CN117229262A - Preparation and application of polyaromatic ring EGFR inhibitor - Google Patents

Preparation and application of polyaromatic ring EGFR inhibitor Download PDF

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CN117229262A
CN117229262A CN202211238113.6A CN202211238113A CN117229262A CN 117229262 A CN117229262 A CN 117229262A CN 202211238113 A CN202211238113 A CN 202211238113A CN 117229262 A CN117229262 A CN 117229262A
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alkyl
optionally
cycloalkyl
egfr
compound
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梁永宏
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Yaoya Technology Shanghai Co ltd
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Yaoya Technology Shanghai Co ltd
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Abstract

The application discloses a selective inhibitor containing multiple aromatic rings and serving as a clinical mutant of EGFR kinase, and particularly discloses a compound shown in a formula I or pharmaceutically acceptable salts, stereoisomers and tautomers thereof, a preparation method thereof, a pharmaceutical composition containing the compound and medical application thereof.

Description

Preparation and application of polyaromatic ring EGFR inhibitor
Technical Field
The present application relates to compounds having multiple aromatic rings as EGFR tyrosine kinase inhibitors.
Foreground technique
EGFR (epidermal growth factor receptor ) -TKI (tyrosine kinase inhibitor, tyrosine kinase inhibitor) is taken as a small molecule inhibitor, and is used for competing with and combining EGFR through an endogenous ligand to inhibit activation of tyrosine kinase, so that an EGFR signal path is blocked, and a series of biological effects of inhibiting proliferation and metastasis of tumor cells, promoting apoptosis of the tumor cells and the like are finally generated, so that the EGFR is one of main targets for lung cancer treatment.
Clinically, EGFR tyrosine kinase inhibitors have been used in the treatment of cancer, the first generation of reversible EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Second generation EGFR tyrosine kinase inhibitors include lenatinib, dacatinib, afatinib, all of which contain electrophilic groups Michael acceptors in their structures. In which afatinib is taken as a drug representative example, the allylic amide structure plays a critical role in the anti-tumor activity of afatinib, and the afatinib acts as Michael acceptor to perform Michael addition reaction with the catalytic site (thiol of new nucleus) of cysteine residue (Cys 797) on EGFR, so that kinase is inactivated, the activity of tyrosine kinase is irreversibly inhibited, and thus the afatisfatinib has good loving resistance. Researchers have completely demonstrated the presence of these covalent bonds at the molecular level by growing crystals of inhibitor and receptor, and have found that afatinib strongly inhibits these enzymes by acting with Cys 805 of HER2 as Cys 803 of HER 4. In vitro testing on wild-type EGFR shows that afatinib has better effect on inhibition of wild-type EGFR and L858R/T790M double mutant compared with gefitinib, erlotinib and lapatinib. Furthermore, afatinib inhibited DER4 30-fold more than Yu Lapa. Osimertinib (Ornitinib, AZD 9291) is a third generation EGFR-TKI targeting drug, and patients also develop drug resistance although it has higher response rate against drug resistance caused by the T790M mutation (Clin cancer; 21 (17), 2015). The drug resistance analysis of 15 patients AZD9291 was first reported in Nature Medicine,21,560-562,2015, 2015, in which the third mutation, EGFR C797S mutation, was obtained as one of the main mechanisms leading to the drug Osimertiinib resistance, accounting for about 40%. A series of compounds having inhibitory activity against EGFRC797S/T790M are reported in WO 2021/133809.
Disclosure of Invention
The application relates to a compound shown as a formula (I) or pharmaceutically acceptable salt thereof
Wherein,
b can be S;
z can be O, NH;
X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 can be independently selected from N, CR 6 ；
R 1 Can be selected from H, D, F, cl, br, I, CN, OH, NR a R b 、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl group, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl groups are each independently optionally substituted with 1,2 or 3R c Substitution;
R 2 can select H, D, F, cl, br, I, CN and NR a R b 、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl group, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl is optionally selected from D, F, cl, br, I, OH, NR a R b 、C 1 -C 2 Alkyl and C 1 -C 2 1 to 3 groups of the alkoxy group are substituted;
R 3 can select H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl;
R 4 can select H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl;
R 5 can select H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl, said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl is optionally selected from D, F, cl, br, I, OH, NR a R b 、C 1 -C 2 Alkyl and C 1 -C 2 1 to 3 groups of the alkoxy group are substituted;
R 6 can select H, D, F, cl, br, I, CN, OH, NR a R b 、C 1 -C 2 Alkoxy and optionally 1 to 3 groups substituted C with a member selected from D, F, cl, br, I 1 -C 2 An alkyl group;
R a 、R b and R is c Are respectively and independently selected from H, D, F, cl, br, I, OH, CN, NH 2 、CH 3 、OCH 3 、CH 2 CH 3 And CF (compact F) 3 ；
In some embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is further represented by formula (II-A), (II-B), (II-C), or (II-D)
The present application also provides a compound as described below, or a pharmaceutically acceptable salt thereof, selected from:
the application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula I of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof. In some embodiments, the pharmaceutical compositions of the present application further comprise pharmaceutically acceptable excipients.
In another aspect, the application relates to a method of treating an EGFR-mediated disease in a subject, comprising administering to a subject, preferably a mammal, more preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof.
In another aspect, the application relates to the use of a compound of formula i, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of EGFR mediated diseases.
In another aspect, the application relates to the use of a compound of formula i, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, for the prevention or treatment of EGFR mediated diseases.
In another aspect, the application relates to a compound of formula i, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, for the prevention or treatment of EGFR mediated diseases.
In some embodiments, the EGFR-mediated disease described herein is selected from EGFR mutant-mediated diseases. Wherein the mutant is selected from one, two, three or four of L858R, T790M, d (e.g., d746-750, which is one of the exon 19 deletion mutations), C797S; in some embodiments, wherein the mutant is selected from two mutants of L858R and T790M; in some embodiments, wherein the mutant is selected from two mutants of d19 and T790M. Further, in some embodiments, wherein the mutant comprises a C797S mutant; still further, wherein the mutant is selected from the group consisting of three mutants of L858R, T790M and C797S; or wherein the mutant is selected from the group consisting of three mutants of d19, T790M and C797S.
In some embodiments, the EGFR-mediated disease described herein is selected from cancer.
In some embodiments, the EGFR-mediated disease described herein is selected from lung cancer.
In some embodiments, the EGFR-mediated disease described herein is selected from non-small cell lung cancer.
The compounds of the application have good kinase and cellular activity (including wild type and mutant, e.g., d19, T790M, C797S and L858R). Stable metabolism in vitro and in vivo, and has excellent in vivo efficacy.
Certain chemical terms
Unless stated to the contrary, the following terms used in the specification and claims.
The expression "C" as used herein has the following meaning x-y "means a range of carbon number wherein x and y are integers, e.g. C 3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8 "also includes any subrange therein, e.g. C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 Etc.
"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of the present application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic mono-or bi-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:
"fused heterocyclyl" means a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"hydroxy" means-OH, "amino" means-NH 2 "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF 3 。
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl groups, and the like.
"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.
"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present application may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
The compounds of the application may also exist as geometric isomers. The present application contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.
The compounds of the application may also exhibit tautomerism, such as keto-enol tautomerism.
It is to be understood that the present application includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.
"isotopes" are all isotopes of atoms that are present in compounds of the application. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Isotopically-labeled compounds of the present application can generally be employed by conventional techniques known to those skilled in the art or by carrying out the procedures recited hereinSimilar methods to those described in the examples use a suitable isotopically labeled reagent instead of a non-isotopically labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
By "prodrug" is meant that the compounds of the application may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present application which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the application are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the application according to well known methods.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the application contain one or more acidic or basic groups, the application also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the application containing acidic groups may be present in salt form and may be used according to the application, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the application containing basic groups may be present in salt form and may be used according to the application in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the application contain both acidic and basic groups in the molecule, the application includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
Thus, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present application has a plurality of crystalline forms, some compounds of the present application may have more than one crystalline form, and the present application encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the application and polymorphs thereof are also within the scope of the present application.
Crystallization often yields solvates of the compounds of the present application, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present application and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present application may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the application may be true solvates, but in other cases the compounds of the application may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the application may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present application are also included within the scope of the present application.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Synthesis method
The application also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the application can be carried out by the following exemplary methods and examples, which, however, should not be regarded as limiting the scope of the application in any way. The compounds described herein may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
Detailed Description
The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present application has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the application without departing from the spirit and scope of the application.
Example 1: preparation of N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) isoquinolin-3-amine (compound 1)
2-chloro-4-aminopyrimidine (1.29 g,0.01 mol), 1- (cyclopropanesulfonyl) -1H-pyrazole-4-boronic acid pinacol ester (2.98 g,0.01 mol) and CS 2 CO 3 A solution of (6.5 g,0.02 mol) and DPPF palladium dichloride (1.45 g,2 mmol) in 1, 4-dioxane (50 mL) was heated at 90℃for 5 hours. The reaction was cooled to room temperature, diluted with EA and washed with water, then with saturated sodium chloride solution. The organic phase was collected, dried over sodium sulfate and concentrated. The white solid, 2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) -4-aminopyrimidine (1.51 g, 62%) was obtained by flash column separation. LC/MS (ESI) m/z=266 [ M+H ]] + 。
2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) -4-aminopyrimidine (0.214 g,1 mmol) was dissolved in 1, 4-dioxane (5 mL) under nitrogen, then 3-chloro-8- [ (2R, 3S) -3- (methylsulfonylmethyl) -2-methylazetidin-l-yl was added]-5- (propan-2-yl) isoquinoline (0.366 g,1 mmol), CS 2 CO 3 (0.65G, 63.2 mmol) and XantphosPd G4 (1.51G, 1.58 mmol). The reaction was stirred at 100℃for 3 hours. The reaction was then cooled to room temperature and diluted with 300mL of water. Extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was isolated and purified by flash column to give N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -5-isopropyl-8- ((2 r,3 s) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) isoquinolin-3-amine (0.34 g, 62%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δppm 10.33(s,1H),9.01(s,1H),8.69(s,1H),8.62(s,1H),8.47(s,1H),8.40(d,1H),7.42(d,1H),7.12(d,1H),6.56(d,1H),4.79(m,1H),4.69(m,1H),3.72-3.42(m,4H),2.98(s,3H),2.88(m,1H),1.42(d,3H),1.31–1.23(m,10H).LC/MS(ESI):m/z＝596[M+H] + 。
Example 2: preparation of N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) -1,3, 5-triazin-2-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) isoquinolin-3-amine (Compound 2)
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Compound 2 (0.37 g,62% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=597 [ M+H ]] + 。
Example 3: preparation of N- (4- ((3S, 4R) -3-fluoro-3-methyl-4-methoxypiperidin-1-yl) -1,3, 5-triazin-2-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) isoquinolin-3-amine (Compound 3)
Compound 3 (0.36 g, 61% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=597 [ M+H ]] + 。
Example 4: preparation of N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) -2, 6-naphthyridin-3-amine (compound 4)
Compound 4 (0.31 g, 52% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=597 [ M+H ]] + 。
Example 5: preparation of N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) -2, 7-naphthyridin-3-amine (compound 5)
Compound 5 (0.35 g, 59% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=597 [ M+H ]] + 。
Example 6: preparation of N- (2- (1- (cyclopropanesulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -5-isopropyl-8- ((2R, 3S) -2-methyl-3- (methylsulfonylmethyl) azetidin-1-yl) pyridine [3,4-d ] pyridazin-7-amine (Compound 6)
Compound 6 (0.44 g, yield 74%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=598 [ M+H ]] + 。
Test example 1: in vitro kinase Activity
1.1 EGFR (WT) inhibitory Activity Screen
With kinase buffer (50 mM HEPES, 10mM MgCl) 2 50 ng/. Mu.L of EGFR (WT, cana) stock was diluted with 2mM DTT, 1mM EGTA, 0.01% Tween 20, 6. Mu.L of 1.67 X0.005 ng/. Mu.L working solution (final concentration of 0.003 ng/. Mu.L) was added to each well, and the various compounds dissolved in DMSO were added to the wells using a nanoliter applicator to give a final concentration of 100nM-0.0244nM, a 4-fold gradient for 7 total concentrations, and a blank control well (containing no enzyme) and a negative control well (containing enzyme, plus vehicle DMSO) were simultaneously set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5 X25. Mu.M ATP (final concentration of 5. Mu.M, sigma) prepared with kinase buffer was mixed with 5 X0.5. Mu.M substrate (final concentration of 0.1. Mu.M, ulight-poly GT, perkinelmer) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate and membrane closure, after 2h of room temperature reaction, 5. Mu.L of 4X 40mM EDTA (final concentration 10 mM) was added to each well, and 5min at room temperature, and then 5. Mu.L of 4X 8nM detection reagent (final concentration 2nM, eu-anti-phospho-tyrosine antibody, perkinelmer) was added to each well, incubated at room temperature for 1h, and a PerkinElmer Envision multifunctional microplate reader was used to read plates (excitation 320nM, emission 665 nM) and IC was calculated by four-parameter fitting 50 . Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
1.2 EGFR (L858R/T790M) inhibitory Activity Screen
Buffer with kinaseLiquid (50 mM HEPES, 10mM MgCl) 2 50 ng/. Mu.L of EGFR (L858R/T790M, carna) stock was diluted with 2mM DTT, 1mM EGTA, 0.01% Tween 20, 6. Mu.L of 1.67X 0.004175 ng/. Mu.L working solution (final concentration of 0.0025 ng/. Mu.L) was added to each well, and the DMSO-dissolved different compounds were added to the wells using a nanoliter-type applicator to give final concentrations of 10nM-0.0024nM, a 4-fold gradient for 7 total, and a blank well (without enzyme) and a negative control well (containing enzyme, plus vehicle DMSO) were set, followed by 2 multiplex wells. After 30min of reaction of the enzyme with the compound or vehicle, 5 X25. Mu. MATP (final concentration 5. Mu.M, sigma) prepared with kinase buffer was mixed with 5 X0.5. Mu.M substrate (final concentration 0.1. Mu.M, ulight-poly GT, perkinelmer) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate and membrane closure, after 2h of room temperature reaction, 5. Mu.L of 4X 40mM EDTA (final concentration 10 mM) was added to each well, and 5min at room temperature, and then 5. Mu.L of 4X 8nM detection reagent (final concentration 2nM, eu-anti-phospho-tyrosine antibody, perkinelmer) was added to each well, incubated at room temperature for 1h, and a PerkinElmer Envision multifunctional microplate reader was used to read plates (excitation 320nM, emission 665 nM) and IC was calculated by four-parameter fitting 50 . Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
1.3 EGFR (d 746-750/T790M) inhibitory activity screening
50 ng/. Mu.L of EGFR (d 746-750/T790M, carna) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl2, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67 X0.005 ng/. Mu.L working solution (final concentration 0.003 ng/. Mu.L) was added to each well, and the DMSO-dissolved different compounds were added to the wells using a nanoliter applicator to give a final concentration of 10nM-0.0024nM, 4-fold gradient, with 7 concentrations of blank wells (containing enzyme) and negative control wells (containing enzyme, plus vehicle DMSO) and 2 multiplex wells. After 30min of reaction of the enzyme with the compound or vehicle, 5 X25. Mu. MATP (final concentration 5. Mu.M, sigma) prepared with kinase buffer was mixed with 5 X0.5. Mu.M substrate (final concentration 0.1. Mu.M, ulight-poly GT, perkinelmer) at 1:1 and added to the wells at 4. Mu.L per well; sealing plate filmAfter 2h of room temperature reaction after sealing, 5. Mu.L of 4X 40mM EDTA (final concentration 10 mM) was added to each well, and the reaction was performed at room temperature for 5min, and then 5. Mu.L of 4X 8nM detection reagent (final concentration 2nM, eu-anti-phospho-tyrosine antibody, perkinelmer) was added to each well, incubated at room temperature for 1h, and a PerkinElmer Envision multifunctional microplate reader was used to read plates (excitation 320nM, emission 665 nM) and IC was calculated by four-parameter fitting 50 . Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
1.4 EGFR (L858R/T790M/C797S) inhibitory Activity Screen
With kinase buffer (50 mM HEPES, 10mM MgCl) 2 50 ng/. Mu.L EGFR (L858R/T790M/C797S, BPS) stock was diluted with 2mM DTT, 1mM EGTA, 0.01% Tween 20, 6. Mu.L 1.67 X0.00167 ng/. Mu.L working solution (final concentration 0.001 ng/. Mu.L) was added to each well, and DMSO-dissolved different compounds were added to the wells using a nanoliter-type-applicator to give final concentrations of 10nM-0.0024nM, a 4-fold gradient, 7 total, and blank wells (without enzyme) and negative control wells (containing enzyme, vehicle DMSO) were set. After 30min of reaction of the enzyme with the compound or vehicle, 5 X25. Mu. MATP (final concentration 5. Mu.M, sigma) prepared with kinase buffer was mixed with 5 X0.5. Mu.M substrate (final concentration 0.1. Mu.M, ulight-poly GT, perkinelmer) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate and membrane closure, after 2h of room temperature reaction, 5. Mu.L of 4X 40mM EDTA (final concentration 10 mM) was added to each well, and 5min at room temperature, and then 5. Mu.L of 4X 8nM detection reagent (final concentration 2nM, eu-anti-phospho-tyrosine antibody, perkinelmer) was added to each well, incubated at room temperature for 1h, and a PerkinElmer Envision multifunctional microplate reader was used to read plates (excitation 320nM, emission 665 nM) and IC was calculated by four-parameter fitting 50 . Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
1.5 EGFR (d 746-750/T790M/C797S) inhibitory Activity Screen
With kinase buffers(50mM HEPES、10mM MgCl 2 50 ng/. Mu.L of EGFR (d 746-750/T790M/C797S, BPS) stock was diluted with 2mM DTT, 1mM EGTA, 0.01% Tween 20, 6. Mu.L of 1.67 X0.05 ng/. Mu.L working solution (final concentration 0.03 ng/. Mu.L) was added to each well, and DMSO-dissolved different compounds were added to the wells using a nanoliter-type-applicator to give final concentrations of 10nM-0.0024nM, a 4-fold gradient, 7 total, and blank wells (without enzyme) and negative control wells (containing enzyme, vehicle DMSO) were set, with 2 multiplex wells. After 30min of reaction of the enzyme with the compound or vehicle, 5 X25. Mu. MATP (final concentration 5. Mu.M, sigma) prepared with kinase buffer was mixed with 5 X0.5. Mu.M substrate (final concentration 0.1. Mu.M, ulight-poly GT, perkinelmer) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate and membrane closure, after 2h of room temperature reaction, 5. Mu.L of 4X 40mM EDTA (final concentration 10 mM) was added to each well, and 5min at room temperature, and then 5. Mu.L of 4X 8nM detection reagent (final concentration 2nM, eu-anti-phospho-tyrosine antibody, perkinelmer) was added to each well, incubated at room temperature for 1h, and a PerkinElmer Envision multifunctional microplate reader was used to read plates (excitation 320nM, emission 665 nM) and IC was calculated by four-parameter fitting 50 The results are shown in Table 1. Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
TABLE 1 in vitro kinase Activity results
In vitro kinase activity shows that the designed compounds have strong inhibition activity on EGFR mutant strains.
Although the application has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the application. The scope of the application is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (5)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
b can be S;
z can be O, NH;
X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 can be independently selected from N, CR 6 ；
R 1 Can be selected from H, D, F, cl, br, I, CN, OH, NR a R b 、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl group, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6
Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl groups are each independently optionally substituted with 1,2 or 3R c Substitution;
R 2 can select H, D, F, cl, br, I, CN and NR a R b 、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy groupor-O-C 3 -C 6 Cycloalkyl group, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1-6 Alkylamino, C 2 -C 6 Alkenyloxy, C 2 -C 6 Alkynyloxy or-O-C 3 -C 6 Cycloalkyl is optionally selected from D, F, cl, br, I, OH, NR a R b 、C 1 -C 2 Alkyl and C 1 -C 2 1 to 3 groups of the alkoxy group are substituted;
R 3 can select H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl;
R 4 can select H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl;
R 5 can select H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl, said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl is optionally selected from D, F, cl, br, I, OH, NR a R b 、C 1 -C 2 Alkyl and C 1 -C 2 1 to 3 groups of the alkoxy group are substituted;
R 6 can select H, D, F, cl, br, I, CN, OH, NR a R b 、C 1 -C 2 Alkoxy and optionally 1 to 3 groups substituted C with a member selected from D, F, cl, br, I 1 -C 2 An alkyl group;
R a 、R b and R is c Are respectively and independently selected from H, D, F, cl, br, I, OH, CN, NH 2 、CH 3 、OCH 3 、CH 2 CH 3
And CF (compact F) 3 ；
2. The compound according to claim 1, wherein the compound is represented by the general formula (II)-A), (II-B), (II-C) or (II-D) represents
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
4. a pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof.
5. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition of claim 3, in the manufacture of a medicament for the prevention or treatment of an EGFR-mediated disease;
optionally, the EGFR-mediated disease is selected from EGFR mutant-mediated diseases;
optionally, the mutant is selected from one, two, three or four of L858R, T790M, d, C797S;
optionally, the mutant is selected from two mutants of L858R and T790M;
optionally, the mutant is selected from two mutants of d19 and T790M;
optionally, the mutant comprises a C797S mutant;
optionally, the mutant is selected from the group consisting of three mutants of L858R, T790M and C797S; or the mutant is selected from three mutants of d19, T790M and C797S;
optionally, the EGFR-mediated disease is selected from cancer;
optionally, the EGFR-mediated disease is selected from lung cancer;
optionally, the EGFR-mediated disease is selected from non-small cell lung cancer.
CN202211238113.6A 2022-10-11 2022-10-11 Preparation and application of polyaromatic ring EGFR inhibitor Pending CN117229262A (en)

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