WO2021209039A1 - 一种喹唑啉类化合物、制备方法及其应用 - Google Patents

一种喹唑啉类化合物、制备方法及其应用 Download PDF

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WO2021209039A1
WO2021209039A1 PCT/CN2021/087774 CN2021087774W WO2021209039A1 WO 2021209039 A1 WO2021209039 A1 WO 2021209039A1 CN 2021087774 W CN2021087774 W CN 2021087774W WO 2021209039 A1 WO2021209039 A1 WO 2021209039A1
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alkyl
compound
methyl
hydrogen
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French (fr)
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张强
杨磊夫
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北京赛特明强医药科技有限公司
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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and relates to a quinazoline compound, a preparation method and an application thereof.
  • Epidermal growth factor receptor is a transmembrane glycoprotein belonging to the tyrosine kinase receptor family. Its expression is very extensive and it plays an important role in growth and development and normal physiological functions. . In addition, EGFR and its mediated signaling pathways play an important role in the occurrence and development of tumors. However, the expression of EGFR is very unstable, and gene amplification and rearrangement often occur, which changes the antigen phenotype on the surface of tumor cells. Among them, epidermal growth factor receptor type III mutants (epidermal growth factor receptor variant III, EGFRvIII) The most common.
  • EGFRvIII is a type of epidermal growth factor receptor (EGFR) mutant that is only expressed on the surface of tumor cells rather than normal tissue cells, discovered in recent years.
  • the abnormal expression of EGFR is related to the occurrence of many malignant tumors, including glioma, lung small cell carcinoma, breast cancer, bladder cancer, ovarian cancer and so on.
  • the 2-7th exons encoding the extracellular ligand binding region of EGFRvIII are deleted, resulting in a deletion of 801 base pairs, making exons 1 and 8 connect and bind in this way.
  • Dot produces a new glycine, resulting in the deletion of amino acids 6 to 273, thus losing the ability to bind to the ligand EGF.
  • EGFRvIII enables unregulated structural activation of tyrosine kinases through dimerization and autophosphorylation, inducing downstream signal transduction and stimulating tumor cell proliferation.
  • EGFRvIII can affect the occurrence and development of tumors by regulating a variety of signal transmission pathways, including Ras/Raf/MEK/ERK, PI3/AKT/mTOR, JAK/STAT and PLC/PKC.
  • the tumorigenicity of EGFRvIII-positive tumor cells is significantly increased, mainly by inhibiting cell apoptosis, promoting tumor angiogenesis, increasing invasiveness and migration, etc., leading to uncontrollable spontaneous proliferation and metastasis of tumor cells.
  • EGFRvIII plays a similar escape function in the process of tumor radiotherapy and chemotherapy.
  • Glioma is a common and highly aggressive malignant tumor, and glioblastoma (GBM) is the most malignant type.
  • GBM glioblastoma
  • the effects of radiotherapy and chemotherapy are not ideal, and recurrence often occurs after surgery.
  • Studies at home and abroad have found that 40% to 60% of GBM significantly express EGFR, and its mutant form is mainly EGFRvIII.
  • EGFRvIII establishes a signal pathway regulation network through receptor-independent autophosphorylation and tyrosine kinase activity, and plays an important role in regulating the growth, metastasis and angiogenesis of GBM.
  • Drugs that target EGFRvIII to treat gliomas not only need to be able to effectively penetrate the blood-brain barrier, but also need to be able to effectively inhibit EGFRvIII.
  • EGFRvIII-driven glioma has important clinical value.
  • most of the listed EGFR and HER2 kinase inhibitors cannot penetrate the blood-brain barrier, and patients with EGFR-driven lung cancer and HER2-driven breast cancer generally have a poor prognosis and a higher risk of brain metastasis. .
  • there is no effective drug approved for the treatment of brain metastases so it is urgent to develop an EGFR inhibitor and/or HER2 inhibitor that can penetrate the blood-brain barrier.
  • One aspect of the present invention provides a compound represented by formula (I), its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof,
  • n 0, 1 or 2;
  • A is halogen, C 1 -C 3 alkyl;
  • Z is NH or O;
  • R 1 is hydrogen, hydroxyl, 4-7 membered heteroalicyclic group or -NR a R b ,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by hydroxy, substituted by C 1- C 3 alkoxy A C 1 -C 6 alkyl group, or a C 1 -C 6 alkyl group substituted by a C 3- C 6 cycloalkyl group;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, -O-(CH 2 )nR 7 ,
  • R 7 is hydrogen, C 1 -C 3 alkyl, 1 to 3 selected from halogen, cyano, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 3 alkynyl, C 2 -C 3 alkenyl or -NR'R" substituted or unsubstituted aryl or heteroaryl , N is an integer of 0-3,
  • the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring
  • the heteroaryl group is a group containing 1-3 heteroatoms selected from N, O, and S as ring atoms
  • R'and R" are each independently H or a C 1 -C 3 alkyl group.
  • A is halogen, C 1 -C 3 alkyl;
  • Z is NH or O;
  • R 1 is hydrogen, hydroxyl, 4-7 membered heteroalicyclic group or -NR a R b ,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by hydroxy, substituted by C 1- C 3 alkoxy A C 1 -C 6 alkyl group, or a C 1 -C 6 alkyl group substituted by a C 3- C 6 cycloalkyl group;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, -O-(CH 2 )nR 7 ,
  • R 7 is hydrogen, C 1 -C 3 alkyl, 1 to 3 selected from halogen, cyano, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 3 alkynyl, C 2 -C 3 alkenyl or -NR'R" substituted or unsubstituted aryl or heteroaryl , N is an integer of 0-3,
  • the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring
  • the heteroaryl group is a group containing 1-3 heteroatoms selected from N, O, and S as ring atoms
  • R'and R" are each independently H or a C 1 -C 3 alkyl group.
  • A is Cl, F or methyl; Z is NH.
  • A is Cl; Z is NH.
  • R 1 is a 4-7 membered heterocyclic group or -NR a R b ,
  • R a, R b are each independently hydrogen, C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, substituted C 1 -C 3 alkoxy C 1 -C 3 alkyl;
  • R 1 is pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2- Group, tetrahydrofuran 3-yl, tetrahydropyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethyl Amino, methylpropylamino or ethylpropylamino.
  • R 1 is dimethylamino.
  • m is 0 or 1
  • R 1 is a 4-7 membered heteroalicyclic group or -NR a R b ,
  • R a and R b are each independently hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl;
  • m is 0 or 1
  • R 1 is 1-methyl-pyrrolidin-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-isopropyl-pyrrolidin-2-yl, methylamino, ethylamino, propyl Amino, isopropylamino, cyclopropylamino, cyclobutylamino, methylisopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, pyrrolidine -1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydro Pyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino,
  • R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -O-(CH 2 ) nR 7 , and at least 3 of R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen,
  • R 7 is hydrogen, methyl, ethyl, propyl, isopropyl or 1 to 3 selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluoromethyl Group, fluoroethyl, trifluoromethyl, cyclopropyl, ethynyl, vinyl or -NR'R" substituted or unsubstituted aryl or heteroaryl, n is an integer of 0-3 ,
  • R'and R" are independently H or methyl, respectively
  • the aryl group is phenyl
  • the heteroaryl group is pyridyl, pyrimidinyl, pyrrolyl, thienyl, furyl, and imidazolyl.
  • R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, fluorine, chlorine, -O-(CH 2 )nR 7 , and R 2 , R 3 , R 4 , R 5 , At least 3 of R 6 are hydrogen,
  • R 7 is substituted by 1 to 3 substituents selected from fluorine, chlorine, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, and trifluoromethyl
  • substituents selected from fluorine, chlorine, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, and trifluoromethyl
  • the aryl group is a phenyl group
  • the heteroaryl group is a pyridyl group.
  • R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, fluorine, chlorine, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy , 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy , 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and at least R 2 , R 3 , R 4 , R 5 , R 6 Three are hydrogen.
  • R 2 , R 3 , R 5 , and R 6 are each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl
  • R 4 is hydrogen, fluorine, chlorine , Methyl, ethyl, propyl, isopropyl, -O-(CH 2 )nR 7
  • at least two of R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen
  • R 7 is hydrogen, methyl, ethyl, propyl, isopropyl or 1 to 3 selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluoromethyl Group, fluoroethyl, trifluoromethyl, cyclopropyl, ethynyl, vinyl or -NR'R" substituted or unsubstituted aryl or heteroaryl, n is an integer of 0-3 ,
  • R'and R" are independently H or methyl, respectively
  • the aryl group is phenyl, and the heteroaryl group is pyridyl, pyrimidinyl, pyrrolyl, thienyl, furyl, or imidazolyl;
  • R 2 , R 3 , R 5 , and R 6 are each independently hydrogen, fluorine, chlorine, and R 4 is hydrogen, fluorine, chlorine, phenoxy, 2-fluorophenoxy, 3-fluoro Phenoxy, 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyl Oxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and R 2 , R 3 , R 4 , R 5 , R 6, at least two of hydrogen.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the present application, its pharmaceutically acceptable salt, isomer, solvate, or prodrug, and one or more A pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition of the present application may also contain one or more other therapeutic agents.
  • the present invention also relates to a method for treating EGFR, HER2 and other kinase-mediated diseases or conditions, which comprises administering to a patient (human or other mammals, especially human) in need a therapeutically effective amount of the one described in the present application
  • a patient human or other mammals, especially human
  • Compounds or salts thereof, the kinase-mediated diseases or disorders such as EGFR, HER2, etc. include those mentioned above.
  • alkyl refers to a saturated linear and branched hydrocarbon group with the specified number of carbon atoms
  • C 1 -C 10 alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms
  • C 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms
  • C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl Basepentyl and so on.
  • substituent terms such as “alkyl” are used in combination with other substituent terms, for example, in the terms “C 1 -C 3 alkoxy C 1 -C 6 alkylthio” or “hydroxy substituted C 1 -C 10 alkyl”
  • this linking substituent term e.g., alkyl or alkylthio
  • C 1 -C 3 alkoxy C 1 -C 6 alkylthio include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio and the like.
  • hydroxyl substituted C 1 -C 10 alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl and the like.
  • the alkoxy group is an alkyl-O- group formed by the previously described linear or branched alkyl group and -O-, for example, a methoxy group, an ethoxy group, and the like.
  • the alkylthio group is an alkyl-S- group formed by the previously described linear or branched alkyl group and -S-, for example, methylthio, ethylthio and the like.
  • Alkenyl and alkynyl include straight chain, branched alkenyl or alkynyl, and the term C 2 -C 6 alkenyl or C 2 -C 6 alkynyl means a straight or branched chain hydrocarbon group having at least one alkenyl or alkynyl group.
  • haloalkyl such as “halo C 1 -C 10 alkyl” means having one or more halogens, which may be the same or different, on one or more carbon atoms of an alkyl moiety including 1 to 10 carbon atoms A group of atoms.
  • halogenated C 1 -C 10 alkyl may include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-Trifluoroethyl and hexafluoroisopropyl, etc.
  • halo C 1 -C 10 alkoxy means a haloalkyl-O- group formed by the halogenated C 1 -C 10 alkyl group and -O-, which can be, for example, trifluoromethyl Oxy, trichloromethoxy and so on.
  • C 1 -C 3 acyl includes formyl (-CHO), acetyl (CH 3 CO-), and acetyl (C 2 H 5 CO-).
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • the term “(C 3 -C 6 )cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C 3 -C 6 )cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl means a group or part containing an aromatic monocyclic or bicyclic hydrocarbon atom group, which contains 6 to 12 carbon ring atoms and has at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and dihydroindenyl (indanyl).
  • the aryl group is a phenyl group.
  • heteroalicyclic group represents an unsubstituted or substituted stable 4- to 8-membered non-aromatic monocyclic saturated ring system, which consists of carbon atoms and N, It is composed of 1 to 3 heteroatoms selected from O, S, among which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will.
  • heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazole Alkyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolane, piperidinyl, piperazinyl, tetrahydrofuranyl Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3 -Oxythiolanyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxa
  • heteroaryl refers to a group or moiety containing an aromatic monocyclic or bicyclic atom group (which contains 5 to 10 ring atoms), which includes 1 to 3 independently selected from nitrogen, oxygen and sulfur Of heteroatoms.
  • the term also includes bicyclic heterocyclic aryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, it represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system.
  • heteroaryl groups can be connected to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole Group, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, iso Benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxolenyl, benzothienyl, indazinyl , Indolyl, isoindolyl, indoline, benzimidazolyl, di
  • carbonyl refers to a -C(O)- group.
  • halogen and “halo” refer to chlorine, fluorine, bromine or iodine substituents.
  • Hydroxo is intended to mean the -OH radical.
  • cyano as used herein refers to the group -CN.
  • each independently means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the compounds, isomers, crystalline forms or prodrugs of formula I and their pharmaceutically acceptable salts can exist in solvated and unsolvated forms.
  • the solvated form may be a water-soluble form.
  • the present invention includes all of these solvated and unsolvated forms.
  • isomers in this application refers to different compounds with the same molecular formula, which may include various isomeric forms such as stereoisomers and tautomers.
  • “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space. Certain compounds described herein contain one or more asymmetric centers, and therefore can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- based on absolute stereochemistry form.
  • the chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures.
  • optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of the compound can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation determination, and the degree of advantage of one stereoisomer over other isomers can be determined.
  • the individual isomers (or isomer-enriched mixtures) of the present invention can be resolved using methods known to those skilled in the art.
  • the resolution can be carried out as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, such as by enzymes Promote oxidation or reduction; or (3) by gas-liquid chromatography or liquid chromatography in a chiral environment, such as on a chiral carrier (such as silica gel bound with a chiral ligand) or in hand In the presence of sexual solvents.
  • a chiral carrier such as silica gel bound with a chiral ligand
  • stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or one enantiomer can be converted into another isomer by asymmetric transformation .
  • Tautomers are structurally different isomers that can be converted into each other through tautomerization.
  • Tautomerization is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered a subset of acid-base chemistry.
  • Proton transfer tautomerization or “proton transfer tautomerization” involves the transfer of protons with bond-level changes, often the exchange of single bonds with adjacent double bonds. When tautomerization is possible (for example, in solution), a chemical equilibrium of tautomers can be reached.
  • An example of tautomerization is keto-enol tautomerization.
  • the compound of the present invention as the active ingredient and the method for preparing the compound are the content of the present invention.
  • the crystalline forms of some compounds can exist as polycrystals, and this form can also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for therapy in free form, or in the form of pharmaceutically acceptable salts or other derivatives where appropriate.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compound of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and has reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting the compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, Or by using methods well known in the art, such as ion exchange methods, these salts can be obtained.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconic acid Salt, hemisulfate, caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Amine cation formed by acid salt.
  • prodrug refers to a compound that can be converted into the compound described in the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent compound in the blood or tissues.
  • the pharmaceutical composition of the present invention comprises the compound described herein or a pharmaceutically acceptable salt thereof, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer drugs, antiviral agents, anti-inflammatory agents, and anti-inflammatory agents.
  • kinase inhibitors small molecules, polypeptides, antibodies, etc.
  • immunosuppressants anticancer drugs, antiviral agents, anti-inflammatory agents, and anti-inflammatory agents.
  • Other active agents of fungal agents, antibiotics or anti-vascular hyperproliferative compounds and any pharmaceutically acceptable carriers, adjuvants or excipients.
  • the compound of the present invention can be used alone, or in combination with one or more other compounds of the present invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy” refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is simultaneous co-administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms, as well as separate separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used simultaneously with other therapies known in the art, for example, the use of radiotherapy or cytostatic agents, cytotoxic agents, other anti-cancer agents and other additional therapies in cancer treatment to improve Cancer symptoms.
  • the present invention is not limited to the order of administration; the compounds of the present invention may be administered previously, concurrently, or after other anticancer agents or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient can be tightly mixed with the pharmaceutical carrier, which is carried out according to the traditional pharmaceutical ingredient technology.
  • the carrier can take various forms according to the preparation form designed according to different administration methods (for example, oral or parenteral administration).
  • Appropriate pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the "Handbook of Pharmaceutical Excipients", which is jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsion; or for topical medications such as ointments and creams; or as suppositories for rectal administration.
  • the pharmaceutical ingredients can also be used in unit dose form suitable for single-time administration of precise doses.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound made according to the current invention as an active ingredient. In addition, it may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be given to mammals instead of humans.
  • the dose of drug used for a mammal will depend on the species of the animal and its disease or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, or tablet potions.
  • the therapeutic compound can also be injected or infused into the animal's body. We prepare these drug forms in a traditional way that meets the standards of veterinary practice.
  • the pharmacological compound can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix with ordinary animal feed.
  • Another object of the present invention is to provide a method for treating cancer in a subject in need, which comprises a method of administering to the subject a therapeutically effective amount of a composition containing the compound of the present invention.
  • the present invention also includes the use of the compound of the present invention or a pharmaceutically acceptable derivative thereof to prepare a medicine for treating cancer and autoimmune diseases related to tyrosine kinase EGFR and HER2.
  • the cancers including non-solid tumors, solid tumors, primary or metastatic cancers, as indicated elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory
  • other diseases including but It is not limited to drugs for fundus diseases, psoriasis, atherogenesis, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.).
  • the cancer includes, but is not limited to: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine cancer Membranous cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain Any of tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary carcinosarcoma, and cholangiocarcinoma.
  • the present invention also provides methods for preparing corresponding compounds.
  • a variety of synthetic methods can be used to prepare the compounds described herein, including the following methods.
  • the compounds of the present invention or their pharmaceutically acceptable salts, isomers or hydrates can be Use the following methods and synthetic methods known in the field of organic chemistry synthesis, or synthesize through variations on these methods understood by those skilled in the art. Preferred methods include but are not limited to the following methods.
  • Reagents and consumables ULightTM-labeled Ploy GT Peptide (Perkin Elmer, catalog number TRF-0100-M); ULightTM-labeled JAK-1 (Try1023) Peptide (Perkin Elmer, catalog number TRF-0121-M); Eu-W1024- labeled Anti-Phosphotyrosine Antibody (PT66) (Perkin Elmer, catalog number AD0068); 10 ⁇ Detection Buffer (Perkin Elmer, catalog number CR97-100); Her2 kinase (Carna Biosciences, catalog number 08-016); EGFR kinase (Carna Biosciences , Catalog number 08-115); HEPES (GIBCO, catalog number 15630-080); EGTA (Sigma, catalog number 03777-10G); EDTA (Sigma, catalog number EDS-100G); MgCl 2 (Sigma, catalog number 63069- 100ML); DTT (Sigma, catalog number 43816-10ML); Tween-20 (Sigma
  • Test compound was dissolved in DMSO to prepare a 10 mM mother solution. Before use, the compound was diluted in DMSO to 0.25 mM (100-fold final concentration dilution), and a 3-fold concentration gradient dilution was made, with 11 gradients. When adding the drug, it is diluted with buffer solution to a dilution solution of 4 times the final concentration.
  • HER2 kinase detection configure buffer, use buffer to configure 40nM 4X Her2 kinase solution, 40 ⁇ M 4X ATP solution, 400nM 4 ⁇ ULight TM -labeled Ploy GT Peptide substrate solution. After the configuration is completed, mix the enzyme with the pre-diluted and configured compounds of different concentrations, and place them at room temperature for 5 minutes, and set up multiple wells for each concentration. Add the corresponding substrate and ATP, and react at room temperature for 120 minutes (in which yin and yang control is set). After the reaction was completed, PT66 detection antibody was added, incubated at room temperature for 60 minutes, and then detected with Envision.
  • EGFR WT kinase detection configure buffer, use buffer to configure 3.48nM 4X EGFR kinase solution, 600 ⁇ M 4X ATP solution, 400nM 4 ⁇ ULight TM -labeled JAK-1 (Try1023) Peptide substrate solution. After the configuration is completed, mix the enzyme with the pre-diluted compound of different concentrations, and leave it at room temperature for 5 minutes, and set up a replicate hole for each concentration. Add the corresponding substrate and ATP, and react at room temperature for 120 minutes (in which yin and yang control is set). After the reaction was completed, PT66 detection antibody was added, incubated at room temperature for 60 minutes, and then detected with Envision.
  • Table 2 shows that the compounds of the present application can inhibit the activity of EGFR WT and HER2 tyrosine kinase, especially some of the compounds show a strong inhibitory effect.
  • the test results are summarized in Table 2 below.
  • Table 2 lists the results of the determination of the inhibitory activity of some compounds in this application on EGFR WT and HER2 tyrosine kinase, where A represents IC 50 less than or equal to 50 nM, B represents IC 50 greater than 50 nM but less than or equal to 500 nM, C represents IC 50 is greater than 500nM but less than or equal to 5000nM, D indicates that IC 50 is greater than 5000nM, and NT indicates that there is no relevant result.
  • This application uses the CCK8 method to test the in vitro antiproliferative activity of the compounds of the present invention on BT474, NCI-N87, HCC-827 and Ba/F3EGFRvIII cell lines cultured in vitro.
  • Reagents and consumables RPMI1640 (ThermoFisher, catalog number C11875500BT); DMEM (ThermoFisher, C11995500BT); fetal bovine serum (Hyclone, catalog number SV30087.03); 0.25% trypsin-EDTA (ThermoFisher, catalog number 25200072); penicillin-chain Hyclone (Hyclone, catalog number SV30010); DSMO (Life Science, catalog number 0231-500ML); CCK8 test kit (Dojindo, catalog number CK04-100); 96-well plate (Corning, catalog number 3599); multi-function reading Trigger (Perkin Elmer, catalog number Envision)
  • BT474 from the Cell Bank of the Chinese Academy of Sciences
  • NCI-N87 from ATCC
  • HCC-827 from ATCC
  • Ba/F3 EGFRvIII from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • BT474 NCI -N87 and Ba/F3 EGFRvIII are cultured with RPMI1640 medium containing 10% fetal bovine serum, 100U/mL penicillin, 100 ⁇ g/mL streptomycin
  • HCC-827 is cultured with 10% fetal bovine serum, 100U/mL penicillin, 100 ⁇ g/mL Streptomycin was cultured in DMEM medium.
  • Table 3 lists the anti-proliferative activity assay results of representative compounds of the present invention on BT474, NCI-N87, HCC-827 and Ba/F3 EGFRvIII cells.
  • A means that IC 50 is less than or equal to 50 nM
  • B means that IC 50 is greater than 50 nM but less than or equal to 500 nM
  • C means that IC 50 is greater than 500 nM but less than or equal to 5000 nM
  • D means that IC 50 is greater than 5000 nM
  • NT means that there is no relevant result.
  • the animals were randomly grouped according to their body weights, and the animals in each group had similar body weights (not more than ⁇ 20% of the average body weight). At the same time, the IV group did not fast, and the PO group fasted overnight (>12 hours) and was given food 2 hours after the administration. All animals drink freely. Table 7 and Table 8 below give the dosing schedule and pharmacokinetic sampling schedule, respectively.
  • the rats were administered according to the above-mentioned protocol, and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing were performed according to conventional methods in the art).
  • the pharmacokinetic parameters will be calculated using WinNonlin software. If applicable plasma drug concentration-time data are available, the following pharmacokinetic parameters will be calculated: CL (clearance); V d (apparent volume of distribution); T 1/2 (elimination half-life); C max (peak Concentration); T max (time to peak); AUC (area under the plasma concentration-time curve); MRT (mean residence time); F% (bioavailability).
  • the test results are shown in the following Tables 9-15.
  • the rat blood concentrations of compounds 1 and 2, 19 and 20, as well as pyrrotinib and leratinib of the Examples of the present application at each time point, and each The pharmacokinetic parameter values also show the concentrations and ratios of compounds 1 and 2, 19 and 20 of the examples of the application, as well as pyrrotinib and leratinib in the brain and blood of rats. From the above results, it can be seen that the compounds 1 and 2, 19, and 20 of the present application all show excellent ability to penetrate the blood-brain barrier, which is far superior to the marketed pyrrotinib and leratinib.
  • the compound of the present application not only has excellent EGFR and HER2 kinase inhibitory activity, and can inhibit cell proliferation at the cellular level, but also has excellent ability to penetrate the blood-brain barrier, and is expected to be applied to EGFR and/or HER2 kinase.
  • Mediated related diseases especially those related to brain metastasis.
  • Example Blood concentration (ng/mL) Brain concentration (ng/g) Brain/blood ratio Pyrotinib 884 25.8 0.0291 Neratinib 440 14.4 0.0366 1 256 373 1.46 2 616 3168 5.45 19 446 788 1.77 20 109 116 1.06
  • Example 1 and Example 2 have excellent pharmacokinetic parameters and are suitable for the development of oral inhibitors.
  • the results in Table 15 show that both Example 1 and Example 2 have extremely strong blood-brain barrier penetrating properties, and are suitable for the treatment of primary brain tumors and the treatment of brain metastatic tumors.
  • the results in Tables 11-12 and Table 15 also show that Examples 19 and 20 also have excellent pharmacokinetic properties, as well as strong blood-brain barrier penetrating properties. Based on the results of Table 3, Table 9, Table 10, Table 11-12 and Table 15, it can be seen that the compound of the present invention is expected to be developed as a therapeutic drug for glioma.
  • the compounds of the present application all show excellent inhibitory activity against EGFR kinase, and also show good to excellent inhibitory activity against HER2 kinase.
  • all the compounds of the present application show excellent inhibitory activity against Ba/F3 EGFRvIII cell lines.
  • Excellent proliferation inhibitory activity; at the same time, the pharmacokinetic test also found that the compound of the present application showed excellent ability to penetrate the blood-brain barrier (much better than the marketed drugs), therefore, especially for EGFRvIII-induced tumors such as neurogel
  • the compounds of the application are expected to become therapeutic drugs for the above-mentioned diseases.
  • the approved quinazoline drugs such as Gefitinib, Erlotinib, Icotinib, Afatinib and Lapatinib Can not effectively penetrate the blood-brain barrier.
  • most of the current compounds with quinazoline as the core are substituted at the 6 and 7 positions of the quinazoline ring, and almost no substitution at the 5 position.
  • the quinazoline An allylamide group is introduced at the 6 position of the ring, and a halogen (for example, Cl) or alkyl (for example, methyl) substitution is introduced at the 5 position, wherein the allylamide group can form an irreversible covalent with EGFR or HER2 target Binding, and the halogen or alkyl introduced at position 5 can lock the orientation of the allylamide group, which is more conducive to the covalent binding of allylamide to the EGFR or HER2 target.
  • This design not only realizes the strong covalent binding ability of the compound of the present invention to the EGFR or HER2 target, but also greatly improves the blood-brain penetration ability of the compound of the present invention.

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Abstract

本发明提供了一种喹唑啉类化合物、制备方法及其应用，具体涉及式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其制备方法及其在制备作为酪氨酸激酶抑制剂的药物中的应用。本发明化合物对EGFR、HER2激酶具有良好的抑制活性，同时展示优异的穿透血脑屏障的性能。

Description

一种喹唑啉类化合物、制备方法及其应用 技术领域
本发明属于医药技术领域，涉及一种喹唑啉类化合物、制备方法及其应用。
背景技术
表皮生长因子受体(epidermal growth factor receptor，EGFR)是一种跨膜糖蛋白，隶属于酪氨酸激酶受体家族，其表达十分广泛，在生长发育和正常的生理功能活动中起着重要作用。另外，EGFR及其介导的信号传递通路在肿瘤的发生和发展的过程中发挥重要作用。然而，EGFR的表达很不稳定，经常出现基因的扩增和重排，使肿瘤细胞表面的抗原表型发生改变，其中以表皮生长因子受体III型突变体(epidermal growthfactor receper variant III，EGFRvIII)最为常见。
EGFRvIII是近年来发现的一类仅表达于肿瘤细胞而非正常组织细胞表面的表皮生长因子受体(epidermal growth factor receptor，EGFR)的突变体。EGFR的异常表达与众多恶性肿瘤的发生相关，包括胶质瘤、肺小细胞癌、乳腺癌、膀胱癌、卵巢癌等。
与EGFR完整的结构相比，编码EGFRvIII胞外配体结合区的第2-7位外显子被删除，导致801个碱基对缺失，使得外显子1和8相连接，并在该结合点产生一个新的甘氨酸，导致其第6～273位氨基酸缺失，因而丧失了与配体EGF结合的能力。EGFRvIII在无配体结合的情况下，以二聚体化和自体磷酸化的方式使酪氨酸激酶不受调控的结构性激活，诱发下游信号传导，刺激肿瘤细胞增殖。
已有研究表明：EGFRvIII可通过调控多种信号传递通路影响肿瘤的发生和发展，包括Ras/Raf/MEK/ERK，PI3/AKT/mTOR，JAK/STAT以及PLC/PKC等。EGFRvIII阳性的肿瘤细胞致瘤性明显增高，主要通过抑制细胞凋亡，促进肿瘤血管发生，增加侵袭性和迁移等导致肿瘤细胞发生不可控制的自发增殖和转移。另外，EGFRvIII在肿瘤的放射治疗和化学药物治疗过程中，发挥类似逃逸的功能。
神经胶质瘤是一种常见的具有高侵袭力的恶性肿瘤，神经胶质母细胞瘤(glioblastoma，GBM)是恶性程度最高的类型。其放疗和化疗的效果均不甚理想，术后常有复发。国内外研究发现：40％～60％的GBM显著表达EGFR，且其突变体形式以EGFRvIII为主。EGFRvIII通过非受体依赖性的自身磷酸化及酪氨酸激酶活性，建立信号通路调控网，在调控GBM的生长、转移和血管生成方面发挥重要作用。
近年来的研究发现针对EGFRvIII分子靶向治疗措施无论是在体外的细胞培养还是体内的动物模型的研究中均显示出良好的抗肿瘤效应。因此，研发新的针对EGFRvIII分子靶向治疗药物将为肿瘤患者特别是神经胶质瘤患者提供更有效和更经济的治疗方案，临床上存在着巨大的未满足需求。
靶向EGFRvIII治疗神经胶质瘤的药物不仅需要能够有效穿透血脑屏障，同时也需要能够有效抑制EGFRvIII。目前尚无这种既能穿透血脑屏障又能抑制EGFRvIII的化合物的报道，因而针对EGFRvIII为驱动的神经胶质瘤的研究具有重要的临床价值。除此之外，绝大多数已上市的EGFR和HER2激酶抑制剂都无法穿透血脑屏障，而EGFR驱动的肺癌以及HER2驱动的乳腺癌患者普遍预后较差，并存在 较高的脑转移风险。目前尚无获批用于脑转移治疗的有效药物，因此亟待开发一种具有穿透血脑屏障的EGFR抑制剂和/或HER2抑制剂。
发明内容
本发明一方面提供一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
Figure PCTCN2021087774-appb-000001
式(I)中，m为0、1或者2；
A为卤素、C 1-C 3烷基；Z为NH或者O；
R 1为氢、羟基、4-7元杂脂环基或-NR aR b，
R a、R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、被羟基取代的C 1-C 6烷基、被C 1-C 3烷氧基取代的C 1-C 6烷基、或被C 3-C 6环烷基取代的C 1-C 6烷基；
所述的4-7元杂脂环基为含有1-2个选自N、O或S的杂原子的杂脂环基，所述杂脂环基未被取代或被C 1-C 3烷基、C 1-C 4烷基酰基、羟基、氰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、氧代(＝O)中的一种或两种取代；
R 2、R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-C 6烷基、-O-(CH 2)n-R 7，
R 7为氢、C 1-C 3烷基、被1至3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，
R'、R”各自独立地为H或C 1-C 3的烷基。
或者，m为1时，式(I)的化合物具有如下通式(II)，
Figure PCTCN2021087774-appb-000002
式(II)中，A为卤素、C 1-C 3烷基；Z为NH或者O；
R 1为氢、羟基、4-7元杂脂环基或-NR aR b，
R a、R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、被羟基取代的C 1-C 6烷基、被C 1-C 3烷氧基取 代的C 1-C 6烷基、或被C 3-C 6环烷基取代的C 1-C 6烷基；
所述的4-7元杂脂环基为含有1-2个选自N、O或S的杂原子的杂脂环基，所述杂脂环基未被取代或被C 1-C 3烷基、C 1-C 4烷基酰基、氨基酰基、羟基、氰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、氧代(＝O)中的一种或两种取代；
R 2、R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-C 6烷基、-O-(CH 2)n-R 7，
R 7为氢、C 1-C 3烷基、被1至3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，
R'、R”各自独立地为H或C 1-C 3的烷基。
根据一个优选的实施方案，A为Cl、F或者甲基；Z为NH。
更优选地，A为Cl；Z为NH。
根据一个优选的实施方案，R 1为4-7元杂环基或-NR aR b，
R a、R b各自独立地为氢、C 1-C 3烷基、被羟基取代的C 1-C 3烷基、被C 1-C 3烷氧基取代的C 1-C 3烷基；
所述4-7元杂脂环基为吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、硫代吗啉基，且上述基团未被取代或被甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、羟基、氰基、氨基酰基、甲基砜基、乙基砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、氧代(＝O)中的一种或两种取代。
更优选地，R 1为吡咯烷-1-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、吗啉基、四氢呋喃2-基、四氢呋喃3-基、四氢吡喃2-基、四氢吡喃3-基、硫代吗啉基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、甲基乙基氨基、甲基丙基氨基或者乙基丙基氨基。
最优选地，R 1为二甲氨基。
根据一个优选的实施方案，m为0或者1，
R 1为4-7元杂脂环基或-NR aR b，
R a、R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基；
所述4-7元杂脂环基为吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、硫代吗啉基，且上述基团未被取代或被甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、羟基、氰基、氨基酰基、甲基砜基、乙基砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、氧代(＝O)中的一种或两种取代。
更优选地，m为0或者1，
R 1为1-甲基-吡咯烷-2-基、1-乙基-吡咯烷-2-基、1-异丙基-吡咯烷-2-基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基氨基、环丁基氨基、甲基异丙基氨基、N-甲基-N-环丙基氨基、N-甲基-N-环丁基氨基、吡咯烷-1-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、吗啉基、四氢呋喃2-基、 四氢呋喃3-基、四氢吡喃2-基、四氢吡喃3-基、硫代吗啉基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、甲基乙基氨基、甲基丙基氨基或者乙基丙基氨基。
根据另一个优选的实施方案，R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、甲基、乙基、丙基、异丙基、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少3个为氢，
R 7为氢、甲基、乙基、丙基、异丙基或者被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基、环丙基、乙炔基、乙烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
R'、R”分别独立的为H或甲基，
所述芳基为苯基，所述杂芳基为吡啶基、嘧啶基、吡咯基、噻吩基、呋喃基、咪唑基。
更优选地，R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少3个为氢，
R 7为被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
所述芳基为苯基，所述杂芳基为吡啶基。
在另一些优选的实施方案中，R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、苯氧基、2-氟苯氧基、3-氟苯氧基、4-氟苯氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-基甲氧基、3-氟苄基氧基、2-氟苄基氧基、4-氟苄基氧基、3-氯苄基氧基、2-氯苄基氧基、4-氯苄基氧基，且R 2、R 3、R 4、R 5、R 6中至少3个为氢。
根据另一个优选的实施方案，R 2、R 3、R 5、R 6各自独立地为氢、氟、氯、甲基、乙基、丙基、异丙基，R 4为氢、氟、氯、甲基、乙基、丙基、异丙基、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少2个为氢，
R 7为氢、甲基、乙基、丙基、异丙基或者被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基、环丙基、乙炔基、乙烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
R'、R”分别独立的为H或甲基，
所述芳基为苯基，所述杂芳基为吡啶基、嘧啶基、吡咯基、噻吩基、呋喃基、咪唑基；
或者，更优选地，R 2、R 3、R 5、R 6各自独立地为氢、氟、氯，R 4为氢、氟、氯、苯氧基、2-氟苯氧基、3-氟苯氧基、4-氟苯氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-基甲氧基、3-氟苄基氧基、2-氟苄基氧基、4-氟苄基氧基、3-氯苄基氧基、2-氯苄基氧基、4-氯苄基氧基，且R 2、R 3、R 4、R 5、R 6中至少2个为氢。
本申请涉及的典型化合物如下：
Figure PCTCN2021087774-appb-000003
Figure PCTCN2021087774-appb-000004
Figure PCTCN2021087774-appb-000005
本发明的另一方面提供一种药物组合物，该药物组合物包含本申请所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，以及一种或多种药学上可接受的载体或赋形剂。
本申请的药物组合物还可以包含一种或多种其他治疗剂。
本发明还涉及一种治疗EGFR、HER2等激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的本申请所述的化合物或其盐，所述EGFR、HER2等激酶介导的疾病或病症包括前述提及的那些。
发明详述
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
除非有特殊说明，烷基表示具有指定数目碳原子的饱和直链、支链烃基，术语C 1-C 10烷基表示含有1至10个碳原子的烷基部分，同理C 1-C 3烷基表示含有1至3个碳原子的烷基部分，比如，C 1-C 6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时，例如在术语“C 1-C 3烷氧基C 1-C 6烷硫基”或“羟基取代C 1-C 10烷基”中，该连接取代基术语(例如烷基或烷硫基)旨在包含二价的部分，其中连接点通过所述连接取代基。“C 1-C 3烷氧基C 1-C 6烷硫基”的实例包括但不限于甲氧基甲硫基、甲氧基乙硫基和乙氧基丙硫基等。“羟基取代C 1-C 10烷基”的实例包括但不限于羟基甲基、羟基乙基和羟基异丙基等。
烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团，例如，甲氧基、乙氧基等等。类似的，烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团，例如，甲硫基，乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基，术语C 2-C 6烯基或者C 2-C 6炔基表示具有至少一个烯基或炔基的直链或支链烃基。
术语“卤代烷基”，例如“卤代C 1-C 10烷基”表示在包括1到10个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C 1-C 10烷基”的实例可以包括但不限于-CF 3(三氟甲基)、-CCl 3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的，术语“卤代C 1-C 10烷氧基”表示由所述的卤代C 1-C 10烷基与-O-形成的卤代烷基-O-基团，可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C 1-C 3酰基”包括甲酰基(-CHO)、乙酰基(CH 3CO-)、乙酰基(C 2H 5CO-)。
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如，术语“(C 3-C 6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C 3-C 6)环烷基”包括环丙基、环 丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分，其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常，在本发明化合物中，芳基为苯基。
在这里使用的术语“杂脂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的4至8元非芳香的单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
在这里使用的术语“杂芳基”表示包含芳香的单环或双环原子团(其含有5到10个环原子)的基团或部分，其包括1到3个独立地选自氮、氧和硫的杂原子。该术语还包括双环杂环芳基，其中含有与杂环烷基环部分稠合的芳基环部分，或者含有与环烷基环部分稠合的杂芳基环部分。除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或10个环原子的苯稠杂芳环体系或二环杂芳环体系，它们由碳原子和由1至3个从N，O，S中选择的杂原子组成，其中N、S杂原子可以被氧化，N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基的示例性实例包括但不限于呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、异噻唑基、吡啶基、氧代-吡啶基(吡啶基-N-氧化物)、哒嗪基、吡嗪基、嘧啶基、三嗪基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、二氢苯并二氧杂环己烯基、苯并噻吩基、吲嗪基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、二氢苯并咪唑基、苯并噁唑基、二氢苯并噁唑基、苯并噻唑基、苯并异噻唑基、二氢苯并异噻唑基、吲唑基、咪唑并吡啶基、吡唑并吡啶基、苯并三唑基、三唑并吡啶基、嘌呤基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、噌啉基、酞嗪基、喹唑啉基、1,5-二氮杂萘基、1,6-二氮杂萘基、1,7-二氮杂萘基、1,8-二氮杂萘基和蝶啶基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分；例如，如果直接连接到碳原子上形成一个羰基部分(C＝O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时，那些取代基可以相同或不同。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本申请中术语“异构体”为具有相同分子式的不同化合物，可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心，且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备，或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析，包括但不限于手性色谱法和旋光测定法，且可确定一种立体异构体超越其他异构体的优势程度。
可使用本领域技术人员已知的方法拆分本发明单独的异构体(或异构体富集的混合物)。例如，可如下进行所述拆分：(1)通过形成非对映异构体盐、复合物或其他衍生物；(2)通过与立体异构体特异性试剂的选择性反应，例如通过酶促氧化或还原；或(3)通过在手性环境中的气-液色谱或液相色谱，所述手性环境例如在手性载体上(例如结合有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解，当将所需立体异构体通过上述分离方法之一转化成另一化学实体时，需要其他步骤来释放所需形式。或者，特异性立体异构体可通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成法来合成，或通过不对称转化将一种对映异构体转化成另一种异构体。
当本文所述的化合物含有烯烃双键时，除非另有说明，其意指该化合物包括各种顺反异构体。
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式，且包括质子移变或质子转移互变异构化，可认为它是酸碱化学的子集。“质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移，往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如，在溶液中)，可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明所述的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用， 给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制备治疗与酪氨酸激酶EGFR、HER2相关的癌症及自身免疫疾病的药物中的应用。所述的癌症(包括非实体瘤、实体瘤、原发性或转移性癌症，如本文别处所指出和包括癌症具有抗性或难治的一种或多种其它治疗)以及其它疾病(包括但不限于眼底疾病、银屑病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化等)的药剂。所述癌症包括但不限于：非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
具体实施方式
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未 注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。本申请部分化合物的命名根据chemdraw命名翻译得到。
中间体的合成
酸类中间体的合成：(E)-4-(二甲基氨基)丁-2-烯酸，(E)-4-(二乙氨基)丁-2-烯酸和(E)-4-(哌啶-1-基)丁-2-烯酸的合成方法
以(E)-4-(二乙氨基)丁-2-烯酸为例。在氩气保护下，向烧瓶中加入2g(27.34mm)二乙胺和20ml THF，在冰浴下加入5g(27.93mM)溴酸甲酯和9g(69.63mM)二异丙基乙胺。反应3小时，用乙酸乙酯和水萃取；通过旋转蒸发除去溶剂，在20ml乙醇中加入液体碱(2g NaOH和2ml H 2O)，搅拌3h，滴加浓盐酸将pH调节至1-2，减压浓缩。加入丙酮(20毫升)重结晶，得到白色固体。
(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯的制备
Figure PCTCN2021087774-appb-000006
将(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酸(160mg,1mmol)加入干燥的二氯甲烷(3ml)中，分别加入草酰氯(130mg,1mmol)，DMF(1滴，催化量)，室温搅拌3小时，反应体系有浑浊变澄清，浓缩，得类白色固体；
胺类中间体B1-B5的合成：
4-((1H-苯并[d][1,2,3]三氮唑-1-基)氧基)-5-氯喹唑啉-6-胺的合成
Figure PCTCN2021087774-appb-000007
条件和试剂:(a)EtOH,乙酸甲脒,80℃,8h；(b)H 2SO 4,HNO 3,-5℃,过夜；(c)CH 3OH,Fe,NH 4Cl,80℃,回流/Ni,H 2,rt；(d)CH 3CN,BOP,DBU,rt
使用2-氨基-6-氯苯甲酸作为起始原料，在80℃下使用乙酸甲脒进行环化，得到化合物5-氯喹唑啉-4(3H)-酮，然后将该化合物溶于浓硫酸溶液中，在-10℃下加入硝酸，通过柱色谱法得到化合物5-氯-6-硝基喹唑啉-4(3H)-酮。然后我们用铁粉还原硝化产物，在酸性环境中(或使用雷尼镍还原氢气环境中的硝化产物)得到化合物5-氯-6-氨基喹唑啉-4(3H)-酮。然后，通过使用BOP，得到4-((1H-苯并[d][1,2,3]三氮唑-1-基)氧基)-5-氯喹唑啉-6-胺。
将化合物4-((1H-苯并[d][1,2,3]三氮唑-1-基)氧基)-5-氯喹唑啉-6-胺(100mg，0.32mM)和一系列胺 类化合物(71-90mg，0.38mM)溶解在i-PrOH(20ml)溶液中，在90℃下搅拌10分钟，然后加入TsOH(7mg，将0.03mM)到混合物中反应5小时。并通过TLC监测反应进度，在反应结束时，添加水并过滤以获得固体。通过柱色谱法(EA：PE＝5：1)纯化得到中间体B1-B5(棕色或绿色固体)，他们的结构和表征如下表1所示。
Figure PCTCN2021087774-appb-000008
表1中间体B1-B5的结构、命名和表征
实施例
合成方法一：
将系列2-烯酸(120mg，0.9mM)溶解在无水DCM(5ml)中，并在冰浴下加入草酰氯(80μL，0.9mM)反应3h。然后蒸发溶剂，得到橙色固体。然后将溶于DCM(1ml)的橙色固体在冰浴下加至B1-B5(100mg，0.3mM)的NMP(2ml)溶液中反应4h。并通过TLC监测反应进度。然后加入碳酸钾溶液以将pH调节至8-9，然后用DCM萃取粗产物。通过柱色谱法(DCM：CH 3OH＝30：1-10：1)纯化。实施例1-7采用该方法一进行合成。
合成方法二：
将(E)-4-溴丁-2-烯酸(150mg，0.9mM)溶解在无水DCM(5ml)中，并在冰浴下加入草酰氯(80μL，0.9mM)反应3h。然后蒸发溶剂，得到橙色固体。然后将溶于DCM(1ml)的橙色固体在冰浴下加至B1-B5(100mg，0.3mM)的NMP(2ml)溶液中反应4h。并通过TLC监测反应进度。然后加入碳酸 钾溶液将pH调节至8-9，然后用DCM萃取粗产物。通过柱色谱法(EA：PE＝5：1-3：1)分离纯产物。然后，将吡咯烷(100-150mg，1.5mM)加入产物的DMA溶液中，在0℃下搅拌4小时。并通过TLC监测反应进度。然后加入碳酸钾溶液以将pH调节至8-9，然后用DCM萃取粗产物。通过柱色谱法(DCM：CH3OH＝30：1-10：1)分离纯产物。实施例8-10采用该方法二进行合成。
实施例1.(E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000009
白色固体；mp:230-232℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ9.98(s,1H),9.51(s,1H),8.53(d,J＝4.8Hz,1H),8.45(s,1H),8.05(d,J＝9.0Hz,1H),7.84–7.81(m,2H),7.68(d,J＝9.0Hz,1H),7.52(d,J＝7.8Hz,2H),7.33–7.29(m,1H),7.20(d,J＝9.0Hz,1H),6.75(dt,J＝15.5,5.9Hz,1H),6.45(d,J＝15.5Hz,1H),5.24(s,2H),3.03(d,J＝5.6Hz,2H),2.13(s,6H). 13C NMR(101MHz,DMSO-d 6,δppm):δ164.35(s),157.23(s),156.74(s),154.22(s),150.81(s),149.61(s),143.11(s),137.63(s),134.45(s),132.84(s),131.97(s),130.12(s),127.46(s),125.59(s),125.50(s),123.90(s),123.59(s),121.96(s),121.52(s),114.67(s),113.36(s),71.66(s),60.20(s),45.62(s).HRMS(ESI)m/z计算值C 26H 24Cl 2N 6O 2 +[M+H] +,523.1416；实测值,523.1456.
实施例2.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000010
白色固体；mp:235-237℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.02(s,1H),9.67(s,1H),8.53(s,1H),8.16(d,J＝8.9Hz,1H),7.79(s,2H),7.46(s,1H),7.29(t,J＝7.8Hz,1H),6.83(dt,J＝15.4,5.8Hz,1H),6.53(d,J＝15.5Hz,1H),3.10(dd,J＝5.8,1.1Hz,2H),2.20(s,6H). 13C NMR(101MHz,DMSO-d 6,δppm):δ164.30(s),153.49(s),153.07(s),143.15(s),134.72(s),132.00(s),130.10(s),127.10(s),126.08(s),125.49(s),125.45(s),125.40(s),121.47(s),120.39(s),120.22(s),113.69(s),109.82(s),60.24(s),45.66(s).HRMS(ESI)m/z计算值C 20H 18Cl 2FN 5O +[M+H] +,434.0951；实测值,434.0923.
实施例3.(E)-N-(5-氯-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000011
白色固体；mp:221-223℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.01(s,1H),9.66(s,1H),8.59(d,J＝16.7Hz,1H),8.16(d,J＝9.0Hz,1H),8.04(d,J＝4.3Hz,1H),7.79–7.66(m,2H),7.45(t,J＝9.0Hz,1H),6.82(dt,J＝15.4,5.8Hz,1H),6.54(d,J＝15.5Hz,1H),3.10(d,J＝5.4Hz,2H),2.20(s,6H). 13C NMR(101 MHz,DMSO-d 6,δppm):δ164.43(s),156.77(s),150.82(s),149.61(s),144.08(s),137.60(s),134.56(s),132.03(s),130.11(s),127.45(s),125.56(s),125.11(s),123.87(s),123.57(s),121.94(s),121.55(s),114.71(s),71.72(s),47.17(s).HRMS(ESI)m/z计算值C 20H 18Cl 2FN 5O +[M+H] +,434.0951；实测值,434.0984.
实施例4.(E)-N-(5-氯-4-((4-苯氧基苯基)氨基)喹唑啉-6-基)-4-(二乙氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000012
白色固体；mp:236-238℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.31(d,J＝8.3Hz,1H),9.64(s,1H),8.51(s,1H),8.08(d,J＝9.0Hz,1H),7.77–7.71(m,3H),7.40(t,J＝7.9Hz,2H),7.12(d,J＝7.4Hz,1H),7.07(d,J＝8.9Hz,2H),7.04–6.99(m,2H),6.92–6.85(m,1H),6.66(d,J＝14.9Hz,1H),3.29(d,J＝7.1Hz,2H),2.69(s,4H),1.08(t,J＝7.0Hz,6H), 13C NMR(101MHz,DMSO-d 6,δppm):δ164.11(s),157.58(s),157.21(s),154.29(s),153.42(s),150.16(s),134.56(s),134.48(s),132.17(s),130.51(s),130.10(s),129.11(s),127.42(s),125.43(s),123.69(s),121.98(s),119.58(s),118.59(s),113.39(s),63.25(s),47.01(s),11.32(s).HRMS(ESI)m/z计算值C 28H 28ClN 5O 2 +[M+H] +,502.2010；实测值,502.2009.
实施例5.(E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-4-(哌啶-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000013
白色固体；mp:240-242℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.03(s,1H),9.57(s,1H),8.55(d,J＝36.7Hz,2H),8.11(d,J＝9.0Hz,1H),7.95–7.83(m,2H),7.73(d,J＝8.9Hz,1H),7.58(d,J＝8.0Hz,2H),7.42–7.32(m,1H),7.26(d,J＝9.0Hz,1H),6.82(dt,J＝15.3,5.8Hz,1H),6.52(d,J＝15.9Hz,1H),5.30(s,2H),3.10(d,J＝5.6Hz,2H),2.36(s,4H),1.59–1.34(m,6H). 13C NMR(101MHz,DMSO-d 6,δppm):δ164.35(s),157.18(s),156.75(s),154.17(s),150.81(s),149.57(s),143.00(s),137.58(s),134.50(s),132.86(s),131.94(s),127.48(s),125.56(s),125.52(s),123.81(s),123.57(s),123.25(s),121.94(s),121.56(s),121.45(s),114.66(s),71.71(s),59.72(s),54.56(s),25.94(s),24.27(s).HRMS(ESI)m/z计算值C 29H 28Cl 2FN 6O 2 +[M+H] +,563.1729；实测值,563.1796.
实施例6.(E)-N-(5-氯-4-((4-((3-氟苄基)氧基)苯基)氨基)喹唑啉-6-基)-4-(哌啶-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000014
白色固体；mp:197-199℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.06(s,1H),9.57(s,1H),8.46(s,1H),8.08(d,J＝9.0Hz,1H),7.72(d,J＝9.0Hz,1H),7.60(d,J＝8.9Hz,2H),7.45(td,J＝8.0,6.1Hz,1H),7.30(t,J＝7.8Hz,2H),7.16(td,J＝8.6,2.2Hz,1H),7.06(d,J＝9.0Hz,2H),6.82(dt,J＝15.4,5.9Hz,1H),6.53(dd,J＝14.1,8.6Hz,1H),5.16(s,2H),3.10(d,J＝5.0Hz,2H),2.36(s,4H),1.55–1.36(m,6H). 13C NMR(101MHz,DMSO-d 6,δppm):δ164.45(s),163.48(s),161.86(s),155.61(s),154.35(s),149.96(s),143.11(s), 140.57(s),140.52(s),134.27(s),131.91(s),130.96(d,J＝8.3Hz),127.36(s),125.48(s),123.86(d,J＝2.5Hz),115.38(s),115.05(s),114.91(s),114.59(s),114.45(s),113.26(s),69.01(s),59.72(s),54.52(s),25.86(s),24.22(s).HRMS(ESI)m/z计算值C 30H 29ClFN 5O 2 +[M+H] +,546.2072；实测值,546.2019.
实施例7.(E)-N-(5-氯-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)-4-(哌啶-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000015
白色固体；mp:233-235℃. 1H NMR(400MHz,DMSO-d 6,δppm):δ10.05(s,1H),9.68(s,1H),8.53(s,1H),8.12(d,J＝9.0Hz,1H),8.01(s,1H),7.80–7.61(m,2H),7.49–7.39(m,1H),6.82(dt,J＝15.4,5.9Hz,1H),6.52(d,J＝15.7Hz,1H),3.10(d,J＝5.5Hz,2H),2.35(s,4H),1.45(d,J＝52.9Hz,6H). 13C NMR(101MHz,DMSO-d 6,δppm):δ164.31(s),157.07(s),154.02(s),150.11(s),143.17(s),136.19(s),134.70(s),132.07(s),127.54(s),125.35(d,J＝17.8Hz),124.22(s),121.24(s),119.35(s),117.20(s),116.98(s),113.43(s),59.76(s),54.62(s),26.02(s),24.32(s).HRMS(ESI)m/z计算值C 23H 22Cl 2FN 5O +[M+H] +,474.1264；实测值,474.1271.
实施例8.(E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-4-(吡咯烷-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000016
白色固体； 1H NMR(400MHz,DMSO-d 6,δppm):δ10.04(s,1H),9.57(s,1H),8.61(d,J＝3.3Hz,1H),8.53(s,1H),8.12(d,J＝9.0Hz,1H),7.96–7.85(m,2H),7.76(d,J＝9.0Hz,1H),7.59(d,J＝6.8Hz,2H),7.38(dd,J＝6.8,5.1Hz,1H),7.28(d,J＝9.0Hz,1H),6.86(dt,J＝15.3,5.7Hz,1H),6.56(d,J＝15.6Hz,1H),5.32(s,2H),3.33–3.28(m,2H),2.66(dd,J＝15.3,13.6Hz,4H),1.76(s,4H).MS:548.9[M+H] +。
实施例9.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(吡咯烷-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000017
白色固体； 1H NMR(400MHz,DMSO-d 6,δppm):δ10.10(s,1H),9.65(s,1H),8.55(s,1H),8.17(d,J＝9.0Hz,1H),7.83(dd,J＝13.2,8.7Hz,1H),7.57–7.43(m,1H),7.37–7.24(m,1H),6.86(dd,J＝13.6,7.7Hz,1H),5.76(s,1H),5.33(d,J＝4.7Hz,1H),3.31(s,2H),2.68(d,J＝1.8Hz,4H),1.24(s,4H).HRMS(ESI)m/z计算值C 22H 20Cl 2FN 5O +[M+H] +,460.1107；实测值,460.1101.
实施例10.(E)-N-(5-氯-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)-4-(吡咯烷-1-基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000018
白色固体； 1H NMR(400MHz,DMSO-d 6,δppm):δ10.04(s,1H),9.67(s,1H),8.58(s,1H),8.15(d,J＝9.0Hz,1H),8.05(dd,J＝6.8,2.6Hz,1H),7.78(d,J＝9.0Hz,1H),7.71(ddd,J＝8.9,4.3,2.7Hz,1H),7.47(t,J＝9.1Hz,1H),6.87(dt,J＝15.4,5.7Hz,1H),6.56(d,J＝15.4Hz,1H),3.32–3.28(m,2H),2.70–2.58(m, 4H),1.75(s,4H).HRMS(ESI)m/z计算值C 22H 20Cl 2FN 5O +[M+H] +,460.1107；实测值,460.1100.
实施例11.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(异丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000019
步骤1)5-氯-N-(3-氯-2-氟苯基)-6-硝基喹唑啉-4-胺的合成
把5-氯-6-硝基喹唑啉-4-醇(1g,4.5mmol)悬浮于二氯亚砜(15mL)中，常温搅拌下，加入DMF(0.5mL)，然后体系升温至105℃反应，待体系澄清后(约3h)，再加热到90℃回流反应2h，LCMS监测(MeOH淬灭体系)，反应完毕，体系直接减压浓缩，得到浅黄色固体；把上述得到的固体(1g,4.4mmol)悬浮于干燥乙腈(15mL)中，超声使分散均匀，冰浴条件下，缓慢滴加3-氯-2-氟苯胺(2.9g,20mmol)，滴毕，撤去冰浴，加热到50℃反应2h，LCMS监测反应完毕，浓缩，加入MeOH打浆，过滤，滤饼收集得到产品目标产物850mg，收率53％，MS:353[M+H] +；
步骤2)5-氯-N-(3-氯-2-氟苯基)喹唑啉-4,6-二胺的合成
5-氯-N-(3-氯-2-氟苯基)-6-硝基喹唑啉-4-胺(350mg,1mmol)，铁粉(280mg,5mmol)和氯化铵(530mg,10mmol)分别加入到乙醇(10ml)与水(1ml)的混合溶液中，搅拌加热至80摄氏度反应1小时，硅藻土过滤，滤液分别用乙酸乙酯和饱和碳酸氢钠洗涤，有机相干燥，浓缩得灰白固体290mg，直接用于下一步，MS:323[M+H] +；
步骤3)(E)-4-溴-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)丁-2-烯酰胺的合成
在冰水浴条件下向5-氯-N-(3-氯-2-氟苯基)喹唑啉-4,6-二胺(65mg,0.2mmol)的NMP(2ml)溶液中加入溴代巴豆酰氯(55mg,0.3mmol)的二氯甲烷溶液，搅拌反应30分钟后，加入饱和碳酸氢钠溶液淬灭，析出固体，过滤，乙酸乙酯洗涤，干燥后直接用于下一步；MS:469,471[M+H] +；
步骤4)(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(异丙基氨基)丁-2-烯酰胺的合成
在冰水浴条件下将(E)-4-溴-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)丁-2-烯酰胺(0.46g,1mmol)，异丙胺(0.2g,3mmol)和二异丙基乙基胺(0.3g,3mmol)分别加入到DMF(5ml)中，加热至50摄氏度搅拌反应2小时，冷却分别加入水，乙酸乙酯，有机相用饱和食盐水洗涤，干燥，浓缩，柱层析纯化得浅黄色固体产物150mg,收率33％；
1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.66(s,1H),8.56(s,1H),8.14(d,J＝9.0Hz,1H),7.82(d,J＝8.9Hz,2H),7.49(t,J＝7.6Hz,1H),7.31(t,J＝8.1Hz,1H),6.89(dt,J＝15.4,5.8Hz,1H),6.60(d,J＝15.4Hz,1H),3.63(s,2H),3.33(br,1H),3.06(s,1H),1.15(d,J＝6.3Hz,6H).MS:448[M+H] +。
实施例12.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(环丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000020
以与实施例11相同的方法进行合成，不同之处在于，用环丙胺代替步骤4)的异丙胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H),9.65(s,1H),8.54(s,1H),8.16(d,J＝9.0Hz,1H),7.89–7.77(m, 2H),7.49(ddd,J＝8.3,6.8,1.6Hz,1H),7.30(td,J＝8.1,1.4Hz,1H),6.92(dt,J＝15.4,5.3Hz,1H),6.49(dt,J＝15.5,1.8Hz,1H),3.43(dd,J＝5.4,1.8Hz,2H),3.33(br,1H),2.16(tt,J＝6.7,3.6Hz,1H),0.43-.039(m,2H),0.32–0.24(m,2H).MS:446[M+H] +。
实施例13.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(甲氨基)丁-2-烯酰胺单三氟乙酸盐
Figure PCTCN2021087774-appb-000021
以与实施例11相同的方法进行合成，不同之处在于，用甲胺盐酸盐代替步骤4)的异丙胺进行反应，纯化经过制备液相制备得到单三氟乙酸盐产物；
1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),9.71(s,1H),8.73(s,2H),8.57(s,1H),8.12(d,J＝9.1Hz,1H),7.82(s,2H),7.49(s,1H),7.31(d,J＝7.2Hz,1H),6.82(dt,J＝15.5,6.5Hz,1H),6.65(d,J＝15.5Hz,1H),3.84(q,J＝5.9Hz,2H),2.67–2.53(m,3H).MS:420[M+H] +。
实施例14.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(环丁基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000022
以与实施例11相同的方法进行合成，不同之处在于，用环丁胺代替步骤4)的异丙胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),9.66(s,1H),8.50(s,1H),8.14(d,J＝9.0Hz,1H),7.78(s,2H),7.45(t,J＝7.5Hz,1H),7.28(t,J＝8.2Hz,1H),6.89(dt,J＝15.4,5.3Hz,1H),6.51(d,J＝15.4Hz,1H),3.29(d,J＝5.3Hz,2H),3.33(br,1H),3.20(p,J＝7.6Hz,1H),2.11(q,J＝8.5,7.9Hz,2H),1.76-1.55(m,4H).MS:460[M+H] +。
实施例15.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(异丙基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000023
以与实施例11相同的方法进行合成，不同之处在于，用异丙基甲基胺代替步骤4)的异丙胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),9.66(s,1H),8.54(s,1H),8.16(d,J＝9.1Hz,1H),7.87–7.75(m,2H),7.46(s,1H),7.28(t,J＝8.2Hz,1H),6.83(dt,J＝15.4,5.7Hz,1H),6.53(dt,J＝15.4,1.8Hz,1H),3.21(dd,J＝5.8,1.6Hz,2H),2.83(p,J＝6.6Hz,1H),2.16(s,3H),0.99(d,J＝6.5Hz,6H).MS:462[M+H] +。
实施例16.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(环丁基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000024
以与实施例11相同的方法进行合成，不同之处在于，用环丁基甲基胺代替步骤4)的异丙胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),9.66(s,1H),8.54(s,1H),8.17(d,J＝9.1Hz,1H),7.88–7.76(m,2H),7.48(s,1H),7.29(t,J＝8.1Hz,1H),6.84(dt,J＝15.4,5.9Hz,1H),6.52(d,J＝15.4Hz,1H),3.09–3.02(m, 2H),2.93–2.81(m,1H),2.06(s,3H),1.99(dd,J＝9.8,7.2Hz,2H),1.80(tt,J＝11.2,8.9Hz,2H),1.61(ddt,J＝18.1,10.4,8.1Hz,2H).MS:474[M+H] +。
实施例17.(E)-N-(5-氯-4-((3-氯-2-氟苯基)氨基)喹唑啉-6-基)-4-(环丙基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000025
以与实施例11相同的方法进行合成，不同之处在于，用环丙基甲基胺代替步骤4)的异丙胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H),9.66(s,1H),8.50(s,1H),8.14(s,1H),7.77(s,2H),7.48–7.42(m,1H),7.28(s,1H),6.85(s,1H),6.49(s,1H),4.11(s,1H),3.16(s,2H),2.29(s,3H),0.46(s,2H),0.35(s,2H).MS:460[M+H] +。
实施例18.(E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-4-(环丙基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000026
以与实施例11相同的方法进行合成，不同之处在于，用3-氯-4-(吡啶-2-基甲氧基)苯胺代替步骤1)的3-氯-2-氟苯胺，用环丙基甲基胺代替步骤4)的异丙胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H),9.57(s,1H),8.60(ddd,J＝4.8,1.8,0.9Hz,1H),8.52(s,1H),8.12(d,J＝9.0Hz,1H),7.94–7.84(m,2H),7.75(d,J＝9.0Hz,1H),7.62–7.54(m,2H),7.38(ddd,J＝7.6,4.8,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.86(dt,J＝15.4,6.1Hz,1H),6.49(dt,J＝15.4,1.6Hz,1H),5.31(s,2H),3.38–3.30(m,2H),2.29(s,3H),1.77(tt,J＝6.6,3.6Hz,1H),0.46(dt,J＝6.1,3.0Hz,2H),0.39–0.31(m,2H).MS:549[M+H] +。
实施例19.(E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-4-(环丁基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000027
以与实施例11相同的方法进行合成，不同之处在于，用3-氯-4-(吡啶-2-基甲氧基)苯胺代替步骤1)的3-氯-2-氟苯胺，用环丁基甲基胺代替步骤4)的异丙胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),9.57(s,1H),8.60(dt,J＝4.9,1.3Hz,1H),8.52(s,1H),8.12(d,J＝9.0Hz,1H),7.94–7.84(m,2H),7.74(d,J＝9.0Hz,1H),7.62–7.55(m,2H),7.37(ddd,J＝7.7,4.8,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.83(dt,J＝15.4,6.0Hz,1H),6.52(dt,J＝15.4,1.8Hz,1H),5.31(s,2H),3.05(dd,J＝6.0,1.6Hz,2H),2.93–2.78(m,1H),2.06(s,3H),2.03–1.95(m,2H),1.87–1.72(m,2H),1.60(tdd,J＝15.0,7.0,4.9Hz,2H).MS:563[M+H] +。
实施例20.(R,E)-N-(5-氯-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2021087774-appb-000028
以与实施例11相同的方法进行合成，不同之处在于，用3-氯-4-(吡啶-2-基甲氧基)苯胺代替步骤1)的3-氯-2-氟苯胺，用(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯代替步骤3)的溴代巴豆酰氯进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H),9.57(s,1H),8.60(d,J＝4.8Hz,1H),8.52(s,1H),8.13(d,J＝9.0Hz,1H),7.89(dd,J＝14.2,5.4Hz,2H),7.75(d,J＝9.0Hz,1H),7.58(d,J＝8.2Hz,2H),7.37(t,J＝6.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.72(dd,J＝15.3,7.5Hz,1H),6.52(d,J＝15.3Hz,1H),5.31(s,2H),3.04(s,1H),2.79(q,J＝8.0Hz,1H),2.22(s,3H),2.18(d,J＝9.2Hz,1H),2.02(dq,J＝14.4,8.3,7.8Hz,1H),1.74(q,J＝8.4Hz,2H),1.61(d,J＝18.1Hz,1H).MS:549[M+H] +。
实施例21.(E)-N-(5-氯-4-((3-氯-2,4-二氟苯基)氨基)喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000029
以与实施例11相同的方法进行合成，不同之处在于，用2,4-二氟-3-氯苯胺代替步骤1)的3-氯-2-氟苯胺，用二甲胺盐酸盐代替步骤4)的异丙胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H),9.58(s,1H),8.50(s,1H),8.17(d,J＝9.0Hz,1H),7.78(s,2H),7.40(s,1H),6.83(dt,J＝15.5,5.8Hz,1H),6.53(dt,J＝15.5,1.7Hz,1H),3.10(dd,J＝5.9,1.6Hz,2H),2.21(s,6H).MS:452[M+H] +。
实施例22.(E)-N-(5-氯-4-((3-氯-2,4-二氟苯基)氨基)喹唑啉-6-基)-4-(异丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000030
以与实施例11相同的方法进行合成，不同之处在于，用2,4-二氟-3-氯苯胺代替步骤1)的3-氯-2-氟苯胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),9.59(s,1H),8.46(s,1H),8.13(d,J＝9.0Hz,1H),7.75(d,J＝14.5Hz,2H),7.44–7.34(m,1H),6.91(dt,J＝15.4,5.3Hz,1H),6.54(dt,J＝15.4,1.8Hz,1H),3.43(dd,J＝5.4,1.8Hz,2H),3.33(br,1H),2.82(p,J＝6.2Hz,1H),1.05(d,J＝6.2Hz,6H).MS:466[M+H] +。
实施例23.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺的合成
Figure PCTCN2021087774-appb-000031
步骤1)5-甲基喹唑啉-4-醇
把2-氨基-6-甲基-苯甲酸(4.53g,30mmol)和醋酸甲脒(3.12g,30.00mmol)加入乙醇(40mL)中，加热80℃至回流反应24h，LCMS监测，反应完毕，体系降至室温，析出大量固体。过滤，滤饼用少量石油醚洗。收集，烘干得到产品5-甲基喹唑啉-4-醇(3.66g,22.85mmol,收率76.17％)；MS:161[M+H] +。
步骤2)5-甲基-6-硝基喹唑啉-4-醇
常温条件下，把5-甲基喹唑啉-4-醇(3.66g,22.85mmol)缓慢加入到H 2SO 4(30mL)，冰盐浴降至-20℃左右，分批加入KNO 3(2.54g,25.14mmol)(20min左右)，控制体系温度在-10℃以下。体系缓慢升温10℃反应2h，HPLC监测，反应完毕体系缓慢倒入碎冰中，析出大量固体，过滤，滤饼用水洗3次，收集，烘干得到产品5-甲基-6-硝基喹唑啉-4-醇(3.2g,15.60mmol,收率68.26％)。
1H NMR(400MHz,DMSO-d 6)δ8.45(s,1H),8.14(d,J＝8.9Hz,1H),7.92(s,1H)7.63(d,J＝8.9Hz,1H),2.77(s,3H).
步骤3)N-(3-氯-2-氟苯基)-5-甲基-6-硝基喹唑啉-4-胺
把5-甲基-6-硝基喹唑啉-4-醇(1g,4.87mmol)悬浮于二氯亚砜(15mL)中，常温搅拌下，加入DMF(0.5mL)，然后体系升温至100℃反应，待体系澄清后(约3h)，再回流反应2h，LCMS监测(MeOH淬灭体系)，反应完毕，体系直接减压浓缩，得到棕色固体；把上述得到的固体(1g,4.47mmol)悬浮于1,2-二氯甲烷(15mL)中，超声使分散均匀，冰浴条件下，缓慢滴加3-氯-2-氟苯胺(2.60g,17.89mmol)，滴毕，撤去冰浴，加热到50℃反应1h，LCMS监测反应完毕，体系减压旋蒸掉溶剂，剩余物加入MeOH,超声分散均匀，过滤，滤饼收集得到产品(990mg,2.98mmol,收率66.54％)。
步骤4)N-(3-氯-2-氟苯基)-5-甲基喹唑啉-4,6-二胺
把N-(3-氯-2-氟-苯基)-5-甲基-6-硝基-喹啉-4-胺基(990mg,2.98mmol)悬浮于甲醇(10mL)中，加入雷尼Ni(34.93mg,595.10μmol)，置换H 2氛3次，常温搅拌30min，体系逐渐溶解澄清，LCMS监测。反应完毕，垫硅藻土过滤，滤液浓缩得到产品(890mg,2.94mmol,收率98.80％)。
步骤5.(E)-4-溴-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)丁-2-烯酰胺
把N-(3-氯-2-氟苯基)-5-甲基喹唑啉-4,6-二胺(50mg,165.16μmol)加入到NMP(3ml)中，常温搅拌下，滴加入(E)-溴代巴豆酰氯(45mg,250μmol)的乙腈溶液，反应15分钟，LCMS监测，反应完毕，体系用过量饱和碳酸氢钠水溶液淬灭，调pH≈8,析出大量固体，过滤，乙酸乙酯洗涤，晾干得700mg粗产物备用,MS:449,451[M+H] +。
步骤6.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺
把(E)-4-溴-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)丁-2-烯酰胺(50mg,165.16μmol)加入到DMF(3mL)中，常温搅拌下，分别加入二甲胺盐酸盐，二异丙基乙基胺，加热至50摄氏度反应2小时，LCMS监测反应完毕，体系用过量饱和碳酸氢钠水溶液淬灭，调pH≈8,析出大量固体，过滤，固体制备板纯化(DCM/MeOH＝10:1)得到目标产物(25mg,60.40μmol,收率36.57％)。
1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),8.89(s,1H),8.41(s,1H),7.69(br,2H),7.19(br,3H),6.76(dt,J＝15.4,5.8Hz,1H),6.40(d,J＝15.5Hz,1H),3.08(d,J＝5.9Hz,2H),2.72(s,3H),2.19(s,6H).MS:414[M+H] +。
实施例24.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(异丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000032
以与实施例23相同的方法进行合成，不同之处在于，用异丙胺代替步骤6)的二甲胺盐酸盐进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),8.91(s,1H),8.48-8.44(m,1H),7.81–7.51(m,2H),7.40–7.02(m,3H),6.90–6.78(m,1H),6.40(d,J＝16.2Hz,1H),3.33(br,1H),2.82-2.79(m,4H),2.71(d,J＝3.6Hz,2H),1.02(d,J＝6.2Hz,6H).MS:428[M+H] +。
实施例25.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(环丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000033
以与实施例23相同的方法进行合成，不同之处在于，用环丙胺代替步骤6)二甲胺盐酸盐进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),8.06(s,1H),7.67(d,J＝8.3Hz,1H),7.39(s,2H),7.33–7.12(m,3H),6.85(dt,J＝15.4,5.1Hz,1H),6.39(d,J＝15.4Hz,1H),3.38–3.33(m,4H),2.80–2.67(s,3H),1.01(d,J＝6.2Hz,4H).MS:426[M+H] +。
实施例26.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000034
以与实施例23相同的方法进行合成，不同之处在于，用甲胺盐酸盐代替步骤6)二甲胺盐酸盐进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.25(s,1H),7.64(br,3H),7.19(s,3H),6.80(d,J＝15.6Hz,1H),6.43(d,J＝15.5Hz,1H),3.45(br,3H),2.72(s,3H),2.40(s,3H).MS:400[M+H] +。
实施例27.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(环丁基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000035
以与实施例23相同的方法进行合成，不同之处在于，用环丁胺代替步骤6)二甲胺盐酸盐进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),8.91(s,1H),8.38(br,1H),7.64(s,2H),7.43–6.90(m,3H),6.82(dt,J＝15.6,5.3Hz,1H),6.39(d,J＝15.4Hz,1H),3.33-3.27(m,3H),3.20(d,J＝7.7Hz,1H),2.72(s,3H),2.11(q,J＝8.2,5.8Hz,2H),1.79–1.48(m,4H).MS:440[M+H] +。
实施例28.(E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(异丙基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000036
以与实施例23相同的方法进行合成，不同之处在于，用异丙基甲基胺代替步骤6)二甲胺盐酸盐进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.95-9.66(m,1H),8.91-8.45(m,1H),7.84(d,J＝23.3Hz,1H),7.68–7.58(m,2H),7.36–6.99(m,3H),6.75(d,J＝15.2Hz,1H),6.39(d,J＝17.9Hz,1H),3.20(d,J＝5.7Hz,2H),2.83(q,J＝6.5Hz,1H),2.72(d,J＝22.2Hz,3H),2.16(s,3H),0.99(d,J＝6.5Hz,6H).MS:442[M+H] +。
实施例29.(R,E)-N-(4-((3-氯-2-氟苯基)氨基)-5-甲基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2021087774-appb-000037
以与实施例23相同的方法进行合成，不同之处在于，用(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯代替步骤5)的溴代巴豆酰氯进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H)8.46(s,1H),7.90–7.80(m,1H),7.61-7.46(m,2H),7.36-6.99(m,3H),6.66(td,J＝19.5,17.8,7.4Hz,1H),6.39(dd,J＝27.3,15.4Hz,1H),3.03(d,J＝8.5Hz,1H),2.26–2.13(m,6H),2.00(d,J＝11.3Hz,2H),1.77(td,J＝6.6,6.0,2.8Hz,2H),1.59(s,2H).MS:440[M+H] +。
实施例30.(E)-N-(4-((3-氯-2,4-二氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000038
以与实施例23相同的方法进行合成，不同之处在于，用3-氯-2,4-二氟苯胺代替步骤3)的3-氯-2-氟苯胺进行反应得到； 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),9.74(s,1H),8.86(s,1H),8.41(s,1H),7.78(s,1H),7.62(s,1H),6.99(s,1H),6.80–6.71(m,1H),6.38(d,J＝15.4Hz,1H),3.08(d,J＝5.9Hz,2H),2.71(s,3H),2.19(s,6H).MS:432[M+H] +。
实施例31.(E)-N-(4-((3-氯-4-氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(二甲氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000039
以与实施例23相同的方法进行合成，不同之处在于，用3-氯-4-氟苯胺代替步骤3)的3-氯-2-氟苯胺进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.99(s,1H),8.51(s,1H),8.02(dd,J＝6.9,2.6Hz,1H),7.83(d,J＝8.8Hz,1H),7.72–7.59(m,2H),7.43(t,J＝9.1Hz,1H),6.78(dt,J＝15.4,5.9Hz,1H),6.45(d,J＝15.5Hz,1H),3.12–3.06(m,2H),2.72(s,3H),2.20(s,6H).MS:414[M+H] +。
实施例32.(E)-N-(4-((3-氯-2,4-二氟苯基)氨基)-5-甲基喹唑啉-6-基)-4-(异丙基氨基)丁-2-烯酰胺
Figure PCTCN2021087774-appb-000040
以与实施例23相同的方法进行合成，不同之处在于，用3-氯-4-氟苯胺代替步骤3)的3-氯-2-氟苯胺，由异丙胺代替步骤6)的二甲胺盐酸盐进行反应得到；
1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.33(s,1H),7.65(br,2H),7.28(br,3H),6.84(dt,J＝15.4,5.7Hz,1H),6.48(d,J＝15.4Hz,1H),3.53(d,J＝5.7Hz,2H),3.33(br,1H),2.96(q,J＝6.3Hz,1H),2.72(s,3H),1.11(d,J＝6.3Hz,6H).MS:446[M+H] +。
实验例1.小分子化合物抑制EGFR WT及HER2激酶活性的测试
试剂和耗材：ULightTM-labeled Ploy GT Peptide(Perkin Elmer，目录号TRF-0100-M)；ULightTM-labeled JAK-1(Try1023)Peptide(Perkin Elmer，目录号TRF-0121-M)；Eu-W1024-labeled Anti-Phosphotyrosine Antibody(PT66)(Perkin Elmer，目录号AD0068)；10×Detection Buffer(Perkin Elmer，目录号CR97-100)；Her2激酶(Carna Biosciences，目录号08-016)；EGFR激酶(Carna Biosciences，目录号08-115)；HEPES(GIBCO，目录号15630-080)；EGTA(Sigma，目录号03777-10G)；EDTA(Sigma，目录号EDS-100G)；MgCl 2(Sigma，目录号63069-100ML)；DTT(Sigma，目录号43816-10ML)；Tween-20(Sigma，目录号P7949-100ML)；DMSO(Life Science，目录号0231-500ML)；384孔板(Perkin Elmer，目录号607290)；多功能读板机(Perkin Elmer，目录号Envision)
化合物溶液配置：受试化合物溶于DMSO配成10mM母液。使用前将化合物在DMSO中稀释至0.25mM(100倍终浓度的稀释液)，并做3倍浓度梯度稀释，11个梯度。加药时用缓冲液稀释成4倍终浓度的稀释液。
HER2激酶检测：配置缓冲液，使用缓冲液配置40nM 4X Her2激酶溶液、40μM 4X ATP溶液、400nM 4×ULight TM-labeled Ploy GT Peptide底物溶液。配置完成后，将酶与预先稀释配置的不同浓度化合物混合，室温放置5分钟，每个浓度设置复孔。加入对应底物以及ATP，室温反应120分钟(其中设置阴阳对照)。反应完毕加入PT66检测抗体，室温孵育60分钟后用Envision检测。
EGFR WT激酶检测：配置缓冲液，使用缓冲液配置3.48nM 4X EGFR激酶溶液、600μM 4X ATP溶液、400nM 4×ULight TM-labeled JAK-1(Try1023)Peptide底物溶液。配置完成后，将酶与预先稀释配置的不同浓度化合物混合，室温放置5分钟，每个浓度设置复孔。加入对应底物以及ATP，室温反应120分钟(其中设置阴阳对照)。反应完毕加入PT66检测抗体，室温孵育60分钟后用Envision检测。
数据计算：用Excel表格计算孔读值和抑制率，孔读值＝10000*(孔EU665值)/(孔EU615值)，抑制率＝[(阳性对照孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)]*100％。将化合物浓度和相应抑制率输入GraphPad Prism处理计算IC 50值。
表2测试显示，本申请的化合物可以抑制EGFR WT及HER2酪氨酸激酶的活性，尤其是其中部分化合物表现出了强力的抑制效应。测试结果总结于下表2中。
表2列出了本申请中部分化合物对EGFR WT及HER2酪氨酸激酶抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM，NT表示未有相关结果。
表2本发明化合物对EGFR及HER2激酶抑制活性测定结果
Figure PCTCN2021087774-appb-000041
实验例2.小分子化合物抑制细胞增殖的测试
本申请采用CCK8方法检测了本发明化合物对体外培养的BT474、NCI-N87、HCC-827和Ba/F3EGFRvIII细胞系的体外抗增殖活性。
试剂和耗材：RPMI1640(ThermoFisher，目录号C11875500BT)；DMEM(ThermoFisher，C11995500BT)；胎牛血清(Hyclone，目录号SV30087.03)；0.25％胰蛋白酶-EDTA(ThermoFisher，目录号25200072)；青霉素-链霉素(Hyclone，目录号SV30010)；DSMO(Life Science，目录号0231- 500ML)；CCK8测试试剂盒(Dojindo，目录号CK04-100)；96孔板(Corning，目录号3599)；多功能读板机(Perkin Elmer，目录号Envision)
细胞系：BT474(来自中国科学院细胞库)，NCI-N87(来自ATCC)和HCC-827(来自ATCC)，Ba/F3 EGFRvIII来自康源博创生物科技(北京)有限公司；其中，BT474、NCI-N87和Ba/F3 EGFRvIII用含10％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI1640培养基培养，HCC-827用10％胎牛血清、100U/mL青霉素、100μg/mL链霉素的DMEM培养基培养。
具体实验方法：
1.用DSMO溶解被受试化合物形成储藏液并进行梯度稀释，然后再用相应培养基稀释得到20倍工作浓度溶液。
2.将处于对数生长期的细胞用培养液稀释调整至特定细胞浓度，添加80μL细胞悬液至96孔板中，使得BT474、NCI-N87、HCC-827和Ba/F3 EGFRvIII的细胞密度分别为10000cells/孔、8000cells/孔、5000cells/孔和8000cells/孔。置于37℃、5％二氧化碳气体培养箱中培养过夜。其中Ba/F3 EGFRvIII细胞直接进入下一步加药处理，BT474、NCI-N87、HCC-827需培养过夜贴壁后再加药物处理。
3.在已接种细胞的96孔板中每孔加入20μL药物溶液。被测化合物最高浓度为10μM，10个浓度，4倍梯度稀释，双复孔。同时设置不加药物的对照组。
4.细胞继培养72小时后，用CCK8检测细胞活力。用GraphPad Prism软件制作量效曲线并计算IC 50。
表3列出了本发明中代表性化合物对BT474、NCI-N87、HCC-827和Ba/F3 EGFRvIII细胞的抗增殖活性测定结果。其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM，NT表示未有相关结果。
表3、本发明代表性化合物对BT474、NCI-N87、HCC-827和Ba/F3 EGFRvIII细胞的抗增殖活性测定结果
Figure PCTCN2021087774-appb-000042
Figure PCTCN2021087774-appb-000043
表3结果显示，本申请的上述化合物对于BT474、NCI-N87和Ba/F3 EGFRvIII细胞均表现出了优异至良好的抗肿瘤增殖活性。而且，本申请的化合物也对HCC-827细胞系表现出了优异的抑制增殖活性。
实验例3.小分子化合物药代动力学试验
本试验通过对SD大鼠单次口服及静脉注射给予本申请部分化合物后，研究了本申请化合物的药代动力学特征，研究了本申请化合物穿透血脑屏障的能力。同时，相应地测试了吡咯替尼(PYROTINIB)、来拉替尼(NERATINIB)，并与本申请化合物进行了对比。
(一)所用试剂、仪器以及动物
表4.试验试剂
Figure PCTCN2021087774-appb-000044
表5.试验仪器
Figure PCTCN2021087774-appb-000045
Figure PCTCN2021087774-appb-000046
表6.试验用鼠
Figure PCTCN2021087774-appb-000047
(二)样品制剂配制
1.静脉注射(IV)组：称取适当数量的待测化合物，完全溶解于适当体积的溶媒(DMSO/Solutol/H 2O＝5/10/85V/V,加入2meq HCl)中，进行搅拌、涡流和/或超声处理。得到溶液后，将逐渐增加溶媒至终体积以达到目标浓度，涡旋、超声，得到均一溶液，用0.22μm的PVDF滤膜过滤。
2.口服(PO)组：称取适当数量的待测化合物，完全溶解于适当体积的溶媒(DMSO/Solutol/H 2O＝5/10/85V/V,加入2meq HCl)中，进行搅拌、涡流和/或超声处理。得到溶液后，将逐渐增加溶媒至终体积以达到目标浓度，涡旋、超声，得到均一溶液。
(三)大鼠给药及取样
根据动物体重对动物随机分组，分组后各组动物体重相当(不超过平均体重的±20％)。同时，IV组不禁食，PO组禁食过夜(>12小时)，并于给药后2小时给予食物。所有动物自由饮水。以下表7和表8分别给出了给药方案和药代动力学采样方案。
表7.给药方案
Figure PCTCN2021087774-appb-000048
表8.药代动力学采样方案
Figure PCTCN2021087774-appb-000049
Figure PCTCN2021087774-appb-000050
按照上述方案对大鼠进行给药，并在预定的时间点进行血液和脑组织样品的采集和处理(采集和处理按本领域常规方法进行)。
(四)样品分析
脑称重，加入4倍的超纯水匀浆。全血样品和脑匀浆液分别加入6倍体积的乙腈，涡旋1min后，4℃，4500rpm离心15min，上清液用超纯水稀释2倍，用LC/MS分析样品。
(五)数据分析：
将用WinNonlin软件进行药代动力学参数计算。如有适用的血浆的药物浓度-时间数据，将计算以下药代动力学参数：CL(清除率)；V d(表观分布容积)；T 1/2(消除半衰期)；C max(达峰浓度)；T max(达峰时间)；AUC(血药浓度-时间曲线下面积)；MRT(平均滞留时间)；F％(生物利用度)。
测试结果示于下表9-15中，分别给出了本申请实施例化合物1和2、19和20、以及吡咯替尼和来拉替尼在各时间点的大鼠血药浓度，以及各药代动力学参数值，同时给出了本申请实施例化合物1和2、19和20、以及吡咯替尼和来拉替尼在大鼠的脑和血液中的浓度及其比值。由上面的结果可知，本申请的化合物1和2、19和20均表现出了优异的穿透血脑屏障的能力，远优于已上市的吡咯替尼和来拉替尼。这也说明本申请的化合物不但具有优异的EGFR、HER2激酶抑制活性，并能在细胞水平上抑制细胞增殖，同时更具有优异的穿透血脑屏障的能力，有望应用于EGFR和/或HER2激酶介导的相关疾病，尤其是脑转移相关的疾病。
表9.本申请实施例化合物1和2的大鼠血药浓度
Figure PCTCN2021087774-appb-000051
表10.本申请实施例1和2的化合物的大鼠药代参数
Figure PCTCN2021087774-appb-000052
表11.本申请实施例化合物19和20的大鼠血药浓度
Figure PCTCN2021087774-appb-000053
表12.本申请实施例19和20的化合物的大鼠药代参数
Figure PCTCN2021087774-appb-000054
Figure PCTCN2021087774-appb-000055
表13.吡咯替尼和来拉替尼的大鼠血药浓度
Figure PCTCN2021087774-appb-000056
表14.吡咯替尼和来拉替尼的大鼠药代参数
Figure PCTCN2021087774-appb-000057
表15.本申请实施例化合物1和2、19和20、以及吡咯替尼和来拉替尼在脑和全血中的浓度及比值(PO10mg/kg，采样时间，给药2h)
实施例 血药浓度(ng/mL) 脑浓度(ng/g) 脑/血比值
Pyrotinib 884 25.8 0.0291
Neratinib 440 14.4 0.0366
1 256 373 1.46
2 616 3168 5.45
19 446 788 1.77
20 109 116 1.06
表9和表10结果显示，实施例1和实施例2具有优异的药代动力学参数，适合于开发口服抑制剂。表15结果显示，实施例1和实施例2同时具有极强的穿透血脑屏障的特性，适用于脑部原发肿瘤的治疗以及脑转移的肿瘤的治疗。表11-12以及表15的结果也显示，实施例19和20也具有优异的药代动力学性质，同时具有很强的穿透血脑屏障的特性。综合表3、表9、表10、表11-12及表15结果可见，本发明的化合物有望开发成为神经胶质瘤的治疗药物。
综上所述，本申请的化合物均对EGFR激酶表现出优异的抑制活性，对HER2激酶也表现出良好至优异的抑制活性；细胞方面，本申请所有化合物均对Ba/F3 EGFRvIII细胞系表现出优异的抑制增殖活性；同时，药代动力学测试也发现本申请化合物表现出优异的穿透血脑屏障的能力(远优于已上市药物)，由此，尤其对于EGFRvIII诱导的肿瘤例如神经胶质瘤或者EGFR/HER2驱动的肿瘤转脑的情况，本申请化合物有望成为上述疾病的治疗药物。
已获批上市的喹唑啉药物诸如吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)、阿法替尼(Afatinib)和拉帕替尼(Lapatinib)均无法有效穿透血脑屏障。同时，目前以喹唑啉为母核的化合物，大部分均在喹唑啉环的6位和7位进行取代，而几乎没有在5位进行取代的，本申请人研究发现，在喹唑啉环的6位引入烯丙酰胺基团，在其5位引入卤素(例如Cl)或烷基(例如甲基)取代，其中，烯丙酰胺基团可以与EGFR或HER2靶点形成非可逆共价结合，而5位引入的卤素或烷基可以锁定烯丙酰胺基团的取向，更有利于烯丙酰胺与EGFR或HER2靶点形成共价结合。这种设计不仅实现了本发明化合物对EGFR或HER2靶点的强大共价结合能力，同时也极大地提高了本发明化合物的血脑穿透能力。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (16)

  1. 一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
    Figure PCTCN2021087774-appb-100001
    式(I)中，m为0、1或者2；
    A为卤素、C 1-C 3烷基；Z为NH或者O；
    R 1为氢、羟基、4-7元杂脂环基或-NR aR b，
    R a、R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、被羟基取代的C 1-C 6烷基、被C 1-C 3烷氧基取代的C 1-C 6烷基、或被C 3-C 6环烷基取代的C 1-C 6烷基；
    所述的4-7元杂脂环基为含有1-2个选自N、O或S的杂原子的杂脂环基，所述杂脂环基未被取代或被C 1-C 3烷基、C 1-C 4烷基酰基、羟基、氰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、氧代(＝O)中的一种或两种取代；
    R 2、R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-C 6烷基、-O-(CH 2)n-R 7，
    R 7为氢、C 1-C 3烷基、被1至3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
    所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，
    R'、R”各自独立地为H或C 1-C 3的烷基。
  2. 根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，所述化合物具有如下通式，
    Figure PCTCN2021087774-appb-100002
    式(II)中，
    A为卤素、C 1-C 3烷基；Z为NH或者O；
    R 1为氢、羟基、4-7元杂脂环基或-NR aR b，
    R a、R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、被羟基取代的C 1-C 6烷基、被C 1-C 3烷氧基取代的C 1-C 6烷基、或被C 3-C 6环烷基取代的C 1-C 6烷基；
    所述的4-7元杂脂环基为含有1-2个选自N、O或S的杂原子的杂脂环基，所述杂脂环基未被取代或被C 1-C 3烷基、C 1-C 4烷基酰基、羟基、氰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、氧代(＝O)中的一种或两种取代；
    R 2、R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-C 6烷基、-O-(CH 2)n-R 7，
    R 7为氢、C 1-C 3烷基、被1至3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
    所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，
    R'、R”各自独立地为H或C 1-C 3的烷基。
  3. 根据权利要求1或2所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，A为Cl、F或者甲基；Z为NH。
  4. 根据权利要求1或2或3所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，R 1为4-7元杂脂环基或-NR aR b，
    R a、R b各自独立地为氢、C 1-C 3烷基、被羟基取代的C 1-C 3烷基、被C 1-C 3烷氧基取代的C 1-C 3烷基；
    所述4-7元杂脂环基为吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、硫代吗啉基，且上述基团未被取代或被甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、羟基、氰基、氨基酰基、甲基砜基、乙基砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、氧代(＝O)中的一种或两种取代。
  5. 根据权利要求4所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，R 1为吡咯烷-1-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、吗啉基、四氢呋喃2-基、四氢呋喃3-基、四氢吡喃2-基、四氢吡喃3-基、硫代吗啉基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、甲基乙基氨基、甲基丙基氨基或者乙基丙基氨基。
  6. 根据权利要求5所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，R 1为二甲氨基。
  7. 根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，m为0或者1，
    R 1为4-7元杂脂环基或-NR aR b，
    R a、R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基；
    所述4-7元杂脂环基为吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、硫代吗啉基，且上述基团未被取代或被甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、羟基、氰基、氨基酰基、甲基砜基、乙基砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、氧代(＝O)中的一种或两种取代；
    优选地，m为0或者1，
    R 1为1-甲基-吡咯烷-2-基、1-乙基-吡咯烷-2-基、1-异丙基-吡咯烷-2-基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基氨基、环丁基氨基、甲基异丙基氨基、N-甲基-N-环丙基氨基、N-甲基-N-环丁基氨基、吡咯烷-1-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、吗啉基、四氢呋喃2-基、四氢呋喃3-基、四氢吡喃2-基、四氢吡喃3-基、硫代吗啉基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、甲基乙基氨基、甲基丙基氨基或者乙基丙基氨基。
  8. 根据权利要求1或2所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、甲基、乙基、丙基、异丙基、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少3个为氢，
    R 7为氢、甲基、乙基、丙基、异丙基或者被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基、环丙基、乙炔基、乙烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
    R'、R”分别独立的为H或甲基，
    所述芳基为苯基，所述杂芳基为吡啶基、嘧啶基、吡咯基、噻吩基、呋喃基、咪唑基。
  9. 根据权利要求8所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少3个为氢，
    R 7为被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
    所述芳基为苯基，所述杂芳基为吡啶基。
  10. 根据权利要求9所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，R 2、R 3、R 4、R 5、R 6各自独立地为氢、氟、氯、苯氧基、2-氟苯氧基、3-氟苯氧基、4-氟苯氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-基甲氧基、3-氟苄基氧基、2-氟苄基氧基、4-氟苄基氧基、3-氯苄基氧基、2-氯苄基氧基、4-氯苄基氧基，且R 2、R 3、R 4、R 5、R 6中至少3个为氢。
  11. 根据权利要求1或7中任一项所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 2、R 3、R 5、R 6各自独立地为氢、氟、氯、甲基、乙基、丙基、异丙基，R 4为氢、氟、氯、甲基、乙基、丙基、异丙基、-O-(CH 2)n-R 7，且R 2、R 3、R 4、R 5、R 6中至少2个为氢，
    R 7为氢、甲基、乙基、丙基、异丙基或者被1至3个选自氟、氯、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氟甲基、氟乙基、三氟甲基、环丙基、乙炔基、乙烯基或-NR'R”中的取代基所取代或非取代的芳基或者杂芳基，n为0-3的整数，
    R'、R”分别独立的为H或甲基，
    所述芳基为苯基，所述杂芳基为吡啶基、嘧啶基、吡咯基、噻吩基、呋喃基、咪唑基；
    优选地，R 2、R 3、R 5、R 6各自独立地为氢、氟、氯，R 4为氢、氟、氯、苯氧基、2-氟苯氧基、3-氟苯氧基、4-氟苯氧基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、吡啶-4-基甲氧基、3-氟苄基氧基、2-氟苄 基氧基、4-氟苄基氧基、3-氯苄基氧基、2-氯苄基氧基、4-氯苄基氧基，且R 2、R 3、R 4、R 5、R 6中至少2个为氢。
  12. 根据权利要求2所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，所述化合物选自：
    Figure PCTCN2021087774-appb-100003
  13. 根据权利要求1或2所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，所述化合物选自：
    Figure PCTCN2021087774-appb-100004
    Figure PCTCN2021087774-appb-100005
  14. 一种药物组合物，包括权利要求1至13中任一项所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，以及一种或多种药学上可接受的载体或赋形剂。
  15. 权利要求14所述的药物组合物，其中，所述药物组合物还包含一种或多种其他治疗剂。
  16. 根据权利要求1-13中任一项所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药在制备治疗与酪氨酸激酶EGFR、HER2相关的癌症及自身免疫疾病的药物中的应用，其中所述癌症及自身免疫疾病包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1218456A (zh) * 1996-04-12 1999-06-02 沃尼尔·朗伯公司 酪氨酸激酶的不可逆抑制剂
WO2003081210A2 (en) * 2002-03-21 2003-10-02 Sunesis Pharmaceuticals, Inc. Identification of kinase inhibitors
CN103998040A (zh) * 2011-03-04 2014-08-20 江苏康缘药业股份有限公司 炔基取代的喹唑啉化合物及其使用方法
CN110343090A (zh) * 2018-04-08 2019-10-18 威尚（上海）生物医药有限公司 喹唑啉衍生物盐型晶型及制备方法和应用
WO2020057511A1 (en) * 2018-09-18 2020-03-26 Suzhou Zanrong Pharma Limited Quinazoline derivatives as antitumor agents

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10307165A1 (de) * 2003-02-20 2004-09-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
CA2629244C (en) * 2005-11-11 2014-08-05 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
CN101824029A (zh) * 2009-03-05 2010-09-08 厦门艾德生物医药科技有限公司 酪氨酸激酶不可逆抑制剂、其药物组合物及其用途
EP2716633B1 (en) * 2011-05-26 2017-05-17 Xuanzhu Pharma Co., Ltd. Quinazoline derivative as tyrosine-kinase inhibitor, preparation method therefor and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1218456A (zh) * 1996-04-12 1999-06-02 沃尼尔·朗伯公司 酪氨酸激酶的不可逆抑制剂
WO2003081210A2 (en) * 2002-03-21 2003-10-02 Sunesis Pharmaceuticals, Inc. Identification of kinase inhibitors
CN103998040A (zh) * 2011-03-04 2014-08-20 江苏康缘药业股份有限公司 炔基取代的喹唑啉化合物及其使用方法
CN110343090A (zh) * 2018-04-08 2019-10-18 威尚（上海）生物医药有限公司 喹唑啉衍生物盐型晶型及制备方法和应用
WO2020057511A1 (en) * 2018-09-18 2020-03-26 Suzhou Zanrong Pharma Limited Quinazoline derivatives as antitumor agents

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