WO2021104305A1 - Nitrogen-containing polycyclic derivative inhibitor, preparation method therefor and application thereof - Google Patents

Nitrogen-containing polycyclic derivative inhibitor, preparation method therefor and application thereof Download PDF

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WO2021104305A1
WO2021104305A1 PCT/CN2020/131472 CN2020131472W WO2021104305A1 WO 2021104305 A1 WO2021104305 A1 WO 2021104305A1 CN 2020131472 W CN2020131472 W CN 2020131472W WO 2021104305 A1 WO2021104305 A1 WO 2021104305A1
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group
amino
alkyl
cycloalkyl
aryl
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PCT/CN2020/131472
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French (fr)
Chinese (zh)
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王峰
张武
苏熠东
蔡家强
包如迪
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN202080006819.2A priority Critical patent/CN113179640A/en
Publication of WO2021104305A1 publication Critical patent/WO2021104305A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a nitrogen-containing polycyclic derivative inhibitor and a preparation method and application thereof.
  • EGFR Epidermal growth factor receptor
  • EGF epidermal growth factor
  • it can Form homodimers or form heterodimers with other receptors in the ErbB family (such as ErbB2, ErbB3, ErbB4), leading to the activation of EGFR tyrosine kinase activity.
  • Activated EGFR can phosphorylate different substrates, thereby activating the downstream PI3K-AKT pathway and RAS-MAPK pathway, etc., and play a role in cell survival, proliferation, and apoptosis.
  • the dysregulation of the EGFR signaling pathway includes increased expression of ligands and receptors, EGFR gene amplification and mutations, etc., which can promote malignant transformation of cells, leading to the occurrence of various tumors.
  • NSCLC non-small cell lung cancer
  • the most common types of mutations are exon 19 deletion mutations (Del19) and exon 21 L858R activating mutations, both occupying the most important part of EGFR mutations.
  • About EGFR exon 20 insertion mutation is another major mutation of EGFR mutation, accounting for 4%-10% of EGFR mutations in NSCLC.
  • the common mutation types are Ex20Ins D770_N771InsSVD, Ex20Ins V769_D770InsASV, etc.
  • EGFR mutations in NSCLC such as the first-generation reversible tyrosinase inhibitors (TKI) gefitinib and erlotinib for classic Del19 mutations and L858R mutations, second-generation
  • TKI first-generation reversible tyrosinase inhibitors
  • the irreversible covalent binding inhibitor afatinib and the third-generation inhibitor osimertinib for the drug-resistant mutant EGFR T790M have very good clinical effects.
  • the current EGFR inhibitors on the market have poor effects on EGFR exon 20 insertion mutations, and the patient's survival period is very short. This target requires more specific inhibitors, and there is a large clinical demand.
  • HER2 is another member of the ErbB family, and its amplification and mutations occur in a variety of cancers. Among them, HER2 mutations in NSCLC account for about 4%, and about 90% of HER2 mutations are exon 20 insertion mutations. The most common type of mutation is p.A775_G776insYVMA, and the currently marketed EGFR inhibitors are generally effective.
  • EGFR inhibitors have strong inhibitory effects on EGFR wild-type, leading to clinical side effects such as skin rashes.
  • the inhibitory activity of EGFR exon 20 insertion mutations and HER2 20 exon insertion mutation targets also needs to be improved, so EGFR and HER2 20 exon mutations have obvious effects and there is still a great demand for compounds with high selectivity for wild-type EGFR, which have a good market prospect.
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • M is selected from CR 1 or N;
  • L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C(O )-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C(O)O-, -NR aa (CH 2 ) n -, -O(CH 2 ) n -, -S(CH 2 ) n -, -C(O)(CH 2 ) n -, -C(O)NR aa (CH 2 ) n -, -NR aa C(O)(CH 2 ) n -, -C(O)O(CH 2 ) n -, -C(O)NR
  • Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 1 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a hydroxyalkyl group, an azido group, a carboxyl group Ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -NR a C( O)R b , -C(O)NR a (CH 2 ) n R b , -NR a C(O)NR b R c , -NR a C(O)NR b (CH 2 ) n R c
  • R a is selected from a hydrogen atom, a deuterium atom, an alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, hydroxyalkyl, azido, alkenyl Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a1 , -(CH 2 ) n NR a1 R b1 , -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 R c1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a
  • R b is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a hydroxyalkyl group, an azido group, an alkene Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a2 , -(CH 2 ) n NR a2 R b2 , -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)R b2 , -NR a2 C(O)NR b2 R c2
  • R aa , R a , R b , R c , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 or R d2 are each independently selected from hydrogen atom, deuterium atom, alkyl group, deuterium Alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group, the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, any The selected ones can be further replaced;
  • x is an integer from 0 to 5;
  • y is an integer from 0 to 5;
  • n is an integer from 0 to 2;
  • n is an integer of 0-4.
  • L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -, -(CH 2 ) n O-, -(CH 2 ) n S -, -(CH 2 ) n C(O)-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C( O)O-, -(CH 2 ) n P(O)R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa -or -(CH 2 ) n NR aa S(O) m -; preferably a bond or -(CH 2 ) n NR aa -; more preferably a bond or
  • ring A is selected from C 6-14 aryl or 5-14 membered heteroaryl; preferably phenyl.
  • ring B is selected from 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably phenyl, benzoheteroaryl or benzo Heterocyclic group; further preferred are the following groups:
  • R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3- 6 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, Thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluorine Me
  • R 3 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, --O(CH 2 ) n R a1 , -NR a1 (CH 2 ) n R b1 or -NR a1 (CH 2 ) n NR b1 R c1 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further Halogen, cyano,
  • R 4 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably hydrogen Atom, methyl, methoxy or ethoxy.
  • R 6 and R 7 are each independently selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably a hydrogen atom or halogen;
  • R 6 and R 7 are linked with the carbon atom to which they are attached to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups are any
  • the selected ones can be further substituted; the following groups are preferred:
  • R 8 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom or halogen.
  • R 9 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom, C 1-6 alkyl group Or a C 3-8 cycloalkyl group; more preferably a hydrogen atom, a methyl group or a cyclopropyl group.
  • R 9 is not a methyl group.
  • M is N or CR 1 ;
  • R 1 is selected from hydrogen, halogen, cyano, trifluoromethyl, cyano, methoxy, ethoxy, -C(O)OCH(CH 3 ) 2 ,
  • Ring B is selected from
  • R b is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, phosphoryl, sulfonyl, aminosulfonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
  • y is 1, 2 or 3, preferably 1.
  • a method for preparing the compound represented by general formula (VI) or its stereoisomer and pharmaceutically acceptable salt thereof comprises the following steps:
  • the general formula (VI-1) reacts with the general formula (VI-2) to obtain the general formula (VI-3), and the general formula (VI-3) continues to react with the general formula (VI-4) to obtain the general formula (VI)
  • X 1 and X 2 are each independently selected from halogen; preferably fluorine, chlorine, bromine or iodine; more preferably chlorine;
  • X 3 is selected from halogen, boric acid or boric acid ester; preferably boric acid ester; more preferably
  • the present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which comprises a therapeutically effective dose of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, and a One or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I), and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of therapeutic kinase inhibitors Application in the agent.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of therapeutic receptors.
  • Application of tyrosine kinase inhibitor (TKI) is also provided.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the preparation of the pharmaceutical composition for the treatment of HER2 inhibition Inhibitors, EGFR inhibitors, EGFR monoclonal antibodies and related drugs in combination, more preferably inhibitors of EGFR exon 20 insertion mutations and HER2 exon 20 insertion mutation targets.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of the treatment of cancer-related diseases
  • the application of the drug cancer is preferably the treatment of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumors, glioma, glioblastoma, leukemia, Lymphoma, myeloma and non-small cell lung cancer.
  • the present invention further relates to a method for preparing the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.
  • the present invention also relates to a method for treating cancer-related diseases, which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the method involves the treatment of disorders such as cancer.
  • the treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides methods for treating diseases including cancer-related diseases in mammals.
  • the method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
  • the third-generation EGFR inhibitors mainly target EGFR activating mutants and T790M drug-resistant mutants.
  • the compounds of the present invention are more effective than the third-generation EGFR inhibitors in terms of EGFR and/or HER2 20 exon insertion mutation targets. Shows the following advantages:
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylic acid ester group, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "Butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugation.
  • ⁇ electronic system It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom.
  • Non-limiting examples include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the membered heterocyclic group is optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably pyrrolidinyl, piperidinyl and piperazinyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) Heteroatoms of m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Member cycloalkyl, benzo 3-6 membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .
  • the ring connected to the parent structure is an aryl ring, and non-limiting examples include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl and oxazolyl Azole.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the thi
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxy
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), where the alkynyl group can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
  • alkenylcarbonyl refers to -C(O)-(alkenyl), where alkenyl is as defined above.
  • alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
  • the alkenylcarbonyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxy
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carbonyl refers to -C(O)-.
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means Otoharu.
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • the liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.
  • the third step (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • the fourth step N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline- Preparation of 6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
  • the first step Preparation of (6-((4-chloro-1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • Steps 2-4 refer to steps 2-4 of Example 1.
  • Example 1 For the preparation method of Example 3, refer to Example 1.
  • Example 1 For the preparation method of Example 4, refer to Example 1.
  • the first step Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • the third step (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • the third step refers to the third step of Example 1
  • the fourth step (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • Step 5 N-(5-((5-cyano-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
  • Example 1 for the preparation method of Example 6.
  • Steps one to three (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide
  • Steps 1-3 refer to steps 1-3 of Example 1.
  • the fourth step (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Preparation of -5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • the fifth step N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline- 6-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
  • Step 5 Refer to Step 4 of Example 1.
  • Example 7 for the preparation method of Example 8.
  • Example 7 for the preparation method of Example 10.
  • Example 12 For the preparation method of Example 12, refer to Example 1.
  • Example 1 for the preparation method of Example 13.
  • Example 1 for the preparation method of Example 14.
  • the first step (6-((4-chloro-1,3,5-triazin-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5 -Base) dimethyl phosphine oxide preparation
  • Steps 2-4 refer to steps 2-4 of Example 1.
  • Example 15 for the preparation method of Example 16.
  • Example 15 for the preparation method of Example 17.
  • Example 15 for the preparation method of Example 18.
  • Example 15 For the preparation method of Example 19, refer to Example 15.
  • Example 15 For the preparation method of Example 20, refer to Example 15.
  • Example 1 for the preparation method of Example 21.
  • Example 15 for the preparation method of Example 22.
  • Example 15 for the preparation method of Example 23.
  • Example 7 for the preparation method of Example 24.
  • Example 7 for the preparation method of Example 25.
  • the first step Preparation of (3-(4-chloro-1,3,5-triazin-2-yl)-1-cyclopropyl-1H-indole
  • Steps 2-4 refer to steps 2-4 of Example 1.
  • Step 1 Preparation of 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
  • reaction was quenched by adding ice water (40 mL), and extracted with dichloromethane (40 mL ⁇ 3).
  • the organic phase is dried and spin-dried, and purified with a chromatography column (petroleum ether) to obtain the product 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-indole (1 g, yield: 56%).
  • reaction solution was poured into water (30 mL), filtered to obtain a solid, and washed with ethyl acetate to obtain the product 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3 , 5-Triazine-2-amine (600 mg, yield: 50%).
  • the third step 4-(1-cyclopropyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5- Preparation of triazine-2-amine
  • Steps 4 to 5 N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
  • Steps 4-5 refer to Steps 3-4 of Example 1.
  • Example 26 for the preparation method of Example 27.
  • Example 15 for the preparation method of Example 28.
  • the third step 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrobenzene (Yl)amino)pyrimidine-5-carbonitrile
  • reaction solution was cooled, evaporated to dryness, adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (35 mL*2), the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain a crude product.
  • the fourth step 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-(dimethylamino)ethyl)( (Methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile
  • Potassium carbonate (214mg, 1.55mmol) was added to N,N,N'-trimethylethylenediamine (58mg, 0.57mmol) and 4-(1-cyclopropyl-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (230mg, 0.52mmol) in acetonitrile (10mL) , The reaction solution was heated to 80°C for 2 hours.
  • the fifth step 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile
  • Iron powder (288mg, 5.2mmol) was added to 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-( ⁇ (Methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (270mg, 0.51mol) in ethanol (10mL) and saturated ammonium chloride In the mixture of aqueous solution (4 mL), the reaction solution was heated to 80° C. and reacted for 2 hours. The reaction solution was filtered hot, washed with solid dichloromethane, and evaporated to dryness in the liquid phase to obtain a crude product.
  • the sixth step 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2- Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide
  • the seventh step N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino) -2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
  • Example 1 for the preparation method of Example 30.
  • Example 29 for the preparation method of Example 31.
  • Example 29 for the preparation method of Example 32.
  • Example 29 for the preparation method of Example 33.
  • Example 29 for the preparation method of Example 34.
  • Example 29 for the preparation method of Example 35.
  • Example 29 for the preparation method of Example 36.
  • Test Example 1 Determination of the inhibitory effect of the compound of the present invention on the kinase activity of EGFR exon 20 insertion mutation
  • the purpose of this test case is to measure the inhibitory ability of the compound on the kinase activity of EGFR 20 exon insertion mutation.
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • the compound of the example of the present invention has a good inhibitory effect in the EGFR 20 exon insertion mutation kinase activity inhibition experiment.
  • Test Example 2 Determination of the inhibitory effect of the compound of the present invention on the activity of EGFR wild-type kinase
  • the purpose of this test case is to measure the inhibitory ability of the compound on the activity of EGFR wild-type kinase.
  • TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer
  • experiment buffer 50mM HEPES, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20
  • experiment buffer 50mM HEPES, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20
  • the compound was diluted to different concentrations with experiment buffer, 2 ⁇ L per well
  • Add to 384-well plate then add 4 ⁇ L of diluted EGFR kinase solution (0.001-0.5nM), incubate at room temperature for 10 minutes, add 4 ⁇ L of ULight-poly GT/ATP mixed solution, incubate at room temperature for 30 minutes to 60 minutes, add 5 ⁇ L of EDTA Terminate the reaction and 5 ⁇ L Eu-labeled antibody detection solution, incubate for 1 hour at room temperature, and measure the 665nm fluorescence signal value
  • the compound of the example of the present invention has less inhibitory effect in the EGFR wild-type kinase inhibition test.
  • Test Example 3 Determination of the inhibitory effect of the compound of the present invention on the proliferation of Ba/F3 EGFR mutant cell lines
  • the purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of Ba/F3 EGFR mutant cell lines.
  • the luminescence signal value was used to calculate the inhibition rate, and the concentration and inhibition rate were fitted with Graphpad Prism software for nonlinear regression curve fitting to obtain the IC 50 value.
  • the specific data are shown in Table 3 below:
  • the purpose of this experiment is to test the stability of the compounds of the examples in rat and human liver microsomes.
  • Compound working solution preparation add the compound stock solution to phosphate buffer, the final concentration is 20 ⁇ M.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • UDPGA uridine diphosphate glucuronic acid
  • Stop solution cold acetonitrile containing 100ng/mL labetalol hydrochloride and 400ng/mL tolbutamide as internal standards.
  • Ion source Electrospray ionization source (ESI);
  • Drying gas N 2 , temperature 500°C;
  • Electrospray voltage 5000V
  • Detection method positive ion detection
  • mice were used as test animals to study the pharmacokinetic behavior of the compounds in mice (plasma) after oral administration.
  • Example compounds of the present invention self-made
  • HEC hydroxyethyl cellulose
  • the compound of the example was weighed and added to a 4-mL glass bottle respectively, and 2.4 mL of the solution was added, followed by sonication for 10 minutes to obtain a colorless and clear solution with a concentration of 1 mg/mL.
  • mice Male; PO respectively after fasting overnight, the dose was 40 mg/kg, and the dose volume was 10 mL/kg.
  • the blood was collected before and after the administration, the blood was placed in an EDTA-2K test tube, and the plasma was separated by centrifugation at 6000 rpm at 4°C for 6 min, and stored at -80°C; food was taken 4 hours after the administration.
  • Test Example 6 In vivo pharmacodynamics study of the compound of the present invention on mouse primary B cell Ba/F3 EGFR-D770-N771ins_SVD transplantation tumor model
  • Fetal Bovine Serum (FBS) 10099-141C, Gibco)
  • PBS Phosphate buffered saline
  • BALB/c nude mice, 6-8 weeks, ⁇ purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.
  • a Take out a Ba/F3 EGFR-D770-N771ins_SVD cell from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640+10% FBS), and place the recovered cells in a cell culture flask (in the bottle wall). Mark the cell type, date, culture name, etc.) and place it in a CO 2 incubator (the temperature of the incubator is 37°C, and the CO 2 concentration is 5%).
  • RPMI-1640 medium RPMI-1640+10% FBS
  • c. Collect the cultured cells, count them with an automatic cell counter, and resuspend the cells in PBS according to the counting results to make a cell suspension (density 2 ⁇ 10 7 /mL), and place in an ice box for later use.
  • test nude mice in turn (each mouse is inoculated with 0.1mL cell suspension).
  • a According to the tumor growth, measure the tumor and calculate the tumor size from 8 to 14 days after inoculation.
  • tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm)/2
  • mice were randomly divided into groups, 5 mice in each group.
  • test drug administration method: oral administration; dosing frequency: 1 time/day; dosing cycle: 14 days; vehicle: 0.5% CMC/1% Tween 80).
  • TGI(%) [(1-Average tumor volume at the end of treatment in a certain treatment group)/Average tumor volume at the end of treatment in the solvent control group] ⁇ 100%.
  • TGI ⁇ 60% the compound is effective in this model
  • TGI ⁇ 60% the compound is not effective in this model.
  • the data in parentheses indicates that this example corresponds to the tumor volume of the Vehicle QD x 2w group (ie, the control group) at the corresponding time.

Abstract

The present invention relates to a nitrogen-containing polycyclic derivative inhibitor, a preparation method therefor and an application thereof. Particularly, the present invention relates to a compound as represented by general formula (I) and a preparation method therefor, a pharmaceutical composition containing the compound, and use of the compound in treating related diseases such as cancers, inflammation, chronic liver diseases, diabetes, cardiovascular diseases, and AIDS as a kinase inhibitor, especially as a receptor tyrosine kinase inhibitor (TKI), more specifically, as an EGFR or HER2 inhibitor. Substituents in general formula (I) have the same definitions as those in the description.

Description

含氮多环类衍生物抑制剂、其制备方法和应用Nitrogen-containing polycyclic derivative inhibitor, preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种含氮多环类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to a nitrogen-containing polycyclic derivative inhibitor and a preparation method and application thereof.
背景技术Background technique
细胞中存在多种信号通路互相作用控制着细胞的增殖、生长、迁移以及凋亡。信号通路的异常激活会导致肿瘤的发生。受体酪氨酸激酶在细胞的调控中发挥重要作用。表皮生长因子受体(EGFR)为跨膜蛋白酪氨酸激酶ErbB受体家族(包括ErbB1，ErbB2，ErbB3，ErbB4)的一员，通过与其配体表皮生长因子(EGF)的结合，可以在膜上形成同源二聚体，或者与ErbB家族中其他的受体(如ErbB2,ErbB3,ErbB4)形成异源二聚体，导致EGFR酪氨酸激酶活性的激活。激活的EGFR可以磷酸化不同的底物，从而激活下游的PI3K-AKT通路以及RAS-MAPK通路等，在细胞存活、增殖以及凋亡等多个过程中发挥作用。There are multiple signal pathways in cells that interact with each other to control cell proliferation, growth, migration and apoptosis. Abnormal activation of signaling pathways can lead to tumors. Receptor tyrosine kinases play an important role in the regulation of cells. Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family of transmembrane protein tyrosine kinases (including ErbB1, ErbB2, ErbB3, and ErbB4). By binding to its ligand epidermal growth factor (EGF), it can Form homodimers or form heterodimers with other receptors in the ErbB family (such as ErbB2, ErbB3, ErbB4), leading to the activation of EGFR tyrosine kinase activity. Activated EGFR can phosphorylate different substrates, thereby activating the downstream PI3K-AKT pathway and RAS-MAPK pathway, etc., and play a role in cell survival, proliferation, and apoptosis.
EGFR信号通路的失调包括配体以及受体的表达升高，EGFR基因扩增以及突变等等，可促进细胞向恶性转化，从而导致多种肿瘤的发生。中国的非小细胞肺癌(NSCLC)患者中约35％左右为EGFR突变，其中最常见的突变类型为19外显子缺失突变(Del19)以及21外显子L858R激活突变，二者占据EGFR突变的约80％左右。EGFR 20外显子插入突变为EGFR突变的另一大突变，占NSCLC中EGFR突变的4％～10％，突变类型多达几十种，常见的突变类型为Ex20Ins D770_N771InsSVD，Ex20Ins V769_D770InsASV等。The dysregulation of the EGFR signaling pathway includes increased expression of ligands and receptors, EGFR gene amplification and mutations, etc., which can promote malignant transformation of cells, leading to the occurrence of various tumors. About 35% of non-small cell lung cancer (NSCLC) patients in China have EGFR mutations. The most common types of mutations are exon 19 deletion mutations (Del19) and exon 21 L858R activating mutations, both occupying the most important part of EGFR mutations. About 80%. EGFR exon 20 insertion mutation is another major mutation of EGFR mutation, accounting for 4%-10% of EGFR mutations in NSCLC. There are dozens of mutation types. The common mutation types are Ex20Ins D770_N771InsSVD, Ex20Ins V769_D770InsASV, etc.
多年来针对NSCLC中EGFR突变研发出了大量的靶向药，比如针对经典Del19突变以及L858R突变的一代可逆性的酪氨酸酶抑制剂(TKI)吉非替尼和厄洛替尼，二代不可逆共价结合抑制剂阿法替尼，以及针对耐药突变EGFR T790M的三代抑制剂奥希替尼，均有非常好的临床效果。但是目前市场上的EGFR抑制剂对于EGFR 20外显子插入突变的作用很差，病人生存期很短，该靶点需要特异性更强的抑制剂，存在较大的临床需求。Over the years, a large number of targeted drugs have been developed for EGFR mutations in NSCLC, such as the first-generation reversible tyrosinase inhibitors (TKI) gefitinib and erlotinib for classic Del19 mutations and L858R mutations, second-generation The irreversible covalent binding inhibitor afatinib and the third-generation inhibitor osimertinib for the drug-resistant mutant EGFR T790M have very good clinical effects. However, the current EGFR inhibitors on the market have poor effects on EGFR exon 20 insertion mutations, and the patient's survival period is very short. This target requires more specific inhibitors, and there is a large clinical demand.
HER2作为ErbB家族的另一成员，其扩增以及突变在多种癌症中均有发生。其中在NSCLC中HER2的突变占4％左右，而HER2突变90％左右为20外显子插入突变，其中最常见的突变类型为p.A775_G776insYVMA，目前上市的EGFR抑制剂对其效果一般。HER2 is another member of the ErbB family, and its amplification and mutations occur in a variety of cancers. Among them, HER2 mutations in NSCLC account for about 4%, and about 90% of HER2 mutations are exon 20 insertion mutations. The most common type of mutation is p.A775_G776insYVMA, and the currently marketed EGFR inhibitors are generally effective.
目前已有多家国内外药企针对EGFR&HER2 20外显子插入突变展开了积极的研究，其中Spectrum公司的Poziotinib、Takeda的TAK-788以及Rain Therapeutics的Tarloxotinib均已进入临床研究，另外Cullinan&Taiho公司的化合物TAS-6417也在临床前实验中展现了较好的活性。At present, many domestic and foreign pharmaceutical companies have carried out active research on EGFR&HER2 exon 20 insertion mutations. Among them, Spectrum’s Poziotinib, Takeda’s TAK-788 and Rain Therapeutics’ Tarloxotinib have all entered clinical studies, and Cullinan&Taiho’s compounds TAS-6417 also showed good activity in preclinical experiments.
由于很多EGFR抑制剂对EGFR野生型抑制作用较强，导致临床上出现皮疹等副作用，而对于EGFR 20外显子插入突变以及HER2 20外显子插入突变靶点的抑制活性也有待提高，因此对EGFR以及HER2 20外显子突变效果明显且对野生型EGFR选择性高的化合物仍存在极大需求，具有很好的市场前景。Many EGFR inhibitors have strong inhibitory effects on EGFR wild-type, leading to clinical side effects such as skin rashes. The inhibitory activity of EGFR exon 20 insertion mutations and HER2 20 exon insertion mutation targets also needs to be improved, so EGFR and HER2 20 exon mutations have obvious effects and there is still a great demand for compounds with high selectivity for wild-type EGFR, which have a good market prospect.
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
Figure PCTCN2020131472-appb-000001
Figure PCTCN2020131472-appb-000001
其中：among them:
M选自CR 1或N； M is selected from CR 1 or N;
L选自键、-(CH 2) n-、-(CH 2) nNR aa-、-(CH 2) nO-、-(CH 2) nS-、-(CH 2) nC(O)-、-(CH 2) nC(O)NR aa-、-(CH 2) nNR aaC(O)-、-(CH 2) nC(O)O-、-NR aa(CH 2) n-、-O(CH 2) n-、-S(CH 2) n-、-C(O)(CH 2) n-、-C(O)NR aa(CH 2) n-、-NR aaC(O)(CH 2) n-、-C(O)O(CH 2) n-、-(CH 2) nP(O)R aa-、-(CH 2) nS(O) m-、-(CH 2) nS(O) mNR aa-或-(CH 2) nNR aaS(O) m-； L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C(O )-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C(O)O-, -NR aa (CH 2 ) n -, -O(CH 2 ) n -, -S(CH 2 ) n -, -C(O)(CH 2 ) n -, -C(O)NR aa (CH 2 ) n -, -NR aa C(O)(CH 2 ) n -, -C(O)O(CH 2 ) n -, -(CH 2 ) n P(O)R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa -or -(CH 2 ) n NR aa S(O) m -;
环A选自环烷基、杂环基、芳基或杂芳基；Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl;
环B选自环烷基、杂环基、芳基或杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、羧酸酯基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a、-(CH 2) nNR aR b、-NR aC(O)R b、-C(O)NR a(CH 2) nR b、-NR aC(O)NR bR c、-NR aC(O)NR b(CH 2) nR c、-C≡CR a、-NR aC(O)CR b＝CH(CH 2) nR c、-NR aC(O)C≡CR b、-C(O)NR aR b、-C(O)OR a、-NR aS(O) mR b、-O(CH 2) nR a、-(CH 2) nP(O)R aR b、-(CH 2) nS(O) mNR aR b、-(CH 2) nC(O)R a、-NR aC(O)OR b、-(CH 2) nS(O) mR a或-(CH 2) nNR aS(O) mR b，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R 1 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a hydroxyalkyl group, an azido group, a carboxyl group Ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -NR a C( O)R b , -C(O)NR a (CH 2 ) n R b , -NR a C(O)NR b R c , -NR a C(O)NR b (CH 2 ) n R c ,- C≡CR a , -NR a C(O)CR b =CH(CH 2 ) n R c , -NR a C(O)C≡CR b , -C(O)NR a R b , -C(O )OR a , -NR a S(O) m R b , -O(CH 2 ) n R a , -(CH 2 ) n P(O)R a R b , -(CH 2 ) n S(O) m NR a R b , -(CH 2 ) n C(O)R a , -NR a C(O)OR b , -(CH 2 ) n S(O) m R a or -(CH 2 ) n NR a S(O) m R b , the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;
R a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a1、-(CH 2) nNR a1R b1、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)R b1、-NR a1C(O)NR b1R c1、-NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1R b1、-C(O)OR a1、-NR a1S(O) mR b1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、 -NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R a is selected from a hydrogen atom, a deuterium atom, an alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, hydroxyalkyl, azido, alkenyl Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a1 , -(CH 2 ) n NR a1 R b1 , -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 R c1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n NR c1 R d1 , -C(O)NR a1 R b1 , -C(O)OR a1 , -NR a1 S(O) m R b1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P(O)R a1 R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -(CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -( CH 2 ) n S(O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group Group, optionally can be further substituted;
R b选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a2、-(CH 2) nNR a2R b2、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)R b2、-NR a2C(O)NR b2R c2、-NR a2C(O)NR b2(CH 2) nR c2、-NR a2C(O)C≡CR b2、-NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2R b2、-C(O)OR a2、-NR a2S(O) mR b2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或-(CH 2) nNR a2S(O) mR b2，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R b is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a hydroxyalkyl group, an azido group, an alkene Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a2 , -(CH 2 ) n NR a2 R b2 , -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)R b2 , -NR a2 C(O)NR b2 R c2 , -NR a2 C(O)NR b2 (CH 2 ) n R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n R c2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 R b2 , -C(O)OR a2 , -NR a2 S(O) m R b2 , -O(CH 2 ) n R a2 , -(CH 2 ) n P(O)R a2 R b2 , -(CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O)R a2 , -NR a2 C(O)OR b2 , -( CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O) m R b2 , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group Group, optionally can be further substituted;
R aa、R a、R b、R c、R a1、R b1、R c1、R d1、R a2、R b2、R c2或R d2各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R aa , R a , R b , R c , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 or R d2 are each independently selected from hydrogen atom, deuterium atom, alkyl group, deuterium Alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group, the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, any The selected ones can be further replaced;
x为0～5的整数；x is an integer from 0 to 5;
y为0～5的整数；y is an integer from 0 to 5;
m为0～2的整数；且m is an integer from 0 to 2; and
n为0～4的整数。n is an integer of 0-4.
在本发明一种优选的实施方式中，L选自键、-(CH 2) n-、-(CH 2) nNR aa-、-(CH 2) nO-、-(CH 2) nS-、-(CH 2) nC(O)-、-(CH 2) nC(O)NR aa-、-(CH 2) nNR aaC(O)-、-(CH 2) nC(O)O-、-(CH 2) nP(O)R aa-、-(CH 2) nS(O) m-、-(CH 2) nS(O) mNR aa-或-(CH 2) nNR aaS(O) m-；优选键或-(CH 2) nNR aa-；更优选键或-NH-。 In a preferred embodiment of the present invention, L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -, -(CH 2 ) n O-, -(CH 2 ) n S -, -(CH 2 ) n C(O)-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C( O)O-, -(CH 2 ) n P(O)R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa -or -(CH 2 ) n NR aa S(O) m -; preferably a bond or -(CH 2 ) n NR aa -; more preferably a bond or -NH-.
在本发明一种优选的实施方式中，环A选自C 6-14芳基或5-14元杂芳基；优选苯基。 In a preferred embodiment of the present invention, ring A is selected from C 6-14 aryl or 5-14 membered heteroaryl; preferably phenyl.
在本发明一种优选的实施方式中，环B选自3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选苯基、苯并杂芳基或苯并杂环基；进一步优选如下基团： In a preferred embodiment of the present invention, ring B is selected from 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably phenyl, benzoheteroaryl or benzo Heterocyclic group; further preferred are the following groups:
Figure PCTCN2020131472-appb-000002
Figure PCTCN2020131472-appb-000002
在本发明进一步优选的实施方式中，R 1选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、叠氮基、C 1-6羧酸C 1-6酯基、C 1-6烷基、C 1-6卤代烷基、C 2-6 烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、取代或未取代的5-14元杂芳基、-NR aC(O)NR b(CH 2) nR c、-C≡CR a、-NR aC(O)CR b＝CHR c、-C(O)NR a(CH 2) nR b、-C(O)OR a、-O(CH 2) nR a、-(CH 2) nS(O) mR a和-(CH 2) nP(O)R aR b；优选氢原子、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-12元杂环基、取代或未取代的5-14元杂芳基、-O(CH 2) nR a或-C(O)OR a；进一步优选如下取代基：氢原子、氟、氯、溴、三氟甲基、氰基、甲氧基、-C(O)OCH(CH 3) 2、
Figure PCTCN2020131472-appb-000003
Figure PCTCN2020131472-appb-000004
In a further preferred embodiment of the present invention, R 1 is selected from hydrogen atom, deuterium atom, halogen, cyano group, amino group, nitro group, hydroxyl group, azido group, C 1-6 carboxylic acid C 1-6 ester group, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl group, substituted or unsubstituted 5-14 membered heteroaryl group, -NR a C(O)NR b (CH 2 ) n R c , -C≡CR a , -NR a C(O)CR b =CHR c , -C(O)NR a (CH 2 ) n R b , -C(O)OR a , -O(CH 2 ) n R a , -( CH 2) n S (O) m R a , and - (CH 2) n P ( O) R a R b; preferably a hydrogen atom, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl , -O(CH 2 ) n R a or -C(O)OR a ; further preferably the following substituents: hydrogen atom, fluorine, chlorine, bromine, trifluoromethyl, cyano, methoxy, -C(O )OCH(CH 3 ) 2 ,
Figure PCTCN2020131472-appb-000003
Figure PCTCN2020131472-appb-000004
在本发明进一步优选的实施方式中，R a选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、取代或未取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1(CH 2) nR b1、-C(O)OR a1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-NR a1S(O) mR b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、-NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1；优选氢原子、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、取代或未取代的3-12元杂环基、5-14元杂芳基、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1或-O(CH 2) nR a1；进一步优选如下取代基：氢原子、甲氧基、-NHC(O)CH＝CH 2、
Figure PCTCN2020131472-appb-000005
Figure PCTCN2020131472-appb-000006
In a further preferred embodiment of the present invention, R a is selected from a hydrogen atom, a deuterium atom, a halogen, cyano, amino, nitro, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 Member heteroaryl, -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n NR c1 R d1 , -C(O)NR a1 (CH 2 ) n R b1 , -C(O )OR a1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P(O)R a1 R b1 , -NR a1 S(O) m R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -(CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -(CH 2 ) n S(O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 ; preferably a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, substituted or unsubstituted 3-12 Membered heterocyclic group, 5-14 membered heteroaryl, -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)C≡CR b1 ,- NR a1 C(O)CR b1 =CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n NR c1 R d1 or -O(CH 2 ) n R a1 ; further The following substituents are preferred: hydrogen atom, methoxy group, -NHC(O)CH=CH 2 ,
Figure PCTCN2020131472-appb-000005
Figure PCTCN2020131472-appb-000006
在本发明一种优选的实施方式中，R b选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)C≡CR b2、-NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2(CH 2) nR b2、-C(O)OR a2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或-(CH 2) nNR a2S(O) mR b2；优选氢原子、卤素、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-8环烷基、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mR a2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2或-C(O)NR a2(CH 2) nR b2；进一步优选如下取代基：氢原子、卤素、环丙基、-C(CH 3) 2(OH)、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3或 -C(O)NHCH 3。 In a preferred embodiment of the present invention, R b is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl , -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n R c2 , -NR a2 C(O)CR b2 =CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 (CH 2 ) n R b2 , -C(O)OR a2 , -O(CH 2 ) n R a2 , -(CH 2 ) n P(O)R a2 R b2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O)R a2 , -NR a2 C(O)OR b2 , -(CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O ) m R b2 ; preferably a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3 -8 cycloalkyl, -(CH 2 ) n P(O)R a2 R b2 , -(CH 2 ) n S(O) m R a2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 or -C(O)NR a2 (CH 2 ) n R b2 ; further preferably the following substituents: hydrogen atom, halogen, cyclopropyl, -C(CH 3 ) 2 ( OH), -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S(O) 2 NHCH 3 or -C(O) NHCH 3 .
在本发明一种优选的实施方式中，R b选自氢、氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C 1-3烷基、C 2-5烯基、C 2-5炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 3-6环烷基、3-10元杂环基、C 6-12芳基或5-12元杂芳基；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、氧代基、硫代基、甲基、乙基、丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、氘代甲基、氘代乙基、氘代丙基、氟甲基、氟乙基、氟丙基、氯甲基、氯乙基、氯丙基、溴甲基、溴乙基、溴丙基、羟甲基、羟乙基、羟丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、环丙基、环丁基、环戊基、环己基、环庚基、环氧丙基、环氧丁基、环氧戊基、环氧己基、环氧庚基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环庚基、噻吩基、吡咯基、吡啶基、吡喃基、哌嗪基、苯基或萘基。 In a preferred embodiment of the present invention, R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3- 6 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, Thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluorine Methyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy , Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, Azepanyl, azepanyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, or naphthyl.
在本发明进一步优选的实施方式中，R aa、R a、R b、R c、R a1、R b1、R c1、R d1、R a2、R b2、R c2或R d2各自独立地选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 1-6环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基任选地进一步被氘、卤素、氨基、氰基、C 1-4烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6卤代烷基、C 2-6烯基羰基、C 1-6羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-12元杂环基、取代或未取代的C 6-14芳基和取代或未取代的5-14元杂芳基取代。 In a further preferred embodiment of the present invention, R aa, R a, R b, R c, R a1, R b1, R c1, R d1, R a2, R b2, R c2 R d2, or are each independently selected from Hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cycloalkyl, 3 -12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group, the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3- 8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are optionally further substituted by deuterium, halogen, amino, cyano, C 1-4 alkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 2-6 alkenylcarbonyl, C 1-6 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, Substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-14 aryl group and substituted or unsubstituted 5-14 membered heteroaryl group.
在本发明进一步优选的实施方式中，提供一种式(II)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000007
Figure PCTCN2020131472-appb-000007
其中：among them:
R 2选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、叠氮基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a1C(O)R b1、-NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1(CH 2) nR b1、-C(O)OR a1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-NR a1S(O) mR b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、-NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1；优选-NR a1C(O)R b1、 -NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1；更优选-NHC(O)CH＝CH 2； R 2 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, azido, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -NR a1 C(O )R b1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n NR c1 R d1 , -C(O)NR a1 (CH 2 ) n R b1 , -C(O)OR a1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P(O)R a1 R b1 , -NR a1 S(O) m R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -( CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -(CH 2 ) n S(O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 ; Preferably -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n NR c1 R d1 ; more preferably -NHC(O)CH=CH 2 ;
R 3选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、--O(CH 2) nR a1、-NR a1(CH 2) nR b1或-NR a1(CH 2) nNR b1R c1，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被卤素、氰基、羟基、巯基、C 1-4烷基、C 1-4腈基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4羟烷基和取代或未取代的3-12元杂环基的一个或多个取代基所取代；优选取代的3-12元杂环基、-NR a1(CH 2) nR b1或-NR a1(CH 2) nNR b1R c1；更优选如下基团： R 3 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, --O(CH 2 ) n R a1 , -NR a1 (CH 2 ) n R b1 or -NR a1 (CH 2 ) n NR b1 R c1 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further Halogen, cyano, hydroxyl, mercapto, C 1-4 alkyl, C 1-4 nitrile, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and substituted or unsubstituted Is substituted by one or more substituents of the 3-12 membered heterocyclic group; preferably substituted 3-12 membered heterocyclic group, -NR a1 (CH 2 ) n R b1 or -NR a1 (CH 2 ) n NR b1 R c1 ; more preferably the following groups:
Figure PCTCN2020131472-appb-000008
Figure PCTCN2020131472-appb-000008
R 4选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子、甲基、甲氧基或乙氧基。 R 4 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably hydrogen Atom, methyl, methoxy or ethoxy.
在本发明进一步优选的实施方式中，提供一种式(III)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (III), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000009
Figure PCTCN2020131472-appb-000009
其中：among them:
R 5选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)C≡CR b2、-NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2(CH 2) nR b2、-C(O)OR a2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或-(CH 2) nNR a2S(O) mR b2；优选氢原子、卤素、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-8环烷基、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mR a2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2或-C(O)NR a2(CH 2) nR b2；进一步优选如下取代基：氢原子、-C(CH 3) 2(OH)、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3或-C(O)NHCH 3； R 5 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 =CH(CH 2 ) n R c2 , -NR a2 C( O)CR b2 = CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 (CH 2 ) n R b2 , -C(O)OR a2 , -O(CH 2 ) n R a2 ,- (CH 2 ) n P(O)R a2 R b2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O ) R a2 , -NR a2 C(O)OR b2 , -(CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O) m R b2 ; preferably hydrogen atom, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, -(CH 2 ) n P(O)R a2 R b2 , -(CH 2 ) n S(O) m R a2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 Or -C(O)NR a2 (CH 2 ) n R b2 ; further preferably the following substituents: hydrogen atom, -C(CH 3 ) 2 (OH), -P(O)(CH 3 ) 2 , -S( O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S(O) 2 NHCH 3 or -C(O)NHCH 3 ;
R 6和R 7各自独立地选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、 C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子或卤素； R 6 and R 7 are each independently selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably a hydrogen atom or halogen;
或者，R 6、R 7与它们所连的碳原子链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代；优选如下基团： Alternatively, R 6 and R 7 are linked with the carbon atom to which they are attached to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups are any The selected ones can be further substituted; the following groups are preferred:
Figure PCTCN2020131472-appb-000010
Figure PCTCN2020131472-appb-000010
R 8选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子或卤素。 R 8 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom or halogen.
在本发明进一步优选的实施方式中，提供一种式(IV)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000011
Figure PCTCN2020131472-appb-000011
在本发明进一步优选的实施方式中，提供一种式(V)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (V), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000012
Figure PCTCN2020131472-appb-000012
在本发明进一步优选的实施方式中，提供一种式(VI)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000013
Figure PCTCN2020131472-appb-000013
其中：among them:
R 9选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子、C 1-6烷基或C 3-8环烷基；更优选氢原子、甲基或环丙基。 R 9 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom, C 1-6 alkyl group Or a C 3-8 cycloalkyl group; more preferably a hydrogen atom, a methyl group or a cyclopropyl group.
在本发明进一步优选的实施方式中，通式(VI)进一步如通式(VI-A)所示：In a further preferred embodiment of the present invention, the general formula (VI) is further as shown in the general formula (VI-A):
Figure PCTCN2020131472-appb-000014
Figure PCTCN2020131472-appb-000014
R 9不为甲基。 R 9 is not a methyl group.
在本发明进一步优选的实施方式中，提供一种式(VII)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (VII), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020131472-appb-000015
Figure PCTCN2020131472-appb-000015
在本发明进一步优选的实施方式中，式(VII)化合物、其立体异构体或其药学上可接受盐，其中：In a further preferred embodiment of the present invention, the compound of formula (VII), its stereoisomer or pharmaceutically acceptable salt thereof, wherein:
M为N或CR 1； M is N or CR 1 ;
R 1选自氢、卤素、氰基、三氟甲基、氰基、甲氧基、乙氧基、-C(O)OCH(CH 3) 2、
Figure PCTCN2020131472-appb-000016
R 1 is selected from hydrogen, halogen, cyano, trifluoromethyl, cyano, methoxy, ethoxy, -C(O)OCH(CH 3 ) 2 ,
Figure PCTCN2020131472-appb-000016
环B选自
Figure PCTCN2020131472-appb-000017
Figure PCTCN2020131472-appb-000018
Ring B is selected from
Figure PCTCN2020131472-appb-000017
Figure PCTCN2020131472-appb-000018
R b选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、磷酰基、磺酰基、氨基磺酰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8 环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3、C 1-6烷基或C 3-8环烷基；更优选氢、甲基、-P(O)(CH 3) 2、-S(O) 2CH 3、或环丙基； R b is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, phosphoryl, sulfonyl, aminosulfonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; Preferably a hydrogen atom, -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S(O) 2 NHCH 3 , C 1-6 Alkyl group or C 3-8 cycloalkyl group; more preferably hydrogen, methyl, -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , or cyclopropyl;
y为1、2或3，优选1。y is 1, 2 or 3, preferably 1.
在本发明进一步优选的实施方式中，提供一种制备通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，包含以下步骤：In a further preferred embodiment of the present invention, a method for preparing the compound represented by general formula (VI) or its stereoisomer and pharmaceutically acceptable salt thereof is provided, which comprises the following steps:
Figure PCTCN2020131472-appb-000019
Figure PCTCN2020131472-appb-000019
通式(VI-1)与通式(VI-2)反应，得到通式(VI-3)，通式(VI-3)继续与通式(VI-4)反应，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；The general formula (VI-1) reacts with the general formula (VI-2) to obtain the general formula (VI-3), and the general formula (VI-3) continues to react with the general formula (VI-4) to obtain the general formula (VI) The indicated compound or its stereoisomers and pharmaceutically acceptable salts thereof;
其中：among them:
X 1和X 2各自独立选自卤素；优选氟、氯、溴或碘；更优选氯； X 1 and X 2 are each independently selected from halogen; preferably fluorine, chlorine, bromine or iodine; more preferably chlorine;
X 3选自卤素、硼酸或硼酸酯；优选硼酸酯；更优选
Figure PCTCN2020131472-appb-000020
X 3 is selected from halogen, boric acid or boric acid ester; preferably boric acid ester; more preferably
Figure PCTCN2020131472-appb-000020
本发明还提供了一种优选方案，还涉及一种药用组合物，其包括治疗有效剂量的所示的通式(I)化合物及其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which comprises a therapeutically effective dose of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, and a One or more pharmaceutically acceptable carriers, diluents or excipients.
本发明还提供了一种优选方案，还涉及所述的通式(I)化合物、及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备制备治疗激酶抑制剂中的应用。The present invention also provides a preferred solution, and also relates to the compound of general formula (I), and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of therapeutic kinase inhibitors Application in the agent.
本发明还提供了一种优选方案，还涉及所述的通式(I)化合物、及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备制备治疗受体酪氨酸激酶抑制剂(TKI)中的应用。The present invention also provides a preferred solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of therapeutic receptors. Application of tyrosine kinase inhibitor (TKI).
本发明还提供了一种优选方案，还涉及所述的通式(I)化合物、及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备制备治疗HER2抑制剂、EGFR抑制剂和EGFR单抗及其联用相关药物中的应用，更优选EGFR 20外显子插入突变和HER2 20外显子插入突变靶点的抑制剂。The present invention also provides a preferred solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the preparation of the pharmaceutical composition for the treatment of HER2 inhibition Inhibitors, EGFR inhibitors, EGFR monoclonal antibodies and related drugs in combination, more preferably inhibitors of EGFR exon 20 insertion mutations and HER2 exon 20 insertion mutation targets.
本发明还提供了一种优选方案，还涉及所述的通式(I)化合物及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治癌症相关疾病中的应用； 所述的药癌症优选治疗乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。The present invention also provides a preferred solution, and also relates to the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of the treatment of cancer-related diseases The application of the drug cancer is preferably the treatment of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumors, glioma, glioblastoma, leukemia, Lymphoma, myeloma and non-small cell lung cancer.
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗癌症相关疾病的方法。The present invention further relates to a method for preparing the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.
本发明还涉及治疗癌症相关疾病的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The present invention also relates to a method for treating cancer-related diseases, which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
在一些实施方案中，本方法涉及诸如癌症相关病症的治疗。In some embodiments, the method involves the treatment of disorders such as cancer.
本文提供的治疗方法包括向受试者施用治疗有效量的本发明的化合物。在一个实施方案中，本发明提供了治疗哺乳动物中包括癌症相关疾病症的方法。该方法包括向所述哺乳动物施用治疗有效量的本发明的化合物，或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods for treating diseases including cancer-related diseases in mammals. The method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
第三代EGFR抑制剂主要是针对EGFR激活突变体和T790M耐药性突变体抑制性高，本发明的化合物在EGFR和/或HER2 20外显子插入突变靶点方面较第三代EGFR抑制剂表现出以下优势：The third-generation EGFR inhibitors mainly target EGFR activating mutants and T790M drug-resistant mutants. The compounds of the present invention are more effective than the third-generation EGFR inhibitors in terms of EGFR and/or HER2 20 exon insertion mutation targets. Shows the following advantages:
1、提高在Ba/F3 EGFR突变细胞株增殖抑制活性，优选化合物高5倍以上；1. Improve the proliferation inhibitory activity in Ba/F3 EGFR mutant cell lines, preferably the compound is more than 5 times higher;
2、在大鼠和人的肝微粒体中代谢稳定性良好，具有一定优势；2. It has good metabolic stability in rat and human liver microsomes and has certain advantages;
3、在小鼠原B细胞Ba/F3 EGFR-D770-N771ins_SVD移植瘤模型上的体内药效肿瘤抑瘤率上表现出显著优势。3. It shows a significant advantage in the in vivo pharmacodynamic tumor suppression rate on the mouse original B cell Ba/F3 EGFR-D770-N771ins_SVD transplantation tumor model.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例 包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylic acid ester group, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" Refers to -(CH 2 ) 3 -, "Butylene" refers to -(CH 2 ) 4 -, etc. The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugation. Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2020131472-appb-000021
等；
Figure PCTCN2020131472-appb-000021
Wait;
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：It also includes a spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom. Non-limiting examples include:
Figure PCTCN2020131472-appb-000022
等。
Figure PCTCN2020131472-appb-000022
Wait.
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2020131472-appb-000023
等。
Figure PCTCN2020131472-appb-000023
Wait.
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020131472-appb-000024
Figure PCTCN2020131472-appb-000024
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子；进一步优选包含1-3氮原子的3-8元杂环基，任选地，被1-2个氧原子、硫原子、氧代基取代，包括含氮单环杂环基、含氮螺杂环基或 含氮稠杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms; further preferably contains 1-3 nitrogen atoms, 3-8 The membered heterocyclic group is optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.
单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选吡咯烷基、哌啶基和哌嗪基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably pyrrolidinyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) Heteroatoms of m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:
Figure PCTCN2020131472-appb-000025
Figure PCTCN2020131472-appb-000025
Figure PCTCN2020131472-appb-000026
等。
Figure PCTCN2020131472-appb-000026
Wait.
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2020131472-appb-000027
Figure PCTCN2020131472-appb-000028
Figure PCTCN2020131472-appb-000029
等。
Figure PCTCN2020131472-appb-000027
Figure PCTCN2020131472-appb-000028
Figure PCTCN2020131472-appb-000029
Wait.
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2020131472-appb-000030
Figure PCTCN2020131472-appb-000031
等。
Figure PCTCN2020131472-appb-000030
Figure PCTCN2020131472-appb-000031
Wait.
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:
Figure PCTCN2020131472-appb-000032
等。
Figure PCTCN2020131472-appb-000032
Wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并3-8元环烷基、苯并3-8元杂烷基，优选苯并3-6元环烷基、苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Member cycloalkyl, benzo 3-6 membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .
其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The ring connected to the parent structure is an aryl ring, and non-limiting examples include:
Figure PCTCN2020131472-appb-000033
Figure PCTCN2020131472-appb-000034
等。
Figure PCTCN2020131472-appb-000033
Figure PCTCN2020131472-appb-000034
Wait.
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、噻吩基、咪唑基、吡唑基、噁唑基、嘧啶基或噻唑基；更有选吡唑基和噁唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl and oxazolyl Azole. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2020131472-appb-000035
Figure PCTCN2020131472-appb-000036
等。
Figure PCTCN2020131472-appb-000035
Figure PCTCN2020131472-appb-000036
Wait.
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧 基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" refers to (CH≡C-), where the alkynyl group can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义如上所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基、丁烯基羰基。烯基羰基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. The alkenylcarbonyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“氨基”指-NH 2。 "Amino" refers to -NH 2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO 2 .
“羰基”指-C(O)-。"Carbonyl" refers to -C(O)-.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" refers to ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N,N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" refers to diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" means Otoharu.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et 2O”指乙醚。 "Et 2 O" means diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" refers to 1,2 dichloroethane.
“DIPEA”指N,N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。 "Pd 2 (dba) 3 "refers to tris(dibenzylideneacetone) dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamide.
“MeLi”指甲基锂。"MeLi" refers to methyl lithium.
“n-BuLi”指正丁基锂。"N-BuLi" refers to n-butyl lithium.
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。 "NaBH(OAc) 3 "means sodium triacetoxyborohydride.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
具体实施方式Detailed ways
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention.
实施例Example
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。The liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm～0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm～0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
实施例1Example 1
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) (Amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000037
Figure PCTCN2020131472-appb-000037
第一步：(6-((2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备Step 1: Preparation of (6-((2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000038
Figure PCTCN2020131472-appb-000038
将(6-氨基喹喔啉-5-基)二甲基氧化膦(300mg,1.36mmol)和2,4-二氯嘧啶(606mg,4.07mmol)溶于N,N-二甲基甲酰胺(10mL)，在-20℃下滴加1M六甲基二硅基胺基钾四氢呋喃溶液(4mL,4mmol)。滴加完毕后反应30分钟。将反应体系温度升至-10℃，继续反应2小时。加入氯化铵水溶液(5mL)淬灭反应，用二氯甲烷(20mL×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品用反相柱纯化(MeCN:H 2O(0.1％TFA)＝40％-50％)得到产物(6-((2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体1-1，120mg,产率：27％)。 (6-Aminoquinoxalin-5-yl)dimethylphosphine oxide (300mg, 1.36mmol) and 2,4-dichloropyrimidine (606mg, 4.07mmol) were dissolved in N,N-dimethylformamide ( 10mL), 1M potassium hexamethyldisilazide tetrahydrofuran solution (4mL, 4mmol) was added dropwise at -20°C. React for 30 minutes after the addition is complete. The temperature of the reaction system was raised to -10°C, and the reaction was continued for 2 hours. Was added aqueous ammonium chloride solution (5mL) The reaction was quenched and extracted with methylene chloride (20mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product purified by reverse phase column (MeCN: H 2 O (0.1 %TFA)=40%-50%) to obtain the product (6-((2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-1, 120mg, Yield: 27%).
MS m/z(ESI):334.1[M+H] +. MS m/z(ESI): 334.1[M+H] + .
第二步：(6-((2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The second step: (6-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Preparation of phosphine oxide
Figure PCTCN2020131472-appb-000039
Figure PCTCN2020131472-appb-000039
将对甲苯磺酸(132mg,0.76mmol)加入到4-氟-2-甲氧基-5-硝基苯胺(114mg,0.61mmol)和中间体1-1(170mg，0.51mmol)的2-戊醇(10ml)溶液中，反应液加热到100℃反应3小时。反应液冷却，蒸干，所得粗产物经硅胶柱分离(二氯甲烷:甲醇＝100:6)得到产物(6-((2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体1-2，130mg，产率：53％)。Add p-toluenesulfonic acid (132mg, 0.76mmol) to 4-fluoro-2-methoxy-5-nitroaniline (114mg, 0.61mmol) and intermediate 1-1 (170mg, 0.51mmol) of 2-pentanol In an alcohol (10ml) solution, the reaction solution was heated to 100°C for 3 hours. The reaction solution was cooled and evaporated to dryness. The crude product obtained was separated by silica gel column (dichloromethane:methanol=100:6) to obtain the product (6-((2-((4-fluoro-2-methoxy-5-nitro Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-2, 130 mg, yield: 53%).
MS m/z(ESI):484.1[M+H] +. MS m/z(ESI): 484.1[M+H] + .
第三步：(6-((2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦The third step: (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000040
Figure PCTCN2020131472-appb-000040
将碳酸钾(112mg,0.81mmol)加入到N,N,N'-三甲基乙二胺(33mg,0.32mmol)和中间体1-2(130mg,0.27mmol)的乙腈(10ml)溶液中，反应液加热到80℃反应2小时。反应液冷却，过滤得到产物(6-((2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体1-3，120mg，产率：79％)。Potassium carbonate (112mg, 0.81mmol) was added to the solution of N,N,N'-trimethylethylenediamine (33mg, 0.32mmol) and Intermediate 1-2 (130mg, 0.27mmol) in acetonitrile (10ml), The reaction solution was heated to 80°C for 2 hours. The reaction liquid was cooled and filtered to obtain the product (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl) Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-3, 120 mg, yield: 79%).
MS m/z(ESI):566.2[M+H] +. MS m/z(ESI): 566.2[M+H] + .
第四步：N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺的制备The fourth step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline- Preparation of 6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000041
Figure PCTCN2020131472-appb-000041
将中间体1-3(130mg，0.23mol)溶于乙醇(10mL)，加入氯化铵水溶液(3mL)和铁粉(128mg,2.3mmol)，反应液在80℃下反应2小时。反应液过滤，有机相加入二氯甲烷(30ml)，水洗(15ml*2)，固体用二氯甲烷(30ml)洗涤，有机相合并，无水硫酸钠干燥，蒸干。残余物溶于四氢呋喃(3mL)，冷却至0℃，加入三乙胺(25mg,0.24mmol)，再加入3-氯丙酰氯(28mg,0.22mmol)，反应在0℃下搅拌1小时。加入3M氢氧化钠溶液(1mL)，反应在室温下搅拌1小时。加入水(10mL)，用二氯甲烷(10mL×2)萃取，有机相用无水硫酸钠干燥，过滤，旋干，粗品用硅胶制备板纯化(二氯甲烷/MeOH：20/1)得到N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯基)丙烯酰基酰胺(化合物1，4.1mg，产率：3％)。Intermediate 1-3 (130 mg, 0.23 mol) was dissolved in ethanol (10 mL), ammonium chloride aqueous solution (3 mL) and iron powder (128 mg, 2.3 mmol) were added, and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was filtered, the organic phase was added with dichloromethane (30ml), washed with water (15ml*2), the solid was washed with dichloromethane (30ml), the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in tetrahydrofuran (3mL), cooled to 0°C, triethylamine (25mg, 0.24mmol) was added, and 3-chloropropionyl chloride (28mg, 0.22mmol) was added, and the reaction was stirred at 0°C for 1 hour. 3M sodium hydroxide solution (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. Water (10mL) was added, extracted with dichloromethane (10mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified with a silica gel preparation plate (dichloromethane/MeOH: 20/1) to obtain N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino) Pyrimidine-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 1, 4.1 mg, yield: 3%).
MS m/z(ESI):590.4[M+H] +. MS m/z(ESI): 590.4[M+H] + .
实施例2Example 2
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000042
Figure PCTCN2020131472-appb-000042
第一步：(6-((4-氯-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The first step: Preparation of (6-((4-chloro-1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000043
Figure PCTCN2020131472-appb-000043
将(6-氨基喹喔啉-5-基)二甲基氧化膦(200mg,0.9mmol)溶于N,N-二甲基甲酰胺(10mL)，加入N,N-二异丙基乙基胺(1.2g,9mmol)和2,4-二氯-1,3,5-三嗪(407mg,2.7mmol)，反应液在80℃下反应3小时。反应液倒入水中(30mL)，加入二氯甲烷(20mL×2)萃取。有机相用无水硫酸钠干燥，蒸干，得到粗品，并用硅胶柱层析分离(二氯甲烷:甲醇＝100:7)得到产物(6-((4-氯-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体2-1，200mg,产率：68％)。Dissolve (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (200mg, 0.9mmol) in N,N-dimethylformamide (10mL), add N,N-diisopropylethyl Amine (1.2g, 9mmol) and 2,4-dichloro-1,3,5-triazine (407mg, 2.7mmol), the reaction solution was reacted at 80°C for 3 hours. The reaction solution was poured into water (30 mL), and dichloromethane (20 mL×2) was added for extraction. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain the crude product, which was separated by silica gel column chromatography (dichloromethane:methanol=100:7) to obtain the product (6-((4-chloro-1,3,5-tri Azin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 2-1, 200 mg, yield: 68%).
MS m/z(ESI):335.1[M+H] +. MS m/z(ESI): 335.1[M+H] + .
第二到四步：N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Steps two to four: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxa (Amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide
第2-4步参照实施例1的第2-4步。Steps 2-4 refer to steps 2-4 of Example 1.
MS m/z(ESI):591.3[M+H] +. MS m/z(ESI): 591.3[M+H] + .
1H NMR(400MHz,Chloroform-d)δ12.91(s,1H),10.10(s,1H),9.43(br s,2H),8.70(d,J＝11.5Hz,2H),8.56(s,1H),8.12(br s,1H),7.56(s,1H),6.86-6.71(m,1H),6.40(br s,2H),5.77-5.63(m,1H),3.86(s,3H),2.93-2.91(m,2H),2.72(s,3H),2.40-2.31(m,8H),2.12(s,3H),2.09(s,3H).1H NMR (400MHz, Chloroform-d) δ 12.91 (s, 1H), 10.10 (s, 1H), 9.43 (br s, 2H), 8.70 (d, J = 11.5 Hz, 2H), 8.56 (s, 1H) ), 8.12 (br s, 1H), 7.56 (s, 1H), 6.86-6.71 (m, 1H), 6.40 (br s, 2H), 5.77-5.63 (m, 1H), 3.86 (s, 3H), 2.93-2.91 (m, 2H), 2.72 (s, 3H), 2.40-2.31 (m, 8H), 2.12 (s, 3H), 2.09 (s, 3H).
实施例3Example 3
N-(5-((5-氯-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000044
Figure PCTCN2020131472-appb-000044
实施例3的制备方法参照实施例1。For the preparation method of Example 3, refer to Example 1.
MS m/z(ESI):624.4[M+H] +. MS m/z(ESI): 624.4[M+H] + .
实施例4Example 4
N-(5-((5-溴-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000045
Figure PCTCN2020131472-appb-000045
实施例4的制备方法参照实施例1。For the preparation method of Example 4, refer to Example 1.
MS m/z(ESI):668.2[M+H] +. MS m/z(ESI): 668.2[M+H] + .
实施例5Example 5
N-(5-((5-氰基-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2- (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000046
Figure PCTCN2020131472-appb-000046
第一步：(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The first step: Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000047
Figure PCTCN2020131472-appb-000047
将(6-氨基喹喔啉-5-基)二甲基氧化膦(200mg,0.9mmol)和5-溴-2,4-二氯嘧啶(618mg,2.7mmol)溶于N,N-二甲基甲酰胺(2mL)。在-20℃条件下滴加1.3M双三甲基硅基胺基锂四氢呋喃溶液(2mL,2.6mmol)，并反应30分钟。将温度升至-10℃，继续反应2小时。加入饱和氯化铵水溶液淬灭反应，加入水(10mL)，用二氯甲烷(10mL)萃取两次。有机相干燥后旋干，用从层析柱(二氯甲烷：甲醇＝20：1)纯化得到产物(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(200mg,产率：54％)。Dissolve (6-aminoquinoxalin-5-yl) dimethyl phosphine oxide (200mg, 0.9mmol) and 5-bromo-2,4-dichloropyrimidine (618mg, 2.7mmol) in N,N-dimethyl Carboxamide (2 mL). A 1.3M lithium bistrimethylsilylamide tetrahydrofuran solution (2mL, 2.6mmol) was added dropwise at -20°C and reacted for 30 minutes. The temperature was raised to -10°C, and the reaction was continued for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution, water (10 mL) was added, and extraction was performed twice with dichloromethane (10 mL). The organic phase is dried and spin-dried, and purified with a chromatography column (dichloromethane: methanol = 20:1) to obtain the product (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxaline- 5-yl) dimethyl phosphine oxide (200 mg, yield: 54%).
MS m/z(ESI):412.0[M+H] + MS m/z(ESI): 412.0[M+H] +
第二步：(6-((5-溴-2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The second step: (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxaline-5- (Base) Preparation of dimethyl phosphine oxide
Figure PCTCN2020131472-appb-000048
Figure PCTCN2020131472-appb-000048
将(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(200mg,0.48mmol)溶于2-戊醇，加入4-氟-2-甲氧基-5-硝基苯胺(95mg,0.51mmol)和对甲苯磺酸(88mg,051mmol)，在100℃下反应16小时。待反应冷却至室温，有固体析出，过滤后滤饼用2-戊醇和石油醚洗涤得到产物(6-((5-溴-2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(280mg,产率：100％)。(6-((5-Bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (200mg, 0.48mmol) was dissolved in 2-pentanol, and 4- Fluoro-2-methoxy-5-nitroaniline (95mg, 0.51mmol) and p-toluenesulfonic acid (88mg, 051mmol) were reacted at 100°C for 16 hours. After the reaction was cooled to room temperature, a solid precipitated out. After filtration, the filter cake was washed with 2-pentanol and petroleum ether to obtain the product (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitro (Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (280 mg, yield: 100%).
MS m/z(ESI):562.0[M+H] + MS m/z(ESI): 562.0[M+H] +
第三步：(6-((5-溴-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The third step: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000049
Figure PCTCN2020131472-appb-000049
第三步参照实施例1的第三步The third step refers to the third step of Example 1
MS m/z(ESI):644.2[M+H] + MS m/z(ESI): 644.2[M+H] +
第四步：(6-((5-溴-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The fourth step: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000050
Figure PCTCN2020131472-appb-000050
将(6-((5-溴-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(100mg,0.16mmol)溶于N,N-二甲基乙酰胺(2mL)，依次加入氰化锌(19mg,0.16mmol)，三(二亚苄基丙酮)二钯(29mg,0.032mmol)，2-二环己基磷-2,4,6-三异丙基联苯(31mg,0.064mmol)和锌粉(10mg,0.16mmol)。置换氮气后，微波95℃条件下反应1.5小时。过滤后加入水(10mL)，用二氯甲烷(10mL)萃取两次。有机相干燥后旋干，用pre-TLC(二氯甲烷：甲醇＝20：1)纯化得到产物(6-((5-溴-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(70mg，产率：76％)。Add (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (100mg, 0.16mmol) was dissolved in N,N-dimethylacetamide (2mL), and zinc cyanide (19mg, 0.16mmol), tris(dibenzylideneacetone)dipalladium (29mg, 0.032mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (31mg, 0.064mmol) and zinc powder ( 10mg, 0.16mmol). After replacing the nitrogen, the reaction was carried out under microwave conditions at 95°C for 1.5 hours. After filtration, water (10 mL) was added, and extraction was performed twice with dichloromethane (10 mL). The organic phase is dried and spin-dried, purified with pre-TLC (dichloromethane: methanol = 20:1) to obtain the product (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl) (Methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (70mg, yield : 76%).
MS m/z(ESI):591.2[M+H] + MS m/z(ESI): 591.2[M+H] +
第五步：N-(5-((5-氰基-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙烯酰基酰胺的制备Step 5: N-(5-((5-cyano-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000051
Figure PCTCN2020131472-appb-000051
第五步参见实施例1第四步。For the fifth step, refer to the fourth step of Example 1.
MS m/z(ESI):615.1[M+H] +. MS m/z(ESI): 615.1[M+H] + .
1H NMR(400MHz,Chloroform-d)δ13.30(s,1H),10.26-9.90(m,1H)9.22–8.99(m,2H),8.71(d,J＝14.2Hz,2H),8.46(s,1H),8.00(s,1H),7.55(s,1H),6.74(s,1H),6.23–5.94(m,2H),5.57–5.43(m,1H),3.87(s,3H),3.39–2.79(m,7H),2.74(s,3H),2.49–2.29(m,3H),2.14(s,3H),2.11(s,3H). 1 H NMR (400MHz, Chloroform-d) δ 13.30 (s, 1H), 10.26-9.90 (m, 1H) 9.22-8.99 (m, 2H), 8.71 (d, J = 14.2 Hz, 2H), 8.46 ( s, 1H), 8.00 (s, 1H), 7.55 (s, 1H), 6.74 (s, 1H), 6.23-5.94 (m, 2H), 5.57-5.43 (m, 1H), 3.87 (s, 3H) , 3.39-2.79 (m, 7H), 2.74 (s, 3H), 2.49-2.29 (m, 3H), 2.14 (s, 3H), 2.11 (s, 3H).
实施例6Example 6
2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-5-羧酸异丙酯2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-((5-( Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-5-isopropyl carboxylate
Figure PCTCN2020131472-appb-000052
Figure PCTCN2020131472-appb-000052
实施例6的制备方法参照实施例1。Refer to Example 1 for the preparation method of Example 6.
MS m/z(ESI):676.3[M+H] +. MS m/z(ESI): 676.3[M+H] + .
实施例7Example 7
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000053
Figure PCTCN2020131472-appb-000053
Figure PCTCN2020131472-appb-000054
Figure PCTCN2020131472-appb-000054
第一到三步：(6-((5-溴-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备Steps one to three: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide
Figure PCTCN2020131472-appb-000055
Figure PCTCN2020131472-appb-000055
第1-3步参照实施例1的第1-3步。Steps 1-3 refer to steps 1-3 of Example 1.
MS m/z(ESI):644.3[M+H] +. MS m/z(ESI):644.3[M+H] + .
第四步：(6-((2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦的制备The fourth step: (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Preparation of -5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020131472-appb-000056
Figure PCTCN2020131472-appb-000056
氮气保护下，将中间体7-3(200mg，0.3mmol)、1-甲基-4-吡唑硼酸频哪醇酯(127mg，0.36mmol)、无水碳酸钾(124mg，0.90mmol)及四(三苯基膦)钯(30mg)溶解于二氧六环(3mL)中，100℃反应过夜。反应液减压浓缩，粗品经柱分离(二氯甲烷：甲醇：浓氨水＝99:1:0.1到94:6:0.6梯度洗脱)得到(6-((2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体7-4，103mg，产率：51％)。Under nitrogen protection, Intermediate 7-3 (200mg, 0.3mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (127mg, 0.36mmol), anhydrous potassium carbonate (124mg, 0.90mmol) and tetrakis (Triphenylphosphine)palladium (30 mg) was dissolved in dioxane (3 mL) and reacted at 100°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column (dichloromethane: methanol: concentrated ammonia water = 99:1:0.1 to 94:6:0.6 gradient elution) to obtain (6-((2-((4-((2 -(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl) Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 7-4, 103 mg, yield: 51%).
MS m/z(ESI):646.2[M+H] +. MS m/z(ESI):646.2[M+H] + .
第五步：N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺的 制备The fifth step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline- 6-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000057
Figure PCTCN2020131472-appb-000057
第5步参照实施例1的第4步。Step 5 Refer to Step 4 of Example 1.
MS m/z(ESI):670.0[M+H] +. MS m/z(ESI): 670.0[M+H] + .
实施例8Example 8
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-(噁唑-2-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-(oxazol-2-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000058
Figure PCTCN2020131472-appb-000058
实施例8的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 8.
MS m/z(ESI):657.3[M+H] +. MS m/z(ESI): 657.3[M+H] + .
实施例9Example 9
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-(吡啶-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-(pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000059
Figure PCTCN2020131472-appb-000059
实施例9的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 9.
MS m/z(ESI):667.5[M+H] +. MS m/z(ESI): 667.5[M+H] + .
实施例10Example 10
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨 基)-5-(四氢-2H-吡喃-4-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000060
Figure PCTCN2020131472-appb-000060
实施例10的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 10.
MS m/z(ESI):674.2[M+H] +. MS m/z(ESI): 674.2[M+H] + .
实施例11Example 11
N-(5-((5-环丙基-4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyclopropyl-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2 -(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000061
Figure PCTCN2020131472-appb-000061
实施例11的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 11.
MS m/z(ESI):630.3[M+H] +. MS m/z(ESI): 630.3[M+H] + .
实施例12Example 12
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-甲氧基嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-methoxypyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000062
Figure PCTCN2020131472-appb-000062
实施例12的制备方法参照实施例1。For the preparation method of Example 12, refer to Example 1.
MS m/z(ESI):620.1[M+H] +. MS m/z(ESI): 620.1[M+H] + .
实施例13Example 13
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-氟嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000063
Figure PCTCN2020131472-appb-000063
实施例13的制备方法参照实施例1。Refer to Example 1 for the preparation method of Example 13.
MS m/z(ESI):608.2[M+H] +. MS m/z(ESI): 608.2[M+H] + .
实施例14Example 14
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)喹喔啉-6-基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl) Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000064
Figure PCTCN2020131472-appb-000064
实施例14的制备方法参照实施例1。Refer to Example 1 for the preparation method of Example 14.
MS m/z(ESI):658.4[M+H] +. MS m/z(ESI): 658.4[M+H] + .
实施例15Example 15
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzene And [b][1,4]dioxin-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000065
Figure PCTCN2020131472-appb-000065
Figure PCTCN2020131472-appb-000066
Figure PCTCN2020131472-appb-000066
第一步：(6-((4-氯-1,3,5-三嗪-2-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基氧化膦的制备The first step: (6-((4-chloro-1,3,5-triazin-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5 -Base) dimethyl phosphine oxide preparation
Figure PCTCN2020131472-appb-000067
Figure PCTCN2020131472-appb-000067
将(6-((4-氯-1,3,5-三嗪-2-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基氧化膦(200mg,0.88mmol)和N,N-二异丙基乙基胺(1.1g,8.8mmol)溶于N,N-二甲基甲酰胺(10mL)，在冰浴下加入2,4-二氯-1,3,5-三嗪(396mg,2.6mmol)，并在室温下反应2小时。反应液倒入水中(30mL)，加入二氯甲烷(20mL×2)萃取。有机相用无水硫酸钠干燥，蒸干，得到粗品，并用柱层析分离(二氯甲烷:甲醇＝100:7)得到产物(6-((4-氯-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基氧化膦(中间体15-1，200mg,产率：67％)。Add (6-((4-chloro-1,3,5-triazin-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Dimethyl phosphine oxide (200mg, 0.88mmol) and N,N-diisopropylethylamine (1.1g, 8.8mmol) were dissolved in N,N-dimethylformamide (10mL) and added under ice bath 2,4-Dichloro-1,3,5-triazine (396 mg, 2.6 mmol), and react at room temperature for 2 hours. The reaction solution was poured into water (30 mL), and dichloromethane (20 mL×2) was added for extraction. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain the crude product, which was separated by column chromatography (dichloromethane:methanol=100:7) to obtain the product (6-((4-chloro-1,3,5-triazine) -2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 15-1, 200 mg, yield: 67%).
MS m/z(ESI):341.1[M+H] +. MS m/z(ESI): 341.1[M+H] + .
第二到四步：N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Steps two to four: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)-2 ,3-Dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl) Preparation of acrylamide
第2-4步参照实施例1的第2-4步。Steps 2-4 refer to steps 2-4 of Example 1.
MS m/z(ESI):597.4[M+H] +. MS m/z(ESI): 597.4[M+H] + .
1H NMR(400MHz,Chloroform-d)δ11.75(s,1H),10.10(s,1H),9.32(s,1H),8.43(s,1H),8.31-8.17(m,1H),7.43(s,1H),6.95(s,1H),6.82-6.68(m,1H),6.49 -6.29(m,2H),5.74-5.60(m,1H),4.25(d,J＝17.7Hz,4H),3.84(s,3H),2.90-2.88(m,2H),2.69(s,3H),2.35-2.30(m,8H),1.87(s,3H),1.84(s,3H). 1 H NMR (400MHz, Chloroform-d) δ 11.75 (s, 1H), 10.10 (s, 1H), 9.32 (s, 1H), 8.43 (s, 1H), 8.31-8.17 (m, 1H), 7.43 (s,1H),6.95(s,1H),6.82-6.68(m,1H),6.49 -6.29(m,2H),5.74-5.60(m,1H),4.25(d,J=17.7Hz,4H ), 3.84 (s, 3H), 2.90-2.88 (m, 2H), 2.69 (s, 3H), 2.35-2.30 (m, 8H), 1.87 (s, 3H), 1.84 (s, 3H).
实施例16Example 16
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((5-(二甲基磷酰基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)-[1,2,4] Triazolo[1,5-a]pyridin-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000068
Figure PCTCN2020131472-appb-000068
实施例16的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 16.
MS m/z(ESI):580.5[M+H]+.MS m/z(ESI): 580.5[M+H]+.
实施例17Example 17
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((8-(二甲基磷酰基)-[1,2,4]三唑并[1,5-a]吡啶-7-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((8-(dimethylphosphoryl)-[1,2,4] Triazolo[1,5-a]pyridin-7-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000069
Figure PCTCN2020131472-appb-000069
实施例17的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 17.
MS m/z(ESI):580.4[M+H] +. MS m/z(ESI): 580.4[M+H] + .
实施例18Example 18
N-(2-(4-(3-(氰基甲基)吖丁啶-1-基)哌啶-1-基)-5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺N-(2-(4-(3-(cyanomethyl)azetidin-1-yl)piperidin-1-yl)-5-((4-((5-(dimethylphosphoryl) -2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxybenzene Base) acrylamide
Figure PCTCN2020131472-appb-000070
Figure PCTCN2020131472-appb-000070
实施例18的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 18.
MS m/z(ESI):674.1[M+H] +. MS m/z(ESI): 674.1[M+H] + .
实施例19Example 19
N-(5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基-2-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)苯基)丙烯酰胺N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1, 3,5-triazin-2-yl)amino)-4-methoxy-2-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl) Phenyl) acrylamide
Figure PCTCN2020131472-appb-000071
Figure PCTCN2020131472-appb-000071
实施例19的制备方法参照实施例15。For the preparation method of Example 19, refer to Example 15.
MS m/z(ESI):679.3[M+H] +. MS m/z(ESI): 679.3[M+H] + .
实施例20Example 20
N-(5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基-2-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)苯基)丙烯酰胺N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1, 3,5-triazin-2-yl)amino)-4-methoxy-2-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)phenyl)propene Amide
Figure PCTCN2020131472-appb-000072
Figure PCTCN2020131472-appb-000072
实施例20的制备方法参照实施例15。For the preparation method of Example 20, refer to Example 15.
MS m/z(ESI):679.4[M+H] +. MS m/z(ESI): 679.4[M+H] + .
实施例21Example 21
N-(5-((5-氯-4-((5-(甲基磺酰基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-chloro-4-((5-(methylsulfonyl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-(二(Methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000073
Figure PCTCN2020131472-appb-000073
实施例21的制备方法参照实施例1。Refer to Example 1 for the preparation method of Example 21.
MS m/z(ESI):626.1[M+H] +. MS m/z(ESI): 626.1[M+H] + .
实施例22Example 22
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((5-((1-甲基乙基)磺酰胺基)-2,3-二氢苯并[b][1,4]二噁英-6-基))氨基)-1,3,5-三嗪-2-基)氨基)-苯基)丙烯酰胺N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-((5-((1-methylethyl) Sulfonamide)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl))amino)-1,3,5-triazin-2-yl)amino)-benzene Base) acrylamide
Figure PCTCN2020131472-appb-000074
Figure PCTCN2020131472-appb-000074
实施例22的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 22.
MS m/z(ESI):642.0[M+H] +. MS m/z(ESI):642.0[M+H] + .
实施例23Example 23
N-(5-((5-氰基-4-((5-(N-甲基氨基磺酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基((1-甲基吡咯烷-2-基)甲基)氨基)苯基)丙烯酰胺N-(5-((5-cyano-4-((5-(N-methylaminosulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-6- (Yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide
Figure PCTCN2020131472-appb-000075
Figure PCTCN2020131472-appb-000075
实施例23的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 23.
MS m/z(ESI):664.3[M+H] +. MS m/z(ESI): 664.3[M+H] + .
实施例24Example 24
2-((2-((5-丙烯酰胺基-2-甲氧基-4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)-5-(噁唑-2-基)嘧啶-4-基)氨基)-N-甲基苯甲酰胺2-((2-((5-acrylamido-2-methoxy-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H) -Yl)phenyl)amino)-5-(oxazol-2-yl)pyrimidin-4-yl)amino)-N-methylbenzamide
Figure PCTCN2020131472-appb-000076
Figure PCTCN2020131472-appb-000076
实施例24的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 24.
MS m/z(ESI):610.4[M+H] +. MS m/z(ESI): 610.4[M+H] + .
实施例25Example 25
N-(5-((4-((4-氯-5-氟-2-(2-羟基丙烷-2-基)苯基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((4-((4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)-5-(1-methyl-1H-pyrazole- 4-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000077
Figure PCTCN2020131472-appb-000077
实施例25的制备方法参照实施例7。Refer to Example 7 for the preparation method of Example 25.
MS m/z(ESI):652.5[M+H] +. MS m/z(ESI): 652.5[M+H] + .
实施例26Example 26
N-(5-((4-(1-环丙基-1H-吲哚-3-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(二(Methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000078
Figure PCTCN2020131472-appb-000078
方法一：method one:
Figure PCTCN2020131472-appb-000079
Figure PCTCN2020131472-appb-000079
第一步：(3-(4-氯-1,3,5-三嗪-2-基)-1-环丙基-1H-吲哚的制备The first step: Preparation of (3-(4-chloro-1,3,5-triazin-2-yl)-1-cyclopropyl-1H-indole
Figure PCTCN2020131472-appb-000080
Figure PCTCN2020131472-appb-000080
将2,4-二氯嘧啶-1,3,5-三嗪(1.80g,12mmol)溶于二氯乙烷(20mL)，冷却至0℃，加入三氯化铁(3.9g,24mmol)，反应在室温下搅拌半小时，加入1-环丙基-1H-吲哚(1.57g,10mmol)，反应在室温下搅拌16小时。加入水(30mL)，过滤，滤液用二氯甲烷(20mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，旋干，粗品用柱层析分离(石油醚/乙酸乙酯：100/1～3/1)纯化得到(3-(4-氯-1,3,5-三嗪-2-基)-1-环丙基-1H-吲哚(中间体26-1，1.32g产率：49％)，为褐色固体。Dissolve 2,4-dichloropyrimidine-1,3,5-triazine (1.80g, 12mmol) in dichloroethane (20mL), cool to 0°C, add ferric chloride (3.9g, 24mmol), The reaction was stirred at room temperature for half an hour, 1-cyclopropyl-1H-indole (1.57 g, 10 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Water (30mL) was added, filtered, the filtrate was extracted with dichloromethane (20mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate: 100/1～3/1) purified to obtain (3-(4-chloro-1,3,5-triazin-2-yl)-1-cyclopropyl-1H-indole (intermediate 26-1, 1.32 g Yield: 49%), brown solid.
MS m/z(ESI):271.1[M+H] +. MS m/z(ESI): 271.1[M+H] + .
第二到四步：N-(5-((4-(1-环丙基-1H-吲哚-3-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Steps two to four: N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
第2-4步参照实施例1的第2-4步。Steps 2-4 refer to steps 2-4 of Example 1.
MS m/z(ESI):527.1[M+H] +. MS m/z(ESI): 527.1[M+H] + .
方法二：Method Two:
Figure PCTCN2020131472-appb-000081
Figure PCTCN2020131472-appb-000081
第一步：1-环丙基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吲哚的制备Step 1: Preparation of 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
Figure PCTCN2020131472-appb-000082
Figure PCTCN2020131472-appb-000082
将三氯化铝(1.53g,11.5mmol)加入到二氯甲烷(27mL)中，依次加入2,6-二甲基吡啶(1mL)和1M三氯化硼(6.7mL,6.7mmol)二氯甲烷溶液。反应30分钟后，加入环丙基吲哚(1g,6.36mmol)。继续反应2小时，在冰浴下，将溶于三乙胺(16.8mL)的频哪醇(1.65g,14mmol)滴加到反应体系中。待滴加完毕，在室温下反应2小时。加入冰水(40mL)淬灭反应，用二氯甲烷(40mL×3)萃取。有机相干燥后旋干，用层析柱(石油醚)纯化得到产物1-环丙基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吲哚(1g,产率：56％)。Add aluminum trichloride (1.53g, 11.5mmol) to dichloromethane (27mL), add 2,6-lutidine (1mL) and 1M boron trichloride (6.7mL, 6.7mmol) in turn Methane solution. After reacting for 30 minutes, cyclopropylindole (1 g, 6.36 mmol) was added. The reaction was continued for 2 hours, and pinacol (1.65 g, 14 mmol) dissolved in triethylamine (16.8 mL) was added dropwise to the reaction system under an ice bath. After the addition is complete, react at room temperature for 2 hours. The reaction was quenched by adding ice water (40 mL), and extracted with dichloromethane (40 mL×3). The organic phase is dried and spin-dried, and purified with a chromatography column (petroleum ether) to obtain the product 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-indole (1 g, yield: 56%).
MS m/z(ESI):284.2[M+H] + MS m/z(ESI): 284.2[M+H] +
第二步：4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的制备Step 2: Preparation of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine
Figure PCTCN2020131472-appb-000083
Figure PCTCN2020131472-appb-000083
将2,4-二氯-1,3,5-三嗪(600mg,4mmol)溶于N,N-二甲基甲酰胺(10mL)，在冰浴下加入N,N-二异丙基乙胺(1g,8mmol)和4-氟-2-甲氧基-5-硝基苯胺(820 mg,4.4mmol)，在室温下反应3小时。将反应液倒入水(30mL)中，过滤得到固体，用乙酸乙酯洗涤得到产物4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(600mg,产率：50％)。Dissolve 2,4-dichloro-1,3,5-triazine (600mg, 4mmol) in N,N-dimethylformamide (10mL), and add N,N-diisopropylethyl in an ice bath Amine (1 g, 8 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (820 mg, 4.4 mmol) were reacted at room temperature for 3 hours. The reaction solution was poured into water (30 mL), filtered to obtain a solid, and washed with ethyl acetate to obtain the product 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3 , 5-Triazine-2-amine (600 mg, yield: 50%).
MS m/z(ESI):300.2[M+H] + MS m/z(ESI): 300.2[M+H] +
第三步：4-(1-环丙基-1H-吲哚-3-基)-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的制备The third step: 4-(1-cyclopropyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5- Preparation of triazine-2-amine
Figure PCTCN2020131472-appb-000084
Figure PCTCN2020131472-appb-000084
将4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(150mg,0.5mmol)溶于1,4-二氧六环(12mL)和水(4mL)，加入1-环丙基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吲哚(142mg,0.5mmol)，四三苯基膦(58mg,0.05mmol)和碳酸钠(106mg,1mmol)。置换氮气后，在100℃下反应16小时。过滤后，加入二氯甲烷(20mL)萃取，有机相干燥后旋干，以层析柱(二氯甲烷：甲醇＝10：1)纯化得到产物4-(1-环丙基-1H-吲哚-3-基)-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(100mg,产率：48％)。Dissolve 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine (150mg, 0.5mmol) in 1,4- Dioxane (12mL) and water (4mL), add 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-indole (142 mg, 0.5 mmol), tetratriphenylphosphine (58 mg, 0.05 mmol) and sodium carbonate (106 mg, 1 mmol). After replacing the nitrogen, the reaction was carried out at 100°C for 16 hours. After filtration, dichloromethane (20mL) was added for extraction, the organic phase was dried and spin-dried, and purified with a chromatography column (dichloromethane: methanol = 10:1) to obtain the product 4-(1-cyclopropyl-1H-indole) -3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine (100 mg, yield: 48%).
MS m/z(ESI):421.2[M+H] + MS m/z(ESI): 421.2[M+H] +
第四到五步：N-(5-((4-(1-环丙基-1H-吲哚-3-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Steps 4 to 5: N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000085
Figure PCTCN2020131472-appb-000085
第4-5步参照实施例1的第3-4步。Steps 4-5 refer to Steps 3-4 of Example 1.
MS m/z(ESI):527.1[M+H] +. MS m/z(ESI): 527.1[M+H] + .
1H NMR(400MHz,Chloroform-d)δ12.56(s,1H),10.29–10.03(m,1H),9.84(s,1H),9.57–9.30(m,1H),9.05–8.84(m,1H),8.72(s,1H),8.67–8.56(m,1H),7.71(s,1H),7.63–7.61(m,1H),7.31–7.28(m,1H),6.80–6.70(m,1H),6.51(d,J＝16.6Hz,1H),5.74(d,J＝10.5Hz,1H),3.90(s,3H),3.51–3.44(m,1H),3.41–3.03(m,3H),2.95–2.60(m,7H),2.43–2.18(m,3H),1.25–1.10(m,4H). 1 H NMR (400MHz, Chloroform-d) δ 12.56 (s, 1H), 10.29-10.03 (m, 1H), 9.84 (s, 1H), 9.57-9.30 (m, 1H), 9.05-8.84 (m, 1H), 8.72(s,1H), 8.67-8.56(m,1H), 7.71(s,1H), 7.63-7.61(m,1H), 7.31-7.28(m,1H), 6.80-6.70(m, 1H), 6.51 (d, J = 16.6 Hz, 1H), 5.74 (d, J = 10.5 Hz, 1H), 3.90 (s, 3H), 3.51–3.44 (m, 1H), 3.41–3.03 (m, 3H) ), 2.95-2.60 (m, 7H), 2.43--2.18 (m, 3H), 1.25-1.10 (m, 4H).
实施例27Example 27
N-(5-((4-(1-环丙基-1H-吲哚-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基-2-(甲基((1-甲基吡咯烷-2-基)甲基)氨基)苯基)丙烯酰胺N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2- (Methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide
Figure PCTCN2020131472-appb-000086
Figure PCTCN2020131472-appb-000086
实施例27的制备方法参照实施例26。Refer to Example 26 for the preparation method of Example 27.
MS m/z(ESI):553.3[M+H] +. MS m/z(ESI): 553.3[M+H] + .
实施例28Example 28
N-(5-((4-((5-(二甲基磷酰基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基-2-(甲基((1-甲基吡咯烷-2-基)甲基)氨基)苯基)丙烯酰胺N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1, 3,5-Triazin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide
Figure PCTCN2020131472-appb-000087
Figure PCTCN2020131472-appb-000087
实施例28的制备方法参照实施例15。Refer to Example 15 for the preparation method of Example 28.
MS m/z(ESI):623.2[M+H] +. MS m/z(ESI): 623.2[M+H] + .
1H NMR(400MHz,Chloroform-d)δ11.76(s,1H),9.70(s,1H),9.56–9.23(m,1H),8.44(s,1H),8.34–8.18(m,1H),7.36(s,1H),7.11–6.84(m,1H),6.69(s,1H),6.44(s,1H),5.78–5.61(m,1H),4.26(d,J＝14.7Hz,4H),3.84(s,3H),3.39–3.12(m,1H),3.06–2.90(m,1H),2.90–2.76(m,1H),2.72(s,3H),2.56(s,3H),2.50–2.36(m,1H),2.11–1.94(m,2H),1.93–1.69(m,9H),1.56–1.46(m,1H). 1 H NMR (400MHz, Chloroform-d) δ 11.76 (s, 1H), 9.70 (s, 1H), 9.56-9.23 (m, 1H), 8.44 (s, 1H), 8.34-8.18 (m, 1H) ,7.36(s,1H),7.11–6.84(m,1H),6.69(s,1H),6.44(s,1H),5.78–5.61(m,1H),4.26(d,J=14.7Hz,4H ), 3.84 (s, 3H), 3.39-3.12 (m, 1H), 3.06-2.90 (m, 1H), 2.90-2.76 (m, 1H), 2.72 (s, 3H), 2.56 (s, 3H), 2.50–2.36(m,1H), 2.11–1.94(m,2H), 1.93–1.69(m,9H), 1.56–1.46(m,1H).
实施例29Example 29
N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000088
Figure PCTCN2020131472-appb-000088
第一步：1-环丙基-1H-吡咯并[2,3-b]吡啶The first step: 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2020131472-appb-000089
Figure PCTCN2020131472-appb-000089
将乙酸铜(6.2g，34mmol)加入到7-氮杂吲哚(4g，34mmol)，环丙基硼酸(5.8g，68mmol)2,2'-联吡啶(5.3g，34mmol)和碳酸钠(7.2g，34mmol)的1，2-二氯乙烷(100mL)混合物中，反应液在氮气保护下加热到85℃，反应12小时。反应液冷却，加入水(150mL)，过滤，固相二氯甲烷(60mL)洗涤，液相分离，水相二氯甲烷萃取(30mL*2)，有机相合并，无水硫酸钠干燥，蒸干，得到粗品。得粗产物经柱分离(石油醚:二氯甲烷＝10：1)得到1-环丙基-1H-吡咯并[2,3-b]吡啶(2.7g，产率：50.4％)。Copper acetate (6.2g, 34mmol) was added to 7-azaindole (4g, 34mmol), cyclopropylboronic acid (5.8g, 68mmol) 2,2'-bipyridine (5.3g, 34mmol) and sodium carbonate ( In a mixture of 7.2 g, 34 mmol) of 1,2-dichloroethane (100 mL), the reaction solution was heated to 85° C. under the protection of nitrogen and reacted for 12 hours. The reaction solution was cooled, water (150mL) was added, filtered, solid phase dichloromethane (60mL) washed, liquid phase separated, water phase dichloromethane extraction (30mL*2), organic phases were combined, dried with anhydrous sodium sulfate, evaporated to dryness , Get the crude product. The obtained crude product was separated by column (petroleum ether:dichloromethane=10:1) to obtain 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (2.7g, yield: 50.4%).
MS m/z(ESI):158.0[M+H] +. MS m/z(ESI): 158.0[M+H] + .
第二步：2-氯-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈The second step: 2-chloro-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile
Figure PCTCN2020131472-appb-000090
Figure PCTCN2020131472-appb-000090
在0℃氮气保护下，将三氯化铝(1.07g，8.1mmol)分批加入到2,4-二氯嘧啶-5-甲腈(700mg，4.0mmol)和1-环丙基-1H-吡咯并[2,3-b]吡啶(637mg，4.0mmol)的混合物中，反应物直接加热到100℃搅拌0.5小时。然后冷却到0℃，缓慢加入甲醇(10mL)和水(30mL)，室温搅拌30分钟，二氯甲烷萃取(30mL*2)，有机相合并，无水硫酸钠干燥，蒸干，得到粗品。得粗产物经柱分离(石油醚:二氯甲烷＝1：1)得到2-氯-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈(735mg，产率：62％)。Under the protection of nitrogen at 0°C, aluminum trichloride (1.07g, 8.1mmol) was added in batches to 2,4-dichloropyrimidine-5-carbonitrile (700mg, 4.0mmol) and 1-cyclopropyl-1H- In a mixture of pyrrolo[2,3-b]pyridine (637 mg, 4.0 mmol), the reactant was directly heated to 100° C. and stirred for 0.5 hour. Then cooled to 0°C, slowly added methanol (10 mL) and water (30 mL), stirred at room temperature for 30 minutes, extracted with dichloromethane (30 mL*2), combined the organic phases, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product. The crude product is separated by column (petroleum ether: dichloromethane=1:1) to obtain 2-chloro-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine -5-carbonitrile (735 mg, yield: 62%).
MS m/z(ESI):296.0[M+H] +. MS m/z(ESI): 296.0[M+H] + .
第三步：4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-氟-2-甲氧基-5-硝基苯基) 氨基)嘧啶-5-甲腈The third step: 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrobenzene (Yl)amino)pyrimidine-5-carbonitrile
Figure PCTCN2020131472-appb-000091
Figure PCTCN2020131472-appb-000091
将对甲苯磺酸单水合物(643mg，3.38mmol)加入到4-氟-2-甲氧基-5-硝基苯胺(189mg，1.01mmol)和2-氯-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈(250mg，0.85mmol)的2-丁醇(15mL)溶液中，反应液加热到90℃12小时。反应液冷却，蒸干，饱和碳酸氢钠水溶液调节Ph为9，二氯甲烷(35mL*2)萃取，有机相无水硫酸钠干燥，蒸干，得到粗品。得粗产物经柱分离(二氯甲烷:乙酸乙酯＝5：1)得到产物4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-5-甲腈(230mg，产率：61％)。Add p-toluenesulfonic acid monohydrate (643mg, 3.38mmol) to 4-fluoro-2-methoxy-5-nitroaniline (189mg, 1.01mmol) and 2-chloro-4-(1-cyclopropyl In a solution of -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg, 0.85mmol) in 2-butanol (15mL), the reaction solution was heated to 90°C for 12 hours. The reaction solution was cooled, evaporated to dryness, adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (35 mL*2), the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain a crude product. The obtained crude product was separated by column (dichloromethane: ethyl acetate = 5:1) to obtain the product 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- ((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (230 mg, yield: 61%).
MS m/z(ESI):446.1[M+H] +. MS m/z(ESI): 446.1[M+H] + .
第四步：4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-5-甲腈The fourth step: 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-(dimethylamino)ethyl)( (Methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile
Figure PCTCN2020131472-appb-000092
Figure PCTCN2020131472-appb-000092
将碳酸钾(214mg，1.55mmol)加入到N,N,N'-三甲基乙二胺(58mg，0.57mmol)和4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-5-甲腈(230mg，0.52mmol)的乙腈(10mL)溶液中，反应液加热到80℃反应2小时。反应液冷却，蒸干，二氯甲烷(30mL)溶解，食盐水(20mL*3)洗涤，有机相无水硫酸钠干燥，蒸干，得到粗品4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-5-甲腈(270mg)。粗品直接用于下一步。Potassium carbonate (214mg, 1.55mmol) was added to N,N,N'-trimethylethylenediamine (58mg, 0.57mmol) and 4-(1-cyclopropyl-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (230mg, 0.52mmol) in acetonitrile (10mL) , The reaction solution was heated to 80°C for 2 hours. The reaction solution was cooled, evaporated to dryness, dissolved in dichloromethane (30mL), washed with brine (20mL*3), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude 4-(1-cyclopropyl-1H-pyrrolo [2,3-b]pyridin-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene (Yl)amino)pyrimidine-5-carbonitrile (270 mg). The crude product was used directly in the next step.
MS m/z(ESI):528.2[M+H] +. MS m/z(ESI): 528.2[M+H] + .
第五步：2-((5-氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧苯基)氨基)-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈The fifth step: 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile
Figure PCTCN2020131472-appb-000093
Figure PCTCN2020131472-appb-000093
将铁粉(288mg，5.2mmol)加入到4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)-2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-5-甲腈(270mg，0.51mol)的乙醇(10mL)和饱和氯化铵水溶液(4mL)混合物中，反应液加热到80℃反应2小时。反应液热过滤，固体二氯甲烷洗涤，液相蒸干得到粗品，后粗品中加入二氯甲烷(30mL)，水洗(15mL*2)，有机相无水硫酸钠干燥，蒸干，得到粗品2-((5-氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧苯基)氨基)-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈(250mg)，直接用于下一步。Iron powder (288mg, 5.2mmol) was added to 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-(二(Methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (270mg, 0.51mol) in ethanol (10mL) and saturated ammonium chloride In the mixture of aqueous solution (4 mL), the reaction solution was heated to 80° C. and reacted for 2 hours. The reaction solution was filtered hot, washed with solid dichloromethane, and evaporated to dryness in the liquid phase to obtain a crude product. Then, dichloromethane (30mL) was added to the crude product, washed with water (15mL*2), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude product 2. -((5-Amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl-1H-pyrrole And [2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg), used directly in the next step.
MS m/z(ESI):498.3[M+H] +. MS m/z(ESI): 498.3[M+H] + .
第六步：3-氯-N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙酰胺The sixth step: 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2- Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide
Figure PCTCN2020131472-appb-000094
Figure PCTCN2020131472-appb-000094
在0℃下，将3-氯丙酰氯(77mg，0.60mmol)加入到2-((5-氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧苯基)氨基)-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-5-甲腈(250mg，0.50mmol)和三乙胺(0.21mL，1.51mmol)的二氯甲烷(10mL)溶液中，反应液在0℃下反应30分钟。后蒸干，粗品3-氯-N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙酰胺(250mg)，直接用于下一步。At 0°C, 3-chloropropionyl chloride (77mg, 0.60mmol) was added to 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- Methoxyphenyl)amino)-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg, 0.50mmol) and triethylamine (0.21 mL, 1.51 mmol) in dichloromethane (10 mL) solution, the reaction solution was reacted at 0°C for 30 minutes. After evaporation to dryness, the crude product 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2 -Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (250mg), used directly in the next step.
MS m/z(ESI):588.3[M+H] +. MS m/z(ESI): 588.3[M+H] + .
第七步：N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙烯酰基酰胺The seventh step: N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino) -2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000095
Figure PCTCN2020131472-appb-000095
将氢氧化钠水溶液(含氢氧化钠(200mg，5mmol)和水(1mL))加入粗品3-氯-N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙酰胺(290mg，0.50mmol)的乙腈(10mL)溶液中，反应液室温搅拌16小时。反应液蒸干，得到粗品。粗品N，N-二甲基甲酰胺(2mL)溶解，制备HPLC分离的产物N-(5-((5-氰基-4-(1-环丙基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙烯酰基酰胺(55mg，产率：20％)。An aqueous sodium hydroxide solution (containing sodium hydroxide (200mg, 5mmol) and water (1mL)) was added to the crude 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxybenzene The reaction solution was stirred at room temperature for 16 hours in a solution of propyl) propionamide (290 mg, 0.50 mmol) in acetonitrile (10 mL). The reaction liquid was evaporated to dryness to obtain a crude product. The crude N,N-dimethylformamide (2mL) was dissolved, and the product N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3- b)Pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (55mg , Yield: 20%).
1H NMR(400MHz,Chloroform-d)δ10.32–9.88(m,1H),9.59–9.18(m,1H),8.92–8.52(m,3H),8.52–8.26(m,1H),7.96–7.61(m,1H),7.24–6.99(m,1H),6.82(s,1H),6.55–6.15(m,2H),5.85–5.52(m,1H),3.89(s,3H),3.72–3.58(m,1H),3.01–2.83(m,2H),2.74(s,3H),2.51–2.19(m,8H),1.30–1.04(m,4H). 1 H NMR (400MHz, Chloroform-d) δ 10.32--9.88 (m, 1H), 9.59--9.18 (m, 1H), 8.92--8.52 (m, 3H), 8.52--8.26 (m, 1H), 7.96-- 7.61(m,1H), 7.24–6.99(m,1H), 6.82(s,1H), 6.55–6.15(m,2H), 5.85–5.52(m,1H), 3.89(s,3H), 3.72– 3.58 (m, 1H), 3.01 - 2.83 (m, 2H), 2.74 (s, 3H), 2.51 - 2.19 (m, 8H), 1.30 - 1.04 (m, 4H).
MS m/z(ESI):552.3[M+H] +. MS m/z(ESI): 552.3[M+H] + .
实施例30Example 30
N-(5-((5-氰基-4-(3-甲基-1H-吲唑-1-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(3-methyl-1H-indazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino) (Ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000096
Figure PCTCN2020131472-appb-000096
实施例30的制备方法参照实施例1。Refer to Example 1 for the preparation method of Example 30.
MS m/z(ESI):526.3[M+H] +. MS m/z(ESI): 526.3[M+H] + .
1H NMR(400MHz,Chloroform-d)δ10.44–9.56(m,1H),9.13(s,1H),8.67(s,1H),8.57–8.27(m,1H),7.80–7.57(m,1H),7.57–7.43(m,1H),7.44–7.24(m,3H),6.96–6.67(m,1H),6.57–6.16(m,1H),5.81–5.50(m,1H),3.86(s,3H),3.45–2.08(m,16H). 1 H NMR (400MHz, Chloroform-d) δ 10.44-9.56 (m, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.57-8.27 (m, 1H), 7.80-7.57 (m, 1H), 7.57--7.43 (m, 1H), 7.44 - 7.24 (m, 3H), 6.96 - 6.67 (m, 1H), 6.57 - 6.16 (m, 1H), 5.81 - 5.50 (m, 1H), 3.86 ( s,3H),3.45-2.08(m,16H).
实施例31Example 31
N-(5-((5-氰基-4-(1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000097
Figure PCTCN2020131472-appb-000097
实施例31的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 31.
MS m/z(ESI):526.3[M+H] +. MS m/z(ESI): 526.3[M+H] + .
实施例32Example 32
N-(5-((5-氰基-4-(1-甲基-1H-吡咯并[3,2-c]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000098
Figure PCTCN2020131472-appb-000098
实施例32的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 32.
MS m/z(ESI):526.2[M+H] +. MS m/z(ESI): 526.2[M+H] + .
实施例33Example 33
N-(5-((5-氰基-4-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000099
Figure PCTCN2020131472-appb-000099
实施例33的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 33.
MS m/z(ESI):526.0[M+H] +. MS m/z(ESI): 526.0[M+H] + .
实施例34Example 34
N-(5-((5-氰基-4-(1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000100
Figure PCTCN2020131472-appb-000100
实施例34的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 34.
MS m/z(ESI):526.2[M+H] +. MS m/z(ESI): 526.2[M+H] + .
实施例35Example 35
N-(5-((5-氰基-4-(6-甲氧基-1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000101
Figure PCTCN2020131472-appb-000101
实施例35的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 35.
MS m/z(ESI):556.4[M+H] +. MS m/z(ESI): 556.4[M+H] + .
实施例36Example 36
N-(5-((5-氰基-4-(6-甲氧基-1-甲基-1H-吡咯并[3,2-c]吡啶-3-基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺N-(5-((5-cyano-4-(6-methoxy-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2020131472-appb-000102
Figure PCTCN2020131472-appb-000102
实施例36的制备方法参照实施例29。Refer to Example 29 for the preparation method of Example 36.
MS m/z(ESI):556.1[M+H] +. MS m/z(ESI): 556.1[M+H] + .
生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The following further describes and explains the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
1.测试酶学实验1. Test the enzyme experiment
测试例1、本发明化合物对EGFR 20外显子插入突变激酶活性抑制作用的测定Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the kinase activity of EGFR exon 20 insertion mutation
实验目的：该测试例的目的是测量化合物对EGFR 20外显子插入突变激酶活性的抑制能力。Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on the kinase activity of EGFR 20 exon insertion mutation.
实验仪器：离心机(Eppendorf 5810R)，酶标仪(BioTek Synergy H1)，移液器(Eppendorf&Rainin)Experimental instruments: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf&Rainin)
实验方法：本实验采用TR-FRET(时间分辨荧光共振能量转移)方法研究化合物对EGFR 20外显子插入突变激酶的抑制活性。本实验在384孔板中展开，配制实验缓冲液(50mM HEPES，1mM EGTA，10mM MgCl 2，2mM DTT，0.01％Tween-20)，使用实验缓冲液将化合物梯度稀释为不同的浓度，每孔2.5μL加入到384孔板中，再加入2.5μL稀释好的EGFR激酶溶液(0.001-0.5nM)，室温孵育10分钟，加入5μL ULight-poly GT/ATP混合溶液，室温孵育30分钟到60分钟，加入5μL EDTA终止反应和5μL Eu标记抗体检测液，室温孵育1小时，酶标仪测定各板孔的665nm荧光信号值。 Experimental method: In this experiment, the TR-FRET (Time Resolved Fluorescence Resonance Energy Transfer) method was used to study the inhibitory activity of the compound on the EGFR 20 exon insertion mutant kinase. This experiment was carried out in a 384-well plate. The experiment buffer (50mM HEPES, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20) was prepared, and the compound was diluted to different concentrations with the experiment buffer, 2.5 per well. Add μL to the 384-well plate, then add 2.5 μL diluted EGFR kinase solution (0.001-0.5nM), incubate at room temperature for 10 minutes, add 5 μL ULight-poly GT/ATP mixed solution, incubate at room temperature for 30 minutes to 60 minutes, 5μL EDTA to stop the reaction and 5μL Eu-labeled antibody detection solution, incubate for 1 hour at room temperature, and measure the 665nm fluorescence signal value of each plate well with a microplate reader.
实验数据处理方法：Experimental data processing method:
使用665nm处的荧光信号值计算抑制率((阳性对照孔值-样品孔值)/(阳性对照孔值-阴性对照孔值))*100％，并将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值，具体数据如下表1所示： Use the fluorescence signal value at 665nm to calculate the inhibition rate ((positive control well value-sample well value)/(positive control well value-negative control well value))*100%, and use Graphpad Prism software to determine the concentration and inhibition rate. The linear regression curve is fitted to obtain the IC 50 value. The specific data are shown in Table 1 below:
表1化合物对EGFR 20外显子插入突变激酶抑制活性IC 50 Table 1 Compound EGFR 20 insertion mutations in exon kinase inhibitory activity IC 50
Figure PCTCN2020131472-appb-000103
Figure PCTCN2020131472-appb-000103
实验结论：Experimental results:
通过以上方案得出本发明的实施例化合物在EGFR 20外显子插入突变激酶活性抑制实验中具有较好的抑制作用。Through the above scheme, it is concluded that the compound of the example of the present invention has a good inhibitory effect in the EGFR 20 exon insertion mutation kinase activity inhibition experiment.
测试例2、本发明化合物对EGFR野生型激酶活性抑制作用的测定Test Example 2. Determination of the inhibitory effect of the compound of the present invention on the activity of EGFR wild-type kinase
实验目的：该测试例的目的是测量化合物对EGFR野生型激酶活性的抑制能力。Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on the activity of EGFR wild-type kinase.
实验仪器：离心机(Eppendorf 5810R)，酶标仪(BioTek Synergy H1)，移液器(Eppendorf&Rainin)Experimental instruments: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf&Rainin)
实验方法：本实验采用TR-FRET(时间分辨荧光共振能量转移)方法研究化合物对EGFR野生型激酶的抑制活性。本实验在384孔板中展开，配制实验缓冲液(50mM HEPES，1mM EGTA，10mM MgCl 2，2mM DTT，0.01％Tween-20)，使用实验缓冲液将化合物梯度稀释为不同的浓度，每孔2μL加入到384孔板中，再加入4μL稀释好的EGFR激酶溶液(0.001-0.5nM)，室温孵育10分钟，加入4μL ULight-poly GT/ATP混合溶液，室温孵育30分钟到60分钟，加入5μL EDTA终止反应和5μL Eu标记抗体检测液，室温孵育1小时，酶标仪测定各板孔的665nm荧光信号值。 Experimental method: In this experiment, the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method was used to study the inhibitory activity of the compound against EGFR wild-type kinase. This experiment was carried out in a 384-well plate, and the experiment buffer (50mM HEPES, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20) was prepared, and the compound was diluted to different concentrations with experiment buffer, 2μL per well Add to 384-well plate, then add 4μL of diluted EGFR kinase solution (0.001-0.5nM), incubate at room temperature for 10 minutes, add 4μL of ULight-poly GT/ATP mixed solution, incubate at room temperature for 30 minutes to 60 minutes, add 5μL of EDTA Terminate the reaction and 5μL Eu-labeled antibody detection solution, incubate for 1 hour at room temperature, and measure the 665nm fluorescence signal value of each well with a microplate reader.
实验数据处理方法：Experimental data processing method:
使用665nm处的荧光信号值计算抑制率((阳性对照孔值-样品孔值)/(阳性对照孔值-阴性对照孔值))*100％，并将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值，具体数据如下表2所示： Use the fluorescence signal value at 665nm to calculate the inhibition rate ((positive control well value-sample well value)/(positive control well value-negative control well value))*100%, and use Graphpad Prism software to determine the concentration and inhibition rate. The linear regression curve is fitted to obtain the IC 50 value. The specific data is shown in Table 2 below:
表2化合物对EGFR野生型激酶抑制活性IC 50 Table 2 Compounds against EGFR wild-type kinase inhibitory activity IC 50
Figure PCTCN2020131472-appb-000104
Figure PCTCN2020131472-appb-000104
实验结论：Experimental results:
通过以上方案得出本发明的实施例化合物在EGFR野生型激酶抑制试验中抑制作用较小。Through the above scheme, it can be concluded that the compound of the example of the present invention has less inhibitory effect in the EGFR wild-type kinase inhibition test.
测试例3、本发明化合物对Ba/F3 EGFR突变细胞株增殖抑制作用的测定Test Example 3. Determination of the inhibitory effect of the compound of the present invention on the proliferation of Ba/F3 EGFR mutant cell lines
实验目的：该测试例的目的是测量化合物对Ba/F3 EGFR突变细胞株增殖活性的抑制作用。Experimental purpose: The purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of Ba/F3 EGFR mutant cell lines.
实验仪器：酶标仪(BioTek Synergy H1)，移液器(Eppendorf&Rainin)Experimental instrument: Microplate reader (BioTek Synergy H1), pipette (Eppendorf&Rainin)
实验方法：experimental method:
培养Ba/F3 EGFR突变细胞至合适的密度时，收集细胞，使用完全培养基将细 胞调整为合适的细胞浓度，将细胞悬液铺于96孔板，每孔90μL，放入37℃，5％CO 2培养箱贴壁过夜，使用DMSO以及培养基配制不同浓度的化合物溶液，设置溶媒对照，将化合物溶液加入到96孔板中，每孔10μL,放入37℃，5％CO 2培养箱中继续培养72h～144h后，加入CellTiter-Glo溶液，振荡混合均匀后，避光孵育10分钟，用BioTek Synergy H1酶标仪进行读数。 After culturing Ba/F3 EGFR mutant cells to a suitable density, collect the cells, adjust the cells to a suitable cell concentration with complete medium, and spread the cell suspension on a 96-well plate, 90μL per well, and put it at 37°C, 5% Stick to the CO 2 incubator overnight, use DMSO and culture medium to prepare compound solutions of different concentrations, set the solvent control, add the compound solution to a 96-well plate, 10 μL per well, and place it in a 37°C, 5% CO 2 incubator After culturing for 72h～144h, add CellTiter-Glo solution, shake and mix well, incubate for 10 minutes in the dark, and read with BioTek Synergy H1 microplate reader.
实验数据处理方法：Experimental data processing method:
使用发光信号值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值，具体数据如下表3所示： The luminescence signal value was used to calculate the inhibition rate, and the concentration and inhibition rate were fitted with Graphpad Prism software for nonlinear regression curve fitting to obtain the IC 50 value. The specific data are shown in Table 3 below:
表3化合物对Ba/F3 EGFR突变细胞株增殖抑制活性IC 50 Table 3 Compounds inhibit the proliferation of Ba/F3 EGFR mutant cell line IC 50
Figure PCTCN2020131472-appb-000105
Figure PCTCN2020131472-appb-000105
实验结论：Experimental results:
通过以上方案得出本发明的实施例化合物在Ba/F3 EGFR突变细胞增殖活性的抑制试验中具有一定的抑制作用。Through the above scheme, it is concluded that the compounds of the examples of the present invention have a certain inhibitory effect in the inhibition test of the proliferation activity of Ba/F3 EGFR mutant cells.
测试例4、肝微粒体代谢稳定性试验Test Example 4. Metabolic stability test of liver microsomes
1.实验目的：1. The purpose of the experiment:
本实验的目的是检测实施例化合物在大鼠和人肝微粒体中的稳定性情况。The purpose of this experiment is to test the stability of the compounds of the examples in rat and human liver microsomes.
2.实验步骤：2. Experimental steps:
2.1配制化合物工作液2.1 Preparation of compound working solution
化合物的工作液配制：将化合物储备溶液加入磷酸缓冲液，终浓度为20μM。Compound working solution preparation: add the compound stock solution to phosphate buffer, the final concentration is 20μM.
2.2配制肝微粒体工作液2.2 Preparation of liver microsome working fluid
用100mM磷酸缓冲液稀释至终浓度为0.625mg/mL。Dilute with 100mM phosphate buffer to a final concentration of 0.625mg/mL.
2.3准备NADPH和UDPGA2.3 Prepare NADPH and UDPGA
称取NADPH(还原型烟酰胺腺嘌呤二核苷酸磷酸)和UDPGA(尿苷二磷酸葡萄糖醛酸)，加入100mM磷酸缓冲液，终浓度均为20mM。Weigh NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronic acid), add 100 mM phosphate buffer, and the final concentration is 20 mM.
2.4准备打孔剂2.4 Prepare the punch
称取1mg Alamethicin(丙甲菌素)加入200μL DMSO，配制成5mg/mL的溶液。再用磷酸缓冲液稀释至终浓度为50μg/mL。Weigh 1mg Alamethicin (Promethocin) and add 200μL DMSO to prepare a 5mg/mL solution. Dilute with phosphate buffer to a final concentration of 50μg/mL.
2.5配制反应终止液2.5 Preparation of reaction stop solution
终止液：含有100ng/mL的盐酸拉贝洛尔和400ng/mL甲苯磺丁脲为内标的冷乙腈。Stop solution: cold acetonitrile containing 100ng/mL labetalol hydrochloride and 400ng/mL tolbutamide as internal standards.
2.6孵育流程2.6 Incubation process
在96孔板中依次加入400μL配制好的肝微粒体、25μL化合物工作液和25μL Alamethicin，于37℃预孵育10min。随后加入50μL配制好的NADPH/UDPGA启动反应，37℃孵育，反应体系的总体积为500μL，各成分最终含量如下：Add 400 μL of prepared liver microsomes, 25 μL of compound working solution and 25 μL of Alamethicin to a 96-well plate in sequence, and pre-incubate at 37°C for 10 minutes. Then add 50μL of the prepared NADPH/UDPGA to start the reaction, and incubate at 37°C. The total volume of the reaction system is 500μL. The final content of each component is as follows:
成分ingredient 含量content
肝微粒体Liver microsomes 0.5mg/mL0.5mg/mL
化合物Compound 1μM1μM
NADPHNADPH 2mM2mM
UDPGAUDPGA 2mM2mM
AlamethicinAlamethicin 2.5μg/mL2.5μg/mL
2.7样品分析2.7 Sample analysis
2.7.1色谱条件：2.7.1 Chromatographic conditions:
仪器：岛津LC-30AD；Instrument: Shimadzu LC-30AD;
色谱柱：
Figure PCTCN2020131472-appb-000106
C18(50*4.6mm，5μm粒径)； Column:
Figure PCTCN2020131472-appb-000106
C18 (50*4.6mm, 5μm particle size);
流动相：A：0.1％甲酸溶液，B：甲醇Mobile phase: A: 0.1% formic acid solution, B: methanol
冲洗梯度：0.2～1.6min 5％A到95％A，3.0～3.1min 95％A到5％AWashing gradient: 0.2～1.6min 5%A to 95%A, 3.0～3.1min 95%A to 5%A
运行时间：4.0min。Running time: 4.0min.
2.7.2质谱条件：2.7.2 Mass spectrometry conditions:
仪器：API5500型液相色谱质谱联用仪，AB Sciex公司；Instrument: API5500 liquid chromatography-mass spectrometer, AB Sciex;
离子源：电喷雾离子化源(ESI)；Ion source: Electrospray ionization source (ESI);
干燥气体：N 2，温度500℃； Drying gas: N 2 , temperature 500℃;
电喷雾电压：5000V；Electrospray voltage: 5000V;
检测方式：正离子检测；Detection method: positive ion detection;
扫描方式：反应监测(MRM)方式。Scanning mode: reaction monitoring (MRM) mode.
3.实验结果：3. Experimental results:
表4实施例化合物的肝微粒体代谢稳定性结果Table 4 Results of liver microsomal metabolic stability of the example compounds
Figure PCTCN2020131472-appb-000107
Figure PCTCN2020131472-appb-000107
备注：固有清除率>47.0(人)，>71.9(大鼠)为快代谢。Remarks: Inherent clearance rate>47.0 (human),>71.9 (rat) is fast metabolism.
4.实验结论：4. Experimental conclusion:
以上数据显示，本发明实施例化合物在大鼠和人的肝微粒体中代谢稳定性良好。The above data show that the compounds of the examples of the present invention have good metabolic stability in rat and human liver microsomes.
测试例5、小鼠药代动力学测定Test Example 5. Determination of pharmacokinetics in mice
1.研究目的：1. Research purpose:
以Balb/c小鼠为受试动物，研究化合物口服给药在小鼠体内(血浆)的药代动力学行为。Balb/c mice were used as test animals to study the pharmacokinetic behavior of the compounds in mice (plasma) after oral administration.
2.试验方案：2. Test plan:
2.1试验药品：2.1 Test drugs:
本发明实施例化合物，自制；Example compounds of the present invention, self-made;
2.2试验动物：2.2 Experimental animals:
Balb/c小鼠，雄性，购自上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。Balb/c mouse, male, purchased from Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.3药物配制：2.3 Drug preparation:
称取5g羟乙基纤维素(HEC，CMC-Na，粘度：800-1200Cps)，溶于1000mL纯净水，加入10g Tween80。混合均匀成澄清溶液。Weigh 5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps), dissolve it in 1000mL of purified water, and add 10g of Tween80. Mix well to form a clear solution.
称取实施例化合物，分别加入4-mL玻璃瓶，加入2.4mL该溶液，超声10分钟，得到无色澄清溶液，浓度为1mg/mL。The compound of the example was weighed and added to a 4-mL glass bottle respectively, and 2.4 mL of the solution was added, followed by sonication for 10 minutes to obtain a colorless and clear solution with a concentration of 1 mg/mL.
2.4给药：2.4 Administration:
Balb/c小鼠，雄性；禁食一夜后分别PO，给药剂量为40mg/kg，给药体积为10mL/kg。Balb/c mice, male; PO respectively after fasting overnight, the dose was 40 mg/kg, and the dose volume was 10 mL/kg.
2.5样品采集：2.5 Sample collection:
于给药前和给药后采血，血液置于EDTA-2K试管中，4℃6000rpm离心6min分离血浆，于-80℃保存；给药后4h进食。The blood was collected before and after the administration, the blood was placed in an EDTA-2K test tube, and the plasma was separated by centrifugation at 6000 rpm at 4°C for 6 min, and stored at -80°C; food was taken 4 hours after the administration.
3.实验结果：3. Experimental results:
应用LCMS/MS方法得到最后测定结果见表5：The final measurement results obtained by the LCMS/MS method are shown in Table 5:
表5化合物的小鼠药代动力学参数Table 5 Mouse pharmacokinetic parameters of compounds
Figure PCTCN2020131472-appb-000108
Figure PCTCN2020131472-appb-000108
4.实验结论：4. Experimental conclusion:
以上数据显示，本发明实施例化合物具有良好的小鼠药代动力学参数。The above data show that the compounds of the examples of the present invention have good mouse pharmacokinetic parameters.
测试例6、本发明化合物在小鼠原B细胞Ba/F3 EGFR-D770-N771ins_SVD移植瘤模型上的体内药效学研究Test Example 6. In vivo pharmacodynamics study of the compound of the present invention on mouse primary B cell Ba/F3 EGFR-D770-N771ins_SVD transplantation tumor model
1.实验目的：1. The purpose of the experiment:
评价化合物在小鼠原B细胞Ba/F3 EGFR-D770-N771ins_SVD移植瘤模型上的体内药效。To evaluate the in vivo efficacy of the compound on mouse primary B cell Ba/F3 EGFR-D770-N771ins_SVD transplanted tumor model.
2.实验仪器与试剂：2. Experimental equipment and reagents:
2.1仪器：2.1 Instrument:
1、生物安全柜(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)1. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)
2、超净工作台(CJ-2F，苏州市冯氏实验动物设备有限公司)2. Ultra-clean workbench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.)
3、CO 2培养箱(Thermo-311，Thermo) 3. CO 2 incubator (Thermo-311, Thermo)
4、离心机(Centrifuge 5720R，Eppendorf)4. Centrifuge (Centrifuge 5720R, Eppendorf)
5、全自动细胞计数仪(Countess II，Life Technologies)5. Automatic cell counter (Countess II, Life Technologies)
6、游标卡尺(CD-6”AX，日本三丰)6. Vernier calipers (CD-6"AX, Mitutoyo, Japan)
7、细胞培养瓶(T75/T225，Corning)7. Cell culture flask (T75/T225, Corning)
8、电子天平(CPA2202S，赛多利斯)8. Electronic balance (CPA2202S, Sartorius)
9、电子天平(BSA2202S-CW，赛多利斯)9. Electronic balance (BSA2202S-CW, Sartorius)
2.2试剂：2.2 Reagents:
1、RPMI-1640培养基(22400-089，Gibco)1. RPMI-1640 medium (22400-089, Gibco)
2、胎牛血清(FBS)(10099-141C，Gibco)2. Fetal Bovine Serum (FBS) (10099-141C, Gibco)
3、磷酸盐缓冲液(PBS)(10010-023，Gibco)3. Phosphate buffered saline (PBS) (10010-023, Gibco)
4、吐温80(30189828，国药试剂)4. Tween 80 (30189828, Sinopharm reagent)
5、羧甲基纤维素钠(30036365，国药试剂)5. Sodium carboxymethyl cellulose (30036365, Sinopharm reagent)
3实验操作及数据处理：3 Experimental operation and data processing:
3.1动物3.1 Animals
BALB/c裸小鼠，6-8周，♀，购自上海西普尔－必凯实验动物有限公司。BALB/c nude mice, 6-8 weeks, ♀, purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.
3.2细胞培养及细胞悬液制备3.2 Cell culture and cell suspension preparation
a,从细胞库中取出一株Ba/F3 EGFR-D770-N771ins_SVD细胞，用RPMI-1640培养基(RPMI-1640+10％FBS)复苏细胞，复苏后的细胞置细胞培养瓶中(在瓶壁标记好细胞种类、日期、培养人名字等)置于CO 2培养箱中培养(培养箱温度为37℃，CO 2浓度为5％)。 a. Take out a Ba/F3 EGFR-D770-N771ins_SVD cell from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640+10% FBS), and place the recovered cells in a cell culture flask (in the bottle wall). Mark the cell type, date, culture name, etc.) and place it in a CO 2 incubator (the temperature of the incubator is 37°C, and the CO 2 concentration is 5%).
b,每三天传代一次，传代后细胞继续置于CO 2培养箱中培养。重复该过程直到细胞数满足体内药效需求。 b. Passage once every three days. After passaging, the cells will continue to be cultured in a CO 2 incubator. Repeat this process until the number of cells meets the requirements for efficacy in the body.
c,收集培养好的细胞，用全自动细胞计数仪计数，根据计数结果用PBS重悬细胞，制成细胞悬液(密度2×10 7/mL)，置于冰盒中待用。 c. Collect the cultured cells, count them with an automatic cell counter, and resuspend the cells in PBS according to the counting results to make a cell suspension (density 2×10 7 /mL), and place in an ice box for later use.
3.3细胞接种3.3 Cell seeding
a,接种前用一次性大小鼠通用耳标标记裸鼠a. Label nude mice with disposable universal ear tags for rats and mice before vaccination
b,接种时混匀细胞悬液，用1mL注射器抽取0.1-1mL细胞悬液、排除气泡，然后将注射器置于冰袋上待用。b. Mix the cell suspension during inoculation. Use a 1 mL syringe to draw 0.1-1 mL of the cell suspension to remove air bubbles, and then place the syringe on an ice bag for later use.
c,左手保定好裸鼠，用75％酒精消毒裸鼠右侧背部靠右肩位置(接种部位)，30秒后开始接种。c. Set the nude mouse with the left hand, disinfect the right shoulder (the inoculation site) on the right back of the nude mouse with 75% alcohol, and start the inoculation 30 seconds later.
d,依次给试验裸鼠接种(每只小鼠接种0.1mL细胞悬液)。d, inoculate test nude mice in turn (each mouse is inoculated with 0.1mL cell suspension).
3.4荷瘤鼠量瘤、分组、给药3.4 Tumor-bearing mice measuring tumor, grouping, and administration
a,根据肿瘤生长情况，在接种后第8-14天量瘤、并计算肿瘤大小。a. According to the tumor growth, measure the tumor and calculate the tumor size from 8 to 14 days after inoculation.
肿瘤体积计算：肿瘤体积(mm 3)＝长(mm)×宽(mm)×宽(mm)/2 Tumor volume calculation: tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm)/2
b,根据荷瘤鼠体重和肿瘤大小，采用随机分组的方法进行分组，每组5只。b. According to the weight and tumor size of the tumor-bearing mice, the mice were randomly divided into groups, 5 mice in each group.
c,根据分组结果，开始给予测试药物(给药方式：口服给药；给药频次：1次/天；给药周期：14天；溶媒：0.5％CMC/1％吐温80)。c. According to the grouping results, start to give the test drug (administration method: oral administration; dosing frequency: 1 time/day; dosing cycle: 14 days; vehicle: 0.5% CMC/1% Tween 80).
d,开始给予测试药物后每周两次量瘤、称重。d. Measure and weigh the tumor twice a week after starting to give the test drug.
e,实验结束后安乐死动物。e. Euthanize the animal after the experiment.
f,用Excel等软件处理数据。f. Use Excel and other software to process the data.
化合物抑瘤率TGI(％)的计算：Calculation of compound tumor inhibition rate TGI (%):
TGI(％)＝[(1-某处理组给药结束时平均瘤体积)/溶剂对照组治疗结束时平均瘤体积]×100％。TGI(%)=[(1-Average tumor volume at the end of treatment in a certain treatment group)/Average tumor volume at the end of treatment in the solvent control group]×100%.
TGI≥60％，化合物在该模型中有效；TGI≥60%, the compound is effective in this model;
TGI<60％，化合物在该模型中无效。TGI<60%, the compound is not effective in this model.
4.试验结果如下表6：4. The test results are as follows in Table 6:
表6化合物的移植瘤小鼠药效参数Table 6 Compounds of the pharmacodynamic parameters of transplanted tumor in mice
Figure PCTCN2020131472-appb-000109
Figure PCTCN2020131472-appb-000109
备注：括号中的数据表示，该实施例对应Vehicle QD x 2w组(即对照组)相应时间的肿瘤体积。Note: The data in parentheses indicates that this example corresponds to the tumor volume of the Vehicle QD x 2w group (ie, the control group) at the corresponding time.
5.实验结果5. Experimental results
以上数据显示：口服连续给药14天后，AZD9291 40mpk在Ba/F3 EGFR-D770-N771ins_SVD药效模型中无效，而实施例26在同等剂量40mpk下有效。The above data shows that after 14 days of continuous oral administration, AZD9291 40mpk is not effective in the Ba/F3 EGFR-D770-N771ins_SVD pharmacodynamic model, while Example 26 is effective at the same dose of 40mpk.

Claims (22)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020131472-appb-100001
    Figure PCTCN2020131472-appb-100001
    其中：among them:
    M选自CR 1或N； M is selected from CR 1 or N;
    L选自键、-(CH 2) n-、-(CH 2) nNR aa-、-(CH 2) nO-、-(CH 2) nS-、-(CH 2) nC(O)-、-(CH 2) nC(O)NR aa-、-(CH 2) nNR aaC(O)-、-(CH 2) nC(O)O-、-NR aa(CH 2) n-、-O(CH 2) n-、-S(CH 2) n-、-C(O)(CH 2) n-、-C(O)NR aa(CH 2) n-、-NR aaC(O)(CH 2) n-、-C(O)O(CH 2) n-、-(CH 2) nP(O)R aa-、-(CH 2) nS(O) m-、-(CH 2) nS(O) mNR aa-或-(CH 2) nNR aaS(O) m-； L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C(O )-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C(O)O-, -NR aa (CH 2 ) n -, -O(CH 2 ) n -, -S(CH 2 ) n -, -C(O)(CH 2 ) n -, -C(O)NR aa (CH 2 ) n -, -NR aa C(O)(CH 2 ) n -, -C(O)O(CH 2 ) n -, -(CH 2 ) n P(O)R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa -or -(CH 2 ) n NR aa S(O) m -;
    环A选自环烷基、杂环基、芳基或杂芳基；Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl;
    环B选自环烷基、杂环基、芳基或杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、羧酸酯基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a、-(CH 2) nNR aR b、-NR aC(O)R b、-C(O)NR a(CH 2) nR b、-NR aC(O)NR bR c、-NR aC(O)NR b(CH 2) nR c、-C≡CR a、-NR aC(O)CR b＝CH(CH 2) nR c、-NR aC(O)C≡CR b、-C(O)NR aR b、-C(O)OR a、-NR aS(O) mR b、-O(CH 2) nR a、-(CH 2) nP(O)R aR b、-(CH 2) nS(O) mNR aR b、-(CH 2) nC(O)R a、-NR aC(O)OR b、-(CH 2) nS(O) mR a或-(CH 2) nNR aS(O) mR b，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, hydroxyalkyl, azido, carboxylate Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -NR a C(O) R b , -C(O)NR a (CH 2 ) n R b , -NR a C(O)NR b R c , -NR a C(O)NR b (CH 2 ) n R c , -C≡ CR a , -NR a C(O)CR b =CH(CH 2 ) n R c , -NR a C(O)C≡CR b , -C(O)NR a R b , -C(O)OR a , -NR a S(O) m R b , -O(CH 2 ) n R a , -(CH 2 ) n P(O)R a R b , -(CH 2 ) n S(O) m NR a R b , -(CH 2 ) n C(O)R a , -NR a C(O)OR b , -(CH 2 ) n S(O) m R a or -(CH 2 ) n NR a S (O) m R b , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R a选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a1、-(CH 2) nNR a1R b1、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)R b1、-NR a1C(O)NR b1R c1、-NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1R b1、-C(O)OR a1、-NR a1S(O) mR b1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、-NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R a is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, hydroxyalkyl group, azido group, an alkenyl group, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a1 , -(CH 2 ) n NR a1 R b1 , -NR a1 (CH 2 ) n R b1 ,- NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 R c1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n NR c1 R d1 , -C(O)NR a1 R b1 , -C(O)OR a1 , -NR a1 S(O) m R b1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P( O)R a1 R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -(CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -(CH 2 ) n S(O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, Optional can be further substituted;
    R b选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、羟烷基、叠氮基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR a2、-(CH 2) nNR a2R b2、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)R b2、-NR a2C(O)NR b2R c2、-NR a2C(O)NR b2(CH 2) nR c2、-NR a2C(O)C≡CR b2、-NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2R b2、 -C(O)OR a2、-NR a2S(O) mR b2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或-(CH 2) nNR a2S(O) mR b2，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R b is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, hydroxyalkyl, azido, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR a2 , -(CH 2 ) n NR a2 R b2 , -NR a2 (CH 2 ) n R b2 ,- NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)R b2 , -NR a2 C(O)NR b2 R c2 , -NR a2 C(O)NR b2 (CH 2 ) n R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n R c2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 R b2 , -C(O)OR a2 , -NR a2 S(O) m R b2 , -O(CH 2 ) n R a2 , -(CH 2 ) n P( O)R a2 R b2 , -(CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O)R a2 , -NR a2 C(O)OR b2 , -(CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O) m R b2 , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, Optional can be further substituted;
    R aa、R a、R b、R c、R a1、R b1、R c1、R d1、R a2、R b2、R c2或R d2各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代； R aa , R a , R b , R c , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 or R d2 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkane Group, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, The alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optional Can be further replaced;
    x为0～5的整数；x is an integer from 0 to 5;
    y为0～5的整数；y is an integer from 0 to 5;
    m为0～2的整数；且m is an integer from 0 to 2; and
    n为0～4的整数。n is an integer of 0-4.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，L选自键、-(CH 2) n-、-(CH 2) nNR aa-、-(CH 2) nO-、-(CH 2) nS-、-(CH 2) nC(O)-、-(CH 2) nC(O)NR aa-、-(CH 2) nNR aaC(O)-、-(CH 2) nC(O)O-、-(CH 2) nP(O)R aa-、-(CH 2) nS(O) m-、-(CH 2) nS(O) mNR aa-或-(CH 2) nNR aaS(O) m-；优选键或-(CH 2) nNR aa-；更优选键或-NH-。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein L is selected from bond, -(CH 2 ) n -, -(CH 2 ) n NR aa -,- (CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C(O)-, -(CH 2 ) n C(O)NR aa -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n C(O)O-, -(CH 2 ) n P(O)R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa -or -(CH 2 ) n NR aa S(O) m -; preferably a bond or -(CH 2 ) n NR aa -; more preferably a bond or -NH-.
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自C 6-14芳基或5-14元杂芳基；优选苯基。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the ring A is selected from C 6-14 aryl or 5-14 membered heteroaryl; preferably phenyl.
  4. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选苯基、苯并杂芳基或苯并杂环基；进一步优选如下基团： The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the ring B is selected from 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heterocyclic group. Aryl; preferably phenyl, benzoheteroaryl or benzoheterocyclyl; further preferably the following groups:
    Figure PCTCN2020131472-appb-100002
    Figure PCTCN2020131472-appb-100002
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选苯并杂芳基、苯并杂环基、吡啶并杂芳基或吡啶并杂环基；进一步优选如下基团： The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the ring B is selected from 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heterocyclic group. Aryl; preferably benzoheteroaryl, benzoheterocyclic, pyridoheteroaryl or pyridoheterocyclyl; further preferably the following groups:
    Figure PCTCN2020131472-appb-100003
    Figure PCTCN2020131472-appb-100003
  6. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1选自氢、氘、卤素、氰基、氨基、硝基、羟基、叠氮基、C 1-6羧酸C 1-6酯基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、取代或未取代的5-14元杂芳基、-NR aC(O)NR b(CH 2) nR c、-C≡CR a、-NR aC(O)CR b＝CHR c、-C(O)NR a(CH 2) nR b、-C(O)OR a、-O(CH 2) nR a、-(CH 2) nS(O) mR a和-(CH 2) nP(O)R aR b；优选氢原子、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-12元杂环基、取代或未取代的5-14元杂芳基、-O(CH 2) nR a或-C(O)OR a；进一步优选如下取代基：氢、氟、氯、溴、三氟甲基、氰基、甲氧基、-C(O)OCH(CH 3) 2、
    Figure PCTCN2020131472-appb-100004
    The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R 1 is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, azido, C 1-6 carboxylic acid C 1-6 ester group, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, -NR a C(O) NR b (CH 2 ) n R c , -C≡CR a , -NR a C(O)CR b =CHR c , -C(O)NR a (CH 2 ) n R b , -C(O)OR a, -O (CH 2) n R a, - (CH 2) n S (O) m R a , and - (CH 2) n P ( O) R a R b; preferably a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocycle Group, substituted or unsubstituted 5-14 membered heteroaryl group, -O(CH 2 ) n R a or -C(O)OR a ; further preferred are the following substituents: hydrogen, fluorine, chlorine, bromine, trifluoromethyl Group, cyano, methoxy, -C(O)OCH(CH 3 ) 2 ,
    Figure PCTCN2020131472-appb-100004
  7. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R a选自氢、氘、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、取代或未取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1(CH 2) nR b1、-C(O)OR a1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-NR a1S(O) mR b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、-NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1；优选氢原子、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、取代或未取代的3-12元杂环基、5-14元杂芳基、-NR a1(CH 2) nR b1、-NR a1(CH 2) nNR b1R c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1或-O(CH 2) nR a1；进一步优选如下取代基：氢、甲氧基、-NHC(O)CH＝CH 2、
    Figure PCTCN2020131472-appb-100005
    Figure PCTCN2020131472-appb-100006
    The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein Ra is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, substituted or unsubstituted 3-12 member Heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O) C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n NR c1 R d1 , -C(O) NR a1 (CH 2 ) n R b1 , -C(O)OR a1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P(O)R a1 R b1 , -NR a1 S(O) m R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -(CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -(CH 2 ) n S (O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 ; preferably a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, substituted or unsubstituted 3-12 membered heterocyclic group, 5-14 membered heteroaryl group, -NR a1 (CH 2 ) n R b1 , -NR a1 (CH 2 ) n NR b1 R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n NR c1 R d1 or -O(CH 2 ) n R a1 ; further preferably the following substituents: hydrogen, methoxy, -NHC(O)CH=CH 2 ,
    Figure PCTCN2020131472-appb-100005
    Figure PCTCN2020131472-appb-100006
  8. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R b选自氢、氘、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)C≡CR b2、-NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2(CH 2) nR b2、-C(O)OR a2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或 -(CH 2) nNR a2S(O) mR b2；优选氢原子、卤素、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-8环烷基、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mR a2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2或-C(O)NR a2(CH 2) nR b2；进一步优选如下取代基：氢、卤素、环丙基、-C(CH 3) 2(OH)、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3或-C(O)NHCH 3。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R b is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 =CH(CH 2 ) n R c2 , -NR a2 C(O)CR b2 =CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 (CH 2 ) n R b2 , -C(O)OR a2 , -O(CH 2 ) n R a2 , -(CH 2 ) n P(O)R a2 R b2 , -NR a2 S(O) m R b2 ,- (CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O)R a2 , -NR a2 C(O)OR b2 , -(CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O) m R b2 ; preferably a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, -(CH 2 ) n P(O)R a2 R b2 , -(CH 2 ) n S(O) m R a2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 or -C(O)NR a2 (CH 2 ) n R b2 ; further preferred are the following substituents: hydrogen, halogen, Cyclopropyl, -C(CH 3 ) 2 (OH), -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S (O) 2 NHCH 3 or -C(O)NHCH 3 .
  9. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R b选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-5烯基、C 2-5炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 3-6环烷基、3-10元杂环基、C 6-12芳基或5-12元杂芳基；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、甲基、乙基、丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、氘代甲基、氘代乙基、氘代丙基、氟甲基、氟乙基、氟丙基、氯甲基、氯乙基、氯丙基、溴甲基、溴乙基、溴丙基、羟甲基、羟乙基、羟丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、环丙基、环丁基、环戊基、环己基、环庚基、环氧丙基、环氧丁基、环氧戊基、环氧己基、环氧庚基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环庚基、噻吩基、吡咯基、吡啶基、吡喃基、哌嗪基、苯基或萘基。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 Halogenated alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, Cyano, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl Group, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, nitrogen Cyclopentyl, azepanyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, or naphthyl.
  10. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R aa、R a、R b、R c、R a1、R b1、R c1、R d1、R a2、R b2、R c2或R d2各自独立地选自氢、氘、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 1-6环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、氰基、C 1-4烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6卤代烷基、C 2-6烯基羰基、C 1-6羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-12元杂环基、取代或未取代的C 6-14芳基和取代或未取代的5-14元杂芳基取代。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R aa , R a , R b , R c , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 or R d2 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 hydroxyalkyl, C 1-6 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen , Amino, cyano, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 2-6 alkenylcarbonyl, C 1-6 hydroxyalkane Group, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-14 aryl and substituted or unsubstituted 5-14 membered hetero Aryl substituted.
  11. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(II)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (II):
    Figure PCTCN2020131472-appb-100007
    Figure PCTCN2020131472-appb-100007
    其中：among them:
    R 2选自氢、氘、卤素、氰基、氨基、硝基、羟基、叠氮基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a1C(O)R b1、-NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1、-C(O)NR a1(CH 2) nR b1、-C(O)OR a1、-O(CH 2) nR a1、-(CH 2) nP(O)R a1R b1、-NR a1S(O) mR b1、-(CH 2) nS(O) mNR a1R b1、-(CH 2) nC(O)R a1、-NR a1C(O)OR b1、-(CH 2) nS(O) mR a1或-(CH 2) nNR a1S(O) mR b1；优选-NR a1C(O)R b1、-NR a1C(O)NR b1(CH 2) nR c1、-NR a1C(O)C≡CR b1、-NR a1C(O)CR b1＝CH(CH 2) nR c1、-NR a1C(O)CR b1＝CH(CH 2) nNR c1R d1；更优选-NHC(O)CH＝CH 2； R 2 is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, azido, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH(CH 2 ) n R c1 , -NR a1 C(O)CR b1 = CH(CH 2 ) n NR c1 R d1 , -C(O)NR a1 (CH 2 ) n R b1 , -C(O)OR a1 , -O(CH 2 ) n R a1 , -(CH 2 ) n P(O)R a1 R b1 , -NR a1 S(O) m R b1 , -(CH 2 ) n S(O) m NR a1 R b1 , -(CH 2 ) n C(O)R a1 , -NR a1 C(O)OR b1 , -(CH 2 ) n S(O) m R a1 or -(CH 2 ) n NR a1 S(O) m R b1 ; preferably -NR a1 C(O)R b1 , -NR a1 C(O)NR b1 (CH 2 ) n R c1 , -NR a1 C(O)C≡CR b1 , -NR a1 C(O)CR b1 ＝CH (CH 2 ) n R c1 , -NR a1 C(O)CR b1 =CH(CH 2 ) n NR c1 R d1 ; more preferably -NHC(O)CH=CH 2 ;
    R 3选自氢、氘、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-O(CH 2) nR a1、-NR a1(CH 2) nR b1或-NR a1(CH 2) nNR b1R c1，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被卤素、氰基、羟基、巯基、C 1-4烷基、C 1-4腈基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4羟烷基和取代或未取代的3-12元杂环基的一个或多个取代基所取代；优选取代的3-12元杂环基、-NR a1(CH 2) nR b1或-NR a1(CH 2) nNR b1R c1；更优选如下基团： R 3 is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -O(CH 2 ) n R a1 , -NR a1 (CH 2 ) n R b1 or -NR a1 (CH 2 ) n NR b1 R c1 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further substituted by halogen, cyano Group, hydroxy, mercapto, C 1-4 alkyl, C 1-4 nitrile, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and substituted or unsubstituted 3- The 12-membered heterocyclic group is substituted by one or more substituents; preferably a substituted 3-12-membered heterocyclic group, -NR a1 (CH 2 ) n R b1 or -NR a1 (CH 2 ) n NR b1 R c1 ; The following groups are more preferred:
    Figure PCTCN2020131472-appb-100008
    Figure PCTCN2020131472-appb-100008
    R 4选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢、甲基、甲氧基或乙氧基。 R 4 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably hydrogen , Methyl, methoxy or ethoxy.
  12. 根据权利要求9所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(III)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 9, wherein the general formula (I) is further represented by the general formula (III):
    Figure PCTCN2020131472-appb-100009
    Figure PCTCN2020131472-appb-100009
    其中：among them:
    R 5选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-NR a2(CH 2) nR b2、-NR a2(CH 2) nNR b2R c2、-NR a2C(O)C≡CR b2、 -NR a2C(O)CR b2＝CH(CH 2) nR c2、-NR a2C(O)CR b2＝CH(CH 2) nNR c2R d2、-C(O)NR a2(CH 2) nR b2、-C(O)OR a2、-O(CH 2) nR a2、-(CH 2) nP(O)R a2R b2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2、-(CH 2) nC(O)R a2、-NR a2C(O)OR b2、-(CH 2) nS(O) mR a2或-(CH 2) nNR a2S(O) mR b2；优选氢原子、卤素、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-8环烷基、-(CH 2) nP(O)R a2R b2、-(CH 2) nS(O) mR a2、-NR a2S(O) mR b2、-(CH 2) nS(O) mNR a2R b2或-C(O)NR a2(CH 2) nR b2；进一步优选如下取代基：氢原子、-C(CH 3) 2(OH)、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3或-C(O)NHCH 3； R 5 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, -NR a2 (CH 2 ) n R b2 , -NR a2 (CH 2 ) n NR b2 R c2 , -NR a2 C(O)C≡CR b2 , -NR a2 C(O)CR b2 ＝CH(CH 2 ) n R c2 , -NR a2 C( O)CR b2 = CH(CH 2 ) n NR c2 R d2 , -C(O)NR a2 (CH 2 ) n R b2 , -C(O)OR a2 , -O(CH 2 ) n R a2 ,- (CH 2 ) n P(O)R a2 R b2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 , -(CH 2 ) n C(O ) R a2 , -NR a2 C(O)OR b2 , -(CH 2 ) n S(O) m R a2 or -(CH 2 ) n NR a2 S(O) m R b2 ; preferably hydrogen atom, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, -(CH 2 ) n P(O)R a2 R b2 , -(CH 2 ) n S(O) m R a2 , -NR a2 S(O) m R b2 , -(CH 2 ) n S(O) m NR a2 R b2 Or -C(O)NR a2 (CH 2 ) n R b2 ; further preferably the following substituents: hydrogen atom, -C(CH 3 ) 2 (OH), -P(O)(CH 3 ) 2 , -S( O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S(O) 2 NHCH 3 or -C(O)NHCH 3 ;
    R 6和R 7各自独立地选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子或卤素； R 6 and R 7 are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; preferably a hydrogen atom or halogen;
    或者，R 6、R 7与它们所连的碳原子链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代；优选如下基团： Alternatively, R 6 and R 7 are linked with the carbon atom to which they are attached to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups are any The selected ones can be further substituted; the following groups are preferred:
    Figure PCTCN2020131472-appb-100010
    Figure PCTCN2020131472-appb-100010
    R 8选自氢、氘、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子或卤素。 R 8 is selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C A 1-6 hydroxyalkyl group, a C 3-8 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group; preferably a hydrogen atom or a halogen.
  13. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IV)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (IV):
    Figure PCTCN2020131472-appb-100011
    Figure PCTCN2020131472-appb-100011
    或者，如通式(V)所示：Or, as shown in general formula (V):
    Figure PCTCN2020131472-appb-100012
    Figure PCTCN2020131472-appb-100012
  14. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(VI)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (VI):
    Figure PCTCN2020131472-appb-100013
    Figure PCTCN2020131472-appb-100013
    其中：among them:
    R 9选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子、C 1-6烷基或C 3-8环烷基；更优选氢、甲基或环丙基。 R 9 is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom, C 1-6 alkyl group Or C 3-8 cycloalkyl; more preferably hydrogen, methyl or cyclopropyl.
  15. 根据权利要求14所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(VI)进一步如通式(VI-A)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 14, wherein the general formula (VI) is further represented by the general formula (VI-A):
    Figure PCTCN2020131472-appb-100014
    Figure PCTCN2020131472-appb-100014
    R 9不为甲基。 R 9 is not a methyl group.
  16. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述通式(I)进一步如通式(VII)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (VII):
    Figure PCTCN2020131472-appb-100015
    Figure PCTCN2020131472-appb-100015
  17. 根据根据权利要求16所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 16, characterized in that:
    M为N或CR 1； M is N or CR 1 ;
    R 1选自氢、卤素、氰基、三氟甲基、氰基、甲氧基、乙氧基、-C(O)OCH(CH 3) 2、
    Figure PCTCN2020131472-appb-100016
    R 1 is selected from hydrogen, halogen, cyano, trifluoromethyl, cyano, methoxy, ethoxy, -C(O)OCH(CH 3 ) 2 ,
    Figure PCTCN2020131472-appb-100016
    环B选自
    Figure PCTCN2020131472-appb-100017
    Figure PCTCN2020131472-appb-100018
    Ring B is selected from
    Figure PCTCN2020131472-appb-100017
    Figure PCTCN2020131472-appb-100018
    R b选自氢原子、氘原子、卤素、氰基、氨基、硝基、羟基、磷酰基、磺酰基、氨基磺酰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；优选氢原子、-P(O)(CH 3) 2、-S(O) 2CH 3、-NHS(O) 2CH(CH 3) 2、-S(O) 2NHCH 3、C 1-6烷基或C 3-8环烷基；更优选氢、甲基、-P(O)(CH 3) 2、-S(O) 2CH 3、或环丙基； R b is selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, phosphoryl, sulfonyl, aminosulfonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; Preferably a hydrogen atom, -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , -NHS(O) 2 CH(CH 3 ) 2 , -S(O) 2 NHCH 3 , C 1-6 Alkyl group or C 3-8 cycloalkyl group; more preferably hydrogen, methyl, -P(O)(CH 3 ) 2 , -S(O) 2 CH 3 , or cyclopropyl;
    y为1、2或3，优选1。y is 1, 2 or 3, preferably 1.
  18. 根据权利要求1～17中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-17, characterized in that it is selected from the following compounds:
    Figure PCTCN2020131472-appb-100019
    Figure PCTCN2020131472-appb-100019
    Figure PCTCN2020131472-appb-100020
    Figure PCTCN2020131472-appb-100020
  19. 一种制备权利要求15所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：A method for preparing the compound represented by general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof according to claim 15, characterized in that it comprises the following steps:
    Figure PCTCN2020131472-appb-100021
    Figure PCTCN2020131472-appb-100021
    通式(VI-1)与通式(VI-2)反应，得到通式(VI-3)，通式(VI-3)继续与通式(VI-4)反应，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；The general formula (VI-1) reacts with the general formula (VI-2) to obtain the general formula (VI-3), and the general formula (VI-3) continues to react with the general formula (VI-4) to obtain the general formula (VI) The indicated compound or its stereoisomers and pharmaceutically acceptable salts thereof;
    其中：among them:
    X 1和X 2各自独立选自卤素；优选氟、氯、溴或碘；更优选氯； X 1 and X 2 are each independently selected from halogen; preferably fluorine, chlorine, bromine or iodine; more preferably chlorine;
    X 3选自卤素、硼酸或硼酸酯；优选硼酸酯；更优选
    Figure PCTCN2020131472-appb-100022
    X 3 is selected from halogen, boric acid or boric acid ester; preferably boric acid ester; more preferably
    Figure PCTCN2020131472-appb-100022
  20. 一种药物组合物，其包括治疗有效剂量的权利要求1～18中所述的化合物及其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of the compound described in claims 1-18 and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients Shape agent.
  21. 根据权利要求1～18中任一项所述的化合物、及其立体异构体或其药学上可接受的盐，或权利要求20所述的药物组合物在制备激酶抑制剂中的应用，优选地，激酶抑制剂为受体酪氨酸激酶抑制剂(TKI)，更优选HER2抑制剂、EGFR抑制剂和EGFR单抗及其联用相关药物中的应用，进一步优选EGFR 20外显子插入突变和HER2 20外显子插入突变靶点的抑制剂。The use of the compound according to any one of claims 1 to 18, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 20 in the preparation of kinase inhibitors, preferably Specifically, the kinase inhibitor is a receptor tyrosine kinase inhibitor (TKI), more preferably HER2 inhibitors, EGFR inhibitors and EGFR monoclonal antibodies and their associated drug applications, and further preferably EGFR 20 exon insertion mutations And HER2 20 exon insertion mutation target inhibitor.
  22. 根据权利要求1～18中任一项所述的化合物及其立体异构体或其药学上可接受的盐，或权利要求20所述的药物组合物在制备治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病和AIDS相关疾病中药物的应用，优选地，癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。The compound according to any one of claims 1 to 18 and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 20 is used for the treatment of cancer, inflammation, chronic liver disease, diabetes , Cardiovascular diseases and AIDS-related diseases. Preferably, the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma , Glioblastoma, Leukemia, Lymphoma, Myeloma and Non-Small Cell Lung Cancer.
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