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WO2023046030A1 - Inhibiteur à petite molécule egfr, composition pharmaceutique le contenant et son utilisation - Google Patents

Inhibiteur à petite molécule egfr, composition pharmaceutique le contenant et son utilisation Download PDF

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Publication number
WO2023046030A1
WO2023046030A1 PCT/CN2022/120630 CN2022120630W WO2023046030A1 WO 2023046030 A1 WO2023046030 A1 WO 2023046030A1 CN 2022120630 W CN2022120630 W CN 2022120630W WO 2023046030 A1 WO2023046030 A1 WO 2023046030A1
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Prior art keywords
alkyl
group
alkoxy
substituted
membered heteroaryl
Prior art date
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PCT/CN2022/120630
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English (en)
Chinese (zh)
Inventor
吕志俭
钟利
杨保成
高安慧
楼洋
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Biopolar Hongye Nantong Pharmaceutical Co Ltd
Henan Shengxiang Pharmatech Ltd
Original Assignee
Biopolar Hongye Nantong Pharmaceutical Co Ltd
Henan Shengxiang Pharmatech Ltd
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Priority to CN202280064128.7A priority Critical patent/CN118139846A/zh
Publication of WO2023046030A1 publication Critical patent/WO2023046030A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the invention relates to a small molecule inhibitor of EGFR, a pharmaceutical composition containing it and use thereof.
  • Epidermal growth factor receptor (EGFR, also known as HER-1 or c-erbB-1) is a 170-kDa transmembrane glycoprotein composed of 1186 amino acids.
  • EGFR is a member of the receptor tyrosine kinase c-erbB family, which regulates cell proliferation, survival, adhesion, migration and differentiation.
  • EGFR consists of three parts: the extracellular receptor region; the transmembrane region; and the intracellular tyrosine kinase region.
  • the confirmed ligands that can bind to EGFR include: epidermal growth factor (EGF), transforming growth factor ⁇ (TGF ⁇ ), two-way regulator, heparin-binding EGF, cytokines, etc.
  • EGFR is overactivated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, and prostate cancer.
  • tumor molecular targeting drugs targeting EGFR are mainly divided into two categories according to their properties: one is a monoclonal antibody that directly acts on the extracellular receptor region; the other is a drug that interferes with the activity of intracellular EGFR tyrosine kinase. small molecule inhibitors.
  • Monoclonal antibody drugs interact with the extramembrane ligand-binding domain of EGFR, so that endogenous ligands such as EGF cannot bind to EGFR, thereby preventing the signal from passing into cells; small molecule drugs interact with the catalytic domain of intracellular tyrosine kinase Binding, inhibiting its catalytic activity, thereby blocking cell proliferation signals.
  • the EGFR-TKI small molecule inhibitors that have been marketed include the first-generation Iressa, Tarceva, and Conmana, the second-generation afatinib and dacomitinib, and the third-generation osimertinib.
  • NSCLC patients benefited from EGFR-TKI therapy.
  • drug-resistant mutations in tumors and resistance are inevitable problems.
  • T790M drug-resistant mutations After treatment with first- and second-generation EGFR-TKIs, about 60% of patients will develop T790M drug-resistant mutations, resulting in the loss of therapeutic effect of first- and second-generation drugs.
  • osimertinib As a third-generation EGFR-TKI, osimertinib has very good inhibitory activity on T790M, thus bringing better therapeutic effect and survival benefits to patients.
  • the third-generation EGFR-TKI the EGFR C797S triple mutation was generated, resulting in the inability of the third-generation inhibitors to covalently bind to protein kinases, making these inhibitors ineffective.
  • the object of the present invention is to provide a class of macrocyclic small molecule compounds with novel structure, which can be used as mutant EGFR inhibitors, for double mutations produced by T790M (such as L858R/T790M or T790M/C797S), and L858R/T790M/C797S , Del19/T790M/C797S and other triple mutations have excellent therapeutic effects, and have good selectivity for wild-type EGFR protein.
  • T790M such as L858R/T790M or T790M/C797S
  • L858R/T790M/C797S Del19/T790M/C797S and other triple mutations have excellent therapeutic effects, and have good selectivity for wild-type EGFR protein.
  • the present invention provides a compound represented by formula I, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate,
  • R 1 , R 2 and the atoms connected to them jointly form a C5-C6 cycloalkyl group, a 5-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group; wherein, the C5-C6 cycloalkane Base, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by 1-3 R;
  • Ring A is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are further optionally substituted by 1-3 R;
  • Ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are optionally substituted by 1-3 R;
  • R 6 , R 7 , R' 6 and R' 7 are each independently selected from the following group: H, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 ring Alkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl are optionally substituted by 1-3 R;
  • R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 al
  • R 8 , R 9 , R' 8 and R' 9 are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C12 cycloalkane Base, 3-12 membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group, C3-C12 cycloalkyl C1-C6 alkyl, 3-12 membered heterocyclic group C1-C6 alkyl, C6 -C10 aryl C1-C6 alkyl, 5-10 membered heteroaryl C1-C6 alkyl;
  • the group connecting ring A to the pyrazole ring One or more of -CH 2 - in is optionally replaced by -SO 2 -;
  • n 1, 2, 3, 4, 5, 6 or 7;
  • n and m' are each independently 0, 1 or 2.
  • X is CH or N, preferably N.
  • ring A is selected from: phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic; wherein, the phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic
  • the group is further optionally substituted by 1-3 groups selected from the group consisting of halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl.
  • ring A is selected from: phenyl, piperidinyl, tolyl; wherein, the phenyl is preferably The piperidinyl is preferably More preferably, the left side of the piperidine ring is connected to the N in the right-NH- in formula I; the tolyl group is preferably More preferably, the left side of the benzene ring is connected to the N in -NH- on the right side of formula I.
  • ring B is selected from: phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic; wherein, the phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic
  • R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 al
  • R 8 , R 9 , R' 8 and R' 9 are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C6 cycloalkane Base, 3-6 membered heterocyclic group, C6-C10 aryl group, 5-6 membered heteroaryl group, C3-C6 cycloalkyl C1-C6 alkyl group, 3-6 membered heterocyclic group C1-C6 alkyl group, C6 -C10 aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl.
  • ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl or 5-10 membered heteroaryl; or, B ring is selected from: Phenyl, 5-6 membered heteroaryl or 6 membered heterocyclic group;
  • H in each of the above groups is further substituted by 1, 2 or 3 R;
  • R is selected from: -NR 8 R 9 ;
  • R is selected from: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl or C1-C6 alkoxyl, and H in each of the above groups is optionally selected from 1 of the following group , 2 or 3 groups are substituted: D, halogen, cyano, nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 ;
  • R9 is selected from: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl or C1-C6 alkoxyl, and H in each of the above groups is further selected from the following group 1, Substitution by 2 or 3 groups: D, halogen, cyano, nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 .
  • ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl or 5-10 membered heteroaryl; or, B ring is selected from: Phenyl, 5-6 membered heteroaryl or 6 membered heterocyclic group;
  • R is selected from: C1-C6 alkoxy, and the C1-C6 alkoxy is further substituted by a 3-7 membered heterocycle or 5-membered heterocyclic group, and the 3-7-membered heterocyclic group or 5-membered heterocyclic group is further substituted by oxo.
  • R can for example be
  • ring B is selected from: phenyl, substituted phenyl, pyridyl, substituted pyridyl, pyrimidyl, substituted pyrimidyl, piperidyl, substituted piperidyl, pyrazine Base, substituted pyrazinyl;
  • the phenyl group is preferably The pyridyl group is preferably The pyrimidinyl group is preferably The piperidinyl is preferably More preferably, the N of the piperidine ring is connected to the pyrazole ring of formula I;
  • the substitution refers to being substituted by one or more groups selected from the following group: D, halogen, cyano, nitro, hydroxyl, amino, carboxyl, -COOCH 3 , -COOCH 2 CH 3 , - OCOCH 3 , -CONHCH 3 , -NHCOCH 3 , -CON(CH 3 ) 2 , -SO 2 CH 3 , -SOCH 3 , -N(CH 3 )SO 2 CH 3 , C1-C6 alkyl, halogenated C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 Aryl, 5-6 membered heteroaryl,
  • the halogen is preferably F or Cl; the C1-C6 alkyl is preferably methyl; the C1-C6 alkoxy is preferably methoxy; the halogenated C1-C6 alkoxy is preferably CF 3 -O-;
  • the 3-6 membered heterocyclic group is preferably morpholinyl, more preferably
  • substitution on ring B refers to substitution by one or more groups selected from the following groups:
  • R 10 and R 11 are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, Halogenated C1-C6 alkoxy;
  • R 1 and R 2 are as defined above.
  • R 1 is H or C1-C3 alkyl, preferably H or methyl.
  • R is selected from: H, F, Cl, Br, I, methyl, ethyl, vinyl, isopropenyl, isopropyl, cyclopropyl, ethynyl, propyne phenyl, halophenyl, trifluoromethyl; or, R and R together with the atoms to which they are attached form substituted or unsubstituted thienyl , thiazolyl, furyl, imidazolyl, pyrrolyl, pyryl Azolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, wherein the substitution refers to being substituted by one or more groups selected from the group: H, D, halogen, cyano, nitro, hydroxyl , C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 al
  • R is selected from: H, F, Cl, Br, I, methyl, phenyl, fluorophenyl, cyclopropyl, propynyl, vinyl, isopropenyl, Ethyl, isopropyl, trifluoromethyl, ethynyl; alternatively, R and R together with the atoms to which they are attached form thienyl, methylimidazolyl, pyrrolyl, methylthienyl, methylpyrrolyl, imidazolyl, methylthiazolyl, furyl, phenyl, pyridyl; wherein, the propynyl is preferably The fluorophenyl group is preferably
  • R 3 is selected from: -P(O)(CH 3 ) 2 , -SO 2 CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHSO 2 CH 3 , -N(CH 3 )SO 2 CH 3 , -N(cyclopropyl)SO 2 CH 3 ,
  • R 4 is H.
  • R 5 is H.
  • R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 al
  • R 8 , R 9 , R' 8 and R' 9 are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C6 cycloalkane Base, 3-6 membered heterocyclic group, C6-C10 aryl group, 5-6 membered heteroaryl group, C3-C6 cycloalkyl C1-C6 alkyl group, 3-6 membered heterocyclic group C1-C6 alkyl group, C6 -C10 aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl.
  • the group that ring A is connected to the pyrazole ring One of the -CH 2 - is replaced by -SO 2 -, the group is preferably
  • the group that ring A is connected to the pyrazole ring H in is optionally substituted by 1, 2, 3, 4 or more than 5 (including 5) R'; wherein R' is as defined above.
  • R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy, for example methyl.
  • R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy, for example methyl.
  • R' is selected from: D,
  • the group that ring A is connected to the pyrazole ring 1, 2, or more than 3 (including 3) of -CH 2 - are replaced by O or NH, and this group can be, for example,
  • the compound has a structure shown in formula II,
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
  • the compound has a structure shown in formula III,
  • each R 12 is the same as the aforementioned R; preferably, the definition of each R 12 is the same as the aforementioned substituent of the B ring.
  • p 0, 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 12 , X, A and B are the groups corresponding to the specific compounds in the examples, and n and p are the groups in the examples The parameters corresponding to each specific compound in .
  • the compound has a structure shown in formula IV:
  • Q is selected from: N or CR 14 ;
  • R 13 , R 14 and R 15 are as defined above for R;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, A and B are the groups corresponding to each specific compound in the examples, and n is the group corresponding to each specific compound in the examples. corresponding parameters.
  • the compound is selected from the following group:
  • the present invention provides a pharmaceutical composition, comprising the compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate ; and a pharmaceutically acceptable carrier.
  • a preparation method of a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the present invention, its stereoisomer, its optical isomer, its pharmaceutical
  • the above acceptable salts, prodrugs or solvates thereof are mixed to form a pharmaceutical composition.
  • the pharmaceutical composition further includes other therapeutic agents.
  • Other therapeutic agents may be EGFR mAbs or MEK inhibitors.
  • the EGFR monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, necituzumab, nimotuzumab, or a combination thereof.
  • the MEK inhibitor is selected from the group consisting of selumetinib, trametinib, PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), or a combination thereof.
  • the present invention provides the compound described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as in the second aspect Use of the pharmaceutical composition in the preparation of medicines for inhibiting EGFR kinase.
  • the compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as described in the second aspect Use of the pharmaceutical composition in the preparation of medicines for EGFR-mediated diseases.
  • the EGFR is mutant EGFR, preferably L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, or a combination thereof; more preferably L858R, T790M, C797S, Del19, Or a combination thereof; more preferably L858R/T790M double mutation, T790M/C797S double mutation, L858R/T790M/C797S triple mutation or Del19/T790M/C797S triple mutation.
  • the drug for inhibiting EGFR kinase is a drug for treating cancer.
  • the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal carcinoma tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, rectal cancer, glioma, or a combination thereof.
  • the drug is used to treat lung cancer caused by EGFR L858R mutation.
  • the drug is used to treat lung cancer caused by EGFR Del19 mutation.
  • the drug is used to treat lung cancer caused by EGFR C797S mutation.
  • the drug is used to treat lung cancer caused by EGFR T790M mutation.
  • the drug is used to treat lung cancer caused by EGFR L858R/T790M mutation.
  • the drug is used to treat lung cancer caused by EGFR T790M/C797S mutation.
  • the drug is used to treat lung cancer caused by EGFR L858R/T790M/C797S mutation.
  • the drug is used to treat lung cancer caused by EGFR Del19/T790M/C797S mutation.
  • the present invention provides a method for treating cancer, which includes the step of: administering an effective amount of the compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutical An acceptable salt, a prodrug or a solvate thereof, or a pharmaceutical composition as described in the second aspect.
  • EGFR-mediated related diseases such as cancer
  • diseases such as cancer
  • present invention has been accomplished on this basis.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • the term "about” when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “comprises” or “includes (comprising)” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of”, or “consisting of”.
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 6 alkyl represents a straight-chain or branched alkyl group having 1-6 (eg 1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert-butyl, etc.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C 2 -C 6 alkenyl refers to a linear or branched alkenyl group having 2-6 (eg 2, 3, 4, 5 or 6) carbon atoms, such as vinyl, allyl, 1-propene group, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C 2 -C 6 alkynyl refers to a straight-chain or branched alkynyl group having 2-6 (eg 2, 3, 4, 5 or 6) carbon atoms, such as ethynyl, propynyl, butynyl group, or similar groups.
  • cycloalkyl refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C12 cycloalkyl” refers to a group having 3-12 (eg 3, 4, 5, 6, 7 , 8, 9, 10, 11 or 12) carbon atom cycloalkyl. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms such as bridged or spiro forms are also possible.
  • cycloalkyl group can also be fused to an aryl, heteroaryl, heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, such as wait.
  • cycloalkyl is intended to include substituted cycloalkyl groups.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having 1-6 carbon atoms (eg 1, 2, 3, 4, 5 or 6); it has Formula C1-C6 alkyl-O- or -C1-C5 alkyl-O-C1-C5 alkyl (eg, -CH 2 -O-CH 2 CH 3 , -CH 2 -O-(CH 2 ) 2 CH 3. -CH 2 CH 2 -O-CH 2 CH 3 ) structure, preferably C1-C6 alkyl-O-, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy base, isobutoxy or tert-butoxy, etc.
  • C1-C6 alkyl-O- for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy base, isobutoxy or tert-butoxy, etc.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O
  • 3-12 membered heterocyclyl refers to having 3-12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) atoms and wherein 1-3 (e.g. 1, 2 or 3) atoms are selected from Saturated or partially saturated cyclic radicals of heteroatoms of groups N, S and O. It may be monocyclic or bicyclic, for example bridged or spiro.
  • the 3-12-membered heterocyclic group is preferably a 3-8-membered heterocyclic group, more preferably a 3-6-membered or 6-8-membered heterocyclic group. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • the heterocyclyl may be fused to a heteroaryl, aryl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heterocyclyl such as wait.
  • aryl refers to an aromatic ring group that does not contain heteroatoms in the ring
  • C6-C12 aryl refers to an aromatic ring group that does not contain heteroatoms in the ring and has 6 to 12 (such as 6, 7, 8 , 9, 10, 11 or 12) carbon atoms of the aromatic ring group, which may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is Aryl ring.
  • phenyl ie six-membered aryl
  • naphthyl etc.
  • the six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl (such as ) and six-membered aryl and 5-6-membered heterocyclic group (such as wait).
  • the C6-C12 aryl group is preferably a C6-C10 aryl group.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 (eg 1, 2 or 3) atoms are heteroatoms selected from the group consisting of N, S and O, "5-12 membered heteroatoms "Aryl” means having 5-12 (e.g. 5, 6, 7, 8, 9, 10, 11 or 12) atoms and wherein 1-3 (e.g. 1, 2 or 3) atoms are selected from Cyclic aromatic radicals of heteroatoms of the groups N, S and O. It may be a single ring or a condensed ring.
  • heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamide, Formyl, formamide, carboxyl and carboxylate groups, etc.
  • halogen refers to F, Cl, Br and I. More preferably, halogen is selected from F, Cl and Br.
  • amino refers to -NH2 .
  • C1-C6 alkylamino refers to C1-C6 alkyl NH 2 , C1-C6 alkyl NH (C1-C6 alkyl) or C1-C6 alkyl-N (C1-C6 alkyl) 2 , preferably C1-C6 alkylamino is CH 2 NH 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NH 2 , CH 2 NHCH 3 , CH 2 CH 2 NHCH 3 , CH 2 CH 2 CH 2 NCH 3. CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 CH 2 N(CH 3 ) 2 .
  • C3-C12 cycloalkyl C1-C6 alkyl refers to -C3-C12 cycloalkyl C1-C6 alkyl or C3-C12 cycloalkyl C1-C6 alkyl-, "3-12 membered hetero "Cycloyl C1-C6 alkyl”, “C6-C10 aryl C1-C6 alkyl”, “5-10 membered heteroaryl C1-C6 alkyl” have similar meanings.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • substituted or unsubstituted the groups described in the present invention can be substituted by substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl.
  • substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl.
  • the structural formulas described herein are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers and geometric isomers (or conformers)): R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers or geometric isomers (or conformers) are within the scope of the present invention.
  • solvate refers to a complex in which a compound represented by formula I coordinates with solvent molecules to form a specific ratio.
  • the compound of the present invention refers to the compound represented by formula I, and also includes stereoisomers, pharmaceutically acceptable salts, prodrugs or solvates of the compound represented by formula I.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may arise in enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • the invention also includes isotopically labeled compounds (ie, isotopically derivatives) equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs.
  • isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Isotopic derivatives of the compounds of the present invention are within the protection scope of the present invention.
  • 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates.
  • Tritium (ie 3 H) and carbon-14 (ie 14 C) labeled compounds are relatively easy to prepare and detect, and are the first choice among isotopes.
  • substitution of heavier isotopes such as deuterium, ie 2 H may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage.
  • Isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the schemes disclosed in the Examples.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine,
  • a specific enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers.
  • the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, and then separated by crystallization or chromatography. Separation by conventional means then gives the pure enantiomers.
  • the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope.
  • substituted refers to replacing a hydrogen radical with a designated structural substituent.
  • substituents may be the same or different for each position.
  • substitution includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence.
  • stable herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.
  • Metabolites of compounds shown in formula I and pharmaceutically acceptable salts thereof, and prodrugs that can be transformed into compounds shown in formula I and pharmaceutically acceptable salts thereof in vivo are also included in the protection scope of the present invention.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
  • the preparation of the compounds of the present invention comprises the steps of:
  • X' is halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, n, A and B are as defined above;
  • Compound I-1 is reacted in an inert solvent (such as tert-butanol) in the presence of a catalyst (p-toluenesulfonic acid) to obtain Compound I.
  • an inert solvent such as tert-butanol
  • a catalyst p-toluenesulfonic acid
  • the synthesis of the compound also includes the steps of:
  • P is an amino protecting group (such as Boc);
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, X', n, A and B are as defined above;
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and/or treat (stabilize, alleviate or cure) EGFR kinase related diseases (such as non-small cell Lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, rectal cancer, glioma or a combination thereof, etc.).
  • diseases such as non-small cell Lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyn
  • the pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound/dose of the present invention, more preferably 10-200 mg of the compound/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” here means that each component in the pharmaceutical composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the compound of the invention is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, For example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) moisturizing (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; ( f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h)
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents, and the release of the compound of the invention in such pharmaceutical compositions may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents, and the release of the compound of the invention in such pharmaceutical compositions may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the compounds of the present invention can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol , 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol , 1,3-butanediol, dimethylformamide and
  • the pharmaceutical compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the compounds of this invention, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances wait.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances wait.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions .
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as EGFR inhibitors.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (such as EGFR inhibitors).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (such as EGFR inhibitors) can be used simultaneously, separately or sequentially with the compound of the present invention Prevention and/or treatment of diseases related to the activity or expression of EGFR kinase.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg,
  • the daily dosage is generally 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the compound of the present invention has novel structure and excellent EGFR kinase inhibitory effect
  • the compounds of the present invention can be used as EGFR kinase inhibitors, especially as mutant EGFR (especially double mutation or triple mutation, such as L858R/T790M, T790M/C797S, L858R/T790M/C797S, Del19/T790M/C797S, etc.) inhibitors.
  • mutant EGFR especially double mutation or triple mutation, such as L858R/T790M, T790M/C797S, L858R/T790M/C797S, Del19/T790M/C797S, etc.
  • the preparative PTLC thin layer chromatography
  • 20 x 20 cm plates 500 micron thick silica gel
  • the silica gel chromatography was performed on a Biotage flash chromatography system.
  • 1 H NMR hydrogen spectrum
  • Bruker AscendTM400 spectrometer 400MHz, 298°K
  • the chemical shift (ppm) of residual proton in deuterated reagent is given as a reference: the ⁇ (chemical shift) of CHCl is 7.26 ppm, the ⁇ of CH 3 OH or CH 3 OD is 3.30 ppm, and the ⁇ of DMSO-d6 is 32.50 ppm.
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • MS mass range 150-750 amu; positive ion electrospray ionization.
  • MS mass range 150-750 amu; positive ion electrospray ionization.
  • MS mass range 150-750 amu; positive ion electrospray ionization.
  • Intermediate M3 was prepared according to the method of intermediate M2, except that intermediate M1 was replaced by m-bromonitrobenzene (1.05g, 5.20mmol, 1.0eq) to obtain intermediate M3 (0.8g, yield 81.3%) ), as a white solid.
  • Compound 36B was prepared according to the same method as compound 1A in Example 1, except that compound 4-aminophenylacetic acid ethyl ester was replaced by compound 36A to obtain compound 36B (2.2 g, yield 61.8%) as a black oil.
  • LCMS: m/z 320[M+H] +.
  • Compound 36C was prepared according to the same method as compound 1B in Example 1, except that compound 1A was replaced by compound 36B to obtain compound 36C (2.0 g, yield 99.7%) as a colorless oil.
  • LCMS: m/z 292[M+H] +.
  • Compound 36D was prepared according to the same method as compound 1C in Example 1, replacing compound 1B with compound 36C to obtain compound 36D (1.5 g, yield 90.5%) as a light-colored oil.
  • LCMS: m/z 242[M+H] +.
  • Compound 36E was prepared according to the same method as compound 1D in Example 1, except that compound 1C and 2,4,5-trichloropyrimidine were replaced by compound 36D (520mg, 2.16mmol, 1.0eq) and 5-bromo- 2,4-dichloropyrimidine to obtain compound 36E (0.42 g, yield 45.0%) as a white solid.
  • LCMS: m/z 432[M+H] +.
  • Compound 36F was prepared according to the same method as compound 1E in Example 1, except that compound 1D was replaced by compound 36E to obtain compound 36F (0.5 g, yield 99%) as a white solid.
  • LCMS: m/z 510[M+H] +.
  • Compound 36G was prepared according to the same method as compound 1F in Example 1, except that compound 1E was replaced by compound 36F (150 mg, 0.29 mmol, 1.0 eq), and intermediate M2 was replaced by intermediate M3 to obtain compound 36G (160 mg, Yield: 91.4%) as a colorless oil.
  • LCMS: m/z 603[M+H] +.
  • Compound 36 was prepared according to the method of compound 1 in Example 1, except that compound 1G was replaced by compound 36H to obtain compound 36 (40 mg, yield 28.1%) as a white solid.
  • reaction solution was concentrated by filtration, diluted with water, extracted three times by adding ethyl acetate, the organic phase was washed with water and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, concentrated by filtration to obtain a crude product, which was prepared and separated by Prep-HPLC to obtain the product compound 38 (10 mg , the yield is 31.6%).
  • Example compounds 2-35, 37, and 39-128 were prepared by referring to the method of Example 1 or Example 2, and the example compounds 1-128 of the present invention are summarized in Table 1 below:
  • A IC 50 ⁇ 10nM
  • E IC 50 >10000nM.
  • "-" means not tested.
  • the compound of the present invention has excellent inhibitory activity on mutant EGFR, especially the double mutation and triple mutation, can overcome drug resistance to early related drugs, and is expected to be further developed as a compound for the preparation of EGFR (L858R/T790M , L858R/T790M/C797S, Del19/T790M/C797S, etc.) kinase activity or drugs for the treatment of EGFR (L858R/T790M, L858R/T790M/C797S, Del19/T790M/C797S, etc.) related diseases.

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Abstract

L'invention concerne un inhibiteur à petite molécule EGFR, une composition pharmaceutique le contenant et son utilisation. Plus particulièrement, l'invention concerne un composé représenté par la formule I, et un stéréoisomère, un isomère optique, un sel pharmaceutiquement acceptable, un promédicament ou un solvate de celui-ci. Le composé peut être utilisé pour prévenir et/ou traiter des maladies associées à médiation par EGFR, et présente en particulier un effet spécifique contre la résistance à des médicaments associés précoces provoqués par deux mutations et trois mutations.
PCT/CN2022/120630 2021-09-23 2022-09-22 Inhibiteur à petite molécule egfr, composition pharmaceutique le contenant et son utilisation Ceased WO2023046030A1 (fr)

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