WO2022194265A1 - 一种喹唑啉类化合物、组合物及其应用 - Google Patents

一种喹唑啉类化合物、组合物及其应用 Download PDF

Info

Publication number
WO2022194265A1
WO2022194265A1 PCT/CN2022/081599 CN2022081599W WO2022194265A1 WO 2022194265 A1 WO2022194265 A1 WO 2022194265A1 CN 2022081599 W CN2022081599 W CN 2022081599W WO 2022194265 A1 WO2022194265 A1 WO 2022194265A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
pyrrolidin
substituted
pyridin
methyl
Prior art date
Application number
PCT/CN2022/081599
Other languages
English (en)
French (fr)
Inventor
张强
杨磊夫
Original Assignee
北京赛特明强医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京赛特明强医药科技有限公司 filed Critical 北京赛特明强医药科技有限公司
Priority to JP2023557350A priority Critical patent/JP2024510312A/ja
Priority to KR1020237034939A priority patent/KR20230156767A/ko
Priority to AU2022235956A priority patent/AU2022235956A1/en
Priority to CA3212079A priority patent/CA3212079A1/en
Priority to EP22770617.3A priority patent/EP4293016A1/en
Publication of WO2022194265A1 publication Critical patent/WO2022194265A1/zh

Links

Images

Classifications

    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of medicine, and relates to a quinazoline compound, a composition and an application thereof.
  • ErbB Epidermal growth factor receptor
  • ErbB family members and some of their ligands are often overexpressed, amplified, or mutated in various forms of malignancies, making them important therapeutic targets.
  • This family of protein kinases includes: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4.
  • EGFR and HER2 are important targets for the development of non-small cell lung cancer and breast cancer drugs (Brumann R., et.al., (2001) Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.
  • EGFR and HER2 are not stable, and gene amplification and rearrangement often occur, which changes the antigenic phenotype on the surface of tumor cells.
  • the existing targeted drugs have great curative effect on different mutations of EGFR and HER2. Among them, the inhibitory ability of Ins20 is the weakest, resulting in Ins20 mutation becoming a drug-resistant mutation, and the current multi-generation targeted drugs are almost ineffective.
  • the exon 20 mutations of the EGFR and HER2 genes occur in similar positions, but there are many types of EGFR exon 20 insertion mutations, and 122 types have been found; in comparison, the HER2 gene exon 20 insertion mutation type is less , the most common is the A775_G776insYVMA site, which accounts for nearly 70% of the mutations.
  • Statistics also show that about 3% of NSCLC patients carry HER2 mutations, of which about 90% are patients with mutations in exon 20 of the HER2 gene. For these patients with EGFR/HER2 exon 20 mutations, the efficacy of existing drugs targeting TKIs is very limited.
  • Poziotinib is a broad-spectrum HER inhibitor developed by Hanmi. Clinical data show that it also has a certain effect on EGFR/HER2 exon 20 mutations, but Poziotinib has a higher adverse reaction rate. At the same time, the marketed pyrotinib is also conducting clinical studies on related exon 20 mutations.
  • EGFRvIII of the epidermal growth factor receptor EGFR which is only expressed on the surface of tumor cells but not normal tissue cells, has also been discovered, which is also a very common EGFR mutant.
  • exons 2-7 encoding the extracellular ligand-binding region of EGFRvIII were deleted, resulting in a deletion of 801 base pairs, so that exons 1 and 8 were connected, and in this binding A new glycine was generated at the point, resulting in the deletion of amino acids 6 to 273, thereby losing the ability to bind to the ligand EGF.
  • EGFRvIII In the absence of ligand binding, EGFRvIII enables unregulated structural activation of tyrosine kinases by dimerization and autophosphorylation, inducing downstream signaling and stimulating tumor cell proliferation. Therefore, there is a huge unmet clinical need to develop new molecularly targeted therapeutic drugs for EGFRvIII to provide more effective and more economical treatment options for tumor patients.
  • TKI drugs on the market are all derived from the structure of quinazoline or quinoline.
  • an aniline group is usually introduced at the 4th position, and substituted at the 6th and 7th positions at the same time.
  • Both neratinib and poccitinib were substituted with alkoxy groups at the 7-position, and a substituent was also introduced at the 6-position.
  • few attempts have been made to construct TKI inhibitors by substitution at position 5.
  • the currently marketed small molecule HER2 inhibitors cannot effectively penetrate the blood-brain barrier, and about 50% of HER2-positive breast cancer patients will develop brain metastases. Given that some of the compounds of the present application can effectively penetrate the blood-brain barrier and have a strong inhibitory effect on HER2-positive tumors, the compounds of the present application are also expected to be used for the treatment of patients with HER2-positive breast cancer brain metastases.
  • One aspect of the present invention provides a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt or a deuterated derivative thereof,
  • Z is -NH- or -O-;
  • T 1 is -(CH 2 ) n -, wherein n is an integer from 0 to 3;
  • R 1 is hydrogen, hydroxyl, 4-7 membered heteroalicyclic 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 hydroxyl, and C 1 -C 3 alkoxy substituted C 1 -C 6 alkyl group, or C 1 -C 6 alkyl group substituted by C 3- C 6 cycloalkyl;
  • the 4-7 membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S, and the heteroalicyclic group is unsubstituted or C 1 -C 3 alkane base, C 1 -C 4 alkyl acyl, hydroxyl, cyano, aminoacyl, mono- or disubstituted C 1 -C 3 aminoacyl, C 1 - C 3 alkoxy substituted C 1 -C 3 alkyl, hydroxyl One or both of the substituted C 1 -C 3 alkyl groups are substituted;
  • L is -O-, -S- or -NH-;
  • R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 6 alkyl, or - (CH 2 )mR 5 ,
  • R 5 is C 3 -C 6 cycloalkyl or 4-6 membered heteroalicyclic group, m is an integer of 0-3,
  • the 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S;
  • T 2 is -M-(CH 2 )p-, wherein M is O, S or NH, and p is an integer of 0-2,
  • R 3 is an aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, and the aryl or heteroaryl group is surrounded by 1 to 3 groups selected from halogen, cyano, hydroxyl, C 1 -C3 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" in the substituent substituted or unsubstituted,
  • R', R" are each independently H or C 1 -C 3 alkyl
  • R 4 is hydrogen, halogen, C 1 -C 3 alkyl or C 1- C 3 alkoxy.
  • Z is -NH-.
  • T 1 is -(CH 2 ) n -, wherein n is an integer from 0 to 2,
  • R 1 is hydrogen, 4-6 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 4 cycloalkyl, C 1 -C 3 alkyl substituted by hydroxyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl group, or C 1 -C 3 alkyl group substituted by C 3- C 6 cycloalkyl;
  • the 4-6-membered heteroalicyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and the above groups are unsubstituted or by methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, hydroxyl, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, Ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, One or two substitutions of isopropoxypropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl.
  • T 1 is -(CH 2 ) n -, wherein n is 0 or 1;
  • R 1 is dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino, ethylpropylamino, methylcyclopropylamino, ethylcyclopropyl Amino, propylcyclopropylamino, isopropylcyclopropylamino, methylcyclobutylamino, ethylcyclobutylamino, propylcyclobutylamino, isopropylcyclobutylamino, pyrrolidine-1 -yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidine -2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxy
  • R 1 is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrole Alkyl-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrole Alkyl-2-yl, 1-(2-hydroxypropyl)pyrrolidin-2-yl.
  • L is -O- or -NH-
  • R 2 is C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl, C 1- C 3 alkoxy substituted C 1 -C 4 alkyl or -( CH 2 )mR 5 ,
  • R 5 is C 3 -C 6 cycloalkyl or 4-6 membered heteroalicyclic group, m is 0 or 1 or 2,
  • the 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S.
  • L is -O-;
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoro Methyl, 3,3,3-trifluoropropyl, 3,3,3-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl , hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, tetrahydr
  • T 2 is -O-(CH 2 )p-, wherein p is 0 or 1;
  • R 3 is phenyl, pyridyl, pyrimidinyl, and said phenyl, pyridyl, pyrimidinyl is 1 to 2 selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl , propoxy, isopropyl, isopropoxy, cyano, hydroxyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoroethyl, Substituents in 2,2-difluoroethyl are substituted or unsubstituted.
  • T 2 is -O-(CH 2 )p-, wherein p is 1;
  • R 3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxy Phenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin 2-yl, 6-methoxy pyridin 2-yl, 5-methylpyridin 2-yl, 5-methoxypyridin 2-yl, 4-methylpyridin 2-yl, 4-methoxypyridin 2-yl, 3-methylpyridine 2 -yl, 3-methoxypyridin 2-yl, 6-fluoropyridin 2-yl, 6-chloropyridin 2-yl.
  • R 4 is hydrogen, fluorine, chlorine, methyl, methoxy, more preferably hydrogen, fluorine, chlorine.
  • the present application provides a compound represented by the following formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and the above groups are unsubstituted or replaced by methyl, ethyl , propyl, isopropyl, aldehyde, acetyl, propionyl, hydroxyl, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethyl oxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, One or two substitutions of hydroxymethyl, hydroxyethyl and hydroxypropyl;
  • R 2 is C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy substituted C 1 -C 4 alkyl, C 1- C 3 alkoxy substituted C 1 -C 4 alkyl or -( CH 2 )mR 5 ,
  • R 5 is C 3 -C 6 cycloalkyl or 4-6 membered heteroalicyclic group, m is 0 or 1 or 2,
  • the 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S;
  • R 3 is phenyl, pyridyl, pyrimidinyl, and said phenyl, pyridyl, pyrimidinyl is 1 to 2 selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl , propoxy, isopropyl, isopropoxy, cyano, hydroxyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoroethyl, Substituents in 2,2-difluoroethyl are substituted or unsubstituted;
  • R 4 is hydrogen, fluorine, chlorine, methyl, methoxy.
  • R 1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin- 2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2- yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin- 2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, 1-(2-hydroxypropyl)pyrrolidin-2-yl;
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoro Methyl, 3,3,3-trifluoropropyl, 3,3,3-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl , hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl;
  • R 3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxy Phenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin 2-yl, 6-methoxy pyridin 2-yl, 5-methylpyridin 2-yl, 5-methoxypyridin 2-yl, 4-methylpyridin 2-yl, 4-methoxypyridin 2-yl, 3-methylpyridine 2 -yl, 3-methoxypyridin 2-yl, 6-fluoropyridin 2-yl, 6-chloropyridin 2-yl;
  • R 4 is fluorine or chlorine.
  • R 1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin- 2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2- yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin- 2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, 1-(2-hydroxypropyl)pyrrolidin-2-yl;
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoro Methyl, 3,3,3-trifluoropropyl, 3,3,3-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl , hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl;
  • R 3 is pyridin-2-yl
  • R 4 is chlorine
  • R 1 is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl;
  • R 2 is methyl, ethyl, propyl, methoxyethyl, methoxypropyl, 2,2-difluoroethyl;
  • R 3 is pyridin-2-yl
  • R 4 is chlorine
  • compositions comprising a compound described herein, a stereoisomer, a pharmaceutically acceptable salt or a deuterated derivative thereof, and one or more pharmaceutical an acceptable carrier or excipient.
  • compositions of the present application may also contain one or more other therapeutic agents.
  • the present application also relates to the use of the compounds, their stereoisomers, pharmaceutically acceptable salts or deuterated derivatives in the preparation of medicaments for the treatment of diseases related to the tyrosine kinase HER2, especially those related to tyrosine kinase HER2. Disorders associated with mutations in exon 20 of the kinase HER2.
  • the disease is preferably cancer or an autoimmune disease, especially fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervix cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin Lymphoma, nasopharyngeal carcinoma, esophageal carcinoma, brain tumor, B-cell and T
  • the present invention also relates to a method of treating a kinase-mediated disease or disorder such as HER2, comprising administering to a patient (human or other mammal, especially human) in need thereof, a therapeutically effective amount of the compound described herein or Salts thereof, the HER2 and other kinase-mediated diseases or disorders include those mentioned above.
  • Figure 1 shows the effect of NERATINIB on the T/C value of tumor-bearing mice over time
  • FIG. 1 shows the effect of PYROTINIB on the T/C value of tumor-bearing mice over time
  • Figure 3 shows the effect of the compound of Example 4 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 4 shows the effect of the compound of Example 8 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 5 shows the effect of the compound of Example 9 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 6 shows the effect of the compound of Example 11 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 7 shows the effect of the compound of Example 24 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 8 shows the effect of the compound of Example 29 of the present application on the T/C value of tumor-bearing mice over time
  • Figure 9 shows the effect of the compound of Example 33 of the present application on the T/C value of tumor-bearing mice over time.
  • alkyl refers to a saturated straight-chain, branched hydrocarbon group having the specified number of carbon atoms
  • C 1 -C 6 alkyl refers to an alkyl moiety containing 1 to 6 carbon atoms
  • C 1 -C 3 Alkyl means an alkyl moiety containing 1 to 3 carbon atoms, eg, C1 - C6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl pentyl, etc.
  • Alkoxy is an alkyl-O- group formed from the previously described straight or branched chain alkyl and -O-, eg, methoxy, ethoxy, and the like.
  • alkylthio is an alkyl-S- group formed from a straight or branched chain alkyl group as previously described and -S-, eg, methylthio, ethylthio, and the like.
  • Alkenyl and alkynyl groups include straight chain, branched chain alkenyl or alkynyl groups, and the term C2 - C6 alkenyl or C2 - C6 alkynyl denotes straight or branched chain hydrocarbon groups having at least one alkenyl or alkynyl group.
  • haloalkyl eg " haloC1 - C6alkyl” means one or more halogens, which may be the same or different, on one or more carbon atoms of an alkyl moiety comprising 1 to 6 carbon atoms group of atoms.
  • halogenated C1 - C6 alkyl may include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-trifluoroethyl and hexafluoroisopropyl.
  • haloC1 -C6alkoxy denotes a haloalkyl-O- group formed from said haloC1 - C6alkyl and -O-, which may be, for example, trifluoromethane oxy, trichloromethoxy, etc.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • (C3 - C6 )cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C3 - C6 )cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon radical containing from 6 to 12 carbon ring atoms and having at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and indenyl (indanyl).
  • the aryl group is phenyl.
  • heteroalicyclic group represents an unsubstituted or substituted stable 4- to 7-membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and from N, It is composed of 1 to 3 heteroatoms selected from O, S, wherein the N, S heteroatom can be freely oxidized, and the N heteroatom can also be randomly quaternized.
  • heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 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 -Oxathiolanyl, 1,3-Dithiane, 1,4-Oxathiolanyl, 1,4-Oxathiolan
  • heteroaryl refers to a group or moiety comprising an aromatic monocyclic or bicyclic radical (which contains 5 to 10 ring atoms) comprising 1 to 3 atoms 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.
  • it represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and can also represent an unsubstituted or substituted benzene-fused heteroaromatic ring system of 9 or 10 ring atoms Or bicyclic heteroaromatic ring systems consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O, S, where the N, S heteroatoms can be oxidized and the N heteroatom can also be quaternized .
  • Heteroaryl groups can be attached 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 base, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, iso benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxenyl, benzothienyl, indolizinyl , indolyl, isoindolyl, indoline, benzimidazolyl, dihydr
  • carbonyl refers to a -C(O)- group.
  • halogen and “halo” represent chlorine, fluorine, bromine or iodine substituents.
  • Hydroxo is intended to mean the -OH radical.
  • cyano as used herein refers to the group -CN.
  • deuterated derivative refers to a derivative of a compound of the present application wherein optionally one or more hydrogen atoms are deuterated.
  • 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.
  • solvated forms can be water soluble forms.
  • present invention includes all such solvated and unsolvated forms.
  • the term “isomer” refers to different compounds with the same molecular formula, which may include various isomeric forms such as stereoisomerism and tautomerism.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. Certain compounds described herein contain one or more asymmetric centers, and thus can give rise to 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 such 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 a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over the other 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. For example, such resolution can be performed: (1) by formation of diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, such as by enzymes Pro-oxidation or reduction; or (3) by gas-liquid chromatography or liquid chromatography in a chiral environment, such as on a chiral support (eg, silica gel to which a chiral ligand is bound) or in hand in the presence of a solvent.
  • a chiral support eg, silica gel to which a chiral ligand is bound
  • stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformations to convert one enantiomer to the other .
  • Tautomers are structurally distinct isomers that are interconvertible by tautomerization.
  • Tautomerization is a form of isomerization and includes protonation or protonation tautomerization, which can be considered a subset of acid-base chemistry.
  • Proton tautomerization or “proton transfer tautomerization” involves the migration of protons accompanied by bond-level shifts, often the exchange of a single bond with an adjacent double bond. When tautomerization is possible (eg, in solution), chemical equilibrium of tautomers can be achieved.
  • An example of tautomerization is keto-enol tautomerization.
  • the compounds of the present invention as active ingredients, as well as methods for preparing the same, are the subject of the present invention.
  • some of the crystalline forms of the compounds may exist as polycrystals, and such forms may also be included in the present invention.
  • some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.
  • the compounds of the present invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention, which are suitable for humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and have reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. Such salts may be formed by reacting a compound of the present invention with a suitable free base or acid.
  • salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, malonic, Alternatively, these salts can be obtained by using methods well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, 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, Lactobate, Lactate, Laurate, Lauryl Sulfate, Malate, Maleate, Methane Sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate, stearate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include appropriate nontoxic ammonium, quaternary ammonium, and salts using compounds such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and arylsulfonates.
  • prodrug refers to a compound that can be converted in vivo to a compound described herein. This conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion of the prodrug to the parent compound in blood or tissue.
  • compositions of the present invention comprise the compounds described herein or pharmaceutically acceptable salts thereof, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressive agents, anticancer agents, antiviral agents, anti-inflammatory agents, anti-inflammatory agents a fungal agent, an antibiotic, or an additional active agent of an antivascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant, or excipient.
  • kinase inhibitors small molecules, polypeptides, antibodies, etc.
  • immunosuppressive agents anticancer agents, antiviral agents, anti-inflammatory agents, anti-inflammatory agents a fungal agent, an antibiotic, or an additional active agent of an antivascular hyperproliferative compound
  • anticancer agents small molecules, polypeptides, antibodies, etc.
  • immunosuppressive agents anticancer agents
  • antiviral agents anti-inflammatory agents
  • anti-inflammatory agents anti-inflammatory agents a fungal agent, an antibiotic, or an additional active agent of an antivascular hyperproliferative compound
  • the compounds of the present invention may be used alone, or in combination with one or more other compounds of the present invention or with one or more other pharmaceutical agents.
  • the therapeutic agents When administered in combination, the therapeutic agents may be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents may be administered as a single composition.
  • “combination therapy” is meant the use of a compound of the present invention in combination with another agent, either by co-administration of each agent at the same time or sequentially with each agent, in either case for the purpose of 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 compounds of the present invention can be used concurrently with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or additional therapy such as cytostatics, cytotoxic agents, other anticancer agents, etc. to improve cancer symptoms.
  • additional therapy such as cytostatics, cytotoxic agents, other anticancer agents, etc. 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 or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient may be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques
  • a pharmaceutical carrier according to conventional pharmaceutical formulation techniques
  • the carrier therein can take a wide variety of forms according to the form of preparation designed for different modes of administration (eg, oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • compositions of the present invention may be in 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 solutions, suspensions, Emulsion; or for topical application such as ointment, cream; or as suppository for rectal administration.
  • the pharmaceutical ingredients may also be in unit dosage form suitable for single administration of precise doses.
  • the pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and the compound formulated in accordance with the present invention as the active ingredient, and may additionally include other medical or pharmaceutical agents, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be administered to mammals other than humans.
  • the dosage of a drug to be administered to a mammal will depend on the species of the animal and its disease state or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, and pill-drops.
  • the therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these pharmaceutical forms in a traditional manner consistent with standards of veterinary practice.
  • the pharmaceutical compound can be mixed with the animal feed and fed to the animals, so that the concentrated feed additive or ready-mix can be prepared for mixing with ordinary animal feed.
  • Yet another object of the present invention is to provide a method for treating cancer in a subject in need thereof, comprising a method of administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.
  • the present invention also includes the use of the compounds of the present invention or pharmaceutically acceptable derivatives thereof to prepare medicines for the treatment of diseases related to tyrosine kinases EGFR and HER2, the diseases may be cancer (including non-solid tumors, solid tumors, etc.) , primary or metastatic cancer, as noted elsewhere herein and including one or more other treatments to which the cancer is resistant or refractory), may in particular be lung cancer or breast cancer.
  • diseases related to tyrosine kinases EGFR and HER2 the diseases may be cancer (including non-solid tumors, solid tumors, etc.) , primary or metastatic cancer, as noted elsewhere herein and including one or more other treatments to which the cancer is resistant or refractory), may in particular be lung cancer or breast cancer.
  • the present invention also provides methods for preparing the corresponding compounds.
  • Various 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 Synthesis is performed using the methods described below with synthetic methods known in the synthetic art of organic chemistry, or by variations of these methods understood by those skilled in the art, and preferred methods include, but are not limited to, the methods described below.
  • Step 1) Synthesis of (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 2) Synthesis of (R,E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester;
  • Step 3) Synthesis of (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethyl acrylate;
  • Step 4) Synthesis of (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylic acid;
  • Step 1) Synthesis of (R,E)-ethyl 3-(1-cyclobutylpyrrolidin-2-yl)acrylate
  • Step 2) Synthesis of (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acrylic acid
  • Acryloyl chloride intermediates are formed by reacting corresponding acrylic compounds under the action of oxalyl chloride, and the following synthesis of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride is as follows: Example to illustrate, other acryloyl chloride intermediates are synthesized by the same method.
  • Step 4) Synthesis of 5-chloro-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine
  • 4,5-Dichloro-6-nitroquinazoline (4.9g, 20mmol) was added to dry acetonitrile, and 3-chloro-4-(pyridin-2-ylmethoxy)aniline ( 7g, 30mmol) and triethylamine (3g, 30mmol), heated to 50 degrees Celsius and reacted for 5 hours, cooled and concentrated, washed with methanol to obtain 6.5g of white solid product, yield 74%; MS: 442 [M+H] + .
  • Step 5) Synthesis of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxy-6-nitroquinazolin-4-amine
  • Step 6) Synthesis of N4-( 3 -chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine
  • N-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxy-6-nitroquinazolin-4-amine (2.2 g, 5 mmol) was added to ethanol , add iron powder and ammonium chloride aqueous solution and heat to 50 degrees Celsius to react for 2 hours, cool and filter, rinse with a large amount of dichloromethane, wash the filtrate with brine, dry, and concentrate to obtain 2g of light purple solid product, yield 98%; MS :408[M+H] + .
  • Step 7) (E)-N-(4-((3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl) Synthesis of -4-(dimethylamino)but-2-enamide
  • N4-( 3 -chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine (40 mg, 0.1 mmol) was added NMP (1 mL)
  • NMP 1 mL
  • a dichloromethane solution (1 mL) of (E)-4-(dimethylamino)but-2-enoyl chloride (24 mg, 0.15 mmol) was added at 0 degrees Celsius, and the reaction was stirred for half an hour, and quenched by adding water.
  • Step 1) to step 6) refer to Example 1;
  • Step 7) N4-( 3 -Chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine (40 mg, 0.1 mmol) was added In the NMP solution, a dichloromethane solution (1 mL) of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride (26 mg) was added at 0 degrees Celsius, and the reaction was stirred for half an hour, and water was added.
  • Control compound 1 Control compound 2:
  • Reagents and consumables ULightTM-labeled Ploy GT Peptide (Perkin Elmer, Cat. No. TRF-0100-M); ULightTM-labeled JAK-1 (Try1023) Peptide (Perkin Elmer, Cat. No. TRF-0121-M); Eu-W1024- labeled Anti-Phosphotyrosine Antibody (PT66) (Perkin Elmer, cat. no. AD0068); 10 ⁇ Detection Buffer (Perkin Elmer, cat. no. CR97-100); Her2 kinase (Carna Biosciences, cat. no. 08-016); EGFR kinase (Carna Biosciences , cat. no.
  • HEPES GENECO, cat. no. 15630-080
  • EGTA Sigma, cat. no. 03777-10G
  • EDTA Sigma, cat. no. EDS-100G
  • MgCl 2 Sigma, cat. no. 63069- 100ML
  • DTT Sigma, cat. no. 43816-10ML
  • Tween-20 Sigma, cat. no. P7949-100ML
  • DMSO Life Science, cat. no. 0231-500ML
  • 384-well plate Perkin Elmer, cat. no. 607290
  • Multi-function plate reader Perkin Elmer, cat. no. Envision
  • Compound solution preparation The test compound was dissolved in DMSO to make a 10 mM stock solution. Compounds were diluted to 0.25 mM in DMSO (100-fold dilution of the final concentration) before use, and 3-fold concentration gradients were made, for a total of 11 gradients. Dilute to a 4-fold final concentration with buffer when adding compounds.
  • HER2 Kinase Assay Prepare buffer, use buffer to prepare 40 nM 4X Her2 Kinase solution, 40 ⁇ M 4X ATP solution, 400 nM 4X ULight TM -labeled Ploy GT Peptide substrate solution. After the preparation is completed, the enzyme is mixed with pre-diluted compounds of different concentrations, and placed at room temperature for 5 minutes, and duplicate wells are set for each concentration. The corresponding substrate and ATP were added, and the reaction was carried out at room temperature for 120 minutes (in which the negative and positive controls were set). After the reaction was completed, PT66 detection antibody was added, and after incubation at room temperature for 60 minutes, Envision was used for detection.
  • EGFR WT kinase assay Prepare buffer, use buffer to prepare 3.48 nM 4X EGFR kinase solution, 600 ⁇ M 4X ATP solution, 400 nM 4X ULight TM -labeled JAK-1 (Try1023) Peptide substrate solution. After the preparation is completed, the enzyme is mixed with pre-diluted compounds of different concentrations, and placed at room temperature for 5 minutes, and duplicate wells are set for each concentration. The corresponding substrate and ATP were added, and the reaction was carried out at room temperature for 120 minutes (in which the negative and positive controls were set). After the reaction was completed, PT66 detection antibody was added, and after incubation at room temperature for 60 minutes, Envision was used for detection.
  • Table 1 lists the assay results of the compounds of the present application on EGFR WT and HER2 tyrosine kinase inhibitory activities, wherein A means IC 50 is less than or equal to 10 nM, B means IC 50 is greater than 10 nM but less than or equal to 100 nM, C means IC 50 is greater than or equal to 100 nM 100nM and less than or equal to 1000nM, NT means no relevant results.
  • the compounds of the present application can inhibit both HER2 and EGFR kinases, especially for HER2 kinase, they all show very excellent inhibitory activity as a whole, and can be used for HER2 kinase-mediated tumors and other diseases. Treatment.
  • the present application uses CTG method to detect the in vitro anti-proliferative activity of the compounds of the present invention on BT474, NCI-N87, Ba/F3-EGFR-VIII and Ba/F3 HER2 A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cell lines cultured in vitro.
  • RPMI1640 ThermoFisher, cat. no. C11875500BT
  • fetal bovine serum Hyclone, cat. no. SV30087.03
  • trypsin-EDTA ThermoFisher, cat. no. 25200-072
  • penicillin-streptomycin Hyclone, cat. no. 25200-072
  • DMSO Amresco, Cat. No. 0231-500ML
  • CTG Assay Kit Promega, Cat. No. G924C
  • 96-Well Plate Corning, Cat. No. 3603)
  • Multi-Plate Reader Perkin Elmer, Cat. No. 3603) Envision
  • Cell lines BT474 (from the Chinese Academy of Sciences Cell Bank), NCI-N87 (from ATCC), Ba/F3-EGFR-VIII, Ba/F3 HER2 A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD (all from Kangyuan Bochuang Biotechnology (Beijing) ) Co., Ltd.); the above cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin.
  • test compound Dissolve with DMSO - the test compound is formed into a stock solution and serially diluted, and then diluted with the corresponding medium to obtain a 5-fold working concentration solution.
  • Ba/F3-EGFR-VIII, Ba/F3 HER2 A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cells directly enter the next step to add compound treatment, while BT474 and NCI-N87 need to be cultured overnight in a 37°C, 5% carbon dioxide gas incubator After adhering to the wall, add compound treatment.
  • Table 2 lists the antiproliferative activity assay results of representative compounds of the present invention on BT474, NCI-N87, Ba/F3-EGFR-VIII, Ba/F3 HER2 A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cells.
  • A means IC50 less than or equal to 1nM
  • B means IC50 greater than 1nM but less than or equal to 5nM
  • C means IC50 greater than 5nM but less than or equal to 10nM
  • D means IC50 greater than 10nM and less than or equal to 100nM
  • NT means no relevant result .
  • Table 2 show that the compounds of the present application exhibited excellent anti-tumor proliferation activity against the various cell lines tested above. Especially for Ba/F3 HER2 A775-G776sYAMA cells, the compounds of the present application showed excellent activity several times or even dozens of times better than the existing drugs neratinib and pyrotinib.
  • mice were randomly divided into groups according to their body weight, and the body weights of each group were equivalent (not more than ⁇ 20% of the mean body weight). Meanwhile, the IV group was not fasted, and the PO group was fasted overnight (>12 hours) and given food 2 hours after dosing. All animals had free access to water.
  • the dosing schedule and pharmacokinetic sampling schedule are given in Tables 6 and 7 below, respectively.
  • Rats were dosed according to the protocol described above, and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing were performed according to routine methods in the art).
  • Pharmacokinetic parameter calculations will be performed with WinNonlin software. From plasma drug concentration-time data, the following pharmacokinetic parameters were 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).
  • Table 8-11 shows the results of pyrotinib, neratinib, control compounds 1 and 2, and some compounds of the present application under the two modes of intravenous injection and oral administration, respectively.
  • the value of each pharmacokinetic parameter The results showed that when the control compounds 1 and 2 were orally administered, they could hardly be absorbed, and effective pharmacokinetic data could not be measured. , neratinib, also showed better bioavailability.
  • Example 9 Example 13 Example 24 Example 29 T 1/2 (hr) 3.94 ⁇ 0.18 4.12 ⁇ 0.22 5.01 ⁇ 0.45 4.86 ⁇ 0.23 AUC 0-t (hr*ng/mL) 949 ⁇ 128 953 ⁇ 105 1513 ⁇ 26 914 ⁇ 129 AUC inf (hr*ng/mL) 955 ⁇ 130 964 ⁇ 104 1553 ⁇ 23 938 ⁇ 134 Cl_obs (mL/min/kg) 53.0 ⁇ 6.7 52.3 ⁇ 5.7 32.2 ⁇ 0.5 54.0 ⁇ 7.4 V d (L/kg) 18.0 ⁇ 2.3 18.7 ⁇ 2.9 14.0 ⁇ 1.3 22.7 ⁇ 2.4
  • Example 9 Example 13 Example 24 Example 29 Tmax (hr) 5.00 ⁇ 3.46 2.0 ⁇ 0.0 5.33 ⁇ 2.89 3.33 ⁇ 3.21 Cmax (ng/mL) 80.3 ⁇ 30.5 53.7 ⁇ 12.4 86.3 ⁇ 32.7 95.3 ⁇ 16.5 T 1/2 (hr) 4.13 ⁇ 0.57 5.42 ⁇ 0.34 7.81 ⁇ 3.71 4.63 ⁇ 0.26 AUC 0-t (hr*ng/mL) 1098 ⁇ 406 719 ⁇ 233 1264 ⁇ 561 1100 ⁇ 107 AUC inf (hr*ng/mL) 1112 ⁇ 403 750 ⁇ 238 1474 ⁇ 655 1134 ⁇ 106 F% 34.9 ⁇ 12.6 23.3 ⁇ 7.4 25.0 ⁇ 11.2 36.3 ⁇ 3.4
  • the compounds of the present application showed a good ability to penetrate the blood-brain barrier, and compared with pyrotinib and neratinib, the brain/blood ratio was significantly improved.
  • Table 11-1 shows that the compounds of the present application not only have excellent EGFR and HER2 kinase inhibitory activities, but also have excellent ability to penetrate the blood-brain barrier, and are expected to be applied to related tumors mediated by EGFR and/or HER2 kinases, especially brain metastases tumor.
  • RPMI1640 ThermoFisher, cat. no. C11875500BT
  • fetal bovine serum Hyclone, cat. no. SV30087.03
  • trypsin-EDTA ThermoFisher, cat. no. 25200072
  • penicillin-streptomycin Hyclone, cat. no. SV30010
  • DSMO Life Science, Cat. No. 0231-500ML
  • Solutol Sigma, 70142-34-6-1kg
  • Test compound preparation Weigh an appropriate weight of the test compound, completely dissolve it in an appropriate volume of solvent (DMSO), vortex or sonicate, then add an appropriate amount of Solutol to mix well, and finally add sterilized drinking water to stir and vortex to mix evenly , to obtain a homogeneous solution or suspension.
  • DMSO solvent
  • Solutol sterilized drinking water
  • the dose of each test substance was set at 30 mg/kg (calculated on the basis of the effective compound concentration), and the test compounds were all prepared as they were.
  • the tumor-bearing diameter was measured twice a week, and the mice were weighed at the same time.
  • Neratinib and Pyrotinib had a certain inhibitory effect at the dose of 30 mg/kg, and the T/C values on the 14th day were 45.9% and 38.3%, respectively.
  • the compounds of Example 4, Example 8, Example 9, Example 11, Example 24, Example 29, and Example 33 of the present application have significant tumor-inhibiting effects at a dose of 30 mg/kg, wherein, Example 4 and Example 3
  • the T/C values of the compound of Example 24 on the 14th day were 2.6% and 12.4%, respectively, and the T/C values of the compounds of Example 8, Example 9 and Example 11 on the 15th day were 5.83% and 3.85, respectively.
  • the T/C values of the compounds of Example 29 and Example 33 on the 11th day were 18.7% and 12.4%, respectively.
  • the compound of the present application not only has the anti-tumor cell proliferation activity against the HER2 exon 20 insertion mutation (HER2 A775_G776insYVMA) in vitro, which is superior to that of Pyrotinib and Neratinib
  • HER2 A775_G776insYVMA anti-tumor cell proliferation activity against the HER2 exon 20 insertion mutation
  • Pyrotinib and Neratinib the Ba/F3 ERBB2 A775_G776insYVMA nude mouse tumor-bearing model, it also showed much better anti-tumor activity than Pyrotinib and Neratinib, all tested compounds achieved significant tumor shrinkage, and at the same dose (30mg/kg), Tumors in the Neratinib and Pyrotinib groups continued to grow significantly.
  • the present application has synthesized a series of compounds by introducing a substituent group at the 5-position of quinazoline and removing the substituent group at the 7-position at the same time.
  • the compounds of the present application exhibited good to excellent inhibitory activity against HER2 and EGFR kinases, as well as proliferation of BT474, NCI-N87, Ba/F3-EGFR-VIII, Ba/F3 HER2 A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cells, especially For the Ba/F3 HER2 A775_G776insYVMA cell model, the compounds of the present application showed significantly better effects than Neratinib and Pyrotinib in the in vivo cell proliferation inhibition test and in vitro tumor-bearing model test, and also in the pharmacokinetic test.

Abstract

提供了一种喹唑啉类化合物、组合物及其应用，具体涉及式(I)所示化合物、其立体异构体、其药学上可接受的盐或氘代衍生物，其组合物及其在制备作为酪氨酸激酶抑制剂的药物中的应用。该化合物对EGFR、HER2激酶及它们的20外显子突变、EGFRviii突变具有良好的抑制活性。

Description

一种喹唑啉类化合物、组合物及其应用 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、组合物及其应用。
背景技术
表皮生长因子受体(ErbB)酪氨酸激酶可通过多种途径调节细胞增殖、迁移、分化、凋亡以及细胞移动。在多种形式的恶性肿瘤中，ErbB家族成员以及其部分配体通常过表达、扩增或突变，这使其成为重要的治疗靶标。该家族蛋白激酶包括：ErbB1/EGFR/HER1、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。其中EGFR和HER2是开发非小细胞肺癌、乳腺癌药物的重要靶点(Dienstmann R.,et.al.,(2001)Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.ONCOTARGET.2(3),165.；Mitri Z.,et.al.(2012)The HER2 Receptor in Breast Cancer:Pathophysiology,Clinical Use,and New Advances in Therapy.,Chemotherapy Research&Practice.,Volum 2012(23),743193.)。目前，也已有数代EGFR和HER2激酶抑制剂上市。
但是，EGFR和HER2的表达并不稳定，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，现有的靶向药对于EGFR和HER2的不同突变的疗效存在非常大差异，其中对于Ins20的抑制能力最弱，导致Ins20突变成为耐药突变，目前的多代靶向药都几乎没有效果。EGFR和HER2基因的20外显子突变发生在相似的位置，但是EGFR20外显子***突变类型很多，现在己发现的就有122种；相比较起来，HER2基因20外显子***突变类型较少，最常见的是A775_G776insYVMA点位，该突变占比接近70％。也有统计显示，约3％的NSCLC患者携带HER2突变，这其中约90％的为HER2基因的20外显子突变型患者。针对这些EGFR/HER2 20外显子突变患者，现有的靶向TKIs药物的疗效都非常有限。
同时，针对EGFR/HER2 Ins20突变，目前也有少量的在研项目。波齐替尼(Poziotinib)是由韩美研发的一款广谱HER抑制剂，临床数据显示，对于EGFR/HER2的20外显子突变也有一定的效果，但是Poziotinib有较高的不良反应率。同时，已上市的吡咯替尼也在进行相关的20外显子突变的临床研究。
另外，近年来还发现了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EGFR的突变体EGFRvIII，这也是一种非常常见的EGFR突变体。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。因此，研发新的针对EGFRvIII分子靶向治疗药物将为肿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。
从化学结构上看，已上市的诸多TKI类药物，以及上文提到的波齐替尼、吡咯替尼(pyrotinib)，均是由喹唑啉或者喹啉的结构衍生所得。如下图所示，通过喹唑啉或者喹啉构建TKI抑制剂时，通常 会在4位引入苯胺类基团，同时在6位和7位进行取代，下图显示的吡咯替尼、来那替尼(neratinib)、波奇替尼均在7位进行了烷氧基取代，而在6位也引入取代基。但是，少有在5位进行取代构建TKI抑制剂的尝试。本申请通过在5位引入取代基团，同时去除了在7位的取代基团，合成了系列喹唑啉类化合物，对HER2以及其20外显子突变表现出极佳的抑制活性，有望用于HER2的20外显子突变的治疗。
值得一提的是，目前已上市的小分子HER2抑制剂均不能有效穿透血脑屏障，而50％左右的HER2阳性乳腺癌患者会发生脑转移。鉴于本申请的部分化合物可以有效穿透血脑屏障，并对HER2阳性的肿瘤具有极强的抑制作用，本申请的化合物也有望用于HER2阳性乳腺癌脑转移患者的治疗。
Figure PCTCN2022081599-appb-000001
发明内容
本发明一方面提供一种式(I)所示化合物、其立体异构体、药学上可接受的盐或氘代衍生物，
Figure PCTCN2022081599-appb-000002
式(I)中，Z为-NH-或者-O-；
T 1为-(CH 2) n-，其中，n为0至3的整数；
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烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基中的一种或两种取代；
L为-O-、-S-或者-NH-；
R 2为C 1-C 6烷基、卤代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基取代C 1-C 6烷基、或者-(CH 2)m-R 5，
R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0-3的整数，
所述的4-6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；
T 2为-M-(CH 2)p-，其中，M为O、S或者NH，p为0-2的整数，
R 3为选自苯基、吡啶基、嘧啶基、吡咯基、中的芳基或杂芳基，且所述芳基或者杂芳基被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，
R'、R”各自独立地为H或C 1-C 3的烷基；
R 4为氢、卤素、C 1-C 3烷基或者C 1-C 3烷氧基。
根据一个优选的实施方案，Z为-NH-。
根据一个优选的实施方案，T 1为-(CH 2) n-，其中，n为0至2的整数，
R 1为氢、4-6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 4环烷基、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、或被C 3-C 6环烷基取代的C 1-C 3烷基；
所述的4-6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、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟基甲基、羟基乙基、羟基丙基中的一种或两种取代。
更优选地，T 1为-(CH 2) n-，其中，n为0或1；
R 1为二甲氨基、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、乙基丙基氨基、甲基环丙基氨基、乙基环丙基氨基、丙基环丙基氨基、异丙基环丙基氨基、甲基环丁基氨基、乙基环丁基氨基、丙基环丁基氨基、异丙基环丁基氨基、吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、1-丙基哌嗪-4-基、1-异丙基哌嗪-4-基、1--(2-羟基乙基)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。
最优选地，R 1为1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基。
根据另一个优选的实施方案，L为-O-或者-NH-；
R 2为C 1-C 4烷基、卤代C 1-C 4烷基、羟基取代C 1-C 4烷基、C 1-C 3烷氧基取代C 1-C 4烷基或者-(CH 2)m-R 5，
R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0或1或2，
所述的4-6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。
更优选地，L为-O-；
R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、环丙基、环丙基甲基、环丁基、四氢呋喃2-基、四氢呋喃3-基。
在另一些优选的实施方案中，T 2为-O-(CH 2)p-，其中，p为0或1；
R 3为苯基、吡啶基、嘧啶基，且所述苯基、吡啶基、嘧啶基被1至2个选自氟、氯、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、异丙氧基、氰基、羟基、氟甲基、2-氟乙基、三氟甲基、二氟甲基、3,3,3-三氟乙基、2,2-二氟乙基中的取代基所取代或非取代。
更优选地，T 2为-O-(CH 2)p-，其中，p为1；
R 3为苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、6-甲基吡啶2-基、6-甲氧基吡啶2-基、5-甲基吡啶2-基、5-甲氧基吡啶2-基、4-甲基吡啶2-基、4-甲氧基吡啶2-基、3-甲基吡啶2-基、3-甲氧基吡啶2-基、6-氟吡啶2-基、6-氯吡啶2-基。
根据一个优选的实施方案，R 4为氢、氟、氯、甲基、甲氧基，更优选为氢、氟、氯。
根据一个优选的实施方案，本申请提供一种下式所示化合物、其立体异构体、或其药学上可接受的盐，
Figure PCTCN2022081599-appb-000003
其中，R 1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、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟基甲基、羟基乙基、羟基丙基中的一种或两种取代；
R 2为C 1-C 4烷基、卤代C 1-C 4烷基、羟基取代C 1-C 4烷基、C 1-C 3烷氧基取代C 1-C 4烷基或者-(CH 2)m-R 5，
R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0或1或2，
所述的4-6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；
R 3为苯基、吡啶基、嘧啶基，且所述苯基、吡啶基、嘧啶基被1至2个选自氟、氯、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、异丙氧基、氰基、羟基、氟甲基、2-氟乙基、三氟甲基、 二氟甲基、3,3,3-三氟乙基、2,2-二氟乙基中的取代基所取代或非取代；
R 4为氢、氟、氯、甲基、甲氧基。
更优选地，R 1为吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基；
R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基；
R 3为苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、6-甲基吡啶2-基、6-甲氧基吡啶2-基、5-甲基吡啶2-基、5-甲氧基吡啶2-基、4-甲基吡啶2-基、4-甲氧基吡啶2-基、3-甲基吡啶2-基、3-甲氧基吡啶2-基、6-氟吡啶2-基、6-氯吡啶2-基；
R 4为氟、氯。
更优选地，R 1为吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基；
R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基；
R 3为吡啶-2-基；
R 4为氯。
更优选地，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；
R 2为甲基、乙基、丙基、甲氧基乙基、甲氧基丙基、2,2-二氟乙基；
R 3为吡啶-2-基；
R 4为氯。
本申请涉及的典型化合物如下：
Figure PCTCN2022081599-appb-000004
Figure PCTCN2022081599-appb-000005
Figure PCTCN2022081599-appb-000006
Figure PCTCN2022081599-appb-000007
本申请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、其立体异构体、药学上可接受的盐或氘代衍生物，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。
本申请还涉及所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物在制备治疗与酪氨酸激酶HER2相关的疾病的药物中的应用，尤其是与酪氨酸激酶HER2的20外显子突变相关的疾病。
所述疾病优选为癌症或者自身免疫疾病，尤其是眼底疾病、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、***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***、结肠直肠癌、黑色素瘤、子宫内膜癌、***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。
本发明还涉及一种治疗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HER2等激酶介导的疾病或病症包括前述提及的那些。
附图说明
从下面结合附图的详细描述中，将会更加清楚地理解本发明的上述及其他目的、特征和其他优点，其中，
图1示出了NERATINIB随时间变化对荷瘤小鼠的T/C值的影响；
图2示出了PYROTINIB随时间变化对荷瘤小鼠的T/C值的影响；
图3示出了本申请实施例4的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图4示出了本申请实施例8的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图5示出了本申请实施例9的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图6示出了本申请实施例11的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图7示出了本申请实施例24的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图8示出了本申请实施例29的化合物随时间变化对荷瘤小鼠的T/C值的影响；
图9示出了本申请实施例33的化合物随时间变化对荷瘤小鼠的T/C值的影响。
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 6烷基表示含有1至6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 6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 6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。
烷氧基为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，烷硫基为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 6烷基”表示在包括1到6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 6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 6烷氧基”表示由所述的卤代C 1-C 6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“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7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、***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***基、***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“氘代衍生物”是指本申请的化合物中，任选一个或多个氢原子被氘代所得到衍生物。
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、立体异构体、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相关的疾病的药物，所述疾病可以为癌症(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)，尤其可以是肺癌或者乳腺癌。
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
中间体1.
(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酸
Figure PCTCN2022081599-appb-000008
步骤1)：(R)-2-甲酰基吡咯烷-1-羧酸叔丁酯的合成；
在冰水浴条件下将(R)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(4g,20mmol)和Dess-Martin试剂(8.5g,20mmol)加入到二氯甲烷(70ml)中，室温搅拌2小时，过滤，洗涤，干燥，浓缩得到油状物4g,直接用于下一步。
步骤2)：(R,E)-2-(3-乙氧基-3-氧代丙-1-烯-1-基)吡咯烷-1-羧酸叔丁酯的合成；
在25℃下向NaH(782mg，19.6mmol)的THF(15mL)溶液中逐滴加入乙酸三乙基膦酰基乙酸酯(3.6mL，18.1mmol)。0.5小时后，将溶液冷却至0℃，滴加Boc-L-脯氨酸(3g，15.1mmol)的THF(60mL)溶液。在0℃下另外搅拌2小时后，加水淬灭，将水相用DCM反萃取几次，并将合并的有机相经无水硫酸钠干燥并浓缩。所得黄色油(4g，定量)直接使用，无需进一步纯化。LCMS:270[M+H] +。
步骤3)：(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酸乙酯的合成；
将(R,E)-2-(3-乙氧基-3-氧代丙-1-烯-1-基)吡咯烷-1-羧酸叔丁酯(0.27g,1mmol)加入到三氟乙酸(1ml)的二氯甲烷(4ml)溶液中，室温搅拌反应2小时，浓缩得黄色油状物加入到溴乙基甲醚(0.3g，2mmol)和碳酸钾(0.45g,3mmol)的乙腈(10ml)溶液中，加热至80摄氏度反应12小时，冷却，乙酸乙酯萃取，水洗三次，有机相干燥浓缩得浅黄色油状物0.12g；LC-MS:228[M+H] +。
步骤4)：(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酸的合成；
将(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酸乙酯(0.12g,0.5mmol)和氢氧化钠(0.04g,1mmol)加入到甲醇(1ml)和水(1ml)的溶液中，室温搅拌反应过夜，反应完毕，乙酸乙酯萃取，取水相用稀盐酸调节pH至4-5，浓缩，二氯甲烷和甲醇混合溶液洗涤，过滤浓缩后用乙腈打浆得白色固体产物；LC-MS:200[M+H] +。中间体2.(R,E)-3-(1-环丁基吡咯烷-2-基)丙烯酸
Figure PCTCN2022081599-appb-000009
步骤1)：(R,E)-3-(1-环丁基吡咯烷-2-基)丙烯酸乙酯的合成
将(R,E)-2-(3-乙氧基-3-氧代丙-1-烯-1-基)吡咯烷-1-羧酸叔丁酯(0.27g,1mmol)加入到三氟乙酸(1ml)的二氯甲烷(3ml)溶液中，室温搅拌反应两小时，浓缩得到黄色油状物；将黄色油状物，环丁基-1-酮(0.1g,1.5mmol)加入到1,2-二氯乙烷中搅拌半个小时，然后加入氰基硼氢化钠(0.13g,2mmol)进行反应，反应完毕后，调节pH至8-9,二氯甲烷萃取，有机相水洗，干燥，浓缩后柱层析纯化得到目标产物。
步骤2)：(R,E)-3-(1-环丁基吡咯烷-2-基)丙烯酸的合成
将(R,E)-3-(1-环丁基吡咯烷-2-基)丙烯酸乙酯(0.12g,0.5mmol)和氢氧化钠(0.04g,1mmol)加入到甲醇(1ml) 和水(1ml)的溶液中，室温搅拌反应过夜，反应完毕，乙酸乙酯萃取，取水相用稀盐酸调节pH至4-5，浓缩，二氯甲烷和甲醇混合溶液洗涤，过滤浓缩后用乙腈打浆得白色固体产物；LC-MS:196[M+H] +。
丙烯酰氯中间体的合成
丙烯酰氯类中间体采用对应的丙烯酸类化合物在草酰氯的作用下反应而成，下面以(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯的合成的合成为例进行说明，其余丙烯酰氯类中间体采用相同的方法合成得到。
Figure PCTCN2022081599-appb-000010
在冰水浴条件下，将(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酸(150mg,1mmol)，草酰氯(1.05mmol)和DMF(1滴)分别加入到干燥的二氯甲烷(2ml)中，室温搅拌反应2小时，浓缩得到的固体可以直接用于下一步反应。
用对应的酸合成如下酰氯中间体：
Figure PCTCN2022081599-appb-000011
实施例1.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺
Figure PCTCN2022081599-appb-000012
步骤1)：5-氯喹唑啉-4(3H)-酮的合成
将2-氨基-6-氯苯甲酸(17.2g,100mmol)和醋酸甲脒(15.6g,150mmol)分别加入到乙醇(150mL)溶液中，加热至回流搅拌反应24小时，冷却过滤得白色固体14g,收率78％；MS:181[M+H] +。
步骤2)：5-氯-6-硝基喹唑啉-4(3H)-酮的合成
将5-氯喹唑啉-4(3H)-酮(7.2g,40mmol)溶于浓硫酸(40mL)中，0摄氏度条件下分批加入硝酸钾(4.2g,41.6mmol)粉末，室温搅拌反应24小时，将产物分批加入碎冰中，搅拌1小时，过滤得浅黄色固体，所得固体加入乙醇中回流，冷却过滤得白色固体产物8.6g,收率95％。
步骤3)：4,5-二氯-6-硝基喹唑啉的合成
将5-氯-6-硝基喹唑啉-4(3H)-酮(4.5g,20mmol)加入二氯亚砜(45mL)，加入DMF(2mL)，加热到80摄氏度回流反应，待产物完全溶清再反应2小时，浓缩，加入甲苯继续再浓缩得白色固体产物4.9g。
步骤4)：5-氯-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-6-硝基喹唑啉-4-胺的合成
将4,5-二氯-6-硝基喹唑啉(4.9g,20mmol)加入干燥乙腈中，0摄氏度条件下分别加入3-氯-4-(吡啶-2-基甲 氧基)苯胺(7g,30mmol)和三乙胺(3g,30mmol)，加热至50摄氏度反应5小时，冷却浓缩，甲醇洗涤得白色固体产物6.5g,收率74％；MS:442[M+H] +。
步骤5)：N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-5-甲氧基-6-硝基喹唑啉-4-胺的合成
在0摄氏度条件下将5-氯-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-6-硝基喹唑啉-4-胺(4.4g,10mmol)加入到DMF(15mL)和甲醇钠溶液(30％甲醇钠的甲醇溶液,15mL)的混合溶液中，搅拌反应2小时，加冰淬灭，过滤干燥得黄色固体产物4.1g,收率94％；MS:438[M+H] +。
步骤6)：N 4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-5-甲氧基喹唑啉-4,6-二胺的合成
将N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-5-甲氧基-6-硝基喹唑啉-4-胺(2.2g,5mmol)加入到乙醇中，加入铁粉和氯化铵水溶液加热至50摄氏度反应2小时，冷却过滤，用大量二氯甲烷冲洗，滤液用食盐水洗涤，干燥，浓缩得浅紫色固体产物2g,收率98％；MS:408[M+H] +。
步骤7)：(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺的合成
N 4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-5-甲氧基喹唑啉-4,6-二胺(40mg,0.1mmol)加入NMP(1mL)溶液中，在0摄氏度条件下加入(E)-4-(二甲基氨基)丁-2-烯酰氯(24mg,0.15mmol)的二氯甲烷溶液(1mL)，搅拌反应半小时，加水淬灭，用碳酸氢钠调pH至9后，用二氯甲烷萃取，饱和食盐水洗涤，干燥浓缩得到的油状物经柱层析纯化得白色固体产物18mg； 1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.86(s,1H),8.60(d,J＝4.8Hz,1H),8.51(s,1H),8.29(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.65–7.53(m,3H),7.37(d,J＝7.6Hz,1H),7.27(d,J＝9.0Hz,1H),6.81(d,J＝15.4,5.9Hz,1H),6.58(d,J＝15.5Hz,1H),5.32(s,2H),3.93(s,3H),3.09(d,J＝5.9Hz,2H),2.20(s,6H).MS:519[M+H] +。
实施例2.(E)-N-(4-((3-氯-4-((3-氟苄基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺
Figure PCTCN2022081599-appb-000013
采用与实施例1相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替换实施例1步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.86(s,1H),8.51(s,1H),8.29(d,J＝9.0Hz,1H),8.09(d,J＝2.6Hz,1H),7.66–7.53(m,2H),7.48(td,J＝8.0,6.0Hz,1H),7.37–7.14(m,4H),6.81(dt,J＝15.4,5.9Hz,1H),6.58(d,J＝15.5Hz,1H),5.28(s,2H),3.92(s,3H),3.11(d,J＝6.1Hz,2H),2.22(s,6H).MS:536[M+H] +。
实施例3.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(环丁基(甲基)氨基)丁-2-烯酰胺
Figure PCTCN2022081599-appb-000014
采用与实施例1相同的方法进行合成，不同之处在于，用(E)-4-(环丁基(甲基)氨基)丁-2-烯酰氯替代实施例1步骤7)中的(E)-4-(二甲基氨基)丁-2-烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.93(s,1H),9.86(s,1H),8.63–8.57(m,1H),8.51(s,1H),8.28(d,J＝9.1Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.65–7.52(m,3H),7.41–7.33(m,1H),7.26(d,J＝9.0Hz,1H),6.82(d,J＝15.4Hz,1H),6.57(d,J＝15.4Hz, 1H),5.31(s,2H),3.93(s,3H),3.05(d,J＝6.1Hz,2H),2.87(p,J＝8.0Hz,1H),2.08–1.92(m,5H),1.88–1.73(m,2H),1.60(dd,J＝20.5,10.0Hz,2H).MS:559[M+H] +。
实施例4.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000015
步骤1)至步骤6)参见实施例1；
步骤7)：N 4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-5-甲氧基喹唑啉-4,6-二胺(40mg,0.1mmol)加入NMP溶液中，在0摄氏度条件下加入(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯(26mg)的二氯甲烷溶液(1mL)，搅拌反应半小时，加水淬灭，用碳酸氢钠调pH至9后，用二氯甲烷萃取，饱和食盐水洗涤，干燥浓缩得到的油状物经柱层析纯化得白色固体产物24mg； 1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),9.86(s,1H),8.60(d,J＝4.9Hz,1H),8.51(s,1H),8.30(d,J＝9.1Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.65–7.53(m,3H),7.37(d,J＝7.6Hz,1H),7.27(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.5Hz,1H),6.56(d,J＝15.3Hz,1H),5.31(s,2H),3.93(s,3H),3.04(d,J＝9.9Hz,1H),2.75(t,J＝7.8Hz,1H),2.22(s,3H),2.22–2.13(m,1H),2.01(d,J＝13.5Hz,1H),1.79–1.68(m,2H),1.58(d,J＝12.3Hz,1H).MS:545[M+H] +。
实施例5.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-乙氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000016
采用与实施例4相同的方法进行合成，不同之处在于，用乙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.91(s,1H),8.60(d,J＝4.8Hz,1H),8.54(s,1H),8.23–8.16(m,2H),7.89(t,J＝7.7Hz,1H),7.62–7.51(m,3H),7.37(d,J＝7.6Hz,1H),7.28(d,J＝9.0Hz,1H),6.69(dd,J＝15.3,7.7Hz,1H),6.52(d,J＝15.4Hz,1H),5.31(s,2H),4.13(q,J＝7.0Hz,2H),3.04(d,J＝9.9Hz,1H),2.77(q,J＝7.9Hz,1H),2.22(s,4H),2.08–1.95(m,1H),1.74(t,J＝8.5Hz,2H),1.65–1.51(m,1H),1.41(t,J＝7.0Hz,3H).MS:559[M+H] +。
实施例6.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(2-羟基乙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000017
采用与实施例4相同的方法进行合成，不同之处在于，用2-羟基乙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.98(s,1H),8.60(d,J＝4.9Hz,1H),8.50(s,1H),8.33(d,J＝9.1Hz,1H),8.09(d,J＝2.5Hz,1H),7.89(td,J＝7.7,1.7Hz,1H),7.67(d,J＝9.0Hz,1H),7.57(t,J＝8.0Hz,2H),7.37(d,J＝7.5Hz,1H),7.24(d,J＝9.0Hz,1H),6.69(dd,J＝15.3,7.7Hz,1H),6.42(d,J＝15.3Hz,1H),5.78–5.59(m,1H),5.30(s,2H),4.08(t,J＝4.1Hz,2H),3.87(q,J＝4.3Hz,2H),3.03(d,J＝9.7Hz,1H),2.75(q,J＝8.0Hz,1H),2.20(s,3H),2.17(t,J＝8.8Hz,1H),2.07–1.94(m,1H),1.74(t,J＝8.7Hz,2H),1.58(d,J＝17.2Hz,1H).MS:575[M+H] +。
实施例7.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(2-氟乙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000018
采用与实施例4相同的方法进行合成，不同之处在于，用2-氟乙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),9.84(s,1H),8.60(d,J＝4.7Hz,1H),8.54(s,1H),8.25(d,J＝9.0Hz,1H),8.08(d,J＝2.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.58(d,J＝8.6Hz,3H),7.37(d,J＝7.6Hz,1H),7.27(d,J＝9.1Hz,1H),6.69(dd,J＝15.3,7.7Hz,1H),6.48(d,J＝15.3Hz,1H),5.30(s,2H),4.96(d,J＝4.8Hz,1H),4.88–4.81(m,1H),4.40–4.33(m,1H),4.32–4.25(m,1H),3.04(d,J＝9.7Hz,1H),2.76(q,J＝8.0Hz,1H),2.21(s,3H),2.18(t,J＝8.8Hz,1H),2.06–1.94(m,1H),1.74(d,J＝12.0Hz,2H),1.65–1.53(m,1H).MS:577[M+H] +。
实施例8.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(2-甲氧基乙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000019
采用与实施例4相同的方法进行合成，不同之处在于，用2-甲氧基乙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.03(s,1H),9.87(s,1H),8.60(d,J＝4.8Hz,1H),8.51(s,1H),8.30(d,J＝9.1Hz,1H),8.00(d,J＝2.6Hz,1H),7.88(td,J＝7.7Hz,1H),7.68(d,J＝9.0Hz,1H),7.58(d,J＝8.4Hz,2H),7.37(d,J＝7.6Hz,1H),7.29(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.6Hz,1H),6.45(d,J＝15.3Hz,1H),5.30(s,2H),4.20–4.13(m,2H),3.83–3.76(m,2H),3.30(s,3H),3.04(d,J＝9.9Hz,1H),2.77(q,J＝8.0Hz,1H),2.22(s,4H),2.08–1.95(m,1H),1.79–1.69(m,2H),1.65–1.51(m,1H).MS:589[M+H] +。
实施例9.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(3-甲氧基丙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000020
采用与实施例4相同的方法进行合成，不同之处在于，用3-甲氧基丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.83(d,J＝17.8Hz,2H),8.63–8.57(m,1H),8.52(s,1H),8.17(d,J＝9.0Hz,1H),8.09(d,J＝2.6Hz,1H),7.89(t,J＝7.7Hz,1H),7.62–7.52(m,3H),7.37(d,J＝7.4Hz,1H),7.28(d,J＝8.9Hz,1H),6.69(dd,J＝15.3,7.7Hz,1H),6.46(d,J＝15.3Hz,1H),5.31(s,2H),4.07(t,J＝6.2Hz,2H),3.53(t,J＝6.0Hz,2H),3.16(s,3H),3.04(d,J＝9.7Hz,1H),2.76(q,J＝7.9Hz,1H),2.21(s,3H),2.20–2.13(m,1H),2.08(t,J＝6.2Hz,2H),2.04–1.95(m,1H),1.78–1.70(m,2H),1.65–1.51(m,1H).MS:603[M+H] +。
实施例10.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(3-氟丙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000021
采用与实施例4相同的方法进行合成，不同之处在于，用3-氟丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),9.80(s,1H),8.60(dt,J＝4.8Hz,1H),8.53(s,1H),8.16–8.09(m,2H),7.89(t,J＝7.7Hz,1H),7.62–7.52(m,3H),7.37(d,J＝7.6Hz,1H),7.27(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.7Hz,1H),6.47(d,J＝15.3Hz,1H),5.31(s,2H),4.75(t,J＝5.7Hz,1H),4.63(t,J＝5.7Hz,1H),4.11(t,J＝6.3Hz,2H),3.07(d,J＝10.1Hz,1H),2.82(d,J＝8.8Hz,1H),2.27–2.18(m,6H),2.10–1.95(m,1H),1.75(t,J＝9.3Hz,2H),1.60(d,J＝18.2Hz,1H).MS:591[M+H] +。
实施例11.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(2,2-二氟乙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000022
采用与实施例4相同的方法进行合成，不同之处在于，用2,2-二氟乙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.64(s,1H),8.64–8.52(m,2H),8.16–8.04(m,2H),7.89(t,J＝7.7Hz,1H),7.64–7.51(m,3H),7.37(d,J＝7.7Hz,1H),7.29(d,J＝9.1Hz,1H),6.70(dd,J＝15.3,7.6Hz,1H),6.55–6.36(m,2H),5.31(s,2H),4.39(t,J＝15.8Hz,2H),3.05(d,J＝9.7Hz,1H),2.78(q,J＝7.9Hz,1H),2.22(s,3H),2.18(d,J＝8.9Hz,1H),2.10–1.95(m,1H),1.80–1.69(m,2H),1.66–1.52(m,1H).MS:595[M+H] +。
实施例12.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(3,3,3-三氟丙氧基)喹唑啉-6-基)-3-(1-甲基 吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000023
采用与实施例4相同的方法进行合成，不同之处在于，用3,3,3-三氟丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),9.57(s,1H),8.60(d,J＝4.9Hz,1H),8.51(s,1H),8.11(d,J＝9.0Hz,1H),7.99(d,J＝2.5Hz,1H),7.89(t,J＝7.7Hz,1H),7.63–7.56(m,2H),7.51(d,J＝8.9Hz,1H),7.38(d,J＝7.5Hz,1H),7.29(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.6Hz,1H),6.48(d,J＝15.3Hz,1H),5.31(s,2H),4.22(t,J＝6.0Hz,2H),3.04(t,J＝11.7Hz,3H),2.80(d,J＝8.1Hz,1H),2.23(s,3H),2.19(d,J＝9.7Hz,1H),2.07–1.95(m,1H),1.75(ddt,J＝12.1Hz,2H),1.66–1.53(m,1H).MS:627[M+H] +。
实施例13.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-丙氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000024
采用与实施例4相同的方法进行合成，不同之处在于，用丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),9.86(s,1H),8.63–8.56(m,1H),8.54(s,1H),8.17(d,J＝2.7Hz,1H),8.09(d,J＝9.0Hz,1H),7.88(t,J＝7.7Hz,1H),7.62–7.49(m,3H),7.37(dd,J＝7.6,4.9Hz,1H),7.28(d,J＝8.9Hz,1H),6.69(dd,J＝15.3,7.6Hz,1H),6.46(d,J＝15.3Hz,1H),5.30(s,2H),3.99(t,J＝6.7Hz,2H),3.03(d,J＝9.8Hz,1H),2.75(q,J＝7.9Hz,1H),2.20(s,3H),2.16(t,J＝8.8Hz,1H),2.00(dt,J＝13.0,8.3Hz,1H),1.91–1.65(m,4H),1.57(dt,J＝15.2,9.2Hz,1H),0.97(t,J＝7.4Hz,3H).MS:573[M+H] +。
实施例14.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-异丁氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000025
采用与实施例4相同的方法进行合成，不同之处在于，用异丁醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.81(d,J＝8.7Hz,2H),8.60(d,J＝4.8Hz,1H),8.54(s,1H),8.12(d,J＝2.6Hz,1H),7.99(d,J＝8.9Hz,1H),7.89(t,J＝7.7Hz,1H),7.62–7.47(m,3H),7.37(d,J＝7.6Hz,1H),7.29(d,J＝9.0Hz,1H),6.68(dd,J＝15.4,7.7Hz,1H),6.40(d,J＝15.4Hz,1H),5.30(s,2H),3.77(d,J＝6.4Hz,2H),3.04(dd,J＝9.5,7.0Hz,1H),2.77(q,J＝7.9Hz,1H),2.27–2.11(m,5H),2.01(d,J＝12.9Hz,1H),1.74(t,J＝8.5Hz,2H),1.64–1.50(m,1H),0.99(d,J＝6.7Hz,6H).MS:587[M+H] +。
实施例15.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(2-羟基-2-甲基丙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000026
采用与实施例4相同的方法进行合成，不同之处在于，用2-甲基-2-羟基丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.91(s,1H),8.63–8.57(m,1H),8.52(s,1H),8.20–8.09(m,2H),7.89(td,J＝7.7Hz,1H),7.68(dd,J＝9.0Hz,1H),7.58(dd,J＝8.4,4.8Hz,2H),7.37(dd,J＝7.6,4.8Hz,1H),7.24(d,J＝9.0Hz,1H),6.67(dd,J＝15.3,7.8Hz,1H),6.30(d,J＝15.3Hz,1H),5.60(s,1H),5.30(s,2H),3.79(s,2H),3.08–2.98(m,1H),2.75(d,J＝7.9Hz,1H),2.19(s,3H),2.17(q,J＝9.0Hz,1H),2.05–1.96(m,1H),1.79–1.67(m,2H),1.57(d,J＝8.2Hz,1H),1.26(s,6H).MS:603[M+H] +。
实施例16.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(3-羟基-3-甲基丁氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000027
采用与实施例4相同的方法进行合成，不同之处在于，用3-甲基-3-羟基丁醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.00(d,J＝6.7Hz,2H),8.60(d,J＝4.8Hz,1H),8.53(s,1H),8.36(d,J＝9.0Hz,1H),8.18(d,J＝2.6Hz,1H),7.89(t,J＝7.7Hz,1H),7.62–7.51(m,3H),7.38(dd,J＝7.6,4.8Hz,1H),7.30(d,J＝9.0Hz,1H),6.69(dd,J＝15.3,7.8Hz,1H),6.51(d,J＝15.3Hz,1H),5.31(s,2H),4.80(s,1H),4.16(t,J＝6.7Hz,2H),3.04(dd,J＝9.8,7.2Hz,1H),2.77(q,J＝7.9Hz,1H),2.26–2.09(m,4H),2.01(q,J＝5.6,4.5Hz,3H),1.80–1.68(m,2H),1.65–1.51(m,1H),1.15(s,6H).MS:617[M+H] +。
实施例17.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(3-羟基丙氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000028
采用与实施例4相同的方法进行合成，不同之处在于，用3-羟基丙醇钠替代实施例4步骤5)中的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.91(d,J＝6.8Hz,2H),8.68–8.57(m,1H),8.52(s,1H),8.33(d,J＝9.1Hz,1H),8.15(d,J＝2.6Hz,1H),7.89(t,J＝7.7Hz,1H),7.62–7.52(m,3H),7.37(dd,J＝7.5,4.8Hz,1H),7.27(d,J＝9.0Hz,1H),6.71(dd,J＝15.3,7.9Hz,1H),6.50(d,J＝15.3Hz,1H),5.30(s,2H),4.97(t,J＝5.2Hz,1H),4.12(t,J＝6.2Hz,2H),3.67(q,J＝5.5Hz,2H),3.08(d,J＝9.6Hz,1H),2.88(s,1H),2.26(br,4H),2.01(dt,J＝12.3,6.1Hz,3H),1.77(dd,J＝11.2,5.7Hz,2H),1.63(d,J＝9.5Hz,1H).MS:589[M+H] +。
实施例18.(R,E)-N-(4-((3-氯-4-((3-氟苄基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-异丙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000029
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替代实施例4步骤4)中的原料3-氯-4-(吡啶-2-基甲氧基)苯胺，用(R,E)-3-(1-异丙基吡咯烷-2-基)丙烯酰氯替代步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),9.86(s,1H),8.51(s,1H),8.27(d,J＝9.1Hz,1H),8.09(d,J＝2.6Hz,1H),7.66–7.53(m,2H),7.47(td,J＝8.0,5.9Hz,1H),7.37–7.23(m,3H),7.18(td,J＝8.7,2.6Hz,1H),6.76-6.60(m,2H),5.28(s,2H),3.92(s,3H),2.87(s,2H),1.99(s,2H),1.75(br,3H),1.09(br,7H).MS:590[M+H] +。
实施例19.(R,E)-N-(4-((3-氯-4-((3-氟苄基氧基)苯基)氨基)-5-乙氧基喹唑啉-6-基)-3-(1-乙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000030
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺，用乙醇钠代替步骤5)的甲醇钠，用(R,E)-3-(1-乙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.99(br,2H),8.54(s,1H),8.18(q,J＝4.1Hz,2H),7.60–7.42(m,3H),7.37–7.24(m,3H),7.18(t,J＝8.8Hz,1H),6.72(s,1H),6.56(s,1H),5.27(s,2H),4.13(q,J＝7.1Hz,2H),3.17(s,1H),2.96(s,1H),2.73(s,1H),2.27–1.93(m,3H),1.78(s,2H),1.60(s,1H),1.41(t,J＝7.0Hz,3H),1.07(s,3H).MS:590[M+H] +。
实施例20.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-乙氧基喹唑啉-6-基)-3-(1-乙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000031
采用与实施例4相同的方法进行合成，不同之处在于，用乙醇钠代替步骤5)的甲醇钠，用(R,E)-3-(1-乙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.00(s,2H),8.60(d,J＝4.9Hz,1H),8.54(s,1H),8.23–8.14(m,2H),7.88(t,J＝7.7Hz,1H),7.62–7.51(m,3H),7.37(dd,J＝7.6,4.8Hz,1H),7.28(d,J＝9.0Hz,1H),6.84–6.64(m,1H),6.56(d,J＝15.1Hz,1H),5.31(s,2H),4.14(q,J＝7.0Hz,2H),3.27–2.94(m,2H),2.77(s,1H),2.25(s,2H),2.03(s,1H),1.79(s,2H),1.62(s,1H),1.41(t,J＝7.0Hz,3H),1.08(t,J＝7.2Hz,3H).MS:573[M+H] +。
实施例21.(R,E)-N-(5-乙氧基-4-((3-氟-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 PCTCN2022081599-appb-000032
采用与实施例4相同的方法进行合成，不同之处在于，用3-氟-4-(吡啶-2-基甲氧基)苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺，用乙醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),10.01(s,1H),8.60(d,J＝5.0Hz,1H),8.54(s,1H),8.17(d,J＝9.0Hz,1H),8.07(d,J＝13.6Hz,1H),7.87(t,J＝7.7Hz,1H),7.56(d,J＝8.6Hz,2H),7.41–7.33(m,2H),7.28(t,J＝9.2Hz,1H),6.70(dd,J＝15.4,7.7Hz,1H),6.56(d,J＝15.4Hz,1H),5.27(s,2H),4.13(q,J＝7.0Hz,2H),3.07(s,1H),2.84(s,1H),2.25(s,4H),2.03(dq,J＝13.7,8.6,8.1Hz,1H),1.77(t,J＝8.5Hz,2H),1.60(s,1H),1.42(t,J＝7.0Hz,3H).MS:543[M+H] +。
实施例22.(R,E)-N-(4-((3-氯-4-((6-甲基吡啶-2-基)甲氧基)苯基)氨基)-5-乙氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000033
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((6-甲基吡啶-2-基)甲氧基)苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺，用乙醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.01(d,J＝8.4Hz,2H),8.53(s,1H),8.23–8.13(m,2H),7.76(t,J＝7.7Hz,1H),7.59–7.51(m,2H),7.36(d,J＝7.7Hz,1H),7.24(dd,J＝14.4,8.3Hz,2H),6.70(dd,J＝15.3,7.7Hz,1H),6.56(d,J＝15.3Hz,1H),5.25(s,2H),4.14(q,J＝7.0Hz,2H),3.07(s,1H),2.84(s,1H),2.49(br,3H),2.25(br,4H),2.03(dq,J＝13.3,7.8Hz,1H),1.81–1.70(m,2H),1.62(q,J＝8.7Hz,1H),1.41(t,J＝7.0Hz,3H).MS:573[M+H] +。
实施例23.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(4-甲氧基丁氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000034
采用与实施例4相同的方法进行合成，不同之处在于，用4-甲氧基丁醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.91(s,1H),8.60(d,J＝4.8Hz,1H),8.53(s,1H),8.14(d,J＝2.6Hz,1H),8.07(d,J＝9.0Hz,1H),7.88(t,J＝7.7Hz,1H),7.61–7.50(m,3H),7.37(dd,J＝7.6,4.8Hz,1H),7.28(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.7Hz,1H),6.49(d,J＝15.3Hz,1H),5.31(s,2H),4.04(t,J＝6.7Hz,2H),3.29(t,J＝6.2Hz,2H),3.15(s,3H),3.05(d,J＝9.2Hz,1H),2.81(s,1H),2.23(s,4H),2.01(d,J＝13.1,7.5Hz,1H),1.91–1.82(m,2H),1.75(d,J＝15.6Hz,2H),1.68–1.56(m,3H).MS:617[M+H] +。
实施例24.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-异丙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000035
采用与实施例4相同的方法进行合成，不同之处在于，用(R,E)-3-(1-异丙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行相同反应； 1H NMR(400MHz,DMSO-d 6)δ10.16–9.92(m,1H),9.86(s,1H),8.60(d,J＝4.8,1.2Hz,1H),8.51(s,1H),8.28(d,J＝9.1Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.65–7.53(m,3H),7.37(dd,J＝7.6,4.9Hz,1H),7.27(d,J＝9.0Hz,1H),6.78(br,1H),6.63(br,1H),5.31(s,2H),3.93(s,3H),2.90(br,2H),2.00(br,2H),1.76(br,3H),1.09(br,7H).MS:573[M+H] +。
实施例25.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000036
采用与实施例4相同的方法进行合成，不同之处在于，用(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.87(s,1H),8.60(d,J＝4.9Hz,1H),8.51(s,1H),8.27(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.89(t,J＝7.7Hz,1H),7.65–7.52(m,3H),7.41–7.33(m,1H),7.27(d,J＝9.0Hz,1H),6.69(dd,J＝15.3,7.6Hz,1H),6.57(d,J＝15.4Hz,1H),5.32(s,2H),3.92(s,3H),3.43(t,J＝6.1Hz,2H),3.24(s,3H),3.15(s,1H),3.02(d,J＝9.8Hz,1H),2.84–2.76(m,1H),2.25(s,2H),1.98(dd,J＝12.1,7.0Hz,1H),1.80–1.71(m,2H),1.55(t,J＝10.1Hz,1H).MS:589[M+H] +。
实施例26.(R,E)-N-(4-((3-氯-4-((3-氟苄基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-(2-甲氧基乙基))吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000037
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替换实施例4步骤4)中的原料3-氯-4-(吡啶-2-基甲氧基)苯胺，用(R,E)-3-(1-(2-甲氧基乙基)吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),9.86(s,1H),8.51(s,1H),8.28(d,J＝9.1Hz,1H),8.09(d,J＝2.6Hz,1H),7.62(d,J＝8.9Hz,1H),7.56(d,J＝9.0Hz,1H),7.47(td,J＝8.0,5.9Hz,1H),7.37–7.24(m,3H),7.18(td,J＝8.7Hz,1H),6.69(dd,J＝15.3,7.7Hz,1H),6.56(d,J＝15.4Hz,1H),5.28(s,2H),3.92(s,3H),3.43(t,J＝6.1Hz,2H),3.24(s,3H),3.15(s,1H),3.00(s,1H),2.84–2.75(m,1H),2.42–2.17(m,2H),1.97(q,J＝8.7,8.2Hz,1H),1.76(t,J＝7.4Hz,2H),1.55(s,1H).MS:606[M+H] +。
实施例27.(R,E)-N-(4-((3-氯-4-((6-甲氧基吡啶-2-基)甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000038
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((6-甲氧基吡啶-2-基)甲氧基)苯胺替换实施例4步骤4)中的原料3-氯-4-(吡啶-2-基甲氧基)苯胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),9.87(s,1H),8.51(s,1H),8.26(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.76(dd,J＝8.3,7.3Hz,1H),7.65–7.52(m,2H),7.27(d,J＝9.0Hz,1H),7.14(d,J＝7.2Hz,1H),6.81–6.57(m,3H),5.22(s,2H),3.93(s,3H),3.86(s,3H),3.06(t,J＝8.2Hz,1H),2.84(s,1H),2.24(br,4H),2.01(br,1H),1.75(t,J＝9.0Hz,2H),1.67–1.54(m,1H).MS:575[M+H] +。
实施例28.(R,E)-N-(4-((3-氯-4-((3-氟苄基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-乙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000039
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替代实施例4步骤4)中的原料3-氯-4-(吡啶-2-基甲氧基)苯胺，用(R,E)-3-(1-乙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),9.86(s,1H),8.51(s,1H),8.27(d,J＝9.0Hz,1H),8.09(d,J＝2.6Hz,1H),7.66–7.53(m,2H),7.47(td,J＝8.0,5.9Hz,1H),7.37–7.23(m,3H),7.18(td,J＝8.7,2.7Hz,1H),6.76(s,1H),6.63(s,1H),5.28(s,2H),3.93(s,3H),3.31–3.07(m,1H),2.83(d,J＝29.9Hz,1H),2.40–2.12(m,3H),2.05(s,1H),1.82(s,2H),1.65(s,1H),1.10(s,3H).MS:576[M+H] +。
实施例29.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-乙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000040
采用与实施例4相同的方法进行合成，不同之处在于，用(R,E)-3-(1-乙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.86(s,1H),8.60(dt,J＝4.8,1.2Hz,1H),8.51(s,1H),8.28(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(td,J＝7.7,1.8Hz,1H),7.64–7.53(m,3H),7.41–7.33(m,1H),7.27(d,J＝9.0Hz,1H),6.73(dd,J＝15.4,7.8Hz,1H),6.58(d,J＝15.5Hz,1H),5.32(s,2H),3.92(s,3H),3.18(s,1H),2.75(s,1H),2.22(s,3H),2.02(s,1H),1.78(d,J＝8.8Hz,2H),1.61(s,1H),1.07(t,J＝7.4Hz,3H).MS:559[M+H] +。
实施例30.(R,E)-N-(4-((3-氟-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000041
采用与实施例4相同的方法进行合成，不同之处在于，用3-氟-4-(吡啶-2-基甲氧基)苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),9.90(s,1H),8.63–8.56(m,1H),8.53(s,1H),8.29(d,J＝9.0Hz,1H),8.00(dd,J＝13.5,2.6Hz,1H),7.87(td,J＝7.7,1.8Hz,1H),7.56(dd,J＝8.4,4.7Hz,2H),7.49–7.33(m,2H),7.27(t,J＝9.3Hz,1H),6.71(dd,J＝15.2,7.5Hz,1H),6.59(d,J＝15.4Hz,1H),5.28(s,2H),3.92(s,3H),3.08(s,1H),2.85(s,1H),2.26(s,4H),2.04(s,1H),1.77(s,2H),1.62(s,1H).MS:529[M+H] +。
实施例31.(R,E)-N-(5-(2-羟基乙氧基)-4-((4-苯氧基苯基)氨基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000042
采用与实施例4相同的方法进行合成，不同之处在于，用4-苯氧基苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺，用2-羟基乙醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),9.98(s,1H),8.49(s,1H),8.34(d,J＝9.1Hz,1H),7.88(d,J＝9.1Hz,2H),7.57(d,J＝9.1Hz,1H),7.39(t,J＝7.8Hz,2H),7.17–6.98(m,5H),6.69(dd,J＝15.3,7.7Hz,1H),6.43(d,J＝15.3Hz,1H),5.69(t,J＝4.5Hz,1H),4.10(t,J＝4.1Hz,2H),3.92–3.85(m,2H),3.09–2.99(m,1H),2.76(q,J＝8.0Hz,1H),2.21(s,3H),2.17(t,J＝8.8Hz,1H),2.01(dtd,J＝13.0,8.2,5.6Hz,1H),1.74(td,J＝8.8,4.5Hz,2H),1.59(td,J＝11.6,4.8Hz,1H).MS:526[M+H] +。
实施例32.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-((3-甲氧基丙基)氨基)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000043
采用与实施例4相同的方法进行合成，不同之处在于，用3-甲氧基丙基氨代替步骤5)的甲醇钠进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),10.23(s,1H),8.83(s,1H),8.61(dd,J＝5.0,1.6Hz,1H),8.12–8.01(m,2H),7.90(td,J＝7.7,1.8Hz,1H),7.59(q,J＝11.3,7.4Hz,3H),7.43–7.32(m,2H),7.29–6.94(m,1H),6.85(dd,J＝15.3,8.8Hz,1H),6.62(d,J＝15.3Hz,1H),5.35(s,2H),5.22(d,J＝12.6Hz,1H),4.13(d,J＝9.4Hz,1H),3.72(s,1H),3.34(t,J＝6.0Hz,2H),3.16(d,J＝7.7Hz,1H),3.11(s,3H),2.96(t,J＝6.9Hz,2H),2.83(s,2H),2.75–2.62(m,1H),2.33(q,J＝4.1,3.0Hz,1H),2.16–1.95(m,1H),1.97–1.84(m,1H),1.75(t,J＝6.5Hz,2H).MS:602[M+H] +。
实施例33.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(甲氧基-d3)喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000044
采用与实施例4相同的方法进行合成，不同之处在于，用三氘代醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.93(s,1H),9.87(s,1H),8.60(d,J＝4.7Hz,1H),8.51(s,1H),8.29(d,J＝9.1Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(td,J＝7.7,1.8Hz,1H),7.64–7.52(m,3H),7.37(dd,J＝7.5,4.9Hz,1H),7.26(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.6Hz,1H),6.57(d,J＝15.4Hz,1H),5.31(s,2H),3.04(dd,J＝9.9,7.2Hz,1H),2.78(q,J＝7.9Hz,1H),2.22(br,4H),2.01(dt,J＝13.2,8.2Hz,1H),1.74(td,J＝9.0,5.5Hz,2H),1.59(dd,J＝12.3,9.4Hz,1H).MS:548[M+H] +。
实施例34.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(甲氧基-d3)喹唑啉-6-基)-3-(1-乙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000045
采用与实施例4相同的方法进行合成，不同之处在于，用三氘代醇钠代替步骤5)的甲醇钠，用(R,E)-3-(1-乙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.87(s,1H),8.60(d,J＝4.7Hz,1H),8.51(s,1H),8.28(d,J＝9.1Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(td,J＝7.7,1.9Hz,1H),7.64–7.52(m,3H),7.37(dd,J＝7.5,4.8Hz,1H),7.27(d,J＝9.0Hz,1H),6.70(dd,J＝15.3,7.7Hz,1H),6.55(d,J＝15.4Hz,1H),5.31(s,2H),3.14(s,1H),2.95(s,1H),2.71(dd,J＝13.0,7.9Hz,1H),2.14(s,2H),1.99(dd,J＝12.8,6.9Hz,1H),1.75(q,J＝8.1,7.6Hz,2H),1.57(t,J＝10.0Hz,1H),1.04(t,J＝7.1Hz,3H).MS:562[M+H] +。
实施例35.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(甲氧基-d3)喹唑啉-6-基)-3-(1-异丙基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000046
采用与实施例4相同的方法进行合成，不同之处在于，用三氘代醇钠代替步骤5)的甲醇钠，用(R,E)-3-(1-异丙基吡咯烷-2-基)丙烯酰氯代替步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.88(d,J＝9.2Hz,2H),8.60(d,J＝4.8Hz,1H),8.51(s,1H),8.28(d,J＝9.1Hz,1H),8.11(d,J＝2.7Hz,1H),7.88(t,J＝7.7Hz,1H),7.64–7.52(m,3H),7.37(dd,J＝7.5,4.8Hz,1H),7.26(d,J＝8.9Hz,1H),6.73(dd,J＝15.3,7.5Hz,1H),6.55(d,J＝15.2Hz,1H),5.31(s,2H),3.41–3.36(m,1H),2.91–2.78(m,2H),2.55(d,J＝7.8Hz,1H),1.95(dd,J＝12.1,7.4Hz,1H),1.70(q,J＝8.0Hz,2H),1.55(q,J＝7.3,6.6Hz,1H),1.05(d,J＝6.6Hz,3H),0.95(d,J＝6.3Hz,3H).MS:576[M+H] +。
实施例36.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(甲氧基-d3)喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯 酰胺
Figure PCTCN2022081599-appb-000047
采用与实施例1相同的方法进行合成，不同之处在于，用三氘代醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.87(s,1H),8.60(dt,J＝4.7,1.3Hz,1H),8.51(s,1H),8.28(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.88(td,J＝7.7,1.8Hz,1H),7.65–7.52(m,3H),7.37(ddd,J＝7.6,4.8,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.80(dt,J＝15.4,5.9Hz,1H),6.58(d,J＝15.5Hz,1H),5.32(s,2H),3.09(dd,J＝6.0,1.5Hz,2H),2.20(s,6H).MS:522[M+H] +。
实施例37.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-环丙氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000048
采用与实施例4相同的方法进行合成，不同之处在于，用环丙醇钠代替步骤5)的甲醇钠进行反应；
1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),10.40(s,1H),8.84(s,1H),8.66–8.60(m,1H),8.34(d,J＝9.0Hz,1H),7.98–7.88(m,2H),7.65(dd,J＝24.5,8.4Hz,2H),7.51(dd,J＝8.9,2.6Hz,1H),7.46–7.32(m,2H),6.90–6.74(m,2H),5.37(s,2H),4.30(tt,J＝6.3,3.0Hz,1H),4.10(t,J＝8.0Hz,1H),3.71(br,1H),3.17(br,1H),2.83(s,3H),2.33(dd,J＝12.6,8.2Hz,1H),2.17–1.87(m,3H),0.98(br,2H),0.68–0.59(m,2H).MS:571[M+H] +。
实施例38.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-(环丙基甲氧基)喹唑啉-6-基)-3-(1-甲基吡咯烷酮-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000049
采用与实施例4相同的方法进行合成，不同之处在于，用环丙基甲醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.94(s,1H),8.60(d,J＝4.9Hz,1H),8.54(s,1H),8.20(d,J＝2.6Hz,1H),8.13(d,J＝9.0Hz,1H),7.89(t,J＝7.7Hz,1H),7.57(dd,J＝9.0,7.3Hz,3H),7.37(dd,J＝7.5,4.8Hz,1H),7.28(d,J＝9.0Hz,1H),6.68(dd,J＝15.3,7.7Hz,1H),6.48(d,J＝15.4Hz,1H),5.30(s,2H),3.96(d,J＝7.4Hz,2H),3.04(dd,J＝9.7,7.2Hz,1H),2.76(q,J＝7.9Hz,1H),2.21(s,3H),2.17(t,J＝8.8Hz,1H),2.06–1.94(m,1H),1.74(dd,J＝14.6,7.2Hz,2H),1.65–1.52(m,1H),1.29(t,J＝7.7Hz,1H),0.55–0.45(m,2H),0.28–0.19(m,2H).MS:585[M+H] +。
实施例39.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-环丁氧基喹唑啉-6-基)-3-(1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000050
采用与实施例4相同的方法进行合成，不同之处在于，用环丁醇钠代替步骤5)的甲醇钠进行反应；
1H NMR(400MHz,DMSO-d 6)δ9.89(d,J＝18.8Hz,2H),8.64–8.57(m,1H),8.54(s,1H),8.21(d,J＝2.6Hz,1H),8.13(d,J＝9.0Hz,1H),7.89(t,J＝7.7Hz,1H),7.62–7.51(m,3H),7.42–7.33(m,1H),7.28(d,J＝9.0Hz,1H),6.68(dd,J＝15.3,7.7Hz,1H),6.47(d,J＝15.4Hz,1H),5.31(s,2H),4.56(t,J＝7.7Hz,1H),3.04(dd,J＝9.6,7.1Hz,1H),2.76(q,J＝8.0Hz,1H),2.29(dd,J＝10.0,8.3Hz,2H),2.25–2.10(m,6H),2.00(d,J＝12.9Hz,1H),1.81–1.68(m,2H),1.69–1.53(m,2H),1.37(t,J＝10.5Hz,1H).MS:585[M+H] +。
实施例40.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-((四氢呋喃-3-基)氧基)喹唑啉-6-基)-3-((R)-1-甲基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000051
采用与实施例4相同的方法进行合成，不同之处在于，用四氢呋喃-3-醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),9.83(s,1H),8.60(dt,J＝4.8Hz,1H),8.54(s,1H),8.17(d,J＝2.7Hz,1H),8.10(d,J＝9.1Hz,1H),7.89(td,J＝7.7Hz,1H),7.67–7.53(m,3H),7.37(dd,J＝7.6,4.8Hz,1H),7.27(d,J＝9.0Hz,1H),6.71(dd,J＝15.4,7.7Hz,1H),6.46(d,J＝15.4Hz,1H),5.30(s,2H),5.05(d,J＝6.2Hz,1H),4.16(d,J＝10.8Hz,1H),3.96(q,J＝7.2Hz,1H),3.68(td,J＝8.5,5.7Hz,1H),3.55(dd,J＝10.7,4.6Hz,1H),3.05(dd,J＝9.7,7.1Hz,1H),2.83–2.76(m,1H),2.26–2.01(m,7H),1.75(dd,J＝12.0,9.0Hz,2H),1.66–1.54(m,1H).MS:601[M+H] +。
实施例41.(R,E)-N-(4-((3-氯-4-((3-氟苄基)氧基)苯基)氨基)-5-环丙氧基喹唑啉-6-基)-3-(1-甲基吡咯烷酮-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000052
采用与实施例4相同的方法进行合成，不同之处在于，用3-氯-4-((3-氟苄基)氧基)苯胺替换实施例4步骤4)中的3-氯-4-(吡啶-2-基甲氧基)苯胺，用环丙醇钠代替步骤5)的甲醇钠进行反应； 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),10.29(s,1H),10.11(s,1H),8.74(s,1H),8.28(d,J＝9.0Hz,1H),8.00(d,J＝2.6Hz,1H),7.65(d,J＝9.0Hz,1H),7.56–7.43(m,2H),7.33(dd,J＝8.2,5.8Hz,3H),7.20(td,J＝8.7,2.6Hz,1H),6.89–6.74(m,2H),5.31(s,2H),4.26(tt,J＝6.5,3.1Hz,1H),4.10(s,1H),3.71(s,1H),3.16(d,J＝10.0Hz,1H),2.83(s,3H),2.33(tq,J＝8.6,4.1,3.5Hz,1H),2.16–1.84(m,2H),0.97(tq,J＝5.7,3.3Hz,2H),0.67–0.60(m,2H).MS:588[M+H] +。
实施例42.(R,E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-3-(1-环丁基吡咯烷-2-基)丙烯酰胺
Figure PCTCN2022081599-appb-000053
采用与实施例4相同的方法进行合成，不同之处在于，用(R,E)-3-(1-环丁基吡咯烷-2-基)丙烯酰氯替换实施例4步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),9.86(s,1H),8.60(d,J＝4.8Hz,1H),8.51(s,1H),8.27(d,J＝9.0Hz,1H),8.11(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.65–7.52(m,3H),7.37(dd,J＝7.5,4.9Hz,1H),7.27(d,J＝9.0Hz,1H),6.75(s,1H),6.54(d,J＝15.2Hz,1H),5.32(s,2H),4.12(q,J＝5.3Hz,2H),3.92(s,3H),3.38(d,J＝7.2Hz,1H),3.0(s,1H),1.93(s,5H),1.75(s,2H),1.62(s,3H).MS:585[M+H] +。
实施例43.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(吡咯烷-1-基)丁-2-烯酰胺
Figure PCTCN2022081599-appb-000054
采用与实施例4相同的方法进行合成，不同之处在于，用(E)-4-(吡咯烷-1-基)丁-2-烯酰氯替换实施例4步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.87(s,1H),8.60(dt,J＝4.8,1.4Hz,1H),8.51(s,1H),8.28(d,J＝9.0Hz,1H),8.12(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.65–7.53(m,3H),7.37(ddd,J＝7.6,4.9,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.91–6.75(m,1H),6.60(d,J＝15.4Hz,1H),5.32(s,2H),3.93(s,3H),3.28(dd,J＝5.7,1.7Hz,2H),2.55–2.52(m,4H),1.73(br,4H).MS:545[M+H] +。
实施例44.(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)-4-(哌啶-1-基)丁-2-烯酰胺
Figure PCTCN2022081599-appb-000055
采用与实施例4相同的方法进行合成，不同之处在于，用(E)-4-(哌啶-1-基)丁-2-烯酰氯替换实施例4步骤7)中的(R,E)-3-(1-甲基吡咯烷-2-基)丙烯酰氯进行反应； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.87(s,1H),8.60(ddd,J＝4.8,1.8,0.9Hz,1H),8.52(s,1H),8.27(d,J＝9.0Hz,1H),8.12(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.65–7.53(m,3H),7.37(ddd,J＝7.6,4.9,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.81(dt,J＝15.5,6.0Hz,1H),6.56(d,J＝15.4Hz,1H),5.32(s,2H),3.92(s,3H),3.12(d,J＝5.9Hz,2H),2.38(s,4H),1.54(p,J＝5.5Hz,4H),1.41(d,J＝6.7Hz,2H).MS:559[M+H] +。
为了对本申请化合物的生物化学活性、药学性质等进行表征，对本申请化合物以及吡咯替尼(pyrotinib)、来 那替尼(neratinib)、对照化合物1和2进行了如下测试。其中，吡咯替尼、对照化合物2的合成参见中国专利CN102471312，对照化合物1为对照化合物2的R构型的立体异构体。
对照化合物1：
Figure PCTCN2022081599-appb-000056
对照化合物2：
Figure PCTCN2022081599-appb-000057
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)
化合物溶液配制：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倍于终浓度的稀释液)，并做3倍浓度梯度稀释，共11个梯度。当加入化合物时用缓冲液稀释成4倍终浓度的稀释液。
HER2激酶检测：配制缓冲液，使用缓冲液配制40nM 4X Her2激酶溶液、40μM 4X ATP溶液、400nM 4×ULight TM-labeled Ploy GT Peptide底物溶液。配制完成后，将酶与预先稀释配制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)。反应完毕后加入PT66检测抗体，室温孵育60分钟后用Envision检测。
EGFR WT激酶检测：配制缓冲液，使用缓冲液配制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。配制完成后，将酶与预先稀释配制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1列出了本申请化合物对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10nM，B表示IC 50大于10nM但小于或等于100nM，C表示IC 50大于100nM且小于等于1000nM，NT表示无相关结果。
表1.本发明化合物对EGFR及HER2激酶抑制活性测定结果
Figure PCTCN2022081599-appb-000058
Figure PCTCN2022081599-appb-000059
由以上表1的结果可见，本申请的化合物均可以抑制HER2和EGFR两种激酶，尤其是对HER2激酶，整体都表现出非常优异的抑制活性，可以用于HER2激酶介导的肿瘤及其他疾病的治疗。
实验例2.小分子化合物抑制细胞增殖的测试
本申请采用CTG方法检测了本发明化合物对体外培养的BT474、NCI-N87、Ba/F3-EGFR-VIII和Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD细胞系的体外抗增殖活性。
试剂和耗材：RPMI1640(ThermoFisher，目录号C11875500BT)；胎牛血清(Hyclone，目录号SV30087.03)；0.25％胰蛋白酶-EDTA(ThermoFisher，目录号25200-072)；青霉素-链霉素(Hyclone，目录号SV30010)；DMSO(Amresco，目录号0231-500ML)；CTG测试试剂盒(Promega，目录号G924C)；96孔板(Corning，目录号3603)；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)，Ba/F3-EGFR-VIII、Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD(均来自康源博创生物科技(北京)有限公司)；以上细胞在培养过程中，均用含10％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI1640培养基培养。
具体实验方法：
1.用DMSO溶解-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5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密度，添加80μL细胞悬液至96孔板中，使得BT474、NCI-N87、Ba/F3-EGFR-VIII、Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD的细胞铺板密度均为3000细胞/孔。其中Ba/F3-EGFR-VIII、Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD细胞直接进入下一步加化合物处理，而BT474和NCI-N87需置于37℃、5％二氧化碳气体培养箱中培养过夜贴壁后再加化合物物处理。
3.在已接种细胞的96孔板中每孔加入20μL化合物溶液。被测化合物最高浓度为10μM，共9个浓度，4倍梯度稀释，双复孔。同时设置不加化合物的对照组。
4.细胞继续培养72小时后，用CTG检测试剂盒检测细胞活力。用多功能读板机(Perkin Elmer)读取信号值，用GraphPad Prism软件制作量效曲线并计算IC 50。
表2列出了本发明中代表性化合物对BT474、NCI-N87、Ba/F3-EGFR-VIII、Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD细胞的抗增殖活性测定结果。其中A表示IC 50小于或等于1nM，B表示IC 50大于1nM但小于或等于5nM，C表示IC 50大于5nM但小于或等于10nM，D表示IC 50大于10nM且小于等于100nM，NT表示无相关结果。
表2.本发明代表性化合物对BT474、NCI-N87、Ba/F3-EGFR-VIII、Ba/F3 HER2A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD细胞的抗增殖活性测定结果
Figure PCTCN2022081599-appb-000060
Figure PCTCN2022081599-appb-000061
表2结果显示，本申请的化合物对于以上所测试的各种细胞系均表现出优异的抗肿瘤增殖活性。尤其是对于Ba/F3 HER2 A775-G776sYAMA细胞，本申请化合物表现出了优于现有药物来那替尼和吡咯替尼数倍乃至数十倍的优异活性。
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。
(一)所用试剂、仪器以及动物
表3.试验试剂
Figure PCTCN2022081599-appb-000062
表4.试验仪器
Figure PCTCN2022081599-appb-000063
Figure PCTCN2022081599-appb-000064
表5.试验用鼠
Figure PCTCN2022081599-appb-000065
(二)样品制剂配制
1.静脉注射(IV)组：称取适当数量的受试化合物，完全溶解于适当体积的溶媒(DMSO/Solutol/H 2O＝5/10/85v/v/v(实施例9的溶媒是DMSO/Solutol/H 2O＝5/10/85v/v/v，加入2摩尔倍马来酸))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：称取适当数量的受试化合物，完全溶解于适当体积的溶媒(DMSO/Solutol/H 2O＝5/10/85v/v/v(实施例9的溶媒是DMSO/Solutol/H 2O＝5/10/85v/v/v，加入2摩尔倍马来酸))中，进行搅拌、涡流和/或超声处理。得到溶液后，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6和表7分别给出了给药方案和药代动力学采样方案。
表6.给药方案
Figure PCTCN2022081599-appb-000066
表7.药代动力学采样方案
Figure PCTCN2022081599-appb-000067
Figure PCTCN2022081599-appb-000068
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
全血样品中加入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。
脑组织称重后，加入4倍的匀浆液(乙腈/水＝1/1v/v)匀浆。脑组织匀浆液中分别加入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。根据血浆的药物浓度-时间数据，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8-11中，表8-11分别给出了吡咯替尼、来那替尼、对照化合物1和2以及本申请部分化合物在静脉注射和口服两种给药方式下的各药代动力学参数值。结果显示，对照化合物1和2进行口服给药时，几乎不能被吸收，无法测量得到有效的药代动力学数据；而本申请的化合物均表现出优秀的药代动力学性质，与吡咯替尼、来那替尼相比，也表现出更好的生物利用度。
表8.部分受试化合物的大鼠药代参数(IV 3mg/kg)
参数 PYROTINIB NERATINIB 对照例1 对照例2 实施例4
T 1/2(hr) 3.45±0.24 4.38±0.55 4.91±0.28 6.50±0.78 4.50±0.21
AUC 0-t(hr*ng/mL) 8310±892 2388±267 678±74 565±40 968±156
AUC inf(hr*ng/mL) 8340±890 2422±252 693±72 595±37 979±161
Cl _obs(mL/min/kg) 6.04±0.63 20.8±2.0 72.7±7.1 84.3±5.1 52.1±9.3
V d(L/kg) 1.81±0.26 7.94±1.71 31.0±4.6 47.5±7.5 20.2±2.6
表9.部分受试化合物的大鼠药代参数(IV 3mg/kg)
参数 实施例9 实施例13 实施例24 实施例29
T 1/2(hr) 3.94±0.18 4.12±0.22 5.01±0.45 4.86±0.23
AUC 0-t(hr*ng/mL) 949±128 953±105 1513±26 914±129
AUC inf(hr*ng/mL) 955±130 964±104 1553±23 938±134
Cl _obs(mL/min/kg) 53.0±6.7 52.3±5.7 32.2±0.5 54.0±7.4
V d(L/kg) 18.0±2.3 18.7±2.9 14.0±1.3 22.7±2.4
表10.部分受试化合物的大鼠药代参数(PO 10mg/kg)
参数 PYROTINIB NERATINIB 对照例1 对照例2* 实施例4
T max(hr) 4.33±2.52 2.67±1.15 NA 0.25±NA 5.33±2.89
C max(ng/mL) 246±76 201±66 NA 6.72±NA 65.7±19.9
T 1/2(hr) 3.60±0.37 2.97±0.27 NA 2.39±NA 3.69±0.31
AUC 0-t(hr*ng/mL) 2789±1109 1466±637 NA 18.7±NA 888±221
AUC inf(hr*ng/mL) 2813±1110 1471±638 NA 23.8±NA 902±223
F％ 10.1±4.0 18.2±7.89 NA 0.992±NA 27.6±6.8
*：3次平行测试只有一次有数据，无法统计SD值
表11.部分受试化合物的大鼠药代参数(PO 10mg/kg)
参数 实施例9 实施例13 实施例24 实施例29
T max(hr) 5.00±3.46 2.0±0.0 5.33±2.89 3.33±3.21
C max(ng/mL) 80.3±30.5 53.7±12.4 86.3±32.7 95.3±16.5
T 1/2(hr) 4.13±0.57 5.42±0.34 7.81±3.71 4.63±0.26
AUC 0-t(hr*ng/mL) 1098±406 719±233 1264±561 1100±107
AUC inf(hr*ng/mL) 1112±403 750±238 1474±655 1134±106
F％ 34.9±12.6 23.3±7.4 25.0±11.2 36.3±3.4
NA:暴露量太低，没有统计。
另一方面，如下表11-1所示，本申请的化合物表现出了良好的穿透血脑屏障的能力，与吡咯替尼、来那替尼相比，脑/血比值有了显著提升。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，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激酶介导的相关肿瘤，尤其是脑转移瘤。
表11-1.本申请受试化合物在脑组织和全血中的浓度及比值(PO 10mg/kg，采样时间，给药2h)
Figure PCTCN2022081599-appb-000069
NA：暴露量太低，没有统计。
实验例4.小分子化合物小鼠荷瘤药效试验
本试验通过对Ba/F3 ERBB2 A775_G776insYVMA-裸鼠荷瘤模型口服给予本申请部分化合物，研究本申请化合物对肿瘤生长的影响。
表12实验仪器:
Figure PCTCN2022081599-appb-000070
表13实验动物和细胞:
Figure PCTCN2022081599-appb-000071
试剂：RPMI1640(ThermoFisher，目录号C11875500BT)；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)；Solutol(Sigma，70142-34-6-1kg)
受试化合物配制：称取适当重量的待测化合物，完全溶解于适当体积的溶媒(DMSO)涡旋或超声处理，再加入适量的Solutol混匀，最后加入灭菌饮用水搅拌、涡旋混匀，得到均一溶液或混悬液。
方法：所有试验均经过动物福利委员会授权同意，取对数生长期的Ba/F3 ERBB2 A775_G776insYVMA接种免疫缺陷裸小鼠(BALB/c nude，雌性，6-7周龄，体重18±2g)右侧背部皮下，细胞接种量为4×10 6/只，待肿瘤生长至150-200mm 3后将动物随机分为给药组和对照组。对于给药组，给予各受试的化合物溶液，对照组给予不含受试物的溶媒溶液，均每天给药一次，共2周左右。各受试物剂量均设为30mg/kg(以有效化合物浓度计)，受试化合物均现用现配。实验过程中，每周2次测量荷瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分组给药时测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：给药组RTV；CRTV：对照组RTV。T和C分别表示给药组和对照组的某一时间点的平均瘤体积。
实验结果示于下表14及图1-9中。如图表内容所示，Neratinib、Pyrotinib在30mg/kg剂量时具有一定的抑瘤作用，在第14天的T/C值分别为45.9％、38.3％。本申请实施例4、实施例8、实施例9、 实施例11、实施例24、实施例29、实施例33的化合物在30mg/kg剂量时具有显著的抑瘤作用，其中，实施例4和实施例24的化合物在第14天的T/C值分别为2.6％、12.4％，实施例8、实施例9和实施例11的化合物在第15天的T/C值分别为5.83％、3.85％、5.71％，实施例29和实施例33的化合物在第11天的T/C值分别为18.7％、12.4％。结合前面对于Ba/F3 HER2 A775-G776sYAMA细胞增殖活性测试的结果可知，本申请的化合物不仅在体外对HER2的20外显子***突变(HER2 A775_G776insYVMA)具有优于Pyrotinib和Neratinib的抗肿瘤细胞增殖活性，同时在Ba/F3 ERBB2 A775_G776insYVMA裸鼠荷瘤模型中也显示出远优于Pyrotinib和Neratinib的抗肿瘤活性，所有测试的化合物均实现了肿瘤的显著缩小，而同等剂量(30mg/kg)下，Neratinib和Pyrotinib组的肿瘤仍明显保持增长。
表14.本申请实施例化合物在Ba/F3 ERBB2 A775_G776insYVMA裸鼠荷瘤模型中T/C(％)
Figure PCTCN2022081599-appb-000072
*QD表示每日给药一次
综合所有测试结果，可以发现，本申请通过在喹唑啉的5位引入取代基团，同时去除了在7位的取代基团，合成了系列化合物。本申请的化合物对于HER2和EGFR激酶，以及BT474、NCI-N87、Ba/F3-EGFR-VIII、Ba/F3 HER2 A775_G776insYVMA和Ba/F3 EGFR D770_N771insSVD细胞的增殖均表现良好至优异的抑制活性，尤其是对于Ba/F3 HER2 A775_G776insYVMA细胞模型，本申请化合物在体内细胞增殖抑制试验和体外荷瘤模型试验中，均表现出显著优于Neratinib和Pyrotinib的效果，同时在药代动力学试验中，也表现出优秀的药代动力学性能，综合性能显著优于Neratinib、Pyrotinib以及对照化合物1和2，可以应用于HER2、EGFR激酶或其20外显子突变或者其他突变介导的相关疾病的治疗中。
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 (15)

  1. 一种式(I)所示化合物、其立体异构体、药学上可接受的盐或氘代衍生物，
    Figure PCTCN2022081599-appb-100001
    式(I)中，
    Z为-NH-或者-O-；
    T 1为-(CH 2) n-，其中，n为0至3的整数；
    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烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基中的一种或两种取代；
    L为-O-、-S-或者-NH-；
    R 2为C 1-C 6烷基、卤代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基取代C 1-C 6烷基、或者-(CH 2)m-R 5，
    R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0-3的整数，
    所述的4-6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；
    T 2为-M-(CH 2)p-，其中，M为O、S或者NH，p为0-2的整数，
    R 3为选自苯基、吡啶基、嘧啶基、吡咯基、中的芳基或杂芳基，且所述芳基或者杂芳基被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，
    R'、R”各自独立地为H或C 1-C 3的烷基；
    R 4为氢、卤素、C 1-C 3烷基或者C 1-C 3烷氧基。
  2. 根据权利要求1所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，Z为-NH-。
  3. 根据权利要求1或2所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，T 1为-(CH 2) n-，其中，n为0至2的整数，
    R 1为氢、4-6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 4环烷基、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、或被C 3-C 6环烷基取代的C 1-C 3烷基；
    所述的4-6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、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟基甲基、羟基乙基、羟基丙基中的一种或两种取代；
    或者，T 1为-(CH 2) n-，其中，n为0或1；
    R 1为二甲氨基、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、乙基丙基氨基、甲基环丙基氨基、乙基环丙基氨基、丙基环丙基氨基、异丙基环丙基氨基、甲基环丁基氨基、乙基环丁基氨基、丙基环丁基氨基、异丙基环丁基氨基、吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基、哌啶-1-基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、1-丙基哌嗪-4-基、1-异丙基哌嗪-4-基、1-(2-羟基乙基)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。
  4. 根据权利要求1或2所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，L为-O-或者-NH-；
    R 2为C 1-C 4烷基、卤代C 1-C 4烷基、羟基取代C 1-C 4烷基、C 1-C 3烷氧基取代C 1-C 4烷基或者-(CH 2)m-R 5，
    R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0或1或2，
    所述的4-6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；
    或者，L为-O-；
    R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、环丙基、环丙基甲基、环丁基、四氢呋喃2-基、四氢呋喃3-基。
  5. 根据权利要求1或2所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，T 2为-O-(CH 2)p-，其中，p为0或1；
    R 3为苯基、吡啶基、嘧啶基，且所述苯基、吡啶基、嘧啶基被1至2个选自氟、氯、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、异丙氧基、氰基、羟基、氟甲基、2-氟乙基、三氟甲基、二氟甲基、3,3,3-三氟乙基、2,2-二氟乙基中的取代基所取代或非取代；
    或者，T 2为-O-(CH 2)p-，其中，p为1；
    R 3为苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、6-甲基吡啶2-基、6-甲氧基吡啶2-基、5-甲基吡啶2-基、5-甲氧基吡啶2-基、4-甲基吡啶2-基、4-甲氧基吡啶2-基、3-甲基吡啶2-基、3-甲氧基吡啶2-基、6-氟吡啶2-基、6-氯吡啶2-基。
  6. 根据权利要求1或2所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中， R 4为氢、氟、氯、甲基、甲氧基；
    或者，R 4为氢、氟、氯。
  7. 根据权利要求1所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，所述化合物具有如下结构式，
    Figure PCTCN2022081599-appb-100002
    R 1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、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟基甲基、羟基乙基、羟基丙基中的一种或两种取代；
    R 2为C 1-C 4烷基、卤代C 1-C 4烷基、羟基取代C 1-C 4烷基、C 1-C 3烷氧基取代C 1-C 4烷基或者-(CH 2)m-R 5，
    R 5为C 3-C 6环烷基或者4-6元杂脂环基，m为0或1或2，
    所述的4-6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；
    R 3为苯基、吡啶基、嘧啶基，且所述苯基、吡啶基、嘧啶基被1至2个选自氟、氯、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、异丙氧基、氰基、羟基、氟甲基、2-氟乙基、三氟甲基、二氟甲基、3,3,3-三氟乙基、2,2-二氟乙基中的取代基所取代或非取代；
    R 4为氢、氟、氯、甲基、甲氧基。
  8. 根据权利要求7所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，
    R 1为吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基；
    R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基；
    R 3为苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、6-甲基吡啶2-基、6-甲氧基吡啶2-基、5-甲基吡啶2-基、5-甲氧基吡啶2-基、4-甲基吡啶2-基、4-甲氧基吡啶2-基、3-甲基吡啶2-基、3-甲氧基吡啶2-基、6-氟吡啶2-基、6-氯吡啶2-基；
    R 4为氟、氯；
    或者，R 1为吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-乙基吡咯烷-2-基、1-丙基吡咯烷-2-基、1-异丙基吡咯烷-2-基、1-(2-甲氧基乙基)吡咯烷-2-基、1-(2-甲氧基丙基)吡咯烷-2-基、1-(2-乙氧基乙基)吡咯烷-2-基、1-(2-乙氧基丙基)吡咯烷-2-基、1-(2-羟基甲基)吡咯烷-2-基、1-(2-羟基乙基)吡咯烷-2-基、1-(2-羟基丙基)吡咯烷-2-基；
    R 2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、氟甲基、2-氟乙基、3-氟丙基、三氟甲基、二氟甲基、3,3,3-三氟丙基、3,3,3-三氟乙基、2,2-二氟乙基、3,3-二氟丙基、羟甲基、羟乙基、羟丙基、羟丁基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基；
    R 3为吡啶-2-基；
    R 4为氯。
  9. 根据权利要求8所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，其中，
    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；
    R 2为甲基、乙基、丙基、甲氧基乙基、甲氧基丙基、2,2-二氟乙基；
    R 3为吡啶-2-基；
    R 4为氯。
  10. 根据权利要求1所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，所述化合物选自：
    Figure PCTCN2022081599-appb-100003
    Figure PCTCN2022081599-appb-100004
    Figure PCTCN2022081599-appb-100005
    Figure PCTCN2022081599-appb-100006
  11. 一种药物组合物，包括权利要求1至10中任一项所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物，以及一种或多种药学上可接受的载体或赋形剂。
  12. 根据权利要求11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。
  13. 根据权利要求1-10中任一项所述的化合物、其立体异构体、药学上可接受的盐或氘代衍生物在制备治疗与酪氨酸激酶HER2相关的疾病的药物中的应用。
  14. 根据权利要求13所述的应用，所述与酪氨酸激酶HER2相关的疾病为与酪氨酸激酶HER2的20外显子突变相关的疾病。
  15. 根据权利要求13或14所述的应用，所述疾病为癌症或者自身免疫疾病，尤其是眼底疾病、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、***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***、结肠直肠癌、黑色素瘤、子宫内膜癌、***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。
PCT/CN2022/081599 2021-03-19 2022-03-18 一种喹唑啉类化合物、组合物及其应用 WO2022194265A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2023557350A JP2024510312A (ja) 2021-03-19 2022-03-18 キナゾリン系化合物、キナゾリン系化合物の組成物及び応用
KR1020237034939A KR20230156767A (ko) 2021-03-19 2022-03-18 퀴나졸린계 화합물, 조성물 및 퀴나졸린계 화합물의 적용
AU2022235956A AU2022235956A1 (en) 2021-03-19 2022-03-18 Quinazoline-based compound, composition, and application of quinazoline-based compound
CA3212079A CA3212079A1 (en) 2021-03-19 2022-03-18 Quinazoline-based compound, composition, and application of quinazoline-based compound
EP22770617.3A EP4293016A1 (en) 2021-03-19 2022-03-18 Quinazoline-based compound, composition, and application of quinazoline-based compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110296394 2021-03-19
CN202110296394.X 2021-03-19

Publications (1)

Publication Number Publication Date
WO2022194265A1 true WO2022194265A1 (zh) 2022-09-22

Family

ID=83322096

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/081599 WO2022194265A1 (zh) 2021-03-19 2022-03-18 一种喹唑啉类化合物、组合物及其应用

Country Status (7)

Country Link
EP (1) EP4293016A1 (zh)
JP (1) JP2024510312A (zh)
KR (1) KR20230156767A (zh)
CN (1) CN115109036A (zh)
AU (1) AU2022235956A1 (zh)
CA (1) CA3212079A1 (zh)
WO (1) WO2022194265A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471312A (zh) 2009-09-14 2012-05-23 江苏恒瑞医药股份有限公司 6-氨基喹唑啉或3-氰基喹啉类衍生物、其制备方法及其在医药上的应用
CN104119350A (zh) * 2013-04-28 2014-10-29 广东东阳光药业有限公司 氨基喹唑啉类衍生物及其盐和使用方法
CN104736155A (zh) * 2012-05-14 2015-06-24 杭州德润玉成生物科技有限公司 双环化合物作为激酶的抑制剂
WO2020057511A1 (en) * 2018-09-18 2020-03-26 Suzhou Zanrong Pharma Limited Quinazoline derivatives as antitumor agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471312A (zh) 2009-09-14 2012-05-23 江苏恒瑞医药股份有限公司 6-氨基喹唑啉或3-氰基喹啉类衍生物、其制备方法及其在医药上的应用
CN104736155A (zh) * 2012-05-14 2015-06-24 杭州德润玉成生物科技有限公司 双环化合物作为激酶的抑制剂
CN104119350A (zh) * 2013-04-28 2014-10-29 广东东阳光药业有限公司 氨基喹唑啉类衍生物及其盐和使用方法
WO2020057511A1 (en) * 2018-09-18 2020-03-26 Suzhou Zanrong Pharma Limited Quinazoline derivatives as antitumor agents

Also Published As

Publication number Publication date
CA3212079A1 (en) 2022-09-22
AU2022235956A1 (en) 2023-10-05
CN115109036A (zh) 2022-09-27
EP4293016A1 (en) 2023-12-20
JP2024510312A (ja) 2024-03-06
KR20230156767A (ko) 2023-11-14

Similar Documents

Publication Publication Date Title
TW200829558A (en) Quinazolines for PDK1 inhibition
TWI669300B (zh) 嘧啶類衍生物、其製備方法、其藥物組合物以及其在醫藥上的用途
CN111196814B (zh) 芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用
CN111484482B (zh) 炔基嘧啶或炔基吡啶类化合物、及其组合物与应用
JP6969800B2 (ja) 増殖性疾患の治療に使用される置換２，４−ジアミノ−キノリン誘導体
CN108299420B (zh) 作为选择性***受体下调剂的五环类化合物及其应用
TWI724753B (zh) 醯胺基橋連雜環類化合物、及其組合物與應用
CN111825719A (zh) 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
WO2022194265A1 (zh) 一种喹唑啉类化合物、组合物及其应用
WO2019223777A1 (zh) 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
CN113087671B (zh) 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用
CN111362924B (zh) 氘代的嘧啶衍生物及其用途
CN110229172B (zh) 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用
CA3090876C (en) Dioxinoquinoline compounds, preparation method and uses thereof
TWI820414B (zh) 喹唑啉類化合物、製備方法及其應用
CN115894486B (zh) 一种氢化吡啶并喹唑啉类化合物、组合物及其应用
CN112442045B (zh) 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用
CN113527215B (zh) 一种喹唑啉类化合物、制备方法及其应用
JP2022512358A (ja) キノリン構造を有するｐａｎ－ＫＩＴキナーゼ阻害剤及びその適用
WO2023051687A1 (zh) 一种喹唑啉类化合物、组合物及其应用
CN112341378A (zh) 脲代炔基嘧啶或脲代炔基吡啶类化合物、及其组合物与应用
CN115894455A (zh) 一种喹唑啉类化合物、组合物及其应用
KR20230163335A (ko) 헤테로아릴 유도체 화합물 및 이의 용도
CN117050055A (zh) 含有酰胺吡啶环的化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22770617

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 3212079

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2022770617

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2022235956

Country of ref document: AU

Ref document number: AU2022235956

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2023557350

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 2022235956

Country of ref document: AU

Date of ref document: 20220318

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2022770617

Country of ref document: EP

Effective date: 20230914

ENP Entry into the national phase

Ref document number: 20237034939

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020237034939

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 11202306845V

Country of ref document: SG