Fused ring compound and use

Abstract

A fused ring compound, a pharmaceutical composition comprising same, and a use. The compound has a structure represented by formula (I) or a tautomer, mesomere, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or eutectic thereof. The compound can be used for treating a cancer caused by KRAS mutations, and said cancer is selected from one or more cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations. In particular, the compound can serve as a G12D inhibitor and has relatively high inhibitory activity.

Description

A condensed ring compound and its application

[0001] Cross-references

[0002] This application claims priority to: (1) Chinese Patent Application No. 2023112927775, filed on October 8, 2023; and (2) Chinese Patent Application No. 2024101686500, filed on February 6, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0003] 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

[0004] 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 with 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.

[0005] 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 AMG510 and Mirati Therapeutics' MRTX849 making the most progress. The former has already received FDA approval. However, G12C is not the most common KRAS mutation subtype. Most KRAS missense mutations occur at codon 12, resulting in the conversion of glycine to other amino acids. KRAS G12D and KRAS G12V mutations are predominant, both found in 90% of pancreatic cancers. KRAS G12D is also the most common KRAS mutation in colon cancer. Unfortunately, because the amino acid residues at the mutation site are difficult to chemically bind, there are currently no marketed drugs for KRAS G12D and KRAS G12V.

[0006] Mirati Therapeutics publicly reported the first KRAS G12D inhibitor compound MRTX1133 (WO2021041671), which can selectively bind to KRAS G12D mutant protein and highly actively inhibit the phosphorylation of downstream ERK. MRTX1133 has a significant tumor-suppressing effect in multiple in vivo models (administered by intraperitoneal injection). However, its oral bioavailability is extremely low, with an AUC of less than 100 ng.h / ml at a dose of 100 mg / kg, and a phase I clinical study was initiated in the first half of 2023. In addition, KUMQUAT BIOSCIENCES INC. also disclosed a KRAS G12D inhibitor compound (WO2022047260), but it also has the problem of poor pharmacokinetic effect. Therefore, finding and developing new and efficient KRAS G12D mutation inhibitors is of great clinical significance.

[0007] Summary of the Invention

[0008] In view of this, the present application provides a fused ring compound, a pharmaceutical composition comprising the same, and an application thereof. The provided compound can be used to treat cancers caused by KRAS mutations, wherein the cancers caused by the KRAS mutations are selected from one or more of cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations. In particular, it can be used as a G12D inhibitor, has high inhibitory activity, good pharmacokinetic properties and good bioavailability, can be used to prepare drugs for preventing and / or treating KRAS G12D-mediated diseases, and has good application prospects.

[0009] The present application specifically 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:

[0010] A1 is selected from C or N;

[0011] 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;

[0012] Z, at each occurrence, is independently selected from H or deuterium;

[0013] 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;

[0014] n1 is an integer selected from 0 to 3, such as 0, 1, 2 or 3;

[0015] Ra2 is selected from -CN, H or none;

[0016] 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;

[0017] n2 is an integer selected from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

[0018] Ring B is a substituted or unsubstituted 4- to 12-membered heterocyclic ring, wherein the heteroatom is N;

[0019] Ring C is a substituted or unsubstituted 4- to 12-membered carbocyclic or heterocyclic ring, wherein the heteroatom is N and / or O;

[0020] 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.

[0021] In the present invention, It refers to Ring A; It is Ring B; It refers to ring C.

[0022] Further, A1 is selected from C;

[0023] Furthermore, Rb1 is selected from halogen, substituted or unsubstituted alkyl or cycloalkyl, and -CN, and the substituents are independently selected from deuterium and halogen.

[0024] Furthermore, Rb1 is selected from Cl, Br, I, -CF3, cyclopropyl, and -CN; and Rb2 is selected from F.

[0025] Furthermore, A2 is selected from S; A3 is selected from C.

[0026] Further, Ra1 is selected from H and halogen; further, Ra1 is selected from H, F, Cl, and Br.

[0027] Furthermore, n1 is selected from 1 or 2.

[0028] Further, Ra2 is selected from -CN.

[0029] in, Select one of the following structures:

[0030] 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;

[0031] n 21 、n 22 are independently selected from integers from 0 to 5, such as 0, 1, 2, 3, 4 or 5;

[0032] Furthermore, C 0-10 Substituted or unsubstituted alkyl is selected from C 1-3 Substituted or unsubstituted alkyl; C 1-10 Substituted or unsubstituted alkyl is selected from C 1-3 Substituted or unsubstituted alkyl; C 1-10 Substituted or unsubstituted heteroalkyl is selected from C 1-3 substituted or unsubstituted heteroalkyl.

[0033] Furthermore, X3 is selected from N.

[0034] Furthermore, ring B is selected from substituted or unsubstituted structures:

[0035] in,

[0036] X1 and X2 are independently selected from hydrogen, deuterium, and halogen; Y is selected from hydrogen or deuterium;

[0037] Rd1 is ring C.

[0038] In the present invention, when Selected from the following structures: Ring B has the following structure: When, Formula I presents the following structure:

[0039] Since Rd1 is ring C, the above structural formula can also be expressed as:

[0040] wherein Ring C is selected from substituted or unsubstituted 4- to 12-membered aryl or heteroaryl, substituted or unsubstituted 4- to 12-membered cycloalkyl or heterocycloalkyl;

[0041] The substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphoryl, sulfonic acid, and phosphoric acid.

[0042] Further, ring C is selected from one of the following:

[0043] 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;

[0044] n3 is independently selected at each occurrence from an integer of 0 to 5, such as 0, 1, 2, 3, 4 or 5;

[0045] 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;

[0046] 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;

[0047] 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.

[0048] Furthermore, 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, C3-10 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;

[0049] 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.

[0050] Further, ring C is selected from:

[0051] 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, 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;

[0052] 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.

[0053] when Selected from the following structures: Ring B has the following structure: Ring C is selected from When, Formula I presents the following structure:

[0054] Furthermore, n3 is selected from 1, 2, 3, 4 or 5.

[0055] Furthermore, n3 is selected from 1, 2 or 3.

[0056] Furthermore, Re1 is not H at the same time.

[0057] Furthermore, each occurrence of Re1 is independently selected from halogen, -CF3, -C2F5, -OCF3, -OCHF2, and -OCH2F.

[0058] Furthermore, each occurrence of Re1 is independently selected from H or halogen.

[0059] Furthermore, Selected from That is, Formula I can present the following structure:

[0060] In the present invention, when Re1 is selected from halogen, F, Cl, etc. may be preferably selected.

[0061] 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:

[0062] 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 to 6, such as 0, 1, 2, 3, 4, 5 or 6.

[0063] Selected from

[0064] Selected from

[0065] Further, Formula I is selected from one of the following:

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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 G12D mutation inhibitor drugs.

[0072] The present application also provides the use of the above-mentioned compounds, their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, metabolites, metabolic precursors, isotope-substituted forms, pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals in the preparation of 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 and colon cancer.

[0073] 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.

[0074] The present application also provides a method for inhibiting KRAS G12D mutation, which comprises administering to the patient a certain effective dose of the above-mentioned compound, its tautomer, mesomorph, 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.

[0075] The present application also provides a method for treating, alleviating or preventing a disease, which comprises administering to a patient a certain effective dose of the above-mentioned compound, its tautomer, mesomer, racemate, enantiomer, diastereoisomer 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; the diseases include but are not limited to: Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal and colon cancer.

[0076] In order to more clearly describe the content of this application, the terms involved are defined as follows:

[0077] 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.

[0078] 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 monophosphate, Pluronic F-68, lecithin, soy lecithin, etc.; solubilizers include Tween-80, bile, glycerol, etc.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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).

[0088] 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.

[0089] The ring structure contains When , it represents that the ring structure is a conjugated system.

[0090] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0091] The term "membered" refers to the number of skeletal atoms constituting the ring.

[0092] The term "one key" in this application means that there is only one connecting key, which can also be understood as "none".

[0093] "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.

[0094] 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.

[0095] "Heteroalkyl" refers to an alkyl group containing heteroatoms, including alkoxy groups.

[0096] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group can be straight-chain or branched.

[0097] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched.

[0098] "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.

[0099] "Sulfonyl" is a chemical structure having the formula -S(=O)2R, including sulfonamide groups, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, and the like;

[0100] "Phosphoryl" is a chemical structure having the formula -P(=O)RR', wherein R and R' are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, amino, etc.;

[0101] "Ester" refers to a chemical structure having the formula -COOR, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0102] "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.

[0103] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent.

[0104] "Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the ring backbone.

[0105] Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0106] "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.

[0107] Typical cycloalkyl groups include, but are not limited to:

[0108] Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0109] Typical heterocycloalkyl groups include, but are not limited to:

[0110] "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.

[0111] Typical heteroaryl groups include, but are not limited to:

[0112] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0113] "Deuterium" refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the element symbol is generally D or 2 H.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] "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.

[0118] "KRAS inhibitor" refers to a drug that inhibits KRAS activity.

[0119] Compared with the prior art, the present application is described in detail as follows:

[0120] The present application provides a novel class of compounds targeting KRAS G12D, which have unexpectedly excellent activity and pharmacokinetic properties.

[0121] 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.

[0122] The compound provided herein can be used to treat cancer caused by KRAS mutation, wherein the cancer caused by KRAS mutation is selected from one or more cancers caused by KRAS G12C, KRAS G12V, KRAS G12A, and G12D mutations.

[0123] The compounds provided in this application can effectively block the binding of KRAS G12D protein to SOS1. The compounds provided in this application have significantly improved KRAS G12D inhibitory activity, liver microsome stability, and rat pharmacokinetics.

[0124] The synthetic method of the present application is simple to operate and has a high yield. DETAILED DESCRIPTION

[0125] In order to enable those skilled in the art to better understand the technical solution of the present application, the present application is further described in detail below in conjunction with specific embodiments.

[0126] In this application, the structures of the compounds are determined by mass spectrometry (MS) and / or nuclear magnetic resonance ( 1 The chemical abbreviations have the following meanings:

[0127] DMF: N,N-dimethylformamide

[0128] THF: Tetrahydrofuran

[0129] DIPEA: N,N-diisopropylethylamine

[0130] PE: Petroleum ether

[0131] EA: ethyl acetate

[0132] DCM: dichloromethane

[0133] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea

[0134] DMSO: dimethyl sulfoxide

[0135] BOP-Cl: Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride

[0136] Synthesis of intermediates

[0137] Preparation of Intermediate 1: 2-Methylpropane-2-yl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0138] Step 1: Synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzene-1-carboxamide

[0139] 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 800 mL of DMF 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 solution was poured into 3000 mL 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%.

[0140] LC / MS: m / z = 267.0 [M+H] + .

[0141] Step 2: Synthesis of 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol

[0142] 2-Amino-4-bromo-5-chloro-3-fluorobenzene-1-carboxamide (23.2 g, 87.2 mmol) was dissolved in 200 mL of 1,4-dioxane. After nitrogen displacement, a solution of thiophosgene (30.0 g, 260.9 mmol) in 50 mL of 1,4-dioxane was added dropwise at room temperature. After the 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 150 mL of a 3 / 1 PE / EA mixture for 1 hour to obtain 23.0 g of an off-white solid (yield: 85.2%).

[0143] LC / MS: m / z=311.1[M+H] + .

[0144] Step 3: Synthesis of 2-methylpropan-2-yl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0145] To a reaction flask, 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (3.1 g, 10.0 mmol), 2-methylprop-2-yl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 11.8 mmol), DIPEA (3.9 g, 30.2 mmol), and 30 mL of dichloromethane were added. After nitrogen was replaced, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (3.8 g, 14.9 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 mL of water and extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain 3.3 g of a light yellow solid, with a yield of 65.5%.

[0146] LC / MS: m / z = 505.0 [M+H] + .

[0147] 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

[0148] Step 1: Synthesis of (6-bromo-2,3-difluorophenyl)methanol

[0149] Dissolve 6-bromo-2,3-difluorobenzene-1-carboxaldehyde (100.0 g, 450 mmol) in 1 L of ethanol. 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 3 L of water 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 is used directly in the next step.

[0150] LC / MS: m / z = 223.1 [M+H] + .

[0151] Step 2: Synthesis of (4-bromo-1,2-difluorophenyl-3-yl)methyl methanesulfonate

[0152] Dissolve (6-bromo-2,3-difluorophenyl)methanol (product from the previous step) and triethylamine (91.6 g, 900 mmol) in 1 L of dichloromethane. Add methanesulfonyl chloride (57.0 g, 500 mmol) dropwise at 0°C. Stir at 0°C for 1 hour. Pour the reaction system into 3 L of water 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%.

[0153] Step 3: Synthesis of (6-bromo-2,3-difluorophenyl)acetonitrile

[0154] 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 1 L of acetonitrile. A solution of tetrabutylammonium fluoride trihydrate (250.9 g, 795.3 mmol) in 500 mL of tetrahydrofuran 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 3 L of saturated brine and extracted with ethyl acetate. The organic phase was backwashed once with saturated brine, dried, and spin-dried to obtain 89.0 g of a yellow solid (yield: 96.0%).

[0155] LC / MS: m / z = 231.2 [M+H] + .

[0156] Step 4: Synthesis of ethyl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate

[0157] 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. After stirring at 0°C for 20 minutes, 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.

[0158] LC / MS: m / z=343.1[M+H] + .

[0159] Step 5: Synthesis of 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile

[0160] Ethyl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate (product from the previous step) was dissolved in 680 mL of DMSO and a 400 mL aqueous solution of sodium hydroxide (112.0 g, 2800 mmol) was added. The mixture was reacted at 100°C overnight. After cooling to room temperature, the reaction solution was poured into 1 L of water 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%.

[0161] LC / MS: m / z = 271.1 [M+H] + .

[0162] Step 6: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)amino]formate

[0163] 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 2 L of water and extract with ethyl acetate. Add 360 g of activated carbon and 50 g of silica gel 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%).

[0164] LC / MS: m / z=371.1[M+H] + .

[0165] 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

[0166] 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 450 mL of dioxane. After nitrogen was replaced, Pd(dppf)Cl2 (2.3 g, 3.2 mmol) was added. The reaction mixture was heated to 100°C and stirred overnight under nitrogen protection. The reaction system was cooled to room temperature and poured into 1.5 L of water. The mixture 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%.

[0167] LC / MS: m / z=405.2[M+H] + .

[0168] 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

[0169] Step 1: Synthesis of (2,6-dibromophenyl)methanol

[0170] Dissolve 2,6-dibromobenzene-1-carboxaldehyde (25.0 g, 94.7 mmol) in 250 mL of ethanol, 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 1000 mL of water 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%).

[0171] LC / MS: m / z=265.0[M+H] + .

[0172] Step 2: Synthesis of (1,3-dibromobenz-2-yl)methyl methanesulfonate

[0173] Dissolve (2,6-dibromophenyl)methanol (15.0 g, 56.4 mmol) and triethylamine (11.4 g, 112.8 mmol) in 150 mL of dichloromethane. 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 500 mL of water 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%).

[0174] Step 3: Synthesis of (2,6-dibromophenyl)acetonitrile

[0175] 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 170 mL of acetonitrile. A solution of tetrabutylammonium fluoride trihydrate (30.4 g, 96.5 mmol) in 90 mL of tetrahydrofuran 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 500 mL of saturated brine and extracted with ethyl acetate. The organic phase was backwashed once with saturated brine, dried, and spin-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%).

[0176] LC / MS: m / z = 273.1 [M+H] + .

[0177] Step 4: Synthesis of ethyl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate

[0178] (2,6-Dibromophenyl)acetonitrile (11.9 g, 43.2 mmol) was dissolved in 120 mL of DMF. After nitrogen displacement, sodium bicarbonate (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 300 mL of water 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%).

[0179] LC / MS: m / z=325.1[M+H] + .

[0180] Step 5: Synthesis of 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile

[0181] Dissolve ethyl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate (11.8 g, 36.2 mmol) in 55 mL of DMSO and add 36 mL of sodium hydroxide (10.1 g, 253.6 mmol). The mixture is reacted at 110°C overnight. After cooling to room temperature, the reaction solution is poured into 300 mL of ice water 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.

[0182] LC / MS: m / z=253.1[M+H] + .

[0183] Step 6: Synthesis of 2-methylpropan-2-yl [(4-bromo-3-cyanobenzo[b]thiophen-2-yl)amino]formate

[0184] 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 300 mL of water and extract with ethyl acetate. The organic phase is dried and spin-dried, then purified 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%.

[0185] LC / MS: m / z=353.0[M+H] + .

[0186] 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

[0187] 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 100 mL of dioxane 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 300 mL of water. 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%.

[0188] LC / MS: m / z = 401.2 [M+H] + .

[0189] Preparation of Intermediate 4: [3-(3,4,5-Trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate)

[0190] Step 1: Synthesis of methyl 2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate

[0191] Magnesium turnings (4.8 g, 200 mmol) were weighed into reaction flask A. 3,4,5-trifluorobromobenzene (1 g, 4.8 mmol), 0.2 g of elemental iodine, and 5 mL of tetrahydrofuran were added. After heating to initiate the reaction, a solution of 3,4,5-trifluorobromobenzene (20.0 g, 95.2 mmol) in 150 mL of tetrahydrofuran 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 250 mL of tetrahydrofuran 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 then added portionwise to reaction flask B. The reaction was allowed to proceed 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%.

[0192] LC / MS: m / z=376.1[M+H] + .

[0193] Step 2: Synthesis of methyl 5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

[0194] 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). Add HCl / MeOH (4 M, 200 mL) at room temperature and stir overnight. The reaction system is directly spin-dried, and 100 mL of saturated sodium bicarbonate solution is added. Extraction is performed with ethyl acetate, and the organic phase is dried and spin-dried to obtain 17.0 g of the product (94.0% yield).

[0195] LC / MS: m / z = 258.1 [M+H] + .

[0196] Step 3: Synthesis of methyl 2-(3-chloropropyl)-5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

[0197] 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 100 mL of DMF and 200 mL of THF. 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 h. The reaction system was poured into 1000 mL of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried and spin-dried to dryness. The crude product was purified by column chromatography (PE / EA = 8 / 1) to afford 16.6 g of an off-white solid in a yield of 75.5%.

[0198] LC / MS: m / z=334.1[M+H] + .

[0199] Step 4: Synthesis of methyl 3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (Trans racemate)

[0200] 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 200 mL of methanol, 2 mL of acetic acid 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, 200 mL of water was added, and the mixture was adjusted to a weak base with sodium carbonate. The mixture was 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. 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%.

[0201] LC / MS: m / z=300.2[M+H] + .

[0202] Step 5: Synthesis of [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans racemate)

[0203] 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 50 mL of tetrahydrofuran. Lithium aluminum hydride (1140 mg, 30 mmol) was added at 0°C and stirred for 1 hour. 200 mL of water 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 91% yield.

[0204] LC / MS: m / z = 272.2 [M+H] + .

[0205] Preparation of Intermediate 5: [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2)

[0206] 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 (Trans isomer 2)

[0207] 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 10 mL of dichloromethane. 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 30 mL of water and extracted with dichloromethane. The organic phase was dried and spin-dried, then 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%.

[0208] LC / MS: m / z = 404.2 [M+H] + .

[0209] Step 2: Synthesis of [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer 2)

[0210] (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 20 mL of water 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.

[0211] LC / MS: m / z = 272.2 [M+H] + .

[0212] Preparation of Intermediate 15: 2-Methylpropan-2-yl {[4-(6-bromo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0213] Step 1: Synthesis of 2-amino-4-bromo-3-fluorobenzamide

[0214] 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 3.5 L of DMF 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 14 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 210 g of the desired product. Total yield: 60.2%.

[0215] LC / MS: m / z = 233.1 [M+H] + .

[0216] Step 2: Synthesis of 2-methylpropan-2-yl {[4-(3-amino-4-formamido-2-fluorophenyl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0217] Add 2-amino-4-bromo-3-fluorobenzamide (68 g, 0.29 mol), potassium tert-butoxide (71.6 g, 0.73 mol) to the reaction bottle. To the mixture was added 111.3 g of diboronic acid pinacol ester (111.3 g, 0.44 mol), 680 ml of dioxane solution was added, the system was replaced with nitrogen three times, Pd (dppf) Cl2 (4.0 g, 0.005 mol) was added, the system was heated to 95 ° C and reacted for three hours, and then 2-methylpropane-2-yl {[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo [b] thiophen-2-yl] amino} carboxylate (8.5 g, 0.19 mol), cesium carbonate (142.4 g, 0.44 mol) and 136 mL of water were added, and finally Pd (dppf) Cl2 (2.0 g, 0.002 mol) was added, and 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 1 L of water. The mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried to obtain 76.5 g of the product, which was used directly in the next step. The yield was N / A.

[0218] LC / MS: m / z=427.1[M+H] + .

[0219] 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

[0220] 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), followed by NMP, and then slowly added NBS (82 mg, 0.46 mmol). The system was reacted at room temperature for 6 min. 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%.

[0221] LC / MS: m / z = 505.2 [M+H] + .

[0222] 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

[0223] 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 5 mL of 1,4-dioxane. After replacing the atmosphere with nitrogen, a solution of thiophosgene (88 mg, 0.78 mmol) in 2 mL of 1,4-dioxane 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%.

[0224] LC / MS: m / z=549.0[M+H] + .

[0225] Preparation of Intermediate 16: 2-Methylpropan-2-yl {[4-(6-iodo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane

[0226] 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

[0227] 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, 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 of a crude product, which was directly used in the next reaction.

[0228] LC / MS: m / z=553.2[M+H] + .

[0229] 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

[0230] 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 26 mL of 1,4-dioxane. After replacing the nitrogen atmosphere, add a solution of thiophosgene (1.6 g, 14.1 mmol) in 26 mL of 1,4-dioxane 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 of crude product.

[0231] LC / MS: m / z=597.10[M+H] + .

[0232] Table 1: Using commercially available reagents as starting materials, the compounds shown in Table 1 were prepared by following procedures similar to those described for Intermediates 4 and 5.

[0233] Example 1

[0234] 2-Amino-4-[6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0235] Step 1: Synthesis of 2-methylprop-2-yl 3-[7-bromo-6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoroquinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Trans racemate)

[0236] 3-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropan-2-yl ester (506 mg, 1.0 mmol), [3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans racemate) (297 mg, 1.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.1 mmol) were weighed and dissolved in DMF / THF (5 mL / 5 mL). Cesium carbonate (652 mg, 2.0 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was added to 30 mL of water and extracted three times with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 460 mg of a light yellow solid. The yield was 60.0%.

[0237] LC / MS: m / z=766.2[M+H] + .

[0238] Step 2: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)carboxylate (Trans racemate)

[0239] 3-[7-bromo-6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoroquinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylprop-2-yl ester (Trans racemate) (460 mg, 0.6 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 (404 mg, 1.0 mmol), cesium carbonate (489 mg, 1.5 mmol) and 6 mL of toluene were added, and the atmosphere was replaced with nitrogen before the addition of Pd(DPEPhos)Cl2 (70 mg, 0.1 mmol). The reaction mixture was heated to 100°C and stirred for 6 hours under nitrogen. The reaction system was cooled to room temperature and poured into 20 mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 210 mg of a yellow solid with a yield of 35.8%.

[0240] LC / MS: m / z = 978.3 [M+H] + .

[0241] Step 3: Synthesis of 2-amino-4-[6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile (Trans racemate)

[0242] 2-Methylpropan-2-yl({4-[6-chloro-2-({[3-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyano-7-fluorobenzo[b]thiophen-2-yl}amino)formate (Trans racemate) (210 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The product was dried by spin drying, added to 10 mL of saturated aqueous NaHCO 3 solution, 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 130 mg of the desired product in a yield of 77.8%.

[0243] LC / MS: m / z=778.2[M+H] + .

[0244] 1 H NMR(400MHz,d6-DMSO)δ1.75-2.02(7H,m),2.12-2.40(4H,m),2.60-3.00( 3H,m),3.75-3.90(1H,m),3.93-4.05(1H,m),4.14-4.18(2H,m),4.35-4.42 (1H,m),4.50-4.75(3H,m),4.95-5.10(1H,m),7.15-7.19(1H,m),7.23-7. 27(1H,m),7.45-7.55(2H,m),7.70-7.77(1H,m),7.95(1H,s),8.17(2H,s).

[0245] Example 2 (Trans isomer 2)

[0246] 2-Amino-4-[6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0247] Example 3 (Trans isomer 2, Axial chiral isomer 1)

[0248] 2-Amino-4-[6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 1)

[0249] Example 4 (Trans isomer 2, Axial chiral isomer 2)

[0250] 2-Amino-4-[6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 2)

[0251] Step 1: Synthesis of 2-methylprop-2-yl 3-[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]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Trans isomer 2)

[0252] 2-Methylprop-2-yl-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 3.95 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methanol (Trans isomer 2) (1.4 g, 5.17 mmol) and 1,4-diazabicyclo[2.2.2]octane (44 mg, 0.39 mmol) were weighed and dissolved in DMF / THF (8 mL / 8 mL). Cesium carbonate (3.8 g, 11.66 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was added to 50 mL of water and extracted three times with ethyl acetate. The organic phase was dried and spin-dried, and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 0.9 g of a light yellow solid. The yield was 31.0%.

[0253] LC / MS: m / z=740.2[M+H] + .

[0254] Step 2: Synthesis of 2-methylpropan-2-yl ({4-[6-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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)

[0255] 3-[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]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylprop-2-yl ester (Trans isomer 2) (1000 mg, 1.35 mmol), {[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl]amino}carboxylic acid-2-methylpropane-2-yl ester (810 mg, 2.03 mmol), cesium carbonate (1542 mg, 4.73 mmol) and 10 mL of toluene, after replacing nitrogen, Pd(DPEPhos)Cl2 (145 mg, 0.20 mmol) was added. The reaction mixture was heated to 100 ° C. and stirred for 2 hours under nitrogen protection. After cooling to room temperature, the reaction system was poured into 50 mL of water and extracted with ethyl acetate. The organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 800 mg of yellow solid, yield: 63.5%.

[0256] LC / MS: m / z = 934.3 [M+H] + .

[0257] Step 3: Synthesis of 2-amino-4-[6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0258] 2-Methylpropan-2-yl({4-[6-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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) (800 mg, 0.86 mmol) was dissolved in 5 mL of dichloromethane. 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was spin-dried, added to 10 mL of saturated NaHCO 3 aqueous solution, 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 300 mg of the target product, which was the compound of Example 2, in a yield of 47.7%.

[0259] LC / MS: m / z=734.2[M+H] + .

[0260] Step 4: Axial chiral resolution of 2-amino-4-[6-chloro-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2)

[0261] The product from the previous step is subjected to SFC separation to obtain a single configuration compound.

[0262] Separation method: Instrument: Waters SFC-80; Column: Chiralcel AD-H, 30 x 250 mm ID, 5 μm; Mobile phase: A (supercritical CO2), B (ethanol containing 0.5% 7 M ammonia in methanol); Gradient: B% = 50%, Flow rate: 45 mL / min; Wavelength: 215 nm; Pressure: 100 bar. Retention time of the first eluent, Rt = 1.801 min; retention time of the second eluent, Rt = 1.801 min.

[0263] The first eluting product (retention time Rt=1.801 min) was defined as the compound of Example 3:

[0264] LC / MS: m / z=734.2[M+H] + .

[0265] 1H NMR(400MHz,d6-DMSO)δ1.50-1.70(7H,m),1.80-1.95(3H,m),2.02-2.22(3H,m),2.30-2 .37(1H,m),3.41-3.55(4H,m),4.12-4.40(5H,m),7.14-7.25(4H,m),7.73-7.84(4H,m).

[0266] The second eluting product (retention time Rt=1.801 min) was defined as the compound of Example 4:

[0267] LC / MS: m / z=734.2[M+H] + .

[0268] 1 H NMR(400MHz,d6-DMSO)δ1.44-1.70(7H,m),1.85-1.94(3H,m),2.06-2.12(2H,m),2.17-2.23(1H,m),2.35-2.37(1H,m),3.41-3.61(4H,m),4 .13-4.22(3H,m),4.26-35(2H,m),7.18(1H,d,J=7.2Hz),7.23(1H,d,J=7.6Hz),7.26-7.31(2H,m),7.79(1H,d,J=7.6Hz),7.83-7.85(3H,m).

[0269] Example 5

[0270] 2-Amino-4-[8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans racemate)

[0271] Step 1: Synthesis of 2-chloro-3-fluoro-5-iodopyridin-4-amine

[0272] 2-Chloro-3-fluoro-4-aminopyridine (14.60 g, 100 mmol) was dissolved in 200 mL of acetonitrile. p-Toluenesulfonic acid (0.86 g, 5 mmol) was added at room temperature, followed by NIS (24.75 g, 110 mmol) in portions. After the addition, the system was stirred at 70°C overnight. The reaction system was poured into 1000 mL of water and extracted with ethyl acetate. The organic phase was backwashed twice with an aqueous solution of sodium hydrosulfite and then with saturated brine. The product was dried and spin-dried, then purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 25.00 g of a yellow solid (yield: 92%).

[0273] LC / MS: m / z = 272.0 [M+H] + .

[0274] Step 2: Synthesis of methyl 4-amino-6-chloro-5-fluoronicotinate

[0275] To a reaction flask, 2-chloro-3-fluoro-5-iodopyridin-4-amine (25.00 g, 91.9 mmol), triethylamine (30.30 g, 300 mmol), and 300 mL of methanol were added. After nitrogen was replaced, Pd(dppf)Cl2 (3.66 g, 5 mmol) was added. The reaction mixture was heated to 80°C under a carbon monoxide atmosphere (2 atm) and stirred overnight. The reaction system was cooled to room temperature and poured into 1000 mL of water. The mixture was extracted with ethyl acetate, and the organic phase was dried and spin-dried before purification by silica gel column chromatography (PE / EA = 3 / 1) to obtain 14.50 g of a yellow solid in a 78% yield.

[0276] LC / MS: m / z = 205.0 [M+H] + .

[0277] Step 3: Synthesis of methyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0278] To a solution of methyl 4-amino-6-chloro-5-fluoronicotinate (6.3 g, 30.9 mmol) in 100 mL of THF was added trichloroacetyl isocyanate (5.8 g, 30.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was spin-dried and the crude product was slurried with methyl tert-butyl ether to obtain 12.5 g of a yellow solid (yield: 100%).

[0279] LC / MS: m / z=392.1[M+H] + .

[0280] Step 4: Synthesis of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

[0281] To a solution of methyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (12.5 g, 31.8 mmol) in 100 mL of methanol was added a 7 M ammonia / methanol solution (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was dried by spin drying, and the crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to afford 6.4 g of a yellow solid in a 94% yield.

[0282] LC / MS: m / z = 216.0 [M+H] + .

[0283] Step 5: Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0284] At room temperature, 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (6.4 g, 29.8 mmol) was dissolved in 40 mL of phosphorus oxychloride. DIPEA (19.3 g, 150 mmol) was added and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was spin-dried and the crude product was used directly in the next step.

[0285] LC / MS: m / z=251.1[M+H] + .

[0286] Step 6: Synthesis of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0287] To a reaction flask, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (crude product from the previous step), DIPEA (25.8 g, 200 mmol), and 100 mL of dichloromethane were added. Tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.6 g, 31 mmol) was then added at -40°C. After stirring at -40°C for 1 hour, the mixture was poured into 1000 mL of water and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by silica gel column chromatography (PE / EA = 3 / 1) to afford 8.1 g of a yellow solid (yield: 64%).

[0288] LC / MS: m / z=428.1[M+H] + .

[0289] Step 7: Synthesis of 2-amino-4-[8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans racemate)

[0290] The above products, intermediate 3 and intermediate 5 were used as raw materials and the same method as in Example 2 was adopted to prepare the compound of Example 5.

[0291] LC / MS: m / z=701.2[M+H] + .

[0292] Example 6

[0293] 2-Amino-4-{8-fluoro-4-[1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl}benzo[b]thiophene-3-carbonitrile (Trans isormer 2)

[0294] Step 1: Synthesis of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0295] At room temperature, tert-butyl 3,8-diazabicyclo[3.2.1]octan-8-carboxylate (2.12 g, 10.0 mmol) was dissolved in 20 mL of dichloromethane. Triethylamine (1.52 g, 15.0 mmol) and triphenylmethane (2.79 g, 10.0 mmol) were added sequentially. The mixture was stirred at room temperature overnight. The reaction solution was poured into 100 mL of saturated aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 3.1 g of a yellow solid in a yield of 68.1%.

[0296] LC / MS: m / z=455.3[M+H] + .

[0297] Step 2: Synthesis of tert-butyl 1-(methyl-d3)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0298] Under nitrogen, a solution of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (455 mg, 1.0 mmol) and N,N,N',N'-tetramethylethylenediamine (232 mg, 2.0 mmol) in 10 mL of tetrahydrofuran was cooled to -30°C. Sec-butyllithium solution (1.3 M, 1.5 mL, 2.0 mmol) was added dropwise, maintaining the reaction temperature at around -30°C. After completion of the addition, the mixture was stirred at 0°C for half an hour. Deuterated iodomethane (145 mg, 1.0 mmol) was added dropwise. After completion of the addition, the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was poured into 30 mL of water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 160 mg of a yellow solid, yield: 33.9%.

[0299] LC / MS: m / z=454.3[M+H] + .

[0300] Step 3: Synthesis of tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0301] Dissolve tert-butyl 1-(methyl-d3)-3-trityl-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (160 mg, 0.34 mmol) in 5 mL of dichloromethane, add 5 mL of glacial acetic acid, react at 50°C for 1 hour, spin dry, pour the crude product into 10 mL of saturated sodium carbonate aqueous solution, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain the crude product, which is used directly in the next step.

[0302] LC / MS: m / z = 212.1 [M+H] + .

[0303] Step 4: Synthesis of 2-amino-4-{8-fluoro-4-[1-(methyl-d3)-3,8-diazabicyclo[3.2.1]oct-3-yl]-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl}benzo[b]thiophene-3-carbonitrile (Transisomer 2)

[0304] The product from the above step was used as the raw material, and the same method as in Example 5 was adopted to prepare the compound of Example 6.

[0305] LC / MS: m / z=700.2[M+H] + .

[0306] Example 19 (Trans isomer 2, Axial chiral isomer 1)

[0307] 2-Amino-4-[6-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 1)

[0308] Example 20 (Trans isomer 2, Axial chiral isomer 2)

[0309] 2-Amino-4-[6-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 2)

[0310] Step 1: Synthesis of 2-methylpropan-2-yl ({4-[6-bromo-2-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate

[0311] 2-Methylpropane-2-yl {[4-(6-bromo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (400 mg, 0.73 mmol) and 2-methylpropane-2-yl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.94 mmol) were dissolved in DCM (8 mL). DIPEA (188 mg, 1.46 mmol) and BOP-Cl (279 mg, 1.10 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to 40 mL of water and extracted three times with DCM. The organic phase was dried and spin-dried to dryness. Purification by silica gel column chromatography (PE / EA = 5 / 1) afforded 420 mg of a light yellow solid (yield: 77.8.0%).

[0312] LC / MS: m / z=743.1[M+H] + .

[0313] Step 2: 2-Methylpropan-2-yl({4-[6-bromo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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 (Transferase 2, Axial isomerization). 1) and synthesis of 2-methylpropan-2-yl({4-[6-bromo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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 ester (Trans isomer 2, Axial isomer 3)

[0314] Weigh out 2-methylpropan-2-yl ({4-[6-bromo-2-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (420 mg, 0.56 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer) and 1% ethanol. 2) (183 mg, 0.67 mmol) and 1,4-diazabicyclo[2.2.2]octane (8 mg, 0.07 mmol) were dissolved in DMF / THF (4 mL / 4 mL), and cesium carbonate (364 mg, 1.12 mmol) was added. The mixture was stirred at 45°C overnight. The reaction solution was added to 30 mL of water and extracted three times with ethyl acetate. The organic phase was dried and the pale yellow crude product was spin-dried. Pre-TLC was used to separate the axial chirality to obtain a single-configuration compound.

[0315] Separation method: Pre-TLC plate: 200 mm x 200 mm; sample load: 30-40 mg; developing solvent: (PE / EA = 1 / 1). Rf of the first eluate = 0.3, Rf of the second eluate = 0.25.

[0316] The first eluted product (Rf=0.3) was defined as Trans isomer 2, Axial chiral isomer 1 compound, and 40 mg was obtained after purification:

[0317] LC / MS: m / z = 978.3 [M+H] + .

[0318] The second eluted product (Rf=0.25) was defined as Trans isomer 2, Axial chiral isomer 2 compound and was purified to obtain 25 mg.

[0319] LC / MS: m / z = 978.3 [M+H] + .

[0320] Step 3: Synthesis of 2-amino-4-[6-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 1)

[0321] 2-Methylpropan-2-yl({4-[6-bromo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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, Axial chiral isomer 1) (40 mg, 0.04 mmol) was dissolved in 1 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was spin-dried, added to 5 mL of saturated aqueous NaHCO 3 solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Pre-TLC (DCM / MeOH=7 / 1) to give 15 mg of the desired product, which was Example 19, in a yield of 47.2%.

[0322] LC / MS: m / z=778.2[M+H] + .

[0323] 1H NMR(400MHz,d6-DMSO)δ1.79-1.94(7H,m),1.96-2.05(3H,m),2.11-2.19(2H,m),2.21-2.28(1H,m),2.35-2.41(1 H,m),3.65-4.05(4H,m),4.19-4.48(5H,m),7.14-7.16(1H,m),7.22-7.35(3H,m),7.79-7.90(3H,m),8.06(1H,s).

[0324] Step 4: Synthesis of 2-amino-4-[6-bromo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 2)

[0325] 2-Methylpropan-2-yl({4-[6-bromo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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, Axial chiral isomer 2) (20 mg, 0.02 mmol) was dissolved in 0.5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was spin-dried, added to 3 mL of saturated aqueous NaHCO 3 solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Pre-TLC (DCM / MeOH=7 / 1) to give 6 mg of the target product, which was Example 20, in a yield of 37.7%.

[0326] LC / MS: m / z=778.2[M+H] + .

[0327] 1H NMR(400MHz,d6-DMSO)δ1.50-1.72(7H,m),1.78-1.99(3H,m),2.04-2.14(2H,m),2.17-2.23(1H,m),2.32-2.40(1H,m),3.51- 3.62(4H,m),4.12-4.33(5H,m),7.15-7.16(1H,m),7.24(1H,t,J=8.0Hz),7.22-7.35(2H,m),7.78-7.82(3H,m),7.99(1H,s).

[0328] Example 21 (Trans isomer 2, Axial chiral isomer 1)

[0329] 2-Amino-4-[6-iodo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 1)

[0330] Example 22 (Trans isomer 2, Axial chiral isomer 2)

[0331] 2-Amino-4-[6-iodo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 2)

[0332] Step 1: Synthesis of 2-methylpropan-2-yl ({4-[6-iodo-2-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methanoate

[0333] 2-Methylpropane-2-yl {[4-(6-iodo-2-chloro-8-fluoro-4-hydroxyquinazolin-7-yl)-3-cyanobenzo[b]thiophen-2-yl]amino}methane (1.0 g, 1.68 mmol) and 2-methylpropane-2-yl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (464 mg, 2.18 mmol) were dissolved in DCM (10 mL). DIPEA (433 mg, 3.36 mmol) and BOP-Cl (640 mg, 2.52 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to 50 mL of water and extracted three times with DCM. The organic phase was dried and spin-dried to dryness. Purification by silica gel column chromatography (PE / EA = 5 / 1) afforded 980 mg of a light yellow solid (yield: 73.8.0%).

[0334] LC / MS: m / z = 791.1 [M+H] +.

[0335] Step 2: 2-Methylpropan-2-yl({4-[6-iodo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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 (Transferase 2, Axial isomerization). 1) and synthesis of 2-methylpropan-2-yl({4-[6-iodo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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 ester (Trans isomer 2, Axial isomer 3)

[0336] Weigh out 2-methylpropan-2-yl ({4-[6-iodo-2-chloro-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]-3-cyanobenzo[b]thiophen-2-yl}amino)methane (400 mg, 0.51 mmol), [3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyridin-7a-yl]methanol (Trans isomer) and 1% ethanol. 2) (166 mg, 0.61 mmol) and 1,4-diazabicyclo[2.2.2]octane (6 mg, 0.05 mmol) were dissolved in DMF / THF (4 mL / 4 mL), and cesium carbonate (332 mg, 1.02 mmol) was added. The mixture was stirred at 45°C overnight. The reaction solution was added to 30 mL of water and extracted three times with ethyl acetate. The organic phase was dried and the pale yellow crude product was spin-dried. Pre-TLC was used to separate the axial chirality to obtain a single-configuration compound.

[0337] Separation method: Pre-TLC plate: 200 mm x 200 mm; sample load: 30-40 mg; developing solvent: (PE / EA = 1 / 1). The first eluate had an Rf = 0.31, and the second eluate had an Rf = 0.24.

[0338] The first eluted product (Rf=0.31) was defined as Trans isomer 2, Axial chiral isomer 1 compound, and 46 mg was obtained after purification:

[0339] LC / MS: m / z = 1026.2 [M+H] +.

[0340] The second eluted product (Rf=0.24) was defined as Trans isomer 2, Axial chiral isomer 2 compound and was purified to obtain 15 mg.

[0341] LC / MS: m / z = 1026.2 [M+H] +.

[0342] Step 3: Synthesis of 2-amino-4-[6-iodo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 1)

[0343] 2-Methylpropan-2-yl({4-[6-iodo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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, Axial chiral isomer 1) (46 mg, 0.045 mmol) was dissolved in 1 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was spin-dried, added to 5 mL of saturated aqueous NaHCO 3 solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Pre-TLC (DCM / MeOH=7 / 1) to give 20 mg of the target product, which was Example 21, in a yield of 54.1%.

[0344] LC / MS: m / z = 826.1 [M+H] +.

[0345] 1H NMR(400MHz,d6-DMSO)δ1.50-1.71(7H,m),1.78-1.94(3H,m),2.02-2.14(2H,m),2.15-2.24(1H,m),2.29-2.35(1 H,m),3.48-3.64(4H,m),4.08-4.34(5H,m),7.05-7.07(1H,m),7.21-7.26(3H,m),7.77-7.80(3H,m),8.19(1H,s).

[0346] Step 4: Synthesis of 2-amino-4-[6-iodo-8-fluoro-2-({[3-(3,4,5-trifluorophenyl)-2,3,5,6,7,7a-hexahydro-1H-pyrin-7a-yl]methyl}oxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl]benzo[b]thiophene-3-carbonitrile (Trans isomer 2, Axial chiral isomer 2)

[0347] 2-Methylpropan-2-yl({4-[6-iodo-8-fluoro-4-(8-{[(2-methylpropan-2-yl)oxy]carbonyl}-3,8-diazabicyclo[3.2.1]octan-3-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, Axial chiral isomer 2) (15 mg, 0.015 mmol) was dissolved in 0.5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was spin-dried, added to 3 mL of saturated NaHCO 3 aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Pre-TLC (DCM / MeOH=7 / 1) to give 4 mg of the target product, which was Example 22, in a yield of 33.3%.

[0348] LC / MS: m / z = 826.1 [M+H] +.

[0349] 1H NMR(400MHz,d6-DMSO)δ1.45-1.75(6H,m),1.81-2.03(4H,m),2.04-2.15(2H,m),2.17-2 .27(1H,m),2.30-2.39(1H,m),3.49-3.72(4H,m),4.09-4.38(5H,m),7.08-7.10(1H,m), 7.17-7.41(3H,m),7.69-7.91(3H,m),8.19(1H,s).

[0350] Table 2: Using the corresponding intermediates as raw materials, the following compounds were prepared according to the synthetic methods described in the previous examples:

[0351] Comparative Example 1

[0352] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0353] That is, compound 19 in patent WO2022047260 was synthesized according to the method disclosed in the patent.

[0354] Efficacy trials

[0355] Test Example 1: Inhibitory activity test of compounds on KRas G12D-mediated ERK phosphorylation

[0356] 1. Test method:

[0357] Day 1: AGS cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% CO2 incubator.

[0358] 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.

[0359] 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 plate upside down for 1 minute. Fluorescence signal was read using an Odyssey CLx.

[0360] ERK phosphorylation was calculated according to the following formula:

[0361] Relative expression: (fluorescence signal ratio of compound – average value of positive control) / (average value of negative control – average value of positive control)

[0362] Negative control: DMSO

[0363] Positive control: 10μM Reference

[0364] XLFit5.0 calculates IC50 values ​​using the parametric formula: Y = Bottom + (Top–Bottom) / (1 + 10^((Log IC50–X)×HillSlope))

[0365] X: log value of compound concentration

[0366] Y: Average relative expression level of p-ERK between replicate wells

[0367] 2. The inhibitory activity of the compounds of the present application on ERK phosphorylation is shown in Table 3.

[0368] Table 3: Inhibitory activity of the compounds of the present application on ERK phosphorylation

[0369] Conclusion: From the above data, it can be seen that the compounds of the present application can effectively inhibit the phosphorylation of ERK, a downstream target of the KRAS pathway. The activities of some compounds are comparable to those of MRTX1133 and Comparative Example 1, and the activities of some compounds are better than those of MRTX1133 and Comparative Example 1, indicating that the compounds of the present application have broad application prospects.

[0370] Experimental Example 2: 3D cell proliferation inhibition test of compounds

[0371] The diluted test compound was added to a 384-well low-adsorption cell culture plate 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 The luminescence value of the 2D reagent was read using an Envision multifunctional microplate reader (the light signal is proportional to the amount of ATP in the system, and the ATP content directly represents the number of viable cells in the system). Finally, the IC50 (half-maximal inhibitory concentration) of the compound was calculated using a nonlinear fitting formula using XLFIT software.

[0372] 1. Experimental methods

[0373] a) Use a nanoliter pipetting system to add the diluted test compound to a 384-well low-adhesion cell culture plate.

[0374] 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.

[0375] c) Join 3D to b) Place in a 384-well cell culture plate, shake in the dark, and incubate at room temperature.

[0376] d) Read the luminescence value using Envision multi-function microplate reader.

[0377] 2. Data Analysis

[0378] The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula using XLFIT software: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)×HillSlope))

[0379] X: log value of compound concentration

[0380] Y: Inhibition rate (%) Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0381] Negative control: DMSO

[0382] Positive control: Medium only

[0383] 3. The 3D cell proliferation inhibitory activity data of some compounds of the present application are shown in Table 4.

[0384] Table 4: Anti-cell proliferation activity data of some compounds

[0385] Conclusion: From the above data, it can be seen that some compounds of the present application can effectively inhibit the proliferation of KRAS G12D mutant cells, and their activity is comparable to that of MRTX1133, and some compounds are more active than MRTX1133.

[0386] Experimental Example 3: Pharmacokinetics of the compound in rats and mice

[0387] Pharmacokinetic studies were conducted using a single oral or intravenous dose of each test compound in male SD rats or female BALB / c mice. 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 oral administration and resumed feeding 4 hours after administration. Pharmacokinetic samples were collected via the jugular vein at pre-dose, 5 minutes (for 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 (6800 rpm, 6 minutes, 2-8°C). Collected plasma was stored at –80°C until analysis. The concentrations of the compounds in plasma samples were determined by LC-MS / MS analysis.

[0388] Table 5: Pharmacokinetic test results of some compounds in SD rats

[0389] Table 6: Pharmacokinetic test results of some compounds in BALB / c mice

[0390] MRTX1133 and the compound of Comparative Example 1 have extremely poor oral pharmacokinetics and very low bioavailability, while the Cmax and AUC of some of the examples of this patent are significantly better than those of MRTX1133 and Comparative Example 1, and have great development potential.

[0391] Experimental Example 4: In vivo pharmacodynamic study of the compound on a BALB / c nude mouse model of subcutaneous xenografts of human colon cancer GP2D cells

[0392] Cell Culture: GP2D tumor cells were cultured in vitro in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) at 37°C in a 5% CO2 incubator. The medium was changed every two days, with a maximum of 4-5 passages. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.

[0393] Tumor cell inoculation and grouping: GP2D tumor cells resuspended in DMEM medium were inoculated subcutaneously on the right side of the experimental animals at a concentration of 1×107+ gel / 0.1 mL. The tumors grew to approximately 200-300 mm. 3 Animals with relatively uniform tumor volumes were divided into groups of 5. Each group was administered with a vehicle (50 mM citrate buffer (pH 5.0) + 10% Captisol) or a test compound (mixed with the vehicle to form a solution) twice a day.

[0394] Tumor volume measurement: Use a vernier caliper to measure the long diameter and short diameter of the tumor and calculate the tumor volume. The volume calculation formula is: volume = 0.5 × long diameter × short diameter 2 During the experiment, tumor volume was measured twice a week.

[0395] The anti-tumor efficacy of the compound was evaluated by TGI (%): Calculation of TGI (%): TGI (%) = [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%.

[0396] Table 7: Pharmacological efficacy results of compounds in mouse GP2D in vivo efficacy model

[0397] Conclusion: Under the same administration conditions, some compounds in this application can significantly inhibit the growth of GP2D tumors, while the control compound MRTX1133 is basically ineffective.

[0398] The above-mentioned compounds provided in the present application can be used to treat cancers caused by KRAS mutations, wherein the cancers caused by the KRAS mutations are selected from one or more of cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations. In particular, they can be used as G12D inhibitors, have high inhibitory activity, have good utilization, can be used to prepare drugs for preventing and / or treating KRAS G12D-mediated diseases, and have good application prospects.

[0399] The above are merely preferred embodiments of the present application. It should be noted that the above preferred embodiments should not be construed as limiting the present application. The scope of protection of the present application should be determined by the scope defined in the claims. Persons skilled in the art will appreciate that improvements and modifications can be made without departing from the spirit and scope of the present application, and such improvements and modifications should also be considered within the scope of protection of the present application.

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; Selected from the following structures: in, X3 is selected from N; 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, amide; n 21 、n 22 are independently selected from integers from 0 to 5; Ring B has the following structure: Wherein, 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 structures: 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 of 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 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.

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: C 1-10 Substituted or unsubstituted alkyl is selected from C 1-3 Substituted or unsubstituted alkyl; C 1-10 Substituted or unsubstituted heteroalkyl is selected from C 1-3 Substituted or unsubstituted heteroalkyl; C 0-10 Substituted or unsubstituted alkyl is selected from C 1-3 Substituted or unsubstituted alkyl.

3. 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: 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.

4. 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; 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.

5. The compound according to claim 4, 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: 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.

6. 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.

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: Selected from Selected from 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: A1 is selected from C; A2 is selected from S; A3 is selected from C.

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: Rb1 is selected from halogen, substituted or unsubstituted alkyl or cycloalkyl, -CN, and the substituents are independently selected from deuterium and halogen; Rb2 is selected from halogen.

10. 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.

11. 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: Ra1 is selected from H and halogen.

12. 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; n3 is selected from 1, 2, 3, 4 or 5.

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: 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: Formula I is selected from one of the following:

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: Formula I is selected from one of the following:

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 KRAS inhibitor drug.

19. The use according to claim 18, characterized in that The KRAS inhibitor is a KRAS G12D mutation inhibitor.

20. The use according to claim 18, characterized in that The use of the compound, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal in the preparation of a drug for treating, alleviating or preventing Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal and colon cancer related diseases or conditions.

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