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

Abstract

The present invention provides a fused-ring aromatic compound having a broad-spectrum inhibitory effect on KRAS mutations, and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in formula (I ₀ ), wherein the definition of each group is detailed in the specification. In addition, the present invention also discloses a pharmaceutical composition comprising the compound, and its use in preparing a kit for treating cancer, immune diseases or evaluating the prognosis 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 condensed-ring aromatic compound having a broad-spectrum KRAS inhibitory effect, a pharmaceutical composition, a preparation method and uses thereof.

Background Art

Kirsten rat sarcoma 2 viral oncogene homolog (KRas) is a small GTPase and a member of the Ras family. KRas protein is inactive when bound to GDP; when extracellular growth and differentiation factors transmit signals to KRAS protein, the protein binds to GTP and activates it, thereby activating KRAS and downstream signals (Nature Review cancer 3:11-22, 2003). Signaling pathways such as RAS-RAF-MEK-ERK and RAS-PI3K-AKT regulate multiple cellular processes, including cell proliferation, differentiation and survival. KRAS mutations can continuously activate downstream cell signals, promote cell proliferation, migration and anti-apoptosis, and induce tumorigenesis.

KRAS mutations are closely related to tumor formation and development. The role of KRAS in malignant tumors has been observed more than 30 years ago (for example, see Santos et al., (1984) Science 223: 661-664). About 20% of all human tumors have abnormal expression of KRAS, and KRAS mutations are detected in 25-30% of lung adenocarcinomas (for example, see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13 (12): 928-942 doi: 10.1038 / nrd428). 80% of KRAS mutations occur at the 12th codon, causing a single amino acid replacement, the most important of which are G12C and G12D. KRAS G12C mutation refers to the mutation of glycine at position 12 of the protein to cysteine. The frequency of occurrence in tumors is as follows: pancreatic cancer (57%), colorectal cancer (35%), bile duct cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer (15%) and ovarian cancer (14%) (Seminars in Cancer Biology. 2019Jun27.pii:S1044-579X(18)30060-9). KRAS G12D mutation refers to the mutation of glycine at position 12 of the protein to aspartic acid. The frequency of occurrence in tumors is pancreatic cancer (25.0%), colorectal cancer (13.3%), rectal cancer (10.1%), non-small cell lung cancer (4.1%) and small cell lung cancer (1.7%) (for example, see The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8):818-831. Dataset Version 4). In addition to G12C and G12D, KRAS has many 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 is also different.

Since KRAS mutations are frequently found in various tumor types, it has become a popular anti-cancer target in the pharmaceutical industry (see MeCormick (2015) Clin Cancer Res. 21(8):1797-1801). The development of KRAS small molecule inhibitors is generally divided into three approaches: (i) competitive ligands to prevent GTP binding; (ii) allosteric modulation to lock KRAS G12C in an inactive state; (iii) protein-protein interaction inhibitors to disrupt KRAS and its effector proteins and guanine nucleotide exchange factors (GEFs) (such as son of sevenless (SOS), RAF, and PI3K).

Over the past few decades, drug development targeting KRAS has mostly ended in failure, so KRAS was once considered undruggable. However, in recent years, with the breakthrough progress in biology and protein structure, including comparative studies of different structures of mutant and wild-type KRAS proteins, small molecule inhibitors targeting KRAS G12C have been successful in clinical practice. Amgen's First-in-Class KRAS G12C inhibitor AMG 510 has been approved for marketing by the US FDA on May 28, 2021 for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations. Mirati and many biopharmaceutical companies at home and abroad are also developing drugs targeting KRAS, but most of them are targeting KRAS G12C or KRAS G12D mutations. As mentioned above, in addition to KRAS G12C or KRASG12D mutations, KRAS has multiple other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. These KRAS mutations play an important role in the formation and development of many types of cancer. Therefore, it is urgent to develop drugs targeting these KRAS mutations. In addition, with the successful launch of drugs targeting KRAS G12C, we expect that cancer patients receiving treatment will develop drug resistance. Therefore, in response to these unmet clinical needs, it is of great significance to develop a new generation of broad-spectrum KRAS inhibitors that are innovative and target multiple KRAS mutations to counteract drug resistance mechanisms.

Summary of the invention

In one aspect of the present invention, a novel substituted fused-ring aromatic compound is provided, which serves as a broad-spectrum inhibitor of KRAS mutations and has high inhibitory activity.

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, wherein the compound is as shown in formula (I ₀ ):

In formula (I ₀ ), R ¹ is selected from hydrogen, -CH ₃ , -OCH ₃ ;

R ² is selected from

wherein R is selected from C _1-3 alkynyl, C _1-3 alkenyl, C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by -CN, -NH ₂ , -N(CH ₃ ) ₂ , -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ OH;

Ring A is selected from

m is 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from -CH ₂ -, -CHR ⁷ - or -C(R ⁷ ) ₂ ;

^R7 at each substitution position is independently selected from -H, -OH, -F, -Cl, -CH3, _-CN , _{-CH2OH, -CH2Cl , -OCH3} , _-CH2CN , -CH( _CH3 ) _2OH , _-NHCH3 , or two ^R7 substituents on the same carbon atom form a 3-6 membered heterocyclic ring or carbonyl group with the carbon atom, and p is optionally 0, 1, 2, 3 or 4;

R ⁴¹ is selected from

Another aspect of the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is as shown in formula (I):

In formula (I),

R ² is selected from

wherein R is selected from C _1-3 alkynyl, C _1-3 alkenyl, C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by -CN, -NH ₂ , -N(CH ₃ ) ₂ , -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ OH;

m is 0 or 1;

q is optionally 0, 1 or 2;

X ¹ is selected from -CH ₂ -, -CHR ⁷ - or -C(R ⁷ ) ₂ ;

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

When R ² is selected from hour, The group is selected from

When R ² is selected from hour, The group is selected from

R ⁴¹ is selected from

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

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

In a preferred embodiment, the compound of formula ( _I0 ) or formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the pharmaceutically acceptable salt includes 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.

Another aspect of the present invention provides a method for preparing the compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, comprising the following steps:

(1) Compound (I-1) and compound (R ¹ 'H) undergo a substitution reaction to generate compound (Ma), wherein the R ¹ ' group is selected from R ⁸ or R ⁸ substituted with a protecting group, and the R ⁸ group is selected from

(2) Compound (Ma) and compound (R ⁴¹ H) undergo coupling reaction to generate compound (Mb);

(3) the compound (Mb) and the compound After Suzuki coupling reaction, compound (Mc) is generated, wherein the R ² 'group is selected from R ² or R ² substituted with a protecting group;

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

R ² , R ⁷ , X ¹ , m, q, p and R ⁴¹ are as defined above.

Another aspect of the present invention provides a pharmaceutical composition, characterized in that the composition comprises the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug and pharmaceutically acceptable excipients.

Another aspect of the present invention provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, and the pharmaceutical composition in the preparation of a kit for treating cancer, immune disease or evaluating the prognosis of cancer patients;

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

Preferably, use in the preparation of a method for treating a disease associated with KRAS mutation;

Preferably, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer and ovarian cancer;

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

Another aspect of the present invention provides a use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug or a pharmaceutical composition described as its prodrug in the preparation of KRAS inhibitors; preferably, use in the preparation of KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRASQ61K, KRAS Y96D and other KRAS mutation inhibitors.

Another aspect of the present invention provides a method for inhibiting mutant KRAS in a biological sample, comprising contacting the biological sample with the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof or the pharmaceutical composition.

DETAILED DESCRIPTION

According to the contents of the present disclosure, in accordance with common technical knowledge and customary means in the art, without departing from the basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes may be made.

In this disclosure, Refers to the chemical bond connection.

Drug or drug 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 a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.

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 can 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 tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing the compound of formula I as the active compound can also introduce beads, microspheres or microcapsules, such as those constructed from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, i.e., administered intravenously (i.v.), intracerebroventricularly (i.c.v.), subcutaneously (s.c.), intraperitoneally (i.p.), intramuscularly (i.m.), subcutaneously (s.d.) or intradermally (i.d.), by direct injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the form of an excipient, in the form of a suspension, solution or emulsion in an oil or aqueous carrier, and can include formulation agents such as anti-settling agents, stabilizers and/or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as a suppository or retention enema (eg, containing a conventional suppository base 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 use of the terms "reduce", "inhibit", "mitigate" or "reduce" is relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, the reduced response in a subject or cell treated with a compound is compared with the response in a subject or cell not treated with a compound. As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dose sufficient to treat, inhibit or alleviate one or more symptoms of a disease state being treated or otherwise provide a desired pharmacological and/or physiological effect. The exact dosage will vary according to a variety of factors, such as variables (e.g., age, immune system health, etc.) on which the subject depends, the disease or illness, and the treatment administered. The effect of an effective amount can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of a subject before or when a drug or drug combination is administered, or in the case of a drug combination, the combined effect can be compared with the effect of administering only one drug.

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

The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

Uses and treatments

The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof amenable to the methods described herein, whether in vitro or in situ. 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 using any amount and any route of administration effective for treating or lessening the severity of a disease associated with KRAS.

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, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioanalysis, gene expression studies, and identification of biological targets.

The method of inhibiting KRAS in a patient disclosed herein comprises the step of administering to the patient a compound disclosed herein or a composition comprising the compound.

The provided compounds are KRAS inhibitors and are therefore useful for treating one or more conditions associated with KRAS activity. Thus, in certain embodiments, the present disclosure provides a method for treating a KRAS-mediated condition 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 in which KRAS or a mutant thereof is known to play a role. Therefore, another embodiment of the present disclosure is directed to treating or lessening the severity of one or more diseases in which KRAS or a mutant thereof is 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 disorder, 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 method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present disclosure to a mammal. In certain embodiments, the mammal is a human.

As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or survival of cancer cells, and/or causing cancer cell death by cytotoxicity, nutrient depletion or induction of apoptosis, either individually or collectively 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 glands, adrenal glands, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, 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, kidney cancer, esophageal cancer, brain cancer, lymphoma or colorectal cancer, etc. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

The compounds of the present disclosure can be used to treat a proliferative disease selected from the group consisting of a benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma or a gastrointestinal cancer (particularly a colorectal cancer or a colorectal adenoma) or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, an undifferentiated tumor, a papillary carcinoma, a seminoma, a melanoma, a MYD88 driven disorder, DLBCL, ABC DLBCL, IL-1 driven disorders, rheumatic or indolent multiple myeloma or leukemia.

Cancers described in the present disclosure include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myelocytic leukemias, acute myeloblastic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), 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., fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumors, the ovarian, ovarian, prostate, squamous cell, basal cell, adenocarcinoma, sweat gland, sebaceous gland, papillary, papillary adenocarcinoma, cystadenocarcinoma, medullary, bronchogenic, renal cell, hepatoma, bile duct, choriocarcinoma, seminoma, embryonal, Wilms' tumor, cervical, uterine, testicular, lung, small cell lung cancer, bladder, epithelial, glioma, astrocytoma, glioblastoma multiforme (GBM), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

In some embodiments, the cancer is a glioma, an astrocytoma, a glioblastoma multiforme (GBM, also known as a glioblastoma), a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, an hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a schwannoma, a neurofibrosarcoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

In some specific embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-multiforme astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, 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 a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or a pediatric patient.

In another specific embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal tract (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, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct cancer or pancreatic cancer; gastrointestinal tract/gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

The term "primary tumor" is relative to secondary tumor. Primary tumor refers to a tumor that first appears in a certain part of the body such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

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 transplant 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 syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (cancer or infection primary or secondary). The allergic disorder may be selected in particular from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollens and related allergens, berylliosis. The respiratory disorder may be selected from, 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 hypertension and emphysema, among others.

The term "viral infection" includes but is not limited to retroviral infection, hepatitis virus infection, COVID-19 novel coronavirus infection, Zika virus infection, dengue virus infection, etc.

Combination therapy approach

The present disclosure provides a combination therapy using compounds as described in the present disclosure and other therapeutic drugs. The term "combination therapy" used in the present disclosure includes the administration of these agents in a sequential manner, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents, or at least two agents, is substantially performed simultaneously. The order of each agent, or substantially simultaneous administration, can be affected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, subcutaneous routes, and direct absorption through mucosal tissue. The agents can be administered by the same route or different routes. For example, the first agent can be administered orally, and the second agent can be administered intravenously. In addition, the selected combination can be administered by intravenous injection, and the other agents of the combination can be administered orally. Alternatively, for example, two or more agents can be administered by intravenous or subcutaneous injection.

II. Embodiment

The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present disclosure to the precise form disclosed, and it is clear that many changes and variations can be made according to the teachings of this application specification. The purpose of selecting and describing exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present disclosure and various different selections and changes.

Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

Instruments and reagents:

NMR: Agilent 400MR DD2 NMR, the solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS). LC-MS: Agilent 1260 Infinity II–InfinityLab LC/MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C185um 150x4.6mm column).

Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plate (Yucheng Chemical (Shanghai) Co., Ltd.), specification 0.2mm＝0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Aiger Fino Claricep Flash amorphous silica gel purification column).

Reagents: 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione, phosphorus oxychloride, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, (3-(ethoxymethoxy)-8-fluoronaphthalen-1-yl)boric acid, tetrakis(triphenylphosphine)palladium, palladium acetate, ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol, (S)-(1-methyl)- 4-(2 ... )-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, 4-methylpiperidin-4-ol, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol, cesium fluoride, thiomorpholine 1,1-dioxide, 4-((tert-butyldiphenylsilyl)oxy)piperidine, (1R,5S)-8-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, 4-methylpiperidin-4-ol, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol, cesium fluoride, thiomorpholine 1,1-dioxide, -azabicyclo[3.2.1]octane, 4-methylpiperidin-4-ol, (1R, 5S)-8-oxo-3-azabicyclo[3.2.1]octane, hydrochloric acid-dioxane and other reagents and starting materials were purchased from Shanghai Bid, Leyan Reagent Company, Jiangsu Aikang Biopharmaceutical R&D Company, Anaiji Chemical Reagent Company, Shanghai McLean Reagent Company, Sane Chemical Reagent Company, etc., or synthesized using methods known in the art. Unless otherwise specified, all reactions disclosed in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon, the solvent is a dry solvent, and the reaction temperature unit is Celsius.

The following are the intermediate numbers:

Intermediate I-1

Intermediate I-1: Synthesis of 2,4,7-trichloro-8-fluoropyrido[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°C for 1 hour. After vacuum concentration, the mixture was purified by Flash column (dichloromethane) to obtain the target product 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 1.31 g, yield 56%), ESI[M+H] ⁺ = 252.0, 254.0.

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-pyridinamine (I-2-1)

Add 4-amino-2,6-dichloropyridine (52g, 320mmol) to acetonitrile (480ml) and N,N-dimethylformamide (480ml), slowly add 83.5 (136g, 360mmol), and react at 80℃ for 3 hours. Quench with water, extract with ethyl acetate, collect the organic phase and backwash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify with Flash column (petroleum ether: ethyl acetate = 0% to 30%) to obtain the target product 2,6-dichloro-3-fluoro-4-pyridinamine (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-pyridinamine (41.3g, 229.5mmol) and 4-dimethylaminopyridine (1.3g, 11.6mmol) were added to tetrahydrofuran (225ml), di-tert-butyl dicarbonate (125.3g, 574.5mmol) was slowly added, and the mixture was reacted at 60°C for 4 hours. The mixture was 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 with a Flash column (petroleum ether: ethyl acetate = 0% to 50%) to obtain the target product tert-butyl (tert-butyloxycarbonyl) (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-butyloxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (I-2-3)

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

n-Butyl lithium (150.5 ml, 240.8 mmol) was slowly added at 78°C under nitrogen protection, and the mixture was reacted at -78°C for 1 hour. Tert-butyl (tert-butyloxycarbonyl) (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.

The reaction was continued at 78°C for 1 hour, and then quenched with acetic acid aqueous 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 purified by Flash column (petroleum ether: ethyl acetate = 0% to 30%) to obtain the target product 4-(tert-butyloxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (I-2-3, 23.1 g, yield 95.1%). ESI [M+H] + = 381.2, 382.3

Intermediate I-2-4: Synthesis of 4-amino-2,6-dichloro-5-fluoronicotinoic acid hydrochloride (I-2-4)

4-(tert-Butyloxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester (22.8 g, 60 mmol) was added to dioxane (90 ml), and then concentrated hydrochloric acid (30 ml) was slowly added to the reaction solution, and the reaction was carried out at 25°C for 16 hours. The reaction solution was directly filtered and the filter cake was dried to obtain the target product 4-amino-2,6-dichloro-

5-Fluoronicotinoic acid hydrochloride (I-2-4, 18.1 g, 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-fluoronicotinoic acid hydrochloride (22.8 g, 60 mmol) was added to thionyl chloride (450 ml), and the reaction was carried out at 50°C for 3 hours. The reaction solution was directly dried by spin drying, dissolved in acetone (90 ml), and thiocyanamide (15.84 g, 138 mmol) was added, and the reaction was carried out at 25°C for 16 hours, filtered, and the filter cake was washed with acetonitrile and dried to obtain the target product 5,7-dichloro-8-fluoro-2-thiopyrido[4,3-d]pyrimidin-4(3H)-one (I-2-5, 17.1 g, 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-thiopyrido[4,3-d]pyrimidin-4(3H)-one (15.0 g, 56.43 mmol) was added to a sodium hydroxide aqueous solution (0.1 M, 90 ml, 56.43 mmol), and then iodomethane (13.3 g, 101.6 mmol) was slowly added to the reaction solution, and the reaction was carried out at 25°C for 16 hours. The reaction solution was poured into water, and the pH value was adjusted to 6. A large amount of white solid precipitated, which was filtered and the filter cake was dried to obtain the target product 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-2, 10.1 g, yield 63.9%). ESI[M+H] ⁺ ＝280.1

Intermediate I-3

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

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

2-Bromo-5-fluoroisonicotinic acid (88g, 400.01mmol) was dissolved in methanol (1000mL), and then thionyl chloride (71.38g, 600.01mmol) was slowly added dropwise. The reaction was stirred at 70°C for 2 hours. The reaction was complete by liquid quality test. The reaction solution was concentrated in a vacuum, and the residue was extracted three times with saturated sodium bicarbonate aqueous solution (700mL) and ethyl acetate (500mL). The organic layer was washed with brine (500mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate = 10:1) was performed to obtain the desired product compound 2-bromo-5-fluoroisonicotinic acid methyl ester (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 5-fluoro-2-methylisonicotinic acid methyl ester (I-3-2)

The compound 2-bromo-5-fluoroisonicotinic acid methyl ester (86g, 367.49mmol) and tetrakistriphenylphosphine palladium (8.49g, 7.35mmol) were dissolved in tetrahydrofuran (1500mL) and stirred at room temperature for 15 minutes. Then the reaction temperature was reduced to 0℃, trimethylaluminum (2M, 220.49mL) was slowly added dropwise and the reaction was stirred at 80℃ for 2 hours. The liquid quality test showed that the reaction was complete. The temperature of the reaction solution was reduced to room temperature, and the reaction solution was slowly poured into a saturated aqueous solution of ammonium chloride (1000mL), extracted three times with ethyl acetate (1000mL), the organic layer was washed with brine (1000mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate = 8:1) was performed to obtain the desired product 5-fluoro-2-methylisonicotinic acid methyl ester (I-3-2, 57.00g, 313.39mmol, yield: 85.28%) as a white solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.48 (d, J = 2.5 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 3.97 (s, 3H), 2.59 (d, J = 1.4 Hz, 3H). ESI[M+H] ⁺ =170.0

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

Dissolve 5-fluoro-2-methylisonicotinate (56g, 331.06mmol) in dichloromethane (500mL), add m-chloroperbenzoic acid (85.70g, 496.59mmol), and stir the reaction at 25°C for 16 hours. Liquid quality detection shows that the reaction is complete. Pour the reaction solution into sodium bicarbonate aqueous solution (500mL), extract three times with dichloromethane (500mL), wash the organic layer with brine (500mL), dry over anhydrous sodium sulfate, and then filter. Concentrate the filtrate and column chromatograph (petroleum ether: ethyl acetate = 1:5) to obtain 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 2-chloro-3-fluoro-6-methylisonicotinate (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 was stirred at 80 ° C for 2 hours. The reaction was complete by liquid quality test. The reaction mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL), poured into a saturated aqueous ammonium chloride solution (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, and then filtered. The filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate = 10: 1) was performed to obtain the compound 2-chloro-3-fluoro-6-methylisonicotinic acid methyl ester (I-3-4, 35.00 g, 166.32 mmol, yield: 43.00%) as a white solid. ¹ H-NMR (400MHz, CDCl ₃ ) 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-methylisonicotinic acid (I-3-5)

Dissolve 2-chloro-3-fluoro-6-methylisonicotinic acid methyl ester (18 g, 88.41 mmol) and lithium hydroxide (6.35 g, 265.23 mmol) in dioxane: water (1:1) (200 mL), and stir the reaction at 25°C for 1 hour. Liquid quality control showed that the reaction was complete. The reaction mixture was adjusted to pH = 3 with dilute hydrochloric acid (1 M), and solid precipitated. The compound 2-chloro-3-fluoro-6-methylisonicotinic acid (I-3-5, 14.90 g, 78.60 mmol, yield: 88.90%) was obtained as a white solid by filtration and spin drying. ¹ H-NMR (400 MHz, CDCl ₃ ) δ7.60 (d, J = 4.4 Hz, 1H), 2.59 (d, J = 0.8 Hz, 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-methylisonicotinic acid (2.1 g, 11.1 mmol) was dissolved in tert-butyl alcohol (150 mL), triethylamine (3.36 g, 33.3 mmol) and diphenylphosphoryl azide (6.1 g, 22.2 mmol) were added and stirred at 80 °C for 16 hours. The reaction was complete as detected by silica gel plate (petroleum ether: ethyl acetate = 3:1). The reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL) three times, the organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then chromatographed by column chromatography (eluent: petroleum ether: ethyl acetate = 1:5) to obtain compound (2-chloro-3-fluoro-6-methylpyridin-4-yl)carbamic acid tert-butyl ester (I-3-6, 2.0 g, 7.69 mmol, yield: 72.9%) 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)

Dissolve (2-chloro-3-fluoro-6-methylpyridin-4-yl)carbamic acid tert-butyl ester (2.0 g, 7.69 mmol) in E dichloromethane (20 mL), add trifluoroacetic acid (4 mL) and stir at room temperature for 2 hours. Detect the reaction completion on a silica gel plate (petroleum ether: ethyl acetate = 3:1). Pour the reaction solution into a saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (20 mL) three times, wash the organic layer with brine (50 mL), dry with anhydrous sodium sulfate, and then filter. Concentrate the filtrate and use column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the compound 2-chloro-3-fluoro-6-methylpyridin-4-amine (I-3-7, 1.1 g, 6.87 mmol, 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) and p-toluenesulfonic acid (1.66 g, 8.72 mmol) were added to acetonitrile (300 mL), and N-iodosuccinimide (47.08 g, 209.25 mmol) was slowly added. The mixture was heated to 70°C and stirred for 12 hours under nitrogen protection. Liquid quality inspection showed that the raw materials reacted completely. The reaction solution was cooled to room temperature and poured into a saturated sodium thiosulfate solution for quenching. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (tetrahydrofuran/petroleum ether = 5-15%) to obtain compound 2-chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (I-3-8, 44.00 g, 150.38 mmol, 86.24% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ6.53 (s, 2H), 2.46 (d, J = 1.1Hz, 3H), ESI [M+H]+ = 286.80

Intermediate I-3-9: Synthesis of 4-amino-6-chloro-5-fluoro-2-methylnicotinate 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), and the mixture was heated to 75 ° C and stirred for 12 hours under a carbon monoxide atmosphere. The liquid quality test showed that the raw materials were completely reacted. The reaction solution was cooled to room temperature, the solvent was evaporated, and the compound 4-amino-6-chloro-5-fluoro-2-methylnicotinate (I-3-9, 35.00 g, crude product) was obtained 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-(2,2,2-trichloroacetyl)ureido)nicotinate ethyl ester (I-3-10)

Dissolve 4-amino-6-chloro-5-fluoro-2-methylnicotinic acid ethyl ester (22g, 100.63mmol) in tetrahydrofuran (300mL), slowly add 2,2,2-trichloroacetyl isocyanate (26.54g, 140.89mmol). After the addition, stir and react at 20°C for 0.5 hours. Liquid quality inspection shows that the raw material reacts completely. The solvent is evaporated and the residue is slurried with methyl tert-butyl ether to obtain the compound 6-chloro-5-fluoro-2-methyl-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinic acid ethyl ester (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-methylpyrido[4,3-d]pyrimidine-2,4-dione (I-3-11)

Dissolve 6-chloro-5-fluoro-2-methyl-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (40 g, 95.00 mmol) in methanol (500 mL), add ammonia methanol solution (35 mL) dropwise, stir and react at 20°C for 1 hour, a white solid precipitates, filter the reaction solution, and slurry the filtered solid with methyl tert-butyl ether to obtain the compound 7-chloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine-2,4-dione (I-3-11, 20.00 g, crude product) as a white solid. ESI[M+H]+＝230.1

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

7-Chloro-8-fluoro-5-methylpyridinium[4,3-d]pyrimidine-2,4-dione (20 g, 87.11 mmol) and N,N-diisopropylethylamine (37.15 g, 287.46 mmol) were added to toluene (400 mL), and phosphorus oxychloride (44.08 g, 287.46 mmol) was slowly added dropwise. After the addition, nitrogen was protected, the temperature was raised to 100°C and stirred for 12 hours. Liquid quality detection showed that the raw materials were basically reacted completely. The reaction solution was evaporated to remove the solvent, and the residue was separated by column chromatography (tetrahydrofuran/petroleum ether = 5-15%) to obtain 2,4,7-trichloro-8-fluoro-5-methylpyridinone[4,3-d]pyrimidine (I-3, 10.50 g, 38.37 mmol, 44.05%) as a white solid. 1HNMR (400MHz, 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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-a)

Dissolve 2,4,7-trichloro-8-fluoropyridinium[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) in dichloromethane (5 ml) and cool to 0°C. Add N,N-diisopropylethylamine (51 mg, 0.4 mmol) and 4-methylpiperidin-4-ol (46 mg, 0.4 mmol) and react at room temperature for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoropyridinium[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-a, 64 mg, yield 48.9%). ESI[M+H] ⁺ = 331.2

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-b)

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

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

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-b, 13 mg, 0.03 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-b, 13 mg, 0.03 mmol), 1-(2 ... The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-c, 10 mg, yield 43.7%). ESI[M+H] ⁺ =804.6

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-c, 10 mg, 0.01 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (15 mg, 0.1 mmol) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-d, 7 mg, yield 87.5%). ESI[M+H] ⁺ =648.3

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1-d, 7 mg, 0.01 mmol) was dissolved in acetonitrile (1 ml), trifluoroacetic acid (0.2 ml) was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (1, 5.1 mg, yield 78.5%). ESI[M+H] ⁺ ＝604.3 ¹ H NMR (400 MHz, CD ₃ OD)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( 1 .35(s,3H).

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

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (150 mg, 0.6 mmol) was dissolved in dichloromethane (4 ml) and cooled to 0°C. N,N-diisopropylethylamine (77 mg, 0.6 mmol) and 4-((tert-butyldiphenylsilyl)oxy)piperidine (202 mg, 0.6 mmol) were added and reacted at room temperature for 1 hour. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (2-a, 117 mg, yield 35.3%).

Step 2: Synthesis of 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (2-b)

4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (2-a, 115 mg, 0.2 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (48 mg, 0.3 mmol), cesium carbonate (65 mg, 0.2 mmol) were added to chloroform (4 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (2-b, 90 mg, yield 64.3%). ESI[M+H] ⁺ = 678.4

Step 3: Synthesis of 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (2-c)

4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (2-b, 70 mg, 0.1 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1, 3,2-dioxybenzaldehyde-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) were dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain 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-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (2-c, 75 mg, yield 71%). ESI[M+H] ⁺ = 1028.4

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

4-(4-(tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (2-c, 75 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (106 mg, 0.7 mmol) was added, and the reaction was carried out at room temperature for 48 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperidin-4-ol (2-d, 41 mg, yield 89.1%). ESI[M+H] ⁺ =634.3

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

Dissolve 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperidin-4-ol (41 mg, 0.06 mmol) in 1,4-dioxane (2 ml), add hydrochloric acid 1,4-dioxane solution (1 ml) in an ice bath, slowly return to room temperature, and react for 1 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)piperidin-4-ol (2,11 mg, yield 21.6%). ESI[M+H] ⁺ =590.3, ¹ H 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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (3)

Step 1: Synthesis of 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (3-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,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. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (3-a, 86 mg, yield 67.2%).

Step 2: Synthesis of 7-chloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (3-b)

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

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

7-Chloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (3-b, 30 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (40 mg, 0.08 mmol), potassium phosphate (41 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (5 mg, 0.007 mmol) were dissolved in tetrahydrofuran (2 ml) and water (0.2 ml). The mixture was replaced with nitrogen three times, and the temperature was raised to 60°C for 6 hours. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (3-c, 28 mg, yield 53%). ESI[M+H] ⁺ =810.4

Step 4: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (3-d)

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

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

4-(4,4-difluoropiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (3-d, 17 mg, 0.03 mmol) was dissolved in acetonitrile (1 ml), trifluoroacetic acid (0.2 ml) was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (3.4 mg, yield 26.1%). ESI[M+H] ⁺ =610.3, ¹ H NMR (400MHz, CD ₃ OD) 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), 5.24–5.2 0(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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (4)

Step 1: Synthesis of 2,7-dichloro-8-fluoro-4-(4-fluoropiperidin-1-yl)pyrido[4,3-d]pyrimidine (4-a)

2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. 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. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-8-fluoro-4-(4-fluoropiperidin-1-yl)pyrido[4,3-d]pyrimidine (4-a, 80 mg, yield 63.5%).

Step 2: Synthesis of 7-chloro-8-fluoro-4-(4-fluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(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, 76 mg, 0.24 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (76 mg, 0.48 mmol), cesium carbonate (156 mg, 0.48 mmol) were added to chloroform (3 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-8-fluoro-4-(4-fluoropiperidin-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (4-b, 44 mg, yield 41.9%). ESI[M+H] ⁺ =443.1

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

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

Step 4: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(4-fluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (4-c, 64 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (121 mg, 0.8 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(4-fluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (4-d, 42 mg, yield 82%). ESI[M+H] ⁺ =636.5

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(4-fluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (4-d, 40 mg, 0.06 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.2 ml) was added on an ice bath, and the reaction was carried out 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-4-(4-fluoropiperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (4, 19.8 mg, yield 54%). ESI[M+H] ⁺ ＝592.6 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol trifluoroacetate (5)

Step 1: Synthesis of (S)-1-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (5-a)

Dissolve 2,4,7-trichloro-8-fluoropyridinium [4,3-d] pyrimidine (I-1, 100 mg, 0.4 mmol) in dichloromethane (5 ml) and cool to -40°C. Add N,N-diisopropylethylamine (52 mg, 0.4 mmol) and (S)-pyrrolidin-3-ol (38 mg, 0.4 mmol) and react at -40°C for 0.5 hours. After concentration under reduced pressure, purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (S)-1-(2,7-dichloro-8-fluoropyridinium [4,3-d] pyrimidin-4-yl) pyrrolidin-3-ol (5-a, 114 mg, yield 94.21%). ESI [M+H] ⁺ = 303.5, 305.2

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

(S)-1-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (5-a, 100 mg, 0.33 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (426 mg, 3.3 mmol), cesium carbonate (538 mg, 1.65 mmol), potassium carbonate (69 mg, 0.5 mmol) were added to acetonitrile (5 ml). The temperature was raised to 80° C. and the reaction was carried out for 16 h. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product (S)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (5-b, 45.8 mg, yield 32.48%). ESI [M+H] ⁺ = 426.5, 428.5

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

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

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

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

Step 5: Synthesis of (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (5-d, 20 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), 1,4-dioxane hydrochloric acid solution (1 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol trifluoroacetate (5, 14.38 mg, yield 69.50%). ESI[M+H] ⁺ ＝576.7, ¹ H NMR (400 MHz, DMSO-d ₆ )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,2 H),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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol trifluoroacetate (6)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-a)

Dissolve 2,4,7-trichloro-8-fluoropyridinium[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) in dichloromethane (5 ml) and cool to -40°C. Add N,N-diisopropylethylamine (52 mg, 0.4 mmol) and 1-(2,7-dichloro-8-fluoropyridinium[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (40 mg, 0.4 mmol) and react at room temperature for 0.5 hours. After concentration under reduced pressure, purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoropyridinium[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-a, 120 mg, yield 94.49%). ESI[M+H] ⁺ = 317.2, 319.2

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

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

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

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-b, 20 mg, 0.045 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydro Benzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (58 mg, 0.113 mmol), potassium phosphate (19 mg, 0.09 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl)palladium (II) (7 mg, 0.01 mmol) were dissolved in 1,4-dioxane (1 ml) and water (0.1 ml). The atmosphere was replaced with nitrogen three times and the temperature was raised to 60°C for reaction for 16 h. After concentration under reduced pressure, the product was purified by TLC (methanol: dichloromethane = 10:1) to obtain the target 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-c, 23 mg, yield 64.7%). ESI [M+H] ⁺ = 790.8, 791.8

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-c, 23 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (26 mg, 0.17 mmol) was added, 25 ℃ for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-d, 19 mg, yield 99.95%). ESI[M+H] ⁺ =634.4, 635.5

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (6-d, 19 mg, 0.03 mmol) was dissolved in acetonitrile (2.5 ml), 1,4-dioxane hydrochloric acid solution (0.5 ml) was added, and the reaction was carried out at 25° C. for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product, 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol trifluoroacetate (6, 13.50 mg, yield 63.95%). ESI = [M+H] ⁺ 590.5. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝12.0,11.5H z,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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (7)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,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. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (R)-2,7-dichloro-8-fluoro-4-(3-fluoropyrrolidin-1-yl)pyrido[4,3-d]pyrimidine (7-a, 78 mg, yield 64.5%).

Step 2: Synthesis of 7-chloro-8-fluoro-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (7-b)

(R)-2,7-dichloro-8-fluoro-4-(3-fluoropyrrolidin-1-yl)pyrido[4,3-d]pyrimidine (7-a, 78 mg, 0.25 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (60 mg, 0.38 mmol), cesium carbonate (82 mg, 0.25 mmol) were added to chloroform (3 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-8-fluoro-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (7-b, 52 mg, yield 47.7%). ESI[M+H] ⁺ = 428.4

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

7-Chloro-8-fluoro-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (7-b, 52 mg, 0.12 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzene) 1,4-dioxane (2 ml) and water (0.2 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (7-c, 60 mg, yield 63.8%). ESI[M+H] ⁺ = 778.5

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

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (7-d, 36 mg, 0.06 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.4 ml) was added on an ice bath, and the reaction was carried out 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-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (7, 13 mg, yield 39.4%). ESI[M+H] ⁺ ＝578.5 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (8)

Step 1: Synthesis of 2,7-dichloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (8-a)

2,4,7-trichloro-8-fluoropyridinium[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,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. Water was added to quench, 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoropyridinium[4,3-d]pyrimidine (8-a, 115 mg, yield 89.8%).

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

2,7-Dichloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (8-a, 115 mg, 0.36 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (57 mg, 0.36 mmol), cesium carbonate (117 mg, 0.36 mmol) were added to chloroform (3 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (8-b, 104 mg, yield 65.8%). ESI[M+H] ⁺ =446.5

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

7-Chloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (8-b, 85 mg, 0.19 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzyl) The mixture was dissolved with triisopropylsilane (97 mg, 0.19 mmol), potassium phosphate (120 mg, 0.57 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (28 mg, 0.04 mmol) in 1,4-dioxane (2 ml) and water (0.2 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (8-c, 141 mg, yield 92.7%). ESI[M+H] ⁺ =796.4

Step 4: Synthesis of 4-(3,3-difluoropyrrolidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (8-c, 141 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (129 mg, 0.85 mmol) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 4-(3,3-difluoropyrrolidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (8-d, 90 mg, yield 79.6%). ESI[M+H] ⁺ =640.5

Step 5: Synthesis of 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (8-d, 80 mg, 0.13 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.5 ml) was added on an ice bath, and the reaction was carried out for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (8, 20 mg, yield 27%). ESI[M+H] ⁺ ＝596.5, ¹ H NMR (400 MHz, DMSO-d ₆ )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,1 H),4.69–4.5 6(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (9)

Step 1: Synthesis of (R)-1-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (9-a)

2,4,7-Trichloro-8-fluoropyridinium[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,N-diisopropylethylamine (51 mg, 0.4 mmol) and (R)-pyrrolidin-3-ol were added and reacted at room temperature for 1 hour. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (R)-1-(2,7-dichloro-8-fluoropyridinium[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (9-a, 112 mg, yield 93.3%).

Step 2: Synthesis of (R)-4-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (9-b)

(R)-1-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (9-a, 100 mg, 0.33 mmol), tert-butyldiphenylsilyl chloride (181 mg, 0.66 mmol), imidazole (45 mg, 0.66 mmol) were added to dichloromethane (4 ml) and reacted at room temperature for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (R)-4-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)-2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidine (9-b, 144 mg, yield 80.4%).

Step 3: Synthesis of 4-((R)-3-((tert-butyldiphenylsilyloxy)pyrrolidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (9-c)

(R)-4-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (9-b, 144 mg, 0.27 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (86 mg, 0.54 mmol), potassium carbonate (76 mg, 0.54 mmol) were added to chloroform (3 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-((R)-3-((tert-butyldiphenylsilyloxy)pyrrolidin-1-yl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (9-c, 45 mg, yield 25.6%). ESI [M+H] ⁺ = 664.5

Step 4: 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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (9-d)

4-((R)-3-((tert-butyldiphenylsilyloxy)pyrrolidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (9-c, 45 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-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) were dissolved in 1% ethanol. ,4-dioxane (2ml) and water (0.2ml). Nitrogen was replaced three times, and the temperature was raised to 60℃ for 16h. Water was added to quench, 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 on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-((R)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (9-d, 47mg, yield 69.1%). ESI)[M+H] ⁺ =1014.5

Step 5: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (9-d, 45 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (76 mg, 0.5 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)pyrrolidine (9-e, 27 mg, yield 95%). ESI[M+H] ⁺ =620.4

Step 6: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)pyrrolidine (9-e, 25 mg, 0.04 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.2 ml) was added on an ice bath, and the reaction was carried out for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (9, 6.5 mg, yield 28.3%). ESI[M+H] ⁺ ＝576.3 ¹ H NMR(400MHz,DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol trifluoroacetate (10)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (4 ml) and cooled to -40°C. N,N-diisopropylethylamine (77 mg, 0.6 mmol) and (S)-3-fluoropyrrolidine hydrochloride (75 mg, 0.6 mmol) were added and reacted at -40°C for 0.5 hours. After concentration under reduced pressure, the target product (S)-2,7-dichloro-8-fluoro-4-(3-fluoropyrrolidin-1-yl)pyrido[4,3-d]pyrimidine (10-a, 80 mg, yield 65.57%) was obtained. ESI[M+H] ⁺ =305.1, 307.0

Step 2: Synthesis of 7-chloro-8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (10-b)

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

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

7-Chloro-8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (10-b, 50 mg, 0.12 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzene) 1,4-dioxane (4 ml) and water (0.4 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 h. The reaction mixture was quenched with water and 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (10-c, 14 mg, yield 18.67%).

Step 4: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (14-c, 14 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (20 mg, 0.13 mmol) was added, and the reaction was carried out at 25°C for 0.5 h. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the target product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (10-d, 13 mg, yield 95.03%). ESI[M+H] ⁺ =622.3, 623.3

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (10-d, 13 mg, 0.02 mmol) was dissolved in acetonitrile (5 ml), and a hydrochloric acid 1,4-dioxane solution (0.5 ml) was added. The mixture was reacted at 25°C for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product, 5-ethynyl-6-fluoro-4-(8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol trifluoroacetate (10, 6.48 mg, yield 46.85%). ESI[M+H] ⁺ ＝578.3 ¹ H NMR (400MHz, DMSO-d ₆ )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=8.8 Hz, 1H), 2.46 (s, 1H), 2.34–2.24 (m, 2H), 2.16 (h, J=7.5, 6.6 Hz, 2H), 2.08–1.97 (m, 1H). Example 11: Synthesis of 4-(4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (11)

Step 1: Synthesis of 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (11-a)

2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 50 mg, 0.2 mmol) was dissolved in dichloromethane (5 ml), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 4,4-difluoropyridine (24 mg, 0.2 mmol) were added and reacted at 25°C for 0.5 hours. After concentration under reduced pressure, the mixture was purified by Flash column (petroleum ether: ethyl acetate = 2:1) to obtain the target product 2,7-dichloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (11-a, 90 mg, yield 100%).

Step 2: Synthesis of 7-chloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(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, 90 mg, 0.27 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (207 mg, 1.3 mmol), cesium carbonate (264 mg, 0.81 mmol) were added to 1,4-dioxane (5 ml). The temperature was raised to 80°C and the reaction was continued for 16 hours. After concentration under reduced pressure, the product was purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 7-chloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (11-b, 60 mg, yield 48.39%). ESI[M+H] ⁺ =460.2, 462.2

Step 3: Synthesis of 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (11-c)

7-Chloro-4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidine (11-b, 60 mg, 0.13 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde (94 mg, 0.26 mmol), potassium phosphate (55 mg, 0.26 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol) were dissolved in tetrahydrofuran (3 ml) and water (0.3 ml). The mixture was replaced with nitrogen three times, and the temperature was raised to 60°C for 16 hours. After concentration under reduced pressure, the mixture was purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (11-c, 75 mg, yield 88.24%). ESI [M+H] ⁺ = 658.4, 659.4

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

4-(4,4-difluoropiperidin-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (11-c, 75 mg, 0.114 mmol) was dissolved in acetonitrile (5 ml), 1,4-dioxane hydrochloride (0.5 ml) was added, and the mixture was reacted at 25°C for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (11, 41.93 mg, yield 59.94%). ESI[M+H] ⁺ ＝614.6. ¹ H NMR (400 MHz, DMSO-d ₆ )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),1.8 5–1.71(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (12)

Step 1: Synthesis of (3-(chloromethyl)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)methanol (12-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.6 mmol) was dissolved in dichloromethane (4 ml), and N,N-diisopropylethylamine (77.4 mg, 0.6 mmol) and (3-(chloromethyl)azetidin-3-yl)methanol (81.4 mg, 0.6 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, 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 with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (3-(chloromethyl)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)methanol (12-a, 130 mg, yield 61.73%). ESI [M+H] ⁺ = 351.26.

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

(3-(Chloromethyl)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)methanol (12-a, 130 mg, 0.37 mmol) was dissolved in chloroform (3 ml), and ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64.8 mg, 0.407 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, 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 and filtered. The filtrate was concentrated and purified using a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol (12-b, 80 mg, yield 45.71%). ESI[M+H] ⁺ =474.21.

Step 3: Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (12-c)

(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol (12-b, 80 mg, 0.169 mmol) was dissolved in 1,4-dioxane (2 ml) and water (0.2 ml), ((2-fluoro-6-(methoxymethoxy)- 8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (86.5 mg, 0.19 mmol), potassium phosphate (71.7 mg, 0.338 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (24.6 mg, 0.0338 mmol) were added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (12-c, 40 mg, yield 28.78%). ESI [M+H] + = 824.56.

Step 4: Synthesis of (3-(chloromethyl)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)methanol (12-d)

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

Step 5: Synthesis of 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)methanol (12-d, 15 mg, 0.022 mmol) was dissolved in acetonitrile (2 ml), trifluoroacetic acid (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (12, 1.68 mg, yield 12.26%). ESI[M+H] ⁺ ＝624.08, ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (13)

Step 1: Synthesis of 2,7-dichloro-8-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-a)

2,4,7-trichloro-8-fluoropyridinium[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,N-diisopropylethylamine (51 mg, 0.4 mmol) and 3,3,4,4-tetrafluoropyrrolidine (72 mg, 0.4 mmol) were added and reacted at room temperature for 1 hour. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-8-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridinium[4,3-d]pyrimidine (13-a, 118 mg, yield 82.5%).

Step 2: Synthesis of 7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-b)

2,7-Dichloro-8-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-a, 118 mg, 0.33 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (105 mg, 0.66 mmol), cesium carbonate (108 mg, 0.33 mmol) were added to chloroform (4 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-b, 138 mg, yield 87.3%). ESI[M+H ^]+ = 482.5

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

7-Chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-b, 48 mg, 0.1 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydropyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine 1,4-dioxane (2 ml) and water (0.2 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-c, 78 mg, yield 94%). ESI[M+H] ⁺ = 832.6

Step 4: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-d)

8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[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 the mixture was reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (13-d, 60 mg, yield 94.8%). ESI[M+H] ⁺ =676.3

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin[4,3-d]pyrimidine (40 mg, 0.06 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.4 ml) was added on an ice bath, and the reaction was carried out 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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (13, 10 mg, yield 27%). ESI[M+H] ⁺ =632.3 ¹ H NMR (400MHz, CD ₃ OD) 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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (14)

Step 1: Synthesis of 2,7-dichloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (14-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,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. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-4-(3,3-difluoroazetidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (14-a, 84 mg, yield 68.3%).

Step 2: Synthesis of 7-chloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (14-b)

2,7-Dichloro-4-(3,3-difluoroazetidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (84 mg, 0.27 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (86 mg, 0.54 mmol), cesium carbonate (88 mg, 0.27 mmol) were added to chloroform (4 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (14-b, 94 mg, yield 80.3%). ESI[M+H] ⁺ =432.5

Step 3: Synthesis of 4-(3,3-difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (14-c)

7-Chloro-4-(3,3-difluoroazetidin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (94 mg, 0.22 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (135 mg, 0.26 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) were dissolved in 1,4-dioxane (2 ml) and water (0.2 ml). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for reaction for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 4-(3,3-difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (14-c, 161 mg, yield 94.6%). ESI[M+H] ⁺ =782.4

Step 4: Preparation of 4-(3,3-difluoroazetidine-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (14-d)

4-(3,3-Difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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 the mixture was reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 4-(3,3-difluoroazetidine-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (14-d, 117 mg, yield 92.1%). ESI[M+H] ⁺ =626.3

Step 5: Preparation of 4-(4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (70 mg, 0.11 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.5 ml) was added in an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (14.7 mg, yield 10.7%). ESI[M+H] ⁺ =582.3 ¹ H NMR(400MHz, CD ₃ OD)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,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol trifluoroacetate (15)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.6 mmol) was dissolved in dichloromethane (4 ml), and N,N-diisopropylethylamine (77.4 mg, 0.6 mmol) and 2-oxa-6-azaspiro[3.3]heptane (59.5 mg, 0.6 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, 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 with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (15-a, 135 mg, yield 71.43%). ESI [M+H] ⁺ = 315.21.

Step 2: Synthesis of 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 135 mg, 0.429 mmol) was dissolved in chloroform (3 ml), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (75 mg, 0.471 mmol) and cesium carbonate (279 mg, 0.857 mmol) were added, followed by reaction at room temperature for 16 h. After the reaction was complete, 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 and filtered. The filtrate was concentrated and purified using a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol (15-b, 70 mg, yield 37.43%). ESI[M+H] ⁺ =438.25.

Step 3: Synthesis of 6-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol (15-b, 70 mg, 0.160 mmol) was dissolved in 1,4-dioxane (2 ml) and water (0.2 ml), ((2-fluoro-6-(methoxymethoxy) )-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (81.9 mg, 0.160 mmol), potassium phosphate (68 mg, 0.320 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (23 mg, 0.032 mmol) were added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 6-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (15-c, 15 mg, yield 11.90%). ESI[M+H]+=788.85.

Step 4: Synthesis of 6-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (15-c, 15 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (14.5 mg, 0.095 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 obtain the target product 6-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (15-d, 10 mg, yield 83.33%). ESI[M+H] ⁺ =632.51.

Step 5: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-oxa-6-azaspiro[3.3]heptane-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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (15-d, 10 mg, 0.0158 mmol) was dissolved in acetonitrile (2 ml), trifluoroacetic acid (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 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,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol trifluoroacetate (15, 1.68 mg, yield 12.26%). ESI[M+H] ⁺ ＝588.26. ¹ H NMR (400MHz, DMSO-d ₆ )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]heptane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (16)

Step 1: Synthesis of 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (16-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,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. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (16-a, 94 mg, yield 75.2%).

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

3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (94 mg, 0.3 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (95 mg, 0.6 mmol), cesium carbonate (98 mg, 0.3 mmol) were added to chloroform (4 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 3-(7-chloro-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (16-b, 96 mg, yield 73.8%). ESI[M+H] ⁺ =438.6

Step 3: Synthesis of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (16-c)

3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (112 mg, 0.22 mmol), potassium phosphate (140 mg, 0.66 mmol) l), 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 atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (16-c, 116 mg, yield 67%). ESI[M+H] ⁺ = 788.4

Step 4: Synthesis of 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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 the mixture was reacted at room temperature for 4 hours. The reaction solution was separated and purified by preparative chromatography to obtain the target product 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1]heptane (16-d, 85 mg, yield 91.2%). ESI[M+H] ⁺ =632.3

Step 5: Synthesis of 4-(4-(6-oxo-3-azabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1]heptane (60 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloride solution (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 4-(4-(6-oxo-3-azabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (16, 10.4 mg, yield 18.6%). ESI[M+H] ⁺ ＝588.4 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-a)

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) in dichloromethane (5 ml) and cool to 0°C. Add N,N-diisopropylethylamine (103 mg, 0.8 mmol) and 3-methylazetidin-3-ol hydrochloride (49 mg, 0.4 mmol) and react at 0°C for 10 min. After concentration under reduced pressure, purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-a, 123 mg, yield 100%). ESI[M+H] ⁺ = 303.1

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidine-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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (323 mg, 2.03 mmol), cesium carbonate (661 mg, 2.03 mmol) were added to 1,4-dioxane (10 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidine-3-ol (17-b, 71.6 mg, yield 41.39%). ESI[M+H] ⁺ =426.2

Step 3: Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-c)

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-b, 35 mg, 0.06 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-b, 35 mg, 0.06 mmol), 1,4-dioxane (3 ml) and water (0.3 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 3 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-c, 21 mg, yield 33.87%). ESI [M+H] ⁺ = 776.4

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidine-3-ol (17-c, 20 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (24 mg, 0.156 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times, 20 ml each time. The organic phase was collected and distilled under reduced pressure to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidine-3-ol (17-d, 15 mg). ESI[M+H] ⁺ =620.4

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17-d, 15 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), and a 1,4-dioxane hydrochloride solution ( 0.5ml), react for 0.5h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (17, 9.72mg, yield 57%). ESI[M+H] ⁺ =576.3, ¹ H NMR (400MHz, DMSO-d ₆ ) 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),2.9 9(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (18)

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

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (509 mg, 10 mmol), cesium carbonate (521 mg, 1.6 mmol) were added to 1,4-dioxane (10 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product: 1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (18-b, 104.7 mg, yield 74.26%). ESI[M+H] ⁺ =440.0,

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

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

Step 4: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (18-c, 8 mg, 0.0125 mmol) was dissolved in acetonitrile (2 ml), 1,4-dioxane hydrochloric acid solution (0.2 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-ol (18, 3.58 mg, yield 48.25%). ESI[M+H] ⁺ =594.4, ¹ H NMR (400MHz, DMSO-d ₆ ) 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (19)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (19-a)

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

Step 2: Preparation of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 120 mg, 0.38 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (302 mg, 1.9 mmol), cesium carbonate (619 mg, 1.9 mmol) were added to 1,4-dioxane (5 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (19-b, 112 mg, yield 67.07%). ESI [M+H] ⁺ = 440.2, 442.2

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

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

Step 4: Synthesis of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (19-c, 30 mg, 0.047 mmol) was dissolved in acetonitrile (5 ml), 1,4-dioxane hydrochloride solution (0.5 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (19, 14.11 mg, yield 50.39%). ESI[M+H] ⁺ ＝594.4, ¹ H NMR (400 MHz, DMSO-d ₆ )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),3.90–3.8 2(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-a)

Dissolve 2,4,7-trichloro-8-fluoropyridinium [4,3-d] pyrimidine (I-1, 100 mg, 0.4 mmol) in dichloromethane (5 ml) and cool to 0°C. Add N,N-diisopropylethylamine (103 mg, 0.8 mmol) and piperidine-4-carbonitrile (44 mg, 0.4 mmol) and react at 0°C for 10 min. After concentration under reduced pressure, purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoropyridinium [4,3-d] pyrimidin-4-yl) piperidine-4-carbonitrile (20-a, 123 mg, yield 100%). ESI [M+H] ⁺ = 326.1

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

1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-a, 132 mg, 0.406 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (323 mg, 2.03 mmol), cesium carbonate (661 mg, 2.03 mmol) were added to 1,4-dioxane (10 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1-H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-b, 71.6 mg, yield 39.39%). ESI[M+H] ⁺ =449.1

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

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1-H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-b, 28 mg, 0.06 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzyl) 1,4-dioxane (3 ml) and water (0.3 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 3 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-c, 25 mg, yield 33.87%). ESI [M+H] ⁺ = 799.4

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-c, 21 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (24 mg, 0.156 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times, 20 ml each time. The organic phase was collected and distilled under reduced pressure to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20-d, 15 mg). ESI[M+H] ⁺ =643.3

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol (20-d, 15 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), and 1% hydrochloric acid was added at 25°C. 4-dioxane solution (0.5 ml), react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile (20, 7.6 mg, yield 37%). ESI[M+H] ⁺ ＝599.3, ¹ H NMR (400 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21)

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

Step 2: Synthesis of (S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 160 mg, 0.5 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (239 mg, 1.5 mmol), cesium carbonate (815 mg, 2.5 mmol) were added to 1,4-dioxane (10 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product (S)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-b, 63 mg, yield 28.64%). ESI[M+H] ⁺ =440.3,

Step 3: Synthesis of (S)-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-c)

(S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-b, 60 mg, 0.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzene) 1,4-dioxane (3 ml) and water (0.3 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 3 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product (S)-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-c, 42 mg, yield 37.84%). ESI[M+H] ⁺ =790.56

Step 4: Synthesis of (S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-c, 42 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (46 mg, 0.3 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times, 20 ml each time. The organic phase was collected and distilled under reduced pressure to obtain the target product (S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-d, 36 mg). ESI[M+H] ⁺ =634.4

Step 5: Synthesis of (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21-d, 36 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), 1,4-dioxane hydrochloric acid solution (0.5 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (21, 15.1 mg, yield 85.36%). ESI[M+H] ⁺ ＝590.3, ¹ H NMR (400 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one formate (22)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (22-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (4 ml), and N,N-diisopropylethylamine (51.27 mg, 0.4 mmol) and piperidin-4-one (39.6 mg, 0.4 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, 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 with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 1-(2,7-dichloro-8-fluoropyrido[4,3d]pyrimidin-4-yl)piperidin-4-one (22-a, 105 mg, yield 84.00%). ESI[M+H] ⁺ = 315.21.

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 130 mg, 0.37 mmol) was dissolved in chloroform (3 ml), and ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64.8 mg, 0.407 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, 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 and filtered. The filtrate was concentrated and purified using a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)piperidin-4-one (22-b, 80 mg, yield 49.69%). ESI[M+H] ⁺ =437.5.

Step 3: Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (22-c)

1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (80 mg, 0.183 mmol) was dissolved in 1,4-dioxane (2 ml) and water (0.2 ml), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5 1-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (86.5 mg, 0.19 mmol), potassium phosphate (71.7 mg, 0.338 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (24.6 mg, 0.0338 mmol) were added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 60°C for reaction for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to give the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro (22-c, 40 mg, yield 27.77%). ESI [M+H] + = 788.55.

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (22-c, 40 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (37 mg, 0.243 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (22-d, 15 mg, yield 45.87%). ESI[M+H] ⁺ =587.6.

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

1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (22-d, 15 mg, 0.0255 mmol) was dissolved in acetonitrile (2 ml), trifluoroacetic acid (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product, 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one formate (22, 2.72 mg, yield 18.12%). ESI[M+H] ⁺ =588.21. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

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

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

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.495 mmol) in dichloromethane (5 ml) and cool to 0°C. Add N,N-diisopropylethylamine (61.3 mg, 0.479 mmol) and 3-fluoroazetidine (66.2 mg, 0.594 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-8-fluoro-4-(3-fluorocyclobutyl)pyrido[4,3-d]pyrimidine (23-a, 60 mg, yield 34.8%). ESI[M+H] ⁺ = 291

Step 2: Synthesis of 7-chloro-8-fluoro-4-(3-fluoroazetidine-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-b)

2,7-Dichloro-8-fluoro-4-(3-fluorocyclobutyl)pyrido[4,3-d]pyrimidine (23-a, 50 mg, 0.172 mmol), cesium carbonate (168.7 mg, 0.519 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (82.3 mg, 0.516 mmol) were added to dioxane (6 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-8-fluoro-4-(3-fluoroazetidine-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-b, 117 mg). ESI[M+H] ⁺ = 414.1

Step 3: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-4-(3-fluorocyclobutyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-c)

(7-chloro-8-fluoro-4-(3-fluoroazetidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-b, 117 mg, 0.16 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2- The mixture was dissolved with triisopropylsilane (285.2 mg, 0.557 mol), potassium phosphate (236.42 mg, 1.113 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (81.1 mg, 0.111 mmol) in tetrahydrofuran (3.7 ml) and water (0.37 ml). The mixture was replaced with nitrogen three times and the temperature was raised to 60°C for reaction for 6 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-4-(3-fluorocyclobutyl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-c, 54 mg, yield 32.83%). ESI[M+H] ⁺ = 764.3

Step 4: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-4-(3-fluoroazetidine-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (23-d)

8-Fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-4-(3-fluorocyclobutyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (23-c, 54 mg, 0.0524 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium fluoride (100 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-4-(3-fluoroazetidine-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (23-d, 40 mg). ESI[M+H] ⁺ =676.6

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-fluoroazetidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidine (23-d, 40 mg, 0.0524 mmol) was dissolved in acetonitrile (2.5 ml), dioxane hydrochloride (0.4 ml) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-fluoroazetidin-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol (23, 4.7 mg). ESI[M+H] ⁺ =610.5 ¹ H NMR (400MHz, DMSO-d ₆ ) 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 100 mg, 0.4 mmol) was dissolved in dichloromethane (4 ml), and N,N-diisopropylethylamine (51.27 mg, 0.4 mmol) and (R)-piperidin-3-ol (49.6 mg, 0.4 mmol) were added and reacted at room temperature for 1 hour. After the reaction was complete, 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 with anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24-a, 105 mg, yield 83.46%). ESI[M+H] ⁺ = 317.52.

Step 2: Synthesis of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (54 mg, 0.339 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, 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 and filtered. The filtrate was concentrated and purified using a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product (R)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24-b, 80 mg, yield 55.17%). ESI[M+H] ⁺ =440.12.

Step 3: Synthesis of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24-c)

(R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(4,4,5, 5-Tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (88.6 mg, 0.181 mmol), potassium phosphate (71.7 mg, 0.362 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (24.6 mg, 0.0362 mmol) were added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24-c, 30 mg, yield 20.89%). ESI [M+H] + = 790.51.

Step 4: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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 reaction was carried out at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)piperidin-3-ol (24-d, 18 mg, yield 75.00%). ESI[M+H] ⁺ =634.66.

Step 5: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)piperidin-3-ol (18 mg, 0.027 mmol) was dissolved in acetonitrile (2 ml), trifluoroacetic acid (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (24, 3.28 mg, yield 19.65%). ESI[M+H] ⁺ =590.21. ¹ H NMR (400MHz, DMSO-d ₆ ) 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25)

Step 1: Preparation of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)diazepam-4-ol (25-a)

2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 200 mg, 0.792 mmol), 4-azepine hydrochloride (120.1 mg, 0.792 mmol), N,N-diisopropylethylamine (292.5 ul, 1.584 mmol) were dissolved in dichloromethane (5 mL) and reacted at 0°C 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 obtain the target product 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azepam-4-ol (25-a, 250 mg, yield 101.2%). ESI[M+H] ⁺ = 313.7

Step 2: Preparation of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)diazepam-4-ol (25-b)

1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azepam-4-ol (250, 0.755 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (25-a, 600.9 mg, 1.51 mmol), and potassium carbonate (521.7 mg, 1.51 mmol) were dissolved in dioxane (5 mL), and the reaction solution was reacted at 80° C. 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 obtain the target product 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)azepam-4-ol (25-b, 210 mg, yield 61.3%) ESI[M+H] ⁺ =454.9

Step 2: Preparation of 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25-c)

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)azepam-4-ol (25-b, 210 mg, 0.463 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-1-yl)ethynyl)triazine Isopropylsilane (474.6 mg, 0.926 mmol), potassium phosphate (196.5 mg, 0.926 mmol), methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (67.5 mg, 0.046 mmol) were dissolved in dioxane/water (10/1, 2.5 ml), and nitrogen was replaced three times. The temperature was raised to 60°C under nitrogen protection and the reaction was carried out 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 obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25-c, 130 mg, yield 34.92%) ESI[M+H] ⁺ =805.0

Step 4: Preparation of 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25-d)

1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepin-4-ol (25-c, 130 mg, 0.162 mmol) and cesium fluoride (147.4 mg, 0.972 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 25°C for 2 h. The reaction mixture was stirred for 2 hours, quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25-d, 85 mg, yield 81.03%) ESI[M+H] ⁺ =648.7

Step 5: Preparation of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)azepine-4-ol (25)

1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25-d, 65 mg, 0.1 mmol) was dissolved in acetonitrile (5 mL), hydrochloric acid/dioxane (1 mL) was added dropwise, reacted at 0°C for 30 minutes, quenched with sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by HPLC to give the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepine-4-ol (25, 24.85 mg, yield 41.17%) ESI[M+H] ⁺ ＝604.7, 1H NMR (600MHz, CDCl ₃ )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,1 H),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),1.9 5–1.84(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-a)

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.6 mmol) in dichloromethane (7 ml) and cool to 0°C. Add N,N-diisopropylethylamine (155 mg, 1.2 mmol) and 4-methylazacycloheptane-4-ol (100 mg, 0.6 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-a, 172 mg, yield 83.5%). ESI[M+H] ⁺ = 345.1

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-b)

1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-a, 172 mg, 0.5 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (38 mg, 2.5 mmol), cesium carbonate (815 mg, 2.5 mmol) were added to dioxane (8 ml). The temperature was raised to 60° C. and the reaction was carried out for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-b, 200 mg, yield 85.5%). ESI[M+H] ⁺ =468.1

Step 3: Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-c)

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-b, 200 mg, 0.43 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-b, 200 mg, 0.43 mmol), 1-(2 ... The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepine-4-ol (26-c, 210 mg, yield 59.7%). ESI[M+H] ⁺ =818.9

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-c, 210 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (237 mg, 1.56 mmol) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-d, 200 mg, yield 50.4%). ESI[M+H] ⁺ ＝662.5

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26-d, 200 mg, 0.3 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (0.5 ml) was added, and the reaction was carried out at room temperature for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepin-4-ol (26, 30 mg, yield 10.5%). ESI[M+H] ⁺ ＝617.1 ¹ H NMR (600 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (28)

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

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.59 mmol) in dichloromethane (10 ml) and cool to 0°C. Add N,N-diisopropylethylamine (76 mg, 0.59 mmol) and (S)-piperidin-3-ylmethanol (75 mg, 0.65 mmol) and react at 0°C for 10 min. After concentration under reduced pressure, purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (S)-(1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-a, 208 mg, yield 100%). ESI[M+H] ⁺ = 331.1

Step 2: Preparation of ((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 208 mg, 0.63 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (301 mg, 1.89 mmol), cesium carbonate (1.026 g, 3.15 mmol) were added to 1,4-dioxane (7 ml). The temperature was raised to 80°C and the reaction was carried out for 3 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product ((S)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-b, 80 mg, yield 27.97%). ESI [M+H] ⁺ = 454.3

Step 3: Preparation of ((S)-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-c)

((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-b, 80 mg, 0.18 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dihydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-b, 80 mg, 0.18 mmol), 1,4-dioxane (4 ml) and water (0.4 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product ((S)-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-c, 36 mg, yield 24.83%). ESI [M+H] ⁺ = 804.5

Step 4: Preparation of ((S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-c, 35 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (4 ml), cesium fluoride (36 mg, 0.24 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times, 20 ml each time. The organic phase was collected and distilled under reduced pressure to obtain the target product ((S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-d, 35 mg). ESI[M+H] ⁺ =648.4

Step 5: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (28-d, 35 mg, 0.054 mmol) was dissolved in acetonitrile (3 ml), 1,4-dioxane hydrochloric acid solution (0.3 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (28, 7.44 mg, yield 22.81%). ESI[M+H] ⁺ ＝604.4, ¹ H NMR (600 MHz, DMSO-d ₆ )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,1 H),1.93–1.69(m,8H).

Example 29: Preparation of (3S,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 120 mg, 0.475 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,N-diisopropylethylamine (123 mg, 0.95 mmol) and (3S,4S)-4-fluoropyridin-3-ol (81 mg, 0.523 mmol) were added and reacted at 0°C for 0.5 h. After concentration under reduced pressure, the mixture was purified by Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (3S,4S)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29-a, 145 mg, yield 91.19%).

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

Preparation of (3S, 4S)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29-a, 145 mg, 0.433 mmol), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (207 mg, 1.299 mmol), cesium carbonate (705 mg, 2.165 mmol) were added to 1,4-dioxane (5 ml). The temperature was raised to 80°C and the reaction was carried out for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC (methanol: dichloromethane = 10:1) to obtain the target product (3S, 4S)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29-b, 70 mg, yield 35.35%). ESI [M+H] ⁺ = 458.3, 460.3

Step 3: Preparation of (3S, 4S)-4-fluoro-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (29-c)

(3S,4S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29-b, 70 mg, 0.153 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- 1,4-dioxane (4 ml) and water (0.4 ml). The mixture was replaced with nitrogen three times and heated to 60°C for 16 hours. The reaction mixture was quenched with water and 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 (3S, 4S)-4-fluoro-1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (29-c, 36 mg, yield 29.03%).

Step 4: Preparation of (3S, 4S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (29-c, 36 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (41 mg, 0.27 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times, 20 ml each time. The organic phase was collected and distilled under reduced pressure to obtain the target product (3S, 4S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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

Step 5: Preparation of (3S,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29-d, 38 mg, 0.058 mmol) was dissolved in acetonitrile (3 ml), 1,4-dioxane hydrochloric acid solution (0.3 ml) was added at 25°C, and the reaction was allowed to react for 0.5 h. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product (3S, 4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (29, 9.62 mg, yield 27.30%). ESI[M+H] ⁺ ＝608.3, ¹ HNMR (600 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30)

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

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.6 mmol) in dichloromethane (7 ml) and cool to 0°C. Add N,N-diisopropylethylamine (78 mg, 0.6 mmol) and (R)-piperidin-3-ylmethanol (69 mg, 0.6 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (R)-(1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-a, 167 mg, yield 84.0%). ESI[M+H] ⁺ = 331.9

Step 2: Synthesis of ((R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-b)

(R)-(1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-a, 167 mg, 0.5 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (398 mg, 2.5 mmol), cesium carbonate (815 mg, 2.5 mmol) were added to dioxane (8 ml). The temperature was raised to 60° C. and the reaction was carried out for 16 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product ((R)-1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-b, 185 mg, yield 81.5%). ESI[M+H] ⁺ =454.6

Step 3: Synthesis of ((R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-c)

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

Step 4: Synthesis of ((R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-c, 106 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium fluoride (118 mg, 0.78 mmol) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product ((R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-d, 36 mg, yield 41.7%). ESI[M+H] ⁺ =648.5

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (30-d, 36 mg, 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 was separated and purified by preparative liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30,6 mg, yield 16.7%). ESI[M+H] ⁺ ＝604.6 ¹ H NMR (400MHz, DMSO-d ₆ )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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31)

Step 1: 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, 200 mg, 0.792 mmol) and N,N-diisopropylethylamine (292.5 uL, 1.584 mmol) were dissolved in dichloromethane (8 ml), and then 4-methylpiperidin-3-ol hydrochloride (120.1 mg, 0.792 mmol) was added and reacted at -40°C for 1 hour. After reduced pressure concentration, column chromatography (petroleum ether: ethyl acetate = 5:1) was used for purification to obtain the target product 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-a, 295 mg, yield 112.5%). ESI[M+H] ⁺ = 330.05

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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, 100 mg, 0.302 mmol) was dissolved in dioxane (2 ml), and then ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (240.4 mg, 1.51 mmol) and potassium carbonate (221.1 mg, 1.51 mmol) were added, and the temperature was raised to 80°C for reaction for 16 h. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-b, 110 mg, yield 80.23%). ESI[M+H] ⁺ =453.17

Step 3: Synthesis of 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-c)

1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-b, 110 mg, 0.242 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalene -1-yl)ethynyl)triisopropylsilane (248.1 mg, 0.484 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (35.2 mg, 0.0484 mmol) and potassium phosphate (102.7 mg, 0.484 mmol) were dissolved in dioxane: water (10:1, 2 ml), heated to 60°C and reacted for 16 h. The mixture was diluted with water, extracted with dichloromethane, and the organic phase was collected and washed with a 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 obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-c, 95 mg, yield 48.84%). ESI[M+H] ⁺ =803.41

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (23-c, 85 mg, 0.106 mmol) was dissolved in DMF (2 ml), cesium fluoride (96.6 mg, 0.636 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After 1 h, the mixture was diluted with water and 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 obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-d, 80 mg, yield 116.5%). ESI[M+H] ⁺ =647.27

Step 5: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31-c, 75 mg, 0.116 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (1 mL) was added, and the temperature was lowered to 0°C for reaction for 30 minutes. The reaction solution was separated and purified by synthetic liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (31, 25 mg, 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol (32)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoro-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidine) (32-a)

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.594 mmol) in dichloromethane (3 ml) and cool to 0°C. Add N,N-diisopropylethylamine (67.3 mg, 0.475 mmol) and 3-methoxypiperidine (68.4 mg, 0.594 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 1-(2,7-dichloro-8-fluoro-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidine) (32-a, 170 mg, yield 86.18%). ESI[M+H] ⁺ = 333.1

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

Step 3: Synthesis of 1-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3d]pyrimidine (32-c)

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

Step 4: Synthesis of 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3d]pyrimidine (32-c, 80 mg, 0.0994 mmol) was dissolved in N,N-dimethylformamide (2.5 ml) and cesium fluoride (15.1 ml) was added. g, 0.994 mmol), and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidine (32-d, 79 mg). ESI[M+H] ⁺ =648.7

Step 5: Synthesis of 1-(5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidine (32-d, 79 mg, 0.1219 mmol) was dissolved in acetonitrile (3 ml), and dioxane hydrochloride (1 mL) was added. ml), and reacted at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 1-(5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol (32, 7.67 mg). ESI[M+H] ⁺ ＝604.2 ¹ H NMR(400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (33)

Step 1: Preparation of (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-a)

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (150 mg, 0.594 mmol) in dichloromethane (3 ml), add N,N-diisopropylethylamine (196 μL, 1.188 mmol) and react at 0°C for 10 minutes. Then dissolve piperidin-4-ylmethanol (68.4 mg, 0.594 mmol) in dichloromethane (1 ml) and add to the reaction and react at 0°C for 20 minutes. Quench with water, extract with ethyl acetate, collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target product (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-a, 201 mg, crude product). ESI[M+H] ⁺ ＝331.1

Step 2: Synthesis of (1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-b)

Dissolve 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-a, 201 mg, 0.607 mmol) in dioxane (4 ml), then add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (241.59 mg, 1.52 mmol) and cesium carbonate (494.43 mg, 1.52 mmol). Heat to 80°C and react for 8 hours. After filtration and concentration under reduced pressure, the product was purified by Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product (1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-b, 101 mg, yield 36.7%). ESI[M+H] ⁺ =454.2

Step 3: Synthesis of (1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-c)

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

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

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

Step 5: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (33-d, 115 mg, 0.1776 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (1 ml) was added and reacted at room temperature for 1 hour. Water was added slowly to quench the reaction, and then the pH of the reaction was adjusted to 8 with a saturated sodium bicarbonate aqueous solution. 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, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(hydroxymethyl)piperidin-1-yl)pyrido[4,3d]pyrimidin-7-yl)naphthalen-2-ol (33, 5.27 mg, yield 4.92%). ESI[M+H] ⁺ ＝604.3 1H NMR (400MHz, DMSO-d ₆ )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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (34)

Step 1: 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, 200 mg, 0.792 mmol) and N,N-diisopropylethylamine (204.7 mg, 1.584 mmol) were dissolved in acetonitrile (8 ml), and then piperidin-3-ylmethanol (91.6 mg, 0.792 mmol) was added and reacted at -40°C for 1 hour. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate = 5:1) was used to purify the target product (1-(2,7-dichloro-8-fluoropyrido[4,3d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-a, 200 mg, yield 75.77%). ESI[M+H]+ = 330.05

Step 2: Synthesis of (1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-b)

Dissolve (1-(2,7-dichloro-8-fluoropyrido[4,3d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-a, 100 mg, 0.302 mmol) in dioxane (2 ml), then add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (240.4 mg, 1.51 mmol) and potassium carbonate (221.1 mg, 1.51 mmol), and heat to 80°C for 16 h. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the target product (1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-b, 43 mg, yield 31.36%). ESI[M+H]+=453.17

Step 3: Synthesis of (1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-c)

(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-b, 40 mg, 0.088 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (90 mg, 0.176 mmol), CataCXium A pa G3 (12 mg, 0.0176 mmol) and potassium phosphate (37 mg, 0.176 mmol) were dissolved in dioxane:water (10:1, 2 ml), the temperature was raised to 60°C and the reaction was carried out for 16 h. The mixture was diluted with water, extracted with dichloromethane, and the organic phase was collected and washed with a 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 obtain the target product (1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-c, 50 mg, yield 70.67%). ESI[M+H] ⁺ =803.41

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

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

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol (34-d, 40 mg, 0.062 mmol) was dissolved in acetonitrile (5 ml), dioxane hydrochloride (1 mL) was added, and the temperature was lowered to 0°C for reaction for 30 minutes. The reaction solution was separated and purified by synthetic liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (34, 20 mg, yield 53.48%). ESI[M+H] ⁺ ＝603.25 1H NMR (400MHz, DMSO-d ₆ )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＝1 6.8,6.8Hz,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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile formate (35)

Step 1: 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, 100 mg, 0.4 mmol) was dissolved in dichloromethane (4 ml), and N,N-diisopropylethylamine (51.27 mg, 0.4 mmol) and 2-(piperidin-3-yl)acetonitrile (49.6 mg, 0.4 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, 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 with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified with a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 2-(1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-a, 105 mg, yield 77.78%). ESI [M+H] ⁺ = 340.55.

Step 2: Preparation of 2-(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 105 mg, 0.3 mmol) was dissolved in chloroform (3 ml), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (54 mg, 0.339 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, 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 and filtered. The filtrate was concentrated and purified using a Flash column (ethyl acetate: petroleum ether = 0% to 30%) to obtain the target product 2-(1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-b, 80 mg, yield 55.94%). ESI[M+H] ⁺ =463.52.

Step 3: Preparation of 2-(1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-c)

2-(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-b, 80 mg, 0.173 mmol) was dissolved in 1,4-dioxane (2 ml) and water (0.2 ml), ((2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (88.6 mg, 0.173 mmol), potassium phosphate (71.7 mg, 0.338 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (24.6 mg, 0.0338 mmol) were added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 60°C for reaction for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 2-(1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-c, 36 mg, yield 25.71%). ESI[M+H] ⁺ =813.55.

Step 4: Preparation of 2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile (35-c, 36 mg, 0.044 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (33.6 mg, 0.221 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was separated and purified by preparative chromatography to obtain the target product 2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)piperidin-3-yl)acetonitrile (35-d, 18 mg, yield 62.07%). ESI[M+H] ⁺ =657.52.

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

2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)piperidin-3-yl)acetonitrile (35-d, 18 mg, 0.027 mmol) was dissolved in acetonitrile (2 ml), trifluoroacetic acid (0.5 ml) was added on an ice bath, and the reaction was carried out for 0.5 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product 2-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile formate (35, 12.2 mg, yield 72.62%). ESI[M+H] ⁺ ＝613.25. ¹ H NMR (400 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropane-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (36)

Step 1: 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-fluoropyrido[4,3-d]pyrimidine (I-1, 130 mg, 0.52 mmol) was dissolved in dichloromethane (7 ml) and cooled to 0°C. 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°C for 1 hour. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2-(1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-a, 136 mg, yield 72.7%). ESI[M+H] ⁺ = 360.1

Step 2: Synthesis of 2-(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 136 mg, 0.38 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (302 mg, 1.9 mmol), cesium carbonate (619 mg, 1.9 mmol) were added to dioxane (8 ml). The temperature was raised to 60° C. and the reaction was carried out for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product (2-(1-(7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-b, 89 mg, yield 48.6%). ESI [M+H] ⁺ = 482.7

Step 3: Synthesis of 2-(1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-b, 77 mg, 0.16 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (164 mg, 0.32 mol), 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) l) was dissolved in dioxane (4) and water (0.4 ml). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for reaction for 6 h. The mixture was quenched with water, extracted with ethyl acetate, and 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 on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 2-(1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-c, 74 mg, yield 55.6%). ESI[M+H] ⁺ =832.8

Step 4: Synthesis of 2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-c, 74 mg, 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 obtain the target product 2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-d, 35 mg, yield 57.3%). ESI[M+H] ⁺ =676.6

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropane-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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)propan-2-ol (36-d, 35 mg, 0.05 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 separated and purified by preparative liquid chromatography to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropane-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (36, 15 mg, yield 47.5%). ESI[M+H] ⁺ ＝632.5 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (37)

Step 1: Synthesis of (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-a)

Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1, 150 mg, 0.594 mmol) in dichloromethane (3 ml) and cool to 0°C. Add N,N-diisopropylethylamine (61.3 mg, 0.4751 mmol) and pyrrolidin-3-ylmethanol (68.4 mg, 0.594 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-a, 180 mg, yield 95.87%). ESI[M+H] ⁺ = 317.1

Step 2: Synthesis of ((1-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 80 mg, 0.2531 mmol), cesium carbonate (246 mg, 0.7594 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (120.8 mg, 0.7594 mmol) were added to dioxane (3.5 ml). The temperature was raised to 60°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product ((1-(7-chloro-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-b, 70 mg, yield 62.89%). ESI[M+H] ⁺ =440.8

Step 3: Synthesis of ((1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-c)

((1-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-b, 70 mg, 0.1591 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzyl) The mixture was mixed with triisopropylsilane (163 mg, 0.3182 mmol), potassium phosphate (135 mg, 0.636 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (46 mg, 0.0636 mmol) in tetrahydrofuran (3.7 ml) and water (0.37 ml). The mixture was replaced with nitrogen three times and the temperature was raised to 60°C for 6 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product ((1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-c, 49 mg, yield 65.96%). ESI[M+H] ⁺ =791.01

Step 4: Synthesis of ((1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((triisopropylmethylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-c, 49 mg, 0.0621 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium fluoride (94.2 mg, 0.621 mmol) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain the target product ((1-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-d, 55 mg, yield>100%). ESI[M+H] ⁺ =634.67

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methanol (37-d, 55 mg, 0.086 mmol) was dissolved in acetonitrile (3 ml), dioxane hydrochloride (1 ml) was added, and the reaction was carried out at room temperature for 0.5 hours. 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (37, 4.5 mg). ESI[M+H] ⁺ ＝590.2 ¹ H NMR(400MHz,DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol carboxylate (38)

Step 1: Synthesis of 2-(2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-a)

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (100 mg, 0.38 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,N-diisopropylethylamine (98 mg, 0.76 mmol) and azetidine-3-ol hydrochloride (86 mg, 0.76 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench the mixture, and the mixture was 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 on a Flash column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-a, 70 mg, yield 53.8%). ESI[M+H] ⁺ ＝343.2

Step 2: Synthesis of 2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-a, 70 mg, 0.2 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (159 mg, 1 mmol), N,N-diisopropylethylamine (77 mg, 0.6 mmol) were added to dioxane (3 ml). The temperature was raised to 90°C and the reaction was carried out for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-b, 50 mg, yield 53.8%). ESI[M+H] ⁺ =465.9

Step 3: Synthesis of 2-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6-ol (38-b, 50 mg, 0.1 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (67 mg, 0.13 mmol), cesium carbonate (107 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (18 mg, 0.022 mmol) were dissolved in dioxane (7) and water (1.75 ml). The atmosphere was replaced with nitrogen three times and the temperature was raised to 135°C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using a Flash column (methanol: dichloromethane = 0% to 10%) to obtain the target product 2-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-c, 50 mg, yield 60.97%). ESI [M+H] ⁺ = 816.1

Step 4: Synthesis of 2-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6-ol (38-c, 50 mg, 0.06 mmol) was dissolved in acetonitrile (2.5 ml) and dioxane hydrochloride was added. (0.5ml), react at room temperature for 0.5 hours. The reaction solution was directly spin-dried to obtain the crude product 2-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-d, 25 mg). ESI[M+H] ⁺ ＝772.0

Step 5: Synthesis of 2-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol carboxylate (38)

2-(8-Fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol (38-d, 25 mg, 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 target product 2-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-6-ol formate (38.2 mg, yield 11.1%). ESI[M+H] ⁺ ＝616.1 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methoxy-4-(3-(methylamino)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (39)

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

Dissolve 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (120 mg, 0.44 mmol) in acetonitrile (6 ml), then add phosphorus oxychloride (162 mg, 1.056 mmol) and N,N-diisopropylethylamine (227 mg, 1.76 mmol), react at 80°C for 0.5 hour, cool the reaction to 0°C, then add N,N-diisopropylethylamine (227 mg, 1.76 mmol) and N-methylpiperidin-3-amine hydrochloride (107 mg, 0.572 mmol), and react at 0°C for 0.5 hour. After concentration under reduced pressure, the mixture was purified by thin layer chromatography on silica gel (methanol: dichloromethane = 1:10) to obtain 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). (ESI) [M+H] ⁺ = 372.1

Step 2: 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, 220 mg, 0.592 mmol) and 4-dimethylaminopyridine (36 mg, 0.296 mmol) were dissolved in acetonitrile (5 ml), and then di-tert-butyl dicarbonate (142 mg, 0.6512 mmol) was added and reacted at room temperature for 16 hours. After adding water to quench the reaction, the mixture was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plates (petroleum ether: ethyl acetate = 3:1) to obtain the target product 1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)carbamic acid tert-butyl ester (39-b, 30 mg, yield 10.75%). (ESI)[M+H] ⁺ ＝472.4

Step 3: 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, 30 mg, 0.064 mmol), potassium carbonate (35 mg, 0.256 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.0128 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (39 mg, 0.0768 mmol) were dissolved in 1,4-dioxane (3 ml) and water (0.75 ml), blown with nitrogen for 1 minute, and reacted at 135°C in a microwave for 1 hour. After concentration under reduced pressure, the reaction mixture was purified by thin layer chromatography on silica gel (petroleum ether:ethyl acetate=3:1) to give 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, 25 mg, yield 47.17%).

Step 4: Synthesis of (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)

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, 25 mg, 0.03 mmol) and m-chloroperbenzoic acid (16 mg, 0.09 mmol) were dissolved in dichloromethane (2 ml). The reaction was carried out at room temperature for 0.5 h. The reaction was quenched by adding water, extracted with dichloromethane, and the organic phase was collected and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target 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

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

Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (25 mg, 0.1539 mmol) in anhydrous tetrahydrofuran (3 ml), then add 60% sodium hydride (156 mg, 0.237 mmol), react at room temperature for 0.5 hours, then add (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)carbamic acid Ester (39-d, 43 mg, 0.0513 mmol), after reacting for 0.5 h, concentrated under reduced pressure and purified by thin layer chromatography on silica gel (dichloromethane: methanol = 25:2) to obtain the target product tert-butyl (1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilylethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)carbamate (39-e, 24 mg, yield 50%). (ESI) [M+H] ⁺ = 933.9

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

Dissolve tert-butyl (1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilylethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)carbamate (39-e, 24 mg, 0.026 mmol) in acetonitrile (5 ml), add 1,4-dioxane hydrochloride solution (0.5 ml) at room temperature, and react for 0.5 h. The reaction solution was distilled under reduced pressure to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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).

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

5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 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. The filtrate was filtered, and the solvent was removed by distillation under reduced pressure through an oil pump. The crude product was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methoxy-4-(3-(methylamino)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (39, 4.67 mg, yield 15.64%). (ESI) [M+H] ⁺ = 633.4. ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(3-(methylamino)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (40)

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

Dissolve 2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) in dichloromethane (5 ml), cool the reaction to -40°C, then add N,N-diisopropylethylamine (289 mg, 2.24 mmol) and N-methylpiperidin-3-amine hydrochloride (126 mg, 0.672 mmol), and react at -40°C for 0.5 hour. The reaction solution is directly purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 11:100) to obtain the target product 1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-a, 210 mg). (ESI)[M+H] ⁺ =344.1

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

1-(2,7-Dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-a, 210 mg, 0.61 mmol) was dissolved in 1,4-dioxane (8 ml), and then N,N-diisopropylethylamine (237 mg, 1.83 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (486 mg, 3. 05mmol), reacted at 90℃ for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 3:25) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-b, 50mg, yield 17.54%). (ESI)[M+H] ⁺ ＝467.5

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

(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-b, 50 mg, 0.107 mmol), cesium carbonate (105 mg, 0.321 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Methane complex (17.48 mg, 0.0214 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (66 mg, 0.1284 mmol) were dissolved in 1,4-dioxane (3 ml) and water (0.75 ml), blown with nitrogen for 1 minute, and reacted at 135°C in a microwave for 1 hour. After concentration under reduced pressure, the reaction mixture was purified by thin layer chromatography on silica gel (methanol: dichloromethane = 3:25) to give the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyridin[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-c, 23 mg, yield 26.44%).

Step 4: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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)

Dissolve 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyridin[4,3-d]pyrimidin-4-yl)-N-methylpiperidin-3-amine (40-c, 23 mg, 0.028 mmol) in acetonitrile (5 ml), add 1,4-dioxane hydrochloride solution (0.5 ml) at room temperature, and react for 0.5 h. The reaction solution was distilled under reduced pressure to obtain the target crude product 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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). (ESI) [M+H] ⁺ = 773.8

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

6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 0.036 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium fluoride (273 mg, 1.8 mmol) was added, and the mixture was reacted at room temperature for 4 hours. Filtered. The filtrate was distilled 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 obtain the target product 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(3-(methylamino)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (40, 7.29 mg, yield 30.55%). (ESI) [M+H] ⁺ = 617.5. ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ylcarboxylate (41)

Step 1: Synthesis of (R)acrylic acid-1-(7-(3-(acryloyloxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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 then triethylamine (51 mg, 0.5 mmol) and acryloyl chloride (45.25 mg, 0.5 mmol) were added and reacted 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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

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

(R)acrylic acid-1-(7-(3-(acryloyloxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl (41-a, 88 mg, 0.124 mmol) was dissolved in acetonitrile (2 ml) and water (0.2 ml), ammonium bicarbonate (392 mg, 4.96 mmol) was added and reacted at room temperature for 16 hours. The mixture was filtered and the filtrate was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product (R) acrylic acid-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ylcarboxylate (41, 5.1 mg, yield 5.75%). (ESI) [M+H] ⁺ = 658.9. ¹ H NMR (600 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl-2-fluoroacrylate formate (42)

Step 1: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((R)-3-((2-fluoroacryloyl)oxy)piperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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), and then N,N'-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) was added at 0°C, 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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.

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

5-Ethynyl-6-fluoro-4-(8-fluoro-4-((R)-3-((2-fluoroacryloyl)oxy)piperidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl-2-fluoroacrylate (42-a, 80 mg, 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. The mixture was filtered and the filtrate was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl-2-fluoroacrylate formate (42, 10.12 mg, yield 13.14%). (ESI) [M+H] ⁺ = 676.1. ¹ H NMR (600 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol formate (43)

Step 1: Synthesis of 1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-3-ol (43-a)

Dissolve 2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (I-2, 50 mg, 0.188 mmol) in dichloromethane (2 ml) and cool to 0°C. Add N,N-diisopropylethylamine (65 μL, 0.376 mmol) and 1,2,3,6-tetrahydropyridine-3-ol (26 mg, 0.188 mmol) and react at 0°C for 20 minutes. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-3-ol (43-a, 56 mg, yield 90.3%). ESI[M+H] ⁺ = 329.2

Step 2: Synthesis of 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-3-ol (43-b)

1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol (43-a, 59 mg, 0.17 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (135.25 mg, 0.85 mmol), N,N-diisopropylethylamine (66 mg, 0.51 mmol) were added to dioxane (2.5 ml). The temperature was raised to 90°C and the reaction was carried out for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-3-ol (43-b, 67 mg, yield 87.0%). ESI[M+H] ⁺ = 452.1

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

1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol (43-b, 67 mg, 0.145 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (92 mg, 0.18 mmol), cesium carbonate (146 mg, 0.45 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride dichloromethane complex (24 mg, 0.03 mmol) were dissolved in dioxane (3) and water (0.75 ml). The mixture was replaced with nitrogen three times, and the temperature was raised to 135°C for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a liquid chromatography column (methanol: dichloromethane = 0% to 10%) to obtain the target product 1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (43-c, 53 mg, yield 44%). ESI[M+H] ⁺ = 802.3

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

1-(8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (43-c, 53 mg, 0.066 mmol) was dissolved in acetonitrile (2 ml), and dioxane hydrochloride (0.4 ml) was added and reacted at room temperature for 1 hour. The reaction solution The crude product 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol (43-d, 45 mg) was obtained by spin drying. ESI[M+H] ⁺ =759.1

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

1-(8-Fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol (43-d, 45 mg, 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 obtain the target product 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3-ol formate (43.9 mg, yield 25.7%). ESI[M+H] ⁺ ＝602.3 ¹ HNMR (400MHz, DMSO-d ₆ )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,3 H),1.81-1.77(m,3H).

Example 44: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (44)

Step 1: Synthesis of (2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)azepine-4-ol (44-a)

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) was dissolved in dichloromethane (3 mL), and then N,N-diisopropylethylamine (0.098 mL, 0.59 mmol) and azerbaijan-4-ol (128 mg, 0.84 mmol) were added. After reacting at 0°C for 1 hour, water was added, extracted with dichloromethane, concentrated under reduced pressure, and purified by thin layer preparation silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)azepine-4-ol (44-a, 101 mg, yield 52.3%). ESI[M+H] ⁺ = 345.1

Step 2: Synthesis of 2,7-dichloro-8-fluoro-4-(4-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (44-b)

1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)azepine-4-ol (44-a, 90 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), and then diethylaminosulfur trifluoride (0.2 mL) was added at 0°C. After reacting at 0°C for 0.5 hours, the mixture was concentrated under reduced pressure and purified by thin layer silica gel preparation (petroleum ether: ethyl acetate = 1:1) to obtain the target product 2,7-dichloro-8-fluoro-4-(4-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (44-b, 49 mg, yield 54.3%). ESI[M+H] ⁺ = 347.1

Step 3: Synthesis of 7-chloro-8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (44-c)

2,7-Dichloro-8-fluoro-4-(4-fluoroazepin-1-yl)-5-methylpyridone[4,3-d]pyrimidine (44-b, 40 mg, 0.11 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (88 mg, 0.55 mmol) were dissolved in 1,4-dioxane (1 mL), and then N,N-diisopropylethylamine (0.057 mL, 0.33 mmol) was added. The reaction was carried out at 90°C for 16 hours under nitrogen protection, and then concentrated under reduced pressure and purified by thin layer silica gel plate (methanol: dichloromethane = 1:10) to obtain the target product 7-chloro-8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (44-c, 32 mg, yield 61.9%). ESI[M+H] ⁺ =470.2

Step 4: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (44-d)

7-Chloro-8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (44-c, 32 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (43 mg, 0.084 mmol) and cesium carbonate (68 mg, 0.21 mmol) were dissolved in a 4:1 mixed solvent of 1,4-dioxane and water (2.5 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11 mg, 0.014 mmol) was added. The reaction was carried out under microwave at 135°C for 1 hour. Water was added, extracted with ethyl acetate, concentrated under reduced pressure, and purified by thin layer preparative silica gel plate (methanol: dichloromethane = 1:10) to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (44-d, 30 mg, yield 52.26%). ESI [M+H] ⁺ = 820.4

Step 5: Synthesis of 6-fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (44-d, 30 mg, 0.036 mmol) was dissolved in acetonitrile (2 mL) and a 1,4-dioxane hydrochloride solution (0.2 mL). The reaction was continued at room temperature for 1 hour. After concentration under reduced pressure, the crude product 6-fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (44-e, 32 mg) was obtained. ESI[M+H] ⁺ =776.4

Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (44)

6-Fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (44-e, 32 mg, 0.04 mmol) was dissolved in N-N-dimethylformamide (2 mL), and cesium fluoride (60.76 mg, 0.4 mmol) was added. The mixture was reacted at room temperature for 4 hours. Saturated brine and water were added, extracted with ethyl acetate, concentrated under reduced pressure and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the target product 5-ethynyl-6-fluoro-4-(8-fluoro-4-(4-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (44,5.89 mg, yield 23.76%). ESI[M+H] ⁺ =620.3 ¹ HNMR(400MHz, DMSO-d ₆ )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)-tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol formate (45)

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

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (100 mg, 0.375 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0°C. N,N-diisopropylethylamine (130 μL, 0.75 mmol) and (R)-piperidin-3-ol hydrochloride (52 mg, 0.375 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench the mixture, and the mixture was 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 column (methanol: dichloromethane = 0% to 5%) to obtain the target product (R)-1-(2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidin-4-yl)piperidin-3-ol (45-a, 105 mg, yield 85.4%). ESI[M+H] ⁺ ＝330.05

Step 2: Synthesis of (R)-1-(7-chloro-8-fluoro-5-methyl-2-(((R)-tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (45-b)

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

Step 3: Synthesis of (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)

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

Step 4: Synthesis of (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)

(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, 110 mg, 0.147 mmol) was dissolved in acetonitrile (2 ml), and dihydrochloric acid was added. Hexacyclic (1 ml), react at room temperature for 1 hour. The reaction solution was dried 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). ESI[M+H] ⁺ =702.34

Step 5: Synthesis of (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 formate (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, 60 mg, 0.085 mmol) was dissolved in N,N-dimethylformamide (3 ml), and cesium fluoride (25 mg, 0.17 mmol) was added. , react 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 target 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 formate (45.8 mg, yield 17.3%). ESI[M+H] ⁺ ＝546.8 ¹ HNMR(400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl methoxycarboxylate (46)

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

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (100 mg, 0.375 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. N,N-diisopropylethylamine (130 μL, 0.375 mmol) and 1,2,3,6-tetrahydropyridine hydrochloride (45 mg, 0.375 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench the mixture, and the mixture was 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 column (methanol: dichloromethane = 0% to 5%) to obtain the target product 2,7-dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (46-a, 111 mg, yield 94.9%). ESI[M+H] ⁺ ＝313.2

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

2,7-Dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (46-a, 111 mg, 0.35 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (279 mg, 1.75 mmol), N,N-diisopropylethylamine (135 mg, 1.05 mmol) were added to dioxane (5 ml). The temperature was raised to 90°C and the reaction was carried out for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a liquid chromatography column (methanol: dichloromethane = 0% to 10%) to obtain the target product 7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-5-methylpyrido[4,3-d]pyrimidine (46-b, 107 mg, yield 88.4%). ESI[M+H] ⁺ = 435.9

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

7-Chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-5-methylpyrido[4,3-d]pyrimidine (46-b, 107 mg, 0.245 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (151 mg, 0.294 mmol), cesium carbonate (329 mg, 0.735 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride dichloromethane complex (30 mg, 0.0245 mmol) Dissolve in dioxane (5) and water (1.25 ml). Replace with nitrogen 3 times, heat to 135 ° C and react for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify with liquid chromatography column (methanol: dichloromethane = 0% to 10%) 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy (46-c, 100 mg, yield 43.3%). ESI[M+H] ⁺ = 786.1

Step 4: Synthesis of 4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl methoxycarboxylate (46)

4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy (46-c, 100 mg, 0.127 mmol) was dissolved in N,N-dimethylformamide (5 ml), and cesium fluoride (115 mg, 0.762 mmol) was added. , react at room temperature for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl methoxy formate (46,15 mg, yield 18.7%). ESI[M+H] ⁺ ＝630.26 ¹ H NMR (400MHz, DMSO-d ₆ )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). Example 47: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (47)

Step 1: Synthesis of 2,7-dichloro-8-fluoro-4-(3-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (47-a)

Dissolve 2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) in acetonitrile (5 ml), cool the reaction to 0°C, then add N,N-diisopropylethylamine (217 mg, 1.68 mmol) and 3-fluoroazepine hydrochloride (86 mg, 0.56 mmol), and react at 0°C for 0.5 hours. Remove the solvent by distillation under reduced pressure, and purify the crude product by thin layer chromatography on silica gel plate (methanol: dichloromethane = 1:200) to obtain the target product 2,7-dichloro-8-fluoro-4-(3-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (47-a, 178 mg, yield 92.27%). (ESI)[M+H] ⁺ = 347.2

Step 2: Synthesis of 7-chloro-8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (47-b)

2,7-Dichloro-8-fluoro-4-(3-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (47-a, 178 mg, 0.513 mmol) was dissolved in 1,4-dioxane (7 ml), and then N,N-diisopropylethylamine (199 mg, 1.539 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (408 mg, 2.56 5mmol), reacted at 90℃ for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 1:20) to obtain the target product 7-chloro-8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (47-b, 180mg, yield 74.69%). (ESI)[M+H] ⁺ ＝470.3

Step 3: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (47-c)

7-Chloro-8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (47-b, 180 mg, 0.383 mmol), cesium carbonate (374 mg, 1.149 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Dichloromethane complex (65 mg, 0.08 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (236 mg, 0.46 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2.5 ml), blown with nitrogen for 1 minute, and reacted in a microwave at 135°C for 1 hour. After concentration under reduced pressure, the crude product was chromatographed on a silica gel plate (methanol: dichloromethane = 2:25) to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (47-c, 65 mg, yield 20.70%). (ESI) [M+H] ⁺ = 820.4

Step 4: Synthesis of 6-fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (47-c, 65 mg, 0.08 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane hydrochloride solution (0.5 ml) was added at room temperature. , react for 0.5h. The reaction solution was distilled under reduced pressure to obtain the target product crude 6-fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (47-d, 75mg). (ESI)[M+H] ⁺ ＝776.5

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (47)

6-Fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (47-d, 75 mg, 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. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure with an oil pump to remove the solvent. The crude product was separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-fluoroaziridine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (47, 20.73 mg, yield 31.14%). (ESI)[M+H] ⁺ =620.4. ¹ H NMR (400MHz, DMSO-d ₆ ) 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),3.13-3.0 0(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-(azepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-1,6-naphthyridin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol formate (48)

Step 1: Synthesis of hexamethyleneimine (48-b)

Dissolve tert-butyl aza-1-carboxylate (48-a, 200 mg, 1.00 mmol) in trifluoroacetic acid (10 ml) and react at 0°C for 0.5 hours. Concentrate under reduced pressure to obtain the target product hexamethyleneimine (48-b, 200 mg), ESI [M+H] ⁺ = 99.18

Step 2: Synthesis of 4-(aza-1-yl)-2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (48-c)

2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (237 mg, 0.88 mmol) was dissolved in dichloromethane (10 ml), and hexamethyleneimine (48-b, 200 mg, 2.01 mmol) and N,N-diisopropylethylamine (260 mg, 2.01 mmol) were added, and the mixture was reacted at 0°C for 2 hours. After concentration under reduced pressure, the mixture was purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 4-(aza-1-yl)-2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (48-c, 240 mg, yield 83.1%) ESI[M+H] ⁺ = 329.20

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

Dissolve 4-(Aza-1-yl)-2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (48-c, 100 mg, 0.30 mmol) in dioxane (4 ml), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (291 mg, 1.82 mmol) and N,N-diisopropylethylamine (118 mg, 0.91 mmol), heat to 90 °C and react for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 4-(aza-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (48-d, 70 mg, yield 51.6%) ESI[M+H] ⁺ =450.96

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

4-(Aza-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (48-d, 70 mg, 0.154 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (119 mg, 0.23 mmol), tetrakistriphenylphosphine 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 atmosphere was replaced with nitrogen three times and the temperature was raised to 135°C for reaction for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 4-(azepine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl]-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (48-e, 40 mg, yield 32.3%) ESI [M+H] ⁺ = 801.08

Step 5: Synthesis of 4-(4-(aza-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (48-e, 40 mg, 0.049 mmol) was dissolved in acetonitrile (2 ml), and dioxane hydrochloride (0. 4ml), react at room temperature for 0.5 hours. The reaction solution was purified to obtain the target product 4-(4-(aza-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (48-f, 40 mg, yield, 107%) ESI[M+H] ⁺ =757.03

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

4-(4-(Aza-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (48-f, 40 mg, 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 separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4-(4-(azepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (48, 4.25 mg, yield 13.5%) ESI[M+H] ⁺ ＝600.69 ¹ H NMR (400 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate formate (49)

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

(4-(4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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), and then 4-dimethylaminopyridine (10 mg, 0.085 mmol), triethylamine (26 mg, 0.255 mmol) and dimethylcarbamoyl chloride (9 mg, 0.085 mmol) were added. l), after reacting at room temperature for 1 hour, the reaction solution was distilled under reduced pressure to remove the solvent, and the crude product was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4-(4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate formate salt (49, 5.84 mg, yield 9.78%). ESI[M+H] ⁺ ＝657.4. ¹ HNMR (400 MHz, DMSO-d ₆ )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,2 H),1.87-1.74(m,3H).

Example 50: Synthesis of 4-(4-(3,3-difluoroazepin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (50)

Step 1: Synthesis of 3-oxoaziridine-1-carboxylic acid benzyl ester (50-b)

Dissolve 3-nitroaniline (50-a, 225 mg, 1.5 mmol) in dichloromethane (9 mL), add N,N-diisopropylethylamine (0.784 mL, 4.5 mmol), then slowly add carbonylbenzyl chloride (0.246 mL, 1.8 mmol) at 0°C, react for 3 hours from 0°C to room temperature, add saturated sodium bicarbonate aqueous solution, extract with dichloromethane, and concentrate under reduced pressure to obtain the crude product 3-oxoaziridine-1-carboxylic acid benzyl ester (50-b, 390 mg). ESI[M+H] ⁺ =248.1

Step 2: Synthesis of 3,3-difluoroaziridine-1-carboxylic acid benzyl ester (50-c)

Dissolve 3-oxoaziridine-1-carboxylic acid benzyl ester (50-b, 450 mg, 1.82 mmol) in dichloromethane (10 mL), then slowly add diethylaminosulfur trifluoride (1701 mg, 10.5 mmol) at 0°C, react for 20 hours from 0°C to room temperature, add saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, and concentrate under reduced pressure to obtain the crude product 3,3-difluoroaziridine-1-carboxylic acid benzyl ester (50-c, 417 mg, yield 85%). ESI[M+H] ⁺ ＝270.1

Step 3: Synthesis of 3.3-difluoroaziridine (50-d)

3,3-Difluoroaziridine-1-carboxylic acid benzyl ester (50-c, 417 mg, 1.5 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 60°C for 2 hours, and then concentrated under reduced pressure to obtain a crude product 3,3-difluoroaziridine (50-d, 352 mg). ESI [M+H] ⁺ = 136.1

Step 4: Synthesis of 2,7-dichloro-4-(3,3-difluoroazepine-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (50-e)

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (200 mg, 0.75 mmol) was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (0.352 mL, 0.75 mmol) and 3.3-difluoroazacyclohexane (50-d, 102 mg, 0.75 mmol) were added. After reacting at 0°C for 0.5 hours, water was added, and the mixture was extracted with dichloromethane. After concentration under reduced pressure, the mixture was purified by thin layer preparation of silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain the target product 2,7-dichloro-4-(3,3-difluoroazepine-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (50-e, 200 mg, yield 54.8%). ESI[M+H] ⁺ = 365.0

Step 5: Synthesis of 7-chloro-4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (50-f)

2,7-Dichloro-4-(3,3-difluoroazepin-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (50-e, 200 mg, 0.55 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (438 mg, 2.75 mmol) were dissolved in 1,4-dioxane (5 mL), and then N,N-diisopropylethylamine (0.287 mL, 1.65 mmol) was added. The reaction was carried out at 90°C for 3 hours under nitrogen protection, and then concentrated under reduced pressure and purified by thin layer silica gel plate (methanol: dichloromethane = 1:10) to obtain the target product 7-chloro-4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (50-f, 110 mg, yield 40.99%). ESI[M+H] ⁺ =488.2

Step 6: Synthesis of 4-(3,3-difluoroazepine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (50 g)

7-Chloro-4-(3,3-difluoroazepin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (50-f, 110 mg, 0.225 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborin-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 4:1 mixed solvent of 1,4-dioxane and water (8 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (37 mg, 0.045 mmol) was added. The reaction was carried out at 135°C for 1 hour. Water was added, extracted with ethyl acetate, concentrated under reduced pressure, and purified by thin layer preparative silica gel plate (dichloromethane: methanol = 10: 1) to obtain the target product 4-(3,3-difluoroazepine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (50-g, 101 mg, yield 53.56%). ESI [M+H] ⁺ = 838.4

Step 7: Synthesis of 4-(4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (50 g, 101 mg, 0.12 mmol) was dissolved in acetonitrile (3 mL), and 1% hydrochloric acid was added. 4-dioxane solution (0.4 mL). Reaction at room temperature for 1 hour. After concentration under reduced pressure, the crude product 4-(4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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

Step 8: Synthesis of 4-(4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (50)

4-(4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (50-h, 100 mg, 0.126 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium fluoride (191.4 mg, 1.26 mmol) was added. The mixture was reacted at room temperature for 8 hours. Saturated brine and water were added, extracted with ethyl acetate, concentrated under reduced pressure and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to give the target product 4-(4-(3,3-difluoroazepine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (50, 2.4 mg, yield 2.99%). ESI[M+H] ⁺ =638.2. ¹ HNMR(400MHz, DMSO-d ₆ )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-(azepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (51)

Step 1: Synthesis of 4,7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (51-a)

Dissolve 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) in acetonitrile (5 ml) and add phosphorus oxychloride (0.271 mL, 3.24 mmol). Heat to 80°C under nitrogen protection and react for 0.5 hours. The target product reaction solution 4,7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (51-a) was obtained, ESI[M+H] ⁺ =294.96

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

Hexamethyleneimine (200 mg, 2.01 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.24 mmol) were added to the reaction solution of 4,7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (51-a) and reacted at 0°C for 1 hour. The mixture was quenched with water and 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 separated 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, 280 mg, yield 88.2%) ESI[M+H] ⁺ =356.84

Step 3: 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)

4-(Aza-1-yl)-7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (51-b, 240 mg, 0.67 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (687 mg, 1.34 mmol), tetrakistriphenylphosphine 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 in a microwave at 135°C for 1 hour under nitrogen protection. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by liquid chromatography to obtain the target 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, 500 mg, crude product) ESI[M+H] ⁺ =707.33

Step 4: 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)

Dissolve 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, 500 mg, 0.71 mmol) in dichloromethane (5 ml). Replace with nitrogen three times and react at room temperature for 0.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 4-(azepine-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, 500 mg, crude) ESI[M+H] ⁺ =738.97

Step 5: Synthesis of 4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 40 mg, 0.049 mmol) was dissolved in tetrahydrofuran (5 ml), sodium hydrogen hydride (50 mg, 2.04 mmol) was added, nitrogen was replaced three times, and the reaction was carried out at 0°C under nitrogen protection for 0.5 hours. ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (325 mg, 2.04 mmol) was dissolved in tetrahydrofuran (3 mL) and added to the reaction system, and the temperature was raised to room temperature for 0.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was 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 obtain the target product 4-(azepine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methoxypyrido[4,3-d]pyrimidine (51-e, 290 mg, crude product) ESI[M+H] ⁺ ＝818.07

Step 6: Synthesis of 4-(azepine-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methoxypyrido[4,3-d]pyrimidine (51-e, 290 mg, 0.35 mmol) was dissolved in acetonitrile (5 ml), and dioxane hydrochloride was added. (100 mL), react at room temperature for 1 hour. After the reaction solution was concentrated, the target product 4-(azepine-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy]-5-methoxypyrido[4,3-d]pyrimidine hydrochloride (51-f, 280 mg, crude product) ESI[M+H] ⁺ ＝774.02

Step 7: 4-(4-(Aza-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol carboxylate (51)

4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methoxypyrido[4,3-d]pyrimidine hydrochloride (51-f, 280 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (274 mg, 1.80 mmol) was added, and the mixture was reacted at room temperature for 5 hours. The mixture was quenched with aqueous solution, extracted with ethyl acetate, and the mixture was collected. The organic phase was collected and washed repeatedly with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 4-(4-(azepine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (51, 14.06 mg, yield 6.2%) ESI [M+H] ⁺ = 618.26 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (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 (52)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (52-a, 70 mg, 0.22 mmol) and 1-(1-methylpyrrolidin-2-yl)ethane-1-ol (85 mg, 0.66 mmol) were dissolved in acetonitrile (3 ml) and reacted at 60°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the 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, 80 mg, crude product) ESI[M+H] ⁺ =405.90

Step 2: 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, 80 mg, 0.2 mmol)((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (154 mg, 0.3 mmol), methanesulfonic acid [n-butyldi(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 mixture was replaced with nitrogen three times, and the temperature was raised to 100°C for 16 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel plate (petroleum ether: ethyl acetate = 1:1) 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)-5-methyl-2-(1-(1-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidine (52-b, 85 mg, yield 57.0%)

Step 3: 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)

Dissolve 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, 85 mg, 0.112 mmol) in acetonitrile (2 ml), add dioxane hydrochloride (0.4 ml), and react at room temperature for 0.5 hour. The reaction solution was purified to obtain the target product 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, 80 mg, yield, crude product)

Step 4: 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-fluoronaphthalen-2-ol formate (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, 80 mg, 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 separated and purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 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 (52.24 mg, yield 38.1%) ESI[M+H] ⁺ =555.63 ¹ H NMR (600 MHz, DMSO-d ₆ )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-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (53)

Step 1: Synthesis of 2,7-dichloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (53-a)

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (250 mg, 0.938 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0°C. N,N-diisopropylethylamine (400 uL, 1.876 mmol) and 3,3-difluoroazetidine hydrochloride (120 mg, 0.938 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench the mixture, and the mixture was 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 plates (petroleum ether: ethyl acetate = 4:1) to obtain the target product 2,7-dichloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (53-a, 115 mg, yield 38.3%). ESI[M+H] ⁺ ＝324.1

Step 2: Synthesis of 7-chloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyridinium[4,3-d]pyrimidine (53-b)

2,7-Dichloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (53-a, 115 mg, 0.356 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (284 mg, 1.78 mmol) were added to dioxane (2.5 ml), and finally N,N-diisopropylethylamine (200 μL, 1.068 mmol) was added. The temperature was raised to 90°C and the reaction was carried out for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane = 1:10) to obtain the target product 7-chloro-4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyridinium[4,3-d]pyrimidine (53-b, 87 mg, yield 55.8%). ESI[M+H] ⁺ = 446.3

Step 3: Synthesis of 4-(3,3-difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (53-c)

7-Chloro-4-(3,3-difluoroazetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (53-b, 87 mg, 0.195 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (120 mg, 0.234 mmol), cesium carbonate (191 mg, 0.585 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride dichloromethane complex (15 mg, 0.039 mmol) were dissolved in dioxane (4 ml) and water (1 ml). The mixture was replaced with nitrogen three times, and the temperature was raised to 135°C for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 4-(3,3-difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (53-c, 96 mg, yield 61.9%). ESI[M+H] ⁺ = 796.6

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

4-(3,3-difluoroazetidine-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (53-c, 96 mg, 0.12 mmol) was dissolved in acetonitrile (2 ml), and dioxane hydrochloride (0.7 ml), react at room temperature for 1 hour. The reaction solution was dried in vortex to obtain the crude product 4-(4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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

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

4-(4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (53-d, 80 mg, 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 obtain the target product 4-(4-(3,3-difluoroazetidine-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (53.8 mg, yield 12.7%). ESI[M+H] ⁺ ＝596.5 ¹ HNMR(600MHz,DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol formate (54)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (250 mg, 0.934 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0°C. N,N-diisopropylethylamine (200 μL, 0.934 mmol) and 3,3-difluoropyrrolidine (100 mg, 0.9384 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench the mixture, and the mixture was 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 plates (petroleum ether: ethyl acetate = 4:1) to obtain the target product 2,7-dichloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (54-a, 280 mg, yield 88.9%). ESI[M+H] ⁺ ＝337.9

Step 2: Synthesis of 7-chloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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, 280 mg, 0.83 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (661 mg, 4.153 mmol) were added to dioxane (2.5 ml), and finally N,N-diisopropylethylamine (500 μL, 2.49 mmol) was added. The temperature was raised to 90°C and the reaction was carried out for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and repeatedly washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane = 1:10) to obtain the target product 7-chloro-4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (54-b, 287 mg, yield 75.1%). ESI[M+H] ⁺ = 460.3

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

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

Step 4: Synthesis of 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy (54-c, 280 mg, 0.346 mmol) was dissolved in acetonitrile (10 ml), and dioxane hydrochloride (1. 5ml), react at room temperature for 1 hour. The reaction solution was dried in vortex to obtain the crude product 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (54-d, 200mg). ESI[M+H] ⁺ =766.7

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

4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (54-d, 200 mg, 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 obtain the target product 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (54,30 mg, yield 18.98%). ESI[M+H] ⁺ ＝610.3 ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate (55)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (250 mg, 0.95 mmol) was dissolved in dichloromethane (10 ml), and pyrrolidine (54 mg, 0.76 mmol) and N,N-diisopropylethylamine (370 mg, 2.85 mmol) were added, and the mixture was reacted at 0°C for 1 hour. After quenching with water, the mixture was extracted with dichloromethane three times, and the organic phase was concentrated 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, 330 mg, crude product) ESI[M+H] ⁺ =301.15

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

Dissolve 2,7-dichloro-8-fluoro-5-methyl-4-(pyrrolidin-1-yl)pyrido[4,3-d]pyrimidine (55-a, 100 mg, 0.33 mmol) in dioxane (4 ml), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (420 mg, 2.64 mmol) and N,N-diisopropylethylamine (129 mg, 0.99 mmol), heat to 90 °C and react for 16 hours. , after concentration under reduced pressure, the target product 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridine (55-b, 65 mg, yield 46.4%) was obtained by liquid chromatography separation. ESI[M+H] ⁺ =424.17

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

7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridine (55-b, 65 mg, 0.15 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (92 mg, 0.18 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium 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). The atmosphere was replaced with nitrogen and the temperature was raised to 135°C for microwave reaction for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with a 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (55-c, 50 mg, crude product). ESI[M+H] ⁺ =773.03

Step 4: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (55-d)

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

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridin-7-yl)naphthalene-2-ol carboxylate (55)

6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (55-d, 50 mg, 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 extracted with ethyl acetate and concentrated, and then separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(pyrrolidin-1-yl)-1,6-naphthyridin-7-yl)naphthalen-2-ol formate (55, 7.85 mg, yield 20%) ESI[M+H] ⁺ ＝573.62 ¹ H 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (56)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (300 mg, 1.125 mmol) was dissolved in dichloromethane (10 ml), and N,N-diisopropylethylamine (292 mg, 2.254 mmol) and azetidine (64 mg, 1.121 mmol) were added and reacted at 0°C for 20 minutes. Water was added to quench, and ethyl acetate was extracted. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (4-(azetidin-1-yl)-2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (56-a, 310 mg, yield 95%), ESI[M+H] ⁺ =287.12

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

Dissolve (4-(azetidin-1-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (56-a, 310 mg, 1.079 mmol) in 1,4-dioxane (10 ml), and add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (860 mg, 5.40 mmol) and N,N-diisopropylethylamine (420 mg, 3.242 mmol) in turn. React at 90°C for 16 h. Add water The reaction mixture was quenched and extracted with ethyl acetate. The organic phase was collected and washed repeatedly with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plates (methanol: dichloromethane = 1:10) to obtain the target product 4-(azetidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (56-b, 110 mg, yield 25%) ESI [M+H] ⁺ = 409.87

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

4-(azetidin-1-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (56-b, 110 mg, 0.268 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxy borane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (275 mg, 0.536 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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 at 135 ° C for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and washed repeatedly with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (methanol: dichloromethane = 1:10) to obtain the target product 4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (56-c, 55 mg, yield 54%) ESI [M+H] ⁺ = 759.99

Step 4: Synthesis of 4-(4-(azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (56-c, 55 mg, 0.072 mmol) was dissolved in acetonitrile (2.5 ml), and dioxane hydrochloride (0. 5ml), react at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the target product 4-(4-(azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (56-d, 55 mg, yield 106%), ESI [M+H] ⁺ = 715.94

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

4-(4-(azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (56-d, 55 mg, 0.076 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (100 mg, 0.658 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 obtain the target product 4-(4-(azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (56-P1, 1.06 mg, yield 2%; 56-P2, 1.83 mg, yield 3%) ESI [M+H] ⁺ = 559.59 56-P2: ¹ H NMR (600 MHz, DMSO-d ₆ )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),3.1 1-2.99(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (57)

Step 1: Synthesis of 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (57-a)

Dissolve 2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) in acetonitrile (5 ml), cool the reaction to 0°C, then add N,N-diisopropylethylamine (217 mg, 1.68 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (60 mg, 0.504 mmol), and react at 0°C for 0.5 hours. Remove the solvent by distillation under reduced pressure, and purify the crude product by thin layer chromatography on silica gel plate (dichloromethane: methanol = 50: 1) to obtain the target product 2,7-dichloro-8-fluoro-4-(3-fluoroaza-1-yl)-5-methylpyridone[4,3-d]pyrimidine (57-a, 145 mg, yield 82.86%). ESI[M+H] ⁺ = 314.2

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

2,7-Dichloro-8-fluoro-4-(3-fluoroazepine-1-yl)-5-methylpyridone[4,3-d]pyrimidine (57-a, 145 mg, 0.463 mmol) was dissolved in 1,4-dioxane (7 ml), and then N,N-diisopropylethylamine (180 mg, 1.389 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (369 mg, 2.315 mm ol), reacted at 90°C for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 7:100) to obtain the target product 4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (57-b, 152 mg, yield 75.25%). ESI[M+H] ⁺ =436.3

Step 3: 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (57-b, 150 mg, 0.344 mmol), cesium carbonate (336 mg, 1.032 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex (56 mg, 0.069 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (212 mg, 0.413 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2.5 ml), blown with nitrogen for 1 minute, and reacted at 135°C in a microwave for 1 hour. After concentration under reduced pressure, the crude product was chromatographed on a silica gel plate (methanol: dichloromethane = 1:20) to obtain 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-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (57-c, 118 mg, yield 43.70%). ESI[M+H] ⁺ = 787.2

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

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

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

4-(4-(3-Azabicyclo[3.1.0]hex-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (57-d, 130 mg, 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. The filtrate was filtered, and the solvent was removed by distillation under reduced pressure with an oil pump. The crude product was separated by preparative liquid chromatography (aqueous 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (57, 31.29 mg, yield 28.19%). ESI[M+H] ⁺ ＝586.8. ¹ H NMR (600 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-D)-5-methylpyridone[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate (58)

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

At -75°C, 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), and the reaction was continued for 1 h. Then, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.55 g, 9.74 mmol) in dichloromethane (5 ml) was added dropwise. The reaction was continued for 1 h, triethylamine (9.85 g, 97.5 mmol) was added to the above reaction solution, the reaction temperature was cooled to room temperature and stirred for 16 h, then the system was diluted with dichloromethane (5 ml), the organic phase was washed with saturated sodium bicarbonate solution (25 ml), and the organic phase was concentrated under reduced pressure to obtain the target product (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-carbaldehyde (58-a, 1.4 g, yield 91.44%).

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

The reaction was carried out at 0°C. (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-carboxaldehyde (58-a, 65 mg, 0.41 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml), sodium deuterated borohydride was added, and the reaction was allowed to react for 1 h. Then methanol (0.5 ml) was added to quench the reaction, H ₂ O (10 ml) was added to dilute the reaction, and ethyl acetate (10 ml) was used to extract three times. Another batch was amplified by 2 times in the same ratio. The organic phases of the two batches were mixed and the solvent was removed by distillation under reduced pressure to obtain the target product (S)-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methane-D-ol (58-b, 108 mg). (ESI) [M+H] ⁺ = 161.4

Step 3: Synthesis of 7-chloro-4-(3,6-dihydropyridin-1(2H)yl)-8-fluoro-2-((S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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-methylpyridone[4,3-d]pyrimidine (70 mg, 0.224 mmol) was dissolved in 1,4-dioxane (8 ml), and then cesium carbonate (220 mg, 0.672 mmol) and (S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methan-D-ol (58-b, 108 mg, 0.67 2mmol), reacted at 90℃ for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (dichloromethane:methanol=50:3) to obtain the target product 7-chloro-4-(3,6-dihydropyridin-1(2H)yl)-8-fluoro-2-((S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-D)-5-methylpyrido[4,3-d]pyrimidine (58-c, 75mg, yield 76.53%). (ESI)[M+H] ⁺ ＝437.3

Step 4: 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-D)-5-methylpyrido[4,3-d]pyrimidine (58-c, 75 mg, 0.17 mmol), cesium carbonate (166 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex (28 mg, 0.034 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (105 mg, 0.204 mmol) were dissolved in 1,4-dioxane (5 ml) and water (1.25 ml), blown with nitrogen for 1 minute, and reacted in a microwave at 135°C for 1 hour. After concentration under reduced pressure, the crude product was chromatographed on a silica gel plate (methanol: dichloromethane = 1:20) 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-(S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy-D)-5-methylpyrido[4,3-d]pyrimidine (58-d, 67 mg, yield 50%). (ESI)[M+H] ⁺ =788.2

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

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

Step 6: Synthesis of 4-(4-(3,6-dihydropyridin-1(2H)yl)-8-fluoro-2-((S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-D)-5-methylpyridone[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate (58)

4-(4-(3,6-dihydropyridin-1(2H)yl)-8-fluoro-2-((S)-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-D)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethyl)naphthalen-2-ol (58-e, 70 mg, 0.094 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium fluoride (715 mg, 4.7 mmol) was added and reacted at room temperature for 4 hours. The filtrate was filtered, and the solvent was removed by distillation under reduced pressure through an oil pump. The crude product was separated by preparative liquid chromatography (aqueous 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-D)-5-methylpyridone[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate (58, 2.03 mg, yield 3.44%). (ESI)[M+H] ⁺ =587.8. ¹ H NMR (600MHz, DMSO-d ₆ )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),3.1 3-3.00(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,2 H),1.70-1.62(m,3H).

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

Step 1: Preparation of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-carbaldehyde (59-a)

At -75°C, 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), and the reaction was continued for 1 h. Then, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.55 g, 9.74 mmol) in dichloromethane (5 ml) was added dropwise. The reaction was continued for 1 h, triethylamine (9.85 g, 97.5 mmol) was added to the above reaction solution, the reaction temperature was cooled to room temperature and stirred for 16 h, then the system was diluted with dichloromethane (5 ml), the organic phase was washed with saturated sodium bicarbonate solution (25 ml), and the organic phase was concentrated under reduced pressure to obtain the target product (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-carbaldehyde (59-a, 1.4 g, yield 91.44%).

Step 2: Synthesis of (S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)ethane-1-ol (59-b)

The reaction was carried out at -40°C. Methylmagnesium bromide (12 ml, 1M) was slowly added to anhydrous tetrahydrofuran (16 ml) of (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-carboxaldehyde (59-a, 600 mg, 3.82 mmol). The reaction system was slowly heated to room temperature and reacted for 16 hours. Tetrahydrofuran (40 ml) and saturated aqueous ammonium chloride solution (2 ml) were added to the reaction system respectively. After vacuum concentration, 20 ml of dichloromethane was added and the mixture was filtered. The filtrate was subjected to vacuum distillation to obtain the crude target product (S)-1-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)ethane-1-ol (59-b, 1.2 g). (ESI)[M+H] ⁺ ＝174.2

Step 3: Synthesis of 7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-((S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylethoxy)-5-methylpyridone[4,3-d]pyrimidine (59-c)

2,7-Dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (100 mg, 0.32 mmol) was dissolved in 1,4-dioxane (5 ml), and then N,N-diisopropylethylamine (124 mg, 0.96 mmol) and (S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)ethan-1-ol (59-b, 332 mg, 1.92 mmol) were added. mol), reacted at 90°C for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 7:100) to obtain the target product 7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-((S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylethoxy)-5-methylpyridone[4,3-d]pyrimidine (59-c, 80 mg, yield 55.56%). (ESI) [M+H] ⁺ = 450.3

Step 4: 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylethoxy)-5-methylpyridone[4,3-d]pyrimidine (59-c, 80 mg, 0.178 mmol), cesium carbonate (174 mg, 0.534 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride dichloromethane complex (29 mg, 0.036 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (109 mg, 0.214 mmol) were dissolved in 1,4-dioxane (5 ml) and water (1.25 ml), blown with nitrogen for 1 minute, and reacted in a microwave at 135°C for 1 hour. After concentration under reduced pressure, the crude product was subjected to thin layer chromatography on silica gel plate (methanol: dichloromethane = 3:50) 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-((S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylethoxy)-5-methylpyrido[4,3-d]pyrimidine (59-d, 78 mg, yield 54.93%). (ESI) [M+H] ⁺ = 801.4

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

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

4-(4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-((S)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-ethoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethyl)naphthalen-2-ol (59-e, 60 mg, 0.079 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (600 mg, 3.95 mmol) was added, and the mixture was reacted at room temperature for 4 hours. The filtrate was filtered, and the solvent was removed by distillation under reduced pressure with an oil pump. The crude product was separated by preparative liquid chromatography (aqueous 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)-1-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylethoxy)-5-methylpyridone[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate (59, 3.26 mg, yield 6.2%). (ESI) [M+H] ⁺ = 600.4. ¹ H NMR (600 MHz, DMSO-d ₆ )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),5.3 4(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydrocyclopentyl[c]pyrrole-2(1H)-acyl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (60)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (150 mg, 0.57 mmol) was dissolved in dichloromethane (5 ml), and octahydrocyclopenta[c]pyrrole (57 mg, 0.513 mmol) and N,N-diisopropylethylamine (222 mg, 1.71 mmol) were added, and the mixture was reacted at 0°C for 1 hour. After quenching with water, the mixture was extracted with dichloromethane three times, and the organic phase was concentrated under reduced pressure to obtain the target product 2,7-dichloro-8-fluoro-4-(hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-methylpyridone[4,3-d]pyrimidine (60-a, 200 mg, crude product), ESI[M+H] ⁺ ＝341.21

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

Dissolve 2,7-dichloro-8-fluoro-4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-5-methylpyrido[4,3-d]pyrimidine (60-a, 200 mg, 0.58 mmol) in dioxane (8 ml), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (461 mg, 2.9 mmol) and N,N-diisopropylethylamine (225 mg, 1.74 mmol), heat to 90°C and react for 16 hours. , after concentration under reduced pressure, the target product 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydrocyclopentyl[c]pyrrole-2(1H)-acyl)-5-methylpyrido[4,3-d]pyrimidine (60-b, 270 mg, crude product) was obtained by liquid chromatography separation, ESI[M+H] ⁺ ＝463.96

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

7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydrocyclopentyl[c]pyrrole-2(1H)-acyl)-5-methylpyrido[4,3-d]pyrimidine (60-b, 270 mg, 0.58 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (356 mg, 0.7 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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). The mixture was replaced with nitrogen, heated to 135°C and microwaved for 1 h. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by liquid chromatography to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (60-c, 250 mg, crude product), ESI [M+H] ⁺ = 814.08

Step 4: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (60-c, 250 mg, 0.3 mmol) was dissolved in acetonitrile (3 ml), and dioxane hydrochloride (1 ml) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain Target product 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 250 mg, crude), ESI[M+H] ⁺ =770.03

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

6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 250 mg, 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 extracted with ethyl acetate and concentrated, and then separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydrocyclopenta[c]pyrrol-2(1H)yl)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (60,25 mg, yield 12.5%) ESI[M+H] ⁺ ＝613.69 ¹ H 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]heptane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol formate (61)

Step 1: Synthesis of 4-(3-azabicyclo[3.2.0]heptane-3-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (61-a)

Dissolve 2,4,7-trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) in acetonitrile (6 ml), cool the reaction to 0°C, then add N,N-diisopropylethylamine (217 mg, 1.68 mmol) and 3-azabicyclo[3.2.0]heptane hydrochloride (75 mg, 0.504 mmol), and react at 0°C for 0.5 hours. Remove the solvent by distillation under reduced pressure, and purify the crude product by thin layer chromatography on silica gel plate (methanol: dichloromethane = 1:50) to obtain the target product 4-(3-azabicyclo[3.2.0]heptane-3-yl)-2,7-dichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (61-a, 160 mg, yield 87.43%). ESI[M+H] ⁺ = 327.2

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

4-(3-Azabicyclo[3.2.0]heptane-3-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (61-a, 160 mg, 0.49 mmol) was dissolved in 1,4-dioxane (7 ml), and then N,N-diisopropylethylamine (190 mg, 1.47 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (390 mg, 2.4 5mmol), reacted at 90℃ for 16h, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography on silica gel plate (methanol: dichloromethane = 3:50) to obtain the target product 4-(3-azabicyclo[3.2.0]heptane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (61-b, 135mg, yield 61.36%). ESI[M+H] ⁺ ＝450.3

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

4-(3-azabicyclo[3.2.0]heptane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (61-b, 135 mg, 0.3 mmol), cesium carbonate (293 mg, 0.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex (56 mg, 0.069 mmol), (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (185 mg, 0.36 mmol) were dissolved in 1,4-dioxane (8 ml) and water (2 ml), blown with nitrogen for 1 minute, and reacted in a microwave at 135°C for 1 hour. After concentration under reduced pressure, the crude product was chromatographed on silica gel plate (dichloromethane:methanol=100:5) to obtain the target product 4-(3-azabicyclo[3.2.0]heptane-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (61-c, 120 mg, yield 50%). ESI[M+H] ⁺ =800.6

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

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

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

4-(4-(3-azabicyclo[3.2.0]heptane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (61-d, 130 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (1.3 g, 8.6 mmol) was added and reacted at room temperature for 4 hours. The filtrate was filtered, and the solvent was removed by distillation under reduced pressure through an oil pump. The crude product was separated by preparative liquid chromatography (aqueous 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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (61, 48.51 mg, yield 43.70%). ESI[M+H] ⁺ ＝601.1. ¹ H NMR (400MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (62)

Step 1: 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-methylpyridone[4,3-d]pyrimidine (100 mg, 0.375 mmol) was dissolved in dichloromethane (5 ml), and 2,5-dihydro-1H-pyrrole (40 mg, 0.375 mmol) and N,N-diisopropylethylamine (146 mg, 1.125 mmol) were added, and the mixture was reacted at 0°C for 0.5 hours. After quenching with water, the mixture was extracted with dichloromethane three times, and the organic phase was concentrated under reduced pressure to obtain the target product 2,7-dichloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (62-a, 200 mg, crude product), ESI[M+H] ⁺ ＝299.13

Step 2: Synthesis of 7-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(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, 200 mg, 0.67 mmol) was dissolved in dioxane (8 ml), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (533 mg, 3.35 mmol) and N,N-diisopropylethylamine (260 mg, 2.00 mmol) were added, and the temperature was raised to 90°C for 16 hours. After concentration under reduced pressure, the target product 7-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (62-b, 200 mg, crude product) was obtained by liquid chromatography separation, ESI [M+H] ⁺ = 421.9

Step 3: 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,7aS)-2-fluorotetrahydro-1H-pyrazine-7a(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,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidine (62-b, 200 mg, 0.48 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (295 mg, 0.576 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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). The mixture was replaced with nitrogen, heated to 135°C and subjected to microwave reaction for 1 h. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by liquid chromatography to obtain the target product 4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy]-5-methylpyrido[4,3-d]pyrimidine (62-c, 350 mg, crude product), ESI[M+H] ⁺ ＝771.0

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

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

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

4-(4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (62-d, 350 mg, 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 extracted with ethyl acetate and concentrated, and separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target 4-(4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (62, 13.12 mg, yield 5%), ESI [M+H] ⁺ = 570.6 ¹ H NMR (400 MHz, DMSO-d ₆ )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,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (63)

Step 1: Synthesis of 2,7-dichloro-8-fluoro-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidine (63-a)

2,4,7-Trichloro-8-fluoro-5-methylpyridone[4,3-d]pyrimidine (150 mg, 0.56 mmol) was dissolved in dichloromethane (5 ml), and 6-azaspiro[2.5]octane (80 mg, 0.56 mmol) and N,N-diisopropylethylamine (217 mg, 1.68 mmol) were added, and the mixture was reacted at 0°C for 0.5 hours. After quenching with water, the mixture was extracted with dichloromethane three times, and the organic phase was concentrated under reduced pressure to obtain the target product 2,7-dichloro-8-fluoro-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyridone[4,3-d]pyrimidine (63-a, 190 mg, crude product), ESI[M+H] ⁺ =341.2

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

Dissolve 2,7-dichloro-8-fluoro-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidine (63-a, 190 mg, 0.56 mmol) in dioxane (8 ml), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (443 mg, 2.78 mmol) and N,N-diisopropylethylamine (217 mg, 1.68 mmol), heat to 90 °C and react for 16 hours. After concentration under reduced pressure, the target product 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidine (63-b, 250 mg, crude product) was obtained by liquid chromatography separation, ESI[M+H] ⁺ =463.0

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

7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidine (63-b, 250 mg, 0.54 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (332 mg, 0.648 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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). The mixture was replaced with nitrogen, heated to 135°C and microwaved for 1 h. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by liquid chromatography to obtain the target product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (63-c, 350 mg, crude product), ESI [M+H] ⁺ = 814.08

Step 4: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy (63-c, 350 mg, 0.43 mmol) was dissolved in acetonitrile (4 ml), and dioxane hydrochloride (1 ml) was added and reacted at room temperature for 1 hour. The reaction solution was concentrated to dryness. The target product 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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, 350 mg, crude product) was obtained, ESI[M+H] ⁺ =770.03

Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate (63)

6-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-(((triisopropylsilyl)ethynyl)naphthalen-2-ol (63-d, 350 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (342 mg, 2.25 mmol) was added and reacted at room temperature. The reaction solution was extracted with ethyl acetate and concentrated, and separated by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol formate (63, 41.10 mg, yield 14.6%) ESI[M+H] ⁺ =613.69 ¹ H NMR (400MHz, DMSO-d ₆ ) 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),2.6 7(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-ERK1/2 (THR202/TYR204) HTRF Test

1.1 Experimental reagents, instruments and consumables

Experimental reagents: FBS, PBS, DMSO, DMEM medium, RPMI-1640 medium, F12K medium, MEM medium, PHOSPHO-ERK1/2 (THR202/TYR204) kit, 0.25% Trypsin-EDTA, the reagents were purchased from Gibco, Beyotime, Cisbio and other manufacturers;

Instruments and consumables: 96-well cell culture plates, 384-well plates, microplate reader, desktop centrifuge, carbon dioxide incubator. Instruments and consumables were purchased from Corning, Greiner and other manufacturers.

1.2 KRAS mutants and cell lines

1.3 Experimental procedures

a) Plating: Cells expressing KRAS mutations were cultured in a culture medium (Gibco) containing fetal bovine serum (Gibco). When the cells were in the logarithmic growth phase, the cells were resuspended in serum-free culture medium to a suitable density, inoculated into a 96-well cell culture plate at 80 μL/well, and placed in a cell culture incubator (37°C, 5% CO ₂ ) for overnight incubation.

b) Compound dilution: After diluting the 10 mM stock solution with serum-free medium, dilute the compound in cell culture serum-free medium at 20 μL/well. Centrifuge at 1000 rpm/min for 1 min and incubate in a cell culture incubator (37°C, 5% CO ₂ ) for 4 h. The initial compound concentration is 6000 nM, and the dilution is 3.5 times.

c) Lysis: Remove the cell supernatant, immediately add 50 μL/well of 1× cell lysis buffer (Cisbio), and incubate at room temperature with shaking for 40 min.

d) Transfer: After shaking evenly, transfer 16 μL of cell lysate from the 96-well cell culture plate to a small-volume (Greiner, 784075) white detection plate. Add 4 μL of the prepared antibody premix solution (Cisbio, 64AERPEH) to the lysate.

e) Incubate overnight at room temperature in the dark.

f) HTRF signals were read in a multifunctional microplate reader (Tecan, Spark 10M). The data were analyzed using a 4-parameter logistic model to calculate IC ₅₀ values.

The HTRF results of phosphorylated-ERK1/2 (THR202/TYR204) are shown in Table 1. From the results, it can be seen that the exemplary compounds of the present invention have high inhibitory activity against AGS cells with Kras G12D mutation, NCI-H358 cells with Kras G12C mutation, NCI-H460 cells with Kras Q61H mutation, wild-type MKN1 cells, SW1116 cells with Kras G12A mutation, SW626 cells with Kras G12V mutation, Calu-6 cells with Kras Q61K mutation, MDA-MB-231 cells with Kras G13D mutation and A549 cells with Kras G12S mutation, and the IC50 thereof is lower than 10 μM; or lower than 1000 nM, or lower than 100 nM, or even lower than 50 nM.

Among them, for _IC50 values, "++++" means _IC50 is between 0 nM and 500 nM; "+++" means _IC50 is between 500 nM and 1 μM; "++" means _IC50 is between 1 μM and 10 μM. "—" means not tested, and blank means no activity.

Table 1

Test Example 2: KRAS nucleotide exchange assay

2.1 Experimental reagents and instruments

Mant-GDP-KRAS (Bioduro), experimental buffer solution (20mM HEPES, 150mM NaCl, 1mM MgCl2, 1mM DTT, Ph 7.2), GTP (Sigma), EDTA (Sigma), DMSO, white 384-well plate (Greiner), multi-function microplate reader (Tecan), centrifuge (Eppendorf).

2.2 Experimental procedures

a) Prepare a buffer solution containing 20 mM HEPES, 150 mM NaCl, and 1 mM MgCl ₂ . Add DTT solution just before use to make the final concentration 1 mM.

b) Mant-GDP-KRAS protein (including mant-GDP-KRAS-WT, G12D, G12C, G12A, G12V, Q61H, Q61K) (Bioduro) was diluted with Buffer and added to a white 384-well plate (Greiner, 784075) at 10 μL/well, and centrifuged using a centrifuge (Eppendorf, 5810R) at 1000 g/min for 1 min. The final concentration of Mant-GDP-KRAS protein was 1 μM.

c) Dilute the compound: dilute the 10mM stock solution with buffer, add 5μL/well to a 384-well plate, mix with the protein solution, centrifuge at 1000g/min for 1min, and incubate at room temperature for 10min. The final concentrations of the compound are 6000, 2400, 960, 384, 154, 61, 25, 9.8, and 3.9nM.

d) Prepare 4 mM GTP (Sigma, G8877) and 40 mM EDTA solution (Sigma, 03690), mix at a ratio of 1:1 (v/v), transfer 5 μL to a 384-well plate, and centrifuge at 1000 g/min for 1 min.

e) Immediately use a multifunctional microplate reader (Tecan, Spark 10M) in kinetic mode to read the signal value within 20 minutes at a wavelength of 360 nm/440 nm.

f) Analyze and process data: calculate the SLOPE value and the inhibition rate according to the following formula.

Inhibition%＝(Sample value–ZPE)/(HPE–ZPE)*100%

HPE＝average sample _{No EDTA} value

ZPE＝average sample _0.5%DMSO value

The data were analyzed using a four-parameter logistic model to calculate the _IC50 value. The results are shown in Table 2. From the results, it can be seen that the exemplary compounds of the present invention have high inhibitory activity against mant-GDP-KRAS-WT and KRAS G12D, G12C, G12A, G12V, Q61H, and Q61K mutant proteins, and their IC50 values are less than 10 μM; or less than 1000 nM, or less than 500 nM.

Wherein, for _IC50 value, "++++" indicates that _IC50 is between 0 nM and 500 nM; "+++" indicates that _IC50 is between 500 nM and 1 μM; "++" indicates that _IC50 is between 1 μM and 10 μM.

Table 2

Test Example 3: Cell proliferation inhibition activity test

3.1 KRAS mutants and cell lines

3.2 Experimental procedures

The cells were cultured in a 37°C, 5% CO ₂ incubator using complete medium. After digesting and counting the cells in the logarithmic growth phase, the density was adjusted to 1.11x10 ⁴ cells/mL using complete medium. The cells were inoculated into a 384-well cell culture plate (Greiner, 781098) at a volume of 45 μL per well and cultured overnight in a 37°C, 5% CO ₂ incubator. The next day, the compound to be tested was prepared into a 10 mM stock solution with DMSO, and a 3-fold gradient dilution was made starting from the highest dose of 10 μM with DMSO, with a total of 8 concentration points. The compound was then diluted in multiples with complete medium to form working solutions of different concentrations, added to the corresponding wells, and 2 parallel wells were set for each well. The DMSO well was set as a negative control, and the DMSO content of all test wells was finally consistent at 0.1%. After continuing to culture in a 37°C, 5% CO ₂ incubator for 72 hours, the cells were cultured using (Promega, G7571) reagent was used for detection, luminescence signal was detected by TECAN microplate reader Luminescence module, and the curve was fitted by GraphPad Prism software 4-parameter method to calculate _IC50 value.

The results are shown in Table 3, and the exemplary compounds of the present invention exhibited strong proliferation inhibition activity against cells with various KRAS mutations.

Wherein, for _IC50 value, "++++" indicates _IC50 between 0 nM and 500 nM; "+++" indicates _IC50 between 500 nM and 1 μM; "++" indicates _IC50 between 1 μM and 10 μM, "—" indicates not tested, and blank indicates inactivity.

Table 3

The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims (10)

1. A compound of formula (I ₀ ), a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof: In formula (I ₀ ), R ¹ is selected from hydrogen, -CH ₃ , -OCH ₃ ; R ² is selected from wherein R is selected from C _1-3 alkynyl, C _1-3 alkenyl, C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by -CN, -NH ₂ , -N(CH ₃ ) ₂ , -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ OH; Ring A is selected from m is 0 or 1; q is optionally 0, 1 or 2; X ¹ is selected from -CH ₂ -, -CHR ⁷ - or -C(R ⁷ ) ₂ ; ^R7 at each substitution position is independently selected from -H, -OH, -F, -Cl, -CH3, _-CN , _{-CH2OH, -CH2Cl , -OCH3} , _-CH2CN , -CH( _CH3 ) _2OH , _-NHCH3 , or two ^R7 substituents on the same carbon atom form a 3-6 membered heterocyclic ring or carbonyl group with the carbon atom, and p is optionally 0, 1, 2, 3 or 4; R ⁴¹ is selected from 2. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: In formula (I), R ² is selected from wherein R is selected from C _1-3 alkynyl, C _1-3 alkenyl, C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by -CN, -NH ₂ , -N(CH ₃ ) ₂ , -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ OH; m is 0 or 1; q is optionally 0, 1 or 2; X ¹ is selected from -CH ₂ -, -CHR ⁷ - or -C(R ⁷ ) ₂ ; R ⁷ at each substitution position is independently selected from -H, -OH, -F, -Cl, -CH ₃ , -CN, -CH ₂ OH, -CH ₂ Cl, -OCH ₃ , -CH ₂ CN, -CH(CH ₃ ) ₂ OH, or two R ⁷ substituents on the same carbon atom form a 4-6 membered heterocyclic ring or carbonyl group with the carbon atom, and p is optionally 0, 1, 2, 3 or 4; When R ² is selected from hour, The group is selected from When R ² is selected from hour, The group is selected from R ⁴¹ is selected from 3. A compound according to any one of claims 1 to 2, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is represented by formula (I-a), formula (I-b), formula (I-c) or formula (I-d), 4. The compound of formula (I ₀ ) according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the following group: 5. The compound of any one of claims 1 to 4, its 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 method for preparing a compound of formula (I) as claimed in claim 2, a pharmaceutically acceptable salt, stereoisomer, solvate or a prodrug thereof, comprising the following steps: (1) Compound (I-1) and compound (R ¹ 'H) undergo a substitution reaction to generate compound (Ma), wherein the R ¹ ' group is selected from R ⁸ or R ⁸ substituted with a protecting group, and the R ⁸ group is selected from (2) Compound (Ma) and compound (R ⁴¹ H) undergo coupling reaction to generate compound (Mb); (3) the compound (Mb) and the compound or After Suzuki coupling reaction, compound (Mc) is generated, wherein the R ² 'group is selected from R ² or R ² substituted with a protecting group; (4) removing the protecting group from the compound (M-c) to generate the compound (M); The definitions of R ² , R ⁷ , X ¹ , m, q, p and R ⁴¹ are as described in any one of claims 1-5. 7. A pharmaceutical composition, characterized in that the composition comprises the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug and pharmaceutically acceptable excipients. 8. Use of the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, and the pharmaceutical composition according to claim 7 in the preparation of a kit for treating cancer, immune diseases or evaluating the prognosis of cancer patients; Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune disease; Preferably, use in the preparation of a method for treating a disease associated with KRAS mutation; Preferably, the cancer includes pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer and ovarian cancer; More preferably, the cancer includes pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer and ovarian cancer. 9. Use of the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof or the pharmaceutical composition according to claim 7 in the preparation of a KRAS inhibitor; preferably, use in the preparation of KRASG12D, 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 to 5, a pharmaceutically acceptable salt, stereoisomer, solvate, a prodrug thereof, or a pharmaceutical composition according to claim 7.