WO2021190413A1 - Compound for targeted degradation of focal adhesion kinase and medical application thereof - Google Patents

Abstract

The present invention relates to a compound for targeted degradation of focal adhesion kinase and a medical application thereof. The present invention belongs to the technical field of medicines and provides a compound represented by general formula (I) or a geometric isomer, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof and a preparation method therefor. The compound has good degradation activity on FAK kinase.

Description

Targeting degradation of focal adhesion kinase compound and its application in medicine Technical field

The present invention relates to the fields of biomedicine and drug synthesis, and relates to a class of compounds that target the degradation of focal adhesion kinase (FAK) protein, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, and methods for their preparation And its use as a therapeutic agent, especially as a FAK degrading agent.

Background technique

Focal adhesion kinase (FAK) is a type of intracellular non-receptor tyrosine kinase, which belongs to the protein tyrosine kinase family. Since 1992, Schaller et al. identified FAK as a substrate of the Src oncogene, and it is a highly phosphorylated protein located at the focal adhesion site. A large number of studies have found that FAK mRNA is highly expressed to varying degrees in human breast cancer, ovarian cancer, liver cancer, lung cancer, pancreatic cancer and other tumor cells. The increase in FAK expression and activity is an important indicator of poor cancer prognosis . Studies have found that FAK can interact with a variety of proteins in the cell, indicating that FAK is a type of multifunctional kinase. By participating in multiple signaling pathways in the cell, it regulates and controls many biological functions, such as cytoskeleton reorganization, cell migration, and In addition to regulating the normal physiological activities of cells, such as apoptosis and mitosis, FAK has also been found to be closely related to the occurrence and development of many diseases, especially the occurrence and development of malignant tumors. Based on the above findings and research, FAK is a potential new anti-tumor drug target.

FAK inhibitors are mostly in the early stages of biological testing and clinical research, and the fastest-growing drug candidates PF-04554878 and GSK2256098 have entered the phase II clinical study. PF-04554878 is a second-generation FAK inhibitor. Its active mechanism is to down-regulate the phosphorylation of FAK Tyr397. In the mesothelioma study, it was found that the phosphorylation of mesothelioma cell Tyr397 decreased by 70 days after treatment of mesothelioma patients. %, and effectively inhibited the growth of mesothelioma cells. Phase II clinical trials are conducting research on malignant pleural mesothelioma and KRAS mutant non-small cell lung cancer. The Phase II clinical trial of GSK2256098 is ongoing for advanced meningioma with smo/NF2 mutation and treatment of advanced pancreatic cancer, treatment of pulmonary hypertension and treatment of advanced solid tumors. Early clinical development of trametinib alone or in combination is still in progress. PND-1186 can inhibit the growth and spontaneous lung metastasis of breast cancer tumors in situ in a homologous mouse model. Phase I clinical trials of PND-1186 are underway in patients with metastatic solid tumors. Both in vivo and in vitro studies of TAE-226 have shown that it has good anti-tumor activity and can improve the survival rate of animals in meningiomas, but there is no clinical research report. However, in recent years, with the development of new technology of protein degradation targeted chimera (PROTAC), drugs that can effectively degrade FAK protein have yet to be developed.

Summary of the invention

The FAK structure can be divided into four parts: the amino-terminal FERM (4.1-ezrin-radixinmoesin) region, the middle kinase catalytic region, the carboxy-terminal focal-adhesion targeting (FAT) region, and a number of rich connection functions. Proline-rich regions (PRRs). Studies have shown that FAK plays its scaffolding function mainly through the FERM domain, regulates the interaction between proteins and triggers a series of downstream signal transduction pathways. The central kinase region of FAK mainly contains two tyrosine phosphorylation sites Tyr576 and Tyr577. Their activation needs to be catalyzed by Src in the central kinase region of FAK under the mediation of integrin. FAK mainly includes kinase-dependent catalytic functions and non-kinase-dependent scaffold functions, both of which are crucial in cancer development, early embryonic development, and reproduction. The active sites of inhibitors currently reported are mainly concentrated in the ATP binding pocket of FAK kinase. They are ATP competitive inhibitors and can only affect or block the function of the kinase domain. It cannot affect the functions of the other three regions of FAK kinase.

Based on the above problems, the inventors designed and synthesized a series of new protein targeted degradation chimera (PROTAC) compound molecules, which are bifunctional molecules, including three parts: one is a ligand targeting the target protein FAK; the other is It is a structure that can recruit protein degradation system (E3 ligase ligand); the middle is connected by a suitable linking chain. After the PROTAC molecule enters the cell, the target protein (POI) ligand in its structure specifically binds to the target protein, and the other end of the E3 ligase ligand (E3 ligand) binds to the E3 ligase (E3 ligase), Thus the POI-PROTAC-E3 ligase ternary complex is formed. The E3 ligase mediates the ubiquitin-conjugating enzyme E2 to ubiquitinate the target protein. After the ternary complex is dissociated, the target protein labeled with ubiquitin will be sent to the protease. The proteasome degrades to selectively reduce the level of the target protein. This process does not require the target protein ligand to occupy the binding site for a long time, and only needs to form a ternary complex for a short time to complete the ubiquitination of the target protein. The protein with the ubiquitination tag will be recognized by the proteasome and be degraded. And PROTAC can play a role in multiple cycles within the cell. This type of molecule can degrade the entire FAK protein, thereby simultaneously affecting the kinase-dependent catalytic function and the kinase-independent scaffold function.

The object of the present invention is to provide a compound represented by the general formula (I), and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

The part F represents the ligand of FAK protein, the part L represents the linking chain, and the part E represents the ligand of E3 ligase.

in,

Part F has a structure represented by the general formula (II),

A is a (C ₆ -C ₁₂ ) aryl group, a heteroaryl group consisting of 5-12 atoms, a (C ₃ -C ₆ ) cycloalkyl group or a heterocyclic group consisting of 3-12 atoms, the heteroaryl group The group or heterocyclic group contains 1-3 N, O or S heteroatoms;

A is replaced by 1, 2, 3, 4 or 5 R ¹ ;

R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally hydroxy, amino or halogen Substituted (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido , 4-7 membered heterocyclic group, -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)SR ² , -C(O)(NR ² R ³ ), -S(O) ₂ NR ² R ³ , -S(O)NR ² R ³ , -NR ² C(O)R ³ , -NR ² S(O) ₂ R ³ , -NR ² S(O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O)NHR ³ , -NR ² S(O) ₂ NHR ³ , -CH ₂ P( O) R ² R ³ ;

R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₆ ) Alkyl or (C ₁ -C ₆ )alkoxy, amino substituted with mono or di (C ₁ -C ₆ alkyl), (C ₁ -C ₆ )alkylamido, 4-7 membered heterocyclic group;

Y is hydrogen, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, Halo (C ₁ -C ₆ )alkyl;

X is C or N.

Among them, the E part has a structure represented by the general formula (III),

R ⁴ or R ⁵ are independently hydrogen, deuterium, hydroxyl, halogen, carbonyl, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkyl;

n ₁ and n ₂ are independently 0, 1 or 2 respectively;

W is N or CR ⁶ ;

R ⁶ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy;

M is NR ⁷ , O or S;

R ⁷ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₂ -C ₆ ) Alkenyl or (C ₂ -C ₆ )alkynyl.

Among them, the L part has a structure represented by the general formula (IV) or (V),

X ₁ or X ₂ are each independently hydrogen,

X ₃ is

R ⁸ is hydrogen, deuterium, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy;

Q is CH or N;

Each t is an integer between 0-12;

Each k is an integer between 0-12.

The preferred compounds of the present invention have the following structures, and their geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

In the general formula (II),

A is a phenyl group, a heteroaryl group consisting of 5-12 atoms, a (C ₃ -C ₆ ) cycloalkyl group or a heterocyclic group consisting of 3-12 atoms, and the heteroaryl or heterocyclic group contains 1 -3 heteroatoms of N, O or S; or

A is a phenyl group, a heteroaryl group consisting of 5-12 carbon atoms, a (C ₃ -C ₆ ) cycloalkyl group or a heterocyclic group consisting of 3-12 atoms, and the heteroaryl or heterocyclic group contains 1-3 heteroatoms of N, O or S;

A is replaced by 1, 2, 3, 4 or 5 R ¹ ;

R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally hydroxy, amino or halogen Substituted (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido , 4-7 membered heterocyclic group, -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)SR ² , -C(O)(NR ² R ³ ), -S(O) ₂ NR ² R ³ , -S(O)NR ² R ³ , -NR ² C(O)R ³ , -NR ² S(O) ₂ R ³ , -NR ² S(O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O)NHR ³ , -NR ² S(O) ₂ NHR ³ , -CH ₂ P( O) R ² R ³ ;

R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₆ ) Alkyl or (C ₁ -C ₆ )alkoxy, amino substituted with mono or di (C ₁ -C ₆ alkyl);

Y is hydrogen, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, Halo (C ₁ -C ₆ )alkyl;

X is C or N.

Preferably,

A is

A is replaced by 1, 2, 3, 4 or 5 R ¹ ;

R ¹ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy (e.g., methoxy), optionally _{(C 1} -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy substituted by hydroxy, amino or halogen, amino substituted by mono or di (C ₁ -C ₆ alkyl), (C ₁ -C ₆ ) Alkyl amido, -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)SR ² , -C (O)(NR ² R ³ ), -S(O) ₂ NR ² R ³ , -S(O)NR ² R ³ , -NR ² C(O)R ³ , -NR ² S(O) ₂ R ³ , -NR ² S(O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O)NHR ³ , -NR ² S(O) ₂ NHR ³ , -CH ₂ P(O) R ² R ³ ;

R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₃ ) Alkyl group or (C ₁ -C ₃ )alkoxy group, amino group substituted by mono or di (C ₁ -C ₃ alkyl group);

Y is hydrogen, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, Halo (C ₁ -C ₆ )alkyl (e.g. trifluoromethyl);

X is C or N.

further,

A is

A is replaced by 1, 2, or 3 R ¹ ;

R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally hydroxy, amino or halogen Substituted (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido , -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)(NR ² R ³ ), -S(O) ) ₂ NR ² R ³ , -NR ² C(O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O) ₂ NHR ³ ;

R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₃ ) Alkyl group or (C ₁ -C ₃ )alkoxy group, amino group substituted by mono or di (C ₁ -C ₃ alkyl group);

Y is hydrogen, halogen, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, halo (C ₁ -C ₆ ) Alkyl;

X is N.

More preferably, the F part has a structure shown in VI-1, VI-2 or VI-3,

Part E has a structure represented by the general formula (III),

Each R ⁴ or R ^{5 is} independently hydrogen, deuterium, hydroxyl, halogen, carbonyl, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ ) alkyl, halogenated (C _1- C ₆ )alkyl;

n ₁ and n ₂ are independently 0, 1 or 2 respectively;

W is N or CR ⁶ ;

R ⁶ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy;

M is NR ⁷ , O or S;

R ⁷ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₂ -C ₆ ) Alkenyl or (C ₂ -C ₆ )alkynyl.

Preferably,

R ⁴ or R ⁵ are each independently hydrogen, deuterium, hydroxyl, F, Cl, Br, carbonyl, amino, cyano, carboxy, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl or tert-butyl;

n ₁ and n ₂ are independently 0, 1 or 2 respectively;

W is N;

M is NR ⁷ ;

R ⁷ is hydrogen, methyl or ethyl.

More preferably, the E part has a structure shown in VII-1 or VII-2,

The L part has a structure represented by the general formula (IV) or (V),

Each X ₁ or X _{2 is} independently hydrogen,

X ₃ is

R ⁸ is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

Q is CH or N;

Each t is an integer between 0-12 (for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12);

Each k is an integer between 0-12 (for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12).

Preferably,

X ₁ or X ₂ are each independently hydrogen,

X ₃ is

R ⁸ is hydrogen, methyl or ethyl;

Q is CH or N;

Each t is an integer between 0-10 (for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10);

Each k is an integer between 0-10 (for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10).

The preferred compounds of the present invention have the following structures, and their geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

Moreover, according to some common methods in the field to which the present invention belongs, some of the compounds of the general formula (I) in the present invention have basic groups and can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the following acid addition salts are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid , Benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. Most preferred is hydrochloric acid.

In addition, the present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are derivatives of the general formula (I), which may have weak or even no activity by themselves, but after administration, under physiological conditions (for example, by metabolism, solvolysis or other means) ) Is converted into the corresponding biologically active form.

The derivative represented by the general formula (I) may be in an unsolvated form and a solvated form containing a pharmaceutically acceptable solvent (such as water, ethanol, etc.). The derivatives represented by the general formula (I) may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, atropisomers and their mixtures (such as racemic mixtures), are included in the scope of the present invention Inside.

The compounds represented by the general formula (I) may exist in different tautomeric forms, and all these forms are included in the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are converted into each other via a low energy barrier.

In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodo; "alkyl" refers to straight or branched chain alkyl; "aryl" refers to the removal of one or two hydrogens in different positions in aromatic hydrocarbons An organic group derived from an atom, such as phenyl and naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S. The ring The system refers to an organic group that is aromatic and removes one or two hydrogen atoms at different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2, 3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, Isoquinolinyl, benzimidazolyl, benzoxazolyl, etc.; heterocyclic group refers to a monocyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, Tetrahydropyrrolidinyl, morpholinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl and tetrahydrothiazolinyl, etc.

The present invention may contain derivatives of general formula (I), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and mixed with pharmaceutically acceptable carriers or excipients to prepare a composition , And prepared into a clinically acceptable dosage form. The above-mentioned pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the field of pharmacy. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The several dosage forms mentioned above can adopt injections, tablets, capsules, aerosols, suppositories, films, dripping pills, external liniments, ointments and other dosage forms of drugs.

The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, non-coloring, and flavoring agents , Preservatives, solubilizers and substrates, etc. Pharmaceutical preparations can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

The derivatives of the present invention containing the general formula (I) can be synthesized by methods including well-known methods in the chemical field, especially according to the description of the present invention. In the present invention, room temperature refers to ambient temperature, which is 10 degrees Celsius to 30 degrees Celsius.

The positive progress effect of the present invention lies in: the present invention provides a class of compounds capable of targeted degradation of focal adhesion kinase (FAK), as well as preparation methods, pharmaceutical compositions and applications thereof. The compound of the present invention has a good degradation effect on FAK kinase, and can be used for the prevention, treatment or adjuvant treatment of various diseases related to the expression or activity of FAK kinase.

For example, the disease may be selected from tumors or cancers, such as meningioma, colorectal cancer, gastric cancer, liver cancer, breast cancer, skin cancer, lung cancer, cervical cancer, ovarian cancer, or breast cancer.

The examples and preparation examples provided by the present invention further illustrate and exemplify the compounds of the present invention and the preparation methods thereof. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way. The compounds of the general formula (I) of the present invention can be prepared according to the following synthetic routes, and all the variable factors used in these routes are as defined in the claims.

Description of the drawings

Figure 1 is a graph of the enzyme inhibitory activity of compounds 1 and 11;

Figure 2 shows the degradation activity of the compound on FAK protein.

Detailed ways

The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are intended to explain the present invention without further elaboration. It is believed that those skilled in the art can make full use of the present invention with the help of the foregoing description. . Therefore, the examples provided below are intended to illustrate rather than limit the scope of the present invention.

Raw materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described in the present invention. Without special instructions, all reagents used are of analytical or chemical purity.

The mass spectrum used for the confirmation of the compound structure was determined by Agilent 1100LC/MSD. The purified product by column chromatography uses 100-200 mesh or 200-300 mesh silica gel produced by Qingdao Ocean Chemical Factory.

synthetic route

Reagents and conditions: a) 1-Boc piperazine, K ₂ CO ₃ , CH ₃ CN, 80°C; b) Pd/C, H ₂ , MeOH, 40°C; c) 2-amino-N-methylbenzyl Amide, DIPEA, isopropanol, 100°C; d) 1-3, CF ₃ COOH, sec-butanol, 120°C; e) CF ₃ COOH, CH ₂ Cl ₂ , 25°C.

a) Add 4-fluoro-2-methoxy-1-nitrobenzene (15.0mmol), 1-Boc piperazine _{(15.0mmol) and K 2} CO ₃ (45.0mmol) into the solvent acetonitrile, and raise the temperature to 80°C Reaction 4h. After cooling to room temperature, the reaction solution was slowly poured into 100 ml ice water, extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 1-2.

b) Intermediate 1-2 (15.0 mmol) was dissolved in methanol, Pd/C (10%) (1.5 mmol) was added to the solution, hydrogen was used as a hydrogen donor, and the reaction was performed at 40°C. TLC detects that the reaction is complete and filtered out Pd/C, the filtrate was spin-dried and mixed, and purified by column chromatography to obtain Intermediate 1-3.

c) Dissolve 2,4,5-trichloropyrimidine (10mmol) in isopropanol, add 2-amino-N-methylbenzamide (12mmol) and diisopropylethylamine (25mmol) to the reaction system ), react at 100°C for 12 h. Solids precipitate out in the reaction system, suction filtration is performed after cooling, and the filter cake is dried in an oven to obtain Intermediate 1-5.

d) Add the intermediates 1-3 (10mmol) and 1-5 (15mmol), trifluoroacetic acid (0.05ml) to sec-butanol (5ml), react at 120°C, TLC detects the completion of the reaction, spin dry and mix directly In this way, Intermediate 1-6 is obtained after purification by column chromatography.

e) Dissolve Intermediate 1-6 (10mmol) in dioxymethane (3ml), add trifluoroacetic acid (0.5ml), and react at 25°C. TLC detects the completion of the reaction and spins to dryness directly to obtain 1-7 trifluoroacetate. Acetate. Then the dichloromethane dissolved product was added to the flask, saturated sodium bicarbonate aqueous solution was added to free the trifluoroacetate salt, and the dichloromethane layer was concentrated under reduced pressure to obtain Intermediate 1-7.

Reagents and conditions: a) 3-aminopiperidine-2,6-dione, NaOAc, AcOH, 140°C; b) DIPEA, DMF, 90°C; c) CF ₃ COOH, CH ₂ Cl ₂ , 25°C; d ) HATU, DIPEA, 25°C; e) Ts-Cl, Et ₃ N, CH ₂ Cl ₂ , 30°C; f) HATU, DIPEA, 40°C.

a) Add 3-aminopiperidine-2,6-dione (50mmol), 2-1 (55mmol) and sodium acetate (55mmol) to the acetic acid, heat up to 140°C for reaction, check by TLC after the reaction is complete, use rotary evaporation The acetic acid was spin-dried directly by the instrument, dissolved in a mixed solvent of dichloromethane and methanol, mixed with the sample, and purified by column chromatography to obtain Intermediate 2-2.

b) Dissolve Intermediate 2-2 (20mmol) in N,N-dimethylformamide, add tert-butylglycine (25mmol) and diisopropylethylamine (30mmol) to the reaction system, and react at 90°C , TLC detects that the reaction is complete, add water, extract with dichloromethane, wash the organic layer with saturated brine, and dry overnight with anhydrous sodium sulfate. The desiccant is filtered off, concentrated under reduced pressure, and column chromatography is used to obtain Intermediate 2-3. Only need to replace the reaction substrate correspondingly, and according to the same preparation method, Intermediate 2-5 and Intermediate 2-8 can be obtained.

c) Dissolve Intermediate 2-3 (10 mmol) in dioxymethane (3ml), add trifluoroacetic acid (0.5ml), react at 25°C, TLC detects the completion of the reaction, and spin dry directly to obtain Intermediate 2-4. Intermediate 2-6 was prepared in the same way.

d) Intermediate 2-6 (10mmol) is dissolved in dioxymethane, and bromine-substituted carboxylic acid chain is added, 2-(7-azabenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU) (12mmol) and diisopropylethylamine (15mmol) are reacted at 25°C. TLC detects the completion of the reaction. Add water, extract with dichloromethane, and wash the organic layer with saturated brine, anhydrous Dry over sodium sulfate overnight. The desiccant was filtered off, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate 2-7.

e) Dissolve Intermediate 2-8 (10mmol) in dioxymethane, add triethylamine (15mmol) and p-toluenesulfonyl chloride (10mmol), react at 30°C, TLC detects that the reaction is complete, add water, dichloromethane After extraction, the organic layer was washed with saturated brine, and dried overnight with anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate 2-9.

f) Intermediate 2-10 (10 mmol) is dissolved in dioxymethane, and bromine-substituted carboxylic acid chain is added, 2-(7-azabenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU) (12mmol) and diisopropylethylamine (15mmol), react at 40°C, TLC detects that the reaction is complete, add water, extract with dichloromethane, wash the organic layer with saturated brine, anhydrous Dry over sodium sulfate overnight. The desiccant was filtered off, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate 2-11. It is only necessary to replace the reaction substrate accordingly, and the intermediate 2-13 can be obtained according to the same preparation method.

Reagents and conditions: a) 1-azido-8-iodooctane, K ₂ CO ₃ , CH ₃ CN, 80°C; b) PPh ₃ , THF/H ₂ 0, 70°C; c) 2-4, HATU, DIPEA, 25°C; d) CF ₃ COOH, CH ₂ Cl ₂ , 25°C; e) 2-6, HATU, DIPEA, 25°C.

a) Add 1-azido-8-iodooctane (10mmol), 1-7 (12mmol) and potassium carbonate (30mmol) into acetonitrile, raise the temperature to 80℃ to react, TLC detects the reaction is complete, add water, dichloride Methane extraction was performed, and the organic layer was washed with saturated brine, and dried overnight with anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and column chromatography to obtain Intermediate 3-1. Only need to replace the reaction substrate accordingly and follow the same preparation method to obtain Intermediate 3-3.

b) Intermediate 3-1 (3mmol) and triphenylphosphine (4.5mmol) were added to a mixed solvent of tetrahydrofuran (10ml) and water (3ml), and reacted at 80°C. After the reaction was completed by TLC detection, it was concentrated under reduced pressure. The tetrahydrofuran spins out. It was extracted with dichloromethane, and the organic layer was washed with saturated brine, and dried overnight with anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure to obtain Intermediate 3-2.

c) Dissolve Intermediate 3-2 (2mmol) in dioxymethane, add Intermediate 2-4 (2.5mmol), 2-(7-azabenzotriazole)-N,N,N', N'-Tetramethylurea hexafluorophosphate (HATU) (3mmol) and diisopropylethylamine (6mmol), react at 25°C, TLC detects the completion of the reaction, add water, extract with dichloromethane, and wash the organic layer with saturated brine , Dry overnight with anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of Example 1.

d) Intermediate 3-3 (2 mmol) is dissolved in dioxymethane (2 ml), trifluoroacetic acid (0.4 ml) is added, and the reaction is performed at 25° C. The reaction is completed by TLC detection, and it is directly spin-dried to obtain Intermediate 3-4.

e) Dissolve Intermediate 3-4 (2mmol) in dioxymethane, add Intermediate 2-6 (2.5mmol), 2-(7-azabenzotriazole)-N,N,N', N'-Tetramethylurea hexafluorophosphate (HATU) (3mmol) and diisopropylethylamine (6mmol), react at 25°C, TLC detects the completion of the reaction, add water, extract with dichloromethane, and wash the organic layer with saturated brine , Dry overnight with anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of Example 2.

Reagents and conditions: a) 2-7, 2-9, 2-11 or 2-13, KI, K ₂ CO ₃ , CH ₃ CN, 80℃; b) CS ₂ , Et ₃ N, DMF, 25-50 ℃.

a) Add Intermediate 1-7 (2mmol), Intermediate 2-9 (2.2mmol), potassium iodide (2.2mmol) and potassium carbonate (5mmol) into acetonitrile, increase the temperature to 80°C for the reaction, and add water after the reaction is detected by TLC , Dichloromethane extraction, the organic layer was washed with saturated brine, and dried overnight with anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and column chromatography was used to obtain the compound of Example 3. It is only necessary to replace the reaction substrate accordingly, and follow the same preparation method to obtain the compounds of Examples 4-18.

b) Intermediate 1-7 (1.5mmol), carbon disulfide (2.2mmol) and triethylamine (5mmol) were dissolved in N,N-dimethylformamide and reacted at 25°C. After the reaction of raw materials 1-7 is detected by TLC, 2-11 (2 mmol) is added to the reaction system, and the temperature is raised to 50°C for reaction. After the reaction is completed by TLC detection, the reaction solution is dropped into ice water. After drying, the cake was dissolved and mixed with samples, and purified by column chromatography to obtain the compounds of Examples 19-20.

Example 1:

¹ H NMR(600MHz, CDCl ₃ )δ10.98(s,1H), 8.67(d,J=8.4Hz,1H), 8.07(t,J=4.3Hz,2H), 7.55(dd,J=8.1, 7.6Hz,1H),7.48(dd,J=7.8,1.2Hz,1H),7.44(t,J=7.8Hz,1H),7.25-7.23(m,2H),7.06(t,J=7.6Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.8, 2.3 Hz, 1H), 6.41 (t, J = 5.6 Hz, 1H), 6.26 (d, J = 4.6 Hz, 1H), 4.93 (dd, J = 12.5, 5.4 Hz, 1H), 3.95 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.20–3.15 (m, 4H), 3.09 (dd, J = 14.7, 7.3 Hz, 2H), 3.02 (d, J = 4.8 Hz, 3H), 2.85–2.73 (m ,3H),2.66(s,4H),2.44–2.39(m,2H),2.15–2.12(m,1H),1.49–1.42(m,12H).HRMS m/z:908.3982[M+H] ⁺ .

Example 2:

¹ H NMR (600MHz, CDCl ₃ ) δ11.00 (s, 1H), 9.85 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.49 –7.46(m,2H),7.41(t,J=7.8Hz,1H),7.32(s,1H),7.06(d,J=7.1Hz,1H),7.03(t,J=7.9Hz,1H) ,6.95(d,J=8.6Hz,2H),6.56(d,J=3.9Hz,1H),6.50(d,J=2.3Hz,1H),6.45-6.40(m,2H),4.88(dd, J = 12.2, 5.5 Hz, 1H), 3.82 (s, 3H), 3.65 (t, J = 5.7 Hz, 2H), 3.52-3.42 (m, 6H), 3.20 (s, 4H), 2.99 (d, J =4.8Hz,3H), 2.85–2.63(m,9H), 2.46(t,J=5.4Hz,2H), 2.09(dd,J=12.8,4.9Hz,1H), 1.87–1.82(m,2H) .HRMS m/z:896.3624[M+H] ⁺ .

Example 3:

¹ H NMR (600MHz, CDCl ₃ ) δ 10.97 (s, 1H), 10.16 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.05 (d, J = 8.8Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.08 (d, J = 7.1 Hz, 1H), 7.04 (t,J=7.5Hz,1H), 6.87(d,J=8.5Hz,1H), 6.51(t,J=5.0Hz,2H), 6.46(dd,J=8.8,2.3Hz,1H), 6.39 (d,J=4.3Hz,1H), 4.87(dd,J=12.3,5.4Hz,1H), 3.83(s,3H), 3.73–3.63(m,12H), 3.45–3.41(m,2H), 3.19(s,4H),3.00(d,J=4.8Hz,3H),2.84-2.64(m,9H),2.12-2.07(m,1H).HRMS m/z:899.3609[M+H] ⁺ .

Example 4:

¹ H NMR (400MHz, CDCl ₃ ) δ 10.97 (s, 1H), 9.41 (s, 1H), 9.13 (s, 1H), 8.79 (d, J = 8.3 Hz, 1H), 8.62 (d, J = 8.2Hz,1H), 8.08–8.00(m,2H), 7.69(t,J=7.7Hz,1H), 7.52(d,J=7.1Hz,1H), 7.46(d,J=7.6Hz,1H) ,7.40(t,J=7.7Hz,1H),7.31(s,1H),7.02(t,J=7.4Hz,1H),6.52(s,1H),6.46(d,J=9.1Hz,2H) ,4.91(dd,J=11.2,4.9Hz,1H),3.83(s,3H),3.19(s,4H),2.99(d,J=4.2Hz,3H),2.87–2.68(m,7H), 2.51(d,J＝7.0Hz,4H),2.11(d,J＝10.6Hz,1H),1.79(d,J＝6.7Hz,2H),1.68(s,2H).HRMS m/z:823.3090 [ M+H] ⁺ .

Example 5:

¹ H NMR (400MHz, CDCl ₃ ) δ 10.98 (s, 1H), 9.42 (s, 1H), 9.08 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H), 8.65 (d, J = 8.4Hz, 1H), 8.07 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.48 –7.39(m,2H),7.30(s,1H),7.03(t,J=7.3Hz,1H), 6.54(d,J=2.2Hz,1H), 6.48(dd,J=8.8,2.3Hz, 1H), 6.35 (d, J = 4.6 Hz, 1H), 4.93 (dd, J = 12.0, 5.3 Hz, 1H), 3.84 (s, 3H), 3.18 (s, 4H), 3.00 (d, J = 4.8 Hz, 3H), 2.91–2.85(m, 1H), 2.81–2.74(m, 2H), 2.66(s, 4H), 2.50–2.43(m, 4H), 2.18–2.13(m, 1H), 1.79( dt,J=15.1,7.5Hz,2H),1.65–1.58(m,2H),1.48–1.40(m,2H).HRMS m/z:837.3241[M+H] ⁺ .

Example 6:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 11.15 (s, 1H), 9.69 (s, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.60 (d, J = 7.5Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.09 (s, 2H), 7.82 (t, J = 7.9 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H) ,7.60(d,J=7.3Hz,1H),7.42(d,J=8.5Hz,1H),7.32(t,J=7.6Hz,1H),7.07(t,J=7.5Hz,1H),6.62 (d,J=1.9Hz,1H), 6.46(d,J=8.7Hz,1H), 5.14(dd,J=12.8,5.4Hz,1H), 3.76(s,3H), 3.13(s,4H) ,2.95–2.85(m,1H), 2.80(d,J=4.4Hz,3H), 2.64–2.52(m,5H), 2.48–2.45(m,3H),2.33(t,J=6.9Hz,2H ),2.09–2.03(m,1H),1.68–1.62(m,2H),1.50–1.45(m,2H),1.30–1.32(m,4H).HRMS m/z:851.3390[M+H] ⁺ .

Example 7:

¹ H NMR (600MHz, CDCl ₃ ) δ 10.98 (s, 1H), 9.46 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.08 (d,J=9.5Hz,2H),7.73-7.68(m,1H),7.54(d,J=7.3Hz,1H),7.48(d,J=7.8Hz,1H),7.44(t,J= 7.8Hz, 1H), 7.29 (s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 6.48 (dd, J = 8.7, 2.2 Hz, 1H) ,6.30(d,J=4.1Hz,1H), 4.93(dd,J=12.1,5.5Hz,1H), 3.85(s,3H), 3.29(s,4H), 3.02(d,J=4.8Hz, 3H), 2.88–2.72(m,7H), 2.58–2.53(m,2H), 2.47(t,J=7.2Hz,2H), 2.18–2.16(m,1H), 1.78–1.72(m,2H) ,1.65–1.61(m,2H),1.40–1.32(m,6H).HRMS m/z:865.3555[M+H] ⁺ .

Example 8:

¹ H NMR (400MHz, CDCl ₃ ) δ 10.98 (s, 1H), 9.47 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 7.4 Hz ,1H), 7.40(t,J=7.8Hz,1H), 7.30(s,1H), 7.02(t,J=7.5Hz,1H), 6.52(d,J=1.9Hz,1H), 6.49–6.43 (m, 2H), 4.91 (dd, J = 11.9, 5.4 Hz, 1H), 3.82 (s, 3H), 3.18 (s, 4H), 2.98 (d, J = 4.7 Hz, 3H), 2.87–2.68 ( m,7H), 2.47-2.40(m,4H), 2.17-2.11(m,1H), 1.78-1.71(m,2H), 1.55(s,2H), 1.43-1.31(m,8H).HRMS m /z:879.3729[M+H] ⁺ .

Example 9:

¹ H NMR (400MHz, CDCl ₃ ) δ 10.98 (s, 1H), 9.46 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.05 (d,J=7.5Hz,2H),7.71(t,J=7.9Hz,1H),7.54(d,J=7.2Hz,1H),7.49–7.40(m,2H),7.32(s,1H) ,7.06(t,J=7.4Hz,1H), 6.54(d,J=1.3Hz,1H), 6.48(dd,J=8.6,1.9Hz,1H), 6.30(d,J=3.8Hz,1H) , 4.92 (dd, J = 11.4, 5.2 Hz, 1H), 3.85 (s, 3H), 3.22 (d, J = 4.7 Hz, 4H), 3.02 (d, J = 4.7 Hz, 3H), 2.88-2.74 ( m, 7H), 2.53-2.45 (m, 4H), 2.21--2.16 (m, 1H), 1.79-1.72 (m, 2H), 1.65-1.56 (m, 2H), 1.45-1.31 (m, 10H). HRMS m/z:893.3857[M+H] ⁺ .

Example 10:

¹ H NMR (600MHz, CDCl ₃ ) δ 10.97 (s, 1H), 9.34 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.07-8.04 (m, 2H), 7.48-7.46 ( m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.95 ( d,J=8.6Hz,1H),6.51(d,J=2.4Hz,1H),6.45-6.40(m,3H),6.36(s,1H),4.87(dd,J=12.3,5.4Hz,1H ), 3.84(s, 3H), 3.50–3.43(m, 4H), 3.16(s, 4H), 3.00(d, J=4.8Hz, 3H), 2.83–2.63(m, 7H), 2.46(t, J=7.1Hz,2H),2.22(td,J=7.3,2.6Hz,2H),2.11–2.06(m,1H),1.70–1.64(m,2H),1.61–1.55(m,2H).HRMS m/z:866.3491[M+H] ⁺ .

Example 11:

¹ H NMR (600MHz, CDCl ₃ ) δ 10.97 (s, 1H), 10.44 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.08-8.03 (m, 2H), 7.49-7.46 ( m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.8, 2.3 Hz, 1H), 6.43-6.38 (m, 2H), 6.15 (s, 1H), 4.87 (dd, J = 12.3, 5.5 Hz, 1H), 3.84 (s, 3H), 3.57-3.52 (m, 1H), 3.45-3.39 (m, 3H), 3.22-3.15 ( m, 4H), 3.00 (d, J = 4.8 Hz, 3H), 2.82–2.66 (m, 7H), 2.44 (dd, J = 14.6, 6.6 Hz, 2H), 2.18 (dt, J = 14.3, 7.2 Hz ,2H),2.12–2.08(m,1H),1.72–1.64(m,2H),1.61–1.54(m,2H),1.38–1.31(m,2H).HRMS m/z:880.3668[M+H ] ⁺ .

Example 12:

¹ H NMR(600MHz, CDCl ₃ )δ10.99(s,1H), 8.60(d,J=8.4Hz,1H), 8.05(d,J=8.7Hz,1H), 8.02(s,1H), 7.50 (d,J=7.6Hz,1H),7.42(dd,J=15.2,7.3Hz,2H),7.25(s,1H),7.03(dd,J=17.7,7.2Hz,2H),6.94(d, J = 8.6Hz, 1H), 6.72 (d, J = 2.5Hz, 1H), 6.63 (d, J = 15.8Hz, 1H), 6.51 (d, J = 2.1Hz, 1H), 6.46-6.40 (m, 2H), 6.12 (s, 1H), 4.73 (dd, J = 9.4, 6.0 Hz, 1H), 3.84 (s, 3H), 3.40 (s, 4H), 3.23 (s, 4H), 2.99 (d, J ＝4.8Hz,3H),2.79(s,4H),2.54-2.44(m,3H),2.33(t,J＝7.2Hz,2H), 2.14(d,J＝7.4Hz,2H),2.03-1.97 (m,1H),1.62--1.58(m,4H),1.31(s,4H).ESI-MS m/z:894.3[M+H] ⁺ .

Example 13:

¹ H NMR(600MHz, CDCl ₃ )δ10.99(s,1H), 9.90(s,1H), 8.63(d,J=8.4Hz,1H), 8.06(s,1H), 8.04(d,J= 8.7Hz,1H),7.49–7.45(m,2H),7.42(t,J=7.8Hz,1H),7.29(s,1H),7.07(d,J=7.1Hz,1H),7.03(t, J = 7.5Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 2.3 Hz, 2H), 6.45 (dd, J = 8.8, 2.2 Hz, 1H), 6.38 (t, J = 5.1Hz, 1H), 6.21 (s, 1H), 4.88 (dd, J = 12.3, 5.4 Hz, 1H), 3.83 (s, 3H), 3.48-3.42 (m, 4H), 3.19 (s, 4H ), 2.99(d,J=4.8Hz,3H), 2.84–2.68(m,7H), 2.45(d,J=7.6Hz,2H), 2.16(t,J=7.5Hz,2H), 2.11–2.06 (m,1H),1.64-1.58(m,2H),1.58-1.52(m,2H),1.35-1.25(m,6H).HRMS m/z:908.3977[M+H] ⁺ .

Example 14:

¹ H NMR(400MHz, CDCl ₃ )δ10.99(s,1H), 9.38(s,1H), 8.64(d,J=8.3Hz,1H), 8.05(d,J=9.1Hz,2H), 7.50 –7.46(m,2H),7.45–7.40(m,1H),7.28(s,1H),7.08(d,J=7.1Hz,1H),7.04(t,J=7.1Hz,1H),6.96( d,J=8.6Hz,1H),6.53(d,J=2.4Hz,1H),6.47(dd,J=8.8,2.4Hz,1H),6.45-6.38(m,2H),6.10(s,1H) ), 4.89 (dd, J = 12.3, 5.3 Hz, 1H), 3.84 (s, 3H), 3.48–3.43 (m, 4H), 3.20 (s, 4H), 3.00 (d, J = 4.8 Hz, 3H) ,2.88–2.67(m,7H), 2.48–2.41(m,2H), 2.16(t,J=7.5Hz,2H), 2.12–2.07(m,1H),1.63–1.52(m,4H),1.32 –1.23(m,10H).HRMS m/z:936.4297[M+H] ⁺ .

Example 15:

¹ H NMR (600MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 11.03 (s, 1H), 9.80 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.61 (s, 1H), 8.10 (d, J = 12.4 Hz, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.42 ( d, J = 8.3Hz, 1H), 7.32 (s, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.64 (s, 1H), 6.48 (d, J = 8.3 Hz, 1H), 5.15 ( dd, J = 13.3, 5.1 Hz, 1H), 4.38 (q, J = 17.4 Hz, 2H), 3.76 (s, 3H), 3.15 (s, 4H), 2.95-2.88 (m, 1H), 2.80 (d ,J=4.4Hz,3H),2.67–2.51(m,6H),2.43–2.32(m,4H),2.06–2.02(m,1H),1.66(dt,J=14.7,7.2Hz,2H), 1.55(s,2H).HRMS m/z:809.3285[M+H] ⁺ .

Example 16:

¹ H NMR(600MHz, CDCl ₃ )δ10.98(s,1H), 8.62(d,J=8.1Hz,1H), 8.33(s,1H), 8.05(s,1H), 8.01(d,J= 8.8Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 15.3, 7.5Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 4.4 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 6.43 (dd, J = 8.9, 2.2Hz, 1H), 4.96 (dd, J = 13.0, 5.0 Hz, 1H), 4.32 (q, J = 16.7 Hz, 2H), 3.82 (s, 3H), 3.13 (s, 4H), 2.98 (d, J=4.8Hz,3H), 2.71–2.58(m,6H), 2.45–2.38(m,4H), 2.15–2.11(m,1H), 2.07–2.04(m,1H), 1.78–1.70(m, 2H),1.59–1.53(m,2H),1.43–1.36(m,2H).HRMS m/z:823.3468[M+H] ⁺ .

Example 17:

¹ H NMR (600MHz, CDCl ₃ ) δ 10.97 (s, 1H), 10.43 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H) ,8.03(d,J=8.7Hz,1H),7.66(d,J=7.4Hz,1H),7.59(d,J=7.8Hz,1H),7.46(dd,J=7.8,1.2Hz,1H) ,7.42(dd,J＝16.4,8.3Hz,2H),7.27(s,1H),7.01(t,J＝7.6Hz,1H),6.54-6.50(m,2H),6.45(dd,J＝8.8 ,2.4Hz,1H),5.06(dd,J=13.1,5.3Hz,1H),4.40–4.26(m,2H),3.83(s,3H),3.18(s,4H),2.99(d,J= 4.8Hz,3H), 2.74–2.61(m,6H), 2.46–2.38(m,4H), 2.21–2.15(m,1H), 2.11–2.07(m,1H), 1.71(dt,J=16.6, 7.1Hz,2H),1.53(t,J=12.8Hz,2H),1.38–1.29(m,6H).HRMS m/z:851.3793[M+H] ⁺ .

Example 18:

¹ H NMR(600MHz,CDCl ₃ )δ10.96(s,1H),8.61(d,J=8.4Hz,1H),8.06(s,1H),8.04(d,J=8.7Hz,1H),7.98 (s,1H),7.67(d,J=7.5Hz,1H),7.54(d,J=7.8Hz,1H),7.47(dd,J=7.8,1.2Hz,1H),7.44-7.40(m, 2H), 7.27 (s, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.8, 2.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43-4.26 (m, 2H), 3.83 (s, 3H), 3.17 (s, 4H), 2.99 (d, J = 4.8 Hz ,3H),2.78–2.65(m,6H),2.42(dd,J＝15.1,7.5Hz,4H), 2.19(qd,J＝13.0,4.1Hz,1H), 2.12–2.07(m,1H), 1.77–1.65(m,2H),1.56–1.50(m,2H),1.35–1.26(m,10H).HRMS m/z:879.4116[M+H] ⁺ .

Example 19:

¹ H NMR (600MHz, CDCl ₃ ) δ 11.03 (s, 1H), 9.42 (s, 1H), 8.82 (d, J = 8.5 Hz, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.50 (s, 1H), 8.12 (d, J = 8.7Hz, 1H), 8.08 (s, 1H), 7.72-7.68 (m, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 7.8, 1.1 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.36 (s, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.8, 2.4 Hz, 1H), 6.28 (d, J = 4.6 Hz, 1H), 4.95 (dd, J = 12.6, 5.3 Hz, 1H), 4.47 (s, 2H), 4.13(s,2H),3.86(s,3H),3.35-3.32(m,2H), 3.23(t,J=4.6Hz,4H),3.02(d,J=4.8Hz,3H), 2.91(dd ,J=16.5,3.3Hz,1H), 2.85–2.71(m,2H), 2.46(t,J=7.5Hz,2H), 2.19–2.15(m,1H), 1.78–1.70(m,4H), 1.49–1.40(m,6H).HRMS m/z:941.3002[M+H] ⁺ .

Example 20:

¹ H NMR (600MHz, CDCl ₃ ) δ11.05 (s, 1H), 9.41 (s, 1H), 8.83 (d, J = 8.5 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.54 (s,1H),8.11(d,J=8.7Hz,1H),8.08(s,1H),7.72-7.68(m,1H),7.53(d,J=7.2Hz,1H),7.49(d, J=8.6Hz,1H),7.44-7.40(m,2H),7.07(t,J=7.5Hz,1H), 6.54(d,J=2.4Hz,1H), 6.47(dd,J=8.8,2.4 Hz, 1H), 6.30 (d, J = 4.5 Hz, 1H), 4.95 (dd, J = 12.6, 5.3 Hz, 1H), 4.50 (s, 2H), 4.14 (s, 2H), 3.86 (s, 3H) ), 3.32(t,J=7.4Hz,2H),3.25-3.20(m,4H),3.02(d,J=4.8Hz,3H),2.91(dd,J=16.6,3.4Hz,1H),2.85 –2.71(m,2H),2.45(t,J=7.6Hz,2H),2.19–2.14(m,1H),1.73(qd,J=14.8,7.5Hz,4H),1.45–1.32(m,10H ).HRMS m/z:969.3297[M+H] ⁺ .

Example 21: Study on the in vitro enzyme inhibitory activity of the compound of the present invention

Experimental Materials:

Tecan

Microplate reader.

Kit (contains biotinylated peptide substrate TK, Eu3+ labeled monoclonal antibody that only targets specific phosphorylation sites, Sa-XL665 labeled streptavidin, KinEASE enzyme reaction buffer), 384 shallow well plate , FAK protein, MgCl ₂ , ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DL-Dithiothreitol, DTT), DMSO.

experimental method:

The first step: Kinase reaction. First, the compound sample was prepared into a 20mM solution with DMSO, and then diluted with kinase reaction buffer solution to 1μM, 0.1μM, etc. according to the needs of the test. Then FAK kinase (concentration of 0.111ng/μl), ATP (20μM), biotin-labeled peptide substrate TK (1μM) and compound samples (4μl) were added to 10μl kinase reaction buffer solution (containing MgCl ₂ 5mM, DTT 1mM) And SEB 0.025μM), incubate at room temperature for 50 minutes, the kinase phosphorylates the substrate. Then add 10μl of detection reagent containing EDTA to detect phosphorylation products.

Step 2: Detection of phosphorylation products. The rare earth element europium (Eu ³⁺ )-labeled antibody recognizes the phosphorylated substrate, and the XL665-labeled streptavidin binds to the biotin on the substrate. Eu ³⁺ is a fluorescent donor, and XL665 is a fluorescent acceptor. When Eu ³⁺ is close ^{to XL665, the energy of Eu 3+ is} transferred to XL665 to generate HTRF signal.

Result evaluation method: the fluorescence signal is generated by the ^{fluorescence absorption signal of Eu 3+} at 620nm and XL665 at 665nm. Therefore, the ratio of the HTRF signal (665/620) of each well is calculated.

Table 1 Example compounds in vitro FAK inhibitory activity percentages at concentrations of 1 μM and 0.1 μM

As shown in the above table, the example compounds of the general formula (I) of the present invention have an inhibitory effect on FAK kinase activity and can bind to FAK protein.

Example 22: Degradation effect of some compounds of the present invention on FAK in A549 cells

experimental method:

The first step: cell sample processing

⑴ Add 4x10^5 cells to each well of the six-well plate and culture for 24h. Add medicine and cultivate for 12h.

⑵ Add 1ml trypsin to each well of cells, place them flat, then gently shake to wash the cells, and add 2ml of culture medium.

⑶ Use a pipette to transfer the cells to a 15ml centrifuge tube, 1000r/min, 5min.

⑷Resuspend the cell cake in 1ml PBS, and transfer the cell suspension to a 1.5ml EP tube at 3000r/min for 5min.

Step 2: Lyse the cells

⑴Calculate the amount of lysate, add 10μl PMSF (100mM) per ml of lysate, shake well and place on ice.

(2) Aspirate the PBS in each ep tube, then add 100μl of lysis solution to each ep tube cell, sonicate it for 2s×3 times, and place it on ice for 30min to lyse.

(3) Centrifuge at 12000r/min for 15min at 4℃.

⑷The supernatant obtained after centrifugation is the desired protein sample, which is divided into 1.5ml centrifuge tubes in the refrigerator at -80℃ for later use, or protein quantification can be performed directly.

The third step: BCA method protein quantification

⑴ Take 1.2ml of protein standard preparation solution and add it to 1 tube of protein standard (30mg BSA), and make a 25mg/ml protein standard solution after fully dissolving. Use it immediately after preparation or store it at -20°C for a long time after packaging.

(2) Take an appropriate amount of 25mg/ml protein standard and dilute to a final concentration of 0.5mg/ml.

⑶ Prepare 0.5, 0.25, 0.1, 0.05, 0.025, 0.0125 mg/ml BSA standard solution by gradient dilution method.

⑷ After the supernatant of each histone is diluted 50 times with TBS, take 20μl of the diluted supernatant and place it in a 96-well plate.

⑸According to the number of samples, according to the ratio of BCA reagent A to reagent B at a ratio of 50:1, prepare an appropriate amount of BCA working solution, prepare it for use now, and mix it thoroughly.

⑹ Add 200μl BCA working solution to each well and incubate at 37°C for 30min.

⑺The microplate reader detects the absorbance of the sample at the wavelength of 562nm, and calculates the concentration of each histone according to the standard curve.

The fourth step: protein sample preparation

⑴ Quantify each histone supernatant with TBS and 5x loading buffer to 2μg/μl.

⑵Heat at 100℃ for 15min to denature the protein and place it in a refrigerator at -80℃ for later use.

Step 5: VSDS-PAGE electrophoresis

⑴Check the glue glass plate before making glue, and clean the glass plate carefully to avoid affecting the quality of glue.

⑵Prepare the separating glue according to the formula according to the needs (see Table 1-1 for the formula), mix well and quickly add the glue to the glass plate, add the glue to a height of about 1.5cm from the edge of the glass plate, and then add isopropanol immediately 200μl sealant. After 1h, after the lower layer of glue has solidified, wash the isopropanol with distilled water.

Table 2-1 SDS-PAGE separation gel formula (8%)

⑶Prepare the layering glue according to the formula (see Table 1-2 for the recipe) according to the needs, quickly add it to the glass plate, and then insert the comb (hole former), 45min after the upper layer glue has solidified, store it in a sealed container at 4°C for later use.

Table 2-2 SDS-PAGE Laminating Adhesive Formula (5%)

⑷ Dilute 10× running buffer to 1× use concentration.

⑸Assemble the electrophoresis device: take out the glass plate with glue, and carefully pull out the comb to avoid shaking. Assemble with an electrophoresis device that matches the glass plate. After the assembly is completed, pour the electrophoresis buffer into the inner tank until the liquid level is flush with the glass plate. After confirming that there is no leakage, continue to add the electrophoresis buffer to the outer tank until the platinum wire is immersed.

⑹Sample loading/electrophoresis: pipette add protein Marker to sample hole and quantify protein sample. Turn on the power, the voltage is 70V for the laminated gel. After the sample front electrophoresis reaches the limit of the two gels, the Marker is separated, and the voltage is changed to 120V for the separation gel. When the bromophenol blue strip at the front of electrophoresis moves to the bottom of the glass plate, it indicates that the electrophoresis is complete, and the power can be turned off.

⑺ Prepare 1x transfer buffer, blocking solution (5% skimmed milk powder/TBS-T), prepare filter paper and PVDF membrane.

⑻ Transfer film: Put the prepared transfer film clip, liner, PVDF film cut according to specifications (pre-activated in methanol for 30s) and 2 layers of filter paper in the transfer liquid to remove air bubbles, and place liners on the black surface of the clip in turn , 1 layer of filter paper, gel, PVDF membrane, 1 layer of filter paper, liner, to avoid air bubbles, strictly pay attention to the order of the contents, and close the clips carefully. Put it as if in a transfer tank. Fill up the transfer liquid, place an ice box, turn on the power, and place the transfer tank in a foam box filled with ice cubes. Constant current 200mA transfer for 1-3h (depending on protein molecular weight).

⑼ Sealing: After the transfer time is up, soak the PVDF membrane in the sealing solution, mark the Marker position, place it on a shaker, and seal at room temperature for 2 hours.

⑽Prepare primary antibody, FAK antibody is diluted with blocking solution at 1:1000, GADPH antibody is diluted with blocking solution at 1:2000, and incubated overnight at 4°C.

⑾ TBS-T membrane wash 15min/time, wash 3 times.

⑿Prepare the secondary antibody, dilute the secondary antibody at 1:4000 with the blocking solution, and incubate at room temperature for 2h.

⒀TBS-T membrane wash 15min/time, wash 3 times.

Step 6: Development

⑴ Prepare an appropriate amount of ECL luminescent working fluid according to the ratio of A liquid: B liquid = 1:1.

⑵ Develop with a developing instrument.

Experimental results show:

1. Most of the compounds have potent degradation activity on FAK protein in A549 cells. After incubating with A549 cells for 12 hours at a concentration of 0.1 μM, Western test results show that FAK protein can be almost completely degraded;

2. Among them, compound 4 has strong degrading activity. At a concentration of 0.01 μM, incubating with A549 cells for 12 hours can almost completely degrade the protein. (See attached picture 2 for Western test development strips)

The compound of general formula (I) in the present invention can be administered alone, but is usually administered as a mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. Each of these compounds is used below. The preparation methods of various pharmaceutical dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, external liniments and ointments, illustrate their new applications in the pharmaceutical field.

Example 23: Tablets

10g containing the compound of claim 1 (taking the compound of Example 8 as an example), mixed with 20g of auxiliary materials according to the general tableting method of pharmacy, and then compressed into 100 tablets, each weighing 300mg.

Example 24: Capsules

Using 10g containing the compound of claim 1 (taking the compound of Example 8 as an example), mixing 20g of the auxiliary materials according to the requirements of pharmaceutical capsules, filling them into hollow capsules, each capsule weighing 300mg.

Example 25: Injection

Use 10g of the compound of claim 1 (take the compound of Example 8 as an example), and perform adsorption on activated carbon in accordance with the conventional method of pharmacy. After filtering through a 0.65μm microporous membrane, fill it into a nitrogen tank to make a water injection preparation. Only 2mL is packed, and 100 bottles are filled in total.

Example 26: Aerosol

Use 10g containing the compound of claim 1 (taking the compound of Example 8 as an example), dissolve it with an appropriate amount of propylene glycol, add distilled water and other radiation materials, and make a 500mL clear solution.

Example 27: Suppositories

Take 10g of the compound containing the compound of claim 1 (take the compound of Example 8 as an example), grind it into an appropriate amount of glycerin, grind it evenly, add the melted glycerin gelatin, grind it evenly, and pour it into the mold that has been coated with lubricant , Made 50 suppositories.

Example 28: Film

Using 10 g of the compound of claim 1 (taking the compound of Example 8 as an example), stir and expand the polyvinyl alcohol, medicinal glycerin, water, etc., and then heat to dissolve, filter with an 80 mesh screen, and then add the compound of Example 18 to Stir and dissolve in the filtrate, and coat 100 pieces of film.

Example 29: Dropping pills

10g containing the compound of claim 1 (taking the compound of Example 8 as an example), heated and melted and mixed with 50g of a base such as gelatin, and then dropped into low-temperature liquid paraffin to prepare a total of 1000 dropping pills.

Example 30: Liniment for external use

It is prepared by using 10 g of the compound of claim 1 (taking the compound of Example 8 as an example), mixing and grinding with 2.5 g of emulsifier and other auxiliary materials according to conventional pharmacy methods, and adding distilled water to 200 mL.

Example 31: Ointment

It is prepared by using 10 g of the compound of claim 1 (taking the compound of Example 8 as an example), grinding it and mixing it with 500 g of an oily base such as petroleum jelly.

Although the present invention has been described through specific embodiments, modifications and equivalent changes are obvious to those skilled in the art, and they are all included in the scope of the present invention.

Claims (11)

1. Compounds represented by general formula (I), and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   

   A is a (C ₆ -C ₁₂ ) aryl group, a heteroaryl group consisting of 5-12 atoms, a (C ₃ -C ₆ ) cycloalkyl group or a heterocyclic group consisting of 3-12 atoms, the heteroaryl group The group or heterocyclic group contains 1-3 N, O or S heteroatoms;

   A is replaced by 1, 2, 3, 4 or 5 R ¹ ;

   R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally hydroxy, amino or halogen Substituted (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido , 4-7 membered heterocyclic group, -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)SR ² , -C(O)(NR ² R ³ ), -S(O) ₂ NR ² R ³ , -S(O)NR ² R ³ , -NR ² C(O)R ³ , -NR ² S(O) ₂ R ³ , -NR ² S(O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O)NHR ³ , -NR ² S(O) ₂ NHR ³ , -CH ₂ P( O) R ² R ³ ;

   R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₆ ) Alkyl or (C ₁ -C ₆ )alkoxy, amino substituted with mono or di (C ₁ -C ₆ alkyl), (C ₁ -C ₆ )alkylamido, 4-7 membered heterocyclic group;

   Y is hydrogen, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, Halo (C ₁ -C ₆ )alkyl;

   X is C or N;

   R ⁴ or R ⁵ are independently hydrogen, deuterium, hydroxyl, halogen, carbonyl, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkyl;

   n ₁ and n ₂ are independently 0, 1 or 2 respectively;

   W is N or CR ⁶ ;

   R ⁶ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy;

   M is NR ⁷ , O or S;

   R ⁷ is hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₂ -C ₆ ) Alkenyl or (C ₂ -C ₆ )alkynyl.

   The L part has a structure represented by the general formula (IV) or (V),

   

   X ₁ or X ₂ are each independently hydrogen,

   

   

   X ₃ is

   

   

   R ⁸ is hydrogen, deuterium, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy;

   Q is CH or N;

   t is an integer between 0-12;

   k is an integer between 0-12.
2. The compound of claim 1, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   in,

   A is a phenyl group, a heteroaryl group consisting of 5-12 atoms, a (C ₃ -C ₆ ) cycloalkyl group or a heterocyclic group consisting of 3-12 atoms, and the heteroaryl or heterocyclic group contains 1 -3 heteroatoms of N, O or S; and/or

   R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₆ ) Alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino.
3. The compound of claim 1 or 2, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   in,

   A is

   

   

   R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, carboxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, optionally hydroxy, amino or halogen Substituted (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di (C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido , -C(O)R ² , -S(O) ₂ R ² , -S(O)R ² , -C(O)OR ² , -C(O)SR ² , -C(O)(NR ² R ³ ), -S(O) ₂ NR ² R ³ , -S(O)NR ² R ³ , -NR ² C(O)R ³ , -NR ² S(O) ₂ R ³ , -NR ² S (O)R ³ , -NR ² C(O)NHR ³ , -NR ² S(O)NHR ³ , -NR ² S(O) ₂ NHR ³ , -CH ₂ P(O)R ² R ³ ; and /or

   R ² and R ³ are hydrogen, deuterium, amino, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, optionally substituted by hydroxyl, amino or halogen (C ₁ -C ₃ ) Alkyl or (C ₁ -C ₃ )alkoxy, amino substituted with mono or di (C ₁ -C ₃ alkyl).
4. The compound according to any one of claims 1 to 3, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   in,

   A is

   

   The R ¹ is hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy;

   X is N;

   Y is halogen, halogenated (C ₁ -C ₆ )alkyl;

   Preferably,

   A is

   

   The R ¹ is hydrogen or methoxy;

   X is N;

   Y is chlorine or trifluoromethyl.
5. The compound of any one of claims 1 to 4, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   R ⁴ or R ⁵ are independently hydrogen, deuterium, hydroxyl, halogen, carbonyl, nitro, amino, cyano, carboxy, oxo, (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) Alkyl;

   W is N; and/or

   M is NR ⁷ ;

   Preferably,

   Part E has the structure shown in VII-1 or VII-2:

   
6. The compound according to any one of claims 1 to 5, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

   in,

   The L part has a structure represented by the general formula (IV) or (V),

   

   Each X ₁ or X _{2 is} independently hydrogen,

   

   

   X ₃ is

   

   

   R ⁸ is hydrogen, methyl or ethyl;

   t is an integer between 0-10; and/or

   k is an integer between 0-10.
7. The following compounds and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

   

   

   

   
8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.
9. The use of the compound according to any one of claims 1-7 and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof or the pharmaceutical composition according to claim 8 in the preparation of FAK protein inhibitors.
10. The compound of any one of claims 1-7, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or the pharmaceutical composition of claim 8 is used for the treatment or prevention of FAK kinase The expression or activity of the drug for diseases (such as tumors or cancers).
11. The application according to claim 10, wherein the disease is meningioma, colorectal cancer, gastric cancer, liver cancer, breast cancer, skin cancer, lung cancer, cervical cancer, ovarian cancer or breast cancer.

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