaHCO solution (10 mL). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to afford 3 mg of the desired product in a yield of 26.1%.

[0488] LC / MS: m / z=797.2[M+H] + .

[0489] Example 15

[0490] 2-Amino-4-[6-amino-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0491] Step 1: Synthesis of 7-bromo-2,6-dichloro-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)quinazoline

[0492] 7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (100 mg, 0.32 mmol), 3-methoxytetrahydropyrrole (32 mg, 0.32 mmol), DIPEA (83 mg, 0.64 mmol), and dichloromethane (3 mL) were added to a reaction flask. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 88 mg of a light yellow solid, with a yield of 69.3%.

[0493] LC / MS: m / z=394.0[M+H] + .

[0494] Step 2: Synthesis of 7-bromo-6-chloro-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate)

[0495] To a reaction flask were added 7-bromo-2,6-dichloro-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)quinazoline (88 mg, 0.22 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (trans racemate) (60 mg, 0.22 mmol), and then DMF / THF (2 mL / 2 mL). CS2CO3 (108 mg, 0.33 mmol) and DABCO (25 mg, 0.22 mmol). The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to afford 51 mg of a light yellow solid (yield: 36.2%).

[0496] LC / MS: m / z=629.1[M+H] + .

[0497] Step 3: Synthesis of 2-methylpropan-2-yl ({4-[6-amino-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0498] To a reaction flask were added 7-bromo-6-chloro-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate) (51 mg, 0.08 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (32 mg, 0.08 mmol), CS2CO3 (39 mg, 0.12 mmol) and toluene (2 mL). After nitrogen replacement, Pd(DPEPhos)Cl2 (5.6 mg, 0.008 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 15 mg of a yellow solid (yield: 22.0%).

[0499] LC / MS: m / z=841.2[M+H] + .

[0500] Step 4: Synthesis of 2-amino-4-[6-amino-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0501] To a reaction flask, add 2-methylpropan-2-yl ({4-[6-amino-8-fluoro-4-(3-methoxytetrahydro-1H-pyrrol-1-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methane (Trans racemate) (15 mg, 0.018 mmol) and dissolve in dichloromethane (3 mL). Add trifluoroacetic acid (1 mL) and stir at room temperature for 30 minutes. The mixture is then spin-dried and added to a saturated aqueous NaHCO solution (10 mL). Extraction is carried out with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to afford 6 mg of the desired product in a yield of 45.5%.

[0502] LC / MS: m / z=741.2[M+H] + .

[0503] 1 H NMR(400MHz,d6-DMSO)δ1.41-1.53(2H,m),1.58-1.64(1H,m),1.81-1.89(1H,m),1.97-2.04(4H,m),2.06-2.10(1H,m),2.15-2.24(1H,m ),3.26-3.30(3H,m),3.48-3.52(1H,m),3.79-4.34(8H,m),5.27-5.38(1H,m),6.61-6.70(1H,m),7.08-7.33(4H,m),8.09-8.15(2H,m).

[0504] Example 16

[0505] 4-[7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-1,4-oxazepane-2-carboxamide (Trans racemate)

[0506] Step 1: Synthesis of 2-methylpropan-2-yl 2-[(dimethylamino)carbonyl]-1,4-oxazepane-4-carboxylate

[0507] 4-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,4-oxazepane-2-carboxylic acid (50 mg, 0.20 mmol), dimethylamine (0.1 mL, 0.30 mmol), DIEA (53 mg, 0.41 mmol), and HBTU (101 mg, 0.27 mmol) were dissolved in THF (2 mL) and stirred at room temperature for 3 hours. The reaction mixture was added to water (10 mL) and extracted three times with ethyl acetate. The organic phase was dried and spin-dried, and purified by Prep-TLC (PE / EA = 1 / 1) to obtain 50 mg of a colorless oil, with a yield of 90.0%.

[0508] LC / MS: m / z = 273.2 [M+H] + .

[0509] Step 2: Synthesis of N,N-dimethyl-1,4-oxazepane-2-carboxamide hydrochloride

[0510] 2-[(Dimethylamino)carbonyl]-1,4-oxazepane-4-carboxylic acid 2-methylprop-2-yl ester (50 mg, 0.18 mmol) was dissolved in hydrochloric acid / dioxane (4 M, 2 mL) and stirred at room temperature for 2 hours. The product was dried to give 43 mg of the crude product, which was used directly in the next reaction.

[0511] LC / MS: m / z = 173.1 [M+H] + .

[0512] Step 3: Synthesis of 4-(7-bromo-2,6-dichloro-8-fluoro-1,2-dihydroquinazolin-4-yl)-N,N-dimethyl-1,4-oxazepane-2-carboxamide

[0513] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (50 mg, 0.16 mmol), N,N-dimethyl-1,4-oxazepane-2-carboxamide hydrochloride (43 mg, 0.21 mmol), DIPEA (62 mg, 0.48 mmol), and dichloromethane (1 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (61 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 40 mg of a light yellow solid, with a yield of 53.5%.

[0514] LC / MS: m / z=465.1[M+H] + .

[0515] Step 4: Synthesis of 4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-1,4-oxazepane-2-carboxamide (Trans racemate)

[0516] To the reaction flask were added 4-(7-bromo-2,6-dichloro-8-fluoro-1,2-dihydroquinazolin-4-yl)-N,N-dimethyl-1,4-oxazepane-2-carboxamide (40 mg, 0.09 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate) (25 mg, 0.09 mmol), and then DMF / THF (2 mL / 2 mL) were added. CS2CO3 (46 mg, 0.14 mmol) and DABCO (10 mg, 0.09 mmol) were added, and the mixture was stirred at 60°C for 5 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane, and the organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain 39 mg of a yellow solid. Yield: 65.0%.

[0517] LC / MS: m / z=700.1[M+H] + .

[0518] Step 5: Synthesis of 2-methylpropan-2-yl {[4-(6-chloro-4-{2-[(dimethylamino)carbonyl]-1,4-oxazepan-4-yl}-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl]amino}methane

[0519] To a reaction flask were added 4-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-1,4-oxazepane-2-carboxamide (Trans racemate) (39 mg, 0.06 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (24 mg, 0.06 mmol), CS2CO3 (29 mg, 0.09 mmol) and toluene (2 mL). After replacing the atmosphere with nitrogen, Pd(DPEPhos)Cl2 (4.2 mg, 0.006 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 12 mg of a yellow solid (yield: 23.5%).

[0520] LC / MS: m / z = 912.2 [M+H] + .

[0521] Step 6: Synthesis of 4-[7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-N,N-dimethyl-1,4-oxazepane-2-carboxamide (Trans racemate)

[0522] To the reaction flask was added 2-methylpropan-2-yl {[4-(6-chloro-4-{2-[(dimethylamino)carbonyl]-1,4-oxazepan-4-yl}-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl]amino}methane (Trans racemate) (12 mg, 0.013 mmol) dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. The product was dried by spin drying, added to saturated aqueous NaHCO 3 solution (10 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to give 3 mg of the desired product in a yield of 28.0%.

[0523] LC / MS: m / z=812.2[M+H] + .

[0524] Example 17

[0525] 2-Amino-4-[6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0526] Step 1: Synthesis of 7-bromo-2,6-dichloro-8-fluoro-4-(1,4-oxazacyclohexan-4-yl)quinazoline

[0527] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (100 mg, 0.32 mmol), morpholine (28 mg, 0.32 mmol), DIPEA (83 mg, 0.64 mmol), and dichloromethane (3 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (122 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 91 mg of a light yellow solid, with a yield of 74.4%.

[0528] LC / MS: m / z=380.1[M+H] + .

[0529] Step 2: Synthesis of 7-bromo-6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate)

[0530] To a reaction flask were added 7-bromo-2,6-dichloro-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline (91 mg, 0.24 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (trans racemate) (65 mg, 0.24 mmol), and then DMF / THF (2 mL / 2 mL). CS2CO3 (117 mg, 0.36 mmol) and DABCO (27 mg, 0.24 mmol). The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain 63 mg of a light yellow solid, a yield of 42.7%.

[0531] LC / MS: m / z=615.1[M+H] + .

[0532] Step 3: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methanoate (Trans racemate)

[0533] To the reaction flask were added 7-bromo-6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazoline (Trans racemate) (63 mg, 0.10 mmol), 2-methylpropan-2-yl {[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluorobenzo[b]thiophen-2-yl]amino}carboxylate (40 mg, 0.10 mmol), CS2CO3 (49 mg, 0.15 mmol) and toluene (2 mL). After nitrogen replacement, Pd(DPEPhos)Cl2 (7.0 mg, 0.001 mmol) was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 19 mg of a yellow solid (yield: 22.4%).

[0534] LC / MS: m / z=827.2[M+H] + .

[0535] Step 4: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0536] To a reaction flask, add 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)methane (Trans racemate) (19 mg, 0.023 mmol) dissolved in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 30 minutes. The mixture is then dried and added to a saturated aqueous NaHCO solution (10 mL). The mixture is extracted with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to afford 10 mg of the desired product in a yield of 59.9%.

[0537] LC / MS: m / z=727.2[M+H] + .

[0538] 1 H NMR(400MHz,d6-DMSO)δ1.41-1.53(2H,m),1.58-1.64(1H,m),1.81-1.89(1H,m),1.97-2.04(4H,m),2.06-2.10(1H,m),2.15-2.24(1H,m ),3.26-3.30(3H,m),3.48-3.52(1H,m),3.79-4.34(8H,m),5.27-5.38(1H,m),6.61-6.70(1H,m),7.08-7.33(4H,m),8.09-8.15(2H,m).

[0539] Example 18

[0540] 2-Amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer2)

[0541] Step 1: Synthesis of 2-amino-4-bromo-3-fluorobenzamide

[0542] To a reaction flask, 2-amino-4-bromo-3-fluorobenzene-1-carboxylic acid (350 g, 284.6 mol), ammonium chloride (280 g, 5.233 mol), and DMF (3.5 L) were added. DIPEA (868 g, 6.729 mmol) and HBTU (850 g, 2.243 mol) were then added sequentially. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (14 L), whereupon a large amount of brown solid precipitated. After stirring for 0.5 hours, the mixture was filtered, the filter cake rinsed with a small amount of water, and then dried to yield 210 g of the desired product. Total yield: 60.2%.

[0543] LC / MS: m / z = 233.1 [M+H] + .

[0544] Step 2: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0545] 2-Amino-4-bromo-3-fluorobenzamide (68 g, 0.29 mol), potassium tert-butoxide (71.6 g, 0.73 mol), and biboronic acid pinacol ester (111.3 g, 0.44 mol) were added to the reaction flask, and then dioxane (680 mL) solution was added. After nitrogen was replaced three times in the system, Pd(dppf)Cl2 (4.0 g, 0.005 mol) was added, and the system was heated to 95 ° C for 3 hours. Then, {[3-cyano-4- 2-Methylpropane-2-yl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylate (8.5 g, 0.19 mol), Cs2CO3 (142.4 g, 0.44 mol), and water (136 mL) were added, followed by Pd(dppf)Cl2 (2.0 g, 0.002 mol). The reaction mixture was heated to 95°C under nitrogen and stirred for 12 hours. The reaction system was cooled to room temperature and poured into water (1 L). The mixture was extracted with ethyl acetate, and the organic phase was dried and spin-dried to obtain 76.5 g, which was used directly in the next step.

[0546] LC / MS: m / z=427.1[M+H] + .

[0547] Step 3: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-6-chloro-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0548] To the reaction flask was added 2-methylpropane-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (2 g, 4.69 mmol), followed by NMP, and then NCS (747 mg, 5.62 mmol) was slowly added. The system was reacted at room temperature overnight. The reaction system was poured into water, extracted with ethyl acetate, and washed twice with saturated brine. The crude product was dried and concentrated to give 1.8 g by Prep-TLC, with a yield of 85%.

[0549] LC / MS: m / z=461.2[M+H] + .

[0550] Step 4: Synthesis of 2-methylpropan-2-yl {[4-(6-chloro-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0551] Dissolve 2-methylpropan-2-yl {[4-(3-amino-6-chloro-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (1.8 g, 3.9 mmol) in 1,4-dioxane (18 mL). After replacing the nitrogen atmosphere, a solution of thiophosgene (1.69 g, 11.7 mmol) in 1,4-dioxane (9 mL) was added dropwise at room temperature. Stir the mixture at room temperature for 1 hour, then heat to 80°C and stir for 0.5 hour. The mixture was added to water, extracted with ethyl acetate, dried, and concentrated to dryness. Prep-TLC yielded 925 mg, a 47% yield.

[0552] LC / MS: m / z = 505.1 [M+H] +

[0553] Step 5: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane

[0554] To a reaction flask, 2-methylpropan-2-yl {[4-(6-chloro-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (900 mg, 1.78 mmol), 6-methyl-1,4-oxazepan-6-ol hydrochloride (440 mg, 2.67 mmol), DIPEA (918 mg, 7.12 mmol), and dichloromethane (10 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (904 mg, 3.56 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 659 mg of the product (yield: 60%).

[0555] LC / MS: m / z=618.1[M+H] + .

[0556] Step 6: Synthesis of 2-methylpropan-2-yl({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0557] To the reaction bottle was added 2-methylpropan-2-yl ({4-[6-chloro-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (600 mg, 0.97 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Transisomer 2) (314 mg, 1.16 mmol), and DMF / THF (7 mL / 7 mL) were added. CS2CO3 (632 mg, 1.94 mmol) and DABCO (32 mg, 0.29 mmol) were added, and the mixture was stirred at 45°C for overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 330 mg of the compound with a yield of 40%.

[0558] LC / MS: m / z=853.1[M+H] + .

[0559] Step 7: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0560] To the reaction flask was added 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (Trans isomer 2) (330 mg, 0.38 mmol) dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was dried by spin drying and added to a saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 120 mg of the desired product in a yield of 42%.

[0561] LC / MS: m / z=753.1[M+H] + .

[0562] 1H NMR(400MHz,d6-DMSO)δ8.54(d,J=26.0Hz,1H),7.89-7.75(m,3H),7.22(ddd,J=23.7,19.3,16.8Hz,4H),4.19(dd,J=47.3,14.9Hz,5H),4.00-3.8 0(m,3H),3.72(d,J=8.2Hz,1H),3.56(d,J=5.6Hz,2H),2.36(s,1H),2.13 (s,2H),2.05-1.80(m,4H),1.56(d,J=83.3Hz,3H),1.15(d,J=8.3Hz,3H).

[0563] Step 8: Resolution of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0564] Separation method: Instrument: Waters SFC-80; Column: Chiralcel AD-3 (4.6*100 mm); Mobile phase: A (supercritical CO2), B (isopropanol, 0.2% 7M ammonia in isopropanol); Gradient: B% = 45%, Flow rate: 1.5 mL / min; Wavelength: 215 nm; Pressure: 2000 psi. Retention time of the first eluent: Rt = 1.915 min, retention time of the second eluent: Rt = 2.066 min, retention time of the third eluent: Rt = 2.955 min, and retention time of the fourth eluent: Rt = 3.606 min.

[0565] The first eluting substance (retention time Rt=1.915 min) was defined as the compound of Example 19:

[0566] LC / MS: m / z=753.1[M+H] + .

[0567] The second eluting product (retention time Rt=2.066 min) was defined as the compound of Example 20:

[0568] LC / MS: m / z=753.1[M+H] + .

[0569] The third eluting product (retention time Rt=2.955 min) was defined as the compound of Example 21:

[0570] LC / MS: m / z=753.1[M+H]+ .

[0571] 1 H NMR (400MHz, d6-DMSO) δ8.50 (s, 1H), 7.89-7.76 (m, 3H), 7.25 (ddd, J = 26.0, 17.0, 7.3Hz, 4 H),5.29(s,1H),4.18(ddd,J=35.7,22.5,12.1Hz,5H),3.96(ddd,J=32.8,19.6,10.8Hz,3H ),3.72(dd,J=9.6,5.0Hz,1H),3.60-3.50(m,2H),2.39-2.31(m,1H),2.20(dd,J=16.3,8. 3Hz,1H),2.09(dt,J=21.8,9.0Hz,2H),1.96-1.79(m,3H),1.69-1.49(m,3H),1.13(s,3H).

[0572] The fourth eluting product (retention time Rt=3.606 min) was defined as the compound of Example 22:

[0573] LC / MS: m / z=797.2[M+H] + .

[0574] Example 23

[0575] 2-Amino-4-[6-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0576] Step 1: Synthesis of 2-amino-4-bromo-3-fluorobenzamide

[0577] To a reaction flask, 2-amino-4-bromo-3-fluorobenzene-1-carboxylic acid (350 g, 284.6 mol), ammonium chloride (280 g, 5.233 mol), and DMF (3.5 L) were added. DIPEA (868 g, 6.729 mmol) and HBTU (850 g, 2.243 mol) were then added sequentially. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (14 L), whereupon a large amount of brown solid precipitated. After stirring for 0.5 hours, the mixture was filtered, the filter cake rinsed with a small amount of water, and then dried to yield 210 g of the desired product. Total yield: 60.2%.

[0578] LC / MS: m / z = 233.1 [M+H]+ .

[0579] Step 2: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0580] 2-Amino-4-bromo-3-fluorobenzamide (68 g, 0.29 mol), potassium tert-butoxide (71.6 g, 0.73 mol), and biboronic acid pinacol ester (111.3 g, 0.44 mol) were added to the reaction flask, and dioxane (680 mL) was added. After nitrogen was replaced three times in the system, Pd(dppf)Cl2 (4.0 g, 0.005 mol) was added, and the system was heated to 95 ° C for 3 hours. Then, {[3-cyano-4-( 2-Methylpropane-2-yl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylate (8.5 g, 0.19 mol), CS2CO3 (142.4 g, 0.44 mol), and water (136 mL) were added, followed by Pd(dppf)Cl2 (2.0 g, 0.002 mol). The reaction mixture was heated to 95°C under nitrogen and stirred for 12 hours. The reaction system was cooled to room temperature and poured into water (1 L). Extraction was performed with ethyl acetate, and the organic phase was dried and spin-dried to yield 76.5 g, which was used directly in the next step.

[0581] LC / MS: m / z=427.1[M+H] + .

[0582] Step 3: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-6-bromo-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0583] To the reaction flask was added 2-methylpropane-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (197 mg, 0.46 mmol), NMP (2 mL) was added, and NBS (82 mg, 0.46 mmol) was slowly added. The system was reacted at room temperature for 6 minutes. The reaction system was poured into water, extracted with ethyl acetate, dried and concentrated to give a crude product, which was purified on a silica gel plate to give 129 mg, with a yield of 55%.

[0584] LC / MS: m / z = 505.2 [M+H] + .

[0585] Step 4: Synthesis of 2-methylpropan-2-yl {[4-(6-bromo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0586] Dissolve 2-methylpropan-2-yl {[4-(3-amino-6-bromo-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (129 mg, 0.26 mmol) in 1,4-dioxane (5 mL). After replacing the nitrogen atmosphere, a solution of thiophosgene (88 mg, 0.78 mmol) in 1,4-dioxane (2 mL) was added dropwise at room temperature. Stir the mixture at room temperature for 1 hour, then heat to 80°C and stir for 0.5 hour. The mixture was added to water, extracted with ethyl acetate, dried, and concentrated to dryness. Purification on silica gel plate afforded 69 mg of the product, yield: 49%.

[0587] LC / MS: m / z=549.0[M+H] + .

[0588] Step 5: Synthesis of 2-methylpropan-2-yl ({4-[6-bromo-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate

[0589] To a reaction flask, 2-methylpropan-2-yl {[4-(6-bromo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (69 mg, 0.13 mmol), 6-methyl-1,4-oxazepan-6-ol hydrochloride (31 mg, 0.20 mmol), DIPEA (49 mg, 0.39 mmol), and dichloromethane (4 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (48 mg, 0.20 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 49 mg of the product (yield: 59%).

[0590] LC / MS: m / z=662.1[M+H] + .

[0591] Step 6: Synthesis of 2-methylpropan-2-yl({4-[6-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0592] To the reaction flask were added 2-methylpropan-2-yl ({4-[6-bromo-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (49 mg, 0.07 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans isomer 2) (24 mg, 0.09 mmol), and DMF / THF (2 mL / 2 mL) were added. CS2CO3 (72 mg, 0.21 mmol) and DABCO (3 mg, 0.03 mmol) were added, and the mixture was stirred at 45°C for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by column chromatography to obtain 29 mg of the compound with a yield of 44%.

[0593] LC / MS: m / z=897.1[M+H] + .

[0594] Step 7: Synthesis of 2-amino-4-[6-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0595] To the reaction flask was added 2-methylpropan-2-yl ({4-[6-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (Trans isomer 2) (29 mg, 0.03 mmol) dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then dried and added to a saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 8 mg of the desired product in a yield of 31%.

[0596] LC / MS: m / z=797.2[M+H] + .

[0597] 1 H NMR(400MHz,d6-DMSO)δ1.15(3H,s),1.55-1.64(4H,m),1.82-1.87(2H,m),1.93-2.01(1H,m),2. 07-2.13(2H,m),2.15-2.21(1H,m),2.33-2.37(1H,m),3.56(2H,s),3.68-3.73(1H,m),3.79-3.8 4(1H,m),3.93-3.97(1H,m),4.11-4.15(2H,m),4.19-4.27(2H,m),5.36(3H,s),7.12(2H,d,J=8. 0Hz),7.22(1H,d,J=8.0Hz),7.25-7.30(2H,m),7.78(1H,d,J=8.0Hz),7.82(2H,s),8.72(1H,s).

[0598] Step 8: Chiral resolution of 2-amino-4-[6-bromo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0599] The product from the previous step is subjected to SFC separation to obtain a single-configuration compound.

[0600] Separation method: Instrument: Waters SFC-80; Column: Chiralcel AD-3 (4.6 x 100 mm); Mobile phase: A (supercritical CO2), B (isopropanol containing 0.2% DEA); Gradient: B% = 45%, Flow rate: 1.5 mL / min; Wavelength: 254 nm; Pressure: 2000 psi. Retention time of the first eluent: Rt = 1.933 min, retention time of the second eluent: Rt = 2.156 min, retention time of the third eluent: Rt = 3.006 min, and retention time of the fourth eluent: Rt = 3.485 min.

[0601] The first eluting substance (retention time Rt=1.933 min) was defined as the compound of Example 24:

[0602] LC / MS: m / z=797.2[M+H] + .

[0603] 1 H NMR(400MHz,d6-DMSO)δ1.16(3H,s),1.53-1.65(4H,m),1.83-1.87(2H,m),1.95-2.00(1H,m ),2.09-2.12(2H,m),2.19-2.22(1H,m),2.33-2.36(1H,m),3.56(2H,s),3.69-3.73(1H,m), 3.79-3.83(1H,m),3.94-3.96(2H,m),4.10-4.47(3H,m),5.42(3H,s),7.13(2H,d,J=8.0Hz) ,7.22(1H,t,J=8.0Hz),7.29-7.34(2H,m),7.79(1H,d,J=8.0Hz),7.82(2H,s),8.72(1H,s).

[0604] The second eluting product (retention time Rt=2.156 min) was defined as the compound of Example 25:

[0605] LC / MS: m / z=797.2[M+H] + .

[0606] 1H NMR(400MHz,d6-DMSO)δ1.15(3H,s),1.55-1.63(4H,m),1.84-1.86(2H,m),1.92-1.95(1H,m),2. 08-2.12(2H,m),2.18-2.20(1H,m),2.34-2.36(1H,m),3.56(2H,s),3.69-3.72(1H,m),3.80-3.8 3(1H,m),3.94-3.96(2H,m),4.10-4.15(2H,m),4.19-4.27(2H,m),5.36(3H,s),7.12(2H,d,J=8. 0Hz),7.22(1H,d,J=8.0Hz),7.24-7.30(2H,m),7.78(1H,d,J=8.0Hz),7.82(2H,s),8.72(1H,s).

[0607] The third eluting product (retention time Rt=3.006 min) was defined as the compound of Example 26:

[0608] LC / MS: m / z=797.2[M+H] + .

[0609] 1 H NMR(400MHz,d6-DMSO)δ1.14(3H,s),1.55-1.64(4H,m),1.84-1.86(2H,m),1.94-2.00(1H,m ),2.09-2.11(2H,m),2.19-2.21(1H,m),2.32-2.35(1H,m),3.55(2H,s),3.71-3.74(1H,m), 3.88-3.92(1H,m),3.94-4.00(2H,m),4.08-4.23(4H,m),5.29(3H,s),7.16(2H,d,J=8.0Hz) ,7.24(1H,t,J=8.0Hz),7.29-7.33(2H,m),7.78(1H,d,J=8.0Hz),7.82(2H,s),8.66(1H,s).

[0610] The fourth eluting product (retention time Rt=3.485 min) was defined as the compound of Example 27:

[0611] LC / MS: m / z=797.2[M+H] + .

[0612] 1H NMR(400MHz,d6-DMSO)δ1.16(3H,s),1.53-1.63(4H,m),1.82-1.85(2H,m),1.90-1.95(1H,m ),2.09-2.13(2H,m),2.19-2.22(1H,m),2.31-2.33(1H,m),3.54(2H,s),3.70-3.74(1H,m), 3.88-3.93(1H,m),3.94-4.01(2H,m),4.05-4.21(4H,m),5.30(3H,s),7.15(2H,d,J=8.0Hz) ,7.22(1H,t,J=8.0Hz),7.29-7.34(2H,m),7.79(1H,d,J=8.0Hz),7.81(2H,s),8.68(1H,s).

[0613] Example 28

[0614] 2-Amino-4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer2)

[0615] Step 1: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-6-iodo-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0616] To the reaction flask was added 2-methylpropane-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (2.0 g, 4.69 mmol), followed by NMP (30 mL), and then slowly added NIS (2.1 g, 9.39 mmol). The system was reacted at room temperature for 12 hours. The reaction system was poured into water, the precipitated solid was filtered and concentrated to obtain 3.3 g (crude product), which was directly used in the next reaction.

[0617] LC / MS: m / z=553.2[M+H] + .

[0618] Step 2: Synthesis of 2-methylpropan-2-yl {[4-(6-iodo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0619] Dissolve 2-methylpropane-2-yl {[4-(3-amino-6-iodo-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (2.6 g, 4.7 mmol) in 1,4-dioxane (26 mL). After replacing the nitrogen atmosphere, add a solution of thiophosgene (1.6 g, 14.1 mmol) in 1,4-dioxane (26 mL) dropwise at room temperature. After addition, heat to 100°C and stir for 1 hour. Add the mixture to water, extract with ethyl acetate, dry, and concentrate to yield 2.38 g (crude product).

[0620] LC / MS: m / z = 597.1.0 [M+H] + .

[0621] Step 3: Synthesis of 2-methylpropan-2-yl ({4-[6-iodo-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate

[0622] To a reaction flask, 2-methylpropan-2-yl {[4-(6-iodo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (2.38 g, 3.99 mmol), 6-methyl-1,4-oxazepan-6-ol hydrochloride (800 mg, 4.79 mmol), DIPEA (1.03 mg, 7.98 mmol), and dichloromethane (25 mL) were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (2.03 g, 7.98 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by column chromatography to obtain 2.0 g of the product. The total yield of the three-step reaction was 60.2%.

[0623] LC / MS: m / z=710.0[M+H] + .

[0624] Step 4: Synthesis of 2-methylpropan-2-yl({4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0625] To the reaction flask were added 2-methylpropan-2-yl ({4-[6-iodo-2-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane ester (2.0 g, 3.29 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2) (1.07 g, 3.95 mmol), DMF / THF (5 mL / 5 mL) was added, CS2CO3 (2.14 g, 6.58 mmol) and DABCO (111 mg, 0.99 mmol) were added, and the mixture was stirred at 45 ° C for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by column chromatography to obtain 1.8 g, yield: 67.7%.

[0626] LC / MS: m / z=897.1[M+H] + .

[0627] Step 5: Synthesis of 2-amino-4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0628] To the reaction flask was added 2-methylpropan-2-yl ({4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2) (1.8 g, 1.91 mmol) dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was spin-dried, added to saturated aqueous NaHCO 3 solution (20 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / NH 3 in MeOH solution = 100 / 1) to give 1.5 g of the desired product in a yield of 60.8%.

[0629] LC / MS: m / z=845.1[M+H] + .

[0630] 1H NMR(400MHz,d6-DMSO)δ1.15(3H,d,J=8.0Hz),1.54-1.63(4H,m),1.83-1.88(2H,m),1 .92-1.98(1H,m),2.04-2.11(2H,m),2.13-2.18(1H,m),2.31-2.36(1H,m),3.55(2H,s) ,3.69-3.75(1H,m),3.80-3.84(1H,m),3.92-3.97(2H,m),4.12-4.23(4H,m),5.29-5. 40(1H,m),7.04-7.07(1H,m),7.21-7.34(3H,m),7.77-7.81(3H,m),7.83-7.87(1H,m).

[0631] Step 6: Resolution of 2-amino-4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0632] The product from the previous step is subjected to SFC separation to obtain a single configuration compound.

[0633] Separation method: Instrument: Waters SFC-80; Column: Chiralcel AD-3 (4.6*100 mm); Mobile phase: A (supercritical CO2), B (isopropanol containing 0.2% DEA); Gradient: B% = 45%, Flow rate: 1.5 mL / min; Wavelength: 254 nm; Pressure: 2000 psi. Retention time of the first eluent: Rt = 1.988 min, retention time of the second eluent: Rt = 2.290 min, retention time of the third eluent: Rt = 3.095 min, and retention time of the fourth eluent: Rt = 3.502 min.

[0634] The first eluting product (retention time Rt=1.988 min) was defined as the compound of Example 29:

[0635] LC / MS: m / z=845.1[M+H] + .

[0636] The second eluting product (retention time Rt=2.290 min) was defined as the compound of Example 30:

[0637] LC / MS: m / z=845.1[M+H] + .

[0638] The third eluting product (retention time Rt=3.095 min) was defined as the compound of Example 31:

[0639] LC / MS: m / z=845.1[M+H] + .

[0640] 1 H NMR(400MHz,d6-DMSO)δ8.83(s,1H),7.79(d,J=8.1Hz,3H),7.35-7.22(m,3H),7.10(d,J= 7.3Hz,1H),5.28(s,1H),4.17(ddd,J=22.0,16.8,8.2Hz,5H),4.02-3.89(m,3H),3.77-3. 70(m,1H),3.55(q,J=12.3Hz,2H),2.38-2.33(m,1H),2.21(dd,J=16.2,8.3Hz,1H),2.15- 2.06(m,2H),1.95(s,1H),1.89-1.81(m,2H),1.64(s,2H),1.58-1.52(m,1H),1.15(s,3H).

[0641] The fourth eluting compound (retention time Rt=3.502 min) was defined as the compound of Example 32:

[0642] LC / MS: m / z=845.1[M+H] + .

[0643] Example 33

[0644] 2-Amino-4-{6-[dimethyl(oxyylidene)-λ5-methylphosphino]-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0645] Step 1: Synthesis of 2-methylpropan-2-yl [(3-cyano-4-{6-[dimethyl(oxyylidene)-λ5-methylphosphino]-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}benzo[b]thiophen-2-yl)amino]methane ester (Trans isomer 2)

[0646] To the reaction flask were added 2-amino-4-[6-iodo-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2) (50 mg, 0.053 mmol), dimethylphosphine oxide (41 mg, 0.53 mmol), potassium phosphate (23 mg, 0.106 mmol), Pd2(dba)3 (3 mg, 0.0033 mmol), and xantphos (3 mg, 0.0066 mmol). 1,4-dioxane (1 mL) was then added, the atmosphere was replaced with nitrogen, and the temperature was raised to 100°C with stirring for 18 hours. The reaction solution was added to water (5 mL) and extracted twice with ethyl acetate. The organic phase was dried and spin-dried, and purified by thin layer chromatography on silica gel (DCM / MeOH=20 / 1) to obtain 20 mg of a yellow solid with a yield of 43.4%.

[0647] LC / MS: m / z=895.3[M+H] + .

[0648] Step 2: Synthesis of 2-amino-4-{6-[dimethyl(oxyylidene)-λ5-methylphosphino]-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl}benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0649] Transomer 2 (20 mg, 0.022 mmol) was weighed and dissolved in DCM (1.5 mL). TFA (0.5 mL) was added and the reaction was stirred at room temperature for 0.5 h. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, and the mixture was extracted with dichloromethane. The organic phase was dried and spin-dried, and purified by thin layer chromatography on silica gel (DCM / NH3 in MeOH solution = 30 / 1) to obtain 1 mg of a yellow solid in a yield of 5.6%.

[0650] LC / MS: m / z=795.2[M+H] + .

[0651] Example 34

[0652] 2-Amino-4-[6-chloro-8-fluoro-4-(1,2,5-oxadiazepan-5-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0653] Step 1: Synthesis of benzyl [bis(2-chloroethyl)amino]methane

[0654] NaHCO₃ (5.96 g, 70.9 mmol) was weighed and dissolved in H₂O (15 mL). Cbz-Cl (6.3 g, 36.9 mmol) was added and allowed to react at room temperature for 10 minutes. Bis(2-chloroethyl)amine (5 g, 35.5 mmol) was then dissolved in H₂O (10 mL). After the system was cooled to 0°C, the aqueous solution of the compound was slowly added dropwise to the reaction system. The temperature was raised to room temperature and the reaction was stirred for 1 hour. The reaction solution was added to water (30 mL) and extracted twice with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 6.37 g of the product, with a yield of 65.3%.

[0655] LC / MS: m / z=276.1[M+H] + .

[0656] Step 2: Synthesis of 2-methylpropan-2-yl 5-[(benzyloxy)carbonyl]-1,2,5-oxadiazepane-2-carboxylate

[0657] N-tert-Butyloxycarbonylhydroxylamine (3.07 g, 23.1 mmol) was weighed and dissolved in DMF (40 mL). The atmosphere was replaced with nitrogen. After the system was cooled to 0°C, NaH (2.032 g, 50.7 mmol, 60%) was added and the reaction was maintained at 0°C for 1 hour. Benzyl [bis(2-chloroethyl)amino]methane (6.37 g, 23.15 mmol) was dissolved in DMF (10 mL) and added to the reaction system. The temperature was raised to 100°C and the reaction was continued for 0.5 hour. The reaction solution was quenched with aqueous ammonium chloride (50 mL), extracted twice with ethyl acetate, and backwashed once with saturated brine. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (PE / EA = 50 / 1) to obtain 4.2 g of the product, with a yield of 53.9%.

[0658] LC / MS: m / z=337.2[M+H] + .

[0659] Step 3: Synthesis of 2-methylpropan-2-yl 1,2,5-oxadiazepane-2-carboxylate

[0660] 5-[(Benzyloxy)carbonyl]-1,2,5-oxadiazepane-2-carboxylic acid-2-methylprop-2-yl ester (2 g, 5.949 mmol) was weighed and dissolved in methanol (50 mL). Pd / C (200 mg, 10% w / w) was added, and the atmosphere was replaced with nitrogen. The reaction was carried out at 50° C. for 18 hours, and the mixture was filtered. The filter cake was rinsed with methanol (20 mL). The mother liquor was spin-dried and purified by silica gel column chromatography (PE / EA=20 / 1) to obtain 990 mg, with a yield of 82.5%.

[0661] LC / MS: m / z = 203.1 [M+H] + .

[0662] Step 4: Synthesis of 2-methylpropan-2-yl 5-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,2,5-oxadiazepane-2-carboxylate

[0663] To the reaction flask were added 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (200 mg, 0.645 mmol), 1,2,5-oxadiazepane-2-carboxylic acid-2-methylpropane-2-yl ester (156 mg, 0.774 mmol), DCM (3 mL), and DIEA (166 mg, 1.29 mmol). After stirring at room temperature for 2 minutes, BoP-Cl (246 mg, 0.968 mmol) was added. The system was stirred at room temperature for 2 hours, water (5 mL) was added, and DCM was used for extraction. The organic phase was dried and dried by rotary evaporation. The organic phase was dried and dried by thin layer chromatography on silica gel (PE / EA=2 / 1) to give 140 mg, yield: 43.9%.

[0664] LC / MS: m / z=495.0[M+H] + .

[0665] Step 5: Synthesis of 2-methylpropane-2-yl 5-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl]-1,2,5-oxadiazepane-2-carboxylate (Trans isomer 2)

[0666] To the reaction flask were added 5-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,2,5-oxadiazepane-2-carboxylic acid-2-methylprop-2-yl ester (140 mg, 0.283 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2) (115 mg, 0.425 mmol), CS2CO3 (186 mg, 0.566 mmol), DABCO (13 mg, 0.113 mmol), and then DMF / THF (2 mL / 2 mL) were added, and the atmosphere was replaced with nitrogen. The reaction was carried out at 45 ° C for 18 hours. Water (10 mL) was added, and the mixture was extracted twice with ethyl acetate. The mixture was backwashed once with saturated brine, and the organic phase was dried and spin-dried. The residue was purified by thin layer chromatography on silica gel (DCM / MeOH = 20 / 1) to give 85 mg, with a yield of 41.1%.

[0667] LC / MS: m / z=730.1[M+H] + .

[0668] Step 6: Synthesis of 2-methylpropan-2-yl 5-{6-chloro-7-[3-cyano-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)benzo[b]thiophen-4-yl]-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-4-yl}-1,2,5-oxadiazepane-2-carboxylate (Trans isomer 2)

[0669] To the reaction flask were added 5-[7-bromo-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methyl}oxy)quinazolin-4-yl]-1,2,5-oxadiazepine-2-carboxylic acid-2-methylprop-2-yl ester (Trans isomer 2) (85 mg, 0.117 mmol), potassium acetate (23 mg, 0.234 mol), and biboronic acid pinacol ester (45 mg, 0.176 mmol), and then 3 mL of dioxane solution was added. The system was purged with nitrogen three times, and then Pd(dppf)Cl2 (8.8 mg, 0.012 mmol) was added. The system was heated to 95 ° C for 3 hours, and then {[3-cyano-4-(4,4,5,5-tetramethyl To the reaction mixture were added 2-methylpropanediol-2-yl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylic acid 2-methylpropanediol ester (47 mg, 0.117 mmol), CS2CO3 (76 mg, 0.234 mmol), and water (0.5 mL). Finally, Pd(dppf)Cl2 (8.8 mg, 0.012 mmol) was added. The reaction mixture was heated to 95°C and stirred under nitrogen for 12 hours. The reaction system was cooled to room temperature and poured into water (1 L). Extraction was carried out with ethyl acetate. The organic phase was dried, spin-dried, and purified on a silica gel plate to obtain 18 mg of the product in a yield of 16.7%.

[0670] Step 7: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(1,2,5-oxadiazepan-5-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0671] Transomer 2 (18 mg, 0.019 mmol) was weighed and dissolved in DCM (1.5 mL). TFA (0.5 mL) was added to the mixture and the reaction was stirred at room temperature for 0.5 h. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, and the product was extracted with dichloromethane. The organic phase was dried and spin-dried, and purified by thin layer chromatography on silica gel (DCM / NH3 in MeOH solution = 30 / 1) to obtain 3.2 mg, with a yield of 22.6%.

[0672] LC / MS: m / z=724.1[M+H] + .

[0673] 1 H NMR(400MHz,d6-DMSO)δ1.62-1.66(2H,m),1.82-1.88(2H,m),1.93-1.98( 2H,m),2.10-2.14(2H,m),2.25-2.34(2H,m),3.20-3.25(2H,m),3.91-3.95 (2H,m),4.00-4.06(2H,m),4.15-4.19(4H,m),4.45-4.49(1H,m),7.10(1H ,s),7.23-7.33(4H,m),7.79(1H,d,J=8.0Hz),7.84(2H,brs),7.98(1H,s).

[0674] Example 35

[0675] 2-Amino-4-[6-chloro-8-fluoro-4-(3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropano[1,2-b][1,4]oxazepan-5-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0676] Step 1: Synthesis of ethyl 2-(benzyloxy)cyclopropane-1-carboxylate

[0677] Benzyl vinyl ether (9 g, 67.08 mmol), dimerized rhodium acetate (296 mg, 0.67 mmol) and DCM (90 mL) were added to a reaction flask. Ethyl diazoacetate (8.42 g, 73.78 mmol) was dissolved in DCM (40 mL) and slowly added dropwise (over 1 hour) to the reaction system at room temperature, and stirred overnight. The reaction solution was concentrated to remove DCM, ethyl acetate and water were added thereto, the organic phase was collected by layers, and washed once with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA=15 / 1) to give 4.1 g of a colorless liquid compound in a yield of 27%.

[0678] Step 2: Synthesis of 2-(benzyloxy)cyclopropane-1-carboxylic acid

[0679] Ethyl 2-(benzyloxy)cyclopropane-1-carboxylate (4 g, 18.1 mmol) was weighed and dissolved in methanol (40 mL). LiOH (2.17 g, 90.5 mmol) and water (16 mL) were added and the reaction was allowed to react at room temperature for 12 hours. The reaction solution was concentrated to dryness, water and MTBE were added, and the layers were separated. The aqueous phase was collected and adjusted to pH ≈ 2-3 with 2M HCl. The solution was extracted with DCM (3 × 75 mL). The organic phase was dried and spin-dried to give 3 g of a colorless oil (yield: 86%).

[0680] LC / MS: m / z = 191.1 [MH] -

[0681] Step 3: Synthesis of benzyl {[2-(benzyloxy)cyclopropyl]amino}methane

[0682] 2-(Benzyloxy)cyclopropane-1-carboxylic acid (3 g, 15.6 mmol), TEA (4.72 g, 46.8 mmol), and DPPA (5.5 g, 20.2 mmol) were dissolved in dioxane (40 mL) and replaced with nitrogen three times. The mixture was allowed to react at room temperature for 20 minutes. Benzyl alcohol (5 g, 46.8 mmol) was then added, and the reaction system was heated to 85°C and allowed to react for 12 hours. The reaction solution was cooled to room temperature and concentrated to dryness. Water and ethyl acetate were then added, and the organic phase was collected and washed once with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 3.3 g of the desired product in a yield of 71.7%.

[0683] LC / MS: m / z=298.1[M+H] + .

[0684] Step 4: Synthesis of 2-methylpropan-2-yl {[2-(benzyloxy)cyclopropyl]amino}methane

[0685] Benzyl {[2-(benzyloxy)cyclopropyl]amino}methane (3 g, 10.1 mmol) and di-tert-butyl dicarbonate (2.4 g, 11.1 mmol) were dissolved in methanol (40 mL). Wet palladium on carbon (300 mg) was added, and the mixture was replaced with a hydrogen balloon three times. The reaction was allowed to react at room temperature for 12 hours. The reaction mixture was concentrated to dryness and purified by silica gel column chromatography to obtain 2.1 g of the desired product in an 80% yield.

[0686] LC / MS: m / z = 286.1 [M+Na] + .

[0687] Step 5: Synthesis of 2-methylpropan-2-yl [(2-hydroxycyclopropyl)amino]methane

[0688] 2-Methylprop-2-yl {[2-(benzyloxy)cyclopropyl]amino}methane ester (2 g, 7.6 mmol) was dissolved in methanol (15 mL). Wet palladium on carbon (250 mg) was added and replaced with a hydrogen balloon three times. The reaction was continued at 40°C for 12 hours. The reaction system was concentrated to dryness to obtain 1.1 g of the desired product in an 84% yield.

[0689] LC / MS: m / z=174.1[M+H] + .

[0690] Step 6: Synthesis of 2-methylprop-2-yl 3-methylidene-2,3,4,5,5a,6a-hexahydrocyclopropane[1,2-b][1,4]oxazepane-5-carboxylate

[0691] 3-Chloro-2-chloromethylpropene (722 mg, 5.7 mmol) and NaH (524 mg, 13.1 mmol) were weighed and dissolved in DMF (12 mL). The mixture was purged with nitrogen three times, and the reaction system was cooled to 0°C. [(2-Hydroxycyclopropyl)amino]methane-2-methylprop-2-yl ester (1 g, 5.7 mmol) was dissolved in DMF (4 mL) and slowly added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to naturally warm to room temperature and reacted for 4 hours. The reaction system was slowly added to an aqueous solution of saturated ammonium chloride to quench the mixture, followed by addition of ethyl acetate, and the organic phase was collected and washed three times with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 560 mg of the desired product in a yield of 43%.

[0692] Step 7: Synthesis of 2-methylpropan-2-yl 4,5,5a,6a-tetrahydro-2H-spiro[cyclopropyl[1,2-b][1,4]oxazepane-3,2'-oxirane]-5-carboxylate

[0693] 2-Methylpropane-2,3,4,5,5a,6a-hexahydrocyclopropane[1,2-b][1,4]oxazepane-5-carboxylate (550 mg, 2.4 mmol) and m-chloroperbenzoic acid (619 mg, 3.6 mmol) were dissolved in DCM (8 mL) and reacted at 25°C for 24 hours. The reaction solution was directly filtered, and the filter cake was rinsed with a small amount of DCM. The filtrate was collected and washed once with saturated sodium bicarbonate solution and once with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 420 mg of the desired product in a yield of 72%.

[0694] Step 8: Synthesis of 2-methylpropan-2-yl 3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepane-5-carboxylate

[0695] 4,5,5a,6a-tetrahydro-2H-spiro[cyclopropyl[1,2-b][1,4]oxazepane-3,2'-oxirane]-5-carboxylic acid-2-methylpropane-2-yl ester (420 mg, 1.7 mmol) was dissolved in THF (6 mL) and replaced with nitrogen three times. The reaction system was cooled to 0°C and then LiAlH4 (76 mg, 2.0 mmol) was added. After the addition was complete, the reaction system was allowed to warm to room temperature and react for 3 hours. The reaction system was slowly added to a saturated aqueous solution of ammonium chloride to quench the reaction. Ethyl acetate was then added to separate the layers. The organic phase was collected and washed once with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 310 mg of the desired product in a yield of 75%.

[0696] Step 9: Synthesis of 3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropane[1,2-b][1,4]oxazepan-3-ol hydrochloride

[0697] 3-Hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepane-5-carboxylic acid-2-methylpropan-2-yl ester (310 mg, 1.27 mmol) was dissolved in 4M HCl / dioxane (4 mL) and reacted at room temperature for 3 hours. The reaction mixture was directly spin-dried to obtain 180 mg of the desired product in an 85% yield.

[0698] LC / MS: m / z=144.1[M+H] + .

[0699] Step 10: Synthesis of 2-methylpropan-2-yl ({3-cyano-4-[2,6-dichloro-8-fluoro-4-(3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropane[1,2-b][1,4]oxazepan-5-yl)quinazolin-7-yl]benzo[b]thiophen-2-yl}amino)methanoate

[0700] 2-Methylpropan-2-yl {[3-cyano-4-(2,6-dichloro-8-fluoro-4-hydroxyquinazolin-7-yl)benzo[b]thiophen-2-yl]amino}methane ester (500 mg, 0.99 mmol), DIEA (383 mg, 2.97 mmol), and 3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropa[1,2-b][1,4]oxazepan-3-ol hydrochloride (180 mg, 1.09 mmol) were dissolved in DCM (8 mL). BOP-Cl (503 mg, 1.98 mmol) was then added and the reaction was allowed to react at room temperature for 4 hours. DCM and water were added to the reaction system, and the organic phase was separated, dried, and purified by silica gel column chromatography to obtain 480 mg of the desired product in a yield of 77%.

[0701] LC / MS: m / z=630.1[M+H] + .

[0702] Step 11: Synthesis of 2-methylpropan-2-yl({4-[6-chloro-8-fluoro-4-(3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0703] Weigh out ({3-cyano-4-[2,6-dichloro-8-fluoro-4-(3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)quinazolin-7-yl]benzo[b]thiophen-2-yl}amino)methane-2-methylpropan-2-yl ester (480 mg, 0.76 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer2) (247 mg, 0.91 mmol) was added to DMF / THF (4 mL / 4 mL), CS2CO3 (495 mg, 1.52 mmol) and DABCO (25 mg, 0.22 mmol), and the mixture was stirred at 45°C for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 227 mg, with a yield of 34%.

[0704] LC / MS: m / z=865.1[M+H] + .

[0705] Step 12: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(3-hydroxy-3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0706] Transomer 2 (220 mg, 0.25 mmol) was dissolved in DCM / TFA (2 mL / 1 mL) and reacted at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction system until the aqueous phase became weakly alkaline. A small amount of DCM was added for extraction. The organic phase was collected, dried, and spin-dried. The organic phase was purified by pre-TLC to obtain 160 mg, with a yield of 83%.

[0707] LC / MS: m / z=765.1[M+H] + .

[0708] Example 36

[0709] 4-[4-(2,3,4,5,5a,6a-hexahydrocyclopropano[1,2-b][1,4]oxazepan-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-2-aminobenzo[b]thiophene-3-carbonitrile (Trans isomer2)

[0710] Step 1: Synthesis of 2-methylpropan-2-yl 2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepane-5-carboxylate

[0711] 1,3-Dichloropropane (326 mg, 2.89 mmol) and NaH (254 mg, 6.35 mmol) were weighed and dissolved in DMF (6 mL). The atmosphere was replaced with nitrogen three times, and the reaction system was cooled to 0°C. 2-Methylprop-2-yl[(2-hydroxycyclopropyl)amino]methane ester (500 mg, 2.89 mmol) was dissolved in DMF (4 mL) and slowly added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to naturally warm to room temperature and react for 8 hours. The reaction system was slowly added to a saturated aqueous solution of ammonium chloride to quench the reaction. Ethyl acetate was then added to separate the layers. The organic phase was collected and washed three times with saturated brine. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 243 mg of the desired product in a yield of 39%.

[0712] Step 2: Synthesis of 2,3,4,5,5a,6a-hexahydrocyclopropane[1,2-b][1,4]oxazepane hydrochloride

[0713] 2-Methylprop-2-yl 2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepane-5-carboxylate (240 mg, 1.1 mmol) was dissolved in 4M HCl / dioxane (4 mL) and reacted at room temperature for 3 hours. The reaction mixture was directly spin-dried to obtain 156 mg of the desired product in a 96% yield.

[0714] LC / MS: m / z=114.1[M+H] + .

[0715] Step 3: Synthesis of 2-methylpropan-2-yl ({4-[4-(2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-2,6-dichloro-8-fluoroquinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate

[0716] 2-Methylpropan-2-yl {[3-cyano-4-(2,6-dichloro-8-fluoro-4-hydroxyquinazolin-7-yl)benzo[b]thiophen-2-yl]amino}methane ester (500 mg, 0.99 mmol), DIEA (383 mg, 2.97 mmol), and 3-methyl-2,3,4,5,5a,6a-hexahydrocyclopropa[1,2-b][1,4]oxazepan-3-ol hydrochloride (150 mg, 1.01 mmol) were dissolved in DCM (8 mL). BOP-Cl (503 mg, 1.98 mmol) was then added and the reaction was allowed to react at room temperature for 4 hours. DCM and water were added to the reaction system, and the organic phase was separated, dried, and purified by silica gel column chromatography to obtain 420 mg of the desired product in a 70% yield.

[0717] LC / MS: m / z=600.1[M+H] + .

[0718] Step 4: Synthesis of 2-methylpropan-2-yl({4-[4-(2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate (Trans isomer 2)

[0719] 2-Methylpropane-2-yl({4-[4-(2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-2,6-dichloro-8-fluoroquinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane(420 mg, 0.7 mmol) and [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl)methanol(Trans isomer 2)(227 mg, 0.84 mmol) were weighed, and DMF / THF(4 mL / 4 mL) was added. CS2CO3(456 mg, 1.4 mmol) and DABCO(22 mg, 0.2 mmol) were added, and the mixture was stirred at 45° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by silica gel column chromatography to obtain 189 mg of the compound with a yield of 32%.

[0720] LC / MS: m / z=835.1[M+H] + .

[0721] Step 5: Synthesis of 4-[4-(2,3,4,5,5a,6a-hexahydrocyclopropyl[1,2-b][1,4]oxazepan-5-yl)-6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)quinazolin-7-yl]-2-aminobenzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0722] Transomer 2 (189 mg, 0.22 mmol) was dissolved in DCM / TFA (2 mL / 1 mL) and reacted at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction system until the aqueous phase became weakly alkaline. A small amount of DCM was added for extraction. The organic phase was collected, dried, and spin-dried. Purification by pre-TLC gave 135 mg of the compound with a yield of 83%.

[0723] LC / MS: m / z=735.1[M+H] + .

[0724] Example 37

[0725] Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]thieno[2,3-c]pyridine-3-carbonitrile (Trans isomer 2)

[0726] Step 1: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanothieno[2,3-c]pyridin-2-yl]amino}methane

[0727] 2-Amino-4-bromo-3-fluorobenzamide (437 mg, 1.88 mmol), bipyraclostrobin (716 mg, 2.82 mol), potassium acetate (368 mg, 3.76 mol) were added to the reaction flask, and then dioxane (20 mL) solution was added. After the system was purged with nitrogen three times, Pd(OAc)2 (43 mg, 0.19 mmol) and n-butyldi(1-adamantyl)phosphine (68 mg, 0.19 mmol) were added, and then the system was heated to 85 ° C for 2 hours. 2-Methylpropane-2-yl[(4-bromo-3-cyanothieno[2,3-c]pyridin-2-yl)amino]methanesulfonate (664 mg, 1.88 mmol), potassium carbonate (519 mg, 3.76 mol), and water (3 mL) were then added to the system. Finally, Pd(OAc)2 (43 mg, 0.19 mmol) and n-butyldi(1-adamantyl)phosphine (68 mg, 0.19 mmol) were added. The reaction mixture was heated to 85°C under nitrogen for 3 hours. The reaction system was cooled to room temperature and poured into water (100 mL). The product was extracted with ethyl acetate, and the organic phase was dried, spin-dried, and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 286 mg of a yellow solid, with a yield of 35.6%.

[0728] LC / MS: m / z=428.1[M+H] + .

[0729] Step 2: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-4-formamido-6-chloro-2-fluorophenyl)-3-cyanothieno[2,3-c]pyridin-2-yl]amino}methane

[0730] To the reaction flask was added 2-methylpropane-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanothieno[2,3-c]pyridin-2-yl]amino}methane (286 mg, 0.67 mmol), followed by DMF (10 mL), and NCS (106 mg, 0.80 mmol) was slowly added. The system was reacted at room temperature overnight. The reaction system was poured into water, extracted with ethyl acetate, dried and concentrated to give a crude product, which was purified on a silica gel plate to give 198 mg of an off-white solid in a yield of 64.1%.

[0731] LC / MS: m / z=462.1[M+H] + .

[0732] Step 3: Synthesis of 2-methylpropan-2-yl {[3-cyano-4-(2,6-dichloro-8-fluoro-4-hydroxyquinazolin-7-yl)thieno[2,3-c]pyridin-2-yl]amino}methane

[0733] 2-Methylpropane {[4-(3-amino-4-formamido-6-chloro-2-fluorophenyl)-3-cyanothieno[2,3-c]pyridin-2-yl]amino}methane (198 mg, 0.47 mmol) was dissolved in 1,4-dioxane (5 mL). After nitrogen displacement, a solution of thiophosgene (162 mg, 0.78 mmol) in 1,4-dioxane (2 mL) was added dropwise at room temperature. After addition, the mixture was stirred at room temperature for 1 hour, then heated to 80°C and stirred for 0.5 hour. The solution was added to water, extracted with ethyl acetate, dried, and concentrated to dryness. Purification on silica gel plate afforded 96 mg of an off-white solid in a yield of 44.3%.

[0734] LC / MS: m / z = 506.0 [M+H] + .

[0735] Step 4: Synthesis of 2-methylpropan-2-yl ({3-cyano-4-[2,6-dichloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]thieno[2,3-c]pyridin-2-yl}amino)methanoate

[0736] To a reaction flask, 2-methylpropan-2-yl {[3-cyano-4-(2,6-dichloro-8-fluoro-4-hydroxyquinazolin-7-yl)thieno[2,3-c]pyridin-2-yl]amino}methane was added (96 mg, 0.19 mmol), 6-methyl-1,4-oxazepan-6-ol hydrochloride (38 mg, 0.23 mmol), DIPEA (74 mg, 0.57 mmol), and dichloromethane (4 mL). After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (74 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified on a silica gel plate to obtain 71 mg of the product (yield: 60.4%).

[0737] LC / MS: m / z=619.1[M+H] + .

[0738] Step 5: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanothieno[2,3-c]pyridin-2-yl}amino)methanoate (Trans isomer 2)

[0739] To the reaction flask were added 2-methylpropan-2-yl ({3-cyano-4-[2,6-dichloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl]thieno[2,3-c]pyridin-2-yl}amino)methane (71 mg, 0.12 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans isomer 2) (38 mg, 0.14 mmol), and DMF / THF (2 mL / 2 mL) were added. Cs2CO3 (78 mg, 0.24 mmol) and DABCO (6 mg, 0.05 mmol) were added, and the mixture was stirred at 45°C for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified on a silica gel plate to obtain 39 mg of an off-white solid with a yield of 39.8%.

[0740] LC / MS: m / z=854.2[M+H] + .

[0741] Step 6: Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulene-3a-yl]methyl}oxy)quinazolin-7-yl]thieno[2,3-c]pyridine-3-carbonitrile (Trans isomer 2)

[0742] To a reaction flask, 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-({[1-(3,4,5-trifluorophenyl)octahydrocyclopenta[1,2-a][5]annulen-3a-yl]methyl}oxy)quinazolin-7-yl]-3-cyanothieno[2,3-c]pyridin-2-yl}amino)methane (Trans isomer 2) (39 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The mixture was then dried in a saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel plate to obtain 16 mg of the desired product in a yield of 46.5%.

[0743] LC / MS: m / z=754.2[M+H] + .

[0744] Efficacy trials

[0745] Experimental Example 1: Inhibitory activity test of compounds on KRas G12D / G12V / G12C / G13D / G12R-mediated ERK phosphorylation

[0746] 1. Test method:

[0747] Day 1: AGS cells, SW480 cells, NCI H358 cells, HCT116 cells, and KP2 cells were seeded into 384-well cell culture plates and cultured overnight in a 37° C., 5% CO 2 incubator.

[0748] The next day: Compounds were added to the plate using Echo550 and incubated at 37°C in a 5% CO2 incubator for 3 hours. Cells were then fixed with paraformaldehyde, permeabilized with methanol, and blocked with blocking buffer. Finally, a mixture of primary antibodies (rabbit anti-pERK, mouse anti-GAPDH) was added and incubated overnight at 4°C.

[0749] Day 3: Discard the primary antibody and add a secondary antibody cocktail (goat anti-rabbit 800CW, goat anti-mouse 680RD). Incubate at room temperature in the dark. Finally, wash with PBST and centrifuge the cell culture plate upside down for 1 minute. Fluorescence signal was read using an Odyssey CLx.

[0750] ERK phosphorylation was calculated according to the following formula:

[0751] Relative expression: (fluorescence signal ratio of compound - average value of positive control) / (average value of negative control - average value of positive control)

[0752] Negative control: DMSO

[0753] Positive control: 10μM Reference

[0754] XLFit 5.0 calculates IC by fitting parameter formula 50 value:

[0755] Y=Bottom+(Top–Bottom) / (1+10^((Log IC50–X)×HillSlope))

[0756] X: log value of compound concentration

[0757] Y: Average relative expression level of p-ERK between replicate wells

[0758] 2. The inhibitory activity of the compounds of the present invention on ERK phosphorylation is shown in Table 1.

[0759] Table 1: Inhibitory activity of the compounds of the present invention on ERK phosphorylation (IC50 , nm)

[0760] Conclusion: From the above data, it can be seen that some compounds of the present invention can effectively inhibit the phosphorylation of ERK, a downstream target of the KRAS pathway, and have broad application prospects.

[0761] Experimental Example 2: 3D cell proliferation inhibition test of compounds

[0762] The diluted test compounds were added to 384-well low-adsorption GP2D, NCI H358, LoVo, RKN, KP2 and other KRAS mutant cell culture plates using a nanoliter pipetting system (LABCYTE, P-0200). The cells were then plated and placed in a 37°C, 5% CO2 incubator for 7 days before addition of 3D reagent, using Envision multifunctional microplate reader to read the luminescence value (the light signal is proportional to the amount of ATP in the system, and the ATP content directly represents the number of living cells in the system). Finally, the IC value of the compound is obtained using XLFIT software using a nonlinear fitting formula. 50 (half inhibitory concentration).

[0763] 1. Experimental methods

[0764] a) Using a nanoliter pipetting system, the diluted test compounds were added to 384-well low-adsorption cell culture plates containing various KRAS mutation types.

[0765] b) The cells were seeded into the 384 culture plate in a), centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%. The cells were incubated in a 37° C., 5% CO 2 constant temperature incubator for 7 days.

[0766] c) Join 3D to b) Place in a 384-well cell culture plate, shake in the dark, and incubate at room temperature.

[0767] d) Read the luminescence value using Envision multi-function microplate reader.

[0768] 2. Data Analysis

[0769] The IC of the compound was obtained using the following nonlinear fitting formula using XLFIT software. 50 (50% inhibitory concentration):

[0770] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0771] X: log value of compound concentration

[0772] Y: inhibition rate (%)

[0773] Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0774] Negative control: DMSO

[0775] Positive control: Medium only

[0776] 3. The 3D cell proliferation inhibitory activity data of some compounds of the present application on GP2D, NCI H358, LoVo, RKN, and KP2 various mutant cells are shown in Table 2.

[0777] Table 2: Inhibitory activity of the compounds of the present invention on cell proliferation of various KRAS mutant subtypes (IC 50 ,nm

[0778] Experimental conclusion: Some of the compounds of the present invention have excellent anti-proliferative effects on cells with mutations of various KRAS subtypes, including GP2D (KRAS G12D), NCIH358 (KRAS G12C), RKN (KRAS G12V), LoVo (KRAS G13D), and KP2 (KRAS G12R).

[0779] Experimental Example 3: Pharmacokinetics of Compounds in Mice

[0780] Pharmacokinetic studies were conducted by oral administration of each test compound to female BALB / c mice. Test compounds were prepared on the day of administration. The oral administration vehicle consisted of 50 mM sodium citrate (pH 5.0) + 10% captisol. Animals were fasted for 10-14 hours prior to administration at a dose of 30 mg / kg, and food was resumed 4 hours after administration. Pharmacokinetic samples were collected transorbitally at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. Three whole blood samples (approximately 0.2 mL) were collected at each time point and anticoagulated with sodium heparin. Blood samples were immediately placed on ice after collection, and plasma was separated by centrifugation within 1 hour (8000 rpm, 1 minute, 2-8°C). Collected plasma was stored at –20°C until analysis. Compound concentrations in plasma were determined by LC-MS / MS.

[0781] Table 3: Pharmacokinetic test results of some compounds in BALB / c mice

[0782] Experimental conclusion: Some of the compounds of the present invention have good oral exposure in mice.

[0783] Test Example 4: Pharmacokinetics of the compound in rats

[0784] Pharmacokinetic studies were conducted in male Sprague-Dawley rats following a single oral administration of each test compound. Test compounds were prepared on the day of administration. The intravenous administration vehicle consisted of 5% DMSO, 10% solutol, and 85% saline; the oral administration vehicle consisted of 50 mM sodium citrate (pH 5.0) and 10% captisol. Animals were fasted for 10-14 hours prior to administration at a dose of 30 mg / kg, and food was resumed 4 hours after administration. Pharmacokinetic samples were collected transorbitally at 5 minutes (intravenous administration), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. Three whole blood samples (approximately 0.2 mL) were collected at each time point and anticoagulated with sodium heparin. Blood samples were immediately placed on ice after collection, and plasma was separated by centrifugation within 1 hour (8000 rpm, 1 minute, 2-8°C). Collected plasma was stored at –20°C until analysis. The concentrations of the compounds in plasma samples were determined by LC-MS / MS analysis.

[0785] Table 4: Pharmacokinetic test results of some compounds in SD rats

[0786] Experimental conclusion: Some of the compounds of the present invention have good oral exposure and bioavailability in rats.

[0787] Experimental Example 5: In vivo efficacy study of compounds in mice

[0788] Test method:

[0789] A human colon cancer GP2D cell subcutaneous xenograft tumor model was established in Balb / c nude mice. GP2D tumor cells resuspended in DMEM medium were cultured at a concentration of 1×10 7 + glue / 0.1mL was inoculated subcutaneously on the right side of the experimental animal. When the tumor grew to about 150-200mm 3 Dosing began at 5:00 AM, with 5 animals per group. On the day of the experiment, animals were administered the corresponding drugs according to their groups. Group 1, G1, was designated as the vehicle group and administered a single oral dose of 50 mM citrate buffer (pH 5.0) + 10% Captisol. Group 2, G2, received a solution of compound 26 in 50 mM citrate buffer (pH 5.0) + 10% Captisol. Group 3, G3, received a solution of compound 31 in 50 mM citrate buffer (pH 5.0) + 10% Captisol. The dosage and schedule are shown in Table 5.

[0790] Table 5: Study on the effect of the test substance on animal tumor size in the human colon cancer GP2D mouse xenograft tumor model

[0791] Note: PO means oral administration, BID means twice daily.

[0792] During the experiment, the body weight and tumor size of the animals were measured twice a week. The clinical symptoms of the animals were observed and recorded every day. The weight of the animals measured most recently was used as a reference for each administration.

[0793] Tumors were measured using a digital vernier caliper to measure length (a) and width (b). Tumor volume (TV) was calculated using the following formula:

[0794] TV=a×b 2 / 2.

[0795] Experimental results:

[0796] Compounds 26 and 31 had significant inhibitory effects on human colon cancer GP2D mouse xenograft tumors. After 28 days of administration, the tumor volume inhibition rate TGI (%) of the second group G2 (30 mg / kg, PO, BID) on day 28 was 72.7; the tumor volume inhibition rate TGI (%) of the third group G3 (30 mg / kg, PO, BID) on day 28 was 86.7. The detailed results are shown in Table 6.

[0797] Table 6: Effects of the test substances on animal tumor size in the human colon cancer GP2D mouse xenograft tumor model

[0798] Note: “ / ” means not tested.

[0799] Experimental conclusion: In terms of in vivo efficacy, some of the compounds of the present invention showed good anti-tumor effects in the GP2D mouse efficacy study.

[0800] Experimental Example 6: In vivo efficacy study of compounds in mice

[0801] Test method:

[0802] A subcutaneous xenograft tumor model of human ovarian cancer RKN (derived from uterine leiomyosarcoma) cells was established in Balb / c nude mice. RKN tumor cells resuspended in Ham's F12 medium were cultured at a rate of 5×10 6 + glue / 0.1mL was inoculated subcutaneously on the right side of the experimental animal, and the tumor grew to about 150-200mm 3Twenty animals with relatively uniform tumor volumes were selected and divided into four groups for drug administration, with five animals in each group. On the day of the experiment, the animals were given the corresponding drugs according to the groups. The first group G1 was set up as the vehicle group and was given 50mM citrate buffer (pH 5.0) + 10% Captisol by gavage alone. The second group G2 was given a solution of compound 21 in 50mM citrate buffer (pH 5.0) + 10% Captisol. The third group G3 was given a solution of compound 26 in 50mM citrate buffer (pH 5.0) + 10% Captisol. The fourth group G4 was given a solution of compound 31 in 50mM citrate buffer (pH 5.0) + 10% Captisol. The dosage and schedule are shown in Table 7.

[0803] Table 7: Study on the effect of the test substance on animal tumor size in the human ovarian cancer RKN mouse xenograft tumor model

[0804] Note: PO means oral administration, BID means twice daily.

[0805] During the experiment, the body weight and tumor size of the animals were measured twice a week. The clinical symptoms of the animals were observed and recorded every day. The weight of the animals measured most recently was used as a reference for each administration.

[0806] Tumors were measured using a digital vernier caliper to measure length (a) and width (b). Tumor volume (TV) was calculated using the following formula:

[0807] TV=a×b 2 / 2.

[0808] Experimental results:

[0809] Compounds 21, 26, and 31 had significant inhibitory effects on human ovarian cancer RKN mouse xenograft tumors. After 28 days of administration, the tumor volume inhibition rate TGI (%) of the second group G2 (50 mg / kg, PO, BID) was 109 on day 28; the tumor volume inhibition rate TGI (%) of the third group G3 (50 mg / kg, PO, BID) was 116 on day 28; and the tumor volume inhibition rate TGI (%) of the fourth group G4 (50 mg / kg, PO, BID) was 116 on day 28. The detailed results are shown in Table 8.

[0810] Table 8: Effects of the test substances on animal tumor size in the human ovarian cancer RKN mouse xenograft tumor model

[0811] Experimental conclusion: In terms of in vivo efficacy, some of the compounds of the present invention showed good anti-tumor effects in the RKN mouse efficacy study.

[0812] The above-mentioned compounds provided by the present invention can be used to treat one or more cancers caused by KRAS mutations. They have high in vitro cell proliferation and ERK phosphorylation inhibitory activity, good exposure and bioavailability in mice and rats, and have demonstrated excellent anti-tumor effects in in vivo efficacy studies in mice. They can be used to prepare drugs for the prevention and / or treatment of KRAS-mediated diseases and have good application prospects.

[0813] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be construed as limiting the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. Persons skilled in the art will appreciate that improvements and modifications may be made without departing from the spirit and scope of the present invention, and such improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A compound as shown in formula I, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal: A1 is selected from C or N; A2 is selected from S, N or C; A3 is selected from N, O or C; and A2 and A3 are not C at the same time; Z at each occurrence is independently selected from H or deuterium; Ra is selected from H, halogen, C(CH3)=CH- or -CH=CH2, -CF=CH2, -CN, OH, NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aroyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclopentenyl, cyclohexyl, cycloheptyl, methyl, ethyl, propyl, butyl, pentyl, vinyl, propenyl, allyl, butenyl, butylene, pentadienyl, dipentenyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy; n1 is an integer selected from 0 to 3; Ra2 is selected from -CN, H or none; Rb1, Rb2, Rb3 are selected from the group consisting of none, hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate, wherein the substituents are independently selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; n2 is an integer selected from 0 to 6; Ring A is selected from one of the following substituted or unsubstituted structures: X1, X2 are independently selected from N or C; X3 is selected from N, O or C; and only one of X1, X2, and X3 is C; Rb4 and Rb5 are independently selected from none, H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxyl, cyano, -C(=O)NRb for each occurrence 41 R 42 、-(CH2)m 121 C(=O)NRb 41 R 42 、-(CH2)m 121 Nb 41 R 42 、-NRb 41 R 42 , -C(=O)Rb 41 、-C(=O)ORb 41 ; Rb 41 , Rb 42 Each of the substituents is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, and phosphate; m 11 An integer selected from 0 to 3; m 12 、m 13 、m 121 are independently selected from integers from 0 to 6; X4, X5 are independently selected from N, O or C; Rb6 is independently selected from none, H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 14 An integer selected from 0 to 3; m 15 An integer selected from 0 to 6; X6 is selected from N or O; X7 is selected from N, O or C; Rb7 is independently selected at each occurrence from none, H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxyl, cyano, carbonyl, -C(=O)NRb 41 R 42 、-(CH2)m 121 C(=O)NRb 41 R 42 、-(CH2)m 121 Nb 41 R 42 、-NRb 41 R 42 , -C(=O)Rb 41 、-C(=O)ORb 41 ; Rb 41 , Rb 42 Each of the substituents is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, and phosphate; m 16 An integer selected from 0 to 6; m 17 An integer selected from 0 to 3; X8 is selected from N, O or C; Rb8 is independently selected at each occurrence from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 18 An integer selected from 0 to 6; X9, X 10 Rb9 is independently selected from N or O; Rb9 is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 19 An integer selected from 0 to 6; X 11 Selected from N, O or C; Rb 20 Each occurrence is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinium, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, Acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 21 An integer selected from 0 to 6; m 20 、m 22 An integer selected from 0 to 3; X 12 , X 13 , X 14 are independently selected from N or O; Rb 21 Each occurrence is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 23 An integer selected from 1 to 3; m 24 An integer selected from 0 to 6; R 22 Each occurrence is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphate, carbonyl, substituted or unsubstituted: alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidinyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; m 25 An integer selected from 0 to 6; m 26 、m 27 An integer selected from 0 to 3; X 15 , X 16 Each is independently selected from O, -NH; X 17 Selected from O or N; Rb 10 , Rb 11 Independently selected from -OH, -CH3, H; Ring B has the following structure: in, X1 and X2 are independently selected from hydrogen, deuterium, and halogen; Y is selected from hydrogen or deuterium; Rd1 is ring C; Ring C is selected from one of the following: Re1, Re2, Re3, at each occurrence, are independently selected from -H, -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, phosphate; n3 is independently selected from an integer from 0 to 5 at each occurrence; n4 is independently selected from 0 or 1 at each occurrence; Or, when n3 is greater than or equal to 2, two adjacent Re1, Re2 or Re3 may also form a 4- to 7-membered ring with the atoms connected therebetween; A4-A8 are independently selected from heteroatoms or C, and not all are C. The number of heteroatoms in A4-A8 is 1, 2 or 3, and the heteroatoms are selected from N and / or O; A9~A 14 are independently selected from heteroatoms or C, and not all are C, A9 to A 14 The number of heteroatoms in is 1 or 2, and the heteroatoms are selected from N and / or O; The substituents of the ring A, ring B and ring C are selected from -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid and phosphate; The aforementioned alkyl group is selected from C 0-10 alkyl.

2. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: The substituted alkyl group is selected from -CF3, -C2F5.

3. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: X4 and X5 are independently selected from N, O or C, and are not O at the same time; X6 is selected from N or O; X7 is selected from N, O or C, and X6 and X7 are not O at the same time; X 12 , X 13 , X 14 are independently selected from N or O, and X 12 , X 13 Not at the same time it is O.

4. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Re1, Re2, and Re3 are each independently selected from -H, -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, phosphate, monomethyl phosphate, dimethyl phosphate, C 1-5 Straight or branched alkyl, C 1-5 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 Alkyl), -OCON(C 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 Aryl, five-membered heteroaryl, six-membered heteroaryl; Or when n3 is greater than or equal to 2, two adjacent Re1, Re2 or Re3 can also form a saturated or unsaturated C 3-8 Cycloalkyl, saturated or unsaturated C 3-8 Heterocycloalkyl, saturated or unsaturated cyclic lactone, C 5-6 Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl, amide substituted.

5. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Ring C is selected from: Re1 is independently selected from -H, -OH, -F, -Cl, -CN, -CF3, -C2F5, -OCF3, monomethylphosphoryl, dimethylphosphoryl, C 1-5 Straight or branched alkyl, C 1-5 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -S(C 0-10 Alkyl), -OCON(C 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 Aryl, five-membered heteroaryl, six-membered heteroaryl; Or when n3 is greater than or equal to 2, two adjacent Re1s form a saturated or unsaturated C 3-8 Cycloalkyl, saturated or unsaturated C 3-8 Heterocycloalkyl, five-membered ring lactone, C 5-6 Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl, amide substituted.

6. The compound according to claim 5, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: When n3 is greater than or equal to 2, two adjacent Re1s can also be connected to the benzene ring to form one of the following structures: Wherein, K2, K3, K4 are fused with a benzene ring to form a saturated or unsaturated five-membered ring, K2, K3, K4 are independently selected from C, N, O, S; K5, K6, K7 are independently selected from C, N, O, S; K8 is independently selected from C, N, O, S; R 50 , R 51 , R 52 , R 53 independently selected from -H, -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, m6, m7, m8, m9 are selected from integers of 0-6.

7. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Ring C is selected from: Re1 at each occurrence is independently selected from halogen, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F.

8. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Selected from Selected from 9. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: In the example, X4 and X5 are selected from one of the following combinations: (1) X4 is O, X5 is C; (2) X4 and X5 are C; (3) X4 is N, X5 is C; (4) X4 is O and X5 is N; m 14 Select from 0, 1 or 2; In, X 15 , X 16 are independently selected from O and -NH, and the two are different; In, X 17 Selected from O; Rb 10 , Rb 11 Choose from one of the following combinations: (1) Rb 10 , Rb 11 are independently selected from -OH and -CH3, and the two are different; (2) Rb 10 , Rb 11 Selected from H.

10. The compound according to claim 9, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Medium, m 14 is selected from 2, and X4 is O, and X5 is C; m 15 Rb6 is selected from 2, each occurrence of which is independently selected from hydroxyl, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted amide; the substituents are independently selected from halogen, alkyl, and hydroxyl.

11. The compound according to claim 10, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: The structure is as follows:

12. The compound according to claim 11, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Each occurrence of Rb6 is independently selected from hydroxyl, substituted or unsubstituted C 1-3 Alkyl; the substituents are independently selected from halogen and hydroxyl.

13. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: A1 is selected from C; A2 is selected from S; A3 is selected from C; Rb1 is selected from halogen, substituted or unsubstituted alkyl or cycloalkyl, -CN, phosphoryl, and the substituents are independently selected from deuterium and halogen; Rb2 is selected from halogen; Ra1 is selected from H and halogen; Ra2 is selected from -CN.

14. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Rb1 is selected from Cl, Br, I, -CF3, cyclopropyl, -CN; Rb2 is selected from F; Ra1 is selected from H, F, Cl, Br.

15. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: n1 is selected from 1 or 2; n2 is selected from 0; n3 is selected from 1, 2, 3, 4 or 5.

16. The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal, characterized in that: Formula I is selected from one of the following:

17. A pharmaceutical composition, characterized in that The active compound of the pharmaceutical composition includes one or more selected from the compound according to any one of claims 1 to 16, its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal.

18. Use of the compound according to any one of claims 1 to 16, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal in the preparation of a medicament for inhibiting KRAS.

19. The use according to claim 18, characterized in that The drug that inhibits KRAS is a drug that inhibits KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12C, KRAS G12R, KRAS G12A or KRAS G13D.

20. The use according to claim 18, characterized in that Use of the compound, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal in the preparation of a drug for treating, alleviating or preventing Noonan syndrome, leopard syndrome, leukemia, neuroblastoma, lymphoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, bone cancer, bile duct cancer, glioma, nasopharyngeal cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, bladder cancer, prostate cancer, testicular cancer, endometrial cancer, pancreatic cancer, pancreatic duct adenocarcinoma, ovarian cancer, rectal and colon cancer related diseases or conditions.

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