Synthesis and Use of a Class of Allosteric Inhibitors of EGFR

Abstract

The present invention relates to the synthesis and use of a class of allosteric EGFR inhibitors, belonging to the field of medicine. The present invention provides a compound of the structure shown by general formula (I) or a salt thereof, and the compound or the salt can selectively inhibit EGFR, and thus can be used for treating or improving abnormal cell proliferation diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to the synthesis and use of a class of allosteric EGFR inhibitors. Background Art

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase of the ErbB receptor family. When it binds to a growth factor ligand (such as epidermal growth factor (EGF)), the receptor can undergo homodimerization with additional EGFR molecules, or heterodimerization with another family member (such as ErbB2 (HER2), ErbB3 (HER3) or ErbB4 (HER4)). The homodimerization and / or heterodimerization of ErbB receptors leads to the phosphorylation of key intracellular tyrosine residues and the stimulation of many intracellular signaling pathways involved in cell proliferation and survival. The dysregulation of ErbB family signal transduction promotes proliferation, invasion, metastasis, angiogenesis and the survival of tumor cells, and is closely related to human cancers such as lung cancer, head and neck cancer, colon cancer, breast cancer, etc.

[0003] Currently, there are four generations of drugs targeting EGFR. The first-generation EGFR TKIs include Gefitinib and Erlotinib, which are mainly used for mutations of deletion at position 19 and L858R; the second generation includes Afatinib and Dacomitinib, which are mainly used to address the most common T790M-mediated drug resistance mechanism and covalently bind to the mutant EGFR protein; the third-generation EGFR TKI is Osimertinib, which has activity against the EGFRTKI-resistant mutation T790M. The fourth-generation EGFR TKIs are mainly divided into two types: ATP-competitive inhibitors and allosteric inhibitors. The representative drug is Mobocertinib, which was recently launched. Currently, many allosteric inhibitor drugs have entered clinical trials.

[0004] In the past decade, molecular targeted therapy represented by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has brought about a huge transformation in cancer treatment. However, the drug resistance of EGFR-TKIs has always been an unresolved problem. For example, EGFR-TKIs are initially effective in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations, but often evolve into acquired drug resistance and lose their therapeutic effect, such as the T790M mutation that causes resistance to the first / second-generation EGFR-TKIs and the C797S mutation that causes resistance to the third-generation EGFR-TKIs. In particular, tumors containing the L858R / T790M / C797S mutations simultaneously are currently beyond the reach of existing EGFR-TKIs. However, all current EGFR TKIs target the ATP site. Although the third-generation irreversible inhibitors (such as osimertinib) can overcome T790M, drug resistance occurs due to the C797S mutation that has emerged in treated patients. Cetuximab (an anti-EGFR antibody) that blocks receptor dimerization is ineffective in EGFR-mutant NSCLC because the mutant activation of the kinase is an effective "downstream" of receptor dimerization. Therefore, an alternative strategy is needed to inhibit EGFR. Currently, suitable compounds with alternative mechanisms of action targeting mutant EGFR are not available.

[0005] As drugs are continuously applied clinically, patients often develop varying degrees of drug resistance. Common drug-resistant mutations include EGFR T790M, EGFR C797X, etc., resulting in a decrease in the ability to compete with ATP. Therefore, there is an urgent need to find new methods to overcome drug resistance. The discovery of allosteric inhibitors has helped researchers find a new binding site, which is located on the back of the ATP pocket. Compounds bind to the allosteric pocket instead of competing with ATP to stabilize the EGFR protein in an inactive conformation and limit the activity of the kinase to inhibit the proliferation of lung cancer cells. This is a completely new strategy for overcoming the current drug resistance situation of the EGFR target.

[0006]

[0007] In 2019, Black Diamond Therapeutics reported a mutant-selective EGFR allosteric inhibitor, BDTX-189. Studies have shown that it has inhibitory effects on EGFR and HER2 ins20 mutations as well as extracellular domain mutations, but its activity still needs to be further improved. Summary of the Invention

[0008] Problems to be Solved by the Invention

[0009] The present invention provides a novel EGFR allosteric inhibitor, and the pharmacodynamic properties of this structural compound are better.

[0010] Furthermore, the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, and uses.

[0011] Solutions for solving problems

[0012] The present invention provides a compound of the structure shown by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Wherein, ring A is selected from a benzene ring, a pyridine ring, a pyrazine ring, R1 is H, C1-4 alkyl, halogen (F, Cl, Br, I), and R2 is halogen (F, Cl, Br, I); or ring A is selected from a benzene ring, a pyrazine ring, R1 is H, C1-4 alkyl, halogen (F, Cl, Br, I), and R2 is H;

[0015] R3 is selected from a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, a heteroaryl group having 5 to 12 carbon atoms, and the substituents are arbitrarily selected from 1, 2, or 3 of the following substituents: H, halogen (F, Cl, Br, I);

[0016] W is -R4(CH2) m -, -O(CH2) m -, where m is selected from 0, 1, 2, and R4 is selected from an alkenyl group, an alkynyl group; the Y ring is selected from a cycloalkyl group having 3 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms; or -W-Y is -OR5, and R5 is selected from C1-4 alkyl;

[0017] Z is selected from: H, -NR6, R6 is selected from H, C1-4 alkyl.

[0018] In some embodiments of the present invention, the heterocyclic group having 3 to 12 carbon atoms is selected from a morpholine ring, a piperidine ring, R7 is selected from C1-4 alkyl.

[0019] In some embodiments of the present invention, R3 is selected from:

[0020] In some embodiments of the present invention, W is -R(CH2) m -, -O(CH2) m -, where R is selected from an alkynyl group, and m is selected from 0, 2;

[0021] In the present invention, the further specifically preferred compound of the structure shown by general formula (I) or a pharmaceutically acceptable salt thereof is selected from:

[0022]

[0023] A compound of the structure shown by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salts are selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, mesylate, tosylate, benzenesulfonate, and salicylate.

[0024] Another object of the present invention is to provide a pharmaceutical composition which contains a compound of the structure shown by the above general formula (I) or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier, excipient or diluent.

[0025] On the other hand, the present invention provides the use of a compound of the structure shown by the above general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug used as an EGFR inhibitor.

[0026] On the other hand, the present invention provides the use of a compound of the structure shown by the above general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of cancer.

[0027] The cancers mentioned in the present invention may be selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer, etc.

[0028] The beneficial effect of the present invention lies in designing a class of compounds with the biological function of inhibiting EGFR, thereby providing a new means for searching for new treatments for cancer, metabolic and immune diseases, cardiovascular diseases, and neurological diseases, etc.

[0029] Effect of the invention:

[0030] A class of compounds with the structure shown by the general formula (I) provided by the present invention can be used for the therapeutic and / or prophylactic treatment of patients with EGFR mutations T790M / L858RT790M / L858R / C797S, L858R, and / or L858R / C797S suffering from cancer, especially non-small cell lung cancer. The treatment includes determining the EGFR activation mutation status of the patient, and then administering the compound of formula I or its medicinal salt as described herein to the patient. Detailed implementation mode

[0031] The technical solutions of the present invention will be described in detail below in conjunction with the embodiments.

[0032] In the present invention, "C 1-6"Alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group having 1 to 6 carbon atoms respectively. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, and 2-methyl-2-propyl.

[0033] In the present invention, "heteroaryl", unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo-fused heteroaromatic ring system or a bicyclic heteroaromatic ring system, which is composed of carbon atoms and 1 to 4 heteroatoms selected from N, O, or S, and wherein said nitrogen or sulfur heteroatom can be selectively oxidized, and said nitrogen heteroatom can be selectively quaternized.

[0034] An aryl group having 6 to 10 carbon atoms is a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0035] A heteroaryl group having 5 to 12 carbon atoms refers to a monocyclic or bicyclic aromatic group having 5 to 12 ring atoms, wherein one or more, preferably one, two, or three ring atoms are heteroatoms selected from N, O, S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, methylindolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.

[0036] In the present invention, "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents.

[0037] In the present invention, "administering" or "giving" an individual compound means providing the compound of the present invention to an individual in need of treatment.

[0038] <Compound or a pharmaceutically acceptable salt thereof>

[0039] The present invention provides a class of novel oxoisoindole compounds or pharmaceutically acceptable salts thereof as inhibitors of epidermal growth factor receptor (EGFR), and their structural formula is shown as general formula (I):

[0040]

[0041] <Pharmaceutical composition>

[0042] The present invention also provides a pharmaceutical composition, comprising the compound of general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0043] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into solid preparations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of general formula (I) of the present invention is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium hydrogen phosphate. Or mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, etc.; (2) binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain conforming silicates and sodium carbonate, etc.; (5) slow solvents, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glycerol monostearate, etc.; (8) adsorbents, such as kaolin, etc.; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Buffering agents may also be included in capsules, tablets, and pills.

[0044] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be coated with coating and shell materials such as enteric coatings and other polymorphic coatings or microencapsulation materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax substances. If necessary, the active ingredient can also be formed in the form of microcapsules with one or more of the above excipients.

[0045] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc. or mixtures of these substances, etc. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances, etc.

[0046] The suspending agents include, for example, ethoxylated octadecanol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, etc. or mixtures of these substances.

[0047] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and their suitable mixtures.

[0048] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into dosage forms for topical administration, including, such as ointments, powders, suppositories, drops, sprays and inhalants, etc. The compound of general formula (I) of the present invention or its pharmaceutically acceptable salt as the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and optionally a preservative, a buffer, and a propellant that may be required if necessary.

[0049] The pharmaceutical compositions of the present invention include the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, as well as pharmaceutically acceptable carriers, excipients, diluents. When preparing the pharmaceutical composition, generally the compound of general formula (I) of the present invention or its pharmaceutically acceptable salt is mixed with a pharmaceutically acceptable carrier, excipient or diluent. The content of the compound of general formula (I) or its pharmaceutically acceptable salt can be 0.01 - 1000 mg, for example 0.05 - 800 mg, 0.1 - 500 mg, 0.01 - 300 mg, 0.01 - 200 mg, 0.05 - 150 mg, 0.05 - 50 mg, etc.

[0050] <Use>

[0051] The present invention also provides the use of the compound of general formula (I) or its pharmaceutically acceptable salt in the preparation for treating cancer in mammals.

[0052] The compound of general formula (I) or its pharmaceutically acceptable salt, the compounds and salts of the present invention can inhibit the activity of epidermal growth factor receptor (EGFR), and are used for the therapeutic and / or prophylactic treatment of mammals including humans, for patients with EGFR-activating mutations suffering from cancer, especially non-small cell lung cancer. The treatment includes determining the EGFR-activating mutation status of the patient, and then administering to the patient a compound of formula I or its medicinal salt as described herein.

[0053] "Therapeutically effective amount" is the amount of the compound of the present invention that is effective in producing a biological or medical response (such as reducing or inhibiting the activity of an enzyme or protein, or improving symptoms, alleviating a condition, slowing or delaying disease progression or preventing a disease) in an individual.

[0054] The cancers mentioned in the present invention include lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the ampulla of Vater, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestinal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) cancer, primary central nervous system lymphoma, spinal axis cancer, brainstem glioma, pituitary adenoma, etc.

[0055] The compounds of the present invention or their pharmaceutically acceptable salts can be administered to mammals including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment, drops) or intratumorally.

[0056] The compounds or their pharmaceutically acceptable salts described in the present invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, in combination with other anti-tumor drugs. This combination therapy can be achieved by simultaneously, sequentially or separately using the respective components of the treatment. The therapeutic agents include, but are not limited to: anti-tumor drugs acting on the chemical structure of DNA, such as cisplatin; anti-tumor drugs affecting nucleotide synthesis, such as methotrexate, 5-fluorouracil, etc.; anti-tumor drugs affecting nucleic acid transcription, such as doxorubicin, epirubicin, aclarubicin, etc.; anti-tumor drugs acting on tubulin synthesis, such as paclitaxel, vinorelbine, etc.; aromatase inhibitors such as aminoglutethimide, letrozole, exemestane, etc.; cell signaling pathway inhibitors such as ALK inhibitors crizotinib, ceritinib, alectinib, lorlatinib, etc. Anti-tumor monoclonal antibodies, immunosuppressants PD-1, PD-L1, etc. The components to be combined can be administered simultaneously or sequentially, in the form of a single preparation or in the form of different preparations. The combination includes not only the combination of one or other active agents of the compounds of the present invention, but also the combination of two or more other active agents of the compounds of the present invention.

[0057] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions.

[0058]

[0059] Preparation of 4-chloro-7-methoxyquinazoline-6-carboxylate (Intermediate 1):

[0060] 4-Chloro-7-methoxyquinazoline-6-carboxylate (80 g, 1.0 eq) was dissolved in thionyl chloride (80 mL), and a catalytic amount of N,N-dimethylformamide (0.2 mL) was added dropwise. The reaction was refluxed at 90 °C for 4 h. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove most of the solvent. The residue was triturated with petroleum ether (50 mL), filtered by suction, and the filter cake was washed with petroleum ether and dried to obtain 4-chloro-7-methoxyquinazoline-6-carboxylate (Intermediate 1) (82.5 g, 95.8%), a gray solid. 1 H NMR (400 MHz, Chloroform-d) δ: 8.97 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 4.05 (s, 3H), 2.42 (s, 3H).

[0061] Preparation of 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl acetate (Intermediate 2):

[0062] 4-Chloro-7-methoxyquinazoline-6-carboxylate (Intermediate 1) (20.0 g, 1.0 eq) was dissolved in N-methylpyrrolidone (200 mL) solution, and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (18.57 g, 1.0 eq) was added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. Water (400 mL) was added, and the mixture was filtered by suction. The filter cake was washed with water and dried in a vacuum drying oven (45 °C, 24 h) to obtain 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl acetate (Intermediate 2) (34.75 g, 97.3%), a red solid. HRMS (m / z): 451.1626 [M+H] + 。

[0063] Preparation of 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-ol (Intermediate 3):

[0064] 4-((3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl acetate (Intermediate 2) (34.7 g, 1.0 eq) was dissolved in methanol (400 mL), potassium carbonate (31.9 g, 3.0 eq) was added, and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was filtered by suction. The filter cake was washed with water and dried in a vacuum drying oven (45 °C, 12 h) to obtain 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-ol (Intermediate 3) (31.1 g, 98.7%), a white solid, which was directly used in the next step without purification. HRMS (m / z): 409.1572 [M+H] + 。

[0065] Preparation of tert-butyl 4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (Intermediate 4):

[0066] 4-((3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-ol (Intermediate 3) (7.7 g, 1.0 eq) was dissolved in DMF (80 mL), tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (8.0 g, 1.2 eq) and potassium carbonate (7.8 g, 3.0 eq) were added, and the temperature was raised to 80 °C. The reaction was carried out overnight. The reaction was monitored by TLC until completion. 500 mL of water was added to the reaction solution, and a solid precipitated. The mixture was filtered by suction. The filter cake was washed with water and dried in a vacuum drying oven (45 °C, 12 h) to obtain a crude product (8.8 g). The crude product was subjected to column chromatography [DCM:MeOH = 20:1 (V / V)] to obtain tert-butyl 4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (Intermediate 4) (4.4 g, 39.4%), a white solid. HRMS (m / z): 592.2416 [M+H]+.

[0067] Preparation of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (Intermediate 5):

[0068] To a reaction flask containing tert-butyl 4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (Intermediate 4) (4.35 g, 1.0 eq) was added dropwise a mixed solvent of dichloromethane:trifluoroacetic acid = 4:1 (V / V) (45 mL). The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC and completed. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to adjust the pH to 8 - 9. A solid precipitated. It was filtered by suction. The filter cake was washed with water and dried in a vacuum drying oven (45 °C, 12 h) to obtain N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (Intermediate 5) (1.73 g, 48.1%), a brown solid, which was directly used in the next step without purification. HRMS (m / z): 492.1802 [M + H] + 。

[0069] Example 1: 1-(4-((4-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one

[0070]

[0071] Preparation of 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene (Intermediate 6):

[0072] Under nitrogen protection, 3-chloro-4-fluoroaniline (20 g, 1.0 eq) was dissolved in a three-necked flask containing N,N-dimethylformamide (200 mL). Cs2CO3 (96.8 g, 2.0 eq) and (3-fluorophenyl)methanol (17.4 g, 1.0 eq) were added successively. The temperature was raised to 80 °C and the reaction was carried out overnight. The reaction was monitored by TLC and completed. It was cooled to room temperature. Ice water (1 L) was added. A white solid precipitated. It was filtered by suction. The filter cake was washed with water and dried to obtain 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene (Intermediate 6) (26.8 g, 69.1%), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 9.2, 2.8 Hz, 1H), 7.48 (td, J = 9.3, 8.5, 2.9 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.21 (td, J = 8.7, 2.6 Hz, 1H), 5.41 (s, 2H). HRMS (m / z): 282.2931 [M + H] + 。

[0073] Preparation of 3-chloro-4-((3-fluorobenzyl)oxy)aniline (Intermediate 7):

[0074] Dissolve 3-chloro-4-((3-fluorobenzyl)oxy)aniline (26.7 g, 1.0 eq) in a mixed solvent of methanol (225 mL) and water (75 mL), add ammonium chloride (35.6 g, 7.0 eq), and add iron powder (26.5 g, 5.0 eq) in three portions with stirring under heating conditions. Heat up to 90 °C and reflux the reaction, stirring overnight. Monitor the completion of the reaction by TLC, cool to room temperature, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain 3-chloro-4-((3-fluorobenzyl)oxy)aniline (Intermediate 7) (718 g, 75.3%), an off-white solid. 1 HNMR (400 MHz, DMSO-d6) δ 7.48 (td, J = 8.0, 5.9 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.25 - 7.15 (m, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 6.52 (dd, J = 8.7, 2.7 Hz, 1H), 5.08 (s, 2H), 5.02 (s, 2H). HRMS (m / z): 252.0578 [M+H] + 。

[0075] Preparation of 4-((3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl acetate (Intermediate 8):

[0076] The preparation of Intermediate 8 refers to the synthesis method of Intermediate 2, where 3-chloro-4-(pyridin-2-ylmethoxy)aniline is replaced by Intermediate 7. HRMS (m / z): 467.9471 [M+H] + 。

[0077] Preparation of 4-((3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-ol (Intermediate 9):

[0078] The preparation of Intermediate 9 refers to the synthesis method of Intermediate 3. HRMS (m / z): 426.1516 [M+H] + 。

[0079] Preparation of tert-butyl 4-((4-((3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (Intermediate 10):

[0080] The preparation of Intermediate 10 refers to the synthesis method of Intermediate 4. 11H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.72 - 8.65 (m, 2H), 8.46 (s, 1H), 7.97 - 7.90 (m, 2H), 7.70 (dd, J = 9.0, 2.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.22 (s, 1H), 5.38 (s, 2H), 3.94 (s, 3H), 3.67 (dd, J = 13.4, 6.9 Hz, 2H), 3.26 (s, 2H), 1.98 (d, J = 10.0 Hz, 2H), 1.64 (d, J = 12.0 Hz, 2H), 1.42 (s, 9H). HRMS (m / z): 593.2106 [M + H] + 。

[0081] Preparation of N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (Intermediate 11):

[0082] The preparation of Intermediate 11 refers to the synthetic method of Intermediate 5. HRMS (m / z): 509.2158 [M + H] + 。

[0083] Preparation of 1-(4-((4-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Example 1):

[0084] The preparation of the compound of Example 1 refers to the synthetic method of Intermediate 6, replacing the base with 2 equivalents of triethylamine. 1 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.46 (s, 1H), 7.95 (d, J = 2.9 Hz, 2H), 7.69 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 (td, J = 8.0, 5.9 Hz, 1H), 7.35 - 7.16 (m, 5H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.69 (dd, J = 10.5, 2.5 Hz, 1H), 5.26 (s, 2H), 4.82 (dq, J = 7.5, 3.8 Hz, 1H), 3.94 (s, 3H), 3.87 (d, J = 11.2 Hz, 2H), 3.58 - 3.45 (m, 2H), 2.02 (s, 2H), 1.71 (s, 2H). HRMS (m / z): 563.1870 [M + H] + 。

[0085] Example 2: 1-(4-((4-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one

[0086]

[0087]

[0088] Preparation of 2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (Intermediate 12):

[0089] The preparation of Intermediate 12 refers to the synthesis method of Intermediate 6. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.4 Hz, 1H), 8.76 - 8.68 (m, 2H), 8.39 (d, J = 2.8 Hz, 1H), 8.28 (dd, J = 9.1, 2.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 5.58 (s, 2H). HRMS (m / z): 266.0032 [M+H] + 。

[0090] Preparation of 3-chloro-4-((3-fluorobenzyl)oxy)aniline (Intermediate 13):

[0091] The preparation of Intermediate 13 refers to the synthesis method of Intermediate 7. 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 1.5 Hz, 1H), 8.69 - 8.62 (m, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 6.48 (dd, J = 8.7, 2.7 Hz, 1H), 5.17 (s, 2H), 5.01 (s, 2H). HRMS (m / z): 236.9606 [M+H] + 。

[0092] Preparation of 4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl acetate (Intermediate 14):

[0093] The preparation of Intermediate 14 refers to the synthesis method of Intermediate 2, where 3-chloro-4-(pyridin-2-ylmethoxy)aniline is replaced by Intermediate 13. HRMS (m / z): 452.1489 [M+H] + 。

[0094] Preparation of 4 - ((3 - chloro - 4 - ((4 - fluorobenzyl)oxy)phenyl)amino)-7 - methoxyquinazolin - 6 - ol (Intermediate 15):

[0095] The preparation of Intermediate 15 refers to the synthesis method of Intermediate 3. HRMS (m / z): 410.1334 [M + H] + 。

[0096] Preparation of tert - butyl 4 - ((4 - ((3 - chloro - 4 - (pyrazin - 2 - ylmethoxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl)oxy)piperidine - 1 - carboxylate (Intermediate 16):

[0097] The preparation of Intermediate 16 refers to the synthesis method of Intermediate 4. 1 H NMR (400 MHz, DMSO - d6) δ 9.41 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.72 - 8.65 (m, 2H), 8.46 (s, 1H), 7.97 - 7.90 (m, 2H), 7.70 (dd, J = 9.0, 2.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.22 (s, 1H), 5.38 (s, 2H), 3.94 (s, 3H), 3.67 (dd, J = 13.4, 6.9 Hz, 2H), 3.26 (s, 2H), 1.98 (d, J = 10.0 Hz, 2H), 1.64 (d, J = 12.0 Hz, 2H), 1.42 (s, 9H). HRMS (m / z): 593.2106 [M + H] + 。

[0098] Preparation of N - (3 - chloro - 4 - (pyrazin - 2 - ylmethoxy)phenyl)-7 - methoxy - 6 - (piperidin - 4 - yloxy)quinazolin - 4 - amine (Intermediate 17):

[0099] The preparation of Intermediate 17 refers to the synthesis method of Intermediate 5. HRMS (m / z): 493.2154 [M + H] + 。

[0100] Preparation of 1 - (4 - ((4 - (3 - chloro - 4 - ((4 - fluorobenzyl)oxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl)oxy)-2 - methylpiperidin - 1 - yl)prop - 2 - en - 1 - one (Example 2):

[0101] The preparation of the compound of Example 2 refers to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1HNMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.87 (s, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.46 (s, 1H), 7.99 - 7.93 (m, 2H), 7.71 (dd, J = 9.0, 2.7 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.22 (s, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.27 - 6.13 (m, 1H), 6.14 - 6.03 (m, 1H), 5.69 (dd, J = 10.5, 2.5 Hz, 1H), 5.39 (s, 2H), 4.81 (tt, J = 7.5, 3.6 Hz, 1H), 3.94 (s, 3H), 3.51 (s, 4H), 2.06 - 2.00 (m, 2H), 1.71 (d, J = 11.9 Hz, 2H). HRMS (m / z): 547.1681 [M + H]+。

[0102] Example 3: 1-(4-((4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-fluoroprop-2-en-1-one

[0103] Preparation of 2-fluoropropanoyl chloride (Intermediate 18):

[0104]

[0105] Methacrylic acid (250 mg, 1.0 eq.) was dissolved in dichloromethane solution (2.5 mL) and added to a three-necked flask. Oxalyl chloride (383 mg, 1.1 eq.) in dichloromethane solution (4 mL) was added dropwise at 0 °C under nitrogen protection, and then a catalytic amount of N,N-dimethylformamide was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, it was concentrated under reduced pressure to obtain 2-fluoropropanoyl chloride, a yellow solid, which was directly used in the next step without purification.

[0106] Preparation of 1-(4-((4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-fluoroprop-2-en-1-one (Example 3):

[0107]

[0108] For the preparation of Example 3, referring to the synthesis method of Intermediate 6, acryloyl chloride was replaced with Intermediate 18, and the base was replaced with 2 equivalents of triethylamine. 11H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.61 (dd, J = 5.0, 1.7 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J = 2.2 Hz, 2H), 7.89 (td, J = 7.7, 1.8 Hz, 1H), 7.68 (dd, J = 8.9, 2.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.5, 4.9 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 5.36 - 5.23 (m, 4H), 4.84 (dp, J = 7.2, 3.5 Hz, 1H), 3.95 (s, 3H), 3.80 (ddd, J = 12.3, 7.7, 3.9 Hz, 2H), 3.54 (ddd, J = 12.5, 7.8, 3.5 Hz, 2H), 2.10 - 2.03 (m, 2H), 1.78 (s, 2H). HRMS (m / z): 564.1910 [M+H] + 。

[0109] Example 4: 1-(4-((4-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-fluoroprop-2-en-1-one

[0110]

[0111] For the preparation of Example 4, refer to the synthesis method of Intermediate 6, replace acryloyl chloride with Intermediate 18, and replace the base with 2 equivalents of triethylamine. 1 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.47 (s, 1H), 8.03 - 7.96 (m, 2H), 7.72 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 (td, J = 8.0, 6.0 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 - 7.22 (m, 2H), 7.19 (ddd, J = 10.3, 8.0, 2.6 Hz, 1H), 5.35 - 5.27 (m, 2H), 5.26 (s, 2H), 4.88 (tt, J = 7.3, 3.6 Hz, 1H), 3.95 (s, 3H), 3.83 (dd, J = 14.4, 6.7 Hz, 2H), 3.55 (d, J = 10.5 Hz, 2H), 2.11 - 2.04 (m, 2H), 1.77 (s, 2H). HRMS (m / z): 581.2318 [M+H] + 。

[0112] Example 5: 1-(4-((4-(3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-fluoroprop-2-en-1-one

[0113]

[0114] For the preparation of Example 5, refer to the synthesis method of Intermediate 6, replace acryloyl chloride with Intermediate 18, and replace the base with 2 equivalents of triethylamine. 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (d, J = 1.4 Hz, 1H), 8.69 (dd, J = 12.8, 2.2 Hz, 2H), 8.47 (s, 1H), 8.00 - 7.94 (m, 2H), 7.72 (dd, J = 9.0, 2.6 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 5.39 (s, 2H), 5.33 - 5.15 (m, 2H), 4.84 (tt, J = 7.1, 3.5 Hz, 1H), 3.95 (s, 3H), 3.80 (ddd, J = 12.4, 7.6, 3.7 Hz, 2H), 3.58 - 3.49 (m, 2H), 2.06 (s, 2H), 1.78 (s, 2H). HRMS (m / z): 565.1766 [M + H] + 。

[0115] Example 6: 1-(4-((4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one

[0116]

[0117]

[0118] Preparation of tert-butyl (R)-4-(chlorocarbonyl)-3-methylpiperazine-1-carboxylate (Intermediate 19):

[0119] Under nitrogen protection at 0 °C, bis(trichloromethyl) carbonate (1.0 eq.) and dichloromethane (15 mL) were added to a three-necked flask, and then pyridine (3.0 eq.) and a dichloromethane (5 mL) solution of tert-butyl (R)-3-methylpiperazine-1-carboxylate (B-1, 1.36 g, 1.0 eq.) were added in sequence. The reaction was carried out overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure to obtain tert-butyl (R)-4-(chlorocarbonyl)-3-methylpiperazine-1-carboxylate (Intermediate 19), a yellow solid. It was used directly in the next step without purification.

[0120] Preparation of 4-(tert-butyl)-1-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)(R)-2-methylpiperazine-1,4-dicarboxylate (Intermediate 20):

[0121] Dissolve Intermediate 3 (6 g, 1.0 eq) in a three-necked flask containing N,N-dimethylformamide (60 mL), add potassium carbonate (6.1 g, 3.0 eq), and add Intermediate 19 () = 4.6 g, 1.2 eq) under nitrogen protection. React at room temperature overnight. Monitor the completion of the reaction by TLC. Add water (400 mL) to the reaction solution. A solid precipitates. Filter by suction. Wash the filter cake with water and dry it in a vacuum drying oven (45 °C, 12 h) to obtain 4-(tert-butyl)-1-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)(R)-2-methylpiperazine-1,4-dicarboxylate (Intermediate 20) (7.9 g, 84.4%), a brown solid. Proceed to the next step without purification. HRMS (m / z): 635.2681 [M+H] + 。

[0122] Preparation of 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-2-methylpiperazine-1-carboxylate (Intermediate 21):

[0123] The preparation of Intermediate 21 refers to the preparation method of Synthesis Method 5. HRMS (m / z): 535.2288 [M+H] + 。

[0124] Preparation of 1-(4-((4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Example 6):

[0125] The preparation of Example 6 refers to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 11H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.64 - 8.53 (m, 2H), 8.31 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.88 (td, J = 7.7, 1.9 Hz, 1H), 7.72 (dd, J = 9.0, 2.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.41 - 7.23 (m, 3H), 6.85 (q, J = 13.9 Hz, 1H), 6.20 (d, J = 16.6 Hz, 1H), 5.78 - 5.73 (m, 1H), 5.29 (s, 2H), 4.60 - 4.03 (m, 3H), 4.01 (s, 1H), 3.94 (s, 3H), 3.47 (d, J = 13.9 Hz, 2H), 2.99 (d, J = 66.5 Hz, 1H), 1.23 (s, 3H). HRMS (m / z): 588.19 [M + H] + 。

[0126] Example 7: 4 - ((3 - chloro - 4 - ((5 - fluoropyridin - 2 - yl)methoxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl (R)-4 - acryloyl - 2 - methylpiperazine - 1 - carboxylate

[0127]

[0128] Preparation of 4 - (tert - butyl) 1 - (4 - ((3 - chloro - 4 - ((4 - fluorobenzyl)oxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl)(R)-2 - methylpiperazine - 1,4 - dicarboxylate (Intermediate 23):

[0129] The preparation of Intermediate 23 refers to the preparation of Intermediate 20. HRMS (m / z): 652.2827 [M + H] + 。

[0130] Preparation of 4 - ((3 - chloro - 4 - ((4 - fluorobenzyl)oxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl (R)-2 - methylpiperazine - 1 - carboxylate (Intermediate 24):

[0131] The preparation of Intermediate 24 refers to the preparation of Intermediate 5. HRMS (m / z): 552.2260 [M + H]+.

[0132] Preparation of 4 - ((3 - chloro - 4 - ((5 - fluoropyridin - 2 - yl)methoxy)phenyl)amino)-7 - methoxyquinazolin - 6 - yl (R)-4 - acryloyl - 2 - methylpiperazine - 1 - carboxylate (Example 7):

[0133] The preparation of Example 7 refers to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.56(s,1H),8.31(s,1H),8.06(d,J=2.6Hz,1H),7.73(dd,J=9.0,2.6Hz,1H),7.47(td,J=8.0,6.0Hz,1H),7.35-7.29(m,3H),7.25(d,J=9.0Hz,1H),7.18(td,J=8.8,2.6Hz,1H),6.86(td,J=16.2,10.3Hz,1H),6.20(dd,J=16.9,5.9Hz,1H),5.78-5.74(m,1H),5.25(s,2H),4.36(dd,J=45.6,13.4Hz,2H),3.99(d,J=13.8Hz,1H),3.94(s,3H),3.47(d,J=14.0Hz,2H),3.29-2.86(m,2H),1.22(s,3H).HRMS(m / z):606.2007[M+H] + 。

[0134] Example 8: 4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-4-acryloyl-2-methylpiperazine-1-carboxylate

[0135]

[0136] Preparation of 4-(tert-butyl) 1-(4-((3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)(R)-2-methylpiperazine-1,4-dicarboxylate (Intermediate 26):

[0137] The preparation of Intermediate 26 refers to the synthesis method of Intermediate 20. HRMS(m / z):636.2162[M+H] + 。

[0138] Preparation of 4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-2-methylpiperazine-1-carboxylate (Intermediate 27):

[0139] The preparation of Intermediate 26 refers to the synthesis method of Intermediate 5. HRMS(m / z):536.2000[M+H] + 。

[0140] Preparation of 4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-4-acryloyl-2-methylpiperazine-1-carboxylate (Example 8):

[0141] For the preparation of Example 8, refer to the synthesis method of Intermediate 6, and replace the base with 2 equivalents of triethylamine. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.64 - 8.51 (m, 2H), 8.32 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.89 (td, J = 7.7, 1.8 Hz, 1H), 7.72 (dd, J = 9.0, 2.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41 - 7.22 (m, 3H), 5.40 - 5.21 (m, 4H), 4.44 (d, J = 71.6 Hz, 1H), 3.95 (s, 3H), 3.01 (s, 6H), 1.20 (d, J = 23.4 Hz, 3H). HRMS (m / z): 590.1628 [M+H] + 。

[0142] Example 9: 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-4-(2-fluoropropenoyl)-2-methylpiperazine-1-carboxylate

[0143]

[0144] For the preparation of Example 9, refer to the synthesis method of Example 3. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.64 - 8.51 (m, 2H), 8.32 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.89 (td, J = 7.7, 1.8 Hz, 1H), 7.72 (dd, J = 9.0, 2.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41 - 7.22 (m, 3H), 5.40 - 5.21 (m, 4H), 4.44 (d, J = 71.6 Hz, 1H), 3.95 (s, 3H), 3.01 (s, 6H), 1.23 (s, 3H). HRMS (m / z): 607.1771 [M+H] + 。

[0145] Example 10: 4-((3-chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-4-(2-fluoropropenoyl)-2-methylpiperazine-1-carboxylate

[0146]

[0147] The preparation of Example 10 refers to the synthesis method of Reference Example 3. 1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.56(s,1H),8.31(s,1H),8.06(d,J=2.6Hz,1H),7.73(dd,J=9.0,2.6Hz,1H),7.47(td,J=8.0,6.0Hz,1H),7.36-7.14(m,5H),5.41-5.22(m,4H),4.53(s,1H),3.95(s,3H),2.81(d,J=63.0Hz,6H),1.28-1.18(m,3H).HRMS(m / z):624.1536[M+H] + 。

[0148] Example 11: 4-((3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl (R)-4-(2-fluoropropenoyl)-2-methylpiperazine-1-carboxylate

[0149]

[0150] The preparation of Example 11 refers to the synthesis method of Reference Example 3. 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.87(d,J=1.5Hz,1H),8.72-8.64(m,2H),8.57(s,1H),8.32(s,1H),8.08(d,J=2.6Hz,1H),7.76(dd,J=9.0,2.6Hz,1H),7.35-7.30(m,2H),5.44-5.29(m,4H),4.52(s,1H),3.95(s,3H),3.18(d,J=5.0Hz,6H),1.23(s,3H).HRMS(m / z):608.1346[M+H] + 。

[0151] Example 12: 1-(4-((4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one

[0152] Preparation of tert-butyl 2-methyl-4-(toluoyloxy)piperidine-1-carboxylate (Intermediate 28):

[0153]

[0154] Dissolve tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (2 g, 1.0 eq) in dichloromethane (20 mL). Sequentially add triethylamine (2.8 g, 3.0 eq) and DMAP (114 mg, 0.1 eq). At 0 °C, add p-toluenesulfonyl chloride (1.77 g, 1.0 eq) in three portions. Under nitrogen protection, stir at room temperature overnight. Monitor the reaction completion by TLC. Concentrate the reaction solution under reduced pressure to obtain a crude white solid (3.1 g). After column chromatography [DCM:MeOH = 10:1 (v / v)], obtain tert-butyl 2-methyl-4-(tosyloxy)piperidine-1-carboxylate (Intermediate 28) (2.5 g, 72.8%), a light pink solid. HRMS (m / z): 392.1988 [M+Na] + 。

[0155]

[0156] Preparation of tert-butyl 4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidine-1-carboxylate (Intermediate 29):

[0157] The synthesis of Intermediate 29 was carried out with reference to the synthesis method of Intermediate 4. HRMS (m / z): 606.2643 [M+H] + 。

[0158] Preparation of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxy-6-((2-methylpiperidin-4-yl)oxy)quinazolin-4-amine (Intermediate 30):

[0159] The synthesis of Intermediate 30 was carried out with reference to the synthesis method of Intermediate 5. HRMS (m / z): 506.2109 [M+H] + 。

[0160] Preparation of 1-(4-((4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one (Example 12):

[0161] The synthesis of Example 12 was carried out with reference to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.45 (s, 1H), 7.95 - 7.88 (m, 2H), 7.67 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (td, J = 8.0, 5.9 Hz, 1H), 7.39 - 7.20 (m, 5H), 6.82 (dd, J = 16.7, 10.5 Hz, 1H), 6.11 (dd, J = 16.6, 2.6 Hz, 1H), 5.67 (dd, J = 10.4, 2.5 Hz, 1H), 5.26 (s, 2H), 5.01 (t, J = 3.2 Hz, 1H), 4.57 (s, 1H), 3.95 (s, 4H), 2.14 - 1.84 (m, 4H), 1.78 (s, 1H), 1.35 (d, J = 6.9 Hz, 3H). HRMS (m / z): 560.2066 [M+H] + 。

[0162] Example 13: 1-(4-((4-(3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one

[0163]

[0164] Preparation of tert-Butyl 4-((4-((3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidine-1-carboxylate (Intermediate 31):

[0165] The synthesis of Intermediate 31 was carried out according to the synthetic method of Intermediate 4. HRMS (m / z): 623.3984 [M+H] + 。

[0166] Preparation of N-(3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)-7-methoxy-6-((2-methylpiperidin-4-yl)oxy)quinazolin-4-amine (Intermediate 32)

[0167] The synthesis of Intermediate 32 was carried out according to the synthetic method of Intermediate 5. HRMS (m / z): 523.1992 [M+H] + 。

[0168] Preparation of 1-(4-((4-(3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one (Example 13):

[0169] The synthesis of Example 13 was carried out according to the synthetic method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine.1 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.45 (s, 1H), 7.96 - 7.87 (m, 2H), 7.67 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (td, J = 8.0, 5.9 Hz, 1H), 7.38 - 7.21 (m, 5H), 6.82 (dd, J = 16.7, 10.5 Hz, 1H), 6.11 (dd, J = 16.6, 2.6 Hz, 1H), 5.67 (dd, J = 10.4, 2.5 Hz, 1H), 5.26 (s, 2H), 5.01 (t, J = 3.2 Hz, 1H), 4.57 (s, 1H), 3.95 (s, 4H), 2.21 - 1.84 (m, 4H), 1.78 (s, 1H), 1.35 (d, J = 6.9 Hz, 3H). HRMS (m / z): 581.2318 [M + H] + 。

[0170] Example 14: 1-(4-((4-(3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one

[0171]

[0172] Preparation of tert-Butyl 4-((4-((3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidine-1-carboxylate (Intermediate 33):

[0173] The synthesis of Intermediate 33 was carried out with reference to the synthesis method of Intermediate 4. HRMS (m / z): 607.1998 [M + H] + 。

[0174] Preparation of N-(3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl)-7-methoxy-6-((2-methylpiperidin-4-yl)oxy)quinazolin-4-amine (Intermediate 34):

[0175] The synthesis of Intermediate 34 was carried out with reference to the synthesis method of Intermediate 5. HRMS (m / z): 507.1949 [M + H]+.

[0176] Preparation of 1-(4-((4-(3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-methylpiperidin-1-yl)prop-2-en-1-one (Example 14):

[0177] The synthesis of Example 14 was carried out with reference to the synthesis method of Example 1. 11H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (d, J = 1.4 Hz, 1H), 8.71 (t, J = 2.0 Hz, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.91 (s, 1H), 7.71 (dd, J = 8.9, 2.6 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.87 - 6.79 (m, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.68 (dd, J = 10.4, 2.5 Hz, 1H), 5.39 (s, 2H), 5.05 - 4.99 (m, 1H), 3.95 (s, 3H), 3.93 (s, 1H), 2.51 (p, J = 1.9 Hz, 2H), 2.19 - 1.84 (m, 4H), 1.35 (d, J = 7.0 Hz, 3H). HRMS (m / z): 561.2033 [M + H] + 。

[0178] Example 15: N-(7-(2-Morpholinoethoxy)-4-(quinolin-6-ylamino)quinazolin-6-yl)acrylamide

[0179]

[0180] Preparation of 4-(1,4-dioxopyrido[4.5]dec-7-en-8-yl)pyridine (Intermediate 35):

[0181] The preparation of Intermediate 35 was carried out according to the synthetic method of Intermediate 1.

[0182] Preparation of 7-fluoro-6-nitro-N-(quinolin-6-yl)quinazolin-4-amine (Intermediate 36):

[0183] The preparation of Intermediate 36 was carried out according to the synthetic method of Intermediate 2, replacing 3-chloro-4-(pyridin-2-ylmethoxy)aniline with quinolin-6-amine. HRMS (m / z): 336.1103 [M + H] + 。

[0184] Preparation of 7-(2-Morpholinoethoxy)-6-nitro-N-(quinolin-6-yl)quinazolin-4-amine (Intermediate 37):

[0185] Intermediate 36 (3 g, 1.0 eq) was dissolved in DMF (30 mL). NaH (0.3 g, 2.0 eq) was added at 0 °C. After stirring for 30 min, 2-morpholinoethanol (1.76 g, 1.5 eq) was added under nitrogen protection. The reaction mixture was transferred to room temperature and reacted overnight. The reaction was monitored by TLC. After completion of the reaction, water (180 mL) was added to the reaction solution, and a solid precipitated. The solid was filtered by suction, and the filter cake was washed with water and dried in a vacuum drying oven (45 °C, 24 h) to obtain 7-(2-morpholinoethoxy)-6-nitro-N-(quinolin-6-yl)quinazolin-4-amine (Intermediate 37) (3.71 g, 93%) as a red solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.32 (s, 1H), 8.84 (d, J = 4.2 Hz, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 4.7 Hz, 2H), 4.44 (t, J = 5.6 Hz, 2H), 3.58 (t, J = 4.7 Hz, 4H), 2.78 (t, J = 5.5 Hz, 2H), 2.51 (s, 4H). HRMS (m / z): 447.1833 [M+H] + 。

[0186] Preparation of 7-(2-morpholinoethoxy)-N 4 -(quinolin-6-yl)quinazolin-4,6-diamine (Intermediate 38):

[0187] Intermediate 37 (3.65 g, 1.0 eq) was dissolved in a solution of methanol:water = (225 mL:75 mL). Ammonium chloride (3.06 g, 7.0 eq) solid was added. Under heating and stirring at 80 °C, iron powder (2.25 g, 5.0 eq) was added in three portions. The reaction mixture was refluxed at 80 °C overnight. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the diatomaceous earth was washed with dichloromethane:methanol = 10:1. The filtrate obtained by concentrating under reduced pressure was separated and purified by silica gel column chromatography to obtain a brown solid (2.99 g, 87.7%). HRMS (m / z): 417.3158 [M+H] + 。

[0188] Preparation of N-(7-(2-morpholinoethoxy)-4-(quinolin-6-ylamino)quinazolin-6-yl)acrylamide (Example 15):

[0189] For the preparation of Example 15, refer to the synthesis method of Intermediate 6, and the base was replaced with 2 equivalents of triethylamine. ESI-MS m / z: 392.2 [M+H]+ .

[0190] Example 16: N-(7-(2-(Piperidin-1-yl)ethoxy)-4-(quinolin-6-ylamino)quinazolin-6-yl)acrylamide

[0191] Preparation of 6-nitro-7-(2-(piperidin-1-yl)ethoxy)-N-(quinolin-6-yl)quinazolin-4-amine (Intermediate 39):

[0192] The preparation of Intermediate 39 refers to the synthesis method of Intermediate 37. 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.32 (s, 1H), 8.84 (d, J = 4.3 Hz, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.52 (d, J = 9.4 Hz, 2H), 4.41 (t, J = 5.7 Hz, 2H), 2.74 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 5.5 Hz, 4H), 1.49 (p, J = 5.6 Hz, 4H), 1.40 - 1.36 (m, 2H). HRMS (m / z): 445.2557 [M + H] + .

[0193] 7-(2-(Piperidin-1-yl)ethoxy)-N 4 -(quinolin-6-yl)quinazolin-4,6-diamine (Intermediate 40) Preparation:

[0194] The preparation of Intermediate 40 refers to the synthesis method of Intermediate 38. HRMS (m / z): 415.3186 [M + H] + .

[0195] Preparation of N-(7-(2-(piperidin-1-yl)ethoxy)-4-(quinolin-6-ylamino)quinazolin-6-yl)acrylamide (Example 16):

[0196] The preparation of Example 16 refers to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 11H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (s, 1H), 8.99 (s, 1H), 8.81 (dd, J = 4.2, 1.7 Hz, 1H), 8.59 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 8.5, 1.6 Hz, 1H), 8.20 (dd, J = 9.1, 2.4 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.36 (s, 1H), 6.72 (dd, J = 17.0, 10.2 Hz, 1H), 6.33 (dd, J = 17.1, 1.9 Hz, 1H), 5.83 (dd, J = 10.1, 2.0 Hz, 1H), 4.35 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.49 (s, 4H), 1.51 (p, J = 5.5 Hz, 4H), 1.39 (q, J = 6.0 Hz, 2H). HRMS (m / z): 469.2755 [M+H] + 。

[0197] Example 17: Preparation of N-(7-(2-Morpholinoethoxy)-4-(naphthalen-2-ylamino)quinazolin-6-yl)acrylamide

[0198] Preparation of 7-Fluoro-N-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (Intermediate 41):

[0199] The preparation of Intermediate 41 was carried out according to the synthetic method of Intermediate 36, replacing 3-chloro-4-(pyridin-2-ylmethoxy)aniline with naphthalen-2-amine. HRMS (m / z): 335.0960 [M+H] + 。

[0200] Preparation of 7-(2-Morpholinoethoxy)-N-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (Intermediate 42):

[0201] The preparation of Intermediate 42 was carried out according to the synthetic method of Intermediate 37. 11H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.31 (s, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 7.98 - 7.86 (m, 4H), 7.49 (h, J = 7.2 Hz, 3H), 4.41 (t, J = 5.6 Hz, 2H), 3.58 (t, J = 4.5 Hz, 4H), 2.76 (t, J = 5.6 Hz, 2H), 2.51 (t, J = 4.1 Hz, 4H). HRMS (m / z):

[0202] 446.0395 [M+H] + 。

[0203] Preparation of 7-(2-morpholinoethoxy)-N4-(naphthalen-2-yl)quinazoline-4,6-diamine (Intermediate 43):

[0204] The preparation of Intermediate 43 was carried out with reference to the synthesis method of Intermediate 38. HRMS (m / z): 416.2068 [M+H] + 。

[0205] Preparation of N-(7-(2-morpholinoethoxy)-4-(naphthalen-2-ylamino)quinazolin-6-yl)acrylamide (Example 17):

[0206] The preparation of Example 17 was carried out with reference to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.70 (s, 1H), 8.97 (s, 1H), 8.58 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.00 - 7.83 (m, 4H), 7.47 (dt, J = 25.5, 7.2 Hz, 2H), 7.35 (s, 1H), 6.72 (dd, J = 17.0, 10.2 Hz, 1H), 6.34 (dd, J = 17.0, 2.0 Hz, 1H), 5.84 (dd, J = 10.0, 2.0 Hz, 1H), 4.36 (t, J = 5.7 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.84 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.4 Hz, 4H). HRMS (m / z): 470.1047 [M+H] + 。

[0207] Example 18: N-(4-(naphthalen-2-ylamino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide

[0208] Preparation of N-(naphthalen-2-yl)-6-nitro-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-amine (Intermediate 44):

[0209] The preparation of Intermediate 44 was carried out with reference to the synthetic method of Intermediate 39. 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.30 (s, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 7.98 - 7.84 (m, 4H), 7.49 (h, J = 7.1 Hz, 3H), 4.39 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.46 (t, J = 5.5 Hz, 4H), 1.49 (p, J = 5.3 Hz, 4H), 1.38 (q, J = 5.6 Hz, 2H). HRMS (m / z): 444.2029 [M+H] + 。

[0210] Preparation of 7-(2-morpholinoethoxy)-N4-(naphthalen-2-yl)quinazoline-4,6-diamine (Intermediate 45):

[0211] The preparation of Intermediate 45 was carried out with reference to the synthetic method of Intermediate 38. HRMS (m / z): 417.2522 [M+H] + 。

[0212] Preparation of N-(4-(naphthalen-2-ylamino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide (Example 18):

[0213] The preparation of Example 18 was carried out with reference to the synthetic method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.74 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.98 - 7.84 (m, 4H), 7.52 - 7.40 (m, 2H), 7.34 (s, 1H), 6.74 (dd, J = 17.0, 10.3 Hz, 1H), 6.33 (dd, J = 17.0, 2.0 Hz, 1H), 5.83 (dd, J = 10.1, 2.0 Hz, 1H), 4.34 (t, J = 5.8 Hz, 2H), 2.82 (s, 2H), 1.52 (p, J = 5.3 Hz, 4H), 1.39 (q, J = 5.9 Hz, 2H). HRMS (m / z): 468.1262 [M+H] + 。

[0214] Example 19: N-(4-((1-Methyl-1H-indol-6-yl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)acrylamide

[0215] Preparation of 1-Methyl-6-nitro-1H-indole (Intermediate 47):

[0216] Compound 6-Nitro-1H-indole (1 g, 1.0 eq) was dissolved in DMF (10 mL), potassium carbonate (2.56 g, 3.0 eq) and methyl iodide (1.3 g, 1.5 eq) were added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until completion. Water was added to the reaction solution, and a solid precipitated. The solid was filtered by suction, and the filtrate was washed with water and dried in a vacuum drying oven (45 °C, 12 h) to obtain 1-Methyl-6-nitro-1H-indole (Intermediate 47) (1.07 g, 98.7%), a yellow solid.

[0217] Preparation of 1-Methyl-1H-indol-6-amine (Intermediate 48):

[0218] Intermediate 47 (1 g, 1.0 eq) was dissolved in methanol (10 mL) solution, palladium on carbon (100 mg, 0.1 eq) was added, and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by TLC until completion. The filtrate was filtered through diatomaceous earth and concentrated under reduced pressure to obtain 1-Methyl-1H-indol-6-amine (Intermediate 48) (686 mg, 82.7%), a yellow solid. HRMS (m / z): 147.0398 [M+H] + 。

[0219] Preparation of 7-Fluoro-N-(1-methyl-1H-indol-6-yl)-6-nitroquinazolin-4-amine (Intermediate 49):

[0220] The preparation of Intermediate 49 was carried out with reference to the synthesis method of Intermediate 36. HRMS (m / z): 336.1103 [M+H] + 。

[0221] Preparation of N-(1-Methyl-1H-indol-6-yl)-7-(2-morpholinoethoxy)-6-nitroquinazolin-4-amine (Intermediate 50):

[0222] The preparation of Intermediate 50 was carried out with reference to the synthesis method of Intermediate 37. 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.28 (s, 1H), 8.57 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 4.42 (t, J = 5.5 Hz, 2H), 3.79 (s, 3H), 3.58 (t, J = 4.6 Hz, 4H), 2.78 (t, J = 5.5 Hz, 2H), 2.52 (s, 4H). HRMS (m / z): 449.2531 [M+H] + 。

[0223] N 4 Preparation of N-(1-methyl-1H-indol-6-yl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine (Intermediate 51):

[0224] The preparation of Intermediate 51 was carried out with reference to the synthetic method of Intermediate 38. HRMS (m / z): 419.2456 [M+H] + 。

[0225] Preparation of N-(4-((1-methyl-1H-indol-6-yl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)acrylamide (Example 19):

[0226] The preparation of Example 19 was carried out with reference to the synthetic method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.70 (s, 1H), 8.97 (s, 1H), 8.58 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.00 - 7.83 (m, 4H), 7.47 (dt, J = 25.5, 7.2 Hz, 2H), 7.35 (s, 1H), 6.72 (dd, J = 17.0, 10.2 Hz, 1H), 6.34 (dd, J = 17.0, 2.0 Hz, 1H), 5.84 (dd, J = 10.0, 2.0 Hz, 1H), 4.36 (t, J = 5.7 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.84 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.4 Hz, 4H). HRMS: (m / z): 473.1913 [M+H] + 。

[0227] Example 20: N-(4-((1-Methyl-1H-indol-6-yl)amino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide

[0228]

[0229] Preparation of N-(1-Methyl-1H-indol-6-yl)-6-nitro-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-amine (Intermediate 52):

[0230] The preparation of Intermediate 52 was carried out with reference to the synthesis method of Intermediate 39. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.28 (s, 1H), 8.58 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.40 (dd, J = 8.5, 1.8 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 6.42 (d, J = 3.1 Hz, 1H), 4.39 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.46 (t, J = 5.4 Hz, 4H), 1.49 (p, J = 5.5 Hz, 4H), 1.38 (q, J = 6.8, 6.2 Hz, 2H). HRMS (m / z): 447.2029 [M+H] + 。

[0231] N 4 -(1-Methyl-1H-indol-6-yl)-7-(2-morpholinoethoxy)quinazolin-4,6-diamine (Intermediate 53) was prepared as follows

[0232] The preparation of Intermediate 53 was carried out with reference to the synthesis method of Intermediate 38. HRMS (m / z): 419.2456 [M+H] + 。

[0233] Preparation of N-(4-((1-Methyl-1H-indol-6-yl)amino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide (Example 20):

[0234] The preparation of Example 20 was carried out with reference to the synthesis method of Intermediate 6, with the base replaced by 2 equivalents of triethylamine. 11H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.64 (s, 1H), 8.92 (s, 1H), 8.46 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 1.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 2H), 6.70 (dd, J = 17.0, 10.2 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 6.32 (dd, J = 16.9, 2.0 Hz, 1H), 5.82 (dd, J = 10.3, 2.0 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 3.78 (s, 3H), 2.80 (t, J = 5.8 Hz, 2H), 2.48 (t, J = 4.3 Hz, 4H), 1.49 (q, J = 5.6 Hz, 4H), 1.38 (q, J = 5.9 Hz, 2H). HRMS (m / z): 471.2119 [M+H] + 。

[0235] Example 21

[0236]

[0237] 1 1H NMR δ 8.07 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 9.0, 2.6 Hz, 1H), 7.46 (td, J = 8.0, 6.0 Hz, 1H), 7.36 - 7.29 (m, 3H), 7.24 (d, J = 9.0 Hz, 1H), 7.18 (td, J = 8.8, 2.6 Hz, 1H), 6.87 (td, J = 16.2, 10.3 Hz, 1H), 6.21 (dd, J = 16.9, 5.9 Hz, 1H), 5.78 - 5.75 (m, 1H), 5.24 (s, 2H), 4.35 (dd, J = 45.6, 13.4 Hz, 2H), 3.99 (d, J = 13.8 Hz, 1H), 3.95 (s, 3H), 3.46 (d, J = 14.0 Hz, 2H), 3.28 - 2.86 (m, 2H), 2.20 (s, 3H), 2.17 - 2.55 (m, 4H), 1.25 (s, 3H). MS: (m / z): 589.21 [M+H] + 。

[0238] Example 22

[0239]

[0240] 11H NMR δ 8.08 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 9.0, 2.6 Hz, 1H), 7.46 (td, J = 8.0, 6.0 Hz, 1H), 7.37 - 7.28 (m, 3H), 7.25 (d, J = 9.0 Hz, 1H), 7.17 (td, J = 8.8, 2.6 Hz, 1H), 6.86 (td, J = 16.2, 10.3 Hz, 1H), 6.22 (dd, J = 16.9, 5.9 Hz, 1H), 5.78 - 5.74 (m, 1H), 5.24 (s, 2H), 4.35 (dd, J = 45.6, 13.4 Hz, 2H), 3.99 (d, J = 13.8 Hz, 1H), 3.97 (s, 3H), 3.46 (d, J = 14.0 Hz, 2H), 3.29 - 2.86 (m, 2H), 2.21 (s, 3H), 2.17 - 2.54 (m, 4H), 1.24 (s, 3H). MS: (m / z): 588.22 [M + H] + 。

[0241] Example 23 Biological Activity Assay

[0242] To determine the inhibitory effect of the compounds of the present invention on the EGFR (L858R + T790M) mutant kinase:

[0243] Operation procedure:

[0244] (1) Prepare 1×Kinase buffer.

[0245] (2) Preparation of compound concentration gradients: Dilute the compound to 100 times the highest inhibitor concentration finally required in the reaction, and dilute with 100% DMSO. Transfer 100 μl of this compound dilution to the wells in a 96-well plate. Add 100 μl of 100% DMSO to two empty wells for compound-free control and enzyme-free control in the same 96-well plate. Label the plate as the source plate. Transfer 40 μL of the compound from the source plate to a new 384-well echo plate as the intermediate plate. Transfer 100 nL of each well from the 384-well echo plate to the 384-well assay plate by echo.

[0246] (3) Add 5 μL of kinase solution to each well of the assay plate, except for the wells without enzyme (add 5 μL of 1x kinase buffer).

[0247] (4) Prepare a substrate solution of substrate and ATP in 1x kinase reaction buffer at a concentration 2 times the final concentration of each reagent required in the assay.

[0248] (5) Add 5 μL of substrate solution to each well of the assay plate.

[0249] (6) Incubate the 384-well assay plate at room temperature for 30 minutes or 60 minutes.

[0250] (7) Prepare detection solutions of the kinase quenching buffer and the antibody at 2-fold the final concentration required for each reagent in the Lance detection buffer.

[0251] (8) Add 10 μL of the detection solution at room temperature for 60 minutes.

[0252] Data (500 nM) on the activity assays of the examples of the present invention and reference compounds are listed in Table 1. The results are shown in Table 1.

[0253] Table 1 Data on the determination of the inhibitory rate of EGFR (L858R + T790M) mutant kinase

[0254] Test article Inhibitory rate of test article (@500 nM) BDTX-189 93.1％±1.1％ Example 1 94.4％±0.4％ Example 2 94.3％±0.4％ Example 11 94.7％±2.1％ Example 12 81.9％±2.7％ Example 14 80.4％±1.1％ Example 15 84.8％±0.8％ Example 17 96.7％±1.1％ Example 18 84.7％±0.5％ Example 19 97.1％±1.6％ Example 20 87.1％±1.6％ Example 21 98.2％±1.1％ Example 22 98.9％±1.2％

[0255] Determine the anti-proliferative effect of the compounds of the present invention in combination with cetuximab on human lung adenocarcinoma cells (NCI-H1975 cells):

[0256] Operation procedure:

[0257] (1) Prepare 1640 complete medium, and the preparation ratio is as follows: 89% of 1640 basal medium, 10% of fetal bovine serum, and 1% of double antibodies.

[0258] (2) Prepare a 5 mM stock solution of the test compound with cell-grade DMSO and store it in a 4 °C refrigerator for later use.

[0259] (3) After quickly thawing the cryopreserved NCI-H1975 cells in a 37 °C constant temperature water bath, transfer them to a centrifuge tube containing 5 mL of complete culture medium, centrifuge at 1000 r for 5 min, resuspend them into a single-cell suspension, and then culture them in a T25 culture flask. Passage the cells when the cell density reaches 80%. The passage method is as follows: rinse with PBS buffer, digest with 2 mL of trypsin for 3 min, add 6 mL of complete culture medium to stop digestion and transfer it to a 15 mL centrifuge tube, centrifuge at 1000 r for 5 min, pour off the supernatant, add 5 mL of complete culture medium, blow it evenly, and then transfer it to a T25 culture flask for continued culture.

[0260] (4) Take the cells in the logarithmic growth phase, make them into a suspension and count, dilute them to 8000 cells / well, plate them in a 96-well plate, 100 μL per well, and culture them in a 37 °C constant temperature incubator for 24 h. After the cells adhere, aspirate the remaining culture medium in each well, add the test compound and cetuximab (1 μg / mL) diluted with the culture medium to different concentrations (9 concentrations), and at the same time set up a blank control group (only add complete culture medium) and a positive control group (add cells and culture medium, without adding drugs), and incubate them in the incubator for 72 h.

[0261] (5) Use the CCK-8 reagent. Add 10 μL of the CCK-8 reagent to each well. After culturing in an incubator for 2 - 4 h, shake the plate (for 4 min) in a microplate reader, and measure the fluorescence (OD) value of each well at 450 nm.

[0262] (6) Use Graphpad Prism 5 software to calculate the IC 50 value according to the following formula:

[0263]

[0264] The data of the cell anti-proliferation activities of the examples of the present invention and the reference compounds are listed in Table 2. The results are shown in Table 2.

[0265] Table 2 Determination results of cell anti-proliferation activities of examples and reference compounds

[0266] Test article <![CDATA[Test article + Cetuximab NCI-H1975 IC 50 (nM)]]> BDTX-189 13.2 Example 1 7.6 Example 2 9.1 Example 11 8.2 Example 17 7.1 Example 18 10.7 Example 19 8.6 Example 21 4.4 Example 22 3.5

[0267] The results show that all compounds of the present invention are highly potent allosteric inhibitors of EGFR.

[0268] Example 24:

[0269] Evaluate the compound stability using human liver microsomes:

[0270] Compare the liver microsomal enzyme stability of the example compounds with BDTX189.

[0271] Determination system: The metabolic stability of the compounds of the present invention is tested using a mixture of male and female liver microsomes with 1 mM NADPH. The samples are analyzed using a mass spectrometer. HRMS is used to determine the peak area response ratio (the peak area corresponding to the test compound or the reference compound divided by the peak area of the analytical internal standard) without running a standard curve. To detect all possible metabolites, HRMS scans are performed within an appropriate m / z range.

[0272] Determination conditions: This determination is carried out with a single incubation (N = 1). Incubate the test compound at 37 °C in a buffer containing 0.5 mg / mL liver microsomal protein. Initiate the reaction by adding cofactors, and sample at 0, 2, 4, 8, 16, 24, 36, 48 hours. Incubate the positive control (5 μM testosterone) in parallel and sample at 0, 2, 4, 8, 16, 24, 36, 48 hours.

[0273] Determination quality control: The control compound testosterone is run in parallel to confirm the enzyme activity of the (liver) microsomes. After the final time point, fluorescence assay is used to confirm the addition of NADPH to the reaction mixture. The T1 / 2 of the reference compound meets the acceptable internal standard.

[0274] Analysis method:

[0275] Liquid chromatography column: Thermo BDS Hypersil C18 30X2.0mm, 3μm, with guard column M.P., buffer: 25 mM formic acid in buffer, pH 3.5; aqueous phase (A): 90% water, 10% buffer; organic phase (B): 90% acetonitrile, 10% buffer; flow rate: 300 μL / min. Autosampler: injection volume 10 μL. The gradient program is shown in Table 3.

[0276] Table 3. Gradient program

[0277] Time (minutes) ％A ％B 0.0 100 0 1.5 0 100 2.0 0 100 2.1 100 0 3.5 100 0

[0278] By using human liver microsomes, Examples 1, 2, 11, 12, and 14 as described in the present invention exhibited a metabolic half-life greater than 20 hours, and Examples 15, 17, 18, 19, 20, 21, and 22 exhibited a metabolic half-life between 13 - 20 hours, significantly greater than the 12-hour metabolic half-life of BDTX189. The relatively long metabolic half-life enables the present invention to have the potential to reduce the medical dosage and extend the dosing time interval.

[0279] For compounds of the general formula (I), the linking group and the substituent groups have an important influence on the pharmacodynamic properties of the compounds. Although the present invention is illustrated by specific examples before, it should not be construed as being limited thereto; rather, the present invention encompasses the general aspects disclosed before. Various modifications can be made and various embodiments can be provided without departing from the spirit and scope of the present invention.

[0280] The examples provided above are not intended to limit the scope covered by the present invention, nor are the described steps intended to limit the order of their execution. Obvious improvements made by those skilled in the art in combination with the existing common general knowledge also fall within the protection scope defined by the claims of the present invention.

Claims

1. A compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof: Specifically selected from: 、 、 、 、 。 2. The compound of the structure shown by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are inorganic salts or organic salts; the inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salts are selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, mesylate, tosylate, benzenesulfonate, salicylate.

3. A pharmaceutical composition, characterized in that, Comprising a compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

4. Use of the compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of a drug for treating or preventing a disease that acts based on EGFR.

5. Use of the compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of an anti-tumor drug.

6. The application according to claim 5, wherein During the application process, the compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof is used as an anti-tumor drug and as an EGFR inhibitor.

7. The application according to claim 5, wherein The tumors are selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, small cell lung cancer or non-small cell lung cancer.

8. The application according to claim 5, characterized in that, The compound of the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof is used in combination with any one of the following anti-tumor agents: (i) Anti-tumor drugs that act on the DNA structure; (ii) Anti-tumor drugs that affect nucleic acid synthesis; (iii) Anti-tumor drugs that affect nucleic acid transcription; (iv) Anti-tumor drugs that affect tubulin synthesis; (v) Cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors; (vi) Anti-tumor monoclonal antibodies.

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