CN116655599A - Synthesis and application of EGFR allosteric inhibitors - Google Patents

Synthesis and application of EGFR allosteric inhibitors Download PDF

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CN116655599A
CN116655599A CN202310556615.1A CN202310556615A CN116655599A CN 116655599 A CN116655599 A CN 116655599A CN 202310556615 A CN202310556615 A CN 202310556615A CN 116655599 A CN116655599 A CN 116655599A
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pharmaceutically acceptable
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cancer
acceptable salt
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唐春雷
袁昕
汪祖练
王栋
范为正
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract

The invention relates to synthesis and application of EGFR allosteric inhibitors, and belongs to the field of medicines. The invention provides a compound with a structure shown in a general formula (I)Or a salt thereof, which is capable of selectively inhibiting EGFR and thus useful in the treatment or amelioration of an abnormal cell proliferative disorder.

Description

Synthesis and application of EGFR allosteric inhibitors
Technical Field
The invention belongs to the field of medicines, and particularly relates to synthesis and application of EGFR allosteric inhibitors.
Background
Epidermal Growth Factor Receptor (EGFR) is one of the transmembrane protein tyrosine kinases of the ErbB receptor family, which when bound to a growth factor ligand (e.g., epidermal Growth Factor (EGF)), can homodimerize with additional EGFR molecules or heterodimerize with another family member (e.g., erbB2 (HER 2), erbB3 (HER 3), or ErbB4 (HER 4)), homodimerization and/or heterodimerization of ErbB receptors resulting in phosphorylation of intracellular critical tyrosine residues and stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Deregulation of ErbB family signaling promotes proliferation, invasion, metastasis, angiogenesis and survival of tumor cells, and is closely related to human cancers such as lung cancer, head and neck cancer, colon cancer, breast cancer, and the like.
Inhibitors against EGFR are currently available in four generations. The first generation EGFR TKIs includes Gefitinib (Gefitinib) and Erlotinib (Erlotinib), mainly for mutations against the 19 th deletion and L858R; the second generation includes Afatinib (Afatinib) and dacominib (dacitinib), primarily to address the most common T790M-mediated drug resistance mechanism, covalently binding to the mutated EGFR protein; the third generation EGFR TKIs is Osimertinib, with activity against the EGFR TKIs resistant mutation T790M. The fourth generation EGFR TKIs is largely divided into two categories: ATP competitive inhibitors and allosteric inhibitors, of which representative drugs are the recently marketed Mobocertinib (Mo Bo tinib), allosteric inhibitors are currently in clinical use in a variety of settings.
In recent decades, molecular targeted therapies represented by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have brought tremendous revolution to cancer treatment, but EGFR-TKI resistance has always been a pending problem. For example, EGFR-TKIs were initially effective in non-small cell lung cancer (NSCLC) patients carrying EGFR mutations, but often evolved to acquired resistance and lost therapeutic effects, such as T790M mutation resulting in first/second generation EGFR-TKI resistance and C797S mutation resulting in third generation EGFR-TKI resistance, and the like, especially tumors containing both L858R/T790M/C797S mutation, for which currently existing EGFR-TKIs are not of interest. However, all current EGFR TKIs target the ATP site, although third generation irreversible inhibitors (e.g., octenib) are able to overcome T790M, drug resistance occurs due to the C797S mutation that has occurred in the treated patient. Cetuximab, an anti-EGFR antibody, which blocks receptor dimerization, is ineffective in EGFR-mutant NSCLC because mutant activation of the kinase is effectively "downstream" of receptor dimerization. Thus, an alternative strategy is to inhibit EGFR. Currently, suitable compounds with alternative mechanisms of action that target mutant EGFR are not available.
With the continuous clinical application of drugs, patients often have different degrees of drug resistance, and common drug resistance mutations are EGFR T790M, EGFR C797X and the like, so that the competition with ATP is reduced. There is therefore an urgent need to find new ways to overcome drug resistance. While allosteric inhibitors have been found to help researchers find new binding sites on the back of the ATP pocket, compounds do not compete with ATP but bind in the allosteric pocket to stabilize the EGFR protein in an inactive conformation, limiting kinase activity to inhibit lung cancer cell proliferation. This is a new strategy to overcome the drug resistance that occurs at the current EGFR targets.
In 2019, a mutation selective EGFR allosteric inhibition BDTX-189 was reported by black diamond therapy. Studies have shown that EGFR and HER2 ins20 mutations and extracellular domain mutations have inhibitory effects, but their activity remains to be further enhanced.
Disclosure of Invention
Problems to be solved by the invention
The invention provides a novel EGFR allosteric inhibitor, and the structural compound has better pharmacodynamic performance.
Further, the invention provides a compound with a general formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition and application.
Solution for solving the problem
The present invention provides a compound having a structure represented by the following general formula (I):
wherein ring A is selected from benzene ring, pyridine ring, pyrazine ring, R 1 H, C1-4 alkyl, halogen (F, cl, br, I), R 2 Halogen (F, cl, br, I); or ring A is selected from benzene ring, pyrazine ring, R 1 H, C1-4 alkyl, halogen (F, cl, br, I), R 2 Is H;
R 3 selected from substituted or unsubstituted C6-10 aryl, C5-12 heteroaryl, optionally selected from 1,2 or 3 substituents as follows: H. halogen (F, cl, br, I);
w is-R 4 (CH 2 ) m -、-O(CH 2 ) m -, wherein m is selected from 0,1,2, R 4 Selected from alkenyl and alkynyl; the Y ring is selected from cycloalkyl of C3-6 and heterocyclic group of C3-12; OR-W-Y is-OR 5 ，R 5 Selected from C1-4 alkyl;
z is selected from: H. -NR 6 、R 6 Selected from H, C1-4 alkyl groups.
In some embodiments of the invention, the C3-12 heterocyclyl is selected from morpholine rings, piperidine rings,R 7 Selected from C1-4 alkyl.
In some embodiments of the invention, R 3 Selected from:
in some embodiments of the invention, W is-R (CH 2 ) m -、-O(CH 2 ) m -wherein R is selected from alkynyl and m is selected from 0,2;
in the present invention, further specifically preferred compounds of the structure represented by the general formula (I) or pharmaceutically acceptable salts thereof are selected from:
The compound with the structure shown in the general formula (I) or pharmaceutically acceptable salt thereof is inorganic salt or organic salt, wherein the inorganic salt comprises hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate and acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
It is still another object of the present invention to provide a pharmaceutical composition comprising a compound having the structure of the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
In another aspect, the invention provides the use of a compound of the structure of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in an EGFR inhibitor.
In another aspect, the invention provides the use of a compound of the structure shown in the general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.
The cancer referred to in the present invention may be selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer (e.g., gastric and colorectal cancer), or lung cancer, etc.
The invention has the beneficial effects of designing a compound with biological functions of inhibiting EGFR, thereby providing a new means for searching new treatment methods of cancers, metabolic and immune diseases, cardiovascular diseases, neurological diseases and the like.
The invention has the advantages that:
the invention provides a class of compounds having a structure according to formula (I) useful in the therapeutic and/or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, having EGFR mutations T790M/L858RT790M/L858R/C797S, L858R and/or L858R/C797S, said treatment comprising determining the EGFR activating mutation status of said patient, and then administering to said patient a compound of formula I as described herein or a pharmaceutically acceptable salt thereof.
Detailed Description
The technical scheme of the present invention will be described in detail with reference to examples.
In the present invention, "C 1-6 Alkyl "refers to a saturated, straight or branched, monovalent hydrocarbon radical of 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.
"heteroaryl" in the context of the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-or 10-membered benzofused heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized.
The aryl group of C6-10 is a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.
Heteroaryl of C5-12 refers to a monocyclic or bicyclic aromatic group having 5 to 12 ring atoms, wherein one or more, preferably one, two or three, of the 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, furanyl, methylindolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
"substituted" in the context of the present invention means that one or more hydrogen atoms in the group are each replaced by the same or different substituents.
In the present invention, "administering" or "administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
< Compound or pharmaceutically acceptable salt thereof >
The invention provides a novel oxo-isoindole compound or pharmaceutically acceptable salt thereof, which can be used as an inhibitor for inhibiting Epidermal Growth Factor Receptor (EGFR), and has a structural formula shown in a general formula (I):
< pharmaceutical composition >
The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention as described above, and a pharmaceutically acceptable carrier, excipient or diluent.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate. Or with the following components: (1) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol, silicic acid and the like; (2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, for example, glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) Wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) adsorbents such as kaolin and the like; (9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers may also be included in capsules, tablets, pills.
The solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be provided with coatings and shell materials such as enteric coatings and other materials known in the art in the form of crystalline coatings or microencapsulations. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, liquid dosage forms may contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular cottonseed, groundnut, corn, olive, castor, sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar-agar, and the like, or mixtures of these.
The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers and, if appropriate, propellants.
The pharmaceutical composition of the invention comprises a compound of a general formula (I) or pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable carriers, excipients and diluents. In preparing pharmaceutical compositions, a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention is typically admixed with a pharmaceutically acceptable carrier, excipient or diluent. Wherein the content of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof may be 0.01 to 1000mg, for example, 0.05 to 800mg, 0.1 to 500mg, 0.01 to 300mg, 0.01 to 200mg, 0.05 to 150mg, 0.05 to 50mg, etc.
< use >
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a mammal.
The compounds of formula (I) or pharmaceutically acceptable salts thereof, which inhibit Epidermal Growth Factor Receptor (EGFR) activity, are useful in the treatment of mammals, including humans, for the therapeutic and/or prophylactic treatment of patients having EGFR activating mutations, particularly non-small cell lung cancer, which treatment comprises determining the status of EGFR activating mutations in said patients, and thereafter administering to said patients a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof.
A "therapeutically effective amount" is an amount of a compound of the invention effective to produce a biological or medical response (e.g., reduce or inhibit the activity of an enzymatically active protein, or ameliorate symptoms, alleviate a condition, slow or delay the progression of a disease, or prevent a disease) in an individual.
Cancers as referred to herein include lung cancer, bone cancer, membranous adenocarcinoma, skin cancer, head or neck cancer, skin melanin cancer or intraocular melanin cancer, uterine cancer, ovarian cancer, rectal cancer, gall bladder cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue meat cancer, urinary tract cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal cancer or ureter cancer, renal cell carcinoma, renal Monday cancer, central Nervous System (CNS) cancer, primary central nervous system lymphoma, spinal cord shaft cancer, brain stem glioma, brain vertical adenoma, and the like.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to mammals, including humans, orally, rectally, parenterally (intravenous, intramuscular or subcutaneous), topically (powders, ointments, drops) or intratumorally.
The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, in combination with other antitumor agents. The combination therapy may be achieved by the simultaneous, sequential or separate use of the individual components of the therapy. Such therapeutic agents include, but are not limited to: antitumor drugs acting on DNA chemical structures such as cisplatin, antitumor drugs affecting nucleotide synthesis such as methotrexate, 5-fluorouracil and the like, antitumor drugs affecting nucleic acid transcription such as doxorubicin, epirubicin, aclacinomycin and the like, antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine and the like, aromatase inhibitors such as aminoglutethimide, letrozole, ryanodine and the like, cell signaling pathway inhibitors such as ALK inhibitors such as crizotinib, ceritinib, ai Leti ni, lazotinib and the like. Anti-tumor monoclonal antibodies, immunosuppressants PD-1, PD-L1, etc., and the individual components to be combined may be administered simultaneously or sequentially, in a single formulation or in different formulations. The combinations include not only combinations of one or more other active agents of the compounds of the present invention, but also combinations of two or more other active agents of the compounds of the present invention.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which specific conditions are not noted in the examples below, is generally followed by conventional conditions.
Preparation of 4-chloro-7-methoxyquinazoline-6-carboxylate (intermediate 1):
4-chloro-7-methoxyquinazoline-6-carboxylate (80 g,1.0 eq) was dissolved in thionyl chloride (80 mL), catalytic amount of N, N-dimethylformamide (0.2 mL) was added dropwise, reflux reaction was performed for 4h at 90℃and TLC was monitored to complete the reaction, cooled to room temperature, the reaction solution was concentrated under reduced pressure to remove most of the solvent, the residue was slurried with petroleum ether (50 mL), suction filtered, the filter cake was washed with petroleum ether, and dried to give 4-chloro-7-methoxyquinazoline-6-carboxylate (intermediate 1) (82.5 g, 95.8%) as a gray solid. 1 H NMR(400MHz,Chloroform-d)δ:8.97(s,1H),7.92(s,1H),7.46(s,1H),4.05(s,3H),2.42(s,3H).
Preparation of 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxyquinazolin-6-yl acetate (intermediate 2):
4-chloro-7-methoxyquinazoline-6-carboxylate (intermediate 1) (20.0 g,1.0 eq) was dissolved in N-methylpyrrolidone (200 mL), 3-chloro-4- (pyridin-2-ylmethoxy) aniline (18.57 g,1.0 eq) was added and reacted at room temperature for 2h. TLC detection of completion of the reaction was performed with water (400 mL), suction filtration, washing of the filter cake with water and drying in a vacuum oven (45 ℃ C., 24 h) gave 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl acetate (intermediate 2) (34.75 g, 97.3%) as a red solid. HRMS (m/z): 451.1626[ M+H ] ] + 。
Preparation of 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-ol (intermediate 3):
4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -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, stirred at room temperature for 4h, TLC monitored for the end of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, suction filtration, the filter cake was washed with water, and dried in a vacuum oven (45 ℃ C., 12 h) to give 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) ammoniaYl) -7-methoxyquinazolin-6-ol (intermediate 3) (31.1 g, 98.7%) as a white solid was used in the next reaction without purification. HRMS (m/z): 409.1572[ M+H ]] + 。
Preparation of tert-butyl 4- ((4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1-carboxylate (intermediate 4):
4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxyquinazolin-6-ol (intermediate 3) (7.7 g,1.0 eq) was dissolved in DMF (80 mL), tert-butyl 4- (toluoyloxy) piperidine-1-carboxylate (8.0 g,1.2 eq), potassium carbonate (7.8 g,3.0 eq) was added, the reaction was warmed to 80 ℃, overnight, TLC monitored the reaction was complete, water (500 mL) was added, the solid precipitated, suction filtered, the filter cake was washed with water, dried in a vacuum oven (45 ℃,12 h) to give the crude product (8.8 g) which was column chromatographed [ DCM: meoh=20:1 (V/V) ] to give tert-butyl 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1-carboxylate (intermediate 4) (4.4 g, 39.4%) as a white solid. HRMS (m/z): 592.2416[ M+H ] +.
Preparation of N- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxy-6- (piperidin-4-yloxy) quinazolin-4-amine (intermediate 5):
4- ((4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (intermediate 4) (4.35 g,1.0 eq) in a reaction flask was added dropwise dichloromethane: trifluoroacetic acid=4:1 (V/V) mixed solvent (45 mL), at room temperature for 2h, tlc monitored the reaction was complete, the reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution was added to adjust pH to 8-9, the solid precipitated out, suction filtered, the filter cake was washed with water, dried in a vacuum oven (45 ℃ for 12 h) to give N- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxy-6- (piperidin-4-yloxy) quinazolin-4-amine (intermediate 5) (1.73 g, 48.1%) as a brown solid, which was directly carried on to the next step without purification. HRMS (m/z): 492.1802[ M+H ]] + 。
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
Preparation of 2-chloro-1- ((3-fluorobenzyl) oxy) -4-nitrobenzene (intermediate 6):
3-chloro-4-fluoroaniline (20 g,1.0 eq) and a three-necked flask dissolved in N, N-dimethylformamide (200 mL) were successively charged with Cs2CO3 (96.8 g,2.0 eq), (3-fluorophenyl) methanol (17.4 g,1.0 eq) under nitrogen atmosphere, and the mixture was heated to 80℃to react overnight. TLC monitored the reaction to completion, cooled to room temperature, ice water (1L) was added, white solid precipitated, suction filtered, the filter cake washed with water and dried to give 2-chloro-1- ((3-fluorobenzyl) oxy) -4-nitrobenzene (intermediate 6) (26.8 g, 69.1%) as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ8.35(d,J＝2.8Hz,1H),8.26(dd,J＝9.2,2.8Hz,1H),7.48(td,J＝9.3,8.5,2.9Hz,2H),7.35-7.31(m,2H),7.21(td,J＝8.7,2.6Hz,1H),5.41(s,2H).HRMS(m/z):282.2931[M+H] + 。
Preparation of 3-chloro-4- ((3-fluorobenzyl) oxy) aniline (intermediate 7):
3-chloro-4- ((3-fluorobenzyl) oxy) aniline (26.7 g,1.0 eq) was dissolved in a mixed solvent of methanol (225 mL) and water (75 mL), ammonium chloride (35.6 g,7.0 eq) was added, and iron powder (26.5 g,5.0 eq) was added three times with stirring under heating, and the mixture was heated to 90℃for reflux reaction, followed by stirring overnight. TLC monitored completion of the reaction, cooled to room temperature, filtered through celite, and the filtrate concentrated under reduced pressure to give 3-chloro-4- ((3-fluorobenzyl) oxy) aniline (intermediate 7) (428 g, 75.3%) as an off-white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.48(td,J＝8.0,5.9Hz,1H),7.36-7.24(m,2H),7.25-7.15(m,1H),6.96(d,J＝8.7Hz,1H),6.70(d,J＝2.7Hz,1H),6.52(dd,J＝8.7,2.7Hz,1H),5.08(s,2H),5.02(s,2H).HRMS(m/z):252.0578[M+H] + 。
Preparation of 4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl acetate (intermediate 8):
preparation of intermediate 8 reference was made to the synthetic procedure of intermediate 2 in which 3-chloro-4- (pyridin-2-ylmethoxy) aniline was replaced with intermediate 7. HRMS (m/z): 467.9471[ M+H ]] + 。
Preparation of 4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-ol (intermediate 9):
preparation of intermediate 9 reference is made to the synthetic method of intermediate 3. HRMS (m/z): 426.1516[ M+H ]] + 。
Preparation of tert-butyl 4- ((4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1-carboxylate (intermediate 10):
Preparation of intermediate 10 reference is made to the synthetic method of intermediate 4. 1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),8.87(d,J＝1.4Hz,1H),8.72-8.65(m,2H),8.46(s,1H),7.97-7.90(m,2H),7.70(dd,J＝9.0,2.6Hz,1H),7.34(d,J＝9.0Hz,1H),7.22(s,1H),5.38(s,2H),3.94(s,3H),3.67(dd,J＝13.4,6.9Hz,2H),3.26(s,2H),1.98(d,J＝10.0Hz,2H),1.64(d,J＝12.0Hz,2H),1.42(s,9H).HRMS(m/z):593.2106[M+H] + 。
Preparation of N- (3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) -7-methoxy-6- (piperidin-4-yloxy) quinazolin-4-amine (intermediate 11):
preparation of intermediate 11 reference is made to the synthetic method of intermediate 5. HRMS (m/z): 509.2158[ M+H ]] + 。
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):
preparation of the compound of example 1 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.45(s,1H),8.46(s,1H),7.95(d,J＝2.9Hz,2H),7.69(dd,J＝8.9,2.6Hz,1H),7.48(td,J＝8.0,5.9Hz,1H),7.35-7.16(m,5H),6.86(dd,J＝16.7,10.5Hz,1H),6.13(dd,J＝16.7,2.5Hz,1H),5.69(dd,J＝10.5,2.5Hz,1H),5.26(s,2H),4.82(dq,J＝7.5,3.8Hz,1H),3.94(s,3H),3.87(d,J＝11.2Hz,2H),3.58-3.45(m,2H),2.02(s,2H),1.71(s,2H).HRMS(m/z):563.1870[M+H] + 。
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
Preparation of 2- ((2-chloro-4-nitrophenoxy) methyl) pyrazine (intermediate 12):
preparation of intermediate 12 reference is made to the synthetic method of intermediate 6. 1 H NMR(400MHz,DMSO-d 6 )δ8.90(d,J＝1.4Hz,1H),8.76-8.68(m,2H),8.39(d,J＝2.8Hz,1H),8.28(dd,J＝9.1,2.8Hz,1H),7.56(d,J＝9.2Hz,1H),5.58(s,2H).HRMS(m/z):266.0032[M+H] + 。
Preparation of 3-chloro-4- ((3-fluorobenzyl) oxy) aniline (intermediate 13):
preparation of intermediate 13 reference is made to the synthetic method of intermediate 7. 1 H NMR(400MHz,DMSO-d 6 )δ8.81(d,J＝1.5Hz,1H),8.69-8.62(m,2H),6.97(d,J＝8.7Hz,1H),6.66(d,J＝2.7Hz,1H),6.48(dd,J＝8.7,2.7Hz,1H),5.17(s,2H),5.01(s,2H).HRMS(m/z):236.9606[M+H] + 。
Preparation of 4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl acetate (intermediate 14):
preparation of intermediate 14 reference was made to a synthetic procedure for intermediate 2 wherein 3-chloro-4- (pyridin-2-ylmethoxy) aniline was replaced with intermediate 13. HRMS (m/z): 452.1489[ M+H ] ] + 。
Preparation of 4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-ol (intermediate 15):
preparation of intermediate 15 reference the synthesis of intermediate 3. HRMS (m/z): 410.1334[ M+H ]] + 。
Preparation of tert-butyl 4- ((4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1-carboxylate (intermediate 16):
preparation of intermediate 16 reference was made to the synthetic method of intermediate 4. 1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),8.87(d,J＝1.4Hz,1H),8.72-8.65(m,2H),8.46(s,1H),7.97-7.90(m,2H),7.70(dd,J＝9.0,2.6Hz,1H),7.34(d,J＝9.0Hz,1H),7.22(s,1H),5.38(s,2H),3.94(s,3H),3.67(dd,J＝13.4,6.9Hz,2H),3.26(s,2H),1.98(d,J＝10.0Hz,2H),1.64(d,J＝12.0Hz,2H),1.42(s,9H).HRMS(m/z):593.2106[M+H] + 。
Preparation of N- (3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) -7-methoxy-6- (piperidin-4-yloxy) quinazolin-4-amine (intermediate 17):
preparation of intermediate 17 reference was made to the synthetic procedure of intermediate 5. HRMS (m/z): 493.2154[ M+H ]] + 。
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):
preparation of the compound of example 2 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,1H),8.87(s,1H),8.71(d,J＝2.5Hz,1H),8.46(s,1H),7.99-7.93(m,2H),7.71(dd,J＝9.0,2.7Hz,1H),7.35(d,J＝8.9Hz,1H),7.22(s,1H),6.85(dd,J＝16.7,10.4Hz,1H),6.27-6.13(m,1H),6.14-6.03(m,1H),5.69(dd,J＝10.5,2.5Hz,1H),5.39(s,2H),4.81(tt,J＝7.5,3.6Hz,1H),3.94(s,3H),3.51(s,4H),2.06-2.00(m,2H),1.71(d,J＝11.9Hz,2H).HRMS(m/z):547.1681[M+H]+。
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
Preparation of 2-fluoroacryloyl chloride (intermediate 18):
methacrylic acid (250 mg,1.0 eq.) was dissolved in methylene chloride solution (2.5 mL) and added to a three-necked flask, followed by dropwise addition of oxalyl chloride (383 mg,1.1 eq.) in methylene chloride solution (4 mL) under nitrogen at 0 ℃ followed by catalytic amounts of N, N-dimethylformamide. The reaction was carried out at room temperature for 4 hours. After the reaction, concentrating under reduced pressure to obtain 2-fluoro-acryloyl chloride as yellow solid, and directly carrying out the next reaction without purification.
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):
preparation of example 3 reference was made to the synthesis of intermediate 6 substituting acryloyl chloride for intermediate 18 and the base for 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H),8.61(dd,J＝5.0,1.7Hz,1H),8.47(s,1H),7.96(d,J＝2.2Hz,2H),7.89(td,J＝7.7,1.8Hz,1H),7.68(dd,J＝8.9,2.6Hz,1H),7.60(d,J＝7.8Hz,1H),7.38(dd,J＝7.5,4.9Hz,1H),7.28(d,J＝9.0Hz,1H),7.23(s,1H),5.36-5.23(m,4H),4.84(dp,J＝7.2,3.5Hz,1H),3.95(s,3H),3.80(ddd,J＝12.3,7.7,3.9Hz,2H),3.54(ddd,J＝12.5,7.8,3.5Hz,2H),2.10-2.03(m,2H),1.78(s,2H).HRMS(m/z):564.1910[M+H] + 。
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
Preparation of example 4 reference was made to the synthesis of intermediate 6 substituting acryloyl chloride for intermediate 18 and base for 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.55(s,1H),8.47(s,1H),8.03-7.96(m,2H),7.72(dd,J＝8.9,2.6Hz,1H),7.48(td,J＝8.0,6.0Hz,1H),7.35-7.30(m,2H),7.28-7.22(m,2H),7.19(ddd,J＝10.3,8.0,2.6Hz,1H),5.35-5.27(m,2H),5.26(s,2H),4.88(tt,J＝7.3,3.6Hz,1H),3.95(s,3H),3.83(dd,J＝14.4,6.7Hz,2H),3.55(d,J＝10.5Hz,2H),2.11-2.04(m,2H),1.77(s,2H).HRMS(m/z):581.2318[M+H] + 。
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
Preparation of example 5 reference was made to the synthesis of intermediate 6 substituting acryloyl chloride for intermediate 18 and base for 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.88(d,J＝1.4Hz,1H),8.69(dd,J＝12.8,2.2Hz,2H),8.47(s,1H),8.00-7.94(m,2H),7.72(dd,J＝9.0,2.6Hz,1H),7.35(d,J＝9.0Hz,1H),7.23(s,1H),5.39(s,2H),5.33-5.15(m,2H),4.84(tt,J＝7.1,3.5Hz,1H),3.95(s,3H),3.80(ddd,J＝12.4,7.6,3.7Hz,2H),3.58-3.49(m,2H),2.06(s,2H),1.78(s,2H).HRMS(m/z):565.1766[M+H] + 。
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
Preparation of tert-butyl (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylate (intermediate 19):
bis (trichloromethyl) carbonate (1.0 eq.) and methylene chloride (15 mL) were added to a three-necked flask under nitrogen at 0deg.C, followed by a solution of pyridine (3.0 eq.) and tert-butyl (R) -3-methylpiperazine-1-carboxylate (B-1, 1.36g,1.0 eq.) in methylene chloride (5 mL) and reacted overnight at room temperature. TLC monitored the end of the reaction and concentrated under reduced pressure to remove solvent to give tert-butyl (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylate (intermediate 19) as a yellow solid. The reaction mixture was used in the next reaction without purification.
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):
intermediate 3 (6 g,1.0 eq) was dissolved in N, N-dimethylformamide (60 mL) in a three-necked flask, potassium carbonate (6.1 g,3.0 eq) was added under nitrogenIntermediate 19 () =4.6 g,1.2 eq), overnight at room temperature, TLC monitored the completion of the reaction, water (400 mL) was added to the reaction solution, solids precipitated, suction filtered, the filter cake was washed with water, and dried in a vacuum oven (45 ℃ for 12 h) to give 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%) as a brown solid. The next step was carried out directly without purification. HRMS (m/z): 635.2681[ M+H ]] + 。
Preparation of 4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxyquinazolin-6-yl (R) -2-methylpiperazine-1-carboxylate (intermediate 21):
the preparation of intermediate 21 is referred to the preparation of synthetic method 5. HRMS (m/z): 535.2288[ M+H ]] + 。
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):
Preparation of example 6 reference was made to the synthetic procedure of intermediate 6, substituting 2 equivalents of triethylamine with the base. 1 H NMR(400MHz,DMSO-d 6 )δ9.57(s,1H),8.64-8.53(m,2H),8.31(s,1H),8.06(d,J＝2.6Hz,1H),7.88(td,J＝7.7,1.9Hz,1H),7.72(dd,J＝9.0,2.7Hz,1H),7.58(d,J＝7.8Hz,1H),7.41-7.23(m,3H),6.85(q,J＝13.9Hz,1H),6.20(d,J＝16.6Hz,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＝13.9Hz,2H),2.99(d,J＝66.5Hz,1H),1.23(s,3H).HRMS(m/z):588.19[M+H] + 。
Example 7:4- ((3-chloro-4- ((5-fluoropyridin-2-yl) methoxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate
Preparation of 4- (tert-butyl) 1- (4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (intermediate 23):
preparation of intermediate 23 reference intermediate 20And (5) preparing. HRMS (m/z): 652.2827[ M+H ]] + 。
Preparation of 4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -2-methylpiperazine-1-carboxylate (intermediate 24):
preparation of intermediate 24 refers to preparation of intermediate 5. HRMS (m/z): 552.2260[ m+h ] +.
Preparation of 4- ((3-chloro-4- ((5-fluoropyridin-2-yl) methoxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate (example 7):
preparation of example 7 reference intermediate 6 synthesis procedure, base substitution with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )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] + 。
Example 8:4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate
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):
preparation of intermediate 26 reference the synthetic method of intermediate 20. HRMS (m/z): 636.2162[ M+H ]] + 。
Preparation of 4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) -7-methoxyquinazolin-6-yl (R) -2-methylpiperazine-1-carboxylate (intermediate 27):
preparation of intermediate 26 reference is made to the synthetic method of intermediate 5. HRMS (m/z): 536.2000[ M+H ]] + 。
4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) -7-methoxyquinazolin-6-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate (example 8) was prepared:
preparation of example 8 reference procedure for the synthesis of intermediate 6, base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.58(s,1H),8.64-8.51(m,2H),8.32(s,1H),8.07(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.72(dd,J＝9.0,2.6Hz,1H),7.59(d,J＝7.8Hz,1H),7.41-7.22(m,3H),5.40-5.21(m,4H),4.44(d,J＝71.6Hz,1H),3.95(s,3H),3.01(s,6H),1.20(d,J＝23.4Hz,3H).HRMS(m/z):590.1628[M+H] + 。
Example 9:4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4- (2-fluoroacryloyl) -2-methylpiperazine-1-carboxylate
Preparation of example 9 reference was made to the synthetic method of example 3. 1 H NMR(400MHz,DMSO-d 6 )δ9.58(s,1H),8.64-8.51(m,2H),8.32(s,1H),8.07(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.72(dd,J＝9.0,2.6Hz,1H),7.59(d,J＝7.8Hz,1H),7.41-7.22(m,3H),5.40-5.21(m,4H),4.44(d,J＝71.6Hz,1H),3.95(s,3H),3.01(s,6H),1.23(s,3H).HRMS(m/z):607.1771[M+H] + 。
Example 10:4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4- (2-fluoroacryloyl) -2-methylpiperazine-1-carboxylate
Preparation of example 10 reference was made to the synthetic method of example 3. 1 H NMR(400MHz,DMSO-d 6 )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] + 。
Example 11:4- ((3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl (R) -4- (2-fluoroacryloyl) -2-methylpiperazine-1-carboxylate
Preparation of example 11 reference was made to the synthetic method of example 3. 1 H NMR(400MHz,DMSO-d 6 )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] + 。
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
Preparation of tert-butyl 2-methyl-4- (toluoyloxy) piperidine-1-carboxylate (intermediate 28):
4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (2 g,1.0 eq) was dissolved in dichloromethane (20 mL), triethylamine (2.8 g,3.0 eq) and DMAP (114 mg,0.1 eq) were added sequentially, p-toluenesulfonyl chloride (1.77 g,1.0 eq) was added in three portions at 0℃under nitrogen protection, stirred overnight at room temperature, TLC monitored for completion of the reaction, and the reaction solution was concentrated under reduced pressure to give crude white solid (3.1 g) which was purified by column chromatography [ DCM: meOH=10:1 (v/v)]Tert-butyl 2-methyl-4- (toluoyloxy) piperidine-1-carboxylate (intermediate 28) (2.5 g, 72.8%) was obtained as a pale pink solid. HRMS (m/z): 392.1988[ M+Na ]] + 。
Preparation of 4- ((4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 29):
The synthesis of intermediate 29 refers to the synthesis of intermediate 4. HRMS (m/z): 606.2643[ M+H ]] + 。
Preparation of N- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxy-6- ((2-methylpiperidin-4-yl) oxy) quinazolin-4-amine (intermediate 30):
synthesis of intermediate 30 refers to the synthesis of intermediate 5. HRMS (m/z): 506.2109[ M+H ]] + 。
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):
the synthesis of example 12 refers to the synthesis of intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),8.45(s,1H),7.95-7.88(m,2H),7.67(dd,J＝8.9,2.7Hz,1H),7.48(td,J＝8.0,5.9Hz,1H),7.39-7.20(m,5H),6.82(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.6,2.6Hz,1H),5.67(dd,J＝10.4,2.5Hz,1H),5.26(s,2H),5.01(t,J＝3.2Hz,1H),4.57(s,1H),3.95(s,4H),2.14-1.84(m,4H),1.78(s,1H),1.35(d,J＝6.9Hz,3H).HRMS(m/z):560.2066[M+H] + 。
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
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):
the synthesis of intermediate 31 refers to the synthesis of intermediate 4. HRMS (m/z): 623.3984[ M+H ]] + 。
Preparation of N- (3-chloro-4- ((4-fluorobenzyl) oxy) phenyl) -7-methoxy-6- ((2-methylpiperidin-4-yl) oxy) quinazolin-4-amine (intermediate 32)
Synthesis of intermediate 32 referring to Synthesis of intermediate 5 The method is as follows. HRMS (m/z): 523.1992[ M+H ]] + 。
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):
the synthesis of example 13 refers to the synthesis of intermediate 6, with the base replaced by 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),8.45(s,1H),7.96-7.87(m,2H),7.67(dd,J＝8.9,2.7Hz,1H),7.48(td,J＝8.0,5.9Hz,1H),7.38-7.21(m,5H),6.82(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.6,2.6Hz,1H),5.67(dd,J＝10.4,2.5Hz,1H),5.26(s,2H),5.01(t,J＝3.2Hz,1H),4.57(s,1H),3.95(s,4H),2.21-1.84(m,4H),1.78(s,1H),1.35(d,J＝6.9Hz,3H).HRMS(m/z):581.2318[M+H] + 。
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
Preparation of 4- ((4- ((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 33):
synthesis of intermediate 33 reference the synthesis of intermediate 4. HRMS (m/z): 607.1998[ M+H ]] + 。
Preparation of N- (3-chloro-4- (pyrazin-2-ylmethoxy) phenyl) -7-methoxy-6- ((2-methylpiperidin-4-yl) oxy) quinazolin-4-amine (intermediate 34):
the synthesis of intermediate 34 refers to the synthesis of intermediate 5. HRMS (m/z): 507.1949[ m+h ] +.
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):
the synthesis of example 14 is referred to the synthesis method of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H),8.88(d,J＝1.4Hz,1H),8.71(t,J＝2.0Hz,1H),8.67(d,J＝2.6Hz,1H),8.47(d,J＝2.7Hz,1H),7.96(d,J＝2.6Hz,1H),7.91(s,1H),7.71(dd,J＝8.9,2.6Hz,1H),7.35(d,J＝9.0Hz,1H),7.22(d,J＝5.2Hz,1H),6.87-6.79(m,1H),6.12(dd,J＝16.7,2.5Hz,1H),5.68(dd,J＝10.4,2.5Hz,1H),5.39(s,2H),5.05-4.99(m,1H),3.95(s,3H),3.93(s,1H),2.51(p,J＝1.9Hz,2H),2.19-1.84(m,4H),1.35(d,J＝7.0Hz,3H).HRMS(m/z):561.2033[M+H] + 。
Example 15: n- (7- (2-morpholinoethoxy) -4- (quinolin-6-ylamino) quinazolin-6-yl) acrylamide
Preparation of 4- (1, 4-dioxopyridin [4.5] dec-7-en-8-yl) pyridine (intermediate 35):
preparation of intermediate 35 refers to the synthetic method of intermediate 1.
Preparation of 7-fluoro-6-nitro-N- (quinolin-6-yl) quinazolin-4-amine (intermediate 36):
preparation of intermediate 36 referring to the synthetic method of intermediate 2, 3-chloro-4- (pyridin-2-ylmethoxy) aniline was replaced with quinolin-6-amine. HRMS (m/z): 336.1103[ M+H ]] + 。
Preparation of 7- (2-morpholinoethoxy) -6-nitro-N- (quinolin-6-yl) quinazolin-4-amine (intermediate 37):
intermediate 36 (3 g,1.0 eq) was dissolved in DMF (30 mL) and NaH (0.3 g,2.0 eq) was added at 0deg.C and after stirring for 30min 2-morpholinoethanol (1.76 g,1.5 eq) was added under nitrogen. The reaction was allowed to stand at room temperature overnight. After completion of TLC detection, water (180 mL) was added to the reaction solution, and the solid precipitated, filtered off with suction, and the filter cake was dried in a vacuum oven (45 ℃ C., 24 h) after washing with water to give 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(400MHz,DMSO-d 6 )δ10.38(s,1H),9.32(s,1H),8.84(d,J＝4.2Hz,1H),8.71(s,1H),8.51(s,1H),8.35(d,J＝8.3Hz,1H),8.17(d,J＝9.3Hz,1H),8.05(d,J＝9.2Hz,1H),7.54(d,J＝4.7Hz,2H),4.44(t,J＝5.6Hz,2H),3.58(t,J＝4.7Hz,4H),2.78(t,J＝5.5Hz,2H),2.51(s,4H).HRMS(m/z):447.1833[M+H] + 。
7- (2-morpholinoethoxy) -N 4 Preparation of- (quinolin-6-yl) quinazoline-4, 6-diamine (intermediate 38):
Intermediate 37 (3.65 g,1.0 eq) was dissolved in methanol: to a solution of water= (225 ml:75 ml), ammonium chloride (3.06 g,7.0 eq) solid was added, iron powder (2.25 g,5.0 eq) was added in three portions with heating and stirring at 80 ℃, and the reaction was refluxed overnight at 80 ℃, the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, celite was used for filtration, and dichloromethane was used: methanol=10: 1 washing celite, concentrating the obtained filtrate under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain brown solid (2.99 g, 87.7%). HRMS (m/z): 417.3158[ M+H ]] + 。
Preparation of N- (7- (2-morpholinoethoxy) -4- (quinolin-6-ylamino) quinazolin-6-yl) acrylamide (example 15):
preparation of example 15 reference intermediate 6 synthesis procedure, base substitution with 2 equivalents of triethylamine. ESI-MS m/z 392.2[ M+H ]] + 。
Example 16: n- (7- (2- (piperidin-1-yl) ethoxy) -4- (quinolin-6-ylamino) quinazolin-6-yl) acrylamide
Preparation of 6-nitro-7- (2- (piperidin-1-yl) ethoxy) -N- (quinolin-6-yl) quinazolin-4-amine (intermediate 39):
preparation of intermediate 39 reference is made to the synthetic method of intermediate 37. 1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),9.32(s,1H),8.84(d,J＝4.3Hz,1H),8.71(s,1H),8.52(s,1H),8.36(d,J＝8.4Hz,1H),8.18(d,J＝9.2Hz,1H),8.05(d,J＝9.1Hz,1H),7.52(d,J＝9.4Hz,2H),4.41(t,J＝5.7Hz,2H),2.74(t,J＝5.7Hz,2H),2.46(t,J＝5.5Hz,4H),1.49(p,J＝5.6Hz,4H),1.40-1.36(m,2H).HRMS(m/z):445.2557[M+H] + 。
7- (2- (piperidin-1-yl) ethoxy) -N 4 Preparation of- (quinolin-6-yl) quinazoline-4, 6-diamine (intermediate 40):
preparation of intermediate 40 reference the synthetic method of intermediate 38. HRMS (m/z): 415.3186[ M+H ] ] + 。
Preparation of N- (7- (2- (piperidin-1-yl) ethoxy) -4- (quinolin-6-ylamino) quinazolin-6-yl) acrylamide (example 16):
preparation of example 16 reference was made to the synthetic procedure of intermediate 6, substituting 2 equivalents of triethylamine with the base. 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),9.67(s,1H),8.99(s,1H),8.81(dd,J＝4.2,1.7Hz,1H),8.59(s,1H),8.49(d,J＝2.3Hz,1H),8.32(dd,J＝8.5,1.6Hz,1H),8.20(dd,J＝9.1,2.4Hz,1H),8.02(d,J＝9.1Hz,1H),7.50(dd,J＝8.3,4.2Hz,1H),7.36(s,1H),6.72(dd,J＝17.0,10.2Hz,1H),6.33(dd,J＝17.1,1.9Hz,1H),5.83(dd,J＝10.1,2.0Hz,1H),4.35(t,J＝5.9Hz,2H),2.82(t,J＝5.8Hz,2H),2.49(s,4H),1.51(p,J＝5.5Hz,4H),1.39(q,J＝6.0Hz,2H).HRMS(m/z):469.2755[M+H] + 。
Example 17: preparation of N- (7- (2-morpholinoethoxy) -4- (naphthalen-2-ylamino) quinazolin-6-yl) acrylamide
Preparation of 7-fluoro-N- (naphthalen-2-yl) -6-nitroquinazolin-4-amine (intermediate 41):
preparation of intermediate 41 referring to the synthetic method of intermediate 36, 3-chloro-4- (pyridin-2-ylmethoxy) aniline was replaced with naphthalen-2-amine. HRMS (m/z): 335.0960[ M+H ]] + 。
Preparation of 7- (2-morpholinoethoxy) -N- (naphthalen-2-yl) -6-nitroquinazolin-4-amine (intermediate 42):
preparation of intermediate 42 reference is made to the synthetic method of intermediate 37. 1 H NMR(400MHz,DMSO-d 6 )δ10.27(s,1H),9.31(s,1H),8.68(s,1H),8.42(s,1H),7.98-7.86(m,4H),7.49(h,J＝7.2Hz,3H),4.41(t,J＝5.6Hz,2H),3.58(t,J＝4.5Hz,4H),2.76(t,J＝5.6Hz,2H),2.51(t,J＝4.1Hz,4H).HRMS(m/z):
446.0395[M+H] + 。
Preparation of 7- (2-morpholinoethoxy) -N4- (naphthalen-2-yl) quinazoline-4, 6-diamine (intermediate 43):
preparation of intermediate 43 refers to the synthetic method of intermediate 38. HRMS (m/z): 416.2068[ M+H ]] + 。
Preparation of N- (7- (2-morpholinoethoxy) -4- (naphthalen-2-ylamino) quinazolin-6-yl) acrylamide (example 17):
preparation of example 17 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),9.70(s,1H),8.97(s,1H),8.58(s,1H),8.40(d,J＝2.0Hz,1H),8.00-7.83(m,4H),7.47(dt,J＝25.5,7.2Hz,2H),7.35(s,1H),6.72(dd,J＝17.0,10.2Hz,1H),6.34(dd,J＝17.0,2.0Hz,1H),5.84(dd,J＝10.0,2.0Hz,1H),4.36(t,J＝5.7Hz,2H),3.58(t,J＝4.6Hz,4H),2.84(t,J＝5.7Hz,2H),2.54(d,J＝4.4Hz,4H).HRMS(m/z):470.1047[M+H] + 。
Example 18: n- (4- (naphthalen-2-ylamino) -7- (2- (piperidin-1-yl) ethoxy) quinazolin-6-yl) acrylamide
Preparation of N- (naphthalen-2-yl) -6-nitro-7- (2- (piperidin-1-yl) ethoxy) quinazolin-4-amine (intermediate 44):
preparation of intermediate 44 refers to the synthetic method of intermediate 39. 1 H NMR(400MHz,DMSO-d 6 )δ10.28(s,1H),9.30(s,1H),8.68(s,1H),8.42(s,1H),7.98-7.84(m,4H),7.49(h,J＝7.1Hz,3H),4.39(t,J＝5.7Hz,2H),2.72(t,J＝5.6Hz,2H),2.46(t,J＝5.5Hz,4H),1.49(p,J＝5.3Hz,4H),1.38(q,J＝5.6Hz,2H).HRMS(m/z):444.2029[M+H] + 。
Preparation of 7- (2-morpholinoethoxy) -N4- (naphthalen-2-yl) quinazoline-4, 6-diamine (intermediate 45):
preparation of intermediate 45 refers to the synthetic method of intermediate 38. HRMS (m/z): 417.2522[ M+H ]] + 。
Preparation of N- (4- (naphthalen-2-ylamino) -7- (2- (piperidin-1-yl) ethoxy) quinazolin-6-yl) acrylamide (example 18):
preparation of example 18 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.94(s,1H),9.74(s,1H),8.99(s,1H),8.56(s,1H),8.39(d,J＝2.0Hz,1H),7.98-7.84(m,4H),7.52-7.40(m,2H),7.34(s,1H),6.74(dd,J＝17.0,10.3Hz,1H),6.33(dd,J＝17.0,2.0Hz,1H),5.83(dd,J＝10.1,2.0Hz,1H),4.34(t,J＝5.8Hz,2H),2.82(s,2H),1.52(p,J＝5.3Hz,4H),1.39(q,J＝5.9Hz,2H).HRMS(m/z):468.1262[M+H] + 。
Example 19: n- (4- ((1-methyl-1H-indol-6-yl) amino) -7- (2-morpholinoethoxy) quinazolin-6-yl) acrylamide
Preparation of 1-methyl-6-nitro-1H-indole (intermediate 47):
the compound 6-nitro-1H-indole (1 g,1.0 eq) was dissolved in DMF (10 mL), potassium carbonate (2.56 g,3.0 eq), methyl iodide (1.3 g,1.5 eq) was added, the reaction was monitored by TLC for 4H, water was added to the reaction solution, the solid precipitated, suction filtration was performed, the filtrate was washed with water, and dried in a vacuum oven (45 ℃ C., 12H) to give 1-methyl-6-nitro-1H-indole (intermediate 47) (1.07 g, 98.7%) as a yellow solid.
Preparation of 1-methyl-1H-indol-6-amine (intermediate 48):
Intermediate 47 (1 g,1.0 eq) was dissolved in methanol (10 mL), palladium on carbon (100 mg,0.1 eq) was added, the reaction was allowed to proceed overnight at room temperature under hydrogen atmosphere, TLC monitored the reaction was complete, celite was assisted to filter, and the filtrate was concentrated under reduced pressure to give 1-methyl-1H-indol-6-amine (intermediate 48) (686 mg, 82.7%) as a yellow solid. HRMS (m/z): 147.0398[ M+H ]] + 。
Preparation of 7-fluoro-N- (1-methyl-1H-indol-6-yl) -6-nitroquinazolin-4-amine (intermediate 49):
preparation of intermediate 49 refers to the synthetic method of intermediate 36. HRMS (m/z): 336.1103[ M+H ]] + 。
Preparation of N- (1-methyl-1H-indol-6-yl) -7- (2-morpholinoethoxy) -6-nitroquinazolin-4-amine (intermediate 50):
preparation of intermediate 50 refers to the synthetic method of intermediate 37. 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.28(s,1H),8.57(s,1H),7.88(s,1H),7.55(d,J＝8.5Hz,1H),7.47(s,1H),7.39(d,J＝8.5Hz,1H),7.33(d,J＝3.0Hz,1H),6.42(d,J＝3.0Hz,1H),4.42(t,J＝5.5Hz,2H),3.79(s,3H),3.58(t,J＝4.6Hz,4H),2.78(t,J＝5.5Hz,2H),2.52(s,4H).HRMS(m/z):449.2531[M+H] + 。
N 4 Preparation of- (1-methyl-1H-indol-6-yl) -7- (2-morpholinoethoxy) quinazoline-4, 6-diamine (intermediate 51):
preparation of intermediate 51 refers to the synthetic method of intermediate 38. HRMS (m/z): 419.2456[ M+H ]] + 。
Preparation of N- (4- ((1-methyl-1H-indol-6-yl) amino) -7- (2-morpholinoethoxy) quinazolin-6-yl) acrylamide (example 19):
preparation of example 19 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),9.70(s,1H),8.97(s,1H),8.58(s,1H),8.40(d,J＝2.0Hz,1H),8.00-7.83(m,4H),7.47(dt,J＝25.5,7.2Hz,2H),7.35(s,1H),6.72(dd,J＝17.0,10.2Hz,1H),6.34(dd,J＝17.0,2.0Hz,1H),5.84(dd,J＝10.0,2.0Hz,1H),4.36(t,J＝5.7Hz,2H),3.58(t,J＝4.6Hz,4H),2.84(t,J＝5.7Hz,2H),2.54(d,J＝4.4Hz,4H).HRMS:(m/z):473.1913[M+H] + 。
Example 20: n- (4- ((1-methyl-1H-indol-6-yl) amino) -7- (2- (piperidin-1-yl) ethoxy) quinazolin-6-yl) acrylamide
Preparation of N- (1-methyl-1H-indol-6-yl) -6-nitro-7- (2- (piperidin-1-yl) ethoxy) quinazolin-4-amine (intermediate 52):
preparation of intermediate 52 refers to the synthetic method of intermediate 39. 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.28(s,1H),8.58(s,1H),7.89(d,J＝1.8Hz,1H),7.55(d,J＝8.5Hz,1H),7.46(s,1H),7.40(dd,J＝8.5,1.8Hz,1H),7.33(d,J＝3.1Hz,1H),6.42(d,J＝3.1Hz,1H),4.39(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.46(t,J＝5.4Hz,4H),1.49(p,J＝5.5Hz,4H),1.38(q,J＝6.8,6.2Hz,2H).HRMS(m/z):447.2029[M+H] + 。
N 4 - (1-methyl-1H-indol-6-yl) -7- (2)Preparation of morpholinoethoxy) quinazoline-4, 6-diamine (intermediate 53):
preparation of intermediate 53 refers to the synthetic method of intermediate 38. HRMS (m/z): 419.2456[ M+H ]] + 。
Preparation of N- (4- ((1-methyl-1H-indol-6-yl) amino) -7- (2- (piperidin-1-yl) ethoxy) quinazolin-6-yl) acrylamide (example 20):
preparation of example 20 referring to the synthetic method of intermediate 6, the base was replaced with 2 equivalents of triethylamine. 1 H NMR(400MHz,DMSO-d 6 )δ9.72(s,1H),9.64(s,1H),8.92(s,1H),8.46(s,1H),7.87(d,J＝1.6Hz,1H),7.52(d,J＝8.5Hz,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.29(d,J＝3.1Hz,2H),6.70(dd,J＝17.0,10.2Hz,1H),6.40(d,J＝3.0Hz,1H),6.32(dd,J＝16.9,2.0Hz,1H),5.82(dd,J＝10.3,2.0Hz,1H),4.31(t,J＝5.9Hz,2H),3.78(s,3H),2.80(t,J＝5.8Hz,2H),2.48(t,J＝4.3Hz,4H),1.49(q,J＝5.6Hz,4H),1.38(q,J＝5.9Hz,2H).HRMS(m/z):471.2119[M+H] + 。
Example 21
1 H NMRδ8.07(d,J＝2.6Hz,1H),7.74(dd,J＝9.0,2.6Hz,1H),7.46(td,J＝8.0,6.0Hz,1H),7.36-7.29(m,3H),7.24(d,J＝9.0Hz,1H),7.18(td,J＝8.8,2.6Hz,1H),6.87(td,J＝16.2,10.3Hz,1H),6.21(dd,J＝16.9,5.9Hz,1H),5.78-5.75(m,1H),5.24(s,2H),4.35(dd,J＝45.6,13.4Hz,2H),3.99(d,J＝13.8Hz,1H),3.95(s,3H),3.46(d,J＝14.0Hz,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] + 。
Example 22
1 H NMRδ8.08(d,J＝2.6Hz,1H),7.75(dd,J＝9.0,2.6Hz,1H),7.46(td,J＝8.0,6.0Hz,1H),7.37-7.28(m,3H),7.25(d,J＝9.0Hz,1H),7.17(td,J＝8.8,2.6Hz,1H),6.86(td,J＝16.2,10.3Hz,1H),6.22(dd,J＝16.9,5.9Hz,1H),5.78-5.74(m,1H),5.24(s,2H),4.35(dd,J＝45.6,13.4Hz,2H),3.99(d,J＝13.8Hz,1H),3.97(s,3H),3.46(d,J＝14.0Hz,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] + 。
Example 23 biological Activity assay
The inhibition of EGFR (L858 R+T790M) mutant kinase by the compounds of the present invention was determined:
the operation flow is as follows:
(1) 1 XKinase buffer was prepared.
(2) Preparing a compound concentration gradient: the compound was diluted to 100 times the final desired highest inhibitor concentration in the reaction, 100% dmso. 100 μl of this compound dilution was transferred to wells in a 96-well plate. Mu.l of 100% DMSO was added to two wells and compound-free and enzyme-free controls were performed in the same 96-well plate. The plate is labeled as the source plate. Transfer 40 μl of compound from the source plate to a new 384 Kong Huisheng plate as an intermediate plate. Each well of 100nL was transferred from 384 Kong Huisheng plates to 384 Kong Ceban by echoing.
(3) To each well of the assay plate 5 μl of kinase solution, enzyme free control Kong Chuwai (5 μl 1x kinase buffer added) was added.
(4) Substrate and ATP substrate solutions were prepared in 1x kinase reaction buffer at a concentration 2 times the final concentration of each reagent required in the assay.
(5) To each well of the assay plate 5 μl of substrate solution was added.
(6) 384 well assay plates were incubated for 30 minutes or 60 minutes at room temperature.
(7) A detection solution of kinase-quenching buffer and antibody was prepared in Lance detection buffer at 2 times the required final concentration of each reagent.
(8) 10. Mu.L of the detection solution was added at room temperature for 60 minutes.
Data (500 nM) for the examples of the invention and the activity assays of the reference compounds are set forth in Table 1. The results are shown in Table 1.
TABLE 1EGFR (L858 R+T790M) mutant kinase inhibition Rate assay data
Test article Test object inhibition Rate (@ 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％
Determination of anti-proliferative effects of the inventive compounds in combination with cetuximab on human lung adenocarcinoma cells (NCI-H1975 cells):
the operation flow is as follows:
(1) Preparing 1640 a complete culture medium, wherein the preparation ratio is as follows: 1640 basal medium 89%, fetal bovine serum 10%, diabody 1%.
(2) The test compounds were prepared as 5mM stock solution in cell-grade DMSO and stored in a refrigerator at 4℃for use.
(3) Rapidly thawing frozen NCI-H1975 cells in a constant-temperature water bath kettle at 37 ℃, transferring into a centrifuge tube containing 5mL of complete culture, centrifuging for 5min at 1000r, suspending into single cell suspension, culturing in a T25 culture flask, and carrying out passage when the cell density is 80%, wherein the passage method is as follows: PBS buffer solution is used for rinsing, 2mL of pancreatin is used for digestion for 3min, 6mL of complete culture medium is added for stopping digestion and transferring into a 15mL centrifuge tube, 1000r of centrifugation is carried out for 5min, the supernatant is poured off, 5mL of complete culture medium is added for uniform blowing, and the culture is carried out continuously in a T25 culture flask.
(4) Cells in the logarithmic growth phase were prepared into suspensions, counted, diluted to 8000 cells/well, plated in 96-well plates, 100. Mu.L per well, and cultured in a constant temperature incubator at 37℃for 24 hours. After the cells are attached, the residual culture medium in each well is sucked out, the culture medium is added to dilute the test compound and cetuximab (1 mug/mL) with different concentrations (9 concentrations), and a blank control group (only the complete culture medium is added) and a positive control group (the cells and the culture medium are added without adding medicines) are simultaneously arranged and incubated in an incubator for 72 hours.
(5) Using CCK-8 reagent, 10. Mu.L of CCK-8 reagent was added to each well, and after 2-4 hours of incubation in an incubator, the plate was shaken in a microplate reader (4 min) to determine the fluorescence (OD) value at 450nm for each well.
(6) IC was performed using Graphpad Prism 5 software according to the following formula 50 Calculating a value:
data for the antiproliferative activity of the cells of the examples of the invention and the reference compounds are presented in table 2. The results are shown in Table 2.
Table 2 examples and results of measurements of antiproliferative activity of reference compound cells
Test article Test substance +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
The results show that all compounds of the invention are highly potent allosteric inhibitors of EGFR.
Example 24:
evaluation of compound stability using human liver microsomes:
liver microsomal enzyme stability of the example compounds was compared to BDTX 189.
Measurement system: the metabolic stability of the compounds of the invention was tested with 1mM NADPH using liver microsomes mixed by men and women. The samples were analyzed using a mass spectrometer. HRMS was used to determine the peak area response ratio (peak area corresponding to test compound or control divided by peak area of the analytical internal standard) without running the standard curve. To detect all possible metabolites, HRMS scans were performed in the appropriate m/z range.
Measurement conditions: the assay was performed with one incubation (n=1). The test compound was incubated at 37℃in a buffer containing 0.5 mg/ml liver microsomal protein. The reaction was initiated by addition of cofactor and sampled at 0, 2, 4, 8, 16, 24, 36, 48 hours, and positive controls (5 μm testosterone) were incubated in parallel and sampled at 0, 2, 4, 8, 16, 24, 36, 48 hours.
And (3) measuring quality control: the control compound testosterone was run in parallel to confirm the enzymatic activity of the (liver) microsomes. After the final time point, NADPH addition to the reaction mixture was confirmed using fluorometry. T1/2 of the control met the acceptable internal standard.
The analysis method comprises the following steps:
liquid chromatographic column: thermo BDS Hypersil C18 30×2.0mm,3 μm with guard column m.p., buffer: 25mM formic acid buffer, pH 3.5; aqueous phase (a): 90% water, 10% buffer; organic phase (B): 90% acetonitrile, 10% buffer; flow rate: 300 microliter/min autosampler: the injection volume was 10 microliters. Gradient procedure is seen in table 3.
TABLE 3 gradient procedure
Time (minutes) ％A ％B
0.0 100 0
1.5 0 100
2.0 0 100
2.1 100 0
3.5 100 0
By using human liver microsomes, examples 1, 2, 11, 12, 14 as described in the present invention exhibited metabolic half-lives greater than 20 hours, examples 15, 17, 18, 19, 20, 21, and 22 exhibited metabolic half-lives between 13-20 hours, significantly greater than the metabolic half-life of BDTX189 at 12 hours. The relatively long metabolic half-life allows the present invention the potential to reduce medical doses and expand dosing intervals.
For compounds of the general formula (I), the linking groups and the substituents have an important influence on the pharmacodynamic properties of the compounds. While the invention has been illustrated by the foregoing specific examples, it should not be construed as being limited thereto; but rather the invention encompasses the generic aspects previously disclosed. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.

Claims (10)

1. A compound of the structure represented by the general formula (I):
wherein ring A is selected from benzene ring, pyridine ring, pyrazine ring, R 1 Is H, C1-4 alkyl, halogen, R 2 Is halogen; or ring A is selected from benzene ring, pyrazine ring, R 1 Is H, C1-4 alkyl, halogen, R 2 Is H;
R 3 selected from substituted or unsubstituted C6-10 aryl, C5-12 heteroaryl, optionally substitutedIs intended to be selected from 1,2 or 3 substituents: H. halogen;
w is-R 4 (CH 2 ) m -、-O(CH 2 ) m -, wherein m is selected from 0,1,2, R 4 Selected from alkenyl and alkynyl; the Y ring is selected from cycloalkyl of C3-6 and heterocyclic group of C3-12; OR-W-Y is-OR 5 ，R 5 Selected from C1-4 alkyl;
z is selected from: H. -NR 6 、R 6 Selected from H, C1-4 alkyl groups.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the C3-12 heterocyclic group is selected from the group consisting of morpholine ring, piperidine ring,R 7 Selected from C1-4 alkyl.
3. The compound of the structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Selected from:
4. the compound of the structure of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an inorganic or organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
5. A pharmaceutical composition comprising a compound of the structure of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
6. Use of a compound of the structure of general formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prophylaxis of a disease in which EGFR-based activity is indicated.
7. The use of a compound of the structure of general formula (I) as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor drug.
8. The use according to claim 7, wherein the compound of the structure of formula (I) or a pharmaceutically acceptable salt thereof is used as an EGFR inhibitor during the use.
9. The use according to claim 7, wherein the tumour is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, small cell lung cancer or non-small cell lung cancer.
10. The use according to claim 7, wherein the compound of the structure of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with any one of the following antitumor agents:
(i) Antitumor drugs acting on DNA structures;
(ii) Antitumor drugs that affect nucleic acid synthesis;
(iii) Antitumor agents that affect transcription of nucleic acids;
(iv) An antitumor drug synthesized by tubulin;
(v) Inhibitors of cell signaling pathways such as inhibitors of epidermal growth factor receptor;
(vi) Anti-tumor monoclonal antibody.
CN202310556615.1A 2023-05-17 2023-05-17 Synthesis and application of EGFR allosteric inhibitors Pending CN116655599A (en)

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