CN118221700A

CN118221700A - Condensed ring aromatic compound, preparation method and application thereof

Info

Publication number: CN118221700A
Application number: CN202410291353.5A
Authority: CN
Inventors: 刘晓辉; 王艳峰; 王英; 巫美凤; 曾炼; 冯学蓉; 余晓慧; 王叶叶
Original assignee: Beijing Huasen Yingnuo Biotechnology Co ltd
Current assignee: Beijing Huasen Yingnuo Biotechnology Co ltd
Priority date: 2023-03-14
Filing date: 2024-03-14
Publication date: 2024-06-21

Abstract

The invention provides a condensed ring aromatic compound with broad-spectrum inhibition effect on KRAS mutation, and pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which is shown as a formula (I ₀), wherein the definition of each group in the formula is shown in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound and application thereof in preparing a kit for treating cancer, immune diseases or prognosis evaluation of cancer patients.

Description

Condensed ring aromatic compound, preparation method and application thereof

Technical Field

The present disclosure relates to the field of medicine, and in particular, to a fused aromatic compound having KRAS broad-spectrum inhibition, a pharmaceutical composition, a preparation method and uses thereof.

Background

The Kirsten rat sarcoma 2 virus oncogene homolog (KRas) is a member of the small gtpase and Ras family. KRas protein is in an inactive state when bound to GDP; when extracellular growth differentiation factors and the like transmit signals to KRAS proteins, the enhancer proteins bind to GTP and bring it into an activated state, thereby activating KRAS and downstream signals (Nature REVIEW CANCER 3:11-22, 2003). Signal pathways such as RAS-RAF-MEK-ERK and RAS-PI3K-AKT regulate a number of cellular processes including cell proliferation, differentiation and survival. KRAS mutations can continuously activate downstream cellular signals, promote cell proliferation, migration and anti-apoptosis, and induce tumor development.

KRAS mutations are closely related to tumor formation and development. The role of KRAS in malignancy has been observed more than 30 years ago (see, e.g., santos et al, (1984) Science 223:661-664). About 20% of all human tumors present abnormal expression of KRAS, and KRAS mutations were detected in 25-30% of lung adenocarcinomas (see, e.g., SAMATAR AND Poulikakos (2014) Nat Rev Drug Disc (12): 928-942doi: 10.1038/nrd) 428). 80% of the KRAS mutations occur at codon 12, leading to single amino acid substitutions, the most predominant of which are G12C and G12D. The KRAS G12C mutation refers to mutation of glycine at position 12 of protein into cysteine, and the occurrence frequency of tumors is pancreatic cancer (57%), colorectal cancer (35%), cholangiocarcinoma (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer (15%), ovarian cancer (14%) and the like (SEMINARS IN CANCER biology.2019jun27.Pii: S1044-579X (18) 30060-9). KRAS G12D mutation refers to mutation of glycine at position 12 of protein into aspartic acid, and the occurrence frequency of tumors is pancreatic Cancer (25.0%), colorectal Cancer (13.3%), rectal Cancer (10.1%), non-small cell lung Cancer (4.1%), small cell lung Cancer (1.7%), etc. (see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7 (8): 818-831.Dataset Version 4), for example. Besides G12C, G12D, KRAS has a number of other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. The frequency of occurrence of different KRAS mutations in different types of cancer cells also varies.

As frequent mutation of KRAS is found in various tumor types, the KRAS becomes a popular anticancer target point in the pharmaceutical industry (see MeCormick (2015) CLIN CANCER Res.21 (8): 1797-1801). Development of KRAS small molecule inhibitors is generally divided into three approaches: (i) a competing ligand prevents GTP binding; (ii) Locking KRAS G12C in an inactive state by allosteric modulation (allosteric modulation); (iii) KRAS is destroyed by protein-protein interaction inhibitors with its effector proteins and guanine nucleotide exchange factors (GEFs) (e.g., son Ofsevenless (SOS), RAF, and PI 3K), etc.

Most of the drug developments targeting KRAS over the past decades have ended with failures, so KRAS has been considered unable to be formulated (undruggable). However, in recent years, with the development of breakthroughs in biological and protein structures, including comparative studies of the different structures of mutant and wild-type KRAS proteins, small molecule inhibitors targeting KRAS G12C have been clinically successful. Amgen's First-in-CLASS KRAS G C inhibitor AMG 510 has been marketed by the United states FDA on day 28 of 5 in 2021 for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations. Mirati and various biopharmaceutical companies at home and abroad are also developing KRAS-targeting drugs, but most are directed against KRAS G12C or KRAS G12D mutations. As described above, in addition to KRAS G12C or KRASG12D mutations, KRAS has other multiple mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. These KRAS mutations play an important role in the formation and progression of various types of cancer. Thus, the development of drugs targeting these KRAS mutations is urgent. In addition, with successful marketing of targeted KRAS G12C drugs, we expect cancer patients receiving treatment to develop drug resistance. Therefore, aiming at the unmet clinical demands, the development of a new generation of broad-spectrum KRAS inhibitor for targeting various KRAS mutations against a drug resistance mechanism has important significance.

Disclosure of Invention

In one aspect of the invention, a novel structure of a substituted fused ring aromatic compound is provided, which has higher inhibition activity as a broad spectrum inhibitor of KRAS mutation.

In one aspect of the present invention, there is provided a compound of formula (I ₀), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which is represented by formula (I ₀):

in formula (I ₀), R ¹ is selected from hydrogen, -CH ₃、-OCH₃;

R ² is selected from

Wherein R is selected from the group consisting of C _1-3 alkynyl, C _1-3 alkenyl, C _1-3 alkyl, said C _1-3 alkyl optionally substituted with-CN, -NH ₂、-N(CH₃)₂, -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably R is selected from the group consisting of ethynyl, vinyl 、-CH₂CH₂CN、-CH₂CH₂NH₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂OH;

Ring A is selected from

M is optionally 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from-CH ₂-、-CHR⁷ -or-C (R ⁷)₂;

R ⁷ at each substitution position is independently selected from -H、-OH、-F、-Cl、-CH₃、-CN、-CH₂OH、-CH₂Cl、-OCH₃、-CH₂CN、-CH(CH₃)₂OH、-NHCH₃、 Or two R ⁷ substituents on the same carbon atom form a 3-to 6-membered heterocyclic ring or carbonyl group with the carbon atom, p is optionally 0, 1, 2, 3 or 4;

r ⁴¹ is selected from

In another aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof, said compound being of formula (I):

In the formula (I) of the present invention,

R ² is selected from

M is optionally 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from-CH ₂-、-CHR⁷ -or-C (R ⁷)₂;

R ⁷ at each substitution position is independently selected from -H、-OH、-F、-Cl、-CH₃、-CN、-CH₂OH、-CH₂Cl、-OCH₃、-CH₂CN、-CH(CH₃)₂OH, or two R ⁷ substituents on the same carbon atom form a 4-6 membered heterocycle or carbonyl with the carbon atom, p is optionally 0, 1, 2, 3 or 4;

When R ² is selected from Time,/>The radicals being selected from

When R ² is selected fromTime,/>The radicals being selected from

R ⁴¹ is selected from

In some preferred embodiments, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in formula (I-a), formula (I-b), formula (I-c) or formula (I-d),

In a preferred embodiment, a compound of formula (I ₀), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the group consisting of:

In a preferred embodiment, the compound of formula (I ₀) or formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, comprises any one or combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, formate, acetate, trifluoroacetate, propionate, mesylate, lactate, besylate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate or malate.

In another aspect of the present invention, there is provided a process for the preparation of the compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof, comprising the steps of:

(1) The compound (I-1) and the compound (R ¹ 'H) are subjected to substitution reaction to generate a compound (M-a), wherein the R ¹' group is selected from R ⁸ or R ⁸ substituted by a protecting group, and the R ⁸ group is selected from

(2) The compound (M-a) and the compound (R ⁴¹ H) undergo a coupling reaction to generate a compound (M-b);

(3) The compound (M-b) and the compound Through Suzuki coupling reaction, a compound (M-c) is generated, wherein the R ²' group is selected from R ² or R ² substituted by a protecting group;

(4) Removing the protecting group from the compound (M-c) to generate a compound (M);

The definition of R ²、R⁷、X¹、m、q、p、R⁴¹ is as described above.

In another aspect, the invention provides a pharmaceutical composition, which is characterized in that the composition comprises the compound, pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs and pharmaceutically acceptable auxiliary materials thereof.

In another aspect of the invention, there is provided the use of the above-described compound, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, said pharmaceutical composition for the preparation of a kit for the treatment of cancer, immune disease or prognosis evaluation of a cancer patient;

Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases;

Preferably, in the manufacture of a medicament for the treatment of a disease associated with KRAS mutations;

preferably, the cancer includes, but is not limited to, pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, etc.;

More preferably, the cancer includes, but is not limited to, pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, and the like.

In another aspect of the present invention, there is provided the use of a compound as described above, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or a pharmaceutical composition thereof, in the preparation of a KRAS inhibitor; preferably, the use in the preparation of KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutation inhibitors.

In another aspect of the invention there is provided a method of inhibiting mutant KRAS in a biological sample comprising contacting the biological sample with the compound, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof or the pharmaceutical composition.

Detailed Description

In light of the disclosure, many other modifications, substitutions, or alterations are also possible in the form of modifications, substitutions, or alterations without departing from the basic technical concepts set forth in this disclosure, as would be apparent to one of ordinary skill in the art and practice of this disclosure.

In the context of the present disclosure of the present invention,Refers to a chemical bond junction.

Medicament or pharmaceutical composition

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acids and bases of the particular compounds without biological adverse effects. Such as acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: THE SCIENCE AND PRACTICE of Pharmacy,20th Edition).

For oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be in the form of a non-toxic, pharmaceutically acceptable adjuvant such as a binder (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweetening agents, natural and synthetic gums (e.g., acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes and the like. For oral administration in liquid form, the pharmaceutical component may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oil esters, ethanol, or fractionated vegetable oils), preserving agents (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid), and the like. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

Tablets containing the active compound may be coated by methods well known in the art. The compositions of the present disclosure comprising as active compound a compound of formula I may also be incorporated into beads, microspheres or microcapsules, for example constructed from polyglycolic acid/lactic acid (PGLA). Liquid formulations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may be suitably formulated so as to provide controlled or delayed release of the active compound.

The medicaments or pharmaceutical compositions of the present disclosure may be administered parenterally, i.e. by intravenous (i.v.), intraventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.), or intradermal (i.d.), by direct injection, via bolus injection or continuous infusion, for example. Formulations for injection may be presented in unit dosage form, for example, in ampules or multi-dose containers with added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, in the form of excipients (vehicles), and may contain formulatory agents such as anti-settling agents, stabilisers and/or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g. sterile pyrogen-free water) prior to use.

The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

The terms "reduce", "inhibit", "reduce" or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate controls for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound. As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacological and/or physiological effect. The precise dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or disorder, and the treatment being administered. The effect of an effective amount may be relative to a control. These controls are known in the art and discussed herein, and may be, for example, the condition of the subject prior to or without administration of the drug or combination of drugs, or in the case of a combination of drugs, the combined effect may be compared to the effect of administration of only one drug.

The term "excipient" is used herein to include any other compound that is not a therapeutically or biologically active compound that may be contained in or on a microparticle. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally non-toxic to the subject. "excipient" includes a single such compound, and is also intended to include multiple compounds.

The term "pharmaceutical composition" means a composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature sensitive materials, temperature adjusting agents, adhesives, stabilizers, suspending agents, and the like.

Use and method of treatment

The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a human.

According to the methods of the present disclosure, the compounds or compositions may be administered in any amount and by any route of administration effective to treat or reduce the severity of a KRAS-related disease.

The present disclosure relates to a method of inhibiting KRAS in a biological sample comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

The term "biological sample" includes, but is not limited to, a cell culture or extract thereof; a biopsy material or extract thereof obtained from a mammal; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof. Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays, gene expression studies, and biological target identification.

A method of inhibiting KRAS in a patient of the present disclosure comprising the step of administering to the patient a compound of the present disclosure or a composition comprising the compound.

The compounds provided are KRAS inhibitors and thus are useful in the treatment of one or more conditions associated with KRAS activity. Thus, in certain embodiments, the present disclosure provides a method for treating a KRAS-mediated disorder comprising the step of administering a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.

As used herein, the term "KRAS-mediated" disorder, disease, and/or condition, as used herein, means any disease or other deleterious condition for which KRAS or mutants thereof are known to function. Thus, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases for which KRAS or mutants thereof are known to play a role.

The present disclosure provides a method for treating one or more disorders, diseases, and/or conditions, wherein the disorder, disease, or condition is a proliferative disease, such as cancer, an inflammatory disorder, or a viral infection.

In certain embodiments, the present disclosure provides a method of treating cancer or another proliferative disorder comprising administering a compound or composition of the present disclosure to a patient suffering from cancer or another proliferative disorder. In certain embodiments, the methods of treating cancer or another proliferative disorder comprise administering to a mammal a compound and composition of the present disclosure. In certain embodiments, the mammal is a human.

As used herein, the terms "inhibit cancer" and "inhibit proliferation of cancer cells" refer to inhibiting growth, division, maturation, or survival of cancer cells, and/or causing death of cancer cells by cytotoxicity, nutrient depletion, or induction of apoptosis, alone or in combination with other cancer cells.

Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and for which the methods described herein are applicable include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

Cancers treated by the compounds or compositions of the present disclosure include, but are not limited to, melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, renal cancer, esophageal cancer, brain cancer, lymphoma, or colorectal cancer, among others. In certain embodiments, the cancer is Primary Exudative Lymphoma (PEL).

The compounds of the present disclosure are useful for treating proliferative diseases selected from the group consisting of: benign or malignant tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone or thyroid, cancer tumors; sarcomas, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancers (especially colorectal or colorectal adenomas) or neck and head tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasias of epithelial character, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, hodgkins and non-Hodgkins lymphomas, breast cancer, follicular carcinoma, undifferentiated tumors, papillary carcinomas, seminomas, melanomas, MYD 88-driven disorders, DLBCL, abcdlbcl, IL-1-driven disorders, and mild or indolent multiple myeloma or leukemia.

Cancers described in the present disclosure include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., hodgkin's disease or non-hodgkin's disease), waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, spinal cord tumor, angiosarcoma, endothelial sarcoma, lymphosarcoma, lymphoendothelioma, synovial carcinoma, mesothelioma, ewing's tumor (Ewing's tumor), leiomyosarcoma, rhabdomyosarcoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cyst adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical carcinoma, testicular carcinoma, lung cancer, small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), neuroblastoma, craniomal tumor, ependymoma, pineal tumor, glioblastoma, auditory cell carcinoma, oligodendroglioma, neuroma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, angioblastoma, auditory neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, the cancer is an acoustic glioma, an astrocytoma (e.g., grade I-wool cell type astrocytoma, grade II-low astrocytoma, grade III-polymorphic astrocytoma, or grade IV-Glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngeal tube tumor, a brain stem glioma, a ependymoma, a mixed glioma, an optic glioma, an ependymal ependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a Primary Neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is of a type more common in children than in adults, such as brain stem glioma, craniopharyngeal tube tumor, ependymoma, juvenile capillary astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primary neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a pediatric or pediatric patient.

In another specific embodiment, the cancer includes (without limitation): mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colorectal cancer, rectal cancer, anal region cancer, gastric cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal cell carcinoma, renal pelvis cancer, non-hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortex cancer, gall bladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystic adenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; bile duct hepatoma; soft tissue and synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; ewing's sarcoma; polymorphic thyroid cancer; adrenal cortex adenoma; pancreatic cancer; pancreatic duct cancer or pancreatic cancer; gastrointestinal/Gastric (GIST) cancer; lymphomas; squamous Cell Carcinoma of Head and Neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 related Malignant Peripheral Nerve Sheath Tumor (MPNST); waldenstrom's macroglobulinemia; or medulloblastoma.

The term "primary tumor" is used to refer to a tumor, which is a tumor that first appears in a certain area such as lung, liver, intestine, head, skin, etc., and may be referred to as primary lung cancer, primary liver cancer, primary intestinal cancer, etc., in contrast to secondary tumor.

The term "inflammatory disease" includes such autoimmune, allergic and inflammatory disorders, for example selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or graft rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, grave's disease, hashimoto's thyroiditis, sjogren's syndrome, and blistering disorders (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndrome, including ANCA-related vasculitis, purpura, and immune complex vasculitis (cancer or primary or secondary infection). The allergic condition may be selected in particular from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, beryllium poisoning. The respiratory disorder may be selected from among, inter alia, asthma, bronchitis, chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary arterial hypertension, emphysema, and the like.

The term "viral infection" includes, but is not limited to, retrovirus infection, hepatitis virus infection, COVID-19 new coronavirus infection, zika virus infection, dengue virus infection, and the like.

Combination therapy method

The present disclosure provides combination therapies using compounds as described in the present disclosure with other therapeutic agents. The term "combination therapy" as used in this disclosure includes the administration of these agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, and the administration of these therapeutic agents, or at least two agents, occurs substantially simultaneously. The sequential, or substantially simultaneous, administration of each agent may be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue. The agents may be administered by the same route or by different routes. For example, a first agent may be administered orally, while a second agent is administered intravenously. In addition, the selected combination agents may be administered by intravenous injection, while the other agents of the combination may be administered orally. Or, for example, two or more agents may be administered by intravenous or subcutaneous injection.

Example II

The present disclosure is further illustrated below with reference to examples. The description of specific exemplary embodiments of the present disclosure is presented for purposes of illustration and description. The description is not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible in light of the teaching of the present specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and its practical application to thereby enable one skilled in the art to make and utilize the present disclosure in various exemplary embodiments and with various modifications as are suited to the particular use contemplated.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.

Instrument and reagents:

And (3) NMR: agilent 400MR DD2 nuclear magnetic resonance apparatus, measuring solvent of deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃), and internal standard of Tetramethylsilane (TMS). LC-MS: agilent 1260 affinity II-InfinityLab LC/MSD mass spectrometer. HPLC: agilent 1260 affinity II high pressure liquid chromatograph (Sunfire C185um 150x4.6mm column).

Thin layer chromatography silica gel plate: HSGF254 silica gel plate (smoke table Jiang You silica gel development Co., ltd.) with a specification of 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plates (in chemical industry (Shanghai) limited), specification 0.2mm = 0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao sea wave silica gel desiccant Co., ltd.) Flash column (Ai Jieer femtomomei CLARICEP FLASH amorphous silica gel purification column).

Reagent: 7-chloro-8-fluoropyrido [4,3-d ] pyrimidine-2, 4 (1H, 3H) -dione, phosphorus oxychloride, 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester, (3- (ethoxymethoxy) -8-fluoronaphthalen-1-yl) boronic acid, tetrakis (triphenylphosphine) palladium, palladium acetate, ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol, (S) - (1-methylpyrrolidin-2-yl) methanol, 4-difluoropyridine, [ N-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II), potassium phosphate, (2- (8-ethyl-7-fluoro-3- (methoxymethoxy) -naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde, N-methyl-L-prolinol, (2-fluoro-6- (4, 5-methoxybenzyl) -2-isopropyl) silane, ((2-methoxy-4, 5-dimethyl-2-ethynyl) phenylmethane,), other reagents and starting materials such aS 7aS s) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol, cesium fluoride, thiomorpholine 1, 1-dioxide, 4- ((tert-butyldiphenylsilane) oxy) piperidine, (1 r,5 s) -8-oxo-3-azabicyclo [3.2.1] octane, 4-methylpiperidin-4-ol, (1 r,5 s) -8-oxo-3-azabicyclo [3.2.1] octane, hydrochloric acid-dioxane were purchased from Shanghai pichia, leven reagent company, jiangsu Aikang biological medicine research and development company, an Naiji chemical reagent company, shanghai microphone reagent company, saen chemical reagent company, and the like, or were synthesized using methods known in the art. All reactions of the present disclosure were performed under continuous magnetic stirring under dry nitrogen or argon, with the solvent being a dry solvent, and the reaction temperature being in degrees celsius, unless otherwise specified.

The following are intermediate numbers:

Intermediate I-1

Intermediate I-1: synthesis of 2,4, 7-trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1)

7-Chloro-8-fluoropyrido [4,3-d ] pyrimidine-2, 4 (1H, 3H) -dione (500 mg,2.3 mmol) and N, N-diisopropylethylamine (6.1 g,46.1 mmol) were added to phosphorus oxychloride (20 ml) and reacted at 110℃for 1 hour. After vacuum concentration and Flash column (dichloromethane) purification, the target product 2,4, 7-trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 1.31g, yield 56%) and ESI [ M+H ] ⁺ =252.0, 254.0 are obtained.

Intermediate I-2

Intermediate I-2: preparation of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one

Intermediate I-2-1: synthesis of 2, 6-dichloro-3-fluoro-4-pyridineamine (I-2-1)

4-Amino-2, 6-dichloropyridine (52 g,320 mmol) was added to acetonitrile (480 ml) and N, N-dimethylformamide (480 ml), 83.5 (136 g,360 mmol) was slowly added and reacted at 80℃for 3 hours. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (petroleum ether: ethyl acetate=0% -30%) to obtain the target product 2, 6-dichloro-3-fluoro-4-pyridine amine (I-2-1, 51g, yield 88.3%). ESI [ m+h ] ⁺ =180.9, 181.9

Intermediate I-2-2: synthesis of tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (I-2-2)

2, 6-Dichloro-3-fluoro-4-pyridineamine (41.3 g,229.5 mmol) and 4-dimethylaminopyridine (1.3 g,11.6 mmol) were added to tetrahydrofuran (225 ml), di-tert-butyl dicarbonate (125.3 g,574.5 mmol) was slowly added and reacted at 60℃for 4 hours. Water quenching, ethyl acetate extraction, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying by Flash column (petroleum ether: ethyl acetate=0% -50%) to obtain target product tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (I-2-2, 42.1g, yield 48.4%). ESI [ m+h ] ⁺ = 381.2, 382.3

Intermediate I-2-3: synthesis of tert-butyl 4- (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinic acid (I-2-3)

Diisopropylamine (24.32 g,240.8 mmol) was added to tetrahydrofuran (200 ml), and cooled to

N-butyllithium (150.5 ml,240.8 mmol) was slowly added under nitrogen protection at 78℃and reacted at-78℃for 1 hour, tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (32.6 g,86 mmol) was dissolved in tetrahydrofuran (100 ml) and then slowly added to the reaction solution, and

The reaction was continued at 78℃for 1 hour, quenched with aqueous acetic acid solution, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then Flash column (petroleum ether: ethyl acetate=0% -30%) was purified to give the desired product, t-butyl 4- (t-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinate (I-2-3, 23.1g, yield 95.1%). ESI [ m+h ] += 381.2, 382.3

Intermediate I-2-4: synthesis of 4-amino-2, 6-dichloro-5-fluoronicotinate hydrochloride (I-2-4)

Tert-butyl 4- (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinic acid (22.8 g,60 mmol) was added to dioxane (90 ml), then concentrated hydrochloric acid (30 ml) was slowly added to the reaction solution, and reacted at 25℃for 16 hours, the reaction solution was directly filtered, and the filter cake was dried to obtain the objective 4-amino-2, 6-dichloro-room-temperature

5-Fluoronicotinic acid hydrochloride (I-2-4, 18.1g, yield greater than 117%). ESI [ m+h ] ⁺ = 225.1 intermediate I-2-5: synthesis of 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4,3-d ] pyrimidin-4 (3H) -one (I-2-5)

4-Amino-2, 6-dichloro-5-fluoronicotinic acid hydrochloride (22.8 g,60 mmol) was added to thionyl chloride (450 ml), reacted at 50℃for 3 hours, the reaction mixture was directly dried by spinning, dissolved in acetone (90 ml), thiocyanate amine (15.84 g,138 mmol) was added, and reacted at 25℃for 16 hours, filtered, and the filter cake was washed with acetonitrile and dried to give the target product 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4,3-d ] pyrimidin-4 (3H) -one (I-2-5, 17.1g, yield greater than 64.1%). ESI [ m+h ] ⁺ =266.1

Intermediate I-2: synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one (I-2)

5, 7-Dichloro-8-fluoro-2-mercaptopyrido [4,3-d ] pyrimidin-4 (3H) -one (15.0 g,56.43 mmol) was added to an aqueous sodium hydroxide solution (0.1M, 90ml,56.43 mmol), methyl iodide (13.3 g,101.6 mmol) was then slowly added to the reaction solution, and reacted at 25℃for 16 hours, the reaction solution was poured into water, pH was adjusted to=6, a large amount of white solid was precipitated, and filtration and cake drying were performed to obtain the objective 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one (I-2, 10.1g, yield 63.9%). ESI [ m+h ] ⁺ =280.1

Intermediate I-3

Intermediate I-3: preparation of 2,4, 7-trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine

Intermediate I-3-1: synthesis of methyl 2-bromo-5-fluoroisonicotinic acid (I-3-1)

2-Bromo-5-fluoroisonicotinic acid (88 g,400.01 mmol) was dissolved in methanol (1000 mL), and thionyl chloride (71.38 g,600.01 mmol) was slowly added dropwise, and the reaction was stirred at 70℃for 2 hours, and the liquid detection reaction was complete. The reaction was concentrated in vacuo, the residue was extracted three times with saturated aqueous sodium bicarbonate (700 mL), ethyl acetate (500 mL), the organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated and column chromatographed (petroleum ether: ethyl acetate=10:1) to give the desired product compound, methyl 2-bromo-5-fluoroisonicotinate (I-3-1, 86.00g,293.99mmol, yield: 73.50%) as a white solid. ESI [ m+h ] ⁺ =233.8

Intermediate I-3-2: synthesis of methyl 5-fluoro-2-methyliisonicotinic acid (I-3-2)

The compound methyl 2-bromo-5-fluoroisonicotinate (86 g,367.49 mmol) and palladium tetraphenylphosphine (8.49 g,7.35 mmol) were dissolved in tetrahydrofuran (1500 mL) and stirred at room temperature for 15 min. Then the reaction temperature was reduced to 0℃and trimethylaluminum (2M, 220.49 mL) was slowly added dropwise and the reaction was stirred at 80℃for 2 hours. The liquid quality detection reaction is complete. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride (1000 mL) was slowly poured into the reaction solution, ethyl acetate (1000 mL) was extracted three times, the organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated and then column-chromatographed (petroleum ether: ethyl acetate=8:1) to give methyl 5-fluoro-2-methyliisonicotinate (I-3-2, 57.00g,313.39mmol, yield: 85.28%) as a white solid as a desired product .¹H-NMR(400MHz,CDCl₃)δ8.48(d,J＝2.5Hz,1H),7.61(d,J＝5.5Hz,1H),3.97(s,3H),2.59(d,J＝1.4Hz,3H).ESI[M+H]⁺＝170.0

Intermediate I-3-3: synthesis of 5-fluoro-4- (methoxycarbonyl) -2-methylpyridine 1-oxide (I-3-3)

Methyl 5-fluoro-2-methylisonicotinate (56 g,331.06 mmol) was dissolved in dichloromethane (500 mL), and m-chloroperoxybenzoic acid (85.70 g,496.59 mmol) was added and the reaction stirred at 25℃for 16 hours. The liquid quality detection reaction is complete. The reaction solution was poured into aqueous sodium hydrogencarbonate (500 mL), extracted three times with dichloromethane (500 mL), the organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated and then column-chromatographed (petroleum ether: ethyl acetate=1:5) to give the compound 5-fluoro-4- (methoxycarbonyl) -2-methylpyridine 1-oxide (I-3-3, 72.00g,317.1mmol, yield: 95.80%) as a white solid. ESI [ m+h ] ⁺ =185.9

Intermediate I-3-4: synthesis of methyl 2-chloro-3-fluoro-6-methyliisonicotinic acid (I-3-4)

5-Fluoro-4- (methoxycarbonyl) -2-methylpyridine 1-oxide (72 g,386.76 mmol) was dissolved in phosphorus oxychloride (300 mL) and the reaction stirred at 80℃for 2 hours. The liquid quality detection reaction is complete. The reaction mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL), poured into saturated aqueous ammonium chloride (3000 mL), the mixture was separated, the aqueous layer was extracted three times with ethyl acetate (300 mL), the organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated and then column chromatographed (petroleum ether: ethyl acetate=10:1) to give methyl 2-chloro-3-fluoro-6-methyliisonicotinic acid (I-3-4, 35.00g,166.32mmol, yield: 43.00%) as a white solid .¹H-NMR(400MHz,CDCl₃)δ7.53(d,J＝4.4Hz,1H),3.98(s,3H),2.56(d,J＝1.1Hz,3H).ESI[M+H]⁺＝203.9

Intermediate I-3-5: synthesis of 2-chloro-3-fluoro-6-methyliisonicotinic acid (I-3-5)

Methyl 2-chloro-3-fluoro-6-methyliisonicotinate (18 g,88.41 mmol) and lithium hydroxide (6.35 g,265.23 mmol) were dissolved in dioxane: water (1:1) (200 mL) and the reaction stirred at 25℃for 1 hour. The liquid quality detection reaction is complete. The reaction mixture was adjusted to ph=3 with dilute hydrochloric acid (1M), and a solid was precipitated, and the resultant was dried by filtration to give the compound 2-chloro-3-fluoro-6-methyliisonicotinic acid (I-3-5, 14.90g,78.60mmol, yield: 88.90%) as a white solid. ¹H-NMR(400MHz,CDCl₃)δ7.60(d,J＝4.4Hz,1H),2.59(d,J＝0.8Hz,3H).ESI[M+H]⁺ = 189.9

Intermediate I-3-6: synthesis of tert-butyl (2-chloro-3-fluoro-6-methylpyridin-4-yl) carbamate (I-3-6)

2-Chloro-3-fluoro-6-methyliisonicotinic acid ((2.1 g,11.1 mmol) was dissolved in tert-butanol (150 mL), triethylamine (3.36 g,33.3 mmol) and diphenyl azide phosphate (6.1 g,22.2 mmol) were added and reacted at 80℃for 16 hours, silica gel plates (petroleum ether: ethyl acetate=3:1) were stirred to detect completion of the reaction, the reaction solution was poured into water (50 mL), ethyl acetate was extracted (20 mL) three times, the organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated by column chromatography (eluent: petroleum ether: ethyl acetate=1:5) to give tert-butyl (I-3-6, 2.0g,7.69mmol, yield: 72.9%) of the compound (2-chloro-3-fluoro-6-methylpyridin-4-yl) as a white solid ESI [ M+H ] + = 203.9,261.0

Intermediate I-3-7: synthesis of 2-chloro-3-fluoro-6-methylpyridin-4-amine (I-3-7)

Tert-butyl (2-chloro-3-fluoro-6-methylpyridin-4-yl) carbamate (2.0 g,7.69 mmol) was dissolved in E dichloromethane (20 mL), and trifluoroacetic acid (4 mL) was added and stirred at room temperature for 2 hours. Silica gel plate (petroleum ether: ethyl acetate=3:1) was examined for reaction completion. The reaction solution was poured into saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL) three times, the organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated and purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give compound 2-chloro-3-fluoro-6-methylpyridin-4-amine (I-3-7, 1.1g,6.87mmol, yield: 84.6%) as a gray solid. ESI [ m+h ] += 161.0

Intermediate I-3-8: synthesis of 2-chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (I-3-8)

2-Chloro-3-fluoro-6-methylpyridin-4-amine (28 g,174.37 mmol), p-toluenesulfonic acid (1.66 g,8.72 mmol) was added to acetonitrile (300 mL) and N-iodosuccinimide (47.08 g,209.25 mmol) was slowly added. The reaction was stirred for 12 hours under nitrogen protection at 70 ℃ until the reaction was completed, the reaction liquid was cooled to room temperature, quenched in saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, and separated by column chromatography (tetrahydrofuran/petroleum ether=5-15%) to give 2-chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (I-3-8, 44.00g,150.38mmol,86.24% yieldd) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d 6) delta 6.53 (s, 2H), 2.46 (d, J=1.1 Hz, 3H), ESI [ M+H ] += 286.80

Intermediate I-3-9: synthesis of 4-amino-6-chloro-5-fluoro-2-methylnicotinic acid ethyl ester (I-3-9)

2-Chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (54 g,188.50 mmol), triethylamine (95.37 g,942.50 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (15.39 g,18.85 mmol) were added to EtOH (500 mL), stirred for 12 hours under carbon monoxide atmosphere, liquid was detected to show complete reaction of the starting materials, cooled to room temperature, solvent was removed by rotary evaporation, and column chromatography was carried out to give ethyl 4-amino-6-chloro-5-fluoro-2-methylnicotinate (I-3-9, 35.00g, crude product) as a white solid .1HNMR(400MHz,DMSO-d6)δ7.03(s,2H),4.29(q,J＝7.1Hz,2H),2.38(d,J＝1.0Hz,3H),1.27(t,J＝7.1Hz,3H),ESI[M+H]+＝233.1

Intermediate I-3-10: synthesis of 6-chloro-5-fluoro-2-methyl-4- (3- (2, 2-trichloroacetyl) ureido) nicotinic acid ethyl ester (I-3-10)

4-Amino-6-chloro-5-fluoro-2-methylnicotinic acid ethyl ester (22 g,100.63 mmol) was dissolved in tetrahydrofuran (300 mL), and 2, 2-trichloroacetyl isocyanate (26.54 g,140.89 mmol) was slowly added dropwise. After the addition, the mixture was stirred and reacted at 20℃for 0.5 hour, the liquid was examined to show that the raw materials were reacted completely, the solvent was removed by rotary evaporation, and the residue was slurried with methyl tert-butyl ether to give ethyl 6-chloro-5-fluoro-2-methyl-4- (3- (2, 2-trichloroacetyl) ureido) nicotinate (I-310, 35.00g,83.13mmol,82.60% yield) as a white solid .1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.06(s,1H),4.26(q,J＝7.0Hz,2H),2.47(s,3H),1.23(s,3H),ESI[M+H]+＝422.0

Intermediate I-3-11: synthesis of 7-chloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine-2, 4-dione (I-3-11)

Ethyl 6-chloro-5-fluoro-2-methyl-4- (3- (2, 2-trichloroacetyl) ureido) nicotinate (40 g,95.00 mmol) is dissolved in methanol (500 mL), ammonia methanol solution (35 mL) is added dropwise, the mixture is stirred at 20 ℃ for 1 hour after the addition, white solid is separated out, the reaction solution is filtered, and the filtered solid is beaten by methyl tert-butyl ether to obtain the compound 7-chloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine-2, 4-dione (I-3-11, 20.00g, crude product) as white solid. ESI [ m+h ] +=230.1

Intermediate I-3: synthesis of 2,4, 7-trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (I-3)

7-Chloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine-2, 4-dione (20 g,87.11 mmol), N, N-diisopropylethylamine (37.15 g,287.46 mmol) was added to toluene (400 mL), and phosphorus oxychloride (44.08 g,287.46 mmol) was slowly added dropwise. After the addition of nitrogen, the temperature is raised to 100 ℃ and the stirring reaction is carried out for 12 hours, liquid detection shows that the raw materials are basically reacted completely, the solvent is removed by rotary evaporation of the reaction liquid, and the residue is separated by column chromatography (tetrahydrofuran/petroleum ether=5-15%), so as to obtain 2,4, 7-trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (I-3, 10.50g,38.37mmol, 44.05%) as white solid. 1H NMR (400 MHz, chloroform-d) δ3.21 (d, J=1.7Hz, 3H), ESI [ M+H ] += 267.80

Example 1: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and 4-methylpiperidin-4-ol (46 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting the organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -5%) to obtain target product 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-a, 64mg, yield 48.9%). ESI [ m+h ] ⁺ =331.2

And a second step of: synthesis (1-b) of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol

1- (2, 7-Dichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (50 mg,0.15 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (1-a, 48mg,0.3 mmol) and cesium carbonate (98 mg,0.3 mmol) were added to chloroform (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-b, 13mg, yield 19.1%). ESI [ m+h ] ⁺ = 454.3

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-b, 13mg,0.03 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (15 mg,0.03 mmol), potassium phosphate (19 mg,0.09 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (2 mg, 0.003mmol) was dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-c, 10mg, yield 43.7%). ESI [ m+h ] ⁺ =804.6

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-c, 10mg,0.01 mmol) was dissolved in N, N-dimethylformamide (1 ml), cesium fluoride (15 mg,0.1 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-d, 7mg, yield 87.5%). ESI [ m+h ] ⁺ = 648.3

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol trifluoroacetate (1)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-4-ol (1-d, 7mg,0.01 mmol) was dissolved in acetonitrile (1 ml), and trifluoroacetic acid (0.2 ml) was added and reacted at room temperature for 16 hours. The reaction solution is separated and purified by preparative liquid chromatography to obtain the target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- ((((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidine-4-yl) -4-methylpiperidin-4-ol (1, 5.1mg, yield) 78.5％).ESI[M+H]⁺＝604.3¹H NMR(400MHz,CD₃OD)δ9.06(s,1H),7.92–7.85(m,1H),7.42–7.29(m,2H),7.23(s,1H),5.64(s,1H),5.51(s,1H),4.77–4.60(m,2H),4.55–4.41(m,2H),4.12–3.81(m,5H),3.52–3.44(m,1H),3.42(d,J＝5.5Hz,1H),2.73–2.56(m,2H),2.48–2.40(m,1H),2.39–2.27(m,2H),2.21–2.12(m,1H),1.91–1.80(m,3H),1.35(s,3H).

Example 2: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (2)

The first step: synthesis of 4- (4- ((tert-butyldiphenylsilyl) oxy) piperidin-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (2-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (150 mg,0.6 mmol) was dissolved in dichloromethane (4 ml) and cooled to 0℃N, N-diisopropylethylamine (77 mg,0.6 mmol) and 4- ((tert-butyldiphenylsilane) oxy) piperidine (202 mg,0.6 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -5%) to obtain target product 4- (4- ((tert-butyl diphenyl silicon based) oxy) piperidin-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (2-a, 117mg, yield 35.3%).

And a second step of: synthesis (2-b) of 4- (4- ((tert-butyldiphenylsilicon) oxy) piperidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine

4- (4- ((Tert-Butyldiphenylsilyl) oxy) piperidin-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (2-a, 115mg,0.2 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (48 mg,0.3 mmol) and cesium carbonate (65 mg,0.2 mmol) were added to chloroform (4 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -10%) to obtain target product 4- (4- ((tert-butyl diphenyl silicon) oxy) piperidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidine (2-b, 90mg, yield 64.3%). ESI [ m+h ] ⁺ = 678.4

And a third step of: synthesis (2-c) of 4- (4- ((tert-butyldiphenylsilyl) oxy) piperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine

4- (4- ((Tert-Butyldiphenylsilicon) oxy) piperidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (2-b, 70mg,0.1 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (51 mg,0.1 mmol), potassium phosphate (64 mg,0.3 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (7 mg,0.01 mmol) was dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 4- (4- ((tert-butyldiphenylsilyl) oxy) piperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (2-c, 75mg, yield 71%). ESI [ m+h ] ⁺ = 1028.4

Fourth step: synthesis (2-d) of 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-4-ol

4- (4- (Tert-Butyldiphenylsilyl) oxy) piperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (2-c, 75mg,0.07 mmol) was dissolved in N, N-dimethylformamide (1 ml), cesium fluoride (106 mg,0.7 mmol) was added and reacted at room temperature for 48 hours. The reaction solution was separated and purified by preparative chromatography to give the objective 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (2-d, 41mg, yield 89.1%). ESI [ m+h ] ⁺ = 634.3

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (2)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (41 mg,0.06 mmol) was dissolved in 1, 4-dioxane (2 ml) and ice-bath added to 1, 4-dioxane hydrochloride solution (1 ml). Slowly return to room temperature and react for 1h. The reaction solution is separated and purified by preparative liquid chromatography to obtain the target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (2, 11mg, yield) 21.6％).ESI[M+H]⁺＝590.3,¹H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.99(s,1H),8.04–7.89(m,1H),7.57–7.33(m,2H),7.24–7.11(m,1H),5.34(s,1H),5.21(s,1H),4.96–4.85(m,1H),4.33–3.81(m,6H),3.74–3.58(m,2H),3.16–2.98(m,3H),2.88–2.73(m,1H),2.21–1.69(m,8H),1.70–1.50(m,2H).

Example 3: synthesis of 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (3)

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The first step: synthesis of 2, 7-dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (3-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and 4, 4-difluoropyridine (48 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (3-a, 86mg, yield 67.2%).

And a second step of: synthesis (3-b) of 7-chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine

2, 7-Dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (3-a, 76mg,0.23 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (54 mg,0.34 mmol), potassium carbonate (95 mg,0.69 mmol) was added to chloroform (2 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 7-chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (3-b, 65mg, yield 63.1%). ESI [ m+h ] ⁺ = 460.2

And a third step of: synthesis (3-c) of 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine

7-Chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (3-b, 30mg,0.07 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (40 mg,0.08 mmol), potassium phosphate (41 mg,0.2 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (5 mg,0.007 mmol) was dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilylethynyl) naphthalen-1-yl) -2- (2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (3-c, 28mg, 53% yield). ESI [ m+h ] ⁺ = 810.4

Fourth step: synthesis (3-d) of 4- (4, 4-difluoropiperidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine

4- (4, 4-Dihalopiperidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (3-c, 28mg,0.03 mmol) was dissolved in N, N-dimethylformamide (1 ml), cesium fluoride (28 mg,0.18 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 4- (4, 4-difluoropiperidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidine (3-d, 17mg, 75% yield). ESI [ m+h ] ⁺ =654.3

Fifth step: synthesis of 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (3)

4- (4, 4-Dihalopiperidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (3-d, 17mg,0.03 mmol) was dissolved in acetonitrile (1 ml), and trifluoroacetic acid (0.2 ml) was added and reacted at room temperature for 16 hours. The reaction solution is separated and purified by preparative liquid chromatography to obtain a target product 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (3, 4mg, yield) 26.1％).ESI[M+H]⁺＝610.3,¹H NMR(400MHz,CD₃OD)δ9.01(s,1H),7.84(dd,J＝9.2,5.7Hz,1H),7.38–7.24(m,2H),7.22–7.11(m,1H),5.38–5.34(m,1H),5.24–5.20(m,1H),4.35–4.22(m,2H),4.17–4.09(m,4H),3.44–3.33(m,1H),3.07–2.95(m,1H),2.34–2.18(m,6H),2.17–1.80(m,5H),1.41–1.17(m,2H).

Example 4: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (4)

The first step: synthesis of 2, 7-dichloro-8-fluoro-4- (4-fluoropiperidin-1-yl) pyrido [4,3-d ] pyrimidine (4-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (51 mg,0.4 mmol) and 4-fluoropiperidine (41 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-8-fluoro-4- (4-fluoropiperidin-1-yl) pyrido [4,3-d ] pyrimidine (4-a, 80mg, yield 63.5%).

And a second step of: synthesis of 7-chloro-8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (4-b)

2, 7-Dichloro-8-fluoro-4- (4-fluoropiperidin-1-yl) pyrido [4,3-d ] pyrimidine (4-a, 76mg,0.24 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (76 mg,0.48 mmol) and cesium carbonate (156 mg,0.48 mmol) were added to chloroform (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (4-b, 44mg, yield 41.9%). ESI [ m+h ] ⁺ =443.1

And a third step of: synthesis of 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (4-c)

7-Chloro-8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (4-b, 44mg,0.1 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (77 mg,0.15 mmol), potassium phosphate (64 mg,0.3 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (15 mg,0.02 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoropiperidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (4-c, 64mg, 81% yield). ESI [ m+h ] ⁺ = 792.4

Fourth step: synthesis of 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (4-d)

8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (4-c, 64mg,0.08 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (121 mg,0.8 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective product 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (4-d, 42mg, yield 82%). ESI [ m+h ] ⁺ =636.5

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (4)

7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (4-d, 40mg,0.06 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane solution (0.2 ml) of hydrochloric acid was added to the solution in ice bath for reaction for 1 hour. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoropiperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (4, 19.8mg, yield) 54％).ESI[M+H]⁺＝592.6 ¹H NMR(400MHz,DMSO-d₆)δ10.88(s,1H),10.25(s,1H),9.11(s,1H),8.02–7.96(m,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.4Hz,1H),7.20(d,J＝2.2Hz,1H),5.66–5.61(m,1H),5.53–5.49(m,1H),5.20–5.08(m,1H),5.08–4.94(m,1H),4.67–4.55(m,2H),4.06–4.00(m,3H),3.95(s,1H),3.93–3.70(m,4H),2.62–2.53(m,1H),2.36–2.29(m,1H),2.25–1.92(m,8H).

Example 5: synthesis of (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol trifluoroacetate (5)

The first step: synthesis of (S) -1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to-40 ℃, N-diisopropylethylamine (52 mg,0.4 mmol) and (S) -pyrrolidin-3-ol (38 mg,0.4 mmol) were added and reacted at-40℃for 0.5 hours. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) is purified to obtain target product (S) -1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidine-4-yl) pyrrolidin-3-ol (5-a, 114mg, yield 94.21%). ESI [ m+h ] ⁺ = 303.5, 305.2

And a second step of: synthesis (5-b) of (S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol

(S) -1- (2, 7-dichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-a, 100mg,0.33 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (426 mg,3.3 mmol), cesium carbonate (178 mg,1.65 mmol), potassium carbonate (69 mg,0.5 mmol) was added to acetonitrile (5 ml). The temperature is raised to 80 ℃ to react for 16h. The reaction was taken up in water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and TLC (methanol: dichloromethane=10:1) was purified to give the target product (S) -1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-b, 45.8mg, yield 32.48%). ESI [ m+h ] ⁺ = 426.5, 428.5

And a third step of: synthesis of (S) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-c)

(S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-b, 45mg,0.11 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (141 mg,0.275 mmol), potassium phosphate (47 mg,0.22 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (15 mg,0.02 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to give the target product (S) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-c, 25mg, yield 29%). ESI [ m+h ] ⁺ = 776.7, 777.7

Fourth step: synthesis (5-d) of (S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol

(S) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-c, 25mg,0.032 mmol) was dissolved in N, N-dimethylformamide, 2 ml), cesium fluoride (29 mg,0.19 mmol) was added and reacted at 25℃for 1 hour. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give (S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-d, 20mg, yield 100%) as the target product. ESI [ m+h ] ⁺ = 620.5, 621.5

Fifth step: synthesis of (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol trifluoroacetate (5)

(S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (5-d, 20mg,0.03 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (1 ml) was added at 25℃and reacted for 0.5H. The reaction solution was separated and purified by preparative liquid chromatography to give the objective (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol trifluoroacetate (5, 14.38mg, yield 69.50％).ESI[M+H]⁺＝576.7,¹H NMR(400MHz,DMSO-d₆)δ10.91(s,1H),10.20(s,1H),9.27(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.45(t,J＝9.0Hz,1H),7.38(d,J＝2.6Hz,1H),7.19–7.14(m,1H),5.61(s,1H),5.48(s,1H),4.59(t,J＝10.9Hz,2H),4.08(d,J＝6.3Hz,1H),3.95–3.87(m,2H),3.85–3.80(m,2H),3.74(d,J＝6.0Hz,3H),3.34–3.21(m,2H),2.52(d,J＝5.1Hz,1H),2.45(s,1H),2.29(d,J＝12.9Hz,2H),2.18–1.99(m,5H).

Example 6: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol trifluoroacetate (6)

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The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to-40 ℃, N-diisopropylethylamine (52 mg,0.4 mmol) and 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (40 mg,0.4 mmol) were added and reacted at room temperature for 0.5 hours. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) is purified to obtain target product 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-a, 120mg, yield 94.49%). ESI [ m+h ] ⁺ =317.2, 319.2

And a second step of: synthesis (6-b) of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol

1- (2, 7-Dichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-a, 100mg,0.32 mmol) cesium carbonate (521 mg,1.6 mmol) tansuanj (66 mg,0.48 mmol) was added to acetonitrile (5 ml). The temperature is raised to 80 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by TLC (methanol: dichloromethane=10:1) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-b, 20mg, yield 14.18%). ESI [ m+h ] ⁺ =440.5

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-b, 20mg,0.045 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (58 mg,0.113 mmol), potassium phosphate (19 mg,0.09 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (7 mg,0.01 mmol) was dissolved in 1, 4-dioxane (1 ml) and water (0.1 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. After concentration under reduced pressure TLC (methanol: dichloromethane=10:1) purification afforded target 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-c, 23mg, yield 64.7%). ESI [ m+h ] ⁺ = 790.8, 791.8

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-c, 23mg,0.03 mmol) was dissolved in N, N-dimethylformamide (2 ml) cesium fluoride (26 mg,0.17 mmol) was added, the reaction mixture was reacted for 1 hour at 25℃with water, ethyl acetate was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the desired product 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (26 mg,0.17 mmol) in water, ethyl acetate, water was added, and the desired product was obtained by distillation under reduced pressure as one of (16H) and was prepared as one of the following steps of preparation

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol trifluoroacetate (6)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (6-d, 19mg,0.03 mmol) was dissolved in acetonitrile (2.5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added and reacted at 25℃for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol trifluoroacetate (6, 13.50mg, yield 63.95％).ESI＝[M+H]⁺590.5.¹H NMR(400MHz,DMSO-d₆)δ10.93(s,1H),10.21(s,1H),9.25(d,J＝32.1Hz,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.45(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.16(dd,J＝14.7,2.6Hz,1H),5.61(d,J＝4.0Hz,1H),5.48(t,J＝3.0Hz,1H),4.56(q,J＝12.0,11.5Hz,2H),4.09(d,J＝6.8Hz,1H),3.90(d,J＝13.4Hz,2H),3.85–3.80(m,2H),3.76–3.70(m,3H),3.30–3.25(m,1H),2.54(d,J＝3.8Hz,1H),2.45(s,1H),2.33–2.22(m,2H),2.18–2.11(m,2H),2.05–1.92(m,3H),1.42(d,J＝2.7Hz,3H).

Example 7: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (7)

The first step: synthesis of (R) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (7-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and (R) -3-fluoropyrrolidine (36 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -5%) to give the desired product (R) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (7-a, 78mg, yield 64.5%).

And a second step of: synthesis of 7-chloro-8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-b)

(R) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (7-a, 78mg,0.25 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (60 mg,0.38 mmol) and cesium carbonate (82 mg,0.25 mmol) were added to chloroform (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase and backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-b, 52mg, yield 47.7%). ESI [ m+h ] ⁺ = 428.4

And a third step of: synthesis of 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-c)

7-Chloro-8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-b, 52mg,0.12 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (61 mg,0.12 mmol), potassium phosphate (76 mg,0.36 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (15 mg,0.02 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating Flash column (methanol: dichloromethane=0% -10%) to obtain target product 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-c, 60mg, yield 63.8%). ESI [ m+h ] ⁺ =778.5

Fourth step: synthesis of 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-d)

8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-c, 60mg,0.08 mmol) was dissolved in N, N-dimethylformamide (2 ml) and cesium fluoride (121 mg,0.8 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective product 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-d, 38mg, yield 79.1%). ESI [ m+h ] ⁺ = 622.6

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (7)

7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (7-d, 36mg,0.06 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.4 ml) was added to the ice bath for 1 hour. Separating and purifying the reaction liquid by a preparative liquid chromatography to obtain a target product of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (7, 13mg, yield) 39.4％).ESI[M+H]⁺＝578.5 ¹H NMR(400MHz,DMSO-d₆)δ10.99(s,1H),10.26(s,1H),9.40–9.25(m,1H),7.99(dd,1H),7.53–7.37(m,2H),7.19(dd,1H),5.67–5.59(m,1H),5.54–5.46(m,1H),4.68–4.56(m,2H),4.35–4.09(m,3H),4.00(s,1H),3.93–3.73(m,4H),3.36–3.15(m,2H),2.61–2.53(m,1H),2.39–2.27(m,2H),2.24–2.00(m,4H).

Example 8: synthesis of 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (8)

The first step: synthesis of 2, 7-dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (8-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and 3, 3-difluoropyrrolidine (43 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (8-a, 115mg, yield 89.8%).

And a second step of: synthesis of 7-chloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (8-b)

2, 7-Dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (8-a, 115mg,0.36 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (57 mg,0.36 mmol) and cesium carbonate (117 mg,0.36 mmol) were added to chloroform (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-4- (3, 3-difluoro pyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluoro tetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidine (8-b, 104mg, yield 65.8%). ESI [ m+h ] ⁺ = 446.5

And a third step of: synthesis of 4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-c)

7-Chloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (8-b, 85mg,0.19 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (97 mg,0.19 mmol), potassium phosphate (120 mg,0.57 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (28 mg,0.04 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, then purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 4- (3, 3-difluoro-pyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropyl silicon) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluoro tetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-c, 141mg, yield 92.7%). ESI [ m+h ] ⁺ = 796.4

Fourth step: synthesis of 4- (3, 3-difluoropyrrolidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-d)

4- (3, 3-Difluoropyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-c, 141mg,0.17 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (129 mg,0.85 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective 4- (3, 3-difluoropyrrolidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-d, 90mg, yield 79.6%). ESI [ m+h ] ⁺ = 640.5

Fifth step: synthesis of 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (8)

4- (3, 3-Difluoropyrrolidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (8-d, 80mg,0.13 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added to the ice bath for reaction for 1 hour. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (8, 20mg, yield) 27％).ESI[M+H]⁺＝596.5,¹H NMR(400MHz,DMSO-d₆)δ10.97(s,1H),10.26(s,1H),9.29(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.51–7.39(m,2H),7.19(d,J＝2.5Hz,1H),5.67–5.62(m,1H),5.53–5.48(m,1H),4.69–4.56(m,2H),4.52–4.20(m,4H),3.96–3.89(m,1H),3.88–3.73(m,3H),3.33–3.29(m,1H),2.72–2.60(m,2H),2.59–2.53(m,1H),2.37–2.27(m,1H),2.25–1.94(m,4H).

Example 9: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (9)

The first step: synthesis of (R) -1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (9-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and (R) -pyrrolidin-3-ol were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -5%) to obtain target product (R) -1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (9-a, 112mg, yield 93.3%).

And a second step of: synthesis of (R) -4- (3- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-1-yl) -2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidine (9-b)

(R) -1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (9-a, 100mg,0.33 mmol), tert-butyldiphenylchlorosilane (181 mg,0.66 mmol), imidazole (45 mg,0.66 mmol) was added to dichloromethane (4 ml) and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying Flash column (methanol: dichloromethane=0% -5%) to obtain target product (R) -4- (3- ((tert-butyl diphenyl silicon base) oxy) pyrrolidin-1-yl) -2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidine (9-b, 144mg, yield 80.4%).

And a third step of: synthesis of 4- ((R) -3- ((tert-butyldiphenylsiloxy) pyrrolidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine) (9-c)

(R) -4- (3- ((tert-Butyldiphenylsilyl) oxy) pyrrolidin-1-yl) -2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidine (9-b, 144mg,0.27 mmol) ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (86 mg,0.54 mmol) and potassium carbonate (76 mg,0.54 mmol) were added to chloroform (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -10%) to obtain target product 4- ((R) -3- ((tert-butyldiphenylsiloxy) pyrrolidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (9-c, 45mg, yield 25.6%). ESI [ M+H ] ⁺ = 664.5

Fourth step: synthesis of 4- ((R) -3- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (9-d)

4- ((R) -3- ((tert-Butyldiphenylsiloxy) pyrrolidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (9-c, 45mg,0.07 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (36 mg,0.07 mmol), potassium phosphate (45 mg,0.21 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (10 mg,0.014 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml) nitrogen was replaced 3 times, reacted to 60℃for 16H, sodium chloride was added, and the aqueous solution was quenched with anhydrous sodium chloride, dried, saturated aqueous solution was quenched by heat-washing, after concentrating under reduced pressure, the Flash column (methanol: dichloromethane=0% -10%) is purified to obtain the target product 4- ((R) -3- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (9-d, 47mg, yield 69.1%). ESI) [ m+h ] ⁺ =1014.5

Fifth step: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) pyrrolidine (9-e)

4- ((R) -3- ((tert-Butyldiphenylsilyl) oxy) pyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (9-d, 45mg,0.05 mmol) was dissolved in N, N-dimethylformamide (2 ml) and cesium fluoride (76 mg,0.5 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was separated and purified by preparative chromatography to give the objective product (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) pyrrolidine (9-e, 27mg, yield 95%). ESI [ m+h ] ⁺ = 620.4

Sixth step: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-ol (9)

(R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) pyrrolidine (9-e, 25mg,0.04 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.2 ml) was added to the ice bath to react for 1 hour. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidine-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidine-4-yl) pyrrolidin-3-ol (9, 6.5mg, yield 28.3％).ESI[M+H]⁺＝576.3¹H NMR(400MHz,DMSO-d₆)δ10.15(s,1H),9.22(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.54–7.33(m,2H),7.17(dd,J＝12.4,2.5Hz,1H),5.35(s,1H),5.26–5.10(m,2H),4.47(s,1H),4.18–3.70(m,6H),3.09(d,J＝9.8Hz,2H),3.02(s,1H),2.88–2.78(m,1H),2.19–1.93(m,6H),1.88–1.74(m,3H).

Example 10: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (10)

The first step: synthesis of (S) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (10-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (4 ml) and cooled to-40 ℃, N-diisopropylethylamine (77 mg,0.6 mmol) and (S) -3-fluoropyrrolidine hydrochloride (75 mg,0.6 mmol) were added and reacted at-40℃for 0.5 hours, and after concentrating under reduced pressure the Flash column (petroleum ether: ethyl acetate=2:1) was purified to give the target product (S) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (10-a, 80mg, 65.57%). ESI [ m+h ] ⁺ =305.1, 307.0

And a second step of: synthesis of 7-chloro-8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (10-b)

(S) -2, 7-dichloro-8-fluoro-4- (3-fluoropyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (10-a, 80mg,0.26 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (207 mg,1.3 mmol) and cesium carbonate (424 mg,1.3 mmol) were added to 1, 4-dioxane (5 ml). The temperature is raised to 80 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by TLC (methanol: dichloromethane=15:1) to give the target product 7-chloro-8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (10-b, 50mg, yield 45.05%). ESI [ m+h ] ⁺ =428.2, 430.2

And a third step of: synthesis of 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (10-c)

7-Chloro-8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (10-b, 50mg,0.12 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (154 mg,0.3 mmol), potassium phosphate (51 mg,0.24 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (17 mg,0.024 mmol) was dissolved in 1, 4-dioxane (4 ml) and water (0.4 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by TLC (methanol: dichloromethane=10:1) to give the target product 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (10-c, 14mg, yield 18.67%).

Fourth step: synthesis of 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (10-d)

8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-c, 14mg,0.022 mmol) was dissolved in N, N-dimethylformamide (1 ml), cesium fluoride (20 mg,0.13 mmol) was added and reacted at 25℃for 0.5H. The reaction solution was added with water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the objective 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (10-d, 13mg, yield 95.03%). ESI [ m+h ] ⁺ =622.3, 623.3

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (10)

7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (10-d, 13mg,0.02 mmol) was dissolved in acetonitrile (5 ml) and 1, 4-dioxane hydrochloride solution (0.5 ml) was added. The reaction was carried out at 25℃for 0.5h. The reaction mixture was separated and purified by preparative liquid chromatography to give the desired product 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((S) -3-fluoropyrrolidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (10, 6.48mg, yield 46.85％).ESI[M+H]⁺＝578.3¹H NMR(400MHz,DMSO-d₆)δ10.92(s,1H),10.21(s,1H),9.31(d,J＝13.6Hz,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.44(d,J＝9.0Hz,1H),7.39(d,J＝2.5Hz,1H),7.16(dd,J＝13.2,2.5Hz,1H),5.61(s,1H),5.48(s,1H),4.67–4.53(m,2H),4.18(q,J＝38.9,35.9Hz,3H),3.97(s,1H),3.89–3.68(m,4H),3.34–3.24(m,2H),2.53(d,J＝8.8Hz,1H),2.46(s,1H),2.34–2.24(m,2H),2.16(h,J＝7.5,6.6Hz,2H),2.08–1.97(m,1H). example 11: synthesis of 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (11)

The first step: synthesis of 2, 7-dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (11-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 50mg,0.2 mmol) was dissolved in dichloromethane (5 ml), N-diisopropylethylamine (26 mg,0.2 mmol) and 4, 4-difluoropyridine (24 mg,0.2 mmol) were added and reacted at 25℃for 0.5 hours. After concentrating under reduced pressure, flash column (petroleum ether: ethyl acetate=2:1) was purified to give the objective 2, 7-dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (11-a, 90mg, yield 100%).

And a second step of: synthesis of 7-chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (11-b)

2, 7-Dichloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (11-a, 90mg,0.27 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (207 mg,1.3 mmol) and cesium carbonate (264 mg,0.81 mmol) were added to 1, 4-dioxane (5 ml). After heating to 80 ℃ for 16H, the target product 7-chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (11-b, 60mg, yield 48.39%) was purified by TLC (methanol: dichloromethane=10:1) after concentration under reduced pressure. ESI [ m+h ] ⁺ = 460.2, 462.2

And a third step of: synthesis of 4- (4, 4-difluoropiperidin-1-yl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (11-c)

7-Chloro-4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidine (11-b, 60mg,0.13 mmol), 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde (94 mg,0.26 mmol), potassium phosphate (55 mg,0.26 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (22 mg,0.03 mmol) was dissolved in tetrahydrofuran (3 ml) and water (0.3 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. After concentration under reduced pressure TLC (methanol: dichloromethane=10:1) purified the target product 4- (4, 4-difluoropiperidin-1-yl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (11-c, 75mg, yield 88.24%). ESI [ m+h ] ⁺ = 658.4, 659.4

Step 4: synthesis of 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (11)

4- (4, 4-Dihalopiperidin-1-yl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (11-c, 75mg,0.114 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane (0.5 ml) hydrochloride was added and reacted at 25℃for 0.5 hours. The reaction solution is separated and purified by preparative liquid chromatography to obtain the target product 4- (4, 4-difluoropiperidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyridyl [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol (11, 41.93mg, yield) 59.94％).ESI[M+H]⁺＝614.6.¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),9.12(s,1H),7.79–7.71(m,1H),7.37–7.28(m,2H),7.00(d,J＝2.4Hz,1H),5.25(d,J＝52.5Hz,1H),4.14(dd,J＝10.4,4.2Hz,1H),4.06(d,J＝2.1Hz,1H),4.02(t,J＝4.2Hz,4H),3.06(d,J＝10.1Hz,2H),2.99(s,1H),2.81(t,J＝7.2Hz,1H),2.26(td,J＝13.9,7.0Hz,5H),2.12(d,J＝5.2Hz,2H),2.05–2.03(m,1H),1.98(s,1H),1.85–1.71(m,3H),0.70(d,J＝14.7Hz,3H).

EXAMPLE 12 preparation of 4- (4- (3- (chloromethyl) -3- (hydroxymethyl) azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (12)

The first step: synthesis of (12-a) methyl (3- (chloromethyl) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.6 mmol) was dissolved in dichloromethane (4 ml), N-diisopropylethylamine (77.4 mg,0.6 mmol), (3- (chloromethyl) azetidin-3-yl) methanol (81.4 mg,0.6 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product (3- (chloromethyl) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol (12-a, 130mg, yield 61.73%). ESI [ m+h ] ⁺ = 351.26.

And a second step of: synthesis of (12-b) methanol (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3- (chloromethyl) azetidin-3-yl)

(3- (Chloromethyl) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol (12-a, 130mg,0.37 mmol) was dissolved in chloroform (3 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (64.8 mg,0.407 mmol) was added, and cesium carbonate (241 mg,0.74 mmol) was reacted at room temperature for 16H. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product (1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3- (chloromethyl) azetidin-3-yl) methanol (12-b, 80mg, yield 45.71%). ESI [ m+h ] ⁺ = 474.21.

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (12-c)

(1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3- (chloromethyl) azetidin-3-yl) methanol (12-b, 80mg,0.169 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (86.5 mg,0.19 mmol), potassium phosphate (71.7 mg, 0.336 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (24.6 mg,0.0338 mmol) was added to the reaction flask. The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then Flash column (methanol: dichloromethane=0% -10%) was purified to give the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (12-c, 40mg, yield 28.78%). ESI [ m+h ] += 824.56.

Fourth step: synthesis of (12-d) methyl alcohol (3- (chloromethyl) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (12-c, 40mg,0.049 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (37 mg,0.243 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to give the objective product (3- (chloromethyl) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol (12-d, 15mg, yield 45.87%). ESI [ m+h ] ⁺ = 668.52.

Fifth step: synthesis of 4- (4- (3- (chloromethyl) -3- (hydroxymethyl) azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (12)

(3- (Chloromethyl) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) azetidin-3-yl) methanol (12-d, 15mg,0.022 mmol) was dissolved in acetonitrile (2 ml), and trifluoroacetic acid (0.5 ml) was added to the solution for reaction for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the objective product 4- (4- (3- (chloromethyl) -3- (hydroxymethyl) azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (12, 1.68mg, yield) 12.26％).ESI[M+H]⁺＝624.08,¹H NMR(400MHz,DMSO-d₆)δ9.42(s,1H),8.41(s,1H),7.96(dd,J＝9.2,5.9Hz,1H),7.51–7.37(m,2H),7.22–7.15(m,1H),5.35(s,1H),5.21(s,1H),4.78(d,J＝6.5Hz,2H),4.44(d,J＝13.0Hz,1H),4.32–4.22(m,2H),4.18–3.97(m,4H),3.12–2.98(m,4H),2.86–2.79(m,1H),2.16–2.10(m,1H),2.07–1.99(m,2H),1.93(d,J＝9.0Hz,1H),1.87–1.75(m,3H).

Example 13: 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (13)

The first step: synthesis of 2, 7-dichloro-8-fluoro-4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (51 mg,0.4 mmol) and 3, 4-tetrafluoropyrrolidine (72 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-8-fluoro-4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-a, 118mg, yield 82.5%).

And a second step of: synthesis of 7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-b)

2, 7-Dichloro-8-fluoro-4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-a, 118mg,0.33 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (105 mg,0.66 mmol) and cesium carbonate (108 mg,0.33 mmol) were added to chloroform (4 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-b, 138mg, yield 87.3%). ESI [ m+h ^]+ =482.5

And a third step of: synthesis of 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-c)

7-Chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-b, 48mg,0.1 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (51 mg,0.1 mmol), potassium phosphate (64 mg,0.3 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (15 mg,0.02 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, then purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluoro tetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-c, 78mg, yield 94%). ESI [ m+h ] ⁺ =832.6

Fourth step: synthesis of 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-d)

8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (78 mg,0.09 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (68 mg,0.45 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective product 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (13-d, 60mg, yield 94.8%). ESI [ m+h ] ⁺ =676.3

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (13)

7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridine [4,3-d ] pyrimidine (40 mg,0.06 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.4 ml) was added to the ice bath to react for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -4- (3, 4-tetrafluoropyrrolidin-1-yl) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (13, 10mg, yield 27％).ESI[M+H]⁺＝632.3¹H NMR(400MHz,CD₃OD)δ9.66–9.59(m,1H),8.93(s,1H),8.72(s,1H),8.29(dd,J＝9.1,5.8Hz,1H),7.82–7.71(m,2H),7.66–7.60(m,1H),5.87(s,1H),5.73(s,1H),5.22–5.11(m,3H),4.90–4.78(m,2H),3.93–3.77(m,3H),3.60–3.51(m,1H),2.90–2.60(m,4H),2.57–2.35(m,4H).

Example 14:4- (4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (14)

The first step: synthesis of 2, 7-dichloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (14-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (100 mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and 3, 3-difluorotrimethyleneimine hydrochloride (52 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-4- (3, 3-difluoro azetidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (14-a, 84mg, yield 68.3%).

And a second step of: synthesis of 7-chloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-b)

2, 7-Dichloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine (84 mg,0.27 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (86 mg,0.54 mmol) and cesium carbonate (88 mg,0.27 mmol) were added to chloroform (4 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-4- (3, 3-difluoro azetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluoro tetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-b, 94mg, yield 80.3%). ESI [ m+h ] ⁺ = 432.5

And a third step of: synthesis of 4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-c)

7-Chloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (94 mg,0.22 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxa-benzaldehyde-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (135 mg,0.26 mmol), potassium phosphate (140 mg,0.66 mmol), [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (32 mg,0.04 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating Flash column (methanol: dichloromethane=0% -10%) to obtain target product 4- (3, 3-difluoro azetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy) -8- (triisopropyl silicon-based) ethynyl) naphthalene-1-yl) -2- (2R, 7 aS) -2-fluoro tetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-c, 161mg, yield 94.6%). ESI [ m+h ] ⁺ = 782.4

Fourth step: preparation of 4- (3, 3-difluoroazetidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-d)

4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (160 mg,0.2 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (152 mg,1.0 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective 4- (3, 3-difluoroazetidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (14-d, 117mg, yield 92.1%). ESI [ m+h ] ⁺ = 626.3

Fifth step: preparation of 4- (4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (14)

4- (3, 3-Difluoroazetidin-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine (70 mg,0.11 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added to the solution in ice bath for 0.5 hours. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product 4- (4- (3, 3-difluoro azetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluoro tetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine-7-yl) -5-ethynyl-6-fluoro-naphthalene-2-ol (14, 7mg, yield) 10.7％).ESI[M+H]⁺＝582.3¹H NMR(400MHz,CD₃OD)δ8.88(s,1H),7.85(dd,J＝9.2,5.7Hz,1H),7.37–7.27(m,2H),7.24–7.17(m,1H),5.43–5.39(m,1H),5.29–5.25(m,1H),5.09–5.01(m,3H),4.42–4.29(m,2H),3.45–3.35(m,2H),3.15–3.02(m,1H),2.53–2.35(m,1H),2.35–2.24(m,2H),2.23–2.10(m,2H),2.09–1.86(m,4H).

Example 15: preparation of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (15)

The first step: synthesis of 6- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.6 mmol) was dissolved in methylene chloride (4 ml), N-diisopropylethylamine (77.4 mg,0.6 mmol) was added, and 2-oxa-6-azaspiro [3.3] heptane (59.5 mg,0.6 mmol) was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product 6- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-a, 135mg, yield 71.43%). ESI [ m+h ] ⁺ = 315.21.

And a second step of: synthesis of 6- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-b)

6- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-a, 135mg,0.429 mmol) was dissolved in chloroform (3 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (75 mg,0.471 mmol) was added, and cesium carbonate (279 mg,0.857 mmol) was reacted at room temperature for 16H. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product (1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3- (chloromethyl) azetidin-3-yl) methanol (15-b, 70mg, yield 37.43%). ESI [ m+h ] ⁺ = 438.25.

And a third step of: synthesis of 6- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-c)

(1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3- (chloromethyl) azetidin-3-yl) methanol (15-b, 70mg,0.160 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (81.9 mg,0.160 mmol), potassium phosphate (68 mg,0.320 mmol) methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (23 mg,0.032 mmol) was added to the reaction. The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 6- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-c, 15mg, yield 11.90%). ESI [ m+h ] += 788.85.

Fourth step: synthesis of 6- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-d)

6- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-c, 15mg,0.019 mmol) was dissolved in N, N-dimethylformamide (2 ml) and cesium fluoride (14.5 mg,0.095 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to give the objective product 6- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-d, 10mg, yield 83.33%). ESI [ m+h ] ⁺ = 632.51.

Fifth step: preparation of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (15)

6- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2-oxa-6-azaspiro [3.3] heptane (15-d, 10mg,0.0158 mmol) was dissolved in acetonitrile (2 ml), and trifluoroacetic acid (0.5 ml) was added to the solution to react for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol trifluoroacetate (15, 1.68mg, yield) 12.26％).ESI[M+H]⁺＝588.26.¹H NMR(400MHz,DMSO-d₆)δ9.42(s,1H),8.41(s,1H),7.96(dd,J＝9.2,5.9Hz,1H),7.51–7.37(m,2H),7.22–7.15(m,1H),5.35(s,1H),5.21(s,1H),4.78(d,J＝6.5Hz,2H),4.44(d,J＝13.0Hz,1H),4.32–4.22(m,2H),4.18–3.97(m,4H),3.12–2.98(m,4H),2.86–2.79(m,1H),2.16–2.10(m,1H),2.07–1.99(m,2H),1.87–1.75(m,3H).

Example 16:4- (4- (6-oxo-3-azabicyclo [3.1.1] heptan-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (16)

The first step: synthesis of 3- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (16-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (51 mg,0.4 mmol) and 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride (54 mg,0.4 mmol) were added and reacted at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying Flash column (methanol: dichloromethane=0% -5%) to obtain target product 3- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidine-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (16-a, 94mg, yield 75.2%).

And a second step of: synthesis of 3- (7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (16-b)

3- (2, 7-Dichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (94 mg,0.3 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (95 mg,0.6 mmol) and cesium carbonate (98 mg,0.3 mmol) were added to chloroform (4 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Water quenching, ethyl acetate extraction, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating, and purifying Flash column (methanol: dichloromethane=0% -10%) to obtain target product 3- (7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidine-7 a (5H) -group) methoxy) pyridine [4,3-d ] pyrimidine-4-group) -6-oxa-3-azabicyclo [3.1.1] heptane (16-b, 96mg, yield 73.8%). ESI [ m+h ] ⁺ = 438.6

And a third step of: synthesis of 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (16-c)

3- (7-Chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (96 mg,0.22 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (112 mg,0.22 mmol), potassium phosphate (140 mg,0.66 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (32 mg,0.04 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating Flash column (methanol: dichloromethane=0% -10%) to obtain target product 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluoro tetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (16-c, 116mg, yield 67%). ESI [ m+h ] ⁺ = 788.4

Fourth step: synthesis of 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1] heptane (16-d)

3- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1.1] heptane (116 mg,0.15 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (114 mg,0.75 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to give the objective product 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1] heptane (16-d, 85mg, yield 91.2%). ESI [ m+h ] ⁺ = 632.3

Fifth step: synthesis of 4- (4- (6-oxo-3-azabicyclo [3.1.1] heptan-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (16)

3- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -6-oxa-3-azabicyclo [3.1] heptane (60 mg,0.1 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added to the ice bath to react for 0.5 hours. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product 4- (4- (6-oxo-3-azabicyclo [3.1.1] heptane-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidine-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (16, 10.4mg, yield) 18.6％).ESI[M+H]⁺＝588.4¹H NMR(400MHz,DMSO-d₆)δ9.42(s,1H),8.41(s,1H),7.96(dd,J＝9.2,5.9Hz,1H),7.51–7.37(m,2H),7.22–7.15(m,1H),5.35(s,1H),5.21(s,1H),4.78(d,J＝6.5Hz,2H),4.44(d,J＝13.0Hz,1H),4.32–4.22(m,2H),4.18–3.97(m,4H),3.12–2.98(m,4H),2.86–2.79(m,1H),2.16–2.10(m,1H),2.07–1.99(m,2H),1.93(d,J＝9.0Hz,1H),1.87–1.75(m,3H).

Example 17: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17)

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The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (103 mg,0.8 mmol) and 3-methylazetidine-3-ol hydrochloride (49 mg,0.4 mmol) were added and reacted at 0℃for 10min. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) was purified to obtain the target product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-a, 123mg, yield 100%). ESI [ m+h ] ⁺ =303.1

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (123 mg,0.406 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (323 mg,2.03 mmol), cesium carbonate (661mg, 2.03 mmol) was added to 1, 4-dioxane (10 ml). The temperature is raised to 80 ℃ to react for 16h. Water was added to the reaction, ethyl acetate was used for extraction, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and TLC (methanol: dichloromethane=10:1) was used to purify the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-b, 71.6mg, yield 41.39%). ESI [ m+h ] ⁺ =426.2

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-b, 35mg,0.06 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (82 mg,0.16 mmol), potassium phosphate (34 mg,0.16 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (12 mg,0.016 mmol) was dissolved in 1, 4-dioxane (3 ml) and water (0.3 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 3 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to give the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-c, 21mg, yield 33.87%). ESI [ m+h ] ⁺ = 776.4

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-c, 20mg,0.026 mmol) was dissolved in N, N-dimethylformamide, (2 ml), cesium fluoride (24 mg,0.156 mmol) was added and reacted at 25℃for 0.5 hours. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give the objective product 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-d, 15 mg). ESI [ m+h ] ⁺ = 620.4

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17)

(1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17-d, 15mg,0.03 mmol) was dissolved in acetonitrile (5 ml), 1, 4-dioxane solution (0.5 ml) of hydrochloric acid was added at 25℃and the reaction solution was reacted for 0.5H, and the reaction solution was purified by preparative liquid chromatography to give the objective product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (17, 9.72mg, yield 57％).ESI[M+H]⁺＝576.3,¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),8.89(s,1H),7.95(dd,1H),7.44(t,1H),7.37(d,1H),7.16–7.11(m,1H),5.88(s,1H),5.35–5.15(m,1H),4.63(d,2H),4.33–4.04(m,3H),4.02–3.92(m,2H),3.07(d,2H),2.99(s,1H),2.80(q,1H),2.10(d,1H),2.04–1.95(m,2H),1.85–1.72(m,3H),1.49(s,3H).

Example 18: synthesis of 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.59 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (84 mg,0.649 mmol) and 3-methylpyrrolidin-3-ol (66 mg,0.65 mmol) were added and reacted at 0℃for 0.5h. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) was purified to obtain the target product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-a, 175mg, yield 93.58%).

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (100 mg,0.32 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (509 mg,10 mmol), cesium carbonate (521 mg,1.6 mmol) was added to 1, 4-dioxane (10 ml). The temperature is raised to 80 ℃ to react for 16h. Water was added to the reaction, extraction was performed with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane=10:1) to give the target product: 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-b, 104.7mg, 74.26% yield). ESI [ M+H ] ⁺ =440.0,

And a third step of: synthesis of 1- (7- (8-ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-b, 40mg,0.09 mmol), 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (65 mg,0.18 mmol), potassium phosphate (38 mg,0.18 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (13 mg, 0.018mmol) was dissolved in 1, 4-dioxane (3 ml) and water (0.3 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to give the target product 1- (7- (8-ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-c, 8mg, 14.04% yield). ESI [ m+h ] ⁺ = 638.49

Fourth step: synthesis of 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18)

1- (7- (8-Ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpyrrolidin-3-ol (18-c, 8mg,0.0125 mmol) was dissolved in acetonitrile (2 ml), and 1, 4-dioxane hydrochloride solution (0.2 ml) was added at 25℃and reacted for 0.5H. The reaction solution is separated and purified by preparative liquid chromatography to obtain a target product 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-4-yl) -3-methylpyrrolidin-3-ol (18, 3.58mg, yield) 48.25％).ESI[M+H]⁺＝594.4,¹H NMR(400MHz,DMSO-d₆)δ9.92(d,1H),9.25(d,1H),7.74(dd,1H),7.37–7.28(m,2H),6.99(dd,1H),5.26(d,1H),4.98(d,1H),4.13(d,2H),4.03(d,1H),3.81(d,2H),3.07(d,2H),2.99(s,1H),2.80(d,1H),2.33(q,1H),2.20–1.87(m,7H),1.84–1.72(m,3H),1.40(s,3H),0.70(q,3H).

Example 19: synthesis of 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.59 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (76 mg,0.59 mmol) and piperidin-4-ol (60 mg,0.59 mmol) were added and reacted at 0℃for 0.5h. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) was purified to obtain the target product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-a, 126mg, 67.38% yield).

And a second step of: preparation of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-a, 120mg,0.38 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (302 mg,1.9 mmol), cesium carbonate (612 mg,1.9 mmol) was added to 1, 4-dioxane (5 ml). The temperature is raised to 80 ℃ to react for 16h. The reaction was taken up in water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) was purified to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-b, 112mg, 67.07% yield). ESI [ m+h ] ⁺ =440.2, 442.2

And a third step of: synthesis of 1- (7- (8-ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-b, 110mg,0.25 mmol), 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (180 mg,0.5 mmol), potassium phosphate (106 mg,0.5 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (36 mg,0.05 mmol) was dissolved in 1, 4-dioxane (5 ml) and water (0.5 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by TLC (methanol: dichloromethane=10:1) to give the target product 1- (7- (8-ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-c, 30mg, 18.87% yield). ESI [ m+h ] ⁺ = 638.4

Fourth step: synthesis of 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19)

1- (7- (8-Ethyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-ol (19-c, 30mg,0.047 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added at 25℃and reacted for 0.5H. The reaction solution is separated and purified by preparative liquid chromatography to obtain the target product 1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-4-yl) piperidin-4-ol (19, 14.11mg, yield) 50.39％).ESI[M+H]⁺＝594.4,¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),9.04(s,1H),7.74(dd,1H),7.37–7.28(m,2H),7.00(d,1H),5.73(s,1H),5.25(d,1H),4.88(d,1H),4.25–4.16(m,2H),4.12(dd,1H),4.02(dd,1H),3.90–3.82(m,1H),3.67(d,2H),3.06(d,2H),2.99(s,1H),2.80(q,1H),2.38–2.26(m,1H),2.13–2.09(m,1H),2.03(d,1H),1.95(d,3H),1.85–1.71(m,3H),1.59(dd,2H),0.70(t,3H).

Example 20: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (103 mg,0.8 mmol) and piperidine-4-carbonitrile (44 mg,0.4 mmol) were added and reacted at 0℃for 10min. After concentrating under reduced pressure, the Flash column (methanol: dichloromethane=0% -5%) is purified to obtain the target product 1- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-a, 123mg, yield 100%). ESI [ m+h ] ⁺ = 326.1

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1-H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-b)

1- (2, 7-Dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-a, 132mg,0.406 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (323 mg,2.03 mmol), cesium carbonate (661mg, 2.03 mmol) was added to 1, 4-dioxane (10 ml). The temperature is raised to 80 ℃ to react for 16h. The reaction was taken up in water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) was purified to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1-H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-b, 71.6mg, 39.39% yield). ESI [ m+h ] ⁺ = 449.1

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1-H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-b, 28mg,0.06 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (82 mg,0.16 mmol), potassium phosphate (34 mg,0.16 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (12 mg,0.016 mmol) was dissolved in 1, 4-dioxane (3 ml) and water (0.3 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 3 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to afford the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-carbonitrile (20-c, 25mg, yield 33.87%). ESI [ m+h ] ⁺ = 799.4

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-c, 21mg,0.026 mmol) was dissolved in N, N-dimethylformamide, (2 ml), cesium fluoride (24 mg,0.156 mmol) was added and reacted at 25℃for 0.5 hours. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give the objective product 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20-d, 15 mg). ESI [ m+h ] ⁺ = 643.3

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20)

(1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylazetidin-3-ol (20-d, 15mg,0.03 mmol) was dissolved in acetonitrile (5 ml) and1, 4-dioxane solution (0.5 ml) was added at 25℃to the reaction solution, 0.5H the reaction solution was purified by preparative liquid chromatography to give the target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidine-4-carbonitrile (20, 7.6mg, yield 37％).ESI[M+H]⁺＝599.3,¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),8.89(s,1H),7.95(dd,1H),7.44(t,1H),7.37(d,1H),7.16–7.11(m,1H),5.88(s,1H),5.35–5.15(m,1H),4.63(d,2H),4.33–4.04(m,4H),4.02–3.92(m,2H),3.07(d,2H),2.99(s,1H),2.80(q,1H),2.10(d,1H),2.04–1.95(m,2H),1.85–1.72(m,3H),1.49(s,3H).

Example 21: synthesis of (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21)

The first step: synthesis of (S) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.59 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (153 mg,1.18 mmol) and (R) -piperidine-3-ol hydrochloride (98 mg,0.71 mmol) were added and reacted at 0℃for 0.5h. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) is purified to obtain target product (S) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-a, 160mg, yield 85.56%).

And a second step of: synthesis of (S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-b)

(S) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-a, 160mg,0.5 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (239 mg,1.5 mmol), cesium carbonate (815 mg,2.5 mmol) was added to 1, 4-dioxane (10 ml). The temperature is raised to 80 ℃ to react for 16h. Water was added to the reaction, ethyl acetate was used for extraction, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and TLC (methanol: dichloromethane=10:1) was used to purify the target product (S) -1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-b, 63mg, yield 28.64%). ESI [ M+H ] ⁺ =440.3,

And a third step of: synthesis of (S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-c)

(S) -1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-b, 60mg,0.14 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (143 mg,0.28 mmol), potassium phosphate (59 mg,0.28 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (22 mg,0.03 mmol) was dissolved in 1, 4-dioxane (3 ml) and water (0.3 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 3 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to give the target product (S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-c, 42mg, 37.84% yield). ESI [ m+h ] ⁺ = 790.56

Fourth step: synthesis of (S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-d)

(S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-c, 42mg,0.05 mmol) was dissolved in N, N-dimethylformamide, (2 ml) cesium fluoride (46 mg,0.3 mmol) was added and reacted at 25℃for 0.5 hours. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give (S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-d, 36 mg) as the target product. ESI [ m+h ] ⁺ = 634.4

Fifth step: synthesis of (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21)

(S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21-d, 36mg,0.03 mmol) was dissolved in acetonitrile (5 ml), and1, 4-dioxane hydrochloride solution (0.5 ml) was added at 25℃and reacted for 0.5H. The reaction solution is separated and purified by preparative liquid chromatography to obtain a target product (S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (21, 15.1mg, yield 85.36％).ESI[M+H]⁺＝590.3,¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),9.05(d,1H),7.95(dd,1H),7.44(t,1H),7.37(d,1H),7.18(dd,1H),5.26(d,1H),5.11(t,1H),4.16(dd,1H),4.09(dd,1H),4.00(dd,1H),3.94(d,2H),3.81(q,1H),3.72(d,1H),3.52(td,1H),3.13–3.02(m,2H),2.99(s,1H),2.81(q,1H),2.11(d,1H),2.03(d,1H),2.00–1.90(m,3H),1.86–1.71(m,3H),1.67–1.51(m,2H).

Example 22: preparation of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one formate salt (22)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (4 ml), N-diisopropylethylamine (51.27 mg,0.4 mmol) was added, and piperidin-4-one (39.6 mg,0.4 mmol) was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the objective 1- (2, 7-dichloro-8-fluoropyrido [4,3d ] pyrimidin-4-yl) piperidin-4-one (22-a, 105mg, yield 84.00%). ESI [ m+h ] ⁺ = 315.21.

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-a, 130mg,0.37 mmol) was dissolved in chloroform (3 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (64.8 mg,0.407 mmol) was added, and cesium carbonate (241 mg,0.74 mmol) was reacted at room temperature for 16H. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) piperidin-4-one (22-b, 80mg, yield 49.69%). ESI [ m+h ] ⁺ =437.5.

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (80 mg, 0.183mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (86.5 mg,0.19 mmol), potassium phosphate (71.7 mg,0.338 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (24.6 mg,0.0338 mmol) was added to the reaction flask. The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenching with water, extracting with ethyl acetate, collecting organic phase, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by Flash column (methanol: dichloromethane=0% -10%) to obtain target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 as) -2-fluorotetrahydro (22-c, 40mg, yield 27.77%). ESI [ M+H ] += 788.55).

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-c, 40mg,0.05 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (37 mg,0.243 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to give the objective product 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-d, 15mg, yield 45.87%). ESI [ m+h ] ⁺ =587.6.

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) piperidin-4-one formate salt (22)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-one (22-d, 15mg,0.0255 mmol) was dissolved in acetonitrile (2 ml) and trifluoroacetic acid (0.5 ml) was added to the ice bath for 0.5 hours. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-4-yl) piperidine-4-ketone formate (22, 2.72mg, yield) 18.12％).ESI[M+H]⁺＝588.21.¹H NMR(400MHz,DMSO-d₆)δ10.35(s,1H),8.44(s,1H),7.91(dd,J＝8.9,4.1Hz,1H),7.87(d,J＝1.9Hz,1H),7.51(t,J＝9.3Hz,1H),7.45(d,J＝1.9Hz,1H),5.43–5.11(m,2H),4.53(s,1H),4.17–3.94(m,4H),3.69–3.56(m,2H),3.14–3.04(m,2H),2.91–2.80(m,1H),2.18–2.00(m,3H),1.90–1.60(m,7H).

Embodiment 23: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (2-hydroxypropan-2-yl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (23)

The first step: synthesis of 2- (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (23-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg, 0.495mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (61.3 mg,0.479 mmol) and 3-fluoroazetidine (66.2 mg,0.594 mmol) were added and reacted at 0℃for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-8-fluoro-4- (3-fluorocyclobutyl) pyrido [4,3-d ] pyrimidine (23-a, 60mg, yield 34.8%). ESI [ m+h ] ⁺ =291

And a second step of: synthesis of 7-chloro-8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-b)

2, 7-Dichloro-8-fluoro-4- (3-fluorocyclobutyl) pyrido [4,3-d ] pyrimidine (23-a, 50mg,0.172 mmol), cesium carbonate (168.7 mg, 0.719 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (82.3 mg,0.516 mmol) was added to dioxane (6 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 7-chloro-8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-b, 117 mg). ESI [ m+h ] ⁺ = 414.1

And a third step of: synthesis of 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluorocyclobutyl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-c)

(7-Chloro-8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-b, 117mg,0.16 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (285.2 mg,0.557 mol), potassium phosphate (236.42 mg,1.113 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (81.1 mg,0.111 mmol) was dissolved in tetrahydrofuran (3.7 ml) and water (0.37 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluorocyclobutyl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-c, 54mg, 32.83% yield). ESI [ m+h ] ⁺ = 764.3

Fourth step: synthesis of 7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (23-d)

8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluorocyclobutyl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (23-c, 54mg,0.0524 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (100 mg,0.75 mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine (23-d, 40 mg). ESI [ m+h ] ⁺ = 676.6

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-7-yl) naphthalen-2-ol (23)

7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine (23-d, 40mg,0.0524 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.4 ml) was added and reacted at room temperature for 0.5 hours. Separating and purifying the reaction liquid by a preparative liquid chromatograph to obtain a target product 5-ethynyl-6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine-7-yl) naphthalen-2-ol (23,4.7mg).ESI[M+H]⁺＝610.5¹H NMR(400MHz,DMSO-d₆)δ8.90(s,1H),8.29(s,1H),7.95(dd,J＝9.2,5.9Hz,1H),7.44(t,J＝9.0Hz,1H),7.37(d,J＝2.6Hz,1H),7.14(d,J＝2.6Hz,1H),5.60(d,J＝57.7Hz,2H),5.25(d,J＝54.5Hz,2H),4.11–3.89(m,4H),2.87–2.69(m,2H),2.12–1.99(m,3H),1.85–1.72(m,3H).

Example 24: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24)

The first step: synthesis of (R) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in dichloromethane (4 ml), N-diisopropylethylamine (51.27 mg,0.4 mmol) was added, and (R) -piperidin-3-ol (49.6 mg,0.4 mmol) was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, an organic phase was collected and backwashed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether=0% -30%) to give the desired product (R) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24-a, 105mg, yield 83.46%). ESI [ m+h ] ⁺ = 317.52.

And a second step of: synthesis of (R) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24-b)

(R) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (105 mg,0.3 mmol) was dissolved in chloroform (3 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (54 mg,0.339 mmol) was added, and cesium carbonate (241 mg,0.74 mmol) was reacted at room temperature for 16H. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the target product (R) -1- (7-chloro-8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24-b, 80mg, yield 55.17%). ESI [ m+h ] ⁺ = 440.12.

And a third step of: synthesis of (R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24-c)

(R) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (80 mg,0.181 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (88.6 mg,0.181 mmol), potassium phosphate (71.7 mg, 0.365 mmol) methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (24.6 mg,0.0362 mmol) was added to the reaction flask. The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Water quenching, ethyl acetate extraction, collecting organic phase and backflushing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, decompressing and concentrating Flash column (methanol: dichloromethane=0% -10%) to obtain target product (R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-group) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -group) methoxy group) pyrido [4,3-d ] pyrimidine-4-group) piperidine-3-alcohol (24-c, 30mg, yield 20.89%). ESI [ m+h ] += 790.51.

Fourth step: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-ol (24-d)

(R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (30 mg,0.038 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (29 mg,0.19 mmol) was added and the mixture was reacted at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to give the objective (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-ol (24-d, 18mg, yield 75.00%). ESI [ m+h ] ⁺ = 634.66.

Fifth step: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (24)

(R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-ol (18 mg,0.027 mmol) was dissolved in acetonitrile (2 ml), and trifluoroacetic acid (0.5 ml) was added in an ice bath for 0.5 hours. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-4-yl) piperidin-3-ol (24, 3.28mg, yield 19.65％).ESI[M+H]⁺＝590.21.¹H NMR(400MHz,DMSO-d₆)δ9.28(s,1H),8.35(s,1H),8.08(s,1H),7.72(s,1H),7.63(s,1H),6.62(s,1H),6.26(s,1H),5.58(d,J＝51.5Hz,2H),5.30(s,2H),4.81(s,2H),4.68(s,2H),3.78(s,6H),2.31(s,2H),2.21(d,J＝18.4Hz,3H),2.05(s,2H),1.50(d,J＝6.9Hz,1H).

Example 25: preparation of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) aza-4-ol (25)

The first step: preparation of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) azepam-4-ol (25-a)

2,4, 7-Trichloro-8-fluoropyrido [4,3-d ] pyrimidine (I-1, 200mg,0.792 mmol), 4-aza Zhuo Chunyan acid salt (120.1 mg,0.792 mmol), N-diisopropylethylamine (292.5 ul, 1.284 mmol) was dissolved in dichloromethane (5 mL) and reacted at 0℃for 12 hours. The reaction system was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give the desired product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) diazepam-4-ol (25-a, 250mg, yield 101.2%). ESI [ m+h ] ⁺ = 313.7

And a second step of: preparation of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) zepan-4-ol (25-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) azepam-4-ol (250, 0.755 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (25-a, 600.9mg,1.51 mmol), potassium carbonate (521.7 mg,1.51 mmol) was dissolved in dioxane (5 mL), and the reaction mixture was reacted at 80℃for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the desired product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) zepam-4-ol (25-b, 210mg, yield 61.3%) ESI [ m+h ] ⁺ = 454.9

And a second step of: preparation of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) azepin-4-ol (25-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) diazepam-4-ol (25-b, 210mg,0.463 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (474.6 mg,0.926 mmol), potassium phosphate (196.5 mg,0.926 mmol) methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (67.5 mg,0.046 mmol) was dissolved in dioxane/water (10/1, 2.5 ml), nitrogen was replaced three times, and the temperature was raised to 16℃under nitrogen protection. The reaction system was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the desired product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) aza-4-ol (25-c, 130mg, yield 34.92%) ESI [ m+h ] ⁺ = 805.0 ]

Fourth step: preparation of 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) azepin-4-ol (25-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) aza-4-ol (25-c, 130mg,0.162 mmol), cesium fluoride (147.4 mg,0.972 mmol) was dissolved in N, N-dimethylformamide (2 mL), reacted for 2 hours at 25 ℃, quenched with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- ((2, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyridin-4-yl) and [ 3-d ] pyrimidin-4-d ] (25H) -yl) pyrido [ 25-03H ] = 25-d ] 5H = 25-yl, yield (39M = 25-25.25+25.25 + ] H = 25.25.25 + (7.25.25.25%) g }

Fifth step: preparation of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) aza-4-ol (25)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) aza-4-ol (25-d, 65mg,0.1 mmol) was dissolved in acetonitrile (5 mL), hydrochloric acid/dioxane (1 mL) was added dropwise, the reaction was allowed to proceed for 30min at 0deg.C, quenched with aqueous sodium bicarbonate, ethyl acetate was extracted, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography to give the target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) aza-ol (25.85 mg) yield 41.17％)ESI[M+H]⁺＝604.7,1H NMR(600MHz,CDCl₃)δ10.17(s,2H),9.08(d,J＝1.6Hz,1H),8.14(s,1H),7.97(dd,J＝9.1,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.4Hz,1H),7.18(s,1H),5.29(d,J＝53.7Hz,1H),4.66(s,1H),4.15(dd,J＝17.5,6.8Hz,1H),4.09–3.92(m,4H),3.85(ddd,J＝29.6,17.9,7.9Hz,2H),3.30–3.01(m,5H),2.86(dd,J＝14.9,8.6Hz,1H),2.16–2.07(m,3H),2.05–1.98(m,1H),1.95–1.84(m,2H),1.83–1.73(m,3H),1.66–1.58(m,1H).

Example 26: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.6 mmol) was dissolved in dichloromethane (7 ml) and cooled to 0℃N, N-diisopropylethylamine (155 mg,1.2 mmol) and 4-methylazepan-4-ol (100 mg,0.6 mmol) were added and reacted at 0℃for 1 hour. Quenching with water, extracting with ethyl acetate, collecting the organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -5%) to obtain the target product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-a, 172mg, yield 83.5%). ESI [ m+h ] ⁺ =345.1

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-a, 172mg,0.5 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (38 mg,2.5 mmol) and cesium carbonate (815 mg,2.5 mmol) were added to dioxane (8 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-b, 200mg, yield 85.5%). ESI [ m+h ] ⁺ = 468.1

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazein-4-ol (26-b, 200mg,0.43 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (440 mg,0.86 mmol), potassium phosphate (182 mg,0.86 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (63 mg,0.086 mmol) was dissolved in dioxane (l 0 ml) and water (1 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazein-4-ol (26-c, 210mg, 59.7% yield). ESI [ m+h ] ⁺ = 818.9

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazein-4-ol (26-c, 210mg,0.26 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (237 mg,1.56 mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-d, 200mg, yield 50.4%). ESI [ m+h ] ⁺ = 662.5

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26-d, 200mg,0.3 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (0.5 ml) was added, and the mixture was reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylazepin-4-ol (26, 30mg, yield) 10.5％).ESI[M+H]⁺＝617.1¹H NMR(600MHz,DMSO-d₆)δ10.13(s,1H),9.05(d,J＝26.0Hz,1H),7.95(dd,J＝9.0,6.0Hz,1H),7.44(t,J＝9.0Hz,1H),7.37(s,1H),7.16(d,J＝25.2Hz,1H),5.26(d,J＝54.2Hz,1H),4.39(s,1H),4.16–4.09(m,1H),4.09–3.99(m,3H),3.97–3.79(m,3H),3.06(d,J＝11.6Hz,2H),3.01(s,1H),2.84–2.78(m,1H),2.23(s,1H),2.11(d,J＝22.5Hz,1H),2.06(d,J＝12.3Hz,1H),2.01–1.93(m,2H),1.85(d,J＝15.3Hz,2H),1.77(d,J＝21.1Hz,3H),1.70–1.62(m,1H),1.57–1.47(m,1H),1.16(d,J＝4.8Hz,3H).

Example 28: preparation of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((S) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (28)

The first step: preparation of (S) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.59 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0℃N, N-diisopropylethylamine (76 mg,0.59 mmol) and (S) -piperidin-3-yl-methanol (75 mg,0.65 mmol) were added and reacted at 0℃for 10min. After concentrating under reduced pressure, flash column (methanol: dichloromethane=0% -5%) is purified to obtain target product (S) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-a, 208mg, yield 100%). ESI [ m+h ] ⁺ = 331.1

And a second step of: preparation of (((S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-b)

Preparation of (S) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-a, 208mg,0.63 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (301 mg,1.89 mmol), cesium carbonate (1.026 g,3.15 mmol) was added to 1, 4-dioxane (7 ml). Heating to 80 ℃ for reaction for 3 hours. The reaction was taken up in water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) was purified to give the target product ((S) -1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-b, 80mg, yield 27.97%). ESI [ m+h ] ⁺ = 454.3

And a third step of: preparation of (((S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-c)

((S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-b, 80mg,0.18 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (101 mg,0.2 mmol), potassium phosphate (76 mg,0.36 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (26 mg,0.036 mmol) was dissolved in 1, 4-dioxane (4 ml) and water (0.4 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) purified to give the target product ((S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-c, 36mg, yield 24.83%). ESI [ m+h ] ⁺ = 804.5

Fourth step: preparation of (((S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-d)

((S) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-c, 35mg,0.04 mmol) was dissolved in N, N-dimethylformamide, (4 ml) cesium fluoride (36 mg,0.24 mmol) was added and reacted at 25 ℃ for 0.5 hours. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give the target product ((S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-d, 35 mg). ESI [ m+h ] ⁺ = 648.4

Fifth step: preparation of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((S) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (28)

((S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (28-d, 35mg,0.054 mmol) was dissolved in acetonitrile (3 ml), and 1, 4-dioxane hydrochloride solution (0.3 ml) was added at 25℃and reacted for 0.5H. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((S) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (28, 7.44mg, yield 22.81％).ESI[M+H]⁺＝604.4,¹H NMR(600MHz,DMSO-d₆)δ10.13(s,1H),8.99(d,1H),7.95(dd,1H),7.44(t,1H),7.37(d,1H),7.18(t,1H),5.32–5.20(m,1H),4.75–4.69(m,1H),4.55–4.46(m,1H),4.38(d,1H),4.09(t,1H),4.01(dd,1H),3.95(d,1H),3.43(dd,1H),3.39–3.35(m,1H),3.28–3.20(m,1H),3.15–2.99(m,4H),2.81(q,1H),2.10(d,1H),2.04(d,1H),1.99(p,1H),1.93–1.69(m,8H).

Example 29: preparation of (3 s,4 s) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29)

The first step: preparation of (3S, 4S) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 120mg,0.475 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0℃N, N-diisopropylethylamine (123 mg,0.95 mmol) and (3S, 4S) -4-fluoropyridine-3-ol (81 mg, 0.423 mmol) were added and reacted at 0℃for 0.5h. After concentration under reduced pressure, flash column (methanol: dichloromethane=0% -5%) was purified to obtain the target product (3 s,4 s) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-a, 145mg, yield 91.19%).

And a second step of: preparation of (3S, 4S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-b)

Preparation of (3 s,4 s) -1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-a, 145mg,0.433 mmol), ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (207 mg,1.299 mmol), cesium carbonate (704 mg,2.165 mmol) was added to 1, 4-dioxane (5 ml). The temperature is raised to 80 ℃ to react for 16h. The reaction was taken up in water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and TLC (methanol: dichloromethane=10:1) was purified to give the target product (3 s,4 s) -1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-b, 70mg, 35.35%) in yield. ESI [ m+h ] ⁺ =458.3, 460.3

And a third step of: preparation of (3S, 4S) -4-fluoro-1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (29-c)

(3S, 4S) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-b, 70mg,0.153 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (118 mg,0.23 mmol), potassium phosphate (65 mg,0.306 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (23 mg,0.031 mmol) was dissolved in 1, 4-dioxane (4 ml) and water (0.4 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by TLC (methanol: dichloromethane=10:1) to give the target product (3 s,4 s) -4-fluoro-1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (29-c, 36mg, 29.03% yield).

Fourth step: preparation of (3 s,4 s) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-d)

(3S, 4S) -4-fluoro-1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (29-c, 36mg,0.045 mmol) was dissolved in N, N-dimethylformamide (5 ml) and cesium fluoride (41 mg,0.27 mmol) was added and reacted at 25℃for 0.5 hours. Water (20 ml) was added to the reaction solution, extraction was performed 3 times with ethyl acetate, 20ml each time, and the organic phase was collected and distilled under reduced pressure to give the target product (3 s,4 s) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-d, 38 mg). ESI [ m+h ] ⁺ = 652.4, 653.4

Fifth step: preparation of (3 s,4 s) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29)

(3S, 4S) -1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29-d, 38mg,0.058 mmol) was dissolved in acetonitrile (3 ml) and 1, 4-dioxane hydrochloride solution (0.3 ml) was added at 25℃and reacted for 0.5H. The reaction solution was separated and purified by preparative liquid chromatography to give the objective (3 s,4 s) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-fluoropiperidin-3-ol (29, 9.62mg, yield) 27.30％).ESI[M+H]⁺＝608.3,¹HNMR(600MHz,DMSO-d₆)δ10.08(s,1H),9.09(d,1H),7.98–7.93(m,1H),7.44(t,1H),7.38(d,1H),7.19(d,1H),5.67(t,1H),5.26(d,1H),4.64(dt,1H),4.26–4.17(m,1H),4.11(dd,1H),4.07–3.98(m,2H),3.92(d,1H),3.87–3.82(m,1H),3.76(ddd,1H),3.59(dt,1H),3.07(t,2H),3.02(d,1H),2.81(q,1H),2.27–2.20(m,1H),2.10(d,1H),2.05(d,1H),1.99(q,1H),1.93–1.87(m,1H),1.85–1.81(m,1H),1.76(td,2H).

Example 30: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((R) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (30)

The first step: synthesis of (R) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.6 mmol) was dissolved in dichloromethane (7 ml) and cooled to 0℃N, N-diisopropylethylamine (78 mg,0.6 mmol) and (R) -piperidin-3-yl-methanol (69 mg,0.6 mmol) were added and reacted at 0℃for 1 hour. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -5%) to give the target product (R) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-a, 167mg, yield 84.0%). ESI [ m+h ] ⁺ = 331.9

And a second step of: synthesis of (30-b) methanol of (((R) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol

(R) - (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-a, 167mg,0.5 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (3998 mg,2.5 mmol) and cesium carbonate (815 mg,2.5 mmol) were added to dioxane (8 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product ((R) -1- (7-chloro-8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-b, 185mg, yield 81.5%). ESI [ m+h ] ⁺ = 454.6

And a third step of: synthesis of (30-c) methanol from (R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy)) -8- ((triisopropylsilylhydinyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl)

((R) -1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-b, 185mg,0.41 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (430 mg,0.84 mmol), potassium phosphate (178 mg,0.84 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (61 mg,0.084 mmol) was dissolved in dioxane (l 0) and water (1 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product ((R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy)) -8- ((triisopropylsilylethynyl) naphthalen-1-yl) -2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-c, 106mg, yield 31.6%). ESI [ m+h ] ⁺ = 820.4

Fourth step: synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-d)

((R) -1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-c, 106mg,0.13 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (118 mg,0.78 mmol) was added and the mixture was reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the target product ((R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-d, 36mg, yield 41.7%). ESI [ m+h ] ⁺ = 648.5

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((R) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (30)

((R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (30-d, 36mg,0.06 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.5 ml) was added and the reaction was carried out at room temperature for 0.5 hours. The reaction solution is separated and purified by preparative liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- ((R) -3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (30, 6mg, yield) 16.7％).ESI[M+H]⁺＝604.6¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.01(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.20(d,J＝2.6Hz,1H),5.38–5.20(m,2H),4.74(dt,J＝9.5,5.1Hz,1H),4.53(dd,J＝17.7,13.1Hz,1H),4.40(d,J＝13.2Hz,1H),4.21–3.95(m,4H),3.17–3.01(m,4H),2.84(q,J＝7.8Hz,1H),2.15(d,J＝4.1Hz,1H),2.09–1.94(m,5H),1.90–1.76(m,7H).

Example 31:1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31)

The first step: synthesis of 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-a)

2,4, 7-Trichloro-8-fluoropyrido [4,3-d ] pyrimidine (I-1, 200mg,0.792 mmol) and N, N-diisopropylethylamine (292.5 uL,1.584 mmol) were dissolved in dichloromethane (8 ml), and then 4-methylpiperidine-3-ol hydrochloride (120.1 mg,0.792 mmol) was added thereto, followed by reaction at 40℃for 1 hour. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate=5:1) was used to purify the desired product 1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-a, 295mg, 112.5% yield). ESI [ m+h ] ⁺ = 330.05

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-b)

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-a, 100mg,0.302 mmol) was dissolved in dioxane (2 ml), followed by the addition of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (240.4 mg,1.51 mmol), potassium carbonate (221.1 mg,1.51 mmol) and reaction at 80℃for 16H. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate=5:1) was performed to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-b, 110mg, yield 80.23%). ESI [ m+h ] ⁺ = 453.17

And a third step of: synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-c)

1- (7-Chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-b, 110mg,0.242 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (248.1 mg, 0.482 mmol) methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (35.2 mg,0.0484 mmol) and potassium phosphate (102.7 mg, 0.284 mmol) were dissolved in dioxane: in water (10:1, 2 ml), the temperature was raised to 60℃and the reaction was continued for 16h. Diluting with water, extracting with dichloromethane, collecting the organic phase, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-c, 95mg, yield 48.84%). ESI [ m+h ] ⁺ = 803.41

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (23-c, 85mg,0.106 mmol) was dissolved in DMF (2 ml), cesium fluoride (96.6 mg,0.636 mmol) was added, after 2 hours reaction at room temperature, diluted with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired product 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-methyl) -4-yl ] piperidin-3-ol (116 mg, yield 80.116 mg). ESI [ m+h ] ⁺ = 647.27

Fifth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (31-c, 75mg,0.116 mmol) was dissolved in acetonitrile (5 mL), dioxane hydrochloride (1 mL) was added, and the temperature was lowered to 0℃for 30 minutes. The reaction solution is separated and purified by synthetic liquid chromatography to obtain a target product 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidine-4-yl) -4-methylpiperidin-3-ol (31, 25mg, yield) 35.71％).ESI[M+H]⁺＝603.25,1HNMR(600MHz,DMSO-d6)δ10.18(s,1H),9.07(dd,J＝85.1,38.0Hz,1H),7.97(dd,J＝8.8,6.1Hz,1H),7.65–7.29(m,1H),7.22(dd,J＝24.0,17.4Hz,1H),5.33–5.08(m,1H),4.92(dd,J＝58.2,4.7Hz,1H),4.52(dd,J＝29.5,15.7Hz,1H),4.42(d,J＝12.5Hz,1H),4.16–3.92(m,1H),3.75(d,J＝40.8Hz,1H),3.64–3.51(m,1H),3.06(dd,J＝25.1,12.1Hz,1H),2.83(dd,J＝14.7,8.1Hz,1H),2.15–1.97(m,1H),1.90–1.73(m,1H),1.59(d,J＝15.3Hz,1H),1.46–1.33(m,1H),1.21(d,J＝25.2Hz,1H),1.11(s,1H),1.08–0.92(m,1H).

Example 32:1- (5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidin-7-yl) naphthalen-2-ol (32)

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The first step: synthesis of 1- (2, 7-dichloro-8-fluoro-4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine) (32-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.594 mmol) was dissolved in dichloromethane (3 ml) and cooled to 0℃N, N-diisopropylethylamine (67.3 mg,0.475 mmol) and 3-methoxypiperidine (68.4 mg,0.594 mmol) were added and reacted at 0℃for 1 hour. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -5%) to give the target product 1- (2, 7-dichloro-8-fluoro-4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine) (32-a, 170mg, yield 86.18%). ESI [ m+h ] ⁺ = 333.1

And a second step of: synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine) (32-b)

1- (2, 7-Dichloro-8-fluoro-4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine) (32-a, 170mg,0.512 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (244.5 mg, 1.534 mmol) and cesium carbonate (499.2 mg,1.536 mmol) were added to dioxane (3 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine) (32-b, 94mg, yield 40.51%). ESI [ m+h ] ⁺ =454.1

And a third step of: synthesis of 1-8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine (32-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine) (32-b, 90mg,0.198 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (203 mg,0.397 mmol), potassium phosphate (168 mg,0.794 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (57.8 mg,0.0793 mmol) was dissolved in dioxane (3.7 ml) and water (0.37 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine (32-c, 80mg, yield 50.10%). ESI [ m+h ] ⁺ = 805.0

Fourth step: synthesis of 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine (32-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidine (32-c, 80mg,0.0994 mmol) was dissolved in N, N-dimethylformamide (2.5 ml) and cesium fluoride (15.1 mg,0.994 mmol) was added thereto, and the reaction mixture was reacted at room temperature for 0.5 hours, and the reaction mixture was purified by preparative liquid chromatography to give the objective 1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine (32-d ] [ 32.1-d ] = 62 m. ⁺ +397j.

Fifth step: synthesis of 1- (5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidin-7-yl) naphthalen-2-ol (32)

1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3-d ] pyrimidine (32-d, 79mg,0.1219 mmol) is dissolved in acetonitrile (3 ml), dioxane hydrochloride (1 ml) is added, and the reaction solution is reacted for 0.5 hour at room temperature, and the reaction solution is subjected to preparative liquid chromatography separation and purification to obtain the target product 1- (5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3-methoxypiperidin-1-yl) pyrido [4,3d ] pyrimidin-7-yl) naphthalen-2-ol (32,7.67mg).ESI[M+H]⁺＝604.2¹H NMR(400MHz,DMSO-d₆)δ10.21(s,1H),9.04(d,J＝31.1Hz,1H),8.02–7.88(m,1H),7.44(t,J＝9.0Hz,1H),7.37(d,J＝2.5Hz,1H),7.18(dd,J＝8.1,2.5Hz,1H),5.26(d,J＝54.4Hz,1H),4.17–3.73(m,8H),3.06(s,3H),2.99(s,1H),2.80(q,J＝8.0Hz,1H),2.11(d,J＝4.2Hz,1H),2.07–1.58(m,10H).

Example 33: preparation of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (4- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (33)

The first step: preparation of (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (150 mg,0.594 mmol) was dissolved in dichloromethane (3 ml), N-diisopropylethylamine (196. Mu.L, 1.188 mmol) was added and reacted at 0℃for 10 minutes. Piperidin-4-yl methanol (68.4 mg,0.594 mmol) was then dissolved in dichloromethane (1 ml) and added to the reaction and reacted at 0℃for 20 minutes. Quenching with water, extracting with ethyl acetate, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain target product (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-a, 201mg, crude product). ESI [ m+h ] ⁺ = 331.1

And a second step of: synthesis of (33-b) methyl alcohol (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol

1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-a, 201mg,0.607 mmol) was dissolved in dioxane (4 ml), followed by ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (241.59 mg,1.52 mmol) and cesium carbonate (494.43 mg,1.52 mmol). The temperature is raised to 80 ℃ for reaction for 8 hours. Filtered, concentrated under reduced pressure and then purified by a Flash column (methanol: dichloromethane=0% -10%) to obtain the target product (1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-b, 101mg, yield 36.7%). ESI [ m+h ] ⁺ =454.2

And a third step of: synthesis of (33-c) methanol from (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl)

(1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-b, 101mg,0.223 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (228.6, 0.446 mmol), potassium phosphate (94.68 mg,0.446 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (32.48 mg,0.0446 mmol) was dissolved in dioxane (2 ml) and water (0.2 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. After filtration and concentration under reduced pressure, flash column (methanol: dichloromethane=0% -10%) was purified to obtain the target product (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-c, 116mg, yield 64.8%). ESI [ m+h ] ⁺ = 804.4

Fourth step: synthesis of (33-d) methanol (1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) method

(1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-c, 116mg,0.144 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (131.24 mg,0.864 mmol) was added and the mixture was reacted at room temperature for 0.5 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product (1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-d, 230mg, crude product). ESI [ m+h ] ⁺ = 648.3

Fifth step: 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (4- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (33)

(1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-4-yl) methanol (33-d, 115mg,0.1776 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (1 ml) was added, and the mixture was reacted at room temperature for 1 hour. Adding water, slowly quenching, regulating pH to 8 with saturated sodium bicarbonate aqueous solution, separating and purifying the reaction solution by preparative liquid chromatography to obtain target product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (4- (hydroxymethyl) piperidin-1-yl) pyrido [4,3d ] pyrimidin-7-yl) naphthalen-2-ol (33, 5.27mg, yield) 4.92％).ESI[M+H]⁺＝604.3 1H NMR(400MHz,DMSO-d₆)δ10.16(s,1H),8.95(s,1H),7.95(dd,J＝9.2,5.9Hz,1H),7.44(t,J＝9.0Hz,1H),7.37(d,J＝2.6Hz,1H),7.17(d,J＝2.6Hz,1H),5.33(s,1H),5.20(s,1H),4.54(dd,J＝26.9,9.3Hz,3H),4.18–3.87(m,3H),3.15–2.98(m,4H),2.81(q,J＝8.1Hz,1H),2.21–1.89(m,4H),1.90–1.70(m,6H),1.38(p,J＝11.7,11.2Hz,2H).

Example 34:1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -4-methylpiperidin-3-ol (34)

The first step: synthesis of (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-a)

2,4, 7-Trichloro-8-fluoropyrido [4,3-d ] pyrimidine (I-1, 200mg,0.792 mmol) and N, N-diisopropylethylamine (204.7 mg, 1.284 mmol) were dissolved in acetonitrile (8 ml), followed by addition of piperidin-3-yl-methanol (91.6 mg,0.792 mmol), and reaction at 40℃for 1 hour. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate=5:1) was performed to obtain the target product (1- (2, 7-dichloro-8-fluoropyrido [4,3d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-a, 200mg, yield 75.77%). ESI [ m+h ] += 330.05

And a second step of: synthesis of (34-b) methyl alcohol (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol

(1- (2, 7-Dichloro-8-fluoropyrido [4,3d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-a, 100mg,0.302 mmol) was dissolved in dioxane (2 ml), and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (240.4 mg,1.51 mmol), potassium carbonate (221.1 mg,1.51 mmol) was then added and the mixture was reacted at 80℃for 16H. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate=5:1) was performed to give the target product (1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-b, 43mg, yield 31.36%). ESI [ m+h ] += 453.17

And a third step of: synthesis of (34-c) methanol from (1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl)

(1- (7-Chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-b, 40mg,0.088 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (90 mg,0.176 mmol), cataCXium A pa G (12 mg,0.0176 mmol) and potassium phosphate (37 mg,0.176 mmol) were dissolved in dioxane: in water (10:1, 2 ml), the temperature was raised to 60℃and the reaction was continued for 16h. Diluting with water, extracting with dichloromethane, collecting the organic phase, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain the target product (1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-c, 50mg, yield 70.67%). ESI [ m+h ] ⁺ = 803.41

Fourth step: synthesis of (34-d) methanol (1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol

(1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-c, 50mg,0.062 mmol) was dissolved in DMF (2 ml), cesium fluoride (56.5 mg,0.372 mmol) was added, after 2 hours of reaction at room temperature, diluted with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired product (1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) pyrido [ 4-d ] piperidin-4-yl) 1, 34-d-piperidinyl, 112-4-yl) in a yield, 45-45% of piperidyl. ESI [ m+h ] ⁺ = 647.27

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (hydroxymethyl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (34)

(1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) methanol (34-d, 40mg,0.062 mmol) was dissolved in acetonitrile (5 mL), dioxane hydrochloride (1 mL) was added, and the temperature was lowered to 0℃for 30 minutes. The reaction solution is separated and purified by synthetic liquid chromatography to obtain a target product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (hydroxymethyl) piperidine-1-yl) pyrido [4,3-d ] pyrimidine-7-yl) naphthalen-2-ol (34, 20mg, yield) 53.48％).ESI[M+H]⁺＝603.251H NMR(400MHz,DMSO-d₆)δ10.21(s,1H),9.01(s,1H),8.15(s,1H),8.02–7.92(m,1H),7.53–7.43(m,1H),7.42–7.33(m,1H),7.24–7.13(m,1H),5.36(s,1H),5.22(s,1H),4.77(s,1H),4.58–4.47(m,1H),4.40(d,J＝12.9Hz,1H),4.18–4.10(m,1H),4.05(dd,J＝16.8,6.8Hz,1H),3.98(d,J＝10.2Hz,1H),3.26(dd,J＝26.8,16.1Hz,4H),3.17(d,J＝35.4Hz,3H),3.06(s,1H),2.85(d,J＝6.1Hz,1H),2.13(d,J＝13.4Hz,1H),2.04(d,J＝21.2Hz,2H),1.82(dd,J＝22.1,11.6Hz,6H),1.29(d,J＝51.4Hz,2H).

Example 35: synthesis of 2- (1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile formate salt (35)

The first step: synthesis of 2- (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-a)

2,4, 7-Trichloro-8-fluoropyrido [4,3-d ] pyrimidine (I-1, 100mg,0.4 mmol) was dissolved in methylene chloride (4 ml), N-diisopropylethylamine (51.27 mg,0.4 mmol) was added, and 2- (piperidin-3-yl) acetonitrile (49.6 mg,0.4 mmol) was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the objective product 2- (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-a, 105mg, yield 77.78%). ESI [ m+h ] ⁺ = 340.55.

And a second step of: preparation of 2- (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-b)

2- (1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-a, 105mg,0.3 mmol) was dissolved in chloroform (3 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (54 mg,0.339 mmol) was added, and cesium carbonate (241 mg,0.74 mmol) was reacted at room temperature for 16H. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with Flash column (ethyl acetate: petroleum ether=0% -30%) to give the objective product 2- (1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-b, 80mg, yield 55.94%). ESI [ m+h ] ⁺ = 463.52.

And a third step of: preparation of 2- (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-c)

2- (1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-b, 80mg,0.173 mmol) was dissolved in 1, 4-dioxane (2 ml) and water (0.2 ml), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (88.6 mg,0.173 mmol), potassium phosphate (71.7 mg,0.338 mmol) methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (24.6 mg,0.0338 mmol) was added to the reaction. The nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then Flash column (methanol: dichloromethane=0% -10%) was purified to give the target product 2- (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-c, 36mg, yield 25.71%). ESI [ m+h ] ⁺ = 813.55.

Fourth step: preparation of 2- (1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-yl) acetonitrile (35-d)

2- (1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile (35-c, 36mg,0.044 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (33.6 mg,0.221 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to give the objective product 2- (1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-yl) acetonitrile (35-d, 18mg, yield 62.07%). ESI [ m+h ] ⁺ = 657.52.

Fifth step: preparation of 2- (1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile formate salt (35)

2- (1- (7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) piperidin-3-yl) acetonitrile (35-d, 18mg,0.027 mmol) was dissolved in acetonitrile (2 ml), and trifluoroacetic acid (0.5 ml) was added to the ice bath for 0.5 hours. The reaction solution is separated and purified by a preparative liquid chromatography to obtain a target product 2- (1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) acetonitrile formate (35, 12.2mg, yield 72.62％).ESI[M+H]⁺＝613.25.¹H NMR(400MHz,DMSO-d₆)δ9.06(s,1H),8.22(s,1H),8.10(dd,J＝9.2,5.9Hz,1H),7.74(s,1H),7.55(t,J＝9.0Hz,1H),7.36(s,1H),5.42(s,2H),5.33(s,1H),5.24(s,1H),4.51(d,J＝12.7Hz,1H),4.36(d,J＝12.6Hz,1H),4.14–4.09(m,1H),4.05–4.00(m,1H),3.99(s,1H),3.75–3.72(m,3H),3.72–3.70(m,2H),3.69–3.62(m,2H),3.14–3.06(m,2H),3.03(s,1H),2.87–2.80(m,1H),2.16–2.10(m,1H),2.08–2.05(m,1H),1.15(t,J＝7.1Hz,3H).

Example 36: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (2-hydroxypropan-2-yl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (36)

The first step: synthesis of 2- (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 130mg,0.52 mmol) was dissolved in dichloromethane (7 ml) and cooled to 0℃N, N-diisopropylethylamine (67 mg,0.52 mmol) and 2- (piperidin-3-yl) propan-2-ol (75 mg,0.52 mmol) were added and reacted at 0℃for 1 hour. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -5%) to give the desired product 2- (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-a, 136mg, yield 72.7%). ESI [ m+h ] ⁺ =360.1

And a second step of: synthesis of 2- (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-b)

2- (1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-a, 136mg,0.38 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (302 mg,1.9 mmol) and cesium carbonate (612 mg,1.9 mmol) were added to dioxane (8 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenching with water, extracting with ethyl acetate, collecting the organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with Flash column (methanol: dichloromethane=0% -10%) to obtain the target product (2- (1- (7-chloro-8-fluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-b, 89mg, yield 48.6%). ESI [ M+H ] ⁺ = 482.7)

And a third step of: synthesis of 2- (1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-c)

(2- (1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-b, 77mg,0.16 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (164 mg,0.32 mmol), potassium phosphate (23 mg,0.32 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (67 mg,0.032 mmol) was dissolved in dioxane (4) and water (0.4 ml), nitrogen was replaced 3 times, warmed to 60 ℃ C. Water was added, ethyl acetate was concentrated to dryness, and the aqueous solution was concentrated to dryness, dried to dryness, concentrated to dryness, washed with aqueous solution (10% aqueous solution) chloride solution was concentrated to obtain ethyl acetate solution, the target product 2- (1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-c, 74mg, yield 55.6%). ESI [ m+h ] ⁺ = 832.8

Fourth step: synthesis of 2- (1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-d)

2- (1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy)) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-c, 74mg,0.09 mmol) was dissolved in N, N-dimethylformamide (3 ml) and cesium fluoride (82 mg,0.54 mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective 2- (1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-d, 35mg, yield 57.3%). ESI [ m+h ] ⁺ = 676.6

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (2-hydroxypropan-2-yl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (36)

2- (1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) propan-2-ol (36-d, 35mg,0.05 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.5 ml) was added and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the objective product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (2-hydroxypropan-2-yl) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (36, 15mg, yield 47.5％).ESI[M+H]⁺＝632.5¹H NMR(400MHz,DMSO-d₆)δ10.20(s,1H),9.03(d,J＝5.5Hz,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.51–7.36(m,2H),7.19(dd,J＝6.4,2.5Hz,1H),5.35(s,1H),5.21(s,1H),4.74(d,J＝13.1Hz,1H),4.51(d,J＝13.9Hz,2H),4.12(td,J＝9.1,7.9,3.7Hz,1H),4.06–3.95(m,2H),3.15–3.00(m,5H),2.82(d,J＝7.4Hz,1H),2.06(dd,J＝30.5,22.1Hz,3H),1.79(ddd,J＝45.0,38.0,15.4Hz,7H),1.42(d,J＝12.2Hz,1H),1.13(dd,J＝23.6,7.9Hz,6H).

EXAMPLE 37 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (hydroxymethyl) pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (37)

The first step: synthesis of (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-a)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (I-1, 150mg,0.594 mmol) was dissolved in dichloromethane (3 ml) and cooled to 0℃N, N-diisopropylethylamine (61.3 mg,0.4751 mmol) and pyrrolidin-3-yl-methanol (68.4 mg,0.594 mmol) were added and reacted at 0℃for 1 hour. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -5%) to give the target product (1- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-a, 180mg, yield 95.87%). ESI [ m+h ] ⁺ =317.1

And a second step of: synthesis of (((1- (7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol) (37-b)

(1- (2, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-a, 80mg,0.2531 mmol), cesium carbonate (246 mg,0.7594 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (120.8 mg,0.7594 mmol) was added to dioxane (3.5 ml). The temperature is raised to 60 ℃ and the reaction is carried out for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product ((1- (7-chloro-8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-b, 70mg, yield 62.89%). ESI [ m+h ] ⁺ = 440.8

And a third step of: synthesis of (37-c) methanol from (1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl)

((1- (7-Chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-b, 70mg,0.1591 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (163 mg,0.3182 mmol) potassium phosphate (135 mg,0.63 mmol), methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (46 mg,0.0636 mmol) was dissolved in tetrahydrofuran (3.7 ml) and water (0.37 ml). Nitrogen is replaced for 3 times, and the temperature is raised to 60 ℃ for reaction for 6 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then Flash column (methanol: dichloromethane=0% -10%) was purified to give the target product ((1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-c, 49mg, yield 65.96%). ESI [ m+h ] ⁺ = 791.01

Fourth step: synthesis of (((1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-d)

((1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-c, 49mg,0.0621 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (94.2 mg,0.621 mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to give the target product ((1- (7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-d, 55mg, yield > 100%). ESI [ m+h ] ⁺ = 634.67

Fifth step: synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (hydroxymethyl) pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (37)

((1- (7- (8-Ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methanol (37-d, 55mg,0.086 mmol) was dissolved in acetonitrile (3 ml), dioxane hydrochloride (1 ml) was added and reacted at room temperature for 0.5 hours. Separating and purifying the reaction liquid by a preparative liquid chromatograph to obtain a target product of 5-ethynyl-6-fluoro-4- (8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (3- (hydroxymethyl) pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine-7-yl) naphthalen-2-ol (37,4.5mg).ESI[M+H]⁺＝590.2¹H NMR(400MHz,DMSO-d₆)δ10.21(s,1H),9.04(d,J＝31.1Hz,1H),8.01–7.90(m,1H),7.44(t,J＝9.0Hz,1H),7.37(d,J＝2.5Hz,1H),7.18(dd,J＝8.1,2.5Hz,1H),5.26(d,J＝54.4Hz,1H),4.11–3.78(m,7H),3.02(d,J＝25.7Hz,4H),2.80(q,J＝8.0Hz,1H),2.11(d,J＝4.2Hz,1H),2.07–1.59(m,10H).

EXAMPLE 38 Synthesis of 2- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol formate salt (38)

First step Synthesis of 2- (2, 7-dichloro-8-fluoro-5-methylpyridin [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol (38-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (100 mg,0.38 mmol) was dissolved in methylene chloride (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (98 mg,0.76 mmol) and azetidine-3-ol hydrochloride (86 mg,0.76 mmol) were added and reacted at 0℃for 20 minutes. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying Flash column (methanol: dichloromethane=0% -5%) to obtain target product 2- (2, 7-dichloro-8-fluoro-5-methylpyridin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol (38-a, 70mg, yield 53.8%). ESI [ m+h ] ⁺ = 343.2

Second step Synthesis of 2- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-b)

2- (2, 7-Dichloro-8-fluoro-5-methylpyridin [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol (38-a, 70mg,0.2 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (159 mg,1 mmol), N, N-diisopropylethylamine (77 mg,0.6 mmol) was added to dioxane (3 ml). The temperature is raised to 90 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified on a Flash column (methanol: dichloromethane=0% -10%) to give the target product 2- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol (38-b, 50mg, yield 53.8%). ESI [ m+h ] ⁺ =465.9

Third step Synthesis of 2- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-c)

2- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-b, 50mg,0.1 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (67 mg,0.13 mmol), cesium carbonate (107 mg,0.33 mmol), 1' -bis diphenylphosphino ferrocene palladium dichloride dichloromethane complex (18 mg,0.022 mmol) was dissolved in dioxane (7) and water (1.75 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then purified by Flash column (methanol: dichloromethane=0% -10%) to give the target product 2- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol (38-c, 50mg, yield 60.97%). ESI [ m+h ] ⁺ = 816.1

Fourth step Synthesis of 2- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-d)

2- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-c, 50mg,0.06 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.5 ml) was added and the reaction was allowed to react at room temperature for 0.5 hours to give crude 2- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-aza-4-yl) -2-azabicyclo [ 2.25-d ] heptan-1-yl) -2- ([ 2.8-fluoro-7-fluoro-8-pyrrolizin-1-yl) methoxy) -2- ([ 2-8-methyl ] butan-4-yl) 5-yl) and (39H-yl) ethanol (39 mg) 25M, 25 ]

Fifth step Synthesis of 2- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol formate salt (38)

2- (8-Fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptan-6-ol (38-d, 25mg,0.03 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (210 mg,1.62 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the objective product 2- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -2-azabicyclo [2.2.1] heptane-6-ol formate (38, 2mg, yield) 11.1％).ESI[M+H]⁺＝616.1¹H NMR(400MHz,DMSO-d₆)δ8.27(s,1H),7.91-7.90(m,1H),7.40-7.38(m,1H),7.33(s,1H),7.21-7.19(m,1H),5.30(s,0.5H),5.25(s,0.5H),4.05-4.03(m,1H),3.98-3.96(m,1H),3.81-3.79(m,2H),3.12(s,2H),3.063.02(m,3H),2.88-2.86(m,2H),2.57-2.53(m,4H),2.11-2.06(m,4H),1.84-1.75(m,6H).

EXAMPLE 39 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (39)

First step Synthesis of 1- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (39-a)

7-Chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one (120 mg,0.44 mmol) was dissolved in acetonitrile (6 ml), phosphorus oxychloride (162 mg,1.056 mmol) and N, N-diisopropylethylamine (227 mg,1.76 mmol) were then added and after reaction at 80℃for 0.5 hours, the reaction was cooled to 0℃and then N, N-diisopropylethylamine (227 mg,1.76 mmol) and N-methylpiperidin-3-amine hydrochloride (107 mg, 0.578mmol) were added and reacted at 0℃for 0.5 hours. After concentrating under reduced pressure, the target product 1- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (39-a, 220 mg) was obtained by purification on a thin layer chromatography silica gel plate (methanol: dichloromethane=1:10). (ESI) [ m+h ] ⁺ =372.1

Second step Synthesis of tert-butyl 1- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-b)

1- (7-Chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (39-a, 220mg, 0.292 mmol), 4-dimethylaminopyridine (36 mg, 0.292 mmol) was dissolved in acetonitrile (5 ml), followed by the addition of di-tert-butyl dicarbonate (142 mg,0.6512 mmol) and reacted at room temperature for 16 hours. After quenching with water, the reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography on a silica gel plate (petroleum ether: ethyl acetate=3:1) to give tert-butyl (39-b, 30mg, yield 10.75%) of the target product 1- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate. (ESI) [ m+h ] ⁺ =472.4

Thirdly, synthesis of tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylthio) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-c)

Tert-butyl 1- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-b, 30mg,0.064 mmol), potassium carbonate (35 mg,0.256 mmol), tetrakis triphenylphosphine palladium (15 mg,0.0128 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (39 mg,0.0768 mmol) was dissolved in 1, 4-dioxane (3 ml) and water (0.75 ml), nitrogen was blown for 1 minute, and the reaction was carried out at 135℃for 1 hour. After concentrating under reduced pressure, the target product tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylthio) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-c, 25mg, yield 47.17%) was purified by thin layer chromatography on a silica gel plate (petroleum ether: ethyl acetate=3:1).

Synthesis of (39-d) tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfinyl) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate

The target product tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylthio) pyridin [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-c, 25mg,0.03 mmol) and m-chloroperoxybenzoic acid (16 mg,0.09 mmol) were dissolved in dichloromethane (2 ml). The reaction was carried out at room temperature for 0.5h. Quenching with water, extracting with dichloromethane, collecting the organic phase, washing with saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the desired product (tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfinyl) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-d, 43 mg) (ESI) [ m+h ] ⁺ = 838.7)

Fifth step Synthesis of tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilylethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methoxypyridine [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-e)

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (25 mg,0.1539 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml), then 60% sodium hydride (156 mg,0.237 mmol) was added, after 0.5 hours of reaction at room temperature, (tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfinyl) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-d, 43mg,0.0513 mmol) was added, after 0.5H of reaction, the target product tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxy) -8- (triisopropylsilylethynyl) naphthalen-1-yl) -2R, 7 aS) -piperidin-3-yl) (methyl) carbamate (39-d, 43mg,0.0513 mmol) was purified by thin layer chromatography on a silica gel plate (dichloromethane: 25:2), 24mg, yield 50%). (ESI) [ m+h ] ⁺ = 933.9

Sixth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (39-f)

Tert-butyl (1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilylethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methoxypyridin [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) (methyl) carbamate (39-e, 24mg,0.026 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added at room temperature and reacted for 0.5H. The reaction solution was distilled under reduced pressure to give 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (39-f, 35 mg) as a target product.

Seventh step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (39)

5-Ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (39-f, 35mg,0.044 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (334 mg,2.2 mmol) was added and reacted at room temperature for 4 hours. Filtering, distilling the filtrate under reduced pressure by an oil pump to remove the solvent, separating the crude product by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxy-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-carboxylate (39, 4.67mg, yield 15.64％).(ESI)[M+H]⁺＝633.4.¹H NMR(400MHz,DMSO-d₆)δ10.16(s,1H),7.95-7.89(m,1H),7.50-7.31(m,2H),7.22-7.18(m,1H),5.31(s,0.5H),5.18(s,0.5H),4.20-4.05(m,2H),4.03-3.92(m,3H),3.86(s,3H),3.07-3.04(d,2H),2.98(s,1H),2.89-2.76(m,2H),2.65-2.56(m,1H),2.32-2.28(d,3H),2.14-2.07(m,1H),2.20-1.92(m,3H),1.85-1.71(m,4H),1.60-1.55(t,1H),1.37-1.25(m,1H).

EXAMPLE 40 Synthesis of 5-ethyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (40)

First step Synthesis of 1- (2, 7-dichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in dichloromethane (5 ml), the reaction was cooled to-40℃and then N, N-diisopropylethylamine (289 mg,2.24 mmol) and N-methylpiperidin-3-amine hydrochloride (126 mg,0.672 mmol) were added thereto, and the reaction was carried out at-40℃for 0.5 hours. The reaction solution was directly purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=11:100) to give the objective 1- (2, 7-dichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-a, 210 mg). (ESI) [ m+h ] ⁺ = 344.1

Second step Synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-b)

1- (2, 7-Dichloro-8-fluoro-5-methylpyridin-4-yl) -N-methylpiperidin-3-amine (40-a, 210mg,0.61 mmol) was dissolved in 1, 4-dioxane (8 ml), N-diisopropylethylamine (237 mg,1.83 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (4816 mg,3.05 mmol) were then added thereto, and after 16H at 90℃the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=3:25) to give the target product 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyridin-4-yl) -N-methylpiperidin-3-amine (40-b, 50mg, 17.54 mg, yield%). (ESI) [ m+h ] ⁺ = 467.5

Third step Synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyridin [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-c)

(1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-b, 50mg,0.107 mmol), cesium carbonate (105 mg,0.321 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (17.48 mg,0.0214 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (66 mg,0.1284 mmol) was dissolved in 1, 4-dioxahexa-ne (3 ml) and water (0.75 ml), nitrogen was blown for 1 minute, and the reaction was carried out at 135℃for 1 hour. After concentration under reduced pressure, the target product 1- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyridin [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-c, 23mg, 26.44%) was obtained via thin layer chromatography on a silica gel plate (methanol: dichloromethane=3:25).

Fourth step Synthesis of 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethyl) naphthalen-2-ol (40-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyridin [4,3-d ] pyrimidin-4-yl) -N-methylpiperidin-3-amine (40-c, 23mg,0.028 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added at room temperature and reacted for 0.5H. The reaction solution was distilled under reduced pressure to give crude 6-fluoro-4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethyl) naphthalen-2-ol (40-d, 28 mg) as the target product (ESI) [ m+h ] ⁺ = 773.8)

Fifth step Synthesis of 5-ethyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (40)

6-Fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethyl) naphthalen-2-ol (40-d, 28mg,0.036 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (273 mg,1.8 mmol) was added and reacted for 4 hours at room temperature, filtration was performed by oil pump distillation, and the solvent was removed from the filtrate by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the target product 5-ethyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (3- (methylamino) piperidin-1-7 a (5H) -yl) pyridin-4-ol, 29mg, yield of 2-naphtalene-7-ol (40 mg) 30.55％).(ESI)[M+H]⁺＝617.5.¹H NMR(400MHz,DMSO-d₆)δ10.16(s,1H),7.95-7.89(q,1H),7.50-7.31(m,2H),7.22-7.18(m,1H),5.31(s,0.5H),5.18(s,0.5H),4.20-4.05(m,2H),4.03-3.92(m,3H),3.86(s,3H),3.07-3.04(d,2H),2.98(s,1H),2.89-2.76(m,2H),2.65-2.56(m,1H),2.30-2.29(d,3H),2.14-2.07(m,1H),2.02-1.92(m,3H),1.85-1.71(m,4H),1.60-1.55(t,1H),1.37-1.25(m,1H).

EXAMPLE 41 Synthesis of (R) acrylic acid-1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) formate salt (41)

First step (R) Synthesis of 1- (7- (3- (acryloyloxy) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl (41-a)

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (30 mg,0.05 mmol) was dissolved in dichloromethane (2 ml), and triethylamine (51 mg,0.5 mmol) and acryloyl chloride (45.25 mg,0.5 mmol) were added to react at room temperature for 4 hours. After concentration under reduced pressure, the crude target product (R) acrylic acid-1- (7- (3- (acryloyloxy) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-2 (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl (41-a, 88 mg) was obtained. (ESI) [ m+h ] ⁺ =712.9

Second step (R) Synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl) carboxylate (41)

(R) acrylic acid-1- (7- (3- (acryloyloxy) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-2 (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl (41-a, 88mg,0.124 mmol) was dissolved in acetonitrile (2 ml) and water (0.2 ml), ammonium bicarbonate (399mg, 4.96 mmol) was added and reacted at room temperature for 16 hours. Filtering, separating filtrate by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain target product (R) acrylic acid-1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidine-3-yl formate (41, 5.1mg, yield) 5.75％).(ESI)[M+H]⁺＝658.9.¹H NMR(600MHz,DMSO-d₆)δ10.22(s,1H),8.41(s,1H),7.96-7.93(t,1H),7.50-7.33(m,2H),7.25-7.08(m,1H),6.36-6.17(m,1H),6.08-5.81(m,2H),5.34(m,0.5H),5.20(m,0.5H),5.13-4.89(m,1H),4.17-4.11(m,1H),4.04-3.98(m,1H),3.96-3.81(m,2H),3.72-3.57(m,2H),3.49-3.48(m,1H),3.09-3.04(m,2H),3.02-3.00(m,1H),2.82-2.78(q,1H),2.68(s,2H),2.63(s,1H),2.09(s,1H),2.07-2.04(m,1H),2.01-1.90(m,3H),1.87-1.78(m,2H),1.78-1.72(m,2H),1.70-1.62(m,1H).

EXAMPLE 42 Synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl-2-fluoroacrylate formate salt (42)

First step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3- ((2-fluoroacryloyl) oxy) piperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-yl-2-fluoroacrylate (42-a)

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (25 mg,0.04 mmol), 2-fluoroacrylic acid (36 mg,0.4 mmol) and dimethylaminopyridine (2.4 mg,0.5 mmol) were dissolved in dichloromethane (2.5 ml), then N, N' -dicyclohexylcarbodiimide (50 mg,0.24 mmol) was added at 0℃and the reaction was transferred to room temperature for 2 hours. After concentration under reduced pressure, the crude target product 5-ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3- ((2-fluoroacryloyl) oxy) piperidin-1-yl) -2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-yl-2-fluoroacrylate (42-a, 80 mg) was obtained. (ESI) [ m+h ] ⁺ = 748.1.

Second step (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl-2-fluoroacrylate formate salt Synthesis (42)

5-Ethynyl-6-fluoro-4- (8-fluoro-4- ((R) -3- ((2-fluoroacryloyl) oxy) piperidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-yl-2-fluoroacrylate (42-a, 80mg,0.107 mmol) was dissolved in acetonitrile (3 ml) and water (0.3 ml), ammonium bicarbonate (338 mg,4.28 mmol) was added and reacted at room temperature for 3 hours. Filtering, separating filtrate by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain target product (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-yl-2-fluoroacrylate formate (42, 10.12mg, yield) 13.14％).(ESI)[M+H]⁺＝676.1.¹H NMR(600MHz,DMSO-d₆)δ10.14-10.12(d,1H),7.97-7.94(q,1H),7.45-7.42(t,1H),7.37-7.36(t,1H),7.29-7.09(m,1H),5.79-5.50(m,1H),5.33-5.01(m,2H),4.19-4.17(d,1H),4.08-3.97(m,1H),3.96-3.76(m,3H),3.64-3.38(m,2H),3.11-3.05(d,3H),2.84(s,1H),2.71-2.67(t,2H),2.62-2.59(d,1H),2.15-1.62(m,11H).

EXAMPLE 43 Synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol formate salt (43)

First step Synthesis of 1- (2, 7-dichloro-8-fluoro-5-methylpyridin-4, 3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyridinone [4,3-d ] pyrimidine (I-2, 50mg,0.188 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0 ℃, N-diisopropylethylamine (65. Mu.L, 0.376 mmol) and 1,2,3, 6-tetrahydropyridin-3-ol (26 mg,0.188 mmol) were added and reacted at 0℃for 20 minutes. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10) to give the target product 1- (2, 7-dichloro-8-fluoro-5-methylpyridin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-a, 56mg, yield 90.3%). ESI [ m+h ] ⁺ =329.2

Second step Synthesis of 1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-b)

1- (2, 7-Dichloro-8-fluoro-5-methylpyridin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-a, 59mg,0.17 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (135.25 mg,0.85 mmol), N, N-diisopropylethylamine (66 mg,0.51 mmol) was added to dioxane (2.5 ml). The temperature is raised to 90 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by liquid chromatography (methanol: dichloromethane=0% -10%) to give the target product 1- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-b, 67mg, yield 87.0%). ESI [ m+h ] ⁺ =452.1

Third step Synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (43-c)

1- (7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-b, 67mg,0.145 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (92 mg,0.18 mmol), cesium carbonate (146 mg,0.45 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex (24 mg,0.03 mmol) was dissolved in dioxane (3) and water (0.75 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with liquid chromatography column (methanol: dichloromethane=0% -10%) to obtain target product 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (43-c, 53mg, yield 44%). ESI [ M+H ] ⁺ =802.3

Fourth step Synthesis of 1- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-d)

1- (8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (43-c, 53mg,0.066 mmol) was dissolved in acetonitrile (2 ml), dioxane hydrochloride (0.4 ml) was added, and the reaction mixture was allowed to react at room temperature for 1 hour to spin dry to give the crude product 1- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-d, 45 mg) ESI [ M+H ] ⁺ = 759.1

Fifth step Synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol formate salt (43)

1- (8-Fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (43-d, 45mg,0.06 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (46 mg,0.3 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol formate (43, 9mg, yield) 25.7％).ESI[M+H]⁺＝602.3¹HNMR(400MHz,DMSO-d₆)δ8.24(s,1H),7.96-7.94(m,1H),7.44-7.42(m,1H),7.38(s,1H),7.22(s,1H),5.99-5.96(m,2H),5.35(s,0.5H),5.21(s,0.5H),4.37(s,1H),4.23-4.21(m,1H),4.13-4.10(m,2H),4.04-4.03(m,1H),4.03-3.99(m,2H),3.86(s,2H),3.09-3.06(m,3H),3.02(s,1H),2.83-2.82(m,1H),2.65(s,2H),2.15-2.11(m,3H),1.81-1.77(m,3H).

EXAMPLE 44 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol-ate (44)

The first step: synthesis of (2, 7-dichloro-8-fluoro-5-methylpyridinone [4,3-d ] pyrimidin-4-yl) aza-4-ol (44-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in dichloromethane (3 mL), then N, N-diisopropylethylamine (0.098 mL,0.59 mmol) and Asbekiang-4-ol (128 mg,0.84 mmol) were added, after 1 hour of reaction, water was added, dichloromethane extraction, vacuum concentration was followed by thin layer preparation of silica gel plate (petroleum ether: ethyl acetate=1:1) purification to give the target product 1- (2, 7-dichloro-8-fluoro-5-methylpyridin [4,3-d ] pyrimidin-4-yl) aza-4-ol (44-a, 101mg, yield 52.3%). ESI [ m+h ] ⁺ =345.1

Second step Synthesis of 2, 7-dichloro-8-fluoro-4- (4-fluoroazepin-1-yl) -5-methylpyrrolidone [4,3-d ] pyrimidine (44-b)

1- (2, 7-Dichloro-8-fluoro-5-methylpyridin-4-yl) aza-4-ol (44-a, 90mg,0.26 mmol) was dissolved in dichloromethane (2 mL), diethylaminosulfur trifluoride (0.2 mL) was added at 0 ℃, reacted for 0.5 hours at 0 ℃, and after concentrating under reduced pressure, a silica gel plate (petroleum ether: ethyl acetate=1:1) was prepared by thin layer purification to give the objective 2, 7-dichloro-8-fluoro-4- (4-fluoroazein-1-yl) -5-methylpyridin-4, 3-d) pyrimidine (44-b, 49mg, yield 54.3%) as a target product. ESI [ m+h ] ⁺ =347.1

Third step Synthesis of 7-chloro-8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (44-c)

2, 7-Dichloro-8-fluoro-4- (4-fluoroazepin-1-yl) -5-methylpyridinone [4,3-d ] pyrimidine (44-b, 40mg,0.11 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (88 mg,0.55 mmol) was dissolved in 1, 4-dioxane (1 mL), followed by N, N-diisopropylethylamine (0.057 mL,0.33 mmol). After reaction at 90 ℃ for 16 hours under nitrogen protection, silica gel plates (methanol: dichloromethane=1:10) were prepared by thin layer purification after concentration under reduced pressure to give the target product 7-chloro-8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (44-c, 32mg, yield 61.9%). ESI [ m+h ] ⁺ =470.2

Fourth step Synthesis of 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoroazepin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (44-d)

7-Chloro-8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (44-c, 32mg,0.07 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (43 mg,0.084 mmol) and cesium carbonate (68 mg,0.21 mmol) were dissolved in a mixed solvent of 1, 4-dioxane and water 4:1 (2.5 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (11 mg,0.014 mmol) was then added. The reaction was carried out at 135℃for 1 hour with microwaves. Adding water, extracting with ethyl acetate, concentrating under reduced pressure, and purifying with thin layer prepared silica gel plate (methanol: dichloromethane=1:10) to obtain target product 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoroazepine-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (44-d, 30mg, yield 52.26%). ESI [ M+H ] ⁺ = 820.4

Fifth step Synthesis of 6-fluoro-4- (8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (44-e)

(8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (44-d, 30mg,0.036 mmol) was dissolved in acetonitrile (2 mL), 1, 4-dioxane hydrochloride solution (0.2 mL) was added and reacted at room temperature for 1 hour, after concentration under reduced pressure the crude product 6-fluoro-4- (8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (44-e, 32 mg) [ ESM ] 39M ] ⁺ = 776.4 was obtained

Sixth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (44)

6-Fluoro-4- (8-fluoro-4- (4-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (44-e, 32mg,0.04 mmol) was dissolved in N-N dimethylformamide (2 mL) and cesium fluoride (60.76 mg,0.4 mmol) was added. The reaction was carried out at room temperature for 4 hours. Adding saturated saline solution and water, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain target product 5-ethynyl-6-fluoro-4- (8-fluoro-4- (4-fluoroazepine-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine-7-yl) naphthalene-2-ol formate (44, 5.89mg, yield) 23.76％).ESI[M+H]⁺＝620.3¹H NMR(400MHz,DMSO-d₆)δ7.52-7.49(m,1H),7.23-7.21(m,1H),7.14-7.07(m,2H),7.06-7.01(m,2H),5.43(s,0.5H),5.33(s,0.5H),4.97-4.63(m,2H),4.47-4.15(m,1H),4.14-3.68(m,5H),3.57-3.31(m,3H),2.98-2.71(m,2H),2.64-2.58(m,2H),2.35-1.97(m,12H).

EXAMPLE 45 Synthesis of (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-5-methyl-2- (((R) -tetrahydrofurane-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol formate salt (45)

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First step (R) -1- (2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol Synthesis (45-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (100 mg,0.375 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0 ℃, N-diisopropylethylamine (130. Mu.L, 0.75 mmol) and (R) -piperidine-3-alkoxide (52 mg,0.375 mmol) were added and reacted at 0℃for 20 minutes. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with liquid chromatography column (methanol: dichloromethane=0% -5%) to obtain target product (R) -1- (2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-a, 105mg, yield 85.4%). ESI [ m+h ] ⁺ = 330.05

Second step (R) -1- (7-chloro-8-fluoro-5-methyl-2- (((R) -tetrahydrofurane-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol Synthesis (45-b)

(R) -1- (2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-a, 105mg,0.32 mmol), (S) - (tetrahydrofuran-2-yl) methanol (162 mg,1.59 mmol), N, N-diisopropylethylamine (152 mg,0.96 mmol) was added to dioxane (5 ml). The temperature is raised to 90 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by a liquid chromatography column (methanol: dichloromethane=0% -10%) to give the desired product (R) -1- (7-chloro-8-fluoro-5-methyl-2- (((R) -tetrahydrofuranyl-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-b, 100mg, yield 78.7%). ESI [ m+h ] ⁺ = 396.85

Third step (R) -Synthesis of 1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (((R) -tetrahydrofurane-2-yl) methoxy ] pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-c)

(R) -1- (7-chloro-8-fluoro-5-methyl-2- (((R) -tetrahydrofuranyl-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-b, 100mg,0.252 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (155 mg,0.303 mmol), cesium carbonate (246 mg,0.756 mmol), 1' -bis diphenylphosphino ferrocene palladium dichloride dichloromethane complex (41 mg,0.05 mmol) was dissolved in dioxane (4 ml) and water (1 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by a liquid chromatography column (methanol: dichloromethane=0% -10%) to give the desired product (R) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (((R) -tetrahydrofuran-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-c, 110mg, yield 58.5%). ESI [ m+h ] ⁺ = 747.3

Fourth step (R) -Synthesis of 1- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- ((((R) -tetrahydrofurane-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-d)

(R) -1- (8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (((R) -tetrahydrofuran-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-c, 110mg,0.147 mmol) was dissolved in acetonitrile (2 ml), dioxane hydrochloride (1 ml) was added, and the reaction was allowed to stand at room temperature for 1 hour, the reaction mixture was dried by spinning to give the crude product (R) -1- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (((((R) -tetrahydrofuran-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-d, 60 mg) [ M+H ] ⁺ = 702.34)

Fifth step (R) -Synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-5-methyl-2- (((R) -tetrahydrofurane-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol formate salt (45)

(R) -1- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- ((((R) -tetrahydrofuran-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45-d, 60mg,0.085 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (25 mg,0.17 mmol) was added and the reaction mixture was reacted at room temperature for 4 hours. The reaction mixture was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the desired product (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-5-methyl-2- (((R) -tetrahydrofuran-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (45, 8mg, yield 17.3％).ESI[M+H]⁺＝546.8¹H NMR(400MHz,DMSO-d₆)δ8.37(s,1H),7.93-7.91(m,1H),7.43-7.40(m,1H),7.35(s,1H),7.25-7.22(m,1H),4.90(s,1H),4.52-4.49(m,2H),3.77(s,3H),2.68-2.61(m,1H),2.56(s,2H),2.27-2.26(m,1H),2.12-2.19(m,1H),1.97-1.93(m,4H),1.53(s,2H),1.40-1.39(m,2H).

EXAMPLE 46 Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy formate salt (46)

First step Synthesis of 2, 7-dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (46-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (100 mg,0.375 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 ℃, N-diisopropylethylamine (130. Mu.L, 0.375 mmol) and1, 2,3, 6-tetrahydropyridine hydrochloride (45 mg,0.375 mmol) were added and reacted at 0℃for 20 minutes. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with liquid chromatography column (methanol: dichloromethane=0% -5%) to obtain target product 2, 7-dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (46-a, 111mg, yield 94.9%). ESI [ m+h ] ⁺ =313.2

Second step Synthesis of 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidine) (46-b)

2, 7-Dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (46-a, 111mg,0.35 mmol) ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (279 mg,1.75 mmol), N, N-diisopropylethylamine (135 mg,1.05 mmol) was added to dioxane (5 ml). The temperature is raised to 90 ℃ to react for 16h. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with liquid chromatography column (methanol: dichloromethane=0% -10%) to obtain target product 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidine (46-b, 107mg, yield 88.4%). ESI [ M+H ] ⁺ = 435.9)

Third step Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy) (46-c)

7-Chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidine (46-b, 107mg,0.245 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (151 mg, 0.284 mmol), cesium carbonate (329 mg,0.735 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex (30 mg,0.0245 mmol) were dissolved in dioxane (5) and water (1.25 ml), nitrogen was displaced 3 times, the reaction was carried out for 1H, the ethyl acetate was extracted, the organic phase was collected and washed repeatedly with saturated sodium chloride, and the aqueous solution was concentrated by filtration of sodium chloride=0% aqueous solution after filtration and purification of dichloromethane column chromatography, to obtain the target product 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy (46-c, 100mg, yield 43.3%). ESI [ M+H ] ⁺ = 786.1

Fourth step Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy formate salt (46)

4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy (46-c, 100mg,0.127 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (115 mg,0.762 mmol) was added and the reaction mixture was reacted for 1 hour at room temperature. Yield 18.7％).ESI[M+H]⁺＝630.26¹H NMR(400MHz,DMSO-d₆)8.08-8.06(m,1H),7.74-7.73(m,1H),7.54(s,1H),7.42-7.41(m,1H),5.91-5.90(m,1H),5.82-5.80(m,1H),5.40-5.38(m,2H),4.28-4.26(m,1H),4.14-4.13(m,1H),4.06-4.04(m,2H),3.81-3.78(m,4H),3.45(s,3H),3.13-3.10(m,2H),3.02(s,1H),2.87-2.84(m,1H),2.66(s,3H),2.40-2.38(m,2H),2.17-2.14(m,2H),2.03-1.96(m,4H). Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol formate (47)

First step Synthesis of 2, 7-dichloro-8-fluoro-4- (3-fluoroazepin-1-yl) -5-methylpyrrolidone [4,3-d ] pyrimidine (47-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in acetonitrile (5 ml), the reaction was cooled to 0℃and then N, N-diisopropylethylamine (217 mg,1.68 mmol) and 3-fluoroazepine hydrochloride (86 mg,0.56 mmol) were added to react for 0.5 hours at 0 ℃. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=1:200) to give the objective 2, 7-dichloro-8-fluoro-4- (3-fluoroazepin-1-yl) -5-methylpyrrolidone [4,3-d ] pyrimidine (47-a, 178mg, yield 92.27%). (ESI) [ m+h ] ⁺ =347.2

Second step Synthesis of 7-chloro-8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (47-b)

2, 7-Dichloro-8-fluoro-4- (3-fluoroazepin-1-yl) -5-methylpyridinone [4,3-d ] pyrimidine (47-a, 178mg,0.513 mmol) was dissolved in 1, 4-dioxane (7 ml), then N, N-diisopropylethylamine (199mg, 1.539 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (408 mg,2.565 mmol) were added, after 16H reaction at 90℃the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (methanol: dichloromethane=1:20) to give the target product 7-chloro-8-fluoro-4- (3-fluoroazepin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (47-b, 180mg, 74.69%). (ESI) [ m+h ] ⁺ =470.3

Third step Synthesis of 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluoroazepin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (47-c)

7-Chloro-8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (47-b, 180mg,0.383 mmol), cesium carbonate (374 mg,1.149 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (65 mg,0.08 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (236 mg,0.46 mmol) was dissolved in 1, 4-dioxane (10 ml) and water (2.5 ml), nitrogen was blown for 1 minute, and the reaction was carried out for 1 hour at 135 ℃. After concentrating under reduced pressure, the crude product was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=2:25) to give the target product 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluoroazepin-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (47-c, 65mg, yield 20.70%) (ESI) [ m+h ] ⁺ = 820.4

Fourth step Synthesis of 6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (47-d)

8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (47-c, 65mg,0.08 mmol) was dissolved in acetonitrile (5 ml), 1, 4-dioxane hydrochloride solution (0.5 ml) was added at room temperature, and the reaction was carried out for 0.5H, the reaction solution was distilled under reduced pressure to give the crude product of 6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (47-d, 75 mg) [ ESI ] (ESI ] - [ 5326 ] M= 776.5 ]

Fifth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate salt (47)

6-Fluoro-4- (8-fluoro-4- (3-fluoroazetidin-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (47-d, 75mg,0.1 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (608 mg,4 mmol) was added and reacted at room temperature for 6 hours. Filtering, distilling the filtrate under reduced pressure by an oil pump to remove the solvent, and separating the crude product by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4- (8-fluoro-4- (3-fluoroazepine-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-carboxylate (47, 20.73mg, yield) 31.14％).(ESI)[M+H]⁺＝620.4.¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),8.00-7.95(m,1H),7.48-7.43(t,1H),7.39-7.37(m,2.6Hz,1H),7.27-7.14(m,1H),5.35(s,0.5H),5.21(s,0.5H),4.17-4.00(m,3H),3.95-3.57(m,3H),3.13-3.00(m,3H),2.86-2.80(m,1H),2.61(s,3H),2.14-2.12(m,1H),2.08-1.35(m,13H).

EXAMPLE 48 Synthesis of 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (48)

First step, synthesis of hexamethyleneimine (48-b)

Tert-butyl aza-1-carboxylate (48-a, 200mg,1.00 mmol) was dissolved in trifluoroacetic acid (10 ml) and reacted at 0℃for 0.5 h. Concentrating under reduced pressure to obtain target product hexamethyleneimine (48-b, 200 mg), ESI [ M+H ] ⁺ = 99.18

Second step Synthesis of 4- (aza-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (48-c)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (237 mg,0.88 mmol) was dissolved in methylene chloride (10 ml), and hexamethyleneimine (48-b, 200mg,2.01 mmol) and N, N-diisopropylethylamine (260 mg,2.01 mmol) were added to react at 0℃for 2 hours. After concentrating under reduced pressure, purifying by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10), the target product 4- (aza-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (48-c, 240mg, yield 83.1%) ESI [ m+h ] ⁺ = 329.20 is obtained

Third step Synthesis of 4- (aza-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (48-d)

4- (Aza-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyridinone [4,3-d ] pyrimidine (48-c, 100mg,0.30 mmol) was dissolved in dioxane (4 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (29 mg,1.82 mmol) and N, N-diisopropylethylamine (118 mg,0.91 mmol) were added and the mixture was heated to 90℃for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10) to give the desired product 4- (aza-1-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (48-d, 70mg, yield 51.6%) ESI [ m+h ] ⁺ = 450.96

Fourth step Synthesis of 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl ] -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (48-e)

4- (Aza-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (48-d, 70mg,0.154 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (119 mg,0.23 mmol), tetrakis triphenylphosphine palladium (18 mg,0.015 mmol) and potassium carbonate (86 mg,0.61 mmol) were dissolved in dioxane (4 ml) and water (1 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10) to give the target product 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl ] -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (48-e, 40mg, yield 32.3%) ESI [ m+h ] ⁺ = 801.08

Fifth step Synthesis of 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (48-f)

4- (Aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl ] -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (48-e, 40mg,0.049 mmol) was dissolved in acetonitrile (2 ml), dioxane hydrochloride (0.4 ml) was added, and the reaction mixture was purified at room temperature for 0.5 hours to give the desired product 4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) naphthalen-2-ol (48-f, 40mg, yield, 107%) and [ M= 757.03 ] ⁺

Sixth step Synthesis of 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate salt (48)

4- (4- (Aza-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (48-f, 40mg,0.052 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (100 mg,0.065 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate (48, 4.25mg, yield) 13.5％)ESI[M+H]⁺＝600.69¹H NMR(400MHz,DMSO-d₆)δ10.09(s,1H),7.96-7.92(m,1H),7.45-7.41(m,1H),7.35(s,1H),7.19(s,1H),5.33(s,1H),4.12-4.09(m,1H),4.03-3.99(m,1H),3.82-3.69(m,6H),3.08(s,2H),3.01(s,1H),2.85-2.81(m,1H),2.11(s,1H),2.07-2.00(m,2H),1.98(s,1H),1.90-1.67(m,8H),1.51(s,4H).

EXAMPLE 49 Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate formate salt (49)

First step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate formate salt (49)

(4- (4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (50 mg,0.085 mmol) was dissolved in dichloromethane (2 ml), then 4-dimethylaminopyridine (10 mg,0.085 mmol), triethylamine (26 mg,0.255 mmol) and dimethylcarbamoyl chloride (9 mg,0.085 mmol) were reacted for 1 hour, the solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the desired product 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- (((7 aS) -2-fluorotetrahydro-1H) -pyrrolizine-7 a (9 mg,0.085 mmol) and dimethylcarbamoyl chloride (9 mg,0.085 mmol) as the target product, 4- (4- (3, 6-dihydropyridin-1H) -8-yl) -8-fluoro-naphthalen-2- (-yl) ethyl-2- (-methyl-5-naphtyl) 9.78％).ESI[M+H]⁺＝657.4.¹HNMR(400MHz,DMSO-d₆)δ8.25-8.15(m,1H),7.97-7.96(m,1H),7.64-7.60(t,1H),7.52(s,1H),5.97-5.75(m,2H),5.35(s,0.5H),5.21(s,0.5H),4.31-4.25(m,1H),4.16-4.12(m,1H),4.07-3.72(m,5H),3.10-3.09(m,5H),3.01(s,1H),2.94(s,3H),2.86-2.80(m,1H),2.66(s,3H),2.40-2.30(m,2H),2.14-2.13(m,1H),2.06-1.96(m,2H),1.87-1.74(m,3H).

EXAMPLE 50 Synthesis of 4- (4- (3, 3-difluoroaza-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-carboxylate (50)

First step Synthesis of benzyl 3-oxo-aziridine-1-carboxylate (50-b)

The azapan-3-one (50-a, 225mg,1.5 mmol) was dissolved in dichloromethane (9 mL), N-diisopropylethylamine (0.784 mL,4.5 mmol) was added, then carbonyl chlorobenzyl chloride (0.246 mL,1.8 mmol) was slowly added at 0deg.C, after 3 hours reaction at 0deg.C to room temperature, saturated aqueous sodium bicarbonate solution was added, dichloromethane extraction, and concentration under reduced pressure afforded the crude product benzyl 3-oxo-aziridine-1-carboxylate (50-b, 390 mg). ESI [ m+h ] ⁺ =248.1

Second step Synthesis of benzyl 3, 3-difluoroaziridine-1-carboxylate (50-c)

Benzyl 3-oxo-aziridine-1-carboxylate (50-b, 450mg,1.82 mmol) was dissolved in dichloromethane (10 mL), diethylaminosulfur trifluoride (1701 mg,10.5 mmol) was then slowly added at 0deg.C, after reaction for 20 hours at 0deg.C to room temperature, saturated aqueous sodium bicarbonate solution was added, extraction with ethyl acetate, and concentration under reduced pressure gave the crude product benzyl 3, 3-difluoro-aziridine-1-carboxylate (50-c, 417mg, 85% yield). ESI [ m+h ] ⁺ =270.1

Third step Synthesis of 3, 3-difluoroazacyclohexane (50-d)

Benzyl 3, 3-difluoroaziridine-1-carboxylate (50-c, 417mg,1.5 mmol) was dissolved in trifluoroacetic acid (5 mL) at 60℃for 2 hours, and concentrated under reduced pressure to give the crude product 3.3-difluoroaziridine (50-d, 352 mg). ESI [ m+h ] ⁺ =136.1

Fourth step Synthesis of 2, 7-dichloro-4- (3, 3-difluoroaza-1-yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (50-e)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (200 mg,0.75 mmol) was dissolved in methylene chloride (5 mL), then N, N-diisopropylethylamine (0.352 mL,0.75 mmol) and 3.3-difluoroazacyclohexane (50-d, 102mg,0.75 mmol) were added, after 0℃for 0.5 hour, water was added, methylene chloride was used for extraction, and after concentrating under reduced pressure, a silica gel plate (petroleum ether: ethyl acetate=1:1) was prepared by thin layer purification to give the objective 2, 7-dichloro-4- (3, 3-difluoroaza-1-yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (50-e, 200mg, yield 54.8%). ESI [ m+h ] ⁺ = 365.0

Fifth step Synthesis of 7-chloro-4- (3, 3-difluoroazepin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (50-f)

2, 7-Dichloro-4- (3, 3-difluoroaza-1-yl) -8-fluoro-5-methylpyridinone [4,3-d ] pyrimidine (50-e, 200mg,0.55 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (438 mg,2.75 mmol) was dissolved in 1, 4-dioxane (5 mL), followed by N, N-diisopropylethylamine (0.287 mL,1.65 mmol). After reaction at 90 ℃ for 3 hours under nitrogen protection, silica gel plates (methanol: dichloromethane=1:10) were prepared by thin layer purification after concentration under reduced pressure to obtain the target product 7-chloro-4- (3, 3-difluoroaza-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (50-f, 110mg, yield 40.99%). ESI [ m+h ] ⁺ = 488.2

Sixth step Synthesis of 4- (3, 3-difluoroaza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (50-g)

7-Chloro-4- (3, 3-difluoroaza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (50-f, 110mg,0.225 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (139 mg,0.27 mmol) and cesium carbonate (73.3 mg,0.675 mmol) were dissolved in a mixed solvent of 1, 4-dioxane and water 4:1 (8 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (37 mg,0.045 mmol) was then added. The reaction was carried out at 135℃for 1 hour with microwaves. Water was added, extracted with ethyl acetate, concentrated under reduced pressure, and purified by thin layer preparation of silica gel plate (dichloromethane: methanol=10:1) to give the target product 4- (3, 3-difluoroaza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (50-g, 101mg, yield 53.56%). ESI [ m+h ] ⁺ = 838.4

Seventh step Synthesis of 4- (4- (3, 3-difluoroaza-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (50-H)

4- (3, 3-Difluoroazepin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (50-g, 101mg,0.12 mmol) was dissolved in acetonitrile (3 mL) and 1, 4-dioxane hydrochloride solution (0.4 mL) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure the crude product 4- (4- (3, 3-difluoroazepin-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (50-H, 100 mg) was obtained. ESI [ m+h ] ⁺ = 794.4

Eighth step Synthesis of 4- (4- (3, 3-difluoroaza-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-carboxylate (50)

4- (4- (3, 3-Difluoroazepin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (50-H, 100mg,0.126 mmol) was dissolved in N, N-dimethylformamide (2 mL) and cesium fluoride (191.4 mg,1.26 mmol) was added. The reaction was carried out at room temperature for 8 hours. Saturated saline solution and water are added, ethyl acetate is used for extraction, and after decompression concentration, the mixture is separated and purified by preparative liquid chromatography (water phase: 0.1 percent formic acid, organic phase: acetonitrile) to obtain a target product 4- (4- (3, 3-difluoro aza-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluoro tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine-7-yl) -5-ethynyl-6-fluoro naphthalene-2-alcohol formate (50, 2.4mg, yield 2.99％).ESI[M+H]⁺＝638.2.¹H NMR(400MHz,DMSO-d₆)δ10.75(s,1H),10.21(s,1H),8.02-7.98(m,1H),7.5-7.4(m,2H),7.24-7.23(m,1H),5.64(s,0.5H),5.51(s,0.5H),4.65-4.56(m,2H),3.92-3.72(m,5H),3.36-3.27(m,3H),3.69(s,3H),2.57-2.54(m,1H),2.33-1.7(m,12H)

EXAMPLE 51 Synthesis of 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxypyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate salt (51)

First step Synthesis of 4, 7-dichloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-a)

7-Chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidin-4 (3H) -one (300 mg,1.08 mmol) and N, N-diisopropylethylamine (1.13 mL,6.48 mmol) were dissolved in acetonitrile (5 mL) and phosphorus oxychloride (0.271mL, 3.24 mmol) was added. The temperature is raised to 80 ℃ under the protection of nitrogen to react for 0.5 hour. Obtaining the target product reaction liquid 4, 7-dichloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-a), ESI [ M+H ] ⁺ = 294.96

Second step Synthesis of 4- (aza-1-yl) -7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-b)

To the reaction solution of 4, 7-dichloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-a) were added hexamethyleneimine (200 mg,2.01 mmol) and N, N-diisopropylethylamine (0.57 mL,3.24 mmol), and the mixture was reacted at 0℃for 1 hour. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by liquid chromatography to obtain the target product 4- (aza-1-yl) -7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-b, 280mg, yield 88.2%) ESI [ M+H ] ⁺ = 356.84

Third step 4-cycloheptyl-8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfanyl) pyrido [4,3-d ] pyrimidine (51-c)

4- (Aza-1-yl) -7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-b, 240mg,0.67 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (687 mg,1.34 mmol), tetrakis triphenylphosphine palladium (78 mg,0.067 mmol) and potassium carbonate (370 mg,2.68 mmol) were dissolved in dioxane (4 ml) and water (1 ml) and reacted under nitrogen for 1 hour at 135 ℃. Quenched with water, extracted with ethyl acetate, the organic phase collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by liquid chromatography to give the desired product 4-cycloheptyl-8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylthio) pyrido [4,3-d ] pyrimidine (51-c, 500mg, crude) ESI [ m+h ] ⁺ = 707.33

Fourth step Synthesis of 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfonyl) pyrido [4,3-d ] pyrimidine (51-d)

4-Cycloheptyl-8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfanyl) pyrido [4,3-d ] pyrimidine (51-c, 500mg,0.71 mmol) was dissolved in dichloromethane (5 ml). Nitrogen is replaced for 3 times, and the reaction is carried out for 0.5h at normal temperature. Quenching with saturated aqueous sodium bicarbonate solution, extracting with dichloromethane, collecting the organic phase, repeatedly washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the target product 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfonyl) pyrido [4,3-d ] pyrimidine (51-d, 500mg, crude) ESI [ m+h ] ⁺ = 738.97

Fifth step Synthesis of 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine (51-e)

4- (Aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methoxy-2- (methylsulfonyl) pyrido [4,3-d ] pyrimidine (51-d, 40mg,0.049 mmol) was dissolved in tetrahydrofuran (5 ml), sodium hydrogen (50 mg,2.04 mmol) was added, nitrogen was replaced three times, and the reaction was carried out at 0℃under nitrogen for 0.5 hours. ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (325 mg,2.04 mmol) was dissolved in tetrahydrofuran (3 mL) and added to the reaction system, and the mixture was allowed to react at room temperature for 0.5 hours. Quenching with saturated aqueous ammonium chloride solution, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by liquid chromatography to obtain target product 4- (aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine (51-e, 290mg, crude product) ESI [ M+H ] ⁺ = 818.07

Sixth step Synthesis of 4- (aza-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine hydrochloride (51-f)

4- (Aza-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine (51-e, 290mg,0.35 mmol) was dissolved in acetonitrile (5 mL), dioxane hydrochloride (100 mL) was added, and the mixture was reacted at room temperature for 1 hour. Concentrating the reaction solution to obtain a target product 4- (aza-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalene-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine hydrochloride (51-f, 280mg, crude product) ESI [ M+H ] ⁺ = 774.02

Seventh step 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxypyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate salt (51)

4- (Aza-1-yl) -7- (8-ethynyl-7-fluoro-3- (methoxy-methoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methoxypyrido [4,3-d ] pyrimidine hydrochloride (51-f, 280mg,0.36 mmol) was dissolved in N, N dimethylformamide (5 ml), cesium fluoride (274 mg,1.80 mmol) was added and reacted at room temperature for 5 hours. 0.1% formic acid, organic phase: acetonitrile) to give the objective 4- (4- (aza-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methoxypyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate (51, 14.06mg, yield) 6.2％)ESI[M+H]⁺＝618.26¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),7.96-7.93(m 1H),7.46-7.42(m,1H),7.36-7.35(m,1H),7.20-7.19(m,1H),5.32(s,1H),4.10-4.05(m,1H),4.02-3.94(m,2H),3.84(s,3H),3.75-3.61(m,4H),3.10-3.05(m,2H),2.99(s,1H),2.83-2.77(m,1H),2.10-2.09(m,1H),2.04-1.94(m,2H),1.89-1.69(m,7H),1.52(s,4H).

EXAMPLE 52 Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (52)

First step Synthesis of 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-a)

2, 7-Dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (52-a, 70mg,0.22 mmol), 1- (1-methylpyrrolidin-2-yl) ethan-1-ol (85 mg,0.66 mmol) was dissolved in acetonitrile (3 ml) and reacted at 60℃for 2 hours. Concentrating under reduced pressure to obtain target product 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-a, 80mg, crude product) ESI [ M+H ] ⁺ = 405.90

Second step Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-b)

7-Chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-a, 80mg,0.2 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (154 mg,0.3 mmol), methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (14 mg,0.02 mmol) and cesium carbonate (195 mg,0.6 mmol) were dissolved in toluene (5 ml) and water (1 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 100 ℃ for reaction for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel plate (petroleum ether: ethyl acetate=1:1) to give the desired product 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-b, 85mg, yield 57.0%)

Third step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (52-c)

4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidine (52-b, 85mg,0.112 mmol) was dissolved in acetonitrile (2 ml), dioxane hydrochloride (0.4 ml) was added and reacted at room temperature for 0.5 hours. The reaction solution was purified to give 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (52-c, 80mg, yield, crude product)

Fourth step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (52)

4- (4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (52-c, 80mg,0.052 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (85 mg,0.562 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methyl-2- (1- (1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate (52, 24mg, yield) 38.1％)ESI[M+H]⁺＝555.63¹H NMR(600MHz,DMSO-d₆)δ10.12(s,1H),7.95-7.92(m,1H),7.43(t,J＝9.2Hz,1H),7.34(s,1H),7.18-7.10(m,1H),5.81(s,1H),4.42-4.09(m,3H),3.97-3.58(m,4H),2.60-2.59(m,3H),2.37-2.33(m,1H),2.05-1.91(m,2H),1.86-1.66(m,2H),1.16-1.07(mz,4H),0.99(d,J＝22.8Hz,2H).

EXAMPLE 53 Synthesis of 4- (4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (53)

First step Synthesis of 2, 7-dichloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (53-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (250 mg,0.938 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0 ℃, N-diisopropylethylamine (400 uL,1.876 mmol) and 3, 3-difluoroazetidine hydrochloride (120 mg,0.938 mmol) were added and reacted at 0℃for 20 minutes. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate=4:1) to give the target product 2, 7-dichloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (53-a, 115mg, yield 38.3%). ESI [ m+h ] ⁺ = 324.1

Second step Synthesis of 7-chloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyridine [4,3-d ] pyrimidine (53-b)

2, 7-Dichloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (53-a, 115mg,0.356 mmol) ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (284 mg,1.78 mmol) was added to dioxane (2.5 ml), followed by the final addition of N, N-diisopropylethylamine (200. Mu.L, 1.068 mmol). The temperature is raised to 90 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel (methanol: dichloromethane=1:10) to give the target product 7-chloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyridine [4,3-d ] pyrimidine (53-b, 87mg, yield 55.8%). ESI [ m+h ] ⁺ =446.3

Third step Synthesis of 4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy group (53-c)

7-Chloro-4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyridine [4,3-d ] pyrimidine (53-b, 87mg,0.195 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (120 mg,0.234 mmol), cesium carbonate (191 mg,0.585 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex (15 mg,0.039 mmol) was dissolved in dioxane (4 ml) and water (1 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10) to give the target product 4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (53-c, 96mg, yield 61.9%). ESI [ m+h ] ⁺ = 796.6

Fourth step Synthesis of 4- (4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (53-d)

4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (53-c, 96mg,0.12 mmol) was dissolved in acetonitrile (2 ml), dioxane hydrochloride (0.7 ml) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was dried to give the crude product 4- (4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (53-d, 80 mg). ESI [ m+h ] ⁺ = 752.8

Fifth step Synthesis of 4- (4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (53)

4- (4- (3, 3-Difluoroazetidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (53-d, 80mg,0.106 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (403 mg,2.65 mmol) was added and reacted at room temperature for 4 hours. The reaction was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the desired product 4- (4- (3, 3-difluoroazetidin-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate (53, 8mg, yield) 12.7％).ESI[M+H]⁺＝596.5¹HNMR(600MHz,DMSO-d₆)δ10.14(s,1H),8.18(s,1H),7.98-7.96(m,1H),7.47-7.45(m,1H),7.39-7.37(m,1H),7.21(s,1H),5.33(s,0.5H),5.24(s,0.5H),4.94-4.90(m,2H),4.71-4.68(m,2H),4.16-4.15(m,1H),4.09-4.04(m,2H),3.08-3.03(m,2H),2.71(s,3H),2.15-2.07(m,4H),1.90-1.80(m,4H).

EXAMPLE 54 Synthesis of 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-carboxylate (54)

First step Synthesis of 2, 7-dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (54-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (250 mg,0.934 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0 ℃, N-diisopropylethylamine (200. Mu.L, 0.934 mmol) and 3, 3-difluoropyrrolidine (100 mg,0.9384 mmol) were added and reacted at 0℃for 20 minutes. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate=4:1) to give the desired product 2, 7-dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (54-a, 280mg, yield 88.9%). ESI [ m+h ] ⁺ =337.9

Second step Synthesis of 7-chloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (54-b)

2, 7-Dichloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (54-a, 280mg,0.83 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (661mg, 4.153 mmol) was added to dioxane (2.5 ml) and finally N, N-diisopropylethylamine (500 μl,2.49 mmol) was added. The temperature is raised to 90 ℃ to react for 16h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel (methanol: dichloromethane=1:10) to give the target product 7-chloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (54-b, 287mg, 75.1% yield). ESI [ m+h ] ⁺ = 460.3

Third step Synthesis of 4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy (54-c)

7-Chloro-4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (54-b, 287mg,0.624 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (641 mg,1.25 mmol), cesium carbonate (610 mg,1.872 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex (161 mg,0.125 mmol) was dissolved in dioxane (12 ml) and water (3 ml). The nitrogen is replaced for 3 times, and the temperature is raised to 135 ℃ for reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:10) to give the target product 4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy (54-c, 280mg, yield 50.4%). ESI [ m+h ] ⁺ = 810.8

Fourth step Synthesis of 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (54-d)

4- (3, 3-Difluoropyrrolidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy (54-c, 280mg, 0.348 mmol) was dissolved in acetonitrile (10 ml), dioxane hydrochloride (1.5 ml) was added and reacted at room temperature for 1 hour. The reaction solution was dried to give the crude product 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (54-d, 200 mg). ESI [ m+h ] ⁺ = 766.7

Fifth step Synthesis of 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-carboxylate (54)

44- (4- (3, 3-Difluoropyrrolidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (54-d, 200mg,0.26 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (990 mg,6.53 mmol) was added and reacted at room temperature for 4 hours. The reaction was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the desired product 4- (4- (3, 3-difluoropyrrolidin-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate (54, 30mg, yield) 18.98％).ESI[M+H]⁺＝610.3¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.16(s,1H),7.99-7.97(m,1H),7.45-7.43(m,1H),7.39-7.38(m,1H),7.24(s,1H),5.35(s,0.5H),5.22(s,0.5H),4.31-4.28(m,2H),4.16-4.13(m,2H),4.04-4.02(m,2H),3.97(s,1H),3.11-3.09(m,2H),2.85-2.80(m,2H),2.62(s,3H),2.15-2.06(m,4H),1.82-1.75(m,4H).

EXAMPLE 55 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate (55)

First step Synthesis of 2, 7-dichloro-8-fluoro-5-methyl-4- (pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (55-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (250 mg,0.95 mmol) was dissolved in methylene chloride (10 ml), and pyrrolidine (54 mg,0.76 mmol) and N, N-diisopropylethylamine (370 mg,2.85 mmol) were added to react at 0℃for 1 hour. Extracting with dichloromethane three times after quenching with water, concentrating the organic phase under reduced pressure to obtain the target product 2, 7-dichloro-8-fluoro-5-methyl-4- (pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (55-a, 330mg, crude) ESI [ M+H ] ⁺ = 301.15

Second step Synthesis of 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridine (55-b)

2, 7-Dichloro-8-fluoro-5-methyl-4- (pyrrolidin-1-yl) pyrido [4,3-d ] pyrimidine (55-a, 100mg,0.33 mmol) was dissolved in dioxane (4 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (420 mg,2.64 mmol) and N, N-diisopropylethylamine (129 mg,0.99 mmol) were added and the mixture was heated to 90℃for 16 hours. Concentrating under reduced pressure, and separating by liquid chromatography to obtain target product 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridine (55-b, 65mg, yield 46.4%) ESI [ M+H ] ⁺ = 424.17

Third step Synthesis of 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (55-c)

7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridine (55-b, 65mg,0.15 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (92 mg,0.18 mmol), 1-bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (24 mg,0.02 mmol) and cesium carbonate (146 mg,0.45 mmol) were dissolved in dioxane (2 ml) and water (0.5 ml). Nitrogen replacement, heating to 135 ℃ and microwave reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by liquid chromatography to give the desired product 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (55-c, 50mg, crude) ESI [ m+h ] ⁺ = 773.03

Fourth step Synthesis of 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (55-d)

8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (4-c, 50mg,0.065 mmol) was dissolved in acetonitrile (3 ml) and dioxane hydrochloride (1 ml) was added and the reaction mixture was concentrated to dryness at room temperature to give the target product 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (55-e, 50mg, crude) ESI [ M+H ] ⁺ = 729.96

Fifth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridin-7-yl) naphthalen-2-ol formate (55)

6-Fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (55-d, 50mg,0.068 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (51 mg,0.34 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was concentrated by extraction with ethyl acetate and subjected to preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (pyrrolidin-1-yl) -1, 6-naphthyridin-7-yl) naphthalen-2-ol formate (55, 7.85mg, yield 20％)ESI[M+H]⁺＝573.62¹H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.16(s,1H),7.95-7.93(m,1H),7.44-7.41(m,1H),7.36-7.34(m,1H),7.20(s,1H),5.31(s,1H),5.22(s,1H),4.11-4.09(m,1H),4.00-3.97(m,2H),3.82-3.74(m,2H),3.53-3.50(m,2H),3.10-3.05(m,2H),3.03-3.01(m,1H),2.83-2.77(m,1H),2.54(s,3H),2.09-2.03(m,2H),1.99-1.82(m,6H),1.79-1.72(m,2H).

EXAMPLE 56 Synthesis of 4- (4- (azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (56)

First step (Synthesis of 4- (azetidin-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (56-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (300 mg,1.125 mmol) was dissolved in dichloromethane (10 ml), N-diisopropylethylamine (292 mg,2.254 mmol) and azetidine (64 mg,1.121 mmol) were added and reacted at 0℃for 20 minutes. Quenching with water, extracting with ethyl acetate, collecting organic phase, repeatedly washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain target product (4- (azetidin-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (56-a, 310mg, yield 95%), ESI [ M+H ] ⁺ = 287.12)

Second step Synthesis of 4- (azetidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (56-b)

(4- (Azetidin-1-yl) -2, 7-dichloro-8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (56-a, 310mg,1.079 mmol) was dissolved in 1, 4-dioxane (10 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (390 mg,5.40 mmol) and N, N-diisopropylethylamine (420 mg,3.242 mmol) were added sequentially, reaction was carried out for 16H at 90 ℃ C., water quench was added, ethyl acetate extraction was carried out, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified via thin layer chromatography silica gel plate (dichloromethane=1:10) to give the target product 4- (azetidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -methoxy) pyrido [ 5-d ] pyrimidine (29 mg, 35H) -5-methyl ] pyrimidine (39 mg, 25 mg, 39 mg) and [ 56-5 ] pyrimidine (25 mg, 39 mg) was obtained after thin layer chromatography

Third step Synthesis of 4- (azetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (56-c)

4- (Azetidin-1-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (56-b, 110mg,0.268 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (275 mg,0.536 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (44 mg,0.053 mmol) and cesium carbonate (262 mg,0.806 mmol) were dissolved in 1, 4-dioxane (6.4 ml) and water (1.6 ml) and reacted for 1H at 135 ℃. Quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by liquid chromatography (methanol: dichloromethane=1:10) to give the target product 4- (azetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (56-c, 55mg, yield 54%) ESI [ m+h ] ⁺ = 759.99

Fourth step Synthesis of 4- (4- (azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (56-d)

4- (Azetidin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (56-c, 55mg,0.072 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.5 ml) was added and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to give 4- (4- (azetidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (56-d, 55mg, yield 106%) ESI [ m+h ] ⁺ = 715.94

Fifth step Synthesis of 4- (4- (azetidin-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (56)

4- (4- (Azetidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (56-d, 55mg,0.076 mmol) was dissolved in N, N-dimethylformamide (2 ml), cesium fluoride (100 mg, 0.618 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective 4- (4- (azetidin-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate (56-P1, 1.06mg, yield 2%;56-P2,1.83mg, yield) 3％)ESI[M+H]⁺＝559.5956-P2:¹H NMR(600MHz,DMSO-d₆)δ7.95-7.92(m,1H),7.44-7.41(m,1H),7.36-7.35(m,1H),7.19(s,1H),5.21(s,1H),4.21-4.17(m,2H),4.11-4.09(m,1H),4.05-3.97(m,2H),3.11-2.99(m,4H),2.57(s,3H),2.43-2.34(m,3H),2.13-1.92(m,4H),1.84-1.75(m,4H).

EXAMPLE 57 Synthesis of 4- (4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (57)

First step Synthesis of 4- (3-azabicyclo [3.1.0] hex-3-yl) -2, 7-dichloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine (57-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in acetonitrile (5 ml), the reaction was cooled to 0℃and then N, N-diisopropylethylamine (217 mg,1.68 mmol) and 3-azabicyclo [3.1.0] hexane hydrochloride (60 mg,0.504 mmol) were added and reacted at 0℃for 0.5 hours. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by thin layer chromatography on a silica gel plate (dichloromethane: methanol=50:1) to give the objective 2, 7-dichloro-8-fluoro-4- (3-fluoroazepin-1-yl) -5-methylpyrrolidone [4,3-d ] pyrimidine (57-a, 145mg, yield 82.86%). ESI [ m+h ] ⁺ = 314.2

Second step Synthesis of 4- (3-azabicyclo [3.1.0] hex-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine) (57-b)

2, 7-Dichloro-8-fluoro-4- (3-fluoroazepin-1-yl) -5-methylpyridinone [4,3-d ] pyrimidine (57-a, 145mg,0.463 mmol) was dissolved in 1, 4-dioxane (7 ml), then N, N-diisopropylethylamine (180 mg,1.389 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (369 mg,2.315 mmol) were added, after 16H reaction at 90℃the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (methanol: dichloromethane=7:100) to give the target product 4- (3-azabicyclo [3.1.0] hex-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (57-b, 75 mg, 75.25% yield). ESI [ m+h ] ⁺ = 436.3

Third step Synthesis of 4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (57-c)

4- (3-Azabicyclo [3.1.0] hex-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (57-b, 150mg,0.344 mmol), cesium carbonate (336 mg,1.032 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (56 mg,0.069 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (212 mg,0.413 mmol) was dissolved in 1, 4-dioxane (10 ml) and water (2.5 ml) and reacted for 1 minute with nitrogen at microwave 135℃for 1 hour. After concentration under reduced pressure the crude product was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=1:20) to give the target product 4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (57-c, 118mg, 43.70% yield). ESI [ m+h ] ⁺ = 787.2

Fourth step Synthesis of 4- (4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (57-d)

4- (3-Azabicyclo [3.1.0] hex-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (57-c, 118mg,0.15 mmol) was dissolved in acetonitrile (10 ml), and 1, 4-dioxane hydrochloride solution (1 ml) was added at room temperature and reacted for 0.5H. The reaction solution was distilled under reduced pressure to give crude 4- (4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (57-d, 130 mg) as the target product. ESI [ m+h ] ⁺ = 743.1

Fifth step Synthesis of 4- (4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (57)

4- (4- (3-Azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (57-d, 130mg,0.175 mmol) was dissolved in N, N-dimethylformamide (7 ml), cesium fluoride (1068 mg,7 mmol) was added and reacted at room temperature for 4 hours. Filtering, distilling the filtrate under reduced pressure by an oil pump to remove the solvent, and separating the crude product by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4- (4- (3-azabicyclo [3.1.0] hex-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate (57, 31.29mg, yield) 28.19％).ESI[M+H]⁺＝586.8.¹H NMR(600MHz,DMSO-d₆)δ10.13(s,1H),7.98-7.95(m,1H),7.47-7.44(m,1H),7.38-7.37(d,J＝2.5Hz,1H),7.22(s,1H),5.33(s,0.5H),5.24(s,0.5H),4.25(s,1H),4.13-4.12(d,J＝10.3Hz,1H),4.03-4.01(m,1H),3.86-3.80(m,3H),3.63-4-3.62(d,J＝11.3Hz,1H),3.26(s,1H),3.13-3.04(m,3H),2.86-2.82(m,1H),2.57(s,3H),2.18-1.68(m,7H),1.64-1.61(m,2H).

EXAMPLE 58 Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyridinone [4,3-D ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol formate salt (58)

First step (Synthesis of (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (58-a)

A solution of dimethyl sulfoxide (3.805 g,48.7 mmol) in dichloromethane (5 ml) was added dropwise to a solution of oxalyl chloride (3.705 g,29.2 mmol) in dichloromethane (5 ml) at-75℃and reacted for 1H, then a solution of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (1.55 g,9.74 mmol) in dichloromethane (5 ml) was added dropwise, the reaction was continued for 1H, triethylamine (9.85 g,97.5 mmol) was added to the above reaction solution, the reaction was cooled to room temperature and stirred for 16H, then the system was diluted with dichloromethane (5 ml), the organic phase was washed with saturated sodium hydrogencarbonate solution (25 ml) and the organic phase was concentrated under reduced pressure to give the objective product (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -formaldehyde (58-a, 1.4g, yield 91.44%).

Second step (S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methane-D-ol Synthesis (58-b)

Reaction (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (58-a, 65mg,0.41 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml), sodium deuterated borohydride was added to react for 1H, then methanol (0.5 ml) was added to quench the reaction, H ₂ O (10 ml) was added to dilute the reaction, ethyl acetate (10 ml) was extracted three times, the other batch was amplified by equal 2-fold ratio, and the organic phases of the two batches were mixed and the solvent was distilled off under reduced pressure to give the target product (S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methane-D-alcohol (58-b, 108 mg). (ESI) [ m+h ] ⁺ =161.4

Third step Synthesis of 7-chloro-4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyrido [4,3-D ] pyrimidine (58-c)

2, 7-Dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-D ] pyrimidine (70 mg,0.224 mmol) was dissolved in1, 4-dioxane (8 ml), then cesium carbonate (220 mg, 0.675mmol) and (S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methane-D-ol (58-b, 108mg,0.67 mmol) were added, after reaction at 90℃for 16H, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on a silica gel plate (dichloromethane: methanol=50:3) to give the target product 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-D) -5-methylpyrimidine [4,3-D ] (58-c) (75 mg, 76.53%). (ESI) [ m+h ] ⁺ =437.3

Fourth step Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy-D) -5-methylpyrido [4,3-D ] pyrimidine (58-D)

7-Chloro-4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-D) -5-methylpyrido [4,3-D ] pyrimidine (58-c, 75mg,0.17 mmol), cesium carbonate (166 mg,0.51 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (28 mg,0.034 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (105 mg,0.204 mmol) was dissolved in 1, 4-dioxane (5 ml) and water (1.25 ml), nitrogen was blown for 1 minute, and the reaction was carried out at 135℃for 1 hour. After concentration under reduced pressure the crude product was purified by thin layer chromatography on silica gel plate (methanol: dichloromethane=1:20) to give the target product 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (S) - ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy-D) -5-methylpyrido [4,3-D ] pyrimidine (58-D, 67mg, yield 50%). (ESI) [ m+h ] ⁺ =788.2

Fifth step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyrido [4,3-D ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (58-e)

4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylmethoxy-D) -5-methylpyrido [4,3-D ] pyrimidine (58-D, 67mg,0.085 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added at room temperature and reacted for 0.5H. The reaction solution was distilled under reduced pressure to give crude 4- (4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyrido [4,3-D ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (58-e, 70 mg) as the target product. (ESI) [ m+h ] ⁺ =744.1

Sixth step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyridinone [4,3-D ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol formate (58)

4- (4- (3, 6-Dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyrido [4,3-D ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (58-e, 70mg,0.094 mmol) was dissolved in N, N-dimethylformamide (3 ml), cesium fluoride (719mg, 4.7 mmol) was added and the reaction was carried out at room temperature for 4 hours. Filtering, distilling the filtrate under reduced pressure by an oil pump to remove the solvent, and separating the crude product by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4- (4- (3, 6-dihydropyridin-1 (2H) yl) -8-fluoro-2- ((S) - ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-D) -5-methylpyrrolidone [4,3-D ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-carboxylate (58, 2.03mg, yield) 3.44％).(ESI)[M+H]⁺＝587.8.¹H NMR(600MHz,DMSO-d₆)δ10.19(s,1H),8.29(s,1H),7.96-7.95(m,1H),7.48-7.44(m,1H),7.25-7.01(m,1H),5.98-5.64(m,2H),5.36-4.83(m,1H),4.41-4.14(m,2H),4.12-3.77(m,3H),3.13-3.00(m,2H),2.86-2.75(m,1H),2.65-2.61(m,2H),2.55-2.53(m,3H),2.30-2.23(m,2H),2.25-2.04(m,2H),2.03-1.91(m,2H),1.86-1.75(m,2H),1.70-1.62(m,3H).

EXAMPLE 59 Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylethoxy) -5-methylpyridinone [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol formate salt (59)

First step (preparation of (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (59-a)

A solution of dimethyl sulfoxide (3.805 g,48.7 mmol) in dichloromethane (5 ml) was added dropwise to a solution of oxalyl chloride (3.705 g,29.2 mmol) in dichloromethane (5 ml) at-75℃and reacted for 1H, then a solution of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (1.55 g,9.74 mmol) in dichloromethane (5 ml) was added dropwise, the reaction was continued for 1H, triethylamine (9.85 g,97.5 mmol) was added to the above reaction solution, the reaction was cooled to room temperature and stirred for 16H, then the system was diluted with dichloromethane (5 ml), the organic phase was washed with saturated sodium hydrogencarbonate solution (25 ml) and the organic phase was concentrated under reduced pressure to give the objective product (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -formaldehyde (59-a, 1.4g, yield 91.44%).

Second step Synthesis of (S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethan-1-ol (59-b)

Reaction to anhydrous tetrahydrofuran (16 ml) of (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (59-a, 600mg,3.82 mmol) was slowly added methyl magnesium bromide (12 ml, 1M) at-40℃and the reaction system was slowly warmed to room temperature and reacted for 16 hours, tetrahydrofuran (40 ml) and saturated aqueous ammonium chloride solution (2 ml) were respectively added to the reaction system, followed by concentrating under reduced pressure, then 20ml of methylene chloride was added, filtration was carried out, and the filtrate was distilled under reduced pressure to obtain crude target product (S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethane-1-ol (59-b, 1.2 g). (ESI) [ m+h ] ⁺ =174.2

Third step Synthesis of 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylethoxy) -5-methylpyridinone [4,3-d ] pyrimidine (59-c)

2, 7-Dichloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (100 mg,0.32 mmol) was dissolved in 1, 4-dioxane (5 ml), then N, N-diisopropylethylamine (124 mg,0.96 mmol) and (S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) ethan-1-ol (59-b, 332mg,1.92 mmol) were added, after 16H reaction at 90℃the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (methanol: dichloromethane=7:100) to give the target product 7-chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylethone-1-ol [ 59-b,332mg,1.92 mmol) and [ 55H ] pyrimidine (59-d ] (80 mg, 57.55%) as a ] as a target product (80 mg, 55.55H%) was obtained by purification through thin layer chromatography of silica gel plate (methanol: dichloromethane=7:100)

Fourth step Synthesis of 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylethoxy) -5-methylpyrido [4,3-d ] pyrimidine (59-d)

7-Chloro-4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylethoxy) -5-methylpyridinone [4,3-d ] pyrimidine (59-c, 80mg,0.178 mmol), cesium carbonate (174 mg, 0.284 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (29 mg,0.036 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (109 mg,0.214 mmol) was dissolved in 1, 4-dioxahexacyclic (5 ml) and water (1.25 ml), nitrogen was blown for 1 minute, and the reaction was carried out at 135℃for 1 hour. After concentration under reduced pressure the crude product was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=3:50) to give the desired product 4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((S) -1- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylethoxy) -5-methylpyrido [4,3-d ] pyrimidine (59-d, 78mg, yield 54.93%). (ESI) [ m+h ] ⁺ =801.4

Fifth step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ethoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (59-e)

4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylethoxy) -5-methylpyrido [4,3-d ] pyrimidine (59-d, 78mg,0.1 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (0.5 ml) was added at room temperature and reacted for 0.5H. The reaction solution was distilled under reduced pressure to give crude 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ethoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (59-e, 60 mg) as the target product (ESI) [ m+h ] ⁺ = 757.5

Sixth step Synthesis of 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ylethoxy) -5-methylpyridinone [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol formate salt (59)

4- (4- (3, 6-Dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -ethoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethyl) naphthalen-2-ol (59-e, 60mg,0.079 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (600 mg,3.95 mmol) was added and reacted for 4 hours at room temperature, filtration was performed, the filtrate was distilled off under reduced pressure by an oil pump to remove the solvent, and the crude product was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the target product 4- (4- (3, 6-dihydropyridin-1 (2H) -yl) -8-fluoro-2- ((S) -1- ((2 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methylethyl) -5-pyridone [3, 3-d ] pyrimidin-7-yl ] -5-fluoro-7 a (5H) -ethyl ] 7-yl formate (26 mg, yield of the desired product 6.2％).(ESI)[M+H]⁺＝600.4.¹H NMR(600MHz,DMSO-d₆)δ10.18(s,1H),8.26(s,1H),7.98-7.95(m,1H),7.47-7.44(t,1H),7.38-7.37(d,J＝2.5Hz,1H),7.26-7.19(m,1H),5.90-5.85(d,J＝49.5Hz,2H),5.34(s,0.5H),5.24(s,0.5H),5.11-5.08(m,1H),4.26-4.21(m,1H),3.98-3.65(m,5H),3.03-2.95(m,3H),2.83-2.79(m,1H),2.65(s,3H),2.35-2.30(m,1H),2.02-1.91(m,2H),1.87-1.84(m,1H),1.79-1.70(m,2H),1.29-1.25(m,3H).

EXAMPLE 60 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol formate salt (60)

First step Synthesis of 2, 7-dichloro-8-fluoro-4- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-methylpyrido [4,3-d ] pyrimidine (60-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.57 mmol) was dissolved in methylene chloride (5 ml), and octahydrocyclopenta [ c ] pyrrole (57 mg,0.513 mmol) and N, N-diisopropylethylamine (222 mg,1.71 mmol) were added to react at 0℃for 1 hour. Extracting with dichloromethane three times after water quenching, concentrating the organic phase under reduced pressure to obtain the target product 2, 7-dichloro-8-fluoro-4- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-methylpyrido [4,3-d ] pyrimidine (60-a, 200mg, crude product), ESI [ M+H ] ⁺ = 341.21

Second step Synthesis of 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidine) (60-b)

2, 7-Dichloro-8-fluoro-4- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-methylpyrido [4,3-d ] pyrimidine (60-a, 200mg,0.58 mmol) was dissolved in dioxane (8 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (463mg, 2.9 mmol) and N, N-diisopropylethylamine (225 mg,1.74 mmol) were added and reacted at 90℃for 16 hours. Concentrating under reduced pressure, and separating by liquid chromatography to obtain target product 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidine (60-b, 270mg, crude product), ESI [ M+H ] ⁺ = 463.96

Third step Synthesis of 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (60-c)

7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidine (60-b, 270mg,0.58 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (356 mg,0.7 mmol), 1-bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (95 mg,0.2 mmol) and cesium carbonate (567 mg,1.74 mmol) were dissolved in dioxane (8 ml) and water (2 ml). Nitrogen replacement, heating to 135 ℃ and microwave reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by liquid chromatography to give the target product 8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (60-c, 250mg, crude) ESI [ m+h ] ⁺ = 814.08

Fourth step Synthesis of 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (60-d)

8-Fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (60-c, 250mg,0.3 mmol) was dissolved in acetonitrile (3 ml), dioxane hydrochloride (1 ml) was added, and reaction was carried out at room temperature for 1 hour, the reaction mixture was concentrated to dryness to give the target product 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (60-d, 250mg, crude product), ESI [ M+H ] ⁺ = 770.03

Fifth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) yl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol formate salt (60)

6-Fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopentyl [ c ] pyrrol-2 (1H) -acyl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (60-d, 250mg,0.32 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (243 mg,1.6 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was concentrated by extraction with ethyl acetate and subjected to preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the objective product 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) yl) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol formate (60, 25mg, yield) 12.5％)ESI[M+H]⁺＝613.69¹H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.15(s,1H),7.97(dd,J＝9.2,6.0Hz,1H),7.45(t,J＝9.2Hz,1H),7.38-7.37(m,1H),7.22(s,1H),5.35(s,1H),4.13-4.10(m,2H),4.02-3.99(m,1H),3.88(s,1H),3.82-3.72(m,1H),3.52-3.46(m,2H),3.10-3.02(m,3H),2.88-2.78(m,1H),2.71(s,2H),2.60(s,3H),2.12-1.96(m,3H),1.87-1.66(m,6H),1.61-1.39(m,3H).

EXAMPLE 61 Synthesis of 4- (4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (61)

First step Synthesis of 4- (3-azabicyclo [3.2.0] heptan-3-yl) -2, 7-dichloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine (61-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in acetonitrile (6 ml), the reaction was cooled to 0℃and then N, N-diisopropylethylamine (217 mg,1.68 mmol) and 3-azabicyclo [3.2.0] heptane hydrochloride (75 mg,0.504 mmol) were added and reacted at 0℃for 0.5 hours. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=1:50) to give 4- (3-azabicyclo [3.2.0] heptane-3-yl) -2, 7-dichloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine (61-a, 160mg, yield 87.43%). ESI [ m+h ] ⁺ =327.2

Second step Synthesis of 4- (3-azabicyclo [3.2.0] heptan-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine) (61-b)

4- (3-Azabicyclo [3.2.0] heptan-3-yl) -2, 7-dichloro-8-fluoro-5-methylpyridine [4,3-d ] pyrimidine (61-a, 160mg,0.49 mmol) was dissolved in 1, 4-dioxane (7 ml), then N, N-diisopropylethylamine (190 mg,1.47 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (390 mg,2.45 mmol) were added, after 16H reaction at 90℃the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=3:50) to give the objective 4- (3-azabicyclo [3.2.0] heptan-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (61 mg, 36 mg, yield: 36%). ESI [ m+h ] ⁺ =450.3

Third step Synthesis of 4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (61-c)

4- (3-Azabicyclo [3.2.0] heptan-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (61-b, 135mg,0.3 mmol), cesium carbonate (293 mg,0.9 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (56 mg,0.069 mmol), (2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (185 mg,0.36 mmol) was dissolved in 1, 4-dioxahexacyclic (8 ml) and water (2 ml), nitrogen gas was blown for 1 minute, and the reaction was carried out at 135℃for 1 hour. After concentration under reduced pressure the crude product was purified by thin layer chromatography on a silica gel plate (dichloromethane: methanol=100:5) to give the target product 4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (61-c, 120mg, yield 50%). ESI [ m+h ] ⁺ =800.6

Fourth step Synthesis of 4- (4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (61-d)

4- (3-Azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (61-c, 120mg,0.15 mmol) was dissolved in acetonitrile (5 ml), and 1, 4-dioxane hydrochloride solution (1 ml) was added at room temperature to react for 0.5H. The reaction solution was distilled under reduced pressure to give 4- (4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (61-d, 130 mg) as a target product. ESI [ m+h ] ⁺ = 756.4

Fifth step Synthesis of 4- (4- (3-azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (61)

4- (4- (3-Azabicyclo [3.2.0] heptan-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (61-d, 130mg,0.17 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (1.3 g,8.6 mmol) was added and the reaction was carried out at room temperature for 4 hours. Filtering, distilling the filtrate under reduced pressure by an oil pump to remove the solvent, and separating the crude product by preparative liquid chromatography (water phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4- (4- (3-azabicyclo [3.2.0] heptane-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate (61, 48.51mg, yield) 43.70％).ESI[M+H]⁺＝601.1.¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),7.99-7.95(m,1H),7.48-7.44(t,1H),7.39-7.38(d,J＝2.6Hz,1H),7.24-7.23(d,J＝2.4Hz,1H),5.37(s,0.5H),5.23(s,0.5H),4.21-4.04(m,3H),3.92-3.79(m,2H),3.65-3.60(m,1H),3.52-3.47(m,2H),3.15-2.98(m,4H),2.89-2.83(m,1H),2.70(s,3H),2.19-2.00(m,5H),1.89-1.74(m,3H),1.65-1.59(m,2H).

EXAMPLE 62 Synthesis of 4- (4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol formate salt (62)

First step Synthesis of 2, 7-dichloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (62-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (100 mg,0.375 mmol) was dissolved in methylene chloride (5 ml), and 2, 5-dihydro-1H-pyrrole (40 mg,0.375 mmol) and N, N-diisopropylethylamine (146 mg,1.125 mmol) were added thereto and reacted at 0℃for 0.5 hours. Extracting with dichloromethane three times after quenching with water, concentrating the organic phase under reduced pressure to obtain the target product 2, 7-dichloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (62-a, 200mg, crude product), ESI [ M+H ] ⁺ =299.13

Second step Synthesis of 7-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (62-b)

2, 7-Dichloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-5-methylpyrido [4,3-d ] pyrimidine (62-a, 200mg,0.67 mmol) was dissolved in dioxane (8 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (53 mg,3.35 mmol) and N, N-diisopropylethylamine (260 mg,2.00 mmol) were added, and the mixture was heated to 90℃to react for 16 hours. Concentrating under reduced pressure, and separating by liquid chromatography to obtain target product 7-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (62-b, 200mg, crude product), ESI [ M+H ] ⁺ = 421.9

Third step Synthesis of 4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (62-c)

7-Chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidine (62-b, 200mg,0.48 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (295 mg,0.576 mmol), 1-bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (78 mg,0.096 mmol) and cesium carbonate (470 mg,1.44 mmol) were dissolved in dioxane (8 ml) and water (2 ml). Nitrogen replacement, heating to 135 ℃ and microwave reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by liquid chromatography to give the desired product 4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (62-c, 350mg, crude) as ESI [ m+h ] ⁺ = 771.0

Fourth step Synthesis of 4- (4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (62-d)

4- (2, 5-Dihydro-1H-pyrrol-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- [ (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy ] -5-methylpyrido [4,3-d ] pyrimidine (62-c, 350mg,0.45 mmol) was dissolved in acetonitrile (4 ml), dioxane hydrochloride (1 ml) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated to dryness to give 4- (4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (62-d, 350mg, crude product) as a target product, ESI [ m+h ] ⁺ = 727.0

Fifth step Synthesis of 4- (4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol formate salt (62)

4- (4- (2, 5-Dihydro-1H-pyrrol-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (62-d, 350mg,0.48 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (365 mg,2.4 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was concentrated by extraction with ethyl acetate and separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the objective 4- (4- (2, 5-dihydro-1H-pyrrol-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -5-methylpyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-carboxylate (62, 13.12mg, yield) 5％),ESI[M+H]⁺＝570.6¹HNMR(400MHz,DMSO-d₆)δ10.17(s,1H),7.98-7.95(m,1H),7.48-7.43(m,1H),7.39-7.38(m,1H),7.24-7.23(m,1H),6.00(s,2H),5.35(s,1H),4.83-4.79(m,2H),4.30-4.278(m,2H),4.18-4.08(m,2H),4.05-4.01(m,1H),3.14-3.00(m,3H),2.86-2.80(m,1H),2.61(s,3H),2.16-1.96(m,3H),1.90-1.72(m,3H).

EXAMPLE 63 Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol formate salt (63)

First step Synthesis of 2, 7-dichloro-8-fluoro-5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-a)

2,4, 7-Trichloro-8-fluoro-5-methylpyrrolidone [4,3-d ] pyrimidine (150 mg,0.56 mmol) was dissolved in methylene chloride (5 ml), and 6-azaspiro [2.5] octane (80 mg,0.56 mmol) and N, N-diisopropylethylamine (217 mg,1.68 mmol) were added to react at 0℃for 0.5 hours. Extracting with dichloromethane three times after water quenching, concentrating the organic phase under reduced pressure to obtain the target product 2, 7-dichloro-8-fluoro-5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-a, 190mg, crude product), ESI [ M+H ] ⁺ = 341.2

Second step Synthesis of 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-b)

2, 7-Dichloro-8-fluoro-5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-a, 190mg,0.56 mmol) was dissolved in dioxane (8 ml), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (447 mg,2.78 mmol) and N, N-diisopropylethylamine (217 mg,1.68 mmol) were added, and the mixture was heated to 90℃to react for 16 hours. Concentrating under reduced pressure, and separating by liquid chromatography to obtain target product 7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-b, 250mg, crude product), ESI [ M+H ] ⁺ =463.0

Third step Synthesis of 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) (63-c)

7-Chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidine (63-b, 250mg,0.54 mmol) ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (336 mg, 0.238 mmol), 1-bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (88 mg,0.108 mmol) and cesium carbonate (578 mg,1.62 mmol) were dissolved in dioxane (8 ml) and water (2 ml). Nitrogen replacement, heating to 135 ℃ and microwave reaction for 1h. Quenched with water, extracted with ethyl acetate, the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by liquid chromatography to give the target product 8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy (63-c, 350mg, crude) ESI [ m+h ] ⁺ = 814.08

Fourth step Synthesis of 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethynyl) naphthalen-2-ol (63-d)

8-Fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy (63-c, 350mg,0.43 mmol) was dissolved in acetonitrile (4 ml), dioxane hydrochloride (1 ml) was added, and the reaction mixture was concentrated to dryness at room temperature to give the target product 6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethynyl) naphthalen-2-ol (63-d, 350mg, crude product), ESI [ M+H ] ⁺ = 770.03

Fifth step Synthesis of 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol formate salt (63)

6-Fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [2.5] oct-6-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5- (((triisopropylsilyl) ethynyl) naphthalen-2-ol (63-d, 350mg,0.45 mmol) was dissolved in N, N-dimethylformamide (5 ml), cesium fluoride (342 mg,2.25 mmol) was added, and the reaction mixture was reacted for 16 hours at room temperature, and the reaction mixture was concentrated by extraction with ethyl acetate to give 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-methyl-4- (6-azaspiro [ 2.25 mmol) pyrido [ 2.5-5-yl ] pyridin-7 a (5H) -yl) methoxy) -5-methyl-4- ([ 6-azaspiro [ 2.5-5-H) -1-oxazin-7 a (5H) -yl) methoxy) after separation of the prepared liquid chromatography (aqueous phase: 0.1% formic acid: acetonitrile) to give a (yield of 1, 10mg, 1-naphtyl) 14.6％)ESI[M+H]⁺＝613.69¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),7.99-7.95(m,1H),7.48-7.43(m,1H),7.38(d,J＝2.4Hz,1H),7.23-7.22(m,1H),5.35(s,1H),4.14-4.00(m,2H),3.85-3.53(m,5H),3.10-2.98(m,3H),2.89-2.79(m,1H),2.67(s,3H),2.13-1.97(m,3H),1.86-1.76(m,3H),1.62-1.46(m,4H),0.48-0.30(m,4H).

Test example 1 phosphorylation-ERK 1/2 (THR 202/TYR 204) HTRF test

1.1 Experimental reagent, instrument and consumables

The experimental reagent ：FBS、PBS、DMSO、DMEM medium、RPMI-1640medium、F12Kmedium、MEM medium、PHOSPHO-ERK1/2(THR202/TYR204)kit、0.25％Trypsin-EDTA, reagent is purchased from Gibco, beyotime, cisbio and other manufacturers;

Instrument and consumable: 96-well cell culture plate, 384-well cell culture plate, enzyme-labeled instrument, desk-top centrifuge, carbon dioxide incubator, instrument and consumable are purchased from Corning, greiner.

1.2KRAS mutants and cell lines

/>

1.3 Experimental procedure

A) And (3) paving: cells expressing the KRAS mutation were cultured in medium (Gibco) containing fetal bovine serum (Gibco). After the cells were in the logarithmic growth phase, the cells were resuspended to the appropriate density in serum-free medium, inoculated into 96-well cell culture plates at 80. Mu.L/well, placed in a cell incubator (37 ℃,5% CO ₂) and incubated overnight.

B) Dilution of the compound: after dilution of the 10mM stock solution with serum-free medium, it was diluted in cell culture serum-free medium with 20. Mu.L/well of the compound. Centrifugation at 1000rpm/min for 1min was carried out in a cell incubator (37 ℃,5% CO ₂) and incubated for 4h. The initial concentration of compound was 6000nM, 3.5-fold dilution.

C) Cracking: cell supernatants were removed and 50. Mu.L/well of 1 Xcell lysate (Cisbio) was immediately added and incubated for 40min with shaking at room temperature.

D) Rotating plate: after shaking, 16 μl of cell lysates were transferred from 96-well cell culture plates to a small volume (Greiner, 784075) white assay plate. To the lysate was added 4. Mu.L of the formulated antibody premix solution (Cisbio, 64 AERPEH).

E) Incubate overnight at room temperature in the dark.

F) HTRF signals were read in a multifunctional microplate reader (Tecan, spark 10M). The data was analyzed using a four parameter logarithmic model (4 parameter logistic model) to calculate IC ₅₀ values.

The phosphorylation-ERK 1/2 (THR 202/TYR 204) HTRF results are shown in Table 1, and from the results, it is clear that the exemplary compounds of the present invention have higher inhibitory activity against AGS cells mutated in Kras G12D, NCI-H358 cells mutated in Kras G12C, NCI-H460 cells mutated in Kras Q61H, wild-type MKN1 cells, SW1116 cells mutated in Kras G12A, SW626 cells mutated in Kras G12V, calu-6 cells mutated in Kras Q61K, MDA-MB-231 cells mutated in Kras G13D, and A549 cells mutated in Kras G12S, with IC50 of less than 10. Mu.M; or less than 1000nM, or less than 100nM, or even less than 50nM.

Wherein, for the IC ₅₀ value, "+++", etc representation IC ₅₀ between 0nM and 500 nM; "+++". Representation of IC ₅₀ is arranged between between 500nM and 1. Mu.M; "++" means that IC ₅₀ is between 1 μM and 10 μM. "-" indicates no test, and blank indicates no activity.

TABLE 1

Test example 2 KRAS nucleotide exchange experiment

2.1 Experimental reagents and instruments

Mant-GDP-KRAS (Bioduro), assay buffer (20mM HEPES,150mM NaCl,1mM MgCl2,1mM DTT,Ph 7.2), GTP (Sigma), EDTA (Sigma), DMSO, white 384-well plates (Greiner), multifunctional microplate reader (Tecan), centrifuge (Eppendorf).

2.2 Experimental procedure

A) A Buffer solution containing 20mM HEPES,150mM NaCl,1mM MgCl ₂ was prepared and DTT solution was added to a final concentration of 1mM just before use.

B) Mant-GDP-KRAS protein (including mant-GDP-KRAS-WT, G12D, G C, G12A, G12V, Q12H, Q K) (Bioduro) was diluted with Buffer and added to a white 384-well plate (Greiner, 784075) at 10. Mu.L/well and centrifuged using a centrifuge (Eppendorf, 5810R), 1000G/min,1min. Mant-GDP-KRAS protein was 1. Mu.M final.

C) Dilution of the compound: after 10mM stock solution was diluted with Buffer, 5. Mu.L/well was added to 384-well plates, mixed with protein solution, centrifuged at 1000g/min for 1min, and incubated at room temperature for 10min. The final concentrations of compounds were 6000, 2400, 960, 384, 154, 61, 25, 9.8, 3.9nM.

D) A solution of 4mM GTP (Sigma, G8877) and 40mM EDTA (Sigma, 03690) was prepared, mixed 1:1 (v/v), transferred to 5. Mu.L to 384 well plates and centrifuged at 1000G/min for 1min.

E) A multifunctional microplate reader (Tecan, spark 10M) was immediately used to read signal values at 360nm/440nm for 20min in kinetic mode.

F) Analyzing and processing data: the SLOPE value is calculated and the inhibition rate is calculated according to the following formula.

Inhibition％＝(Sample value–ZPE)/(HPE–ZPE)*100％

HPE＝average sample_{No EDTA}value

ZPE＝average sample_0.5％DMSOvalue

The data were analyzed using a four-parameter logarithmic model (4 parameter logistic model) to calculate IC ₅₀ values, and the results are shown in table 2, from which it can be seen that the exemplary compounds of the present invention have higher inhibitory activity against both mant-GDP-KRAS-WT and KRAS G12D, G12C, G12A, G12V, Q61H, Q K muteins with IC50 below 10 μm; or less than 1000nM, or less than 500nM.

Wherein, for the IC ₅₀ value, "+++", etc representation IC ₅₀ between 0nM and 500 nM; "+++". Representation of IC ₅₀ is arranged between between 500nM and 1. Mu.M; "++" means that IC ₅₀ is between 1 μM and 10 μM.

TABLE 2

Test example 3 test of cell proliferation inhibition Activity

3.1KRAS mutant and cell lines

3.2 Experimental procedure

Cells were cultured in an incubator at 37℃with 5% CO ₂, the density was adjusted to 1.11x10 ⁴ cells/mL with complete medium after cell digestion counting in the logarithmic growth phase, and the cells were inoculated in 384-well cell culture plates (Greiner, 781098) at a volume of 45. Mu.L per well and incubated overnight in a incubator at 37℃with 5% CO ₂. The next day, the test compound was prepared as a 10mM stock solution with DMSO, and was diluted 3-fold in a gradient starting with the highest dose of 10. Mu.M with DMSO, 8 concentration points were set up altogether, and then diluted to working solutions of different concentrations with complete medium-fold ratio, added to the corresponding wells, 2 parallel wells were set up per well, DMSO wells were set up as negative controls, and finally all test wells had consistent DMSO content of 0.1%. After continuous cultivation in a 5% CO ₂ incubator at 37℃for 72h, useThe reagent (Promega, G7571) was used for detection, the Luminescence signal was detected by a TECAN microplate reader Luminescence module, and a curve was fitted by GRAPHPAD PRISM software 4 parameter method to calculate IC ₅₀ values.

The results are shown in Table 3, where the exemplary compounds of the present invention exhibit potent proliferation inhibitory activity against each mutated cell of KRAS.

Wherein, for the IC ₅₀ value, "+++", etc representation IC ₅₀ between 0nM and 500 nM; "+++". Representation of IC ₅₀ is arranged between between 500nM and 1. Mu.M; "++" indicates that IC ₅₀ is between 1 μM and 10 μM, "-" indicates no test, and blank indicates no activity.

TABLE 3 Table 3

The foregoing descriptions of specific exemplary embodiments of the present invention are presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims

1. A compound of formula (I ₀), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

in formula (I ₀), R ¹ is selected from hydrogen, -CH ₃、-OCH₃;

R ² is selected from

Ring A is selected from

M is optionally 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from-CH ₂-、-CHR⁷ -or-C (R ⁷)₂;

r ⁴¹ is selected from

2. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

In the formula (I) of the present invention,

R ² is selected from

M is optionally 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from-CH ₂-、-CHR⁷ -or-C (R ⁷)₂;

When R ² is selected from Time,/>The radicals being selected from

When R ² is selected fromTime,/>The radicals being selected from

R ⁴¹ is selected from

3. The compound according to any one of claim 1 to 2, which is represented by the formula (I-a), the formula (I-b), the formula (I-c) or the formula (I-d), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof,

4. The compound of formula (I ₀), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, of claim 1, wherein the compound is selected from the group consisting of:

5. The compound of any one of claims 1-4, a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the pharmaceutically acceptable salt comprises any one or a combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, formate, acetate, trifluoroacetate, propionate, methanesulfonate, lactate, benzenesulfonate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate, or malate.

6. A process for the preparation of a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof as claimed in claim 2, comprising the steps of:

(3) The compound (M-b) and the compound Or/>Through Suzuki coupling reaction, a compound (M-c) is generated, wherein the R ²' group is selected from R ² or R ² substituted by a protecting group;

the definition of R ²、R⁷、X¹、m、q、p、R⁴¹ is as defined in any one of claims 1 to 5.

7. Pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a prodrug thereof and a pharmaceutically acceptable adjuvant.

8. Use of a compound according to any one of claims 1-5, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, a pharmaceutical composition according to claim 7, for the preparation of a kit for the treatment of cancer, an immune disease or a prognostic evaluation of a cancer patient;

Preferably, the cancer includes pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, and the like;

More preferably, the cancer comprises pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer, and ovarian cancer.

9. Use of a compound of any one of claims 1-5, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or a pharmaceutical composition of claim 7 for the preparation of a KRAS inhibitor; preferably, the use in the preparation of KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutation inhibitors.

10. A method of inhibiting mutant KRAS in a biological sample comprising contacting the biological sample with a compound according to any one of claims 1-5, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or the pharmaceutical composition of claim 7.