WO2023103523A1 - Substituted bicyclic heteroaryl compound as kras g12d inhibitor - Google Patents

Abstract

Provided in the present invention is a substituted bicyclic heteroaryl compound as a KRAS G12D inhibitor. Further provided in the present invention are a pharmaceutical composition containing the compound and the use thereof in the treatment of cancers.

Description

Substituted bicyclic heteroaryl compounds as KRAS G12D inhibitors technical field

The invention belongs to the field of medicine, in particular to a substituted bicyclic heteroaryl compound, which can be used as a KRAS G12D inhibitor.

Background technique

The human RAS gene family includes three types of RAS genes KRAS, NRAS and HRAS, encoding four different RAS proteins (KRAS-4A, KRAS-4B, NRAS and HRAS). RAS protein belongs to the GTPase protein family, it is in an inactive state when it binds to GDP, and it is in an active state after binding to GTP, which can lead to the activation of downstream RAF-MAPK, PI3K-Akt and other signaling pathways, leading to the anti-apoptosis and anti-apoptosis of cells. Proliferation (Cell, 2017; 170(1):17-33; Cell, 2020; 183(4):850-859; Nat Rev Drug Discov, 2020; 19(8):533-552.). Activating mutations in the RAS gene are the most prevalent oncogenic driver genes in human cancers, among which KRAS is the most frequent oncogenic activating mutation. For example, KRAS has a mutation rate of 86-96% in pancreatic cancer, 40-54% in colorectal cancer, and 27-39% in lung cancer (PNAS, 2019; 116(32):15823-15829 ; Pathol Res Pract, 2009; 205, 858–862; Nature, 2012; 491, 399–405; Nature, 2014; 511, 543–550).

Oncogenic driver mutations can occur at multiple sites in the KRAS gene, the most common mutations occur at the G12 site, including G12C, G12D, G12V, etc. These mutations can reduce the GTPase activity of the KRAS protein, resulting in a long-term Active state, leading to malignant transformation of cells and carcinogenesis (Cell, 2017; 170(1): 17-33; Nat Rev Drug Discov, 2020; 19(8): 533-552). In different cancer types, the frequently occurring KRAS mutation types are different. For example, about 13% of lung cancer patients have G12C mutations (N Engl Med J, 2021; 384(25):2382-2393); in pancreatic cancer, G12D mutation occurred in 33.8% of patients, but only 1.7% of patients developed G12C mutation; in colorectal cancer, about 10-12% of patients had G12D mutation, while the incidence of G12C mutation was less than 3% (Nat Rev Cancer 2018;18(12):767-777).

Unlike ATP-dependent protein kinases (the affinity between protein and ATP is at the micromolar level), the affinity between KRAS protein and GDP/GTP is at the picomolar level, and it is difficult for compounds to compete effectively with GDP/GTP to inhibit the KRAS signaling pathway. This has seriously hindered the development of KRAS inhibitors (Cell, 2017; 170(1): 17-33; Cell, 2020; 183(4): 850-859; Nat Rev Drug Discov, 2020; 19(8): 533- 552.). In recent years, an "allosteric" binding cavity that can compete with non-GDP/GTP that can effectively bind small molecules has been discovered on the KRAS protein. These discoveries have greatly promoted the development of targeted drugs targeting KRAS mutation-driven tumors. Currently, MRTX-849 (Adagrasib) and AMG510 (Sotorasib) targeting KRAS G12C have demonstrated excellent efficacy in clinical studies (N Engl J Med.2020; 383(13):1207-1217; Cancer Discov.2020; 10 (1):54-71), and AMG510 has successfully obtained FDA approval for marketing in May 2021. Compared with the development of KRAS G12C drugs, the development of drugs targeting KRAS G12D mutations is still at an early stage; however, as shown above, there are very high KRAS G12D mutation rates in various tumors, and the development of KRAS G12D inhibitors is extremely important meaning.

Mirati Corporation of the United States reported the KRAS G12D small molecule MRTX1133 for intravenous administration, but it has not yet entered clinical research. The KRAS G12D-targeted small molecule drug of the present invention has excellent in vivo efficacy and greater safety, in order to solve the unmet clinical needs .

Contents of the invention

In one aspect, the invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Said compound is selected from:

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also comprises other therapeutic agents.

In another aspect, the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating and/or preventing KRAS G12D mutein-mediated diseases.

In another aspect, the present invention provides a method for treating and/or preventing a KRAS G12D mutein-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention.

In another aspect, the present invention provides the compound of the present invention or the composition of the present invention for the treatment and/or prevention of KRAS G12D mutein-mediated diseases.

In specific embodiments, the diseases treated by the present invention include cancers selected from the group consisting of: acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancers, uterine Endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastric Intestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular Melanoma, islet cell tumor, pancreatic neuroendocrine tumor, renal cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, Midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasm, multiple myeloma, Meck Myeloid cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), Oral cancer, lip and mouth cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary Central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cellular lymphoma , testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers , preferably pancreatic cancer, colorectal cancer or non-small cell lung cancer.

Other objects and advantages of the present invention will become apparent to those skilled in the art from the ensuing detailed description, examples and claims.

definition

The term "KRAS G12D" refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12.

As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.

"Subjects" for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"Disease", "disorder" and "condition" are used interchangeably herein.

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.

specific implementation plan

Herein, "the compound of the present invention" refers to the following compounds, their pharmaceutically acceptable salts, enantiomers, diastereoisomers, solvates, hydrates or isotopic variants, and their mixture.

In one embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Said compound is selected from:

The compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, eg, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereoisomers or geometric isomers (eg cis and trans isomers), or may be in the form of a mixture of stereoisomers, Racemic mixtures and mixtures enriched in one or more stereoisomers are included. Isomers can be separated from mixtures by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.

The compounds of the invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.

Those skilled in the art will appreciate that organic compounds may form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates". When the solvent is water, the complex is called a "hydrate". The invention covers all solvates of the compounds of the invention.

The term "solvate" refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that combines with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R.x H ₂ O, where R is the compound, and x is a number greater than zero. A given compound may form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R _0.5H2 O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R·2H ₂ O) and hexahydrate (R·6H ₂ O)).

The compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described herein, but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replace. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. The compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention. Certain isotopically-labeled compounds of the invention, eg, those incorporating radioactive isotopes (eg, ^{3H and14C} ), are useful in drug and/or substrate tissue distribution assays. Tritium, ^ie3H , and carbon-14, ^ie14C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ^ie2H , may be preferred in some circumstances since greater metabolic stability may afford therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following Schemes and/or Examples and Preparations.

Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo to its active form having a medical effect, for example by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, per intro This article is for reference.

Pharmaceutical compositions and kits

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.

A pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols and lanolin.

The invention also includes kits (eg, pharmaceutical packs). Provided kits can include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, a compound of the invention and other therapeutic agent provided in a first container and a second container are combined to form a unit dosage form.

medication

The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal cavity administration, buccal administration, vaginal administration Drugs, by implants, or by other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal, intralesional, and intracranial injection or infusion techniques, preferably intravenously.

Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered can be determined by the physician according to the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .

When used to prevent a condition described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice and supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.

Long-term administration of the pharmaceutical compositions provided herein ("chronic administration") can also be used. Long-term administration refers to administering a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, For example, the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within the therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, pharmaceutical compositions may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to effective levels. The bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose provides slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV intravenous infusion) ) can be delivered more rapidly, so that the concentration of the active ingredient in the blood rises rapidly to effective levels. In other embodiments, the pharmaceutical compositions may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions will be presented in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful for forming the desired administration form. Carriers or excipients and processing aids.

For oral dosages, a typical regimen is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.

In order to provide blood levels similar to, or lower than, the injected dose, the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dosage levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially 24 to 96 hours. A preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given in order to achieve adequate steady state levels. For a human patient of 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may comprise, for example, any of the following components, or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl sylate or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. In such compositions, as previously mentioned, the active compound is typically a minor component, often from about 0.05 to 10% by weight, the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated in an ointment, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream, with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and generally include other ingredients for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

The compounds of the invention may also be administered by transdermal devices. Thus, transdermal administration can be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

The foregoing components of compositions for oral administration, injection or topical administration are representative only. Other materials and processing techniques, etc. are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

The compounds of the invention may also be administered in sustained release form, or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins composed of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally including a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, eg, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (eg, 10-50% in water).

Example

The reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.

The specific reaction scheme or steps of the following examples are used in the present invention, specifically as follows:

Example 1

Preparation of key intermediate a1-a30

Synthesis of intermediate a1

Step 1: Dissolve the raw material 2-amino-3-fluoro-4-bromobenzoic acid a1-1 (15g, 64.1mmol) in 100mL DMF, slowly add N-chlorosuccinimide (8.56g, 64.1mmol) , the temperature was raised to 80° C. for 16 hours, and the reaction was stopped. The reaction solution was poured into 500 mL of ice water, filtered with suction to obtain a filter cake, and dried to obtain intermediate a1-2 (13.2 g, 49.2 mmol). Yield: 77%. LC-MS: [MH] ^- = 267.

Step 2: Add urea (35.3g, 588mmol) and intermediate a1-2 (10.5g, 39.2mmol) into a 200mL round bottom flask, and heat up to 200°C for 12 hours. After cooling down to 80°C, 100 mL of water was added to the system, refluxed for 10 minutes, cooled to room temperature, filtered to obtain a filter cake, washed with water, and dried in an oven to obtain intermediate a1-3 (4.0 g, 13.7 mmol). Yield: 35%. LC-MS: [M+H] ⁺ =294.

Step 3: Dissolve the intermediate a1-3 (4.0g, 13.7mmol) and N,N-diisopropylethylamine (5.3g, 41.1mmol) in 15mL phosphorus oxychloride, and heat up to 120°C After reacting for 8 hours, stop the reaction. The solvent was evaporated under reduced pressure and separated by column chromatography to obtain intermediate a1 (1.9 g, 5.8 mmol). Yield: 42%. LC-MS: [M+H] ⁺ = 331.

Synthesis of intermediates a2, a3, a16, a30

Step: At room temperature, intermediate a1 (1.9g, 5.8mmol) and raw material 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl a2-1 (1.85g, 8.7mmol ) was dissolved in 20 mL of dichloromethane, N,N-diisopropylethylamine (2.3 g, 17.4 mmol) was added, and reacted at room temperature for 8 hours. Add 60 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain a light yellow solid a2 (1.2 g, 2.4 mmol). Yield: 41%. LC-MS: [M+H] ⁺ = 507.

Referring to the synthetic route of intermediate a2, the following intermediate was synthesized.

Synthesis of Intermediates a4-a6, a8-a13

Step 1: Under ice bath, dissolve 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid a4-2 (3.0g, 20.8mmol) in 60mL of dichloromethane, slowly add oxalyl chloride (10.5g, 83.3 mmol), added 5 drops of anhydrous DMF, and reacted at 0° C. for 20 minutes. The ice bath was removed, the temperature was raised to room temperature and stirring was continued for 1 hour, and the solvent was evaporated under reduced pressure. The mixture was dissolved in 40 mL of dichloromethane, N,N-diisopropylethylamine (5.4 g, 41.2 mmol) and tetrahydropyrrole a4-1 (1.78 g, 25.0 mmol) were added, and reacted at room temperature for 3 hours. Stop the reaction, evaporate the solvent under reduced pressure, and separate by flash column chromatography to obtain intermediate a4-3 (2.6 g, 13.2 mmol). Yield: 64%. LC-MS: [M+H] ⁺ =198.

Step 2: At -78°C, the intermediate a4-3 (2.6g, 13.2mmol) was dissolved in 30mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (26.4mL, 1M) was added slowly. The temperature was raised to room temperature for 2 hours, and the reaction was stopped. Slowly pour 80 mL of ice water into the reaction solution, evaporate the organic solvent under reduced pressure, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain intermediate a4 (900 mg, 5.8 mmol). Yield: 44%. LC-MS: [M+H] ⁺ = 156.

Referring to the synthetic route of intermediate a4, the following intermediate was synthesized.

Synthesis of intermediate a7

Step 1: Under ice bath, dissolve 6-bromo-2,3-difluorobenzaldehyde a7-1 (25g, 113mmol) in 250mL of methanol, slowly add sodium borohydride (8.54g, 226mmol), and stir for 20 minutes , the temperature was raised to room temperature and the reaction was continued for 1 hour, and the reaction was stopped. The reaction solution was slowly poured into saturated aqueous NH ₄ Cl solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid a7-2 (23.9 g, 107 mmol). Yield: 95%.

Step 2: Dissolve intermediate a7-2 (23.9g, 107mmol) and N,N-diisopropylethylamine (20.7g, 161mmol) in 200mL anhydrous tetrahydrofuran under ice bath, and slowly add methylsulfonate Acid anhydride (20.5 g, 118 mmol), after stirring for 20 minutes, the ice bath was removed, and the reaction was continued at room temperature for 18 hours, and the reaction was stopped. The reaction solution was slowly poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain oil a7-3 (19 g, 63.1 mmol). Yield: 59%.

Step 3: Dissolve the above intermediate a7-3 (19g, 63.1mmol) in 240mL of a mixed solution of ethanol and water (v/v, 6/1), and add potassium cyanide (4.49g, 69mmol). React under reflux condition for 1 hour, stop the reaction. The organic solvent was evaporated under reduced pressure, the reaction solution was poured into saturated sodium carbonate solution, stirred for 20 minutes, extracted with dichloromethane, concentrated, and separated by column chromatography to obtain intermediate a7-4 (10.4g, 44.8mmol). Yield: 71%. LC-MS: [M+H] ⁺ =233.

Step 4: Under ice bath, dissolve the intermediate a7-4 (10.4g, 44.8mmol) in 80mL DMF, slowly add potassium tert-butoxide (5.3g, 47.2mmol), and stir for 20 minutes, the solution turns red , DMF solution (6.2 g, 47.2 mmol, 5 mL) of ethyl isothiocyanatoformate (6.2 g, 47.2 mmol, 5 mL) prepared in advance was slowly added dropwise. After continuing to stir the reaction liquid for 1 hour, the temperature was raised to 100° C. for 30 minutes to react. After cooling to room temperature, the reaction solution was slowly poured into ice water to quench the reaction, and the filter cake was obtained by suction filtration, washed with n-hexane, and dried in a vacuum oven to obtain intermediate a7-5 (13.7 g, 40.0 mmol). Yield: 89%. LC-MS: [M+H] ⁺ = 344.

Step 5: The above intermediate a7-5 (6.7g, 19.5mmol) was dissolved in 30mL DMSO, and 30mL aqueous sodium hydroxide solution (5M) was added. React under reflux conditions for 4 hours, stop the reaction. After cooling to room temperature, 100 mL of ice water was slowly added to the reaction liquid to quench the reaction, and the filter cake was obtained by suction filtration, washed with water, and dried in a vacuum oven to obtain the crude intermediate a7-6 (3.8 g). LC-MS: [M+H] ⁺ =272.

Step 6: Dissolve the above crude product a7-6 (3.8g) and DMAP (122mg, 1mmol) in a mixed solution of 30mL THF/DMF (v/v, 1/1), add Boc anhydride (4.3g, 19.5mmol ). React at room temperature for 12 hours, then stop the reaction. Add 80 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude intermediate a7-7 (3.3 g).

Step 7: Under the protection of nitrogen, the crude product a7-7 (3.3g) and raw material a7-8 (6.01g, 26.7mmol) were dissolved in 30mL 1,4-dioxane, and potassium acetate (2.62g, 26.7 mmol) and Pd(DPEphos)Cl ₂ (643mg, 0.9mmol), the temperature was raised to 100°C for 1 hour, and the reaction was stopped. Cool to room temperature, filter, wash with saturated brine, extract with dichloromethane, dry, concentrate, and separate by flash column chromatography to obtain intermediate a7 (2.5g, 6.2mmol). LC-MS: [M+H] ⁺ = 405.

Synthesis of intermediates a14, a17

Step: Under the protection of nitrogen, the intermediate a2 (50g, 98.77mmol) was dissolved in 750mL of anhydrous DMF, CsF (45g, 29.63mmol) was added, the temperature was raised to 60°C for 8h, and the reaction was stopped. The reaction solution was added to 1L of water, and the mixture was extracted three times with 750 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain intermediate a14 with a yield of 90%. LC-MS: [M+H] ⁺ = 489.

Referring to the synthetic route of intermediate a14, the following intermediate was synthesized.

Synthesis of intermediates a15, a18

Step 1: Dissolve starting material 3-methoxy-2,2-dimethyl-3-oxalonic acid a15-1 (1.0g, 6.8mmol) and starting material a5-1 (850mg, 6.8mmol) in 20mL without Add EDCI (1.56g, 8.2mmol), N,N-diisopropylethylamine (1.77g, 13.6mmol) and HOBt (1.1g, 8.2mmol) to water dichloromethane, react at room temperature for 16h, stop reaction. Add 60 mL of ice water to the reaction solution, extract with dichloromethane, and dry over anhydrous sodium sulfate. The mixture was separated by Flash column chromatography to obtain intermediate a15-2 (1.04g, 4.6mmol) with a yield of 68%. LC-MS: [M+H] ⁺ = 218.

Step 2: At -78°C, the intermediate a15-2 (1.04g, 4.6mmol) was dissolved in 15mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (350mg, 9.2mmol) was added slowly. The temperature was raised to 0°C for 1 hour, and the reaction was stopped. Slowly add 2 mL of 10% NaOH aqueous solution to the reaction liquid, precipitate flocs, filter with suction, concentrate the filtrate under reduced pressure, and separate by flash column chromatography to obtain intermediate a15 (700 mg, 4.0 mmol). Yield: 87%. LC-MS: [M+H] ⁺ =176.

Referring to the synthetic route of intermediate a15, the following intermediate was synthesized.

Synthesis of intermediate a19-a23

Step 1: Add (3S,4R)-4-fluoro-3-hydroxypyrrolidine a19-1 (300mg, 2.86mmol) and intermediate a19-2 (1.06g, 3.14mmol) into a 50mL reaction flask, add 5mL without Aqueous THF dissolves. After stirring for 5 minutes, NaBH(OAc) ₃ (1.81g, 8.58mmol) and 5 drops of acetic acid were added to the reaction solution, reacted at room temperature for 10 hours, and the reaction was stopped. The reaction solution was poured into 150mL of ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.1 g of the crude intermediate a19-3 as a colorless oil, LC-MS: [M+H] ⁺ =428.

Step 2: Dissolve 1.1g of intermediate a19-3 (1.1g) of the crude product in the previous step in 15mL of anhydrous THF, add 3,4-dihydro-2H-pyran (390mg) and p-toluenesulfonic acid (200mg), After stirring at room temperature for 1 hour, TLC showed that the reaction was complete. The reaction solution was poured into 80 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain 1.5 g of crude intermediate a19-4, LC-MS: [M+H] ⁺ =514.

Step 3: The above intermediate a19-4 (1.5g) was dissolved in 15mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.5g) was added. The reaction was carried out at room temperature for 3 hours, and the reaction was complete as monitored by TLC. The reaction solution was dissolved in 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE/EA=1/1) to obtain a19 (200 mg, 0.73 mmol) as a colorless oil , Yield: 35%, LC-MS: [M+H] ⁺ =274.

Referring to the synthetic route of intermediate a19, the following intermediate was synthesized.

Synthesis of intermediate a24

Step 1: Add raw material 3,3-difluorocyclobutane-1-amine a24-1 (1.0g, 9.34mmol) and intermediate a19-2 (3.16g, 9.34mmol) in a 100mL reaction flask, 40mL anhydrous THF dissolves. After stirring for 5 minutes, NaBH(OAc) ₃ (2.57g, 12.34mmol) and 10 drops of acetic acid were added to the reaction solution, reacted at room temperature for 10 hours, and the reaction was stopped. The reaction solution was poured into 200mL of ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography (PE/EA, 1/1) to obtain 2.62g of a colorless oily intermediate a24-2, LC-MS: [M+H ] ⁺ =430.

Step 2: Add intermediate a24-2 (2.62g, 5.91mmol) and aqueous formaldehyde (0.26mL) into a 100mL reaction flask, and dissolve in 40mL THF. After stirring for 5 minutes, NaBH(OAc) ₃ (1.63g, 7.68mmol) and 10 drops of acetic acid were added to the reaction solution, reacted at room temperature for 2 hours, and the reaction was stopped. The reaction solution was poured into 100mL of ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography (PE/EA, 10/1) to obtain 2.0 g of a colorless oily intermediate a24-3, LC-MS: [M+H ] ⁺ = 444.

Step 3: The above intermediate a24-3 (2.0 g, 4.51 mmol) was dissolved in 20 mL of tetrahydrofuran, and tetrabutylammonium fluoride (2.2 g, 9.0 mmol) was added. The reaction was carried out at room temperature for 12 hours, and the reaction was complete as monitored by TLC. The reaction solution was dissolved in 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (DCM/MeOH, 1/1) to obtain a24 (800 mg, 0.73 mmol) as a colorless oil , Yield: 87%, LC-MS: [M+H] ⁺ =206.

Synthesis of intermediate a25

Step 1: Dissolve raw material a25-1 (1.0g, 4.5mmol) and raw material a5-1 (680mg, 5.4mmol) in 50mL of anhydrous dichloromethane, add EDCI (1.29g, 6.75mmol), N,N- Diisopropylethylamine (1.74g, 13.5mmol) and HOBt (910mg, 6.75mmol) were reacted at room temperature for 4h, and the reaction was stopped. Add 80 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate a25-2 (1.21 g), LC-MS: [M+H] ⁺ =294.

Step 2: Intermediate a25-2 (1.21g, 4.13mmol) was dissolved in 25mL of anhydrous THF under ice bath, and lithium aluminum hydride (310mg, 8.3mmol) was added slowly. The temperature was raised to room temperature for 2 hours, and the reaction was stopped. Slowly add 2 mL of 10% NaOH aqueous solution to the reaction liquid, precipitate flocs, filter with suction, concentrate the filtrate under reduced pressure, and separate by flash column chromatography to obtain intermediate a25 (180 mg, 0.76 mmol). Yield: 18%. LC-MS: [M+H] ⁺ =238.

Synthesis of intermediate a26

Step 1: Add oxetane-3,3-diyldimethanol a26-1 (4.1g, 33.9mmol) and triethylamine (4.11g, 40.63mmol) in a 50mL reaction flask, 40mL of anhydrous dichloro Methane dissolves. After stirring for 5 minutes, tert-butyldiphenylchlorosilane (7.18g, 33.86mmol) was added to the reaction liquid, reacted at room temperature for 2 hours, stopped the reaction, poured the reaction liquid into 200mL ice water, extracted with dichloromethane, organic The phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 12 g of crude intermediate a26-2.

Step 2: At -10°C, dissolve the crude intermediate a26-2 (12.0 g) from the previous step in 40 mL of tetrahydrofuran, add pyridine sulfur trioxide (12.8 g, 81.0 mmol), and react under ice cooling for 3 hours to stop the reaction. The reaction solution was poured into 100 mL of ice water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain intermediate a26-3 (8.0 g, 22.7 mmol), two Step yield: 67%.

Step 3: Add intermediate a26-3 (8.0 g, 22.7 mmol) and intermediate a5-1 (3.4 g, 27.1 mmol) of the previous step into a 100 mL reaction flask, and dissolve in 40 mL of anhydrous THF. After stirring for 5 minutes, NaBH(OAc) ₃ (7.18g, 33.86mmol) and 10 drops of acetic acid were added to the reaction solution, reacted at room temperature for 10 hours, and the reaction was stopped. The reaction solution was poured into 200mL of ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 5.0 g of crude intermediate a26-4, LC-MS: [M+H] ⁺ =428.

Step 4: The above crude product a26-4 (5.0 g, 11.69 mmol) was dissolved in 30 mL of tetrahydrofuran, and tetrabutylammonium fluoride (4.58 g, 17.5 mmol) was added. The temperature was raised to 40° C. for 12 hours, and the reaction was complete as monitored by TLC. The reaction solution was dissolved in 150mL water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (DCM/MeOH, 1/1) to obtain a colorless oil a26 (1.9g, 10.2mmol ), yield: 88%, LC-MS: [M+H] ⁺ =190.

Synthesis of intermediate a27-a28

Step 1: Dissolve intermediate a1 (3.0g, 9.15mmol) and raw material 4,7-diazaspiro[2.5]octane-4-carboxylate tert-butyl a27-1 (2.12g, 10.1mmol) at room temperature In 30 mL of tetrahydrofuran, N,N-diisopropylethylamine (2.3 g, 17.4 mmol) was added, and reacted at room temperature for 8 hours. Add 100 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain a light yellow solid a27-2 (3.74 g, 7.4 mmol). Yield: 81%. LC-MS: [M+H] ⁺ = 505.

Step 2: Under the protection of nitrogen, the intermediate a27-2 (3.74g, 7.4mmol) was dissolved in 75mL of anhydrous DMF, CsF (3.4g, 22.2mmol) was added, the temperature was raised to 60°C for 8h, and the reaction was stopped. The reaction solution was added to 300 mL of water, the mixture was extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain intermediate a27 with a yield of 90%. LC-MS: [M+H] ⁺ = 489.

Referring to the synthetic route of intermediate a27, the following intermediate was synthesized.

Synthesis of intermediate a29

Step 1: Dissolve 2-fluoro-3-methyl-4-bromopyridine a29-1 (4.5g, 23.9mmol) in 25mL carbon tetrachloride, slowly add N-bromosuccinimide NBS (6.35g , 35.8mmol) and azobisisobutyronitrile AIBN (390mg, 2.3mmol), reacted at room temperature for 3 hours, and stopped the reaction. The reaction solution was slowly poured into 150 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE/EtOAc, 5/1) to obtain oil a29-2 (6.1 g, 22.9 mmol). Yield: 94%.

Step 2: Intermediate a29-2 (5.2g, 3.7mmol) and trimethylcyanosilane TMSCN (2.9g, 5.6mmol) were dissolved in 20mL of acetonitrile, and a solution of tetrahydrofuran (29mL) containing TBAF (5.5mmol) was added , reacted at room temperature for 16 hours, and stopped the reaction. The solvent was evaporated under reduced pressure and separated by column chromatography (PE/EtOAc, 5/1) to obtain oil a29-3 (3.4g, 15.9mmol). Yield: 81%.

Step 3: Under ice bath, dissolve the above intermediate a29-3 (3.4g, 15.9mmol) in 20mL DMF, slowly add NaH (2.9g, 19.1mmol), stir for 30 minutes, the solution turns red, slowly gradually A DMF solution of ethyl isothiocyanate (1.8 g, 15.9 mmol, 5 mL) prepared in advance was added dropwise. The reaction solution was heated up to 100° C. to react for 1 hour, and then cooled to room temperature. The reaction solution was slowly poured into ice water to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product was separated by column chromatography (PE/EtOAc, 1/1) to obtain a light yellow solid a29-4 (1.05g ,3.2mmol). Yield: 20%. LC-MS: [M+H] ⁺ = 325.

Step 4: Dissolve the intermediate a29-4 (1.0 g, 3.1 mmol) in 10 mL of DMSO, and add 10 mL of aqueous sodium hydroxide solution (5M). React under reflux conditions for 4 hours, stop the reaction. After cooling to room temperature, 100 mL of ice water was slowly added to the reaction solution to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product was separated by column chromatography (PE/EtOAc, 1/1) to obtain a light yellow solid a29- 5 (450 mg, 1.8 mmol). Yield: 20%. LC-MS: [M+H] ⁺ = 254.

Step 5: Dissolve the intermediate a29-5 (450mg, 1.8mmol) and DMAP (5mg, 0.04mmol) in 20mL THF/DMF mixed solution (v/v, 1/1), add Boc anhydride (465mg ,2.16mmol). React at room temperature for 12 hours, then stop the reaction. Add 50 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude intermediate a29-6 (760 mg).

Step 6: Under nitrogen protection, the crude product a29-6 (760mg) and raw material a7-8 (590mg, 2.6mmol) were dissolved in 10mL 1,4-dioxane, and potassium acetate (432mg, 4.32mmol) and Pd(DPEphos)Cl ₂ (46mg, 0.065mmol), the temperature was raised to 100°C for 1 hour, and the reaction was stopped. Cool to room temperature, filter, wash with saturated brine, extract with dichloromethane, dry, concentrate, and separate by flash column chromatography to obtain intermediate a29 (320mg, 0.82mmol). LC-MS: [M+H] ⁺ =388.

Preparation of key intermediate b1-b2

Synthesis of intermediate b1

Step 1: Dissolve raw material b1-1 (10.00g, 56.8mmol), methoxylamine hydrochloride (6.73g, 83.2mmol) and pyridine (5.69g, 68.10mmol) in 10mL absolute ethanol at room temperature. The reaction solution was reacted at room temperature for 2 hours, then the reaction was stopped, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with dilute hydrochloric acid (2N), saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product b1-2 (11.30g ,55.1mmol). LC-MS: [M+H] ⁺ = 206.

Step 2: Dissolve the above intermediate b1-2 (1.0g, 4.9mmol), palladium acetate (55mg, 0.24mmol) and NBS (0.87g, 4.87mmol) in 10mL of anhydrous acetic acid, and heat the reaction solution to 80°C The reaction was stopped for 1 hour, cooled to room temperature, the reaction liquid was poured into water, filtered, and the filter cake was dried to obtain a brown solid b1-3 (1.03 g, 3.6 mmol). LC-MS: [M+H] ⁺ =284.

Step 3: Dissolve the intermediate b1-3 (12.5g, 43.99mmol) in the above step in a mixed solution of 60mL concentrated hydrochloric acid and 100mL 1,4-dioxane. The reaction solution was heated to reflux and stirred for 1 hour, then the reaction was stopped, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium hydroxide solution (1N) and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography (PE/EA=4/1) to obtain a yellow solid b1- 4 (10.9 g, 42.7 mmol), yield: 97%. LC-MS: [M+H] ⁺ = 255.

Step 4: Under nitrogen protection, the intermediate b1-4 (7.90g, 30.97mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoro Borate) salt (Selectfluor, 16.46g, 46.5mmol) was dissolved in 80mL of methanol, and 0.3mL of concentrated sulfuric acid was slowly added dropwise. The reaction solution was heated to 50° C. for 5 hours, then the reaction was stopped, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by flash column chromatography (PE/EA=10/1) to obtain a red solid b1-5 (6.37g, 23.35mmol ), yield: 75%. LC-MS: [M+H] ⁺ =273.

Step 5: Under the protection of nitrogen, the intermediate b1-5 (32.0g, 117.2mmol) and pyridinium tribromide salt (41.22g, 128.89mmol) were dissolved in 300mL of acetonitrile, and the temperature was raised to 60°C for 0.5 hours to stop the reaction , and distill off the solvent under reduced pressure. Washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE/EA=10/1) to obtain a yellow solid b1-6 (36.0g, 102.3mmol). Rate: 87%. LC-MS: [M+H] ⁺ =350.

Step 6: Under the protection of nitrogen, the intermediate b1-6 (36.0g, 102.3mmol) and lithium bromide (19.5g, 225mmol) were dissolved in 100mL DMF, and the temperature was raised to 100°C for 0.5 hours to stop the reaction. Add 300 mL of water to the system, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was separated by flash column chromatography (PE/EA=10/1) to obtain a pale yellow solid b1-7 (21.0 g, 77.5 mmol), yield: 75%. LC-MS: [M+H] ⁺ =271.

Step 7: In ice bath, under the protection of nitrogen, the intermediate b1-7 (21.0 g, 77.5 mmol) and pyridine (18.38 g, 232.41 mmol) were dissolved in 200 mL of dichloromethane. Trifluoromethanesulfonic anhydride (26.2 g, 92.96 mmol) was slowly added dropwise to the reaction solution, and the mixture was slowly raised to room temperature for 1 hour to stop the reaction, and the solvent was evaporated under reduced pressure. The crude product was washed with saturated brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography (PE/EA=8/1) to obtain a yellow solid b1-8 (27.50g, 68.2mmol), Yield: 88%. LC-MS: [M+H] ⁺ =403.

Step 8: Under nitrogen protection, intermediate b1-8 (1.0g, 2.48mmol), zinc cyanide (146mg, 1.24mmol), Pd ₂ (dba) ₃ (114mg, 0.12mmol) and 1,1'-bis (Diphenylphosphine)ferrocene (dppf, 137 mg, 0.25 mmol) was dissolved in 10 mL of anhydrous DMF. The reaction liquid was heated to 70° C. for 3 hours and then cooled to room temperature. The crude product was poured into 50 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE/EA=5/1) to obtain a white solid b1-9 (270 mg, 0.96 mmol), yield: 38%. LC-MS: [M+H] ⁺ =208.

Step 9: Dissolve intermediate b1-9 (50mg, 0.18mmol) in 2mL dichloromethane at -78°C under nitrogen protection, and slowly add 0.44mL boron tribromide dichloromethane solution (concentration 2M) dropwise. The system was heated slowly to 0°C for 16 hours, and 10 mL of methanol was added to quench the reaction. The solvent was evaporated under reduced pressure, and the crude product was separated by flash column chromatography (PE/EA=3/1) to obtain a white solid b1-10 (20 mg, 0.075 mmol), yield: 42%. LC-MS: [M+H] ⁺ = 266.

Step 10: Under nitrogen protection, intermediate b1-10 (430mg, 26.7mmol), pinacol diboronate (823mg, 3.24mmol), potassium acetate (477mg, 4.86mmol), Pd ₂ (dba) ₃ (74mg , 0.081mmol) and tricyclohexylphosphine (45mg, 0.016mmol) were dissolved in 8mL 1,4-dioxane, heated to 105°C and reacted for 10 hours to stop the reaction. Cool to room temperature, filter, pour the system into 30 mL of ice water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash column chromatography (PE/EA=3/1) to obtain light yellow solid b1 (350 mg, 6.2 mmol), yield: 69%. LC-MS: [M+H]+=314.

Synthesis of intermediate b2

Step 1: Dissolve the raw material 4-fluorophenylacetic acid b2-1 (50.0g, 324.4mmol) and cyclo(ethylene)isopropyl malonate b2-2 (51.4g, 356.8mmol) in 500mL of acetonitrile, add 4- Dimethylaminopyridine (DMAP, 3.57 g, 29.2 mmol) and DIEA (88.0 g, 681.2 mmol). After stirring for 5 minutes, pivaloyl chloride (43.0 g, 356.8 mmol) was slowly added dropwise. The reaction solution was heated to 45°C and stirred for 3 hours, then cooled to room temperature. Put the reaction solution under an ice bath, add dropwise 4N hydrochloric acid aqueous solution to adjust the pH to about 5, continue stirring for 1 hour, dilute with water, and adjust the pH of the reaction solution to about 2 with 4N hydrochloric acid again, a large amount of solids are precipitated, filter with suction , washed the filter cake with water, dried to obtain a white solid b2-3 (104g, 371.1mmol), and the yield was quantitative. LC-MS: [M+H] ⁺ =281.

Step 2: Slowly add intermediate b2-3 (54.0 g, 192.7 mmol) in the above step into trifluoromethanesulfonic acid (228.5 g, 1.5 mol). The reaction solution was stirred at room temperature for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was slowly poured into 500 mL of ice water, solids precipitated out, filtered with suction, the filter cake was washed with water, and dried to obtain a brown solid b2-4 (66.0 g, 295.96 mmol). Yield: 93%, LC-MS: [M+H] ⁺ =223.

Step 3: Dissolve the intermediate b2-4 (66.0g, 295.96mmol) in the above step in a mixed solution of 660mL acetonitrile and water (v/1, 1/1), raise the temperature to 80°C for 13 hours, and stop the reaction. The solvent was evaporated under reduced pressure, washed with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain pale yellow compound b2-5 (51.8 g, 291.01 mmol), yield: 97%. LC-MS: [M+H] ⁺ =179.

Step 4: Under nitrogen protection, the crude product b2-5 (20.0g, 112.3mmol), (2-bromoethynyl)triisopropylsilane (30.8g, 112.3mmol), potassium acetate (22.0g, 224.5mmol) and Dichlorobis(4-methylisopropylphenyl)ruthenium(II) (2.06g, 3.4mmol) was dissolved in 200mL of 1,4-dioxane, heated to 100°C for 4 hours, monitored by LC-MS The reaction is complete and filtered. The solvent was evaporated under reduced pressure, 100 mL of water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE/EA=10/1) to obtain light yellow solid b2-6 (28.0 g, 78.2 mmol), yield: 69%. LC-MS: [M+H] ⁺ = 359.

Step 5: Dissolve the intermediate b2-6 (28g, 78.2mmol) and DIEA (20.19g, 156.20mmol) in 300mL of dichloromethane, and slowly add triisopropylchlorosilane TIPSCl (18.1g, 93.7mmol) ), after dropping, the reaction solution was stirred at room temperature for 1 hour, and the LC-MS monitoring reaction was complete. The reaction solution was poured into 500 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain crude magenta oily compound b2-7. LC-MS: [M+H] ⁺ = 515.

Step 6: Under nitrogen protection, at -40°C, the crude product b2-7 (58.4g, 113.43mmol) and DIEA (51.3g, 397.0mmol) were dissolved in 300mL of dichloromethane, and trifluoromethanesulfonic anhydride (54.4 g, 192.8mmol), after 3 hours of dripping, the stirring was continued for 0.5 hour, and the reaction was stopped. The reaction solution was poured into 500 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE/EA=10/1) to obtain light red oily compound b2-8 (57.7g, 89.2mmol), yield: 78%. LC-MS: [M+H] ⁺ = 647.

Step 7: Under nitrogen protection, the intermediate b2-8 (61.6g, 95.2mmol), triethylamine (38.5g, 380.9mmol) and pinacol borane (48.7g, 380.9mmol) were dissolved in 600mL of acetonitrile, After stirring for 5 minutes, the catalyst Pd(dppf) _Cl2 (4.2 g, 5.7 mmol) was added. The reaction solution was heated to 80°C and stirred for 4 hours, then cooled to room temperature. The mixture was slowly quenched with MeOH, keeping the temperature below 25 °C, and a solid precipitated out. After suction filtration, the filter cake was washed with MeOH and dried to obtain compound b2 (45.9 g, 73.4 mmol) as a white solid, yield: 77%. LC-MS: [M+H] ⁺ = 625.

Preparation of key intermediates c1-c12

Synthesis of intermediates c1-c8

Step 1: Dissolve raw material c1-1 (20.0g, 81.5mmol) and TEA (16.5g, 163.1mmol) in 250mL dichloromethane under ice bath, and slowly add methanesulfonic anhydride (15.6g, 89.7mmol) to the system After dropping, the temperature was raised to room temperature for 2 hours, and the reaction was stopped. Add 300 mL of ice water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain crude product c1-2, LC-MS: [M+H] ⁺ =324.

Step 2: Dissolve the crude product c1-2 (25g, 77.3mmol) in 300mL DMF, add sodium methylthiolate (6.5g, 92.8mmol) at room temperature, raise the temperature to 90°C and stir for 16 hours to stop the reaction. The reaction solution was poured into 500 mL ice water, extracted with ethyl acetate, washed with saturated brine, concentrated, and the crude product was separated by column chromatography to obtain compound c1-3 (10 g, 36.4 mmol), with a yield of 47%. LC-MS: [M+H] ⁺ = 275.

Step 3: Dissolve the intermediate c1-3 (16.5g, 51.0mmol) in 200mL of anhydrous tetrahydrofuran at -78°C under the protection of nitrogen, slowly add LDA (12.8g, 76.6mmol) dropwise, and continue stirring for 0.5 Hour. 1-Bromo-3-chloropropane (40.2 g, 255.2 mmol) was slowly added dropwise to the system. After the dropwise addition was completed, the temperature was raised to room temperature to continue the reaction for 1 hour, and 100 mL of ice water was added to the reaction liquid to quench it. Extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product c1-4, LC-MS: [M+H] ⁺ =352.

Step 4: Dissolve the crude product c1-4 in the previous step in 50 mL of dichloromethane, add 150 mL of trifluoroacetic acid, stir at room temperature for 1 hour, and stop the reaction. The solvent was evaporated under reduced pressure, the mixture was adjusted to weak alkaline with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound c1-5 (2.5 g) and c1- 6 (1.3 g), LC-MS: [M+H] ⁺ =252.

Step 5: Dissolve intermediate c1-5 (2.5g, 10.5mmol), potassium iodide (0.17g, 1.1mmol) and potassium carbonate (6.9g, 21.0mmol) in 25mL of methanol, react at room temperature for 16 hours, and stop the reaction. Add 100 mL of ice water to the system, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product c1-7, LC-MS: [M+H] ⁺ =216.

Step 6: In an ice bath, dissolve the crude product c1-7 (2.1 g, 9.8 mmol) in 20 mL of tetrahydrofuran, add lithium aluminum hydride (750 mg, 19.5 mmol), and continue stirring for 1 hour to stop the reaction. Add 10 mL of methanol to the system to quench, filter, concentrate under reduced pressure, add 50 mL of water to the mixture, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain crude product c1 (directly used in the next reaction). LC-MS: [M+H] ⁺ =188.

Step 7: Substitution of intermediate c1-5 by c1-6 yields intermediate c2.

Referring to the synthetic route of intermediate c1, the following intermediates were synthesized.

Synthesis of intermediate c9

Step 1: In ice bath, dissolve raw material c9-1 (15.0 g, 71.0 mmol) in 150 mL of anhydrous tetrahydrofuran (150 mL), slowly add sodium borohydride (806 mg, 21.3 mmol), and react under ice bath for 3 hours, Stop responding. The solvent was evaporated under reduced pressure, 50 mL of ice water was added to the mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography to obtain intermediate c9-2 (12.0 g, 56.3 mmol). LC-MS: [M+H] ⁺ =214.

Step 2: In an ice bath, the intermediate c9-2 (12.0 g, 56.3 mmol) and triethylamine (17.3 g, 170.5 mmol) were dissolved in 120 mL of dichloromethane. After stirring for 5 minutes, a dichloromethane solution (20 mL) of methanesulfonic anhydride (14.9 g, 85.2 mmol) was added dropwise to the reaction liquid, and the stirring was continued for 1 hour after the dropping was complete. Stop the reaction, add 200 mL of ice water to the system, extract with dichloromethane, and concentrate under reduced pressure to obtain the crude product to c9-3.

Step 3: The crude product c9-3 and potassium thioacetate (9.4 g, 82.4 mmol) were dissolved in 150 mL of DMF, and the temperature was raised to 60° C. for 15 hours to stop the reaction. Add 300mL ice water to the system, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, the crude product is separated by column chromatography to obtain intermediate c9-4 (15g, 55.4 mmol), two-step yield: 10%. LC-MS: [M+H] ⁺ =272.

Step 4: In ice bath, the intermediate c9-4 (15g, 55.4mmol) of the previous step was dissolved in 300mL of anhydrous tetrahydrofuran, and lithium aluminum tetrahydride (5.2g, 138mmol) was added. After stirring for 5 minutes, the ice bath was removed, and the temperature was raised to 60° C. to react for 2 hours. Stop responding. Dilute hydrochloric acid was added to the system to quench the reaction, and the pH was adjusted to about 7. A solid was precipitated, filtered with suction, and the filter cake was washed with ethyl acetate to obtain intermediate c9. LC-MS: [M+H] ⁺ =174.

Synthesis of intermediate c10

Step: Intermediate c9 (2.0 g, 11.5 mmol) was dissolved in 20 mL of DMF, and NaH (920 mg, 23 mmol) was added. React at room temperature for 30 minutes. The temperature was lowered to -40°C, and a DMF solution (5 mL) of trifluoroiodomethane (3.4 g, 17.3 mmol) was added to the system. Slowly warm to room temperature and continue stirring for 1 hour to stop the reaction. 50 mL of ice water was added to the reaction liquid, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and separated by flash column chromatography to obtain intermediate c10 (1.3 g, 5.4 mmol) with a yield of 47%. LC-MS: [M+H] ⁺ = 242.

Synthesis of intermediate c11

Step: In ice bath, the intermediate c9 (2.2g, 12.7mmol) was dissolved in 30mL DMSO, and sodium hydride (1.02g, 25.9mmol) was added. After stirring for 30 minutes, bromocyclopropane (2.3 g, 19.0 mmol) was added and reacted at room temperature for 1 hour to stop the reaction. Add 100 mL of ice water to the system, extract with ethyl acetate, wash with saturated brine, and concentrate under reduced pressure to obtain intermediate c11. LC-MS: [M+H] ⁺ =214.

Synthesis of intermediate c12

Step: In ice bath, the intermediate c9 (1.6g, 9.2mmol) was dissolved in 30mL DMSO, and sodium hydride (738mg, 18.4mmol) was added. After stirring for 30 minutes, bromocyclobutane (1.87 g, 13.9 mmol) was added and reacted at room temperature for 1 hour to stop the reaction. After reacting at room temperature for 1 hour, the reaction was stopped. Add 100 mL of ice water to the system, extract with ethyl acetate, wash with saturated brine, and concentrate under reduced pressure to obtain intermediate c12. LC-MS: [M+H] ⁺ = 228.

Example 2:

Step 1: Under the protection of nitrogen, the intermediate a3 (2.4g, 5.61mmol) was dissolved in 50mL of dioxane, and the raw material P1-1 (1.34g, 8.42mmol) and N,N-diisopropylethylamine were added DIEA (1.45 g, 11.2 mmol). The reaction solution was stirred at 80°C for 12 hours and cooled to room temperature. Add 100mL water to the system, extract with ethyl acetate, dry, filter, evaporate the solvent under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound P1-2 (2.7g, 4.9mmol ). Yield: 87%, LC-MS: [M+H] ⁺ =552.

Step 2: Under nitrogen protection, compound P1-2 (300mg, 0.54mmol) and potassium phosphate (229mg, 1.08mmol) in the previous step were mixed in 6mL of anhydrous toluene, and then intermediate a7 (262mg, 0.65mmol) was added in turn, Xphos Pd G3 (93 mg, 0.11 mmol) and Xphos (53 mg, 0.11 mmol). Under nitrogen protection, the reaction solution was reacted at 100° C. for 1 hour. The reaction was stopped, cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was separated by TLC chromatography to obtain compound P1-3 (120 mg, 0.15 mmol). Yield: 28%, LC-MS: [M+H] ⁺ =807.

Step 3: Dissolve P1-3 (120 mg, 0.15 mmol) in 4 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. The reaction solution was placed under nitrogen protection to continue the reaction for 1 hour, and then the reaction was stopped. Slowly add saturated sodium bicarbonate solution to the system and adjust the pH to about 8. After extraction with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC chromatography to obtain the target compound P1 (10.2 mg). LC-MS: [M+H] ⁺ = 607.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07(s, 1H), 8.08(s, 2H), 7.41(dd, J=8.4, 5.3Hz, 1H), 7.14(dd, J=9.5, 8.4 Hz, 1H), 5.27(br, J=72Hz, 1H), 4.42(d, J=12.3Hz, 2H), 4.13(d, J=10.4Hz, 1H), 4.03(d, J=10.3Hz, 1H ),3.71–3.52(m,4H),3.13–3.06(m,2H),3.01(s,1H),2.83(q,J＝8.5Hz,1H),2.35–2.27(m,1H),2.17– 2.10(m,1H),2.08–1.98(m,2H),1.88–1.74(m,3H),1.65(d,J=6.6Hz,2H),1.56(d,J=7.5Hz,2H).

Referring to the synthetic route of compound P1, using a similar skeleton structure, the following target molecules were synthesized.

Example 3:

Step 1: Under the protection of nitrogen, the intermediate a2 (500mg, 0.99mmol) was dissolved in 6mL of anhydrous DMF, then the raw material P1-1 (314mg, 2.0mmol) and cesium carbonate (966mg, 2.96mmol) were added, and the , the reaction solution was reacted at 140° C. for 2 hours, the reaction was stopped, and cooled to room temperature. Add 30 mL of water to the system, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The residue was purified by TLC chromatography (petroleum ether: ethyl acetate = 1:4) to obtain pale yellow solid H1-1 (110 mg, 0.18 mmol). Yield: 18%, LC-MS: [M+H] ⁺ =630.

Step 2: Under nitrogen protection, H1-1 (210mg, 0.34mmol) was dissolved in 5mL of anhydrous toluene, and intermediate a7 (189mg, 0.47mmol), Pd(DPEPhos)Cl ₂ (72mg, 0.10mmol) and Anhydrous cesium carbonate (273mg, 0.84mmol). Under the protection of nitrogen, the reaction solution was reacted at 105° C. for 6 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by TLC chromatography (petroleum ether: ethyl acetate = 1:2) to obtain yellow solid H1-2 (80 mg, 0.10 mmol). Yield: 28%, LC-MS: [M+H] ⁺ =841.

Step 3: Dissolve H1-2 (80 mg, 0.10 mmol) in 3 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction solution was reacted at room temperature for 0.5 hours, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative SFC (Xselect CSH C18OBD) to give target compounds H1a (4.0 mg) and H1b (4.1 mg).

H1a: ¹ H NMR (300MHz, DMSO-d ₆ )δ8.23(s,1H),8.11(s,1H),7.85(s,1H),7.26(dd,J＝8.4,5.3Hz,1H), 7.15(dd, J＝9.5, 8.4Hz, 1H), 5.27(br, J＝72Hz, 1H), 4.29(dd, J＝20.9, 12.2Hz, 3H), 4.14–3.91(m, 2H), 3.67– 3.39(m,5H),3.21–2.95(m,3H),2.92–2.70(m,1H),2.14(d,J＝6.8Hz,1H),2.09–1.93(m,2H),1.88–1.52( m,6H).

H1b: ¹ H NMR (400MHz, DMSO-d ₆ )δ8.21(s,1H),8.09(s,2H),7.84(s,1H),7.26(dd,J＝8.4,5.3Hz,1H), 7.18–7.11(m,1H),5.27(br,J=72Hz,1H),4.27(dd,J=19.6,12.0Hz,2H),4.08(d,J=10.3Hz,1H),3.99(d, J＝10.3Hz, 1H), 3.49–3.55(m, 3H), 3.08(d, J＝9.5Hz, 3H), 3.02(d, J＝11.5Hz, 2H), 2.81(s, 1H), 2.14– 2.12(m,1H),2.02(d,J=18.1Hz,2H),1.91–1.71(m,4H),1.66–1.54(m,4H).

Example 3:

Step 1: Dissolve intermediate a5 (420 mg, 2.42 mmol) in 10 mL of anhydrous THF in a 50 mL reaction flask, add potassium tert-butoxide (340 mg, 3.64 mmol), and stir at room temperature for 30 minutes to obtain solution S1. In another 50mL reaction flask, the intermediate a2 (1.0g, 2.0mmol) was dissolved in 10mL of anhydrous THF, and the prepared solution S1 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction. The reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain pale yellow solid H2-1 (916 mg, 1.42 mmol). Yield: 71%, LC-MS: [M+H] ⁺ =644.

Step 2: Under nitrogen protection, H2-1 (480mg, 0.75mmol) was dissolved in 10mL of anhydrous toluene, and intermediate a7 (414mg, 1.02mmol), Pd(DPEPhos)Cl ₂ (22mg, 0.03mmol) and Cesium carbonate (438 mg, 1.35 mmol). Under nitrogen protection, the reaction solution was reacted at 105° C. for 10 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain yellow solid H2-2 (450 mg, 0.53 mmol). Yield: 70%, LC-MS: [M+H] ⁺ =854.

Step 3: Dissolve H2-2 (600 mg, 0.70 mmol) in 10 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography to obtain yellow solid H2 (320 mg, 0.49 mmol), LC-MS: [M+H] ⁺ =654. Yield: 70%.

Purify H2 through a chiral column: Unichiral CMD-5H to obtain the target compounds H2a (peak1) and H2b (peak2).

Referring to the synthetic route of compound H2a or H2b, the following target molecules were synthesized using similar skeleton structures.

*or

Represents the chiral site; * represents no chiral resolution;

Example 4:

Step 1: Dissolve intermediate a5 (170 mg, 0.94 mmol) in 10 mL of anhydrous THF in a 50 mL reaction flask, add potassium tert-butoxide (180 mg, 1.56 mmol), and stir at room temperature for 30 minutes to obtain solution S2. In another 50mL reaction flask, the intermediate a17 (400mg, 0.78mmol) was dissolved in 10mL of anhydrous THF, and the prepared solution S2 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction. The reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain pale yellow solid H11-1 (300 mg, 0.41 mmol). Yield: 44%, LC-MS: [M+H] ⁺ =734.

Step 2: Under nitrogen protection, H11-1 (300mg, 0.41mmol) and CuCN (150mg, 1.64mmol) were dissolved in 8mL of anhydrous DMF, and the reaction solution was reacted at 100°C for 6 hours, then cooled to room temperature to stop the reaction. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a yellow solid H11-2 ( 110 mg, 0.17 mmol). Yield: 42%, LC-MS: [M+H] ⁺ =633.

Step 3: Under nitrogen protection, H11-2 (110mg, 0.17mmol) was dissolved in 10mL of anhydrous toluene, and intermediate a7 (94mg, 0.22mmol), Pd(DPEPhos)Cl ₂ (22mg, 0.03mmol) and Cesium carbonate (160mg, 0.48mmol). Under the protection of nitrogen, the reaction solution was reacted at 110° C. for 6 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain yellow solid H11-3 (90 mg, 0.11 mmol). Yield: 63%, LC-MS: [M+H] ⁺ =845.

Step 4: Dissolve H11-3 (90 mg, 0.11 mmol) in 8 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography to obtain yellow solid H11 (30 mg, 0.05 mmol), LC-MS: [M+H] ⁺ =645. Yield: 43%.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(s,1H),8.26(s,2H),7.35(dd,J=8.4,5.2Hz,1H),7.21(t,J=8.8Hz, 1H), 4.58(d, J=13.6Hz, 1H), 4.47(d, J=12.8Hz, 1H), 4.34(s, 2H), 4.15(d, J=16.8Hz, 2H), 4.02(d, J＝13.6Hz, 2H), 3.88(d, J＝12.8Hz, 2H), 3.52-3.16(m, 4H), 1.96-1.83(m, 6H), 1.23(s, 2H), 0.85–0.74(m ,4H).

Referring to the synthetic route of compound H11, using a similar skeleton structure, the following target molecules were synthesized.

*or

Represents the chiral site; * represents no chiral resolution;

Example 5:

Step 1: In a 50 mL reaction flask, the intermediate a19 (150 mg, 0.55 mmol) was dissolved in 5 mL of anhydrous THF, potassium tert-butoxide (93 mg, 0.82 mmol) was added, and stirred at room temperature for 30 minutes to obtain solution S3. In another 50mL reaction flask, the intermediate a2 (280mg, 0.58mmol) was dissolved in 5mL of anhydrous THF, and the prepared solution S3 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction. The reaction solution was poured into 50 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain pale yellow solid H13-1 (205 mg, 0.28 mmol). Yield: 51%, LC-MS: [M+H] ⁺ =744.

Step 2: Under nitrogen protection, H13-1 (205mg, 0.28mmol) was dissolved in 6mL of anhydrous toluene, and intermediate a7 (200mg, 0.50mmol), Pd(DPEPhos)Cl ₂ (13mg, 0.015mmol) and Cesium carbonate (175 mg, 0.54 mmol). Under nitrogen protection, the reaction solution was reacted at 105° C. for 10 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain yellow solid H13-2 (120 mg, 0.13 mmol). Yield: 45%, LC-MS: [M+H] ⁺ =955.

Step 3: Dissolve H13-2 (120 mg, 0.13 mmol) in 6 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography to obtain yellow solid H13 (32 mg), LC-MS: [M+H] ⁺ =671.

¹ H NMR (400MHz,DMSO-d ₆ )δ8.26(s,2H),7.97(d,J＝11.2Hz,1H),7.38–7.09(m,2H),5.88–5.43(m,2H), 4.70–4.37(m,2H),4.29–4.00(m,6H),3.82-3.64(m,,4H),3.74–3.36(m,4H),1.93(m,4H),1.60-1.50(m, 2H),1.40-1.20(m,2H).

Referring to the synthetic route of compound H13, using a similar skeleton structure, the following target molecule was synthesized.

*or

Represents the chiral site; * represents no chiral resolution;

Embodiment 6:

Step 1: Under the protection of nitrogen, the intermediate H1-1 (1.0g, 1.59mmol) was dissolved in 12mL of methanol, then sodium methoxide (102mg, 4.77mmol) was added, and the reaction solution was heated to 60°C for 2 hours to stop the reaction , cooled to room temperature. Add 40 mL of water to the system, extract with ethyl acetate, and distill off the solvent under reduced pressure. The residue was separated by flash column chromatography to obtain pale yellow solid P5-1 (305 mg, 0.48 mmol). Yield: 30%, LC-MS: [M+H] ⁺ =640.

Step 2: Under nitrogen protection, dissolve P5-1 (305mg, 0.48mmol) in 5mL of anhydrous toluene, add intermediate a7 (270 mg, 0.67mmol), Pd(DPEPhos)Cl ₂ (90mg, 0.14mmol) in sequence and anhydrous cesium carbonate (330mg, 0.96mmol). Under the protection of nitrogen, the reaction solution was reacted at 105° C. for 8 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (PE/EA, 1/2) to obtain yellow solid P5-2 (327 mg, 0.38 mmol). Yield: 80%, LC-MS: [M+H] ⁺ =853.

Step 3: Dissolve P5-2 (327 mg, 0.38 mmol) in 4 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography to obtain the target compound P5 (74 mg, 0.11 mmol). Yield: 30%, LC-MS: [M+H] ⁺ = 653.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.16 (s, 2H), 7.87 (d, J = 0.8Hz, 1H), 7.29 (dd, J = 8.4, 5.3Hz, 1H), 7.22–7.11 ( m,1H),5.68-5.54(m,1H),4.28(dt,J=35.0,17.4Hz,2H),4.06(dd,J=35.9,10.3Hz,2H),3.56(t,J=18.0Hz ,4H),3.21(s,3H),3.18–3.08(m,2H),3.03(s,1H),2.90–2.76(m,1H),2.19–1.75(m,6H),1.63(dd,J= 20.6,9.9Hz,4H).

Referring to the synthetic route of compound P5, using a similar skeleton structure, the following target molecules were synthesized.

*or

Represents the chiral site; * represents no chiral resolution;

Embodiment 7:

Step 1: In ice bath, under the protection of nitrogen, the intermediate H2-1 (500mg, 0.78mmol) and trifluoroethanol (156mg, 1.56mmol) were dissolved in 10mL of tetrahydrofuran, then NaH (94mg, 2.34mmol) was added, and the reaction solution Raise the temperature to room temperature and react for 3 hours, stop the reaction, and cool to room temperature. Add 30 mL of water to the system, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The residue was separated by flash column chromatography to obtain pale yellow solid P7-1 (337mg, 0.47mmol). Yield: 60%, LC-MS: [M+H] ⁺ =722.

Step 2: Under nitrogen protection, dissolve P7-1 (305mg, 0.42mmol) in 5mL of anhydrous toluene, add intermediate a7 (270mg, 0.67mmol), Pd(DPEPhos)Cl ₂ (90mg, 0.14mmol) and Anhydrous cesium carbonate (330mg, 0.96mmol). Under the protection of nitrogen, the reaction solution was reacted at 105° C. for 8 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (PE/EA, 1/2) to obtain yellow solid P7-2 (313 mg, 0.34 mmol). Yield: 80%, LC-MS: [M+H] ⁺ =934.

Step 3: Dissolve P7-2 (313 mg, 0.34 mmol) in 5 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography to obtain the target compound P7 (82 mg, 0.11 mmol). Yield: 33%, LC-MS: [M+H] ⁺ =734.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.02(s,2H),7.82(s,1H),7.20(dd,J=8.3,5.4Hz,1H),7.12(t,J=8.9Hz, 1H), 5.24-5.10(m, 1H), 4.96–4.75(m, 2H), 4.24(dd, J＝10.8, 4.4Hz, 2H), 3.65(d, J＝13.2Hz, 4H), 3.51(d ,J=12.1Hz,2H),2.84(dd,J=23.1,10.0Hz,2H),2.72–2.58(m,1H),2.48(s,1H),2.36(dt,J=15.9,9.7Hz, 2H),2.21–1.76(m,2H),1.76–1.60(m,4H),0.66–0.60(m,2H),0.46–0.41(m,2H).

Embodiment 8:

Step 1: In ice bath, under nitrogen protection, intermediate H2-1 (500mg, 0.78mmol) and 4-methoxybenzyl alcohol (215mg, 1.56mmol) were dissolved in 10mL THF, then NaH (94mg, 2.34mmol) was added ), the reaction solution was warmed up to room temperature and reacted for 3 hours, then the reaction was stopped and cooled to room temperature. Add 30 mL of water to the system, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The residue was separated by flash column chromatography to obtain pale yellow solid P8-1 (385 mg, 0.51 mmol). Yield: 65%, LC-MS: [M+H] ⁺ =760.

Step 2: Under nitrogen protection, dissolve P8-1 (319mg, 0.42mmol) in 5mL of anhydrous toluene, add intermediate a7 (270mg, 0.67mmol), Pd(DPEPhos)Cl ₂ (90mg, 0.14mmol) and Anhydrous cesium carbonate (330mg, 0.96mmol). Under the protection of nitrogen, the reaction solution was reacted at 105° C. for 8 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (PE/EA, 1/2) to obtain yellow solid P8-2 (122 mg, 0.13 mmol). Yield: 30%, LC-MS: [M+H] ⁺ =972.

Step 3: Dissolve P8-2 (122 mg, 0.13 mmol) in 5 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography to obtain the target compound P8 (19 mg, 0.03 mmol). Yield: 23%, LC-MS: [M+H] ⁺ =653.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.02(s,2H),7.82(s,1H),7.20(dd,J=8.3,5.4Hz,1H),7.12(t,J=8.9Hz, 1H),5.32-5.18(m,1H),4.24(dd,J=10.8,4.4Hz,2H),3.65(d,J=13.2Hz,4H),3.51(d,J=12.1Hz,2H), 2.84(dd,J＝23.1,10.0Hz,2H),2.72–2.58(m,1H),2.48(s,1H),2.36(dt,J＝15.9,9.7Hz,2H),2.21–1.76(m, 2H),1.76–1.60(m,4H),0.68–0.60(m,2H),0.48–0.41(m,2H).

Embodiment 9:

Step 1: In ice bath, under the protection of nitrogen, intermediate a3 (900mg, 2.1mmol) and intermediate a5 (360mg, 2.1mmol) were dissolved in 15mL of tetrahydrofuran, then NaH (100mg, 4.2mmol) was added, and the reaction solution was heated to React at 40°C for 3 hours, stop the reaction, and cool to room temperature. Add 30 mL of water to the system, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The residue was separated by flash column chromatography to obtain yellow solid P9-2 (490 mg, 0.81 mmol). Yield: 38%, LC-MS: [M+H] ⁺ =565.

Step 2: Under nitrogen protection, dissolve P9-2 (440mg, 0.78mmol) in 6mL of a mixed solution of 1,4-dioxane and water (v/v, 5/1), and add raw materials P9-1 ( 480mg, 0.94mmol), Xphos Pd G1 (180mg, 0.23mmol) and anhydrous cesium carbonate (1.02g, 3.12mmol). Under nitrogen protection, the reaction solution was reacted at 95° C. for 3 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography (PE/EA, 1/2) to obtain yellow solid P9-3 (500mg, 0.55mmol). Yield: 70%, LC-MS: [M+H] ⁺ =915.

Step 3: The above intermediate P9-3 (500 mg, 0.55 mmol) was dissolved in 20 mL of tetrahydrofuran, and tetrabutylammonium fluoride (220 mg, 0.9 mmol) was added. The reaction was carried out at room temperature for 12 hours, and the reaction was complete as monitored by TLC. The reaction solution was dissolved in 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product P9-4 (400 mg), LC-MS: [M+H] ⁺ =759.

Step 4: The crude product P9-4 (400 mg, 0.53 mmol) was dissolved in 5 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography to obtain the target compound P9 (45 mg, 0.07 mmol). Yield: 14%, LC-MS: [M+H] ⁺ =615.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.30(s, 1H), 9.10(s, 1H), 7.98(dd, J=9.2, 6.0Hz, 1H), 7.47(t, J=9.0Hz, 1H), 7.41(d, J=2.4Hz, 2H), 7.37(s, 1H), 7.24(s, 1H), 7.22(s, 2H), 7.11(s, 1H), 4.65(d, J=13.7 Hz,1H),4.49(s,1H),4.35(s,3H),4.18(s,4H),4.0-3.90(m,6H),1.97(m,7H).

Referring to the synthetic route of compound P9, using a similar skeleton structure, the following target molecules were synthesized.

Example 10:

Step 1: Dissolve intermediate a5 (142mg, 0.82mmol) in 5mL anhydrous THF in a 20mL reaction flask, add potassium tert-butoxide (138mg, 2.34mmol), and stir at room temperature for 30 minutes to obtain solution S4. In another 20mL reaction flask, the intermediate a27 (400mg, 0.82mmol) was dissolved in 5mL of anhydrous THF, and the prepared solution S4 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction. The reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain pale yellow solid P12-1 (420 mg, 0.66 mmol). Yield: 80%, LC-MS: [M+H] ⁺ =642.

Step 2: Under nitrogen protection, P12-1 (420mg, 0.66mmol) was dissolved in 5mL of anhydrous toluene, and intermediate a7 (352mg, 0.87mmol), Pd(DPEPhos)Cl ₂ (22mg, 0.03mmol) and Cesium carbonate (438 mg, 1.35 mmol). Under nitrogen protection, the reaction solution was reacted at 105° C. for 10 hours, the reaction was stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain yellow solid P12-2 (450 mg, 0.53 mmol). Yield: 80%, LC-MS: [M+H] ⁺ =854.

Step 3: Dissolve P12-2 (450 mg, 0.53 mmol) in 6 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography to obtain yellow solid P12 (104 mg, 0.16 mmol), LC-MS: [M+H] ⁺ =654. Yield: 30%.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.15(s, 2H), 7.81(s, 1H), 7.26(dd, J=8.4, 5.3Hz, 1H), 7.15(t, J=8.9Hz, 1H),5.24–5.10(m,1H),4.22(dt,J＝19.4,10.7Hz,2H),3.86–3.62(m,4H),3.01(s,2H),2.87–2.75(m,2H) ,2.42-2.33(m,3H),2.20–1.95(m,2H),1.91–1.75(m,1H),0.67–0.38(m,8H).

Referring to the synthetic route of compound P12, using a similar skeleton structure, the following target molecules were synthesized.

Example 11:

Step 1: In an autoclave, dissolve the raw material 4-bromo-2,6-difluorobenzonitrile a5 (100g, 459mmol) in 240mL of ethanol, add 400mL of ammonia water, heat up to 90°C for 16 hours, and cool to room temperature, stop the reaction. The solvent was evaporated under reduced pressure, 100 mL of ice water was added to the reaction solution, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 9/1) to obtain yellow solid P14-2 (74.9g, 352mmol). Yield: 77%, LC-MS: [M+H] ⁺ =215.

Step 2: Under nitrogen protection, 2,2-diethoxyethanol (33.8g, 252mmol) was dissolved in 450mL of anhydrous DMF, NaH (10.08g, 252mmol) was slowly added at 0°C, and after stirring for 1 hour, The intermediate P14-2 (45 g, 210 mmol) of the previous step was added. The ice bath was removed, and the temperature was raised to 50° C. to react for 2 hours. The reaction was stopped, cooled to room temperature, 1 L of water was added to the system, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether/ethyl acetate, 10/1) to obtain yellow solid P14-3 (25.3 g, 77.1 mmol). Yield: 37%, LC-MS: [M+H] ⁺ =329.

Step 3: Add 100 mL of toluene to polyphosphoric acid (10.42 g), raise the temperature to 100°C, add the intermediate P14-3 (10.0 g, 30.4 mmol) in the previous step, continue to react at this temperature for 2 hours, and stop the reaction. The reaction solution was slowly poured into a large amount of ice water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether/ethyl acetate, 10/1) to obtain yellow solid P14-4 (1.04 g, 4.4 mmol), yield: 14%. LC-MS: [M+H] ⁺ = 236.

Step 4: Dissolve the intermediate P14-4 (8.3g, 35.0mmol) in 150mL of ethanol, add KOH aqueous solution (7.94g, 50mL), heat up to 90°C for 4 hours, and stop the reaction. The organic solvent was evaporated under reduced pressure, 100 mL of ice water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether/dichloromethane, 2/1) to obtain yellow solid P14-5 (4.0 g, 15.7 mmol), yield: 45%. LC-MS: [M+H] ⁺ = 256.

Step 5: Under the protection of nitrogen, the intermediate P14-5 (3.3g, 13.0mmol) in the previous step was dissolved in 33mL of anhydrous THF, and a tetrahydrofuran solution containing triphosgene (3.6g, 12.4mmol) was slowly added dropwise at 0°C (20mL). The temperature was raised to room temperature for 2 hours, and the reaction was stopped. 100 mL of water was added to the system, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to obtain crude product P14-6 (2.8 g). LC-MS: [M+H] ⁺ =282.

Step 6: Under the protection of nitrogen, dissolve the crude product P14-6 (2.8 g) from the previous step in 50 mL of phosphorus oxychloride, add 5 mL of N,N-diisopropylethylamine, and heat up to 100 ° C for 2 hours. The solvent was evaporated under reduced pressure, 100 mL of water was added to the system, extracted with ethyl acetate, concentrated, and the residue was separated by flash column chromatography (petroleum ether/ethyl acetate, 3/1) to obtain a yellow solid P14-7 (1.1 g, 3.5 mmol), two-step yield: 27%. LC-MS: [M+H] ⁺ = 319.

Step 7: At room temperature, intermediate P14-7 (1.0g, 3.15mmol) and raw material 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl a2-1 (670mg, 3.15mmol) was dissolved in 20mL 1,4-dioxane, N,N-diisopropylethylamine (1.7mL, 9.5mmol) was added, and the reaction was carried out at 50°C for 2 hours. Add 60 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain white solid P14-8 (900 mg, 1.82 mmol). Yield: 58%. LC-MS: [M+H] ⁺ = 495.

Step 8: Under nitrogen protection, dissolve intermediate P14-8 (520mg, 1.05mmol) and cesium carbonate (684mg, 2.10mmol) in 5mL DMF, add intermediate a5 (363mg, 2.10mmol), and heat up to 140°C React for 2 hours. Cool to room temperature, add 60 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (petroleum ether/ethyl acetate, 1/1) to obtain a yellow solid P14-9 (155 mg, 0.25 mmol). Yield: 23%. LC-MS: [M+H] ⁺ =630.

Step 9: Under the protection of nitrogen, the intermediate P14-9 (155mg, 0.25mmol) and cesium carbonate (200mg, 0.62mmol) were dissolved in 5mL of toluene, and the intermediate a7 (139mg, 0.34mmol) and Pd(DPEPhos)Cl were added ₂ (52mg, 0.074mmol), heated to 105°C and reacted for 3 hours. Cool to room temperature, add 30 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (petroleum ether/ethyl acetate, 1/4) to obtain a yellow solid P14-10 (85 mg, 0.25 mmol). Yield: 41%. LC-MS: [M+H] ⁺ = 842.

Step 10: Dissolve P14-10 (65 mg, 0.077 mmol) in 3 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by preparative HPLC chromatography (X Bridge Shield RP18OBD column, 19*150mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 25mL/min), to obtain a white Solid P14 (9.2 mg), LC-MS: [M+H] ⁺ =642.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.11 (d, J=4.0Hz, 1H), 7.97 (brs, 2H), 7.36-7.31 (m, 2H), 7.17-7.11 (m, 1H), 6.57(d,J=4.0Hz,1H),5.17(d,J=56.0Hz,1H),4.31-4.18(m,2H),4.07-4.03(m,1H),3.93-3.89(m,1H) ,3.49-3.45(m,2H),2.89-2.73(m,3H),2.41-2.27(m,3H),2.17-2.08(m,2H),1.93-1.79(m,3H),1.66-1.62( m,2H),1.32(s,1H),0.64-0.61(m,2H),0.45-0.42(m,2H).

Example 12:

Step 1: In ice bath, dissolve intermediate c1 (330 mg, 1.76 mmol) in 1 mL of anhydrous THF, add NaH (85 mg, 3.52 mmol), warm to room temperature and stir for 0.5 hours, and the reaction solution is set aside. Intermediate a3 (350mg, 0.82mmol) was dissolved in 1mL of anhydrous tetrahydrofuran, added to the above reaction solution, reacted at room temperature for 1 hour, and stopped the reaction. Concentrated under reduced pressure, the crude product was separated by flash column chromatography to obtain compound P18-1 (240mg, 0.42mmol), with a yield of 24%. LC-MS: [M+H] ⁺ = 579.

Step 2: Under nitrogen protection, compound P18-1 (240mg, 0.42mmol), intermediate b2 (270mg, 0.44mmol), cesium carbonate (270mg, 0.83mmol) and methanesulfonic acid [n-butylbis(1-adamantine Alkyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (Pd-G3,10mg,0.014mmol) was dissolved in a mixed solution of 2mL1,4-dioxane and water ( v/v, 5/1), the temperature was raised to 95° C. for 1 hour, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the crude product was separated by flash column chromatography to obtain compound P18-2 (300 mg, 0.29 mmol), with a yield of 70%. LC-MS: [M+H] ⁺ = 1041.

Step 3: Compound P18-2 (270 mg, 0.26 mmol) and cesium fluoride (80 mg, 0.52 mmol) were dissolved in 1 mL of DMF, heated to 50° C. for 1 hour, and the reaction was stopped. Add 5 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product P18-3. LC-MS: [M+H] ⁺ =729.

Step 4: Dissolve the crude product P18-3 from the previous step in 1 mL of hydrogen chloride in 1,4-dioxane solution (4M concentration), react at room temperature for 1 hour, and slowly add saturated aqueous sodium bicarbonate solution to the system to adjust the pH to 8 Left and right, extracted with ethyl acetate, concentrated under reduced pressure, and purified by TLC thin layer chromatography to obtain compound P18 (50 mg). LC-MS: [M+H] ⁺ = 629.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.17(s, 1H), 9.06(s, 1H), 7.99(dd, J=9.2, 5.9Hz, 1H), 7.48(t, J=9.0Hz, 1H), 7.41(d, J=2.5Hz, 1H), 7.19(t, J=2.2Hz, 1H), 4.49(d, J=11.4Hz, 1H), 4.33(d, J=12.6Hz, 1H) ,4.12(dd,J＝10.5,3.4Hz,1H),4.02(dd,J＝10.6,2.7Hz,1H),3.95(s,1H),3.69–3.53(m,4H),3.45–3.25(m ,2H),2.95–2.85(m,1H),2.72–2.64(m,1H),2.57–2.52(m,1H),2.47–2.32(m,2H),2.09(s,3H),1.95–1.72 (m,4H),1.90–1.60(m,4H),1.51(t,J＝11.7Hz,1H).

Referring to the synthetic route of compound P18, using a similar skeleton structure, the following target molecules were synthesized.

Example 13:

Under ice-cooling, raw material P29-1 (305 mg, 2.4 mmol) and intermediate a3 (500 mg, 1.98 mmol) were dissolved in 10 mL of dichloromethane, triethylamine (301 mg, 2.97 mmol) was added, and reacted at room temperature for 2 hours. Add 30 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain white solid P29-2 (650 mg, 1.9 mmol), yield: 95%. LC-MS: [M+H] ⁺ = 344.

In ice bath, in a 50 mL reaction flask, compound P29-2 (300 mg, 0.87 mmol) was dissolved in 6 mL of anhydrous THF, sodium hydride (70 mg, 1.74 mmol) was added, and stirred for 30 minutes to obtain solution S1. The intermediate a18 was added to the solution S1, the temperature was raised to 70°C and the reaction was carried out for 16 hours, and then cooled to room temperature to stop the reaction. Add 30 mL of ice water to the system to quench the reaction, extract with ethyl acetate, and concentrate under reduced pressure to remove the solvent. The residue was purified by flash column chromatography (DCM/MeOH=10/1) to obtain white solid P29-3 (200 mg, 0.40 mmol), yield: 46%. LC-MS: [M+H] ⁺ = 495.

Under the protection of nitrogen, the compound P29-3 (450mg, 0.91mmol) and the raw material P9-1 (560mg, 1.1mmol) were dissolved in 10mL of 1,4-dioxane and 2mL of water, and the catalyst XPhos Pd G2 (215mg, 0.3 mmol) and cesium carbonate (1.18g, 3.64mmol). The reaction solution was reacted at 95° C. for 2 hours, and the reaction was stopped. The solvent was removed by concentration under reduced pressure, and the residue was separated by flash column chromatography (DCM/MeOH=20/1) to obtain a yellow solid P29-4 (500 mg, 0.59 mmol). Yield: 65%, LC-MS: [M+H]+=845.

Compound P29-4 (200 mg, 0.24 mmol) was dissolved in 4 mL of tetrahydrofuran at room temperature, tetrabutylammonium fluoride (TBAF, 130 mg, 0.48 mmol) was added, and reacted at room temperature for 1 hour. Add 20 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude yellow oil P29-5 (160 mg, 0.23 mmol). Yield: 98%. LC-MS: [M+H] ⁺ = 689.

Dissolve the crude product P29-5 (163 mg, 0.24 mmol) from the previous step in 2 mL of dichloromethane, add 1 mL of hydrogen chloride in 1,4-dioxane solution (concentration 4 N) dropwise, react at room temperature for 1 hour, and stop the reaction. Slowly add saturated sodium bicarbonate solution to the system to adjust the pH to about 8, extract with ethyl acetate, and concentrate under reduced pressure. The residue was separated by flash column chromatography to obtain 10 mg of yellow solid P29. LC-MS: [M+H] ⁺ = 645.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.16(s, 1H), 9.34(s, 1H), 8.77(s, 1H), 8.01(dd, J=9.2, 5.9Hz, 1H), 7.49( t,J=9.0Hz,1H),7.42(d,J=2.4Hz,1H),7.19(t,J=3.5Hz,1H),5.30–5.02(m,1H),4.54–4.41(m,2H ),4.22-4.05(m,1H),4.00-3.92(m,1H),3.87-3.68(m,1H),2.85–2.60(m,5H),2.42-2.20(m,7H),2.16–1.67 (m,14H).

Example 14:

The compound is tested for the inhibition of p-ERK mediated by KRAS G12D (directly reflecting the inhibitory effect of the test compound on the cellular level). details as follows:

AGS cells cultured in F-12K medium (Gibco, Cat.No.30-2004) containing 10% fetal calf serum and 1% penicillin were seeded on 384-well microplates at 37°C, 5% Incubate overnight under carbon dioxide conditions. 200 microliters of compounds at different concentrations (0.5% dimethyl sulfoxide final concentration) were added to each well and incubated at 37°C for 3 hours. Then, the cells were fixed in 8% fixative solution (Solarbio, Cat. No. P1112) and washed once with phosphate buffered saline (PBS). After washing, a blocking solution (LI-COR, Cat. No. 927-40000) was added to each well to block for 1 hour at room temperature. After removing the blocking solution, add phospho-p44/42MAPK (T202/Y204) Rabbit mAb (CST, Cat.No.97166S) and GAPDH (D4C6R) Mouse mAb (CST, Cat.No.4370S) antibodies to work in each well solution, incubated overnight at 4°C. Wash the microplate three times with PBS solution (PBST) containing 0.1% Tween-80, add IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat.No.926-32211) and IRDye 680RD Goat anti Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solution, incubate the microplate at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and read with an Odyssey CLx (LI-COR) instrument and the signal value was recorded.

Calculation formula of IC ₅₀

Compound _IC50 values were calculated using nonlinear regression equation: Y=lower plateau signal+(upper plateau signal-lower plateau signal)/(1+10^(( _LogIC50 -X)*Hill slope)); X=compound concentration logarithm.

Table 1: Inhibitory effect of compounds on p-ERK half effective concentration [MRTX1133 as positive control]

compound	p-ERK/IC 50 /nM	compound	p-ERK/IC 50 /nM
H1a	0.29	P1	54
H1b	4.6	P2	534

H2a	42	P3	450
H2b	1.1	P4	twenty one
H3a	40	P5	169
H3b	0.33	P6	117
H4	2.6	P7	>1000
H5a	>1000	P8	13
H5b	42	P9	0.88
H6	4.1	P10	1.9
H7	10	P11	2.8
H8	40	P12	259
H9	10	P13	18
H10a	98	P14	633
H10b	0.51	P15	158
H11	4.0	P16	94
H12a	112	P17	72
H12b	0.94	P18	7.9
H13	780	P19	3.6
H14	358	P20	0.77
H15	5.5	P21	13
H16	twenty four	P22	3.0
H17	4.0	P23	13
H18	twenty one	P24	0.42
H19a	>1000	P25	5.2
H19b	7.5	P26	1.4
H20	3.2	P27	1.2
H21	51	P28	1.9
H22	twenty three	P29	105
MRTX1133	1.0	the	the

MRTX1133 structure:

Example 15: Inhibitory activity of compounds against GTP-KRAS

Dilute the test compound with a 4-fold concentration gradient, use ECHO (Labcyte) to transfer 0.1 μL of different concentrations of the test compound to each well of a 384-well microplate, and add 5 μL of diluted Tag2-KRAS G12D&GTP or Tag2-KRAS to each well WT&GTP, centrifuge at 1000RPM for 1 minute; then add 5μL of diluted Tag1-cRAF to each well, centrifuge at 1000RPM for 1 minute, incubate at 25°C for 15 minutes; add 10μL of anti-Tag1-Tb3 and anti-Tag2-XL665 to each well The mixture was centrifuged at 1000RPM for 1 minute and incubated at 4°C for 3 hours; the plate was scanned at 665/615nm using Envision and the signal value was recorded.

In the above analysis, the relevant detection reagents of KRAS-G12D were all from the commercially available kit KRAS-G12D/cRAF BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB21PEG); in the detection of KRAS-WT, GTP was purchased from Sigma (Cat. No.V900868), GST-cRAF was prepared by Beijing Pharmaron (Cat.No.20190718), MAb Anti GST-Tb cryptate was purchased from Cisbio (Cat.No.61GSTTLA), and other key reagents were from the commercially available kit KRAS- WT/SOS1BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB15PEH).

Analyze the calculation results according to the following formula:

Relative ratio (relative ratio, RR) = (Ratio _665/615 -Ratio _background )

Inhibition percentage=[1-(RR _compound -RR _{positive control} well average value)/(RR _{negative control} well average value-RR _{positive control well} average value)]×100

IC ₅₀ calculation: Y=lower plateau signal+(upper plateau signal-lower plateau signal)/(1+10^(LogIC ₅₀ -X)×Hill slope). X, logarithmic value of compound concentration; Y: inhibition percentage.

This result shows that the molecule of the present invention has an excellent inhibitory effect on KRAS G12D protein activation.

Example 16:

3D antiproliferative effect of compounds on KRAS G12D mutated pancreatic cancer AsPC-1 cell line. details as follows:

Cell culture: In T75 culture flasks (Corning, catalog number 430641), AsPC-1 pancreatic cancer cells were cultured in a medium containing 10% fetal bovine serum (Ausgenex, catalog number FBS500-S) and 1% penicillin/streptomycin (Gibco, Cat. No. 15140-122) in RPMI 1640 Medium (Hyclone, Cat. No. SH3080901B).

Experimental process: Add the diluted compound to be tested into a 384-well low-adsorption cell culture plate (Labcyte, catalog number PP-0200) using a nanoliter pipetting system (LABCYTE, catalog number Echo550). After the cells are spread, place the culture plate Incubate at 37°C, 5% CO ₂ incubator. The compound to be tested (1μM as the initial concentration, diluted 3 times, a total of 10 concentrations) was co-incubated with the cells for 7 days, and added to each well

3D reagent (Promega, catalog number G9683), read the luminescence value with Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104), the light signal is directly proportional to the amount of ATP in the system, and the content of ATP directly characterizes the amount of ATP in the system Viable cell count. Finally, XLFIT software was used to obtain the IC ₅₀ (half inhibitory concentration) of the compound with a nonlinear fitting formula.

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

Negative control: DMSO. Positive control: culture medium.

Table 2: Anti-proliferation effect of compounds on AsPC-1 cell half effective concentration

compound	IC 50 /nM
H1a	4.2
H1b	49
H2b	twenty three
P4	851
P11	50
P20	47

This result shows that the molecule of the present invention has a good anti-proliferation effect on KRAS G12D mutated tumor cell lines.

Example 17:

Liver microsomal stability assay of compounds. details as follows:

Carry out liver microsome stability test research on the compound of the present invention, the compound to be tested is co-incubated with liver microsomes of different species with or without adding NADPH, the final concentration of the compound to be tested in the test system is 1 μM, and the final concentration of NADPH 1mM, the final concentration of liver microsomes is 0.5mg/ml. Detect the concentration of the compound in the incubation supernatant at different time points within 60 minutes and calculate the pharmacokinetic parameters (such as clearance rate Clint).

This result shows that the molecule of the present invention has better metabolic stability (especially in human body, it has better metabolic stability).

Some molecules (such as H1b, H10b, P20, P24, etc.) have a lower clearance rate and slower metabolism in humans than the control MRTX1133.

Example 18:

Drug efficacy experiment in BALB/c nude mice. details as follows:

Colorectal cancer tumor cell GP2D with KRAS G12D mutation was cultured, and the tumor cells were inoculated into 6-8 week old female BALB/c nude mice (body weight about 20 g), and all mice were inoculated subcutaneously. Mice were raised in an SPF-grade experimental environment, and all mice had free access to commercially certified standard diets. Daily intraperitoneal (ip) administration of the test compound began when the average tumor volume of the mice had grown to approximately 150 mm ³ . The dosage is: blank group vehicle (10% Captisol in 50mM citrate buffer pH 5.0). The dosage of the administration group was 10mg/kg, twice a day. Tumor volumes were measured with two-dimensional calipers three times a week, and animals were weighed daily. After 10 days of continuous administration, the inhibition rate (TGI/100%) was calculated according to the final tumor volume. The volume calculation formula is: V=1/2a*b ² , where a represents the long diameter of the tumor, and b represents the short diameter of the tumor.

Test drug	Dosage	TGI
blank group	0	0%
MRTX1133	10mg/kg, BID	186%
P20	10mg/kg, BID	187%

The results show that the molecule of the present invention has better drug efficacy in vivo, can inhibit the growth of KRAS G12D mutant tumors, and the effect is better than MRTX1133.

Example 19:

In vivo safety experiment of the compound of the present invention in animals. details as follows:

Qualified healthy ICR mice (aged 6-8 weeks, body weight 18-20g) were selected, 3 in each group, for single intravenous administration respectively. First, a single intravenous administration test was carried out, and the dose was explored from 2mg/kg. If no death was observed, the dose was increased, and if death occurred, the increase would be stopped.

The intravenous administration solution of MRTX1133 and the compound P20 intravenous administration vehicle are: DMSO/Tween80/Solutol/normal saline (the volume ratio of the four is 5/3/10/82), vortex ultrasonic to make it fully dissolved, and carry out administration disposal .

compound	Method of administration	Dosage	Mortality/3
MRTX1133	vein iv	2mpk	0/3
MRTX1133	vein iv	4mpk	1/3

P20	vein iv	2mpk	0/3
P20	vein iv	4mpk	0/3
P20	vein iv	8mpk	0/3
P20	vein iv	16mpk	2/3

Qualified healthy ICR mice (age 6-8 weeks, body weight 18-20g) were selected, 3 mice in each group, for single infusion administration respectively. Start with the maximum dose administered intravenously and increase the dose if no deaths are seen and stop if deaths occur. MRTX1133 infusion administration solution and compound P20 infusion administration vehicle are: DMSO/Tween80/Solutol/normal saline (the volume ratio of the four is 5/3/10/82), vortex ultrasonic to make it fully dissolved, then administer Drug disposal.

compound	Method of administration	Dosage	Mortality/3
MRTX1133	Infuse inf	4mpk	0/3
MRTX1133	Infuse inf	8mpk	0/3
MRTX1133	Infuse inf	16mpk	0/3
MRTX1133	Infuse inf	32mpk	2/3
P20	Infuse inf	16mpk	0/3
P20	Infuse inf	32mpk	0/3
P20	Infuse inf	96mpk	0/3
P20	Infuse inf	150mpk	0/3

The results show that the molecule of the present invention has better in vivo safety, and the safety is far superior to MRTX1133 no matter it is administered intravenously or infused.

Claims (7)

1. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from:

   

   
2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof, and pharmaceutically acceptable Acceptable excipients; preferably, also contain other therapeutic agents.
3. The compound of claim 1 or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotope variant is used for the treatment and/or prevention of KRAS G12D mutant protein in the preparation Use in medicines for mediated diseases.
4. A method for treating and/or preventing KRAS G12D mutant protein-mediated diseases in a subject, the method comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to the subject, Enantiomers, diastereomers, solvates, hydrates or isotopic variants or the pharmaceutical composition of claim 2.
5. The compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof or the pharmaceutical composition of claim 2 for use in the treatment of And/or prevent KRAS G12D mutant protein-mediated diseases.
6. The use of claim 3 or the method of claim 4 or the use of the compound or composition of claim 5, wherein the disease mediated by the KRAS G12D mutant protein is selected from acute myeloid leukemia, acute myeloid leukemia, juvenile cancer , childhood adrenocortical carcinoma, AIDS-related cancers (such as lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone Carcinoma, brainstem glioma, brain tumor, breast cancer, bronchial neoplasm, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, Childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma , Extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancers, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors Tumors, eye cancer, fibrous histiocytoma of the bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS) , Lung cancer, Lymphoma, Metastatic squamous neck cancer with occult primary, Midline tract cancer, Oral cavity cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma/plasmacytoma, Mycosis fungoides, Myelodysplastic syndrome myelodysplasia/myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma cancer, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, thyroid cancer Parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus carcinoma, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, trophoblastic tumor, rare in children Cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.
7. The use of claim 3 or the method of claim 4 or the use of the compound or composition of claim 5, wherein the disease mediated by the KRAS G12D mutant protein is selected from pancreatic cancer, colorectal cancer or non-small cell lung cancer.