CN117466917A

CN117466917A - Heterocyclic derivative, preparation method and medical application thereof

Info

Publication number: CN117466917A
Application number: CN202210882152.3A
Authority: CN
Inventors: 黄贤贵; 晏青燕; 叶成; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2022-07-22
Filing date: 2022-07-22
Publication date: 2024-01-30

Abstract

The invention relates to heterocyclic derivatives, a preparation method and medical application thereof. In particular, the invention relates to heterocyclic derivatives shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application of the heterocyclic derivatives as therapeutic agents, particularly as KRAS G12D inhibitors, wherein each substituent in the general formula (I) is defined as the specification.

Description

Heterocyclic derivative, preparation method and medical application thereof

Technical Field

The invention relates to a heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the heterocyclic derivative as a therapeutic agent, particularly as a KRAS GTPase inhibitor.

Background

RAS represents a closely related group of monomeric globular proteins (21 kDa molecular weight) with 189 amino acids and which are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, the RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. RAS functions as a molecular switch, the on/off state of the RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When the RAS contains bound GDP, it is in a dormant or quiescent or off state and is "inactive". When cells are exposed to certain growth promoting stimuli in response, the RAS is induced to convert the bound GDP to GTP. As GTP is bound, the RAS is "on" and is able to interact with and activate other proteins (its "downstream targets"). RAS proteins themselves have a very low inherent ability to hydrolyze GTP back to GDP and thereby turn themselves into an off state. Conversion of the RAS to shut down requires exogenous proteins called Gtpase Activating Proteins (GAPs) that interact with the RAS and greatly promote the conversion of GTP to GDP. Any mutation in the RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus produce a prolonged signal to the cell that signals it to continue growth and division. These signals may therefore cause cell growth and division, and overactivated RAS signaling may ultimately lead to cancer.

Structurally, RAS proteins contain a G domain responsible for enzymatic activity of the ras— guanine nucleotide binding and hydrolysis (gtpase reaction). It also includes a C-terminal extension region, called CAAX box, which can be post-translationally modified and targets the protein to a membrane. The G domain is approximately 21-25kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket in the protein that binds the nucleotide and is a rigid part of the domain with conserved amino acid residues that are necessary for nucleotide binding and hydrolysis (glycine 12, threonine 26 and lysine 16). The G domain also contains so-called switch I regions (residues 30-40) and switch II regions (residues 60-76), which are both dynamic parts of the protein, often denoted as "spring-loaded" mechanisms due to the ability of the dynamic parts to switch between resting and loaded states. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains their active conformation in switch I and switch II, respectively. After hydrolysis of GTP and release of phosphate, both relax to an inactive GDP conformation.

Among RAS family members, oncogenic mutations are most common in KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in three major deadly cancer types in the united states: pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (25%), KRAS mutations are also found in other cancer types including multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell carcinoma, etc., whereas KRAS mutations are rarely found (< 2%) in breast, ovarian and brain cancers. In non-small cell lung cancer (NSCLC), KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D. In non-small cell lung cancer, the increase in the frequency of specific allelic mutations comes mostly from classical smoking-induced classical mutations (G: C to T: A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutations.

Large genomics studies indicate that lung cancer KRAS mutations, including G12C, are mutually exclusive from other known driving oncogenic mutations in NSCLC, including EGFR, ALK, ROS, RET, and BRAF, indicating the uniqueness of KRAS mutations in lung cancer. While at the same time KRAS mutations often coincide with certain co-mutations, such as STK11, KEAP1 and TP53, which in cooperation with the mutated RAS transform the cells into highly malignant and invasive tumor cells.

Three RAS oncogenes constitute the most frequently mutated gene family in human cancers. It is disappointing that despite thirty years of research efforts, there is still no clinically effective anti-RAS therapy, and targeting the gene using small molecules is a challenge. Thus, there is an urgent need in the art for small molecules for targeting RAS (e.g., KRAS, HRAS and/or NRAS) and using the same to treat a variety of diseases, such as cancer.

At present, the clinic development of KRAS G12D inhibitor at home and abroad is very competitive, wherein KRAS G12D inhibitor MRTX-1133 developed by Mirati Therapeutics Inc company already enters the preclinical stage and is used for treating diseases such as large intestine tumor, non-small cell lung cancer, pancreatic cancer and the like. There are a few published KRAS G12D inhibitor patent applications including WO2021041671 from Mirati Therapeutics Inc. Although research and use of KRAS G12D inhibitors has advanced somewhat, there is still a tremendous space for improvement and there is still a need to continue to research and develop new KRAS G12D inhibitors.

Disclosure of Invention

The invention provides a compound shown in a general formula (I) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from aryl, heteroaryl or fused ring;

X ₁ 、X ₂ each independently selected from N or CR ^a And X is ₁ 、X ₂ At least one selected from N;

y is selected from the group consisting of bond, -O-or-NR ^b ；

R ^b Selected from hydrogen atoms or alkyl groups;

R ^a each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, -C (O) R ³ or-C (O) NR ⁴ R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

R ³ 、R ⁴ 、R ⁵ each independently selected from a hydrogen atom or an alkyl group;

l is selected from bond, C ₁ -C ₃ Alkylene group,Wherein said alkylene is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, alkyl or alkoxySubstituted; and wherein one or more methylene groups of said alkylene group are optionally substituted with one or more O, C (O) or NR ^c Substituted;

R ^c selected from hydrogen atoms or alkyl groups;

R ^d 、R ^e each independently selected from hydrogen, halogen, alkyl, alkoxy, or cyano;

R ¹ selected from-L ¹ -cycloalkyl, -L ¹ -heterocyclyl, -L ¹ -aryl, -L ¹ -heteroaryl or-L ¹ -a fused ring; wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl OR fused ring is optionally further substituted with one OR more substituents selected from alkyl, halo, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ Is substituted by a substituent of (2);

L ¹ each independently selected from a bond or C ₁ -C ₆ An alkylene group, wherein said alkylene group is optionally further substituted with one or more R ^A Substituted;

R ^A each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl;

alternatively, two R's attached to the same carbon atom ^A Together with the attached carbon atom, form a cycloalkyl group; preferably cyclopropyl;

R ² identical OR different, each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Wherein saidOptionally further substituted with one OR more groups selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ Is substituted by a substituent of (2);

alternatively, two R ² Together with the same carbon atom to which it is attached, form a C (=o);

R ⁶ each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl group, heterocyclic group, aryl group, heteroaryl, =o, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

R ⁷ and R is ⁸ Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

alternatively, R ⁷ And R is ⁸ Together with the atoms to which they are attached form a 4-to 8-membered heterocyclic group,wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

R ⁹ 、R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;

n is selected from 0, 1, 2, 3 or 4;

r is 0, 1 or 2.

In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II), (III) or (IV):

wherein:

R ^a each independently selected from the group consisting of hydrogen, halogen, cyano, -C (O) R ³ or-C (O) NR ⁴ R ⁵ ；

R ³ 、R ⁴ 、R ⁵ Each independently selected from a hydrogen atom or a methyl group;

ring A, Y, L, R ¹ 、R ² And n is as defined in formula (I).

In a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Y is-O-;

in a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from-L ¹ -a heterocyclyl group; wherein said heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, halogen, alkoxy or =o; wherein said halogen is preferably fluorine;

L ¹ selected from bonds or C ₁ -C ₃ An alkylene group.

In a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ¹ Is methylene.

In a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ Selected from the following groups:

in a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, C ₁ -C ₃ Alkylene group,Wherein one or more methylene groups of said alkylene group are optionally substituted with one or more O, C (O) or NR ^c Substituted;

R ^c is a hydrogen atom;

R ^d 、R ^e each independently selected from a hydrogen atom or a halogen;

in a preferred embodiment of the invention, a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereofA construct, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, -CH ₂ O-、-CH ₂ CH ₂ -、-CH ₂ CH ₂ O-、-NHC(O)-、-C(O)-、

In a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from:

phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzothiazolyl, tetrahydronaphthyl,

In a preferred embodiment of the invention, a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r is R ² The same or different, each independently selected from hydrogen atom, alkyl, halogen, alkoxy, alkynyl, hydroxy, amino, hydroxyalkyl, haloalkyl or haloalkoxy; r is R ² Preferably a hydrogen atom, methyl, methoxy, fluoro, chloro, bromo, iodo, hydroxy, amino, hydroxymethyl or ethynyl.

selected from the following groups:

typical compounds of the present invention include, but are not limited to:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

In another aspect, the invention provides a method of inhibiting KRAS G12D enzyme, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III) or (IV), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

The invention also provides the use of a compound of formula (I), (II), (III) or (IV), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease mediated by a KRAS G12D mutation, wherein the disease mediated by a KRAS G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, stomach cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, large intestine tumor, rectal cancer and lung cancer; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

In another aspect, the present invention provides the use of a compound of formula (I), (II), (III) or (IV), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a KRAS G12D inhibitor.

Another aspect of the invention relates to a method for preventing and/or treating KRAS G12D mutation mediated diseases comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II), (III) or (IV) or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

The invention also provides the use of a compound of general formula (I), (II), (III) or (IV), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer selected from the group consisting of cardiac myxoma, lung cancer, stomach cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, large intestine tumor, rectal cancer and lung cancer; wherein the lung cancer is preferably non-small cell lung cancer.

The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.

Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.

When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Cyclodextrins, e.g., targeting ligands attached to nanoparticles, e.g., accursinTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) Water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Solid dosage forms (e.g., capsules, dragees, powders, granules and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) Binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) an absorption accelerator, such as a quaternary ammonium compound; (7) Humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

In addition to the active compounds, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the active compounds, the powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:

"bond" means that the indicated substituent is absent and that the two end portions of the substituent are directly linked to form a bond.

"alkyl" when taken as a group or part of a group is meant to include C ₁ -C ₂₀ Straight chainOr branched aliphatic hydrocarbon groups. Preferably C ₁ -C ₁₀ Alkyl, more preferably C ₁ -C ₆ An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"alkylene" means saturated C ₁ -C ₂₀ Straight-chain or branched aliphatic hydrocarbon radicals having 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably C ₁ -C ₁₀ Alkylene, more preferably C ₁ -C ₆ An alkylene group. Examples of alkylene groups include, but are not limited to, methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 1, 3-propylene, 1, 4-butylene, and the like. The alkylene group may be substituted or unsubstituted.

"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be optionally substituted or unsubstituted.

"alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be straight or branched. Preferably selected is C ₂ -C ₁₀ More preferably C ₂ -C ₆ Alkynyl, most preferably C ₂ -C ₄ Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-,2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"cycloalkyl" means saturated or partially saturated monocyclic, fused, bridged, anda spiro carbocyclic ring. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₃ -C ₆ Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

"fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 18 members, two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.

"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.

"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _r (wherein r is selected from 0, 1 or 2) heteroatoms including monocyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1]Octyl and piperazinyl. The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds in the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl and 5-oxaspiro [2.4 ]]A heptyl group.

"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxane) or

"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]And (3) a decyl group.

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C ₆ -C ₁₀ Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Preferred bicyclic heteroaryl groups, examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoisoxazolyl, benzothiophenyl, benzofuranyl, and the like,

Heteroaryl groups may be substituted or unsubstituted. "fused ring" means a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, wherein at least one ring has a fully conjugated pi-electron aromatic system, while one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more members selected from nitrogen, oxygen, or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) ₁ -C ₆ Is a preferred choice. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"haloalkyl" refers to a group wherein the alkyl is optionally further substituted with one or more halogens, where alkyl is as defined herein.

"hydroxyalkyl" refers to a group in which the alkyl group is optionally further substituted with one or more hydroxyl groups, where alkyl is as defined herein.

"aminoalkyl" refers to a group in which the alkyl group is optionally further substituted with one or more amino groups, where alkyl is as defined herein.

"hydroxymethyl" refers to a group that is optionally further substituted with one or more hydroxyl groups.

"haloalkoxy" refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.

"hydroxy" refers to an-OH group.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"benzyl" means-CH ₂ -phenyl.

"carboxy" means-C (O) OH.

"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"Ts" refers to p-toluenesulfonyl.

"T3P" refers to propyl phosphoric anhydride.

"DPPA" refers to diphenyl azide phosphate.

"DEA" refers to diethylamine.

"X-PHOS Pd G2" chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II).

"MOM" refers to methoxymethyl.

"TBS" means t-butyldimethylsilyl.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -C (O) R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ Is substituted by a substituent of (2);

alternatively, R ⁷ And R is ⁸ Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

r is 0, 1 or 2.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.

"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) or (II) may be metal salts, amine salts with suitable acids.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Synthesis method of compound of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the preparation method of the compound shown in the general formula (I) or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out substitution reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under alkaline conditions, and further removing protecting groups to obtain a compound of the general formula (I);

wherein:

q is halogen or methanesulfonyl, preferably chlorine;

PG is a protecting group, preferably t-butoxycarbonyl;

ring A, R ¹ 、R ² 、L、X ₁ 、X ₂ The definitions of Y and n are as described in the general formula (I).

Further, the preparation method of the compound shown in the general formula (I) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof comprises the following steps:

carrying out substitution reaction on the compound of the general formula (IC) and the compound of the general formula (ID) under alkaline conditions, and further removing protecting groups to obtain a compound of the general formula (I);

Wherein:

z is halogen, preferably chlorine;

PG is a protecting group, preferably t-butoxycarbonyl;

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. ¹ HNMR spectra were determined using a Bruker instrument (400 MHz) and chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ HNMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai Haohong biological medicine technologies, shanghai Shaoshao reagent, shanghai Pico medicine, saen chemical technologies (Shanghai) and Shanghai Ling Kai medicine technologies, and the like.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound using an eluent system of column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol, wherein the volume ratio of the solvent is different according to the polarity of the compound, and small amount of acidic or alkaline reagent can be added for the conditions such as acetic acid or triethylamine.

Room temperature: 20-30 ℃.

Example 1

4-(((6-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)oxy)methyl)naphthalen-2-ol

4- (((6- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) oxy) methyl) naphthalen-2-ol

First step

ethyl 3-(methoxymethoxy)-1-naphthoate

3- (methoxymethoxy) -1-naphthoic acid ethyl ester

1-bromo-3- (methoxymethoxy) naphthalene 1a (1 g,3.74mmol, self-made according to published patent WO 2021106231), triethylamine (1.14 g,11.23mmol,1.58 mL) and ditriphenylphosphine palladium dichloride (582.51 mg, 748.73. Mu. Mol) were added sequentially to ethanol (50 mL), carbon monoxide gas was displaced three times, and heated to 85℃under carbon monoxide atmosphere and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give ethyl 3- (methoxymethoxy) -1-naphthoate 1B (650 mg), yield: 66.71%.

MS m/z(ESI)：261.0[M+H] ⁺

Second step

(3-(methoxymethoxy)naphthalen-1-yl)methanol

(3- (methoxymethoxy) naphthalen-1-yl) methanol

Ethyl 3- (methoxymethoxy) -1-naphthoate 1b (650 mg,2.50 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (169.41 mg,4.99 mmol) was added in portions under ice and stirred for 2 hours. The reaction was quenched by the sequential addition of water (0.17 mL) and aqueous sodium hydroxide (0.17 mL, 15%), the solids were removed by filtration, the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give (3- (methoxymethoxy) naphthalen-1-yl) methanol 1c (520 mg), yield: 95.41 percent.

MS m/z(ESI)：219.0[M+H] ⁺

Third step

tert-butyl(1R,5S)-3-(2,6-dichloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (2, 6-dichloropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

2,4, 6-Trichloropyrimidine 1d (750 mg,4.09mmol, commercially available) and 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1e (824.62 mg,3.88mmol, commercially available) were dissolved in dichloromethane (7.80 mL), N-diisopropylethylamine (1.59 g,12.27mmol,2.20 mL) was added under ice water bath, and stirred at room temperature for 2 hours. Quenched with water (10 mL), extracted with dichloromethane (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl (1R, 5S) -3- (2, 6-dichloropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 1f (1.15 g), yield: 78.29%.

MS m/z(ESI)：359.2[M+H] ⁺

Fourth step

tert-butyl(1R,5S)-3-(2-chloro-6-((3-(methoxymethoxy)naphthalen-1-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (2-chloro-6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(3- (methoxymethoxy) naphthalen-1-yl) methanol 1c (108.44 mg, 496.87. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), sodium hydride (25.85 mg, 993.74. Mu. Mol) was added under ice-water bath, stirred for 0.5 hours, tert-butyl (1R, 5S) -3- (2, 6-dichloropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 1f (170 mg, 473.21. Mu. Mol) was added, and stirring was continued at room temperature for 2 hours. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: B system) to give (1R, 5S) -3- (2-chloro-6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1g (220 mg), yield: 85.93%.

MS m/z(ESI)：541.0[M+H] ⁺

Fifth step

tert-butyl(1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((3-(methoxymethoxy)naphthalen-1-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (134.25 mg, 843.27. Mu. Mol, homemade according to published patent WO 2020146613) (161.84 mg,1.02 mmol) was dissolved in N, N-diisopropylethylamine (5 mL), sodium hydride (88.14 mg,2.03mmol,60% oil dispersion) was added under ice-water bath, stirred for 0.5H, tert-butyl (1R, 5S) -3- (2-chloro-6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 1g (220 mg, 406.63. Mu. Mol) was added and stirred for 5H at 50 ℃. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (eluent: B system) to give (1R, 5S) -3- (2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1i (150 mg), yield: 55.57%.

MS m/z(ESI)：664.0[M+H] ⁺

Sixth step

Will be%1R, 5S) -3- (2- (((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 1i (150 mg, 225.98. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (4M, 2 mL) and acetonitrile (2 mL) of hydrogen chloride, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- (((6- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) oxy) methyl) naphthalen-2-ol 1 (48 mg), yield: 29.83%.

MS m/z(ESI)：634.0[M+H] ⁺

Example 2

4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)oxy)methyl)naphthalen-2-ol

4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,3, 5-triazin-2-yl) oxy) methyl) naphthalen-2-ol

First step

tert-butyl(1R,5S)-3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (4, 6-dichloro-1, 3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 1e (661.92 mg,3.12 mmol) was added to tetrahydrofuran (10 mL), potassium carbonate (749.47 mg,5.42 mmol) was added, 2,4, 6-trichloro-1, 3, 5-triazine 2a (500 mg,2.71 mmol) was added under ice-water bath, and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, dissolved in methylene chloride (20 mL), washed with water (20 mL), and collectedThe organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R, 5S) -3- (4, 6-dichloro-1, 3, 5-triazin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester 2b (900 mg), yield: 92.14, and directly put into the next reaction. MS m/z (ESI): 360.0[ M+H ]] ⁺

Second step

tert-butyl(1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (4-chloro-6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (80 mg, 502.51. Mu. Mol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (43.57 mg,1.01mmol,60% oil dispersion) was added, stirred for 0.5 hours, and (1R, 5S) -3- (4, 6-dichloro-1, 3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 2b (199.13 mg, 552.76. Mu. Mol) was added, and stirred at room temperature for 1 hour. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give (1R, 5S) -3- (4-chloro-6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 2c (120 mg), yield: 49.44%.

MS m/z(ESI)：483.3[M+H] ⁺

Third step

tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((3-(methoxymethoxy)naphthalen-1-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (4- (((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(3- (methoxymethoxy) naphthalen-1-yl) methanol 1c (59.65 mg, 273.30. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), sodium hydride (26.93 mg, 621.15. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, (1R, 5S) -3- (4-chloro-6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 2c (120 mg, 248.46. Mu. Mol) was added and stirred at room temperature for 1 hour. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: B system) to give tert-butyl (1R, 5S) -3- (4- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 2d (40 mg), yield: 24.22%.

MS m/z(ESI)：665.3[M+H] ⁺

Fourth step

(1R, 5S) -3- (4- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) -1,3, 5-triazin-2-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 2d (40 mg, 60.17. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (4M, 1.5 mL) and acetonitrile (1.5 mL) of hydrogen chloride, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -6- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,3, 5-triazin-2-yl) oxy) methyl) naphthalen-2-ol 2 (5 mg), yield: 10.72%.

MS m/z(ESI)：521.3[M+H] ⁺

Example 3

4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-2-yl)oxy)methyl)naphthalen-2-ol

4- (((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-2-yl) oxy) methyl) naphthalen-2-ol

First step

tert-butyl(1R,5S)-3-(2-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (2-chloro-6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (252.59 mg,1.59 mmol) was dissolved in N, N-dimethylformamide (3 mL), sodium hydride (146.97 mg,3.67mmol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, and (1R, 5S) -3- (2, 6-dichloropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] was added ]Tert-butyl octane-8-carboxylate 1f (600 mg,1.67 mmol) was stirred at room temperature for 1 hour. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was isolated and purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (1 r,5 s) -3- (2-chloro-6- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester 3a (500 mg), yield: 62.11%.

MS m/z(ESI)：482.3[M+H] ⁺

Second step

tert-butyl(1R,5S)-3-(6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-((3-

(methoxymethoxy)naphthalen-1-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (6- (((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -2- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(3- (methoxymethoxy) naphthalen-1-yl) methanol 1c (88.30 mg, 404.57. Mu. Mol) was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (32.37 mg, 809.15. Mu. Mol,60% oil content) was added, stirred at room temperature for 0.5 hours, and (1R, 5S) -3- (2-chloro-6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3a (150 mg, 311.21. Mu. Mol) was added, and the mixture was heated to 55℃and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1 r,5 s) -3- (6- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -2- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3b (150 mg), yield: 72.61% and directly put into the next reaction.

MS m/z(ESI)：664.4[M+H] ⁺

Third step

(1R, 5S) -3- (6- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -2- ((3- (methoxymethoxy) naphthalen-1-yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester 3b (150 mg,225.98 μm)ol) was dissolved in a mixed solvent of 1, 4-dioxane (4M, 1.5 mL) and acetonitrile (1.5 mL) of hydrogen chloride, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -6- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-2-yl) oxy) methyl) naphthalen-2-ol 3 (30 mg), yield: 17.18%.

MS m/z(ESI)：520.1[M+H] ⁺

Example 4

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(naphthalen-2-yl)pyrimidine-5-carbonitrile

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (naphthalen-2-yl) pyrimidine-5-carbonitrile

First step

tert-butyl(1R,5S)-3-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1e (203.70 mg, 959.54. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), diisopropylethylamine (372.03 mg,2.88mmol, 516.71. Mu.L) was added, 4, 6-dichloro-2- (methylthio) pyrimidine-5-carbonitrile 4a (211.18 mg, 959.54. Mu. Mol, commercially available) was added under ice-water bath, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, dichloromethane (25 mL) was added, washed with water (15 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1 r,5 s) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 4b (300 mg), yield: 78.97, and directly put into the next reaction.

MS m/z(ESI)：396.0[M+H] ⁺

Second step

tert-butyl(1R,5S)-3-(5-cyano-2-(methylthio)-6-(naphthalen-2-yl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (methylsulfanyl) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4b (250 mg, 631.46. Mu. Mol), naphthalene-2-ylboronic acid 4c (434.42 mg,2.53mmol, commercially available), sodium carbonate (267.72 mg,2.53 mmol) and tetrakis (triphenylphosphine) palladium (72.97 mg, 63.15. Mu. Mol) were sequentially added to a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and the mixture was replaced with argon three times, and the mixture was stirred at 100℃for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (1 r,5 s) -3- (5-cyano-2- (methylthio) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4d (220 mg), yield: 71.45%.

MS m/z(ESI)：488.3[M+H] ⁺

Third step

tert-butyl(1R,5S)-3-(5-cyano-2-(methylsulfonyl)-6-(naphthalen-2-yl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (methylsulfonyl) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (5-cyano-2- (methylsulfanyl) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4d (80 mg, 164.06. Mu. Mol) was added to dichloromethane (3 mL), m-chloroperoxybenzoic acid (84.94 mg, 492.19. Mu. Mol) was added and stirred overnight at room temperature. To the reaction solution was added saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1 r,5 s) -3- (5-cyano-2- (methylsulfonyl) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 4e (80 mg), yield: 93.84% and directly put into the next step.

MS m/z(ESI)：520.0[M+H] ⁺

Fourth step

tert-butyl(1R,5S)-3-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(naphthalen-2-yl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (31.86 mg, 200.15. Mu. Mol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (17.35 mg, 400.30. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, and (1R, 5S) -3- (5-cyano-2- (methylsulfonyl) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4e (80 mg, 153.96. Mu. Mol) was added and stirred overnight at room temperature. Quenched with water (10 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1 r,5 s) -3- (5-cyano-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4f (60 mg) which is directly taken to the next step.

Fifth step

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (naphthalen-2-yl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 4f (60 mg, 100.22. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (4M, 1 mL) and acetonitrile (1 mL) of hydrogen chloride, roomStirring was carried out for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (naphthalen-2-yl) pyrimidine-5-carbonitrile 4 (10 mg), yield: 15.93%.

MS m/z(ESI)：499.0[M+H] ⁺

Example 5

4-(1-naphthoyl)-6-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidine-5-carboxamide

4- (1-naphthoyl) -6- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidine-5-carboxamide

First step

tert-butyl(1R,5S)-3-(6-(1-naphthoyl)-5-cyano-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4b (236.69 mg,1.52 mmol), 1-naphthaldehyde 5a (284.87 mg,1.82 mmol), 1, 3-dimethylimidazole-1-iodo (339.54 mg,1.52 mmol), sodium hydride (75.78 mg,1.89mmol,60% oil dispersion) were added sequentially to tetrahydrofuran (10 mL), and the mixture was stirred at 70℃for 18 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl (1 r,5 s) -3- (6- (1-naphthoyl) -5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 5B (200 mg), yield: 30.71%.

MS m/z(ESI)：516.3[M+H] ⁺

Second step

tert-butyl(1R,5S)-3-(6-(1-naphthoyl)-5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 5b (100 mg, 193.94. Mu. Mol) and m-chloroperoxybenzoic acid (100.40 mg, 581.82. Mu. Mol) were added sequentially to dichloromethane (3 mL) and stirred at room temperature for 2 hours. To the reaction solution was added saturated sodium hydrogencarbonate solution (10 mL), extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 5c (106.50 mg), which was directly introduced into the next reaction.

MS m/z(ESI)：492.0[M-56+H] ⁺

Third step

tert-butyl(1R,5S)-3-(6-(1-naphthoyl)-5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (40.25 mg, 252.81. Mu. Mol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (21.92 mg, 505.62. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, tert-butyl (1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 5c (106.50 mg, 194.47. Mu. Mol) was added and stirred overnight at room temperature. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 5d (50 mg) which was directly taken to the next step.

Fourth step

(1R, 5S) -3- (6- (1-naphthoyl) -5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Tert-butyl octane-8-carboxylate 5d (50 mg, 79.78. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (4M, 1 mL) and acetonitrile (1 mL) of hydrogen chloride, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- (1-naphthoyl) -6- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrimidine-5-carboxamide 5 (28 mg) in 42% yield.

MS m/z(ESI)：545.26[M+H] ⁺

Example 6

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(naphthalen-1-yl)vinyl)pyrimidine-5-carbonitrile

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile

First step

tert-butyl(1R,5S)-3-(5-cyano-2-(methylthio)-6-((E)-2-(naphthalen-1-yl)vinyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (methylsulfanyl) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4b (200 mg, 505.17. Mu. Mol), (E) -4, 5-tetramethyl-2- (2- (naphthalen-1-yl) vinyl) -1,3, 2-dioxaborane 6a (169.84 mg, 606.20. Mu. Mol), sodium carbonate (214.17 mg,2.02 mmol) and tetrakis (triphenylphosphine) palladium (58.38 mg, 50.52. Mu. Mol) were sequentially added to a mixed solvent of 1, 4-dioxane (5 mL) and water (0.2 mL), argon was replaced three times, and the mixture was stirred at 100℃for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl (1 r,5 s) -3- (5-cyano-2- (methylthio) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 6B (240 mg), yield: 64.74%.

Second step

tert-butyl(1R,5S)-3-(5-cyano-2-(methylsulfonyl)-6-((E)-2-(naphthalen-1-yl)vinyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (methylsulfonyl) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (5-cyano-2- (methylthio) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 6b (240 mg, 467.24. Mu. Mol) and m-chloroperoxybenzoic acid (161.26 mg, 934.48. Mu. Mol) were added sequentially to methylene chloride (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was added with saturated sodium hydrogencarbonate solution (10 mL), extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatographySeparating and purifying by an analytical method (eluent: B system) to obtain (1R, 5S) -3- (5-cyano-2- (methylsulfonyl) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester 6c (200 mg), yield: 78.45%. MS m/z (ESI): 546.3[ M-56+H] ⁺

Third step

tert-butyl(1R,5S)-3-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(naphthalen-1-yl)vinyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (96.28 mg, 604.78. Mu. Mol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (52.43 mg,1.21mmol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, (1R, 5S) -3- (5-cyano-2- (methylsulfonyl) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6c (220 mg, 403.19. Mu. Mol) was added and stirred overnight at room temperature. Quenched with water (10 mL), extracted with ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (1 r,5 s) -3- (5-cyano-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6d (150 mg) which was directly taken to the next step.

Fourth step

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalene-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate 6d (150 mg, 240.10. Mu. Mol) was dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and acetonitrile (2 mL) of hydrogen chloride, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 6 (40 mg), yield: 23.19%.

MS m/z(ESI)：525.3[M+H] ⁺

Example 7

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(naphthalen-1-yl)vinyl)pyrimidine-5-carboxamide

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidine-5-carboxamide

4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 6 (27 mg, 51.46. Mu. Mol), potassium carbonate (28.45 mg, 205.86. Mu. Mol) and hydrogen peroxide (0.1 mL) were added sequentially to dimethyl sulfoxide (1 mL), and heated to 40℃for reaction for 3 hours. The reaction solution was filtered to remove solids, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (naphthalen-1-yl) vinyl) pyrimidine-5-carboxamide7 (6 mg), yield: 14.38%.

MS m/z(ESI)：543.3[M+H] ⁺

Example 8

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(2-(3-hydroxynaphthalen-1-yl)ethoxy)pyrimidine-5-carbonitrile

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (2- (3-hydroxynaphthalen-1-yl) ethoxy) pyrimidine-5-carbonitrile

First step

ethyl 2-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)acetate

2- (3- ((tert-Butyldimethylsilyl) oxy) naphthalen-1-yl) acetic acid ethyl ester

Ethyl 2- (3-hydroxynaphthalen-1-yl) acetate 8a (480 mg,2.08mmol, homemade according to the method of published patent WO 2003082859), 4-dimethylaminopyridine (50.94 mg, 416.92. Mu. Mol), t-butyldimethylchlorosilane (1.25 g,8.34 mmol) and imidazole (567.68 mg,8.34 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: B system) to give ethyl 2- (3- ((tert-butyldimethylsilyl) oxy) naphthalen-1-yl) acetate 8B (500 mg), yield: 69.62%.

MS m/z(ESI)：345.3[M+H] ⁺

Second step

2-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)ethan-1-ol

2- (3- ((tert-butyldimethylsilyl) oxy) naphthalen-1-yl) ethan-1-ol

Ethyl 2- (3- ((tert-butyldimethylsilyl) oxy) naphthalen-1-yl) acetate 8b (500 mg,1.45 mmol) was added to tetrahydrofuran (5 mL), lithium aluminum hydride (59.07 mg,1.74 mmol) was added under ice-bath, and stirred for 1 hour. To the reaction solution was successively added water (0.06 mL) and a 15% aqueous sodium hydroxide solution (0.06 mL), stirred for 15 minutes, insoluble solids were removed by filtration, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), washed successively with 1N diluted hydrochloric acid (10 mL), a saturated sodium bicarbonate solution (10 mL) and a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: B system) to give 2- (3- ((tert-butyldimethylsilyl) oxy) naphthalen-1-ol 8c (380 mg), yield: 86.56%.

MS m/z(ESI)：303.2[M+H] ⁺

Third step

tert-butyl(1R,5S)-3-(5-cyano-6-(2-(3-hydroxynaphthalen-1-yl)ethoxy)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-6- (2- (3-hydroxynaphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

2- (3- ((tert-Butyldimethylsilyl) oxy) naphthalen-1-ol 8c (92 mg, 304.15. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), sodium hydride (26.37 mg, 608.30. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 h, and (1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] was added ]Tert-butyl octane-8-carboxylate 4b (132.46 mg, 334.57. Mu. Mol), was heated to 70℃and reacted for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give (1R, 5S) -3- (5-cyano-6- (2- (3-hydroxynaphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester 8d (110 mg), yield: 66.04%. MS m/z (ESI): 548.3[ M+H ]] ⁺

Fourth step

tert-butyl(1R,5S)-3-(5-cyano-6-(2-(3-(methoxymethoxy)naphthalen-1-yl)ethoxy)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (5-cyano-6- (2- (3-hydroxynaphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 8d (180 mg, 328.67. Mu. Mol) was dissolved in dichloromethane (3 mL), N-diisopropylethylamine (127.43 mg, 986.00. Mu. Mol, 176.99. Mu. L) and chloromethyl methyl ether (52.92 mg, 657.33. Mu. Mol, 49.93. Mu. L) were added in this order and stirred overnight at room temperature. Quenched with water (10 mL), extracted with dichloromethane (15 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: B system) to give tert-butyl (1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 8e (110 mg), yield: 56.56%.

Fifth step

tert-butyl(1R,5S)-3-(5-cyano-6-(2-(3-(methoxymethoxy)naphthalen-1-yl)ethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 8e (110 mg, 185.90. Mu. Mol) and m-chloroperoxybenzoic acid (64.16 mg, 371.80. Mu. Mol) were added to dichloromethane (2 mL) and stirred at room temperature for 2 hours. Saturated sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give (1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 8f (90 mg), yield: 77.62%.

MS m/z(ESI)：646.3[M+23] ⁺

Sixth step

tert-butyl(1R,5S)-3-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(2-(3-(methoxymethoxy)naphthalen-1-yl)ethoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (34.46 mg, 216.44. Mu. Mol) was added to tetrahydrofuran (3 mL), sodium hydride (18.77 mg, 432.89. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, and (1R, 5S) -3- (5-cyano-6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] was added]Tert-butyl octane-8-carboxylate 8f (90 mg, 144.30. Mu. Mol) was stirred overnight at room temperature. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]8g (50 mg) of tert-butyl octane-8-carboxylate was directly fed to the next step. MS m/z (ESI): 703.2[ M+H ]] ⁺

Seventh step

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluoro)tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (2- (3- (methoxymethoxy) naphthalen-1-yl) ethoxy) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]8g (50 mg, 71.14. Mu. Mol) of tert-butyl octane-8-carboxylate was dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and acetonitrile (2 mL) of hydrogen chloride, stirred at room temperature for 0.5 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- (2- (3-hydroxynaphthalen-1-yl) ethoxy) pyrimidine-5-carbonitrile 8 (5 mg), yield: 6.58%.

MS m/z(ESI)：559.3[M+H] ⁺

Example 9 and example 10

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(3-methoxynaphthalen-1-yl)vinyl)pyrimidine-5-carbonitrile

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 9

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(3-hydroxynaphthalen-1-yl)vinyl)pyrimidine-5-carbonitrile

4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-hydroxynaphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 10

First step

tert-butyl((3-methoxynaphthalen-1-yl)ethynyl)dimethylsilane

Tert-butyl ((3-methoxynaphthalen-1-yl) ethynyl) dimethylsilane

To a 50mL three-necked flask, 1-bromo-3-methoxynaphthalene 9a (1.2 g,5.06mmol, commercially available), cuprous iodide (192.16 mg,1.01 mmol), triphenylphosphine (266.23 mg,1.01 mmol), tetrakis (triphenylphosphine) palladium (584.87 mg, 506.13. Mu. Mol) and triethylamine (4.10 mL) were successively added to tetrahydrofuran (4.10 mL), and the mixture was replaced with argon three times, and the mixture was stirred at 90℃for 18 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl ((3-methoxynaphthalen-1-yl) ethynyl) dimethylsilane 9B (1.29 g), yield: 100.00%.

Second step

1-ethynyl-3-methoxynaphthalene

Tert-butyl ((3-methoxynaphthalen-1-yl) ethynyl) dimethylsilane 9b (1.29 g,5.07 mmol) and cesium fluoride (1.54 g,10.14 mmol) were added to N, N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give 1-ethynyl-3-methoxynaphthalene 9c (900 mg), yield: 97.40%.

Third step

(E)-2-(2-(3-methoxynaphthalen-1-yl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(E) -2- (2- (3-methoxynaphthalen-1-yl) vinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

1-ethynyl-3-methoxynaphthalene 9c (200 mg,1.10 mmol), pinacol borane (210.70 mg,1.65 mmol) and tretafloborate (9.76 mg, 54.88. Mu. Mol) were dissolved in N, N-dimethylformamide (3 mL), and the mixture was stirred at 80℃for 18 hours. The reaction solution is cooled to room temperature and concentrated under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain (E) -2- (2- (3-methyl)Oxynaphthalen-1-yl) vinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 9d (330 mg), yield: 96.93%. MS m/z (ESI): 311.0[ M+H ]] ⁺

Fourth step

tert-butyl(1R,5S)-3-(5-cyano-6-((E)-2-(3-methoxynaphthalen-1-yl)vinyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (6-chloro-5-cyano-2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4b (200 mg, 505.17. Mu. Mol), (E) -2- (2- (3-methoxynaphthalen-1-yl) vinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 9d (282.06 mg, 909.31. Mu. Mol), sodium carbonate (214.17 mg,2.02 mmol) and tetrakis (triphenylphosphine) palladium (58.38 mg, 50.52. Mu. Mol) were sequentially added to a mixed solvent of 1, 4-dioxane (5 mL) and water (0.2 mL), argon was replaced three times, and the temperature was raised to 100℃for reaction for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (1 r,5 s) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 9E (230 mg), yield: 50.25%.

Fifth step

tert-butyl(1R,5S)-3-(5-cyano-6-((E)-2-(3-methoxynaphthalen-1-yl)vinyl)-2-(methylsulfonyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1R, 5S) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylthio) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 9E (230 mg, 423.04. Mu. Mol) and m-chloroperoxybenzoic acid (146.01 mg, 846.09. Mu. Mol) were added to dichloromethane (2 mL) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give (1R, 5S) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 9f (160 mg), yield: 65.70%.

MS m/z(ESI)：576.3[M+H-56] ⁺

Sixth step

tert-butyl(1R,5S)-3-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((E)-2-(3-methoxynaphthalen-1-yl)vinyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (66.37 mg, 416.90. Mu. Mol) was added to tetrahydrofuran (3 mL), sodium hydride (36.15 mg, 833.80. Mu. Mol,60% oil dispersion) was added under ice-water bath, stirred for 0.5 hours, and (1R, 5S) -3- (5-cyano-6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) -2- (methylsulfonyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 9f (160 mg, 277.93. Mu. Mol) was added and stirred at room temperature overnight. Quenched with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: B system) to give (1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 9g (90 mg), yield: 49.46%.

Seventh step

(1R, 5S) -3- (5-cyano-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]9g (90 mg, 137.45. Mu. Mol) of tert-butyl octane-8-carboxylate was dissolved in methylene chloride (1.89 mL), and boron tribromide (344.35 mg,1.37mmol, 102.79. Mu.L) was added to the solution in ice water, followed by stirring overnight at room temperature. Quenched with methanol (1 mL) and the organic phase concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-methoxynaphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 9 (1.97 mg) and 4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6- ((E) -2- (3-hydroxynaphthalen-1-yl) vinyl) pyrimidine-5-carbonitrile 10 (6 mg).

9：MS m/z(ESI)：541.1[M+H] ⁺

10：MS m/z(ESI)：555.2[M+H] ⁺

Biological evaluation

Test example 1, inventive compound pair KRAS G12D: inhibition ability assay for RAF1 protein interactions

The following method was used to determine that the compounds of the invention block KRAS G12D under in vitro conditions: the ability of RAF1 proteins to interact. The method uses KRAS-G12C/SOS1 BINDING ASSAY KITS kit (63 ADK000CB21 PEG) from Cisbio, and the detailed experimental operation can be referred to the instruction manual of the kit.

The experimental procedure is briefly described as follows: the working fluid concentrations of Tag1-RAF1 and Tag2-KRAS-G12D proteins were set to 5X using a current buffer (cat. No. 62 DLBDDF) for use. Test compounds were dissolved in DMSO to prepare 10mM stock solutions, which were then diluted using a diluet buffer for use. Firstly, adding 2uL of a tested compound (the final concentration of a reaction system is 10000nM-0.1 nM) into a hole, then adding 4uL of a working solution of Tag1-RAF1 5X and 4uL of a working solution of Tag2-KRAS-G12D 5X, centrifuging and uniformly mixing, and standing for 15 minutes; then 10uL of pre-mixed anti-Tag1-Eu is added ³⁺ And anti-Tag2-XL665, incubated for 4 hours at room temperature; finally, the fluorescence intensities of the wells at excitation wavelengths of 304nM, at which the emission wavelengths of 620nM and 665nM are measured in the TF-FRET mode using an enzyme-labeled instrument, and the fluorescence intensity ratio of 665/620 is calculated for each well. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC ₅₀ Values, results are shown in Table 1.

IC of the inventive Compounds ₅₀ The value results are indicated as A, B, C, respectively:

"A" means IC ₅₀ Less than or equal to 1 mu M; "B" means 1. Mu.M<IC ₅₀ Less than or equal to 10 mu M; "C" means IC ₅₀ >10μM。

Table 1 the compounds of the invention are directed to KRAS G12D: inhibition activity table of RAF1 protein interactions

Examples numbering	IC ₅₀ (μM)
		1	C
2	C
		3	C
4	C
		5	C
6	C
		8	C
9	C
		10	C

Conclusion: the compound of the invention has the following characteristics of KRAS G12D: the RAF1 protein interaction has better inhibition effect.

Test example 2 determination of AGS cell proliferation inhibition by Compounds of the invention

The following methods were used to determine the effect of the compounds of the invention on AGS cell proliferation. AGS cells (containing KRAS G12D mutation) were purchased from Shanghai institute of life sciences cell resource center, china academy of sciences and cultured in F-12K medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability byLuminescent Cell ViabiThe quality Assay kit (Promega, cat# G7573) was used for the measurement.

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were prepared by first dissolving the test compounds in DMSO to prepare a 10mM stock solution, and then diluting the stock solution with medium to prepare test samples, wherein the final concentration of the compounds ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well in 96-well cell culture plates at 37℃with 5% CO ₂ The culture was continued overnight in the incubator, followed by the addition of the test compound and continued for 72 hours. After the incubation was completed, a 50uL volume of CellTiter-Glo assay was added to each well, and after shaking for 5 minutes, the wells were allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation ₅₀ Values, results are shown in Table 2.

"A" means IC ₅₀ Less than or equal to 1 mu M; "B" means 1. Mu.M<IC ₅₀ Less than or equal to 10 mu M; "C" means IC ₅₀ >10μM；

TABLE 2 inhibition of AGS cell proliferation by Compounds of the invention

Examples numbering	IC ₅₀ (μM)
		5	C
6	A
		8	B
10	B

Conclusion: the compound has obvious inhibition effect on proliferation of AGS cells.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from aryl, heteroaryl or fused ring;

Y is selected from the group consisting of bond, -O-or-NR ^b ；

R ^b Selected from hydrogen atoms or alkyl groups;

l is selected from bond, C ₁ -C ₃ Alkylene group,Wherein saidAlkylene is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy; and wherein one or more methylene groups of said alkylene group are optionally substituted with one or more O, C (O) or NR ^c Substituted;

R ^c selected from hydrogen atoms or alkyl groups;

R ² identical OR different, each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-NHC(O)R ⁶ 、-NHC(O)OR ⁶ 、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-CH ₂ NHC(O)OR ⁶ 、-CH ₂ NR ⁷ R ⁸ or-S (O) _r R ⁶ Is substituted by a substituent of (2);

or,R ⁷ and R is ⁸ Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

n is selected from 0, 1, 2, 3 or 4;

r is 0, 1 or 2.

2. The compound according to claim 1, which is a compound represented by the general formula (II), (III) or (IV), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein: r is R ^a Each independently selected from the group consisting of hydrogen, halogen, cyano, -C (O) R ³ or-C (O) NR ⁴ R ⁵ ；

ring A, Y, L, R ¹ 、R ² And n is as defined in claim 1.

3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Y is-O-.

4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

L ¹ selected from bonds or C ₁ -C ₃ An alkylene group.

5. The compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L ¹ Is methylene.

6. A compound according to claim 4 or 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ¹ Selected from the following groups:

7. a compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected from a bond, C ₁ -C ₃ Alkylene group,Wherein one or more methylene groups of said alkylene group are optionally substituted with one or more O, C (O) or NR ^c Substituted;

R ^c is a hydrogen atom;

R ^d 、R ^e each independently selected from a hydrogen atom or a halogen.

8. The compound of claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, -CH ₂ O-、-CH ₂ CH ₂ -、-CH ₂ CH ₂ O-、-NHC(O)-、-C(O)-、

9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from:

10. A compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: r is R ² The same or different, each independently selected from hydrogen atom, alkyl, halogen, alkoxy, alkynyl, hydroxy, amino, hydroxyalkyl, haloalkyl or haloalkoxy; r is R ² Preferably a hydrogen atom, methyl, methoxy, fluoro, chloro, bromo, iodo, hydroxy, amino, hydroxymethyl or ethynyl.

11. A compound according to claim 9 or 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

selected from the following groups:

12. a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

13. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

14. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a KRAS G12D inhibitor.

15. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of a disease mediated by a KRAS G12D mutation, wherein the disease mediated by a KRAS G12D mutation is preferably selected from cancer, wherein the cancer is preferably selected from cardiac myxoma, lung cancer, stomach cancer, large intestine tumour, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, large intestine tumour, rectal cancer and lung cancer.

16. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of cancer, wherein the cancer is preferably selected from the group consisting of cardiac myxoma, lung cancer, stomach cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, large intestine tumor, rectal cancer and lung cancer.

17. The use according to claim 15 or 16, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.