WO2019034128A1 - Pyrrolotriazine derivative, preparation method and use thereof - Google Patents

Pyrrolotriazine derivative, preparation method and use thereof Download PDF

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WO2019034128A1
WO2019034128A1 PCT/CN2018/100901 CN2018100901W WO2019034128A1 WO 2019034128 A1 WO2019034128 A1 WO 2019034128A1 CN 2018100901 W CN2018100901 W CN 2018100901W WO 2019034128 A1 WO2019034128 A1 WO 2019034128A1
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group
compound
formula
stereoisomer
pharmaceutically acceptable
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PCT/CN2018/100901
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French (fr)
Chinese (zh)
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别平彦
安泉林
曹琪
张磊涛
陈磊
白骅
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浙江海正药业股份有限公司
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Priority to CN201880047124.1A priority Critical patent/CN110891953B/en
Publication of WO2019034128A1 publication Critical patent/WO2019034128A1/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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to novel pyrrolotriazine derivatives, processes for their preparation and pharmaceutical compositions comprising such derivatives and their use as therapeutic agents, in particular as c-KIT inhibitors.
  • c-KIT also known as KIT, CD117 and stem cell factor receptor
  • KIT c-KIT
  • CD117 and stem cell factor receptor a transmembrane tyrosine kinase protein that acts as a type III receptor.
  • the c-KIT proto-oncogene located on chromosome 4q11-21 encodes the c-KIT receptor and its ligand is a stem cell factor.
  • the receptor has tyrosine protein kinase activity and binding to the ligand SCF results in autophosphorylation of c-KIT and its association with a substrate such as phosphatidylinositol 3-kinase (PI3K).
  • PI3K phosphatidylinositol 3-kinase
  • Phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signaling and can mediate signals of major cellular processes such as proliferation, survival, differentiation, apoptosis, ligation, invasion and migration.
  • c-KIT mutations are commonly found in DNA encoding the membrane proximal domain (exon 11). They also appear in exons 7, 8, 9, 13, 14, 17 and 18 at a lower frequency. Mutations make c-KIT function independent of activation by SCF, resulting in high cell division rates and possible genomic instability.
  • c-KIT has been used in gastrointestinal stromal tumors, acute myeloid leukemia, systemic mastocytosis, melanoma, breast adenoma, ovarian tumor, cervical cancer, seminoma, dysplasia, teratoma, hypertrophy It has been found in tissues such as cell leukemia, and its protein expression level is closely related to the occurrence and development of tumors.
  • Gastrointestinal stromal tumor GIST
  • GIST Gastrointestinal stromal tumor
  • the platelet-derived growth factor receptor is a cell surface tyrosine kinase receptor that is a member of the platelet-derived growth factor (PDGF) family.
  • the PDGF subunits PDGF-A and PDGF-B are important regulators of cell proliferation, cell differentiation, cell growth, development, and many diseases including cancer.
  • one of the objects of the present application is to provide a novel pyrrolotriazine derivative of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.
  • the compounds of the present application have large structural differences from the compounds disclosed in the prior art, and diseases such as gastrointestinal stromal tumors and systemic mastocytosis can be treated or prevented by modulating c-KIT activity.
  • E is a hydrogen atom
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and/or heteroaryl; preferably aryl; more preferably phenyl;
  • W and Q are each independently selected from C and/or N, but the two are not simultaneously C; W and Q are preferably N;
  • D is selected from a chemical bond, -(alkylene)-, -(alkenylene)-, -(alkynylene)-, -(cycloalkylene)-, -(heterocyclylene)-, -C( O)-, -O-, -S-, -S(O)-, -SO 2 -, -NR 6 -, -O-(alkylene)-, -(alkylene)-O-, - NR 6 -C(O)-, -C(O)-NR 6 -, -(alkylene)-NR 6 -, -NR 6 -(alkylene)-, -NR 6 -C(O)- (alkylene)-, -C(O)-NR 6 -(alkylene)-, -NR 6 -SO 2 -, -SO 2 -NR 6 -, -NR 6 -SO 2 -, -SO 2 -NR 6 -
  • R 1 and R 3 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a hydroxyl group, a cyano group, a nitro group, a halogen, and/or —NR 6 R 7 , wherein the alkane a group, an alkoxy group, a cycloalkyl group or a heterocyclic group is optionally further substituted by one or more halogens; R 1 and R 3 are preferably a hydrogen atom;
  • R 2 and R 5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a hydroxyl group, a cyano group, a nitro group, a halogen group, a heterocyclic group, an aryl group, a heteroaryl group, and -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 , Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 6 R 7
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further isolated by one or a plurality of selected from the group consisting of halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , Substituted with a substituent of -C(O)R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
  • R 6 , R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group.
  • alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC Substituting (O) a substituent of R 11 , —S(O) p NR 9 R 10 and/or —NR 9 C(O)R 10 ;
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group,
  • the aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and / or substituted with a substituent of a carboxylate group;
  • n is selected from 1, 2, 3, 4 and/or 5;
  • n is selected from 1, 2, 3 and/or 4;
  • p is selected from 0, 1 and/or 2.
  • D is -(alkylene)-; preferably methylene;
  • alkylene group is further substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyl group, a halogen, and/or -NR 6 R 7 ;
  • R 6 and R 7 are as defined in formula (I).
  • the compound of the formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
  • R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
  • R 1 -R 7 , m and n are as defined in formula (I).
  • the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
  • R 1 -R 7 , m and n are as defined in formula (I).
  • the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
  • R 1 -R 7 , m and n are as defined in formula (I).
  • the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
  • R 1 -R 7 , m and n are as defined in formula (I).
  • the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof An acceptable salt wherein each R 2 is a hydrogen atom.
  • the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts where:
  • R 4 is heteroaryl, preferably pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl, more preferably pyrazolyl, wherein said pyrrolyl Or pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl optionally further selected from one or more selected from C1-6 alkyl, 4-6 membered heterocyclyl and Substituted by a substituent of -C(O)R 8 ;
  • R 8 is a C 1-6 alkyl group.
  • the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts where:
  • R 4 is a tetrahydropyridinyl group, wherein the tetrahydropyridinyl group is further further selected from one or more selected from the group consisting of C 1-6 alkyl, 4-6 membered heterocyclic, and/or -C(O)R 8 Substituted by a substituent;
  • R 8 is a C 1-6 alkyl group
  • tetrahydropyridyl group is preferably
  • the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts where:
  • R 5 is selected from a hydrogen atom, a halogen, an alkyl group and/or an alkoxy group
  • the halogen is preferably F or Cl
  • the alkyl group is preferably a C 1-6 alkyl group; more preferably a methyl group;
  • the alkoxy group is preferably a C 1-6 alkoxy group; more preferably a methoxy group.
  • the compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein:
  • R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
  • R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
  • R 1 , R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group
  • R 4 is a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is further optionally further selected from one or more selected from C 1-6 alkyl, 3-8 membered cycloalkyl, 4-6 Heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O) Substituted by a substituent of R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
  • R 5 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and/or a C 1-6 alkoxy group;
  • R 6 and R 7 are each independently a hydrogen atom or a C 1-6 alkyl group
  • R 8 is a C 1-6 alkyl group
  • n is selected from 1, 2, 3, 4 and/or 5;
  • n is selected from 1, 2, 3 and/or 4;
  • p is selected from 0, 1 and/or 2.
  • the present application provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • the R 4 substituted boronate is preferably:
  • X 1 is halogen, preferably Br
  • R 1 -R 5 , R a , R b , m and n are as defined in formula (II).
  • the present application further provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
  • R a is an alkyl group
  • R b is a hydroxyl group
  • R 1 -R 5 , m and n are as defined in formula (II).
  • R a is an alkyl group
  • R b is -NR 6 R 7 ;
  • R 6 and R 7 are a hydrogen atom
  • R f is -NH-S(O)R e ;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 5 , m and n are as defined in formula (II).
  • X 1 is halogen, preferably Br
  • R 1 -R 3 , R 5 , R a , R b , m and n are as defined in the formula (II).
  • the compound of the formula (IIA) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof is of the formula (IIIA), (IVA) Or a compound of (VA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • X 1 is halogen, preferably Br
  • R 1 -R 3 , R 5 , R b , m and n are as defined in formula (II).
  • R 1 -R 5 , m and n are as defined in formula (II).
  • R a is an alkyl group
  • R f is -NH-S(O)R e ;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 5 , m and n are as defined in formula (II).
  • the present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
  • R a is an alkyl group
  • R b is a hydroxyl group
  • X 1 is halogen, preferably Br
  • R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
  • the present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the (S) form or the (R) form; preferably the (S) form; and the formula (IIk) is obtained.
  • a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm);
  • a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);
  • the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
  • X 1 is halogen, preferably Br
  • R a is an alkyl group
  • R b is -NR 6 R 7 ;
  • R 6 and R 7 are a hydrogen atom;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
  • the present application provides a process for the preparation of a compound of formula (IIB), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • X 2 is halogen, preferably Cl or Br
  • R 1 -R 5 , m and n are as defined in formula (IIB).
  • the present application provides a process for the preparation of a compound of formula (IIC), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
  • the R 4 substituted boronate is preferably:
  • X 1 is halogen, preferably Br
  • R a is an alkyl group
  • R f is -NH-S(O)R e ;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 5 , m and n are as defined in formula (IIC).
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the application provides a method of inhibiting c-KIT comprising the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.
  • the application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof
  • a salt, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease mediated by c-KIT or a mutant c-KIT
  • the c-KIT or mutant c-KIT mediated disease is preferably selected From gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia More preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation c- The mutation of KIT is at exon 9, 11, 13, 14, 17,
  • the application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof Use of a salt, or a pharmaceutical composition thereof, for the preparation of a c-KIT inhibitor.
  • the application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof
  • a salt, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease mediated by a mutant or wild-type PDFGR ⁇
  • the PDFGR ⁇ or mutant PDFGR ⁇ -mediated disease is preferably selected from the group consisting of a gastrointestinal tract Tumor, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; more preferably selected from the stomach Intestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGR ⁇ is located in exon 18 And/or at amino acid residue position 842,
  • the present application provides a method of treating a disease mediated by c-KIT or a mutant c-KIT comprising administering to a patient a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula a compound of (V), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein said c-KIT or mutated c-KIT mediated disease is preferably selected From gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia More preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation c- The mutation of
  • the present application provides a method of treating a disease mediated by PDFGR ⁇ or a mutated PDFGR ⁇ comprising administering to a patient a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PDFGR ⁇ or mutated PDFGR ⁇ mediated disease is preferably selected from the group consisting of gastrointestinal stromal tumors , systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; more preferably selected from the gastrointestinal Teratoma, systemic mastocytosis, and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGR ⁇ is located in ex
  • alkyl as a group or part of a group is meant to include C 1 -C 20 linear or branched saturated aliphatic hydrocarbon groups having chain.
  • C 1 -C 20 means 1 to 20 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms , 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylp
  • Alkylene is a divalent alkyl group as defined above. It is preferably a C 1 -C 10 alkylene group, more preferably a C 1 -C 6 alkylene group.
  • C 1 -C 10 means 1 to 10 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms.
  • alkylene groups include, but are not limited to, methylene, ethylene, Acetylene and so on. The alkylene group may be substituted or unsubstituted.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group can be optionally substituted or unsubstituted.
  • the alkenyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.
  • Alkenylene refers to a divalent alkenyl group as defined above.
  • Preferred is a C 2 -C 10 alkenylene group, more preferably a C 2 -C 6 alkenylene group, and most preferably a C 2 -C 4 alkenylene group.
  • alkenylene groups include, but are not limited to, ethenylene, i2-propenyl, sub-1, 2- or 3-butenyl, and the like.
  • the alkenylene group may be substituted or unsubstituted.
  • the alkenylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, either straight or branched. Preference is given to C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups, most preferably C 2 -C 4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted.
  • An alkynyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.
  • Alkynylene means a divalent alkynyl group as defined above, preferably a C 2 -C 10 alkynylene group, more preferably a C 2 -C 6 alkynylene group, most preferably a C 2 -C 4 alkynylene group .
  • alkynylene groups include, but are not limited to, ethynylene, propylene-1-propynyl, 2-propynyl, sub-1, 2- or 3-butynyl, and the like.
  • the alkynylene group may be substituted or unsubstituted.
  • the alkynylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.
  • Cycloalkyl refers to a saturated (“cycloalkyl”) or partially saturated monocyclic, fused, bridged, and spiro carbon ring, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Cycloalkylene is a divalent cycloalkyl group as defined above. It is preferably a C 3 -C 12 cycloalkylene group, more preferably a C 3 -C 8 cycloalkylene group, and most preferably a C 3 -C 6 cycloalkylene group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. A cycloalkylene group can be substituted or unsubstituted.
  • “Spirocyclyl” refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), one or more of which may contain One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused ring group” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures that share a carbon atom with each other, one or more of which may contain one or more double bonds, However, none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge ring group” means 5 to 18 members, containing two or more cyclic structures, sharing two carbon-polycyclic groups which are not directly bonded to each other, and one or more of the rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring o [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclic group may be substituted or unsubstituted.
  • the heterocyclic group may contain 3 to 14 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) atoms.
  • “Spiroheterocyclyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and one or more of the rings may contain one or more a double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and/or S(O) p (where p is selected from 0, 1, and/or 2 1, 2, 3 or 4 heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • Spiroheterocyclyl groups may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, 13, four, fifteen, fifteen , 16, 17, or 18) atoms.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more of which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen and/or S(O) p (where p is selected from 0, 1 and/or 2) heteroatoms, the remaining ring atoms For carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1.
  • the fused heterocyclic group may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, threeteen, fourteen, fifteen, 15 , 16, 17, or 18) atoms.
  • “Bridge heterocyclyl” refers to a polycyclic group of 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two atoms which are not directly bonded to each other, one or more rings thereof An aromatic system which may contain one or more double bonds, but none of which has a fully conjugated ⁇ -electron, wherein one or more ring atoms are selected from nitrogen, oxygen and/or S(O) p (where p is selected from 0 a hetero atom of 1, 1 and/or 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the bridge heterocyclic group may contain 3 to 18 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, or 18) atoms.
  • Heterocyclylene means a divalent heterocyclic group as described above. It preferably has a 5- to 7-membered monocyclic heterocyclic group or a 7 to 10 membered bicyclic heterocyclic group or a tricyclic heterocyclic group, which may contain 1, 2, 3 or 4 selected from nitrogen, oxygen and/or sulfur. The atom.
  • the heterocyclylene group may be substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system comprising one, two or more rings, wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group may contain from 6 to 10 carbon atoms, for example, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • the aryl group can be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, ox
  • Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can contain from 6 to 10 (eg, 6, 7, 8, 9, or 10) atoms.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C 1 -C 6 are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • Boc refers to a tert-butoxycarbonyl group.
  • DMSO dimethyl sulfoxide
  • 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 by 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 will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • R 6 , R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group.
  • alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC Substituting (O) a substituent of R 11 , -S(O) P NR 9 R 10 and/or -NR 9 C(O)R 10 ;
  • R 6 and R 7 together with the attached N atom form a 4-8 membered heterocyclic group wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) p atoms, and 4
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group,
  • the aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid And/or substituted with a substituent of a carboxylic acid ester;
  • p is selected from 0, 1 and/or 2.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and which are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt or an amine salt formed with a suitable acid.
  • “Pharmaceutical composition” means a mixture comprising a compound of the present application, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the present application adopts the following technical solutions.
  • the R 4 substituted boronate is preferably:
  • X 1 is halogen, preferably Br
  • R 1 -R 5 , R a , R b , m and n are as defined in formula (II).
  • R a is an alkyl group
  • R b is a hydroxyl group
  • R 1 -R 5 , m and n are as defined in formula (II).
  • Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R a is an alkyl group
  • R b is an amino group
  • R f is -NH-S(O)R e ;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 5 , m and n are as defined in formula (II).
  • the compound of formula (IIa) is subjected to a Suzuki coupling reaction with a compound of formula (IIb) to give a compound of formula (IIc); the compound of formula (IIc) is hydrolyzed to give a compound of formula (IId); under basic conditions, The compound of (IId) is subjected to a condensation reaction in the presence of a condensing agent to obtain a compound of the formula (IIe); the compound of the formula (IIe) is deprotected to give a compound of the formula (IIf); and under basic conditions, the compound of the formula (IIf) The compound is subjected to a substitution reaction with a compound of the formula (IIg) to give a compound of the formula (IIh); the compound of the formula (IIh) is further reacted with a Grignard reagent (IIi) to give a compound of the formula (IIj); a compound of the formula (IIj) Reacting with a Grignard
  • X 1 is halogen, preferably Br
  • X 2 -X 3 are each independently halogen, preferably Cl or Br;
  • R a is an alkyl group
  • R b is a hydroxyl group
  • R c is an amino protecting group, preferably a tert-butoxycarbonyl group
  • R d is an alkyl group, preferably a methyl group or an ethyl group
  • R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
  • Another method for preparing a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to the present application, comprises the steps of:
  • the compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIq); the compound of the formula (IIq) is deprotected to give a compound of the formula (IIr); under basic conditions, the formula (IIr) Substituting a compound with a compound of formula (IIg) to give a compound of formula (IIj); a compound of formula (IIj) is reacted with a Grignard reagent to provide a compound of formula (IIA);
  • X 1 is halogen, preferably Br
  • X 2 is halogen, preferably Cl or Br
  • R a is an alkyl group
  • R b is a hydroxyl group
  • R c is an amino protecting group, preferably a tert-butoxycarbonyl group
  • R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
  • a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the (S) form or the (R) form; preferably the (S) form; and the formula (IIk) is obtained.
  • a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm);
  • a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);
  • the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
  • X 1 is halogen, preferably Br
  • R a is an alkyl group
  • R b is -NR 6 R 7 ;
  • R 6 and R 7 are a hydrogen atom
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
  • the compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIn); the compound of the formula (IIn) is deprotected to give a compound of the formula (IIp); under basic conditions, the formula (IIp) Substituting a compound with a compound of formula (IIs) to give a compound of formula (IIB);
  • X 2 is halogen, preferably Cl or Br
  • R c is an amino protecting group, preferably a tert-butoxycarbonyl group
  • R 1 -R 5 , m and n are as defined in formula (IIB).
  • Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the R 4 substituted boronate is preferably:
  • X 1 is halogen, preferably Br
  • R a is an alkyl group
  • R f is -NH-S(O)R e ;
  • R e is an alkyl group, preferably a tert-butyl group
  • R 1 -R 5 , m and n are as described in (IIC).
  • the compound of the formula (II), when R b is selected from different substituents, can be converted between the groups, in particular, the compound of the formula (II-2) or the compound of the formula (II-2) or A method of preparing a pharmaceutically acceptable salt, comprising the steps of:
  • R b1 is a hydroxyl group
  • R b2 is F
  • R 1 -R 5 , R a , m and n are as defined in formula (II).
  • the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and/or 4-dimethylamine.
  • Pyridine preferably diisopropylethylamine and triethylamine
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and/or potassium hydride, preferably cesium carbonate and potassium carbonate.
  • Condensing reagents include, but are not limited to, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, bis(2-oxo-3- Oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, o-benzotriazole-N,N,N'N'- Tetramethylurea borate (TBTU), preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate bis(2-oxo-3- Oxazolidinyl)phosphoryl chloride
  • Coupling reagents include, but are not limited to: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) Dipalladium or tri-tert-butylphosphine palladium is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide.
  • Figure 1 is a voltage program diagram of whole cell patch clamp in the hERG potassium ion channel test in Test Example 3.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. -0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution.
  • the compound is purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Methyl chloride and ethyl acetate; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C two Methyl chloride and ethyl acetate
  • the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • 6-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1a (4.8 g, 22.43 mmol) was dissolved in 100 mL of phosphorus oxychloride and reacted at 130 ° C. 3 hours. The organic layer was extracted with dichloromethane (100 mL ⁇ 3), and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. Drying and concentration under reduced pressure gave 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b (5.15 g, brown solid).
  • reaction solution was diluted with 150 mL of dichloromethane, and washed with water (20 mL ⁇ 2), 1M aqueous hydrochloric acid (20 mL), saturated aqueous sodium hydrogen carbonate (20 mL) and saturated aqueous sodium chloride (20 mL). Drying over sodium sulfate, EtOAc (EtOAc) 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.18 g, white solid), yield: 83.1%.
  • N-Methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide 8a (9.94 g, 40.1 mmol) was dissolved in 100 mL of dichloro N,N-diisopropylethylamine (31.03 g, 240.5 mmol) was added dropwise to methane, and stirred at room temperature for 5 min, then 6-bromo-4-chloropyrrolo[2,1-f][1,2, 4] Triazine 1b (9.72 g, 42.1 mmol) was reacted at room temperature for 3 hours.
  • EtOAc EtOAc m. Drying over sodium sulfate and concentrating under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: C system) to give (2-(1-(6-bromopyrrolo[2,1-f][1 , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-chlorophenyl)methanone 8c (1.5 g, light Yellow solid), yield: 75%.
  • reaction was quenched by the addition of 50 mL of ice water, and the mixture was evaporated to dryness, and the residue was evaporated to ethyl acetate (60 mL ⁇ 3), and the organic phase was washed with 50 mL of saturated aqueous sodium chloride.
  • Oxetane-3-alcohol 14a (2.0 g, 27.0 mmol), triethylamine (10.9 g, 108.0 mmol) and 4-dimethylaminopyridine (330 mg, 2.7 mmol) were dissolved in 20 mL of dichloromethane and added p-Toluenesulfonic acid (10.3 g, 54.0 mmol) was reacted at room temperature for 12 hours. The organic layer was extracted with water (25 mL ⁇ 3), saturated aqueous sodium chloride (25 mL ⁇ 1), and the organic phase was anhydrous sulfuric acid.
  • magnesium swarf (294 mg, 12.1 mmol) and 1 iodine were dissolved in 10 mL of tetrahydrofuran, and 4-bromo-1,2-difluorobenzene 16a (3.9 g, 20.4 mmol) was dissolved in 2 mL of tetrahydrofuran.
  • 0.2 mL was added dropwise to the above reaction solution, and the bottom of the reaction flask was blown with a hair dryer to initiate a reaction, and then the remaining 4-bromo-1,2-difluorobenzene solution was slowly added dropwise to the reaction solution, and kept.
  • the reaction was slightly refluxed, and the reaction was carried out for 1 hour at room temperature.
  • (3,4-difluorophenyl)magnesium bromide 16b (12 mL, m.p.
  • magnesium chips (520 mg, 22.0 mmol) and 1 iodine were dissolved in 15 mL of tetrahydrofuran, and 1 mL of 2-bromo-1,3-difluorobenzene 24a (3.86 g, 20.0 mmol) was dissolved in 5 mL of tetrahydrofuran.
  • the reaction was initiated by heating, and then the remaining 2-bromo-1,3-difluorobenzene 24a (2.0 mL, 16.89 mmol) in tetrahydrofuran was slowly added, and the reaction was kept to reflux slightly, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, (2,6-difluorophenyl)magnesium bromide 24b (20 mL, light brown solution, 1.0 M/THF) was obtained.
  • Test Example 1 Determination of c-KIT [WT], c-KIT [D816V], PDGFR ⁇ [D842V] kinase activity by the compounds of the present application
  • This method uses the company of Cisbio KinEASE-TK Tyrosine Kinase Kit (Cat. No. 62TK0PEB), the kit principle is based on time-resolved fluorescence energy resonance transfer (TF-FRET), which is reflected by measuring the degree of phosphorylation of protein-mediated biotinylated peptide substrates. Compounds inhibit the activity of protein kinases. For detailed experimental procedures, refer to the kit instructions.
  • TF-FRET time-resolved fluorescence energy resonance transfer
  • c-KIT [WT] Recombinant human c-KIT [WT], c-KIT [D816V] and PDGFR ⁇ [D842V] protein kinases were purchased from Carna bioscience (Japan, item number c-KIT[WT]#08-156, c-KIT[D816V] #08-505, PDFGR ⁇ [D842V]#08-506).
  • the experimental procedure is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, followed by serial dilution with a buffer provided in the kit, and the final concentration of the test compound in the reaction system ranges from 10 ⁇ M to 0.1 nM.
  • the concentration of the ATP solution used in the test (Biotech (Shanghai) Co., Ltd., #A600311) was determined by pre-determined ATP Km concentration for each kinase, where c-KIT[WT], c-KIT[D816V]
  • the ATP Km values corresponding to PDGFR ⁇ [D842V] were 100 ⁇ M, 30 ⁇ M, and 30 ⁇ M, respectively.
  • the reaction was carried out in a 384-well microplate. First, the test compound and 0.66 ng of the test protein were added to the well, and incubated at room temperature for 5 minutes, and then the ATP solution and the biotinylated polypeptide substrate were added to the reaction solution. After incubating for 50 minutes at room temperature with shaking at room temperature, an anti-phosphotyrosine antibody conjugated with a lanthanide compound and streptavidin coupled with modified allophycocyanin XL665 were added to the reaction. Incubate for 1 hour at room temperature with continued shaking.
  • the fluorescence intensity values of the respective wells at an excitation wavelength of 304 nm and emission wavelengths of 620 nM and 665 nM were measured in a TF-FRET mode by a microplate reader.
  • the percentage inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the compound IC was obtained by nonlinear regression analysis of the compound concentration-inhibition rate by GraphPad Prism 5 software. 50 values, see Tables 1-1 and 1-2.
  • Avapritinib is as follows, and is prepared according to the published patent application WO 2015057873.
  • Test Example 2 Determination of P815 activity in mouse mastocytoma by the compound of the present application
  • the experimental method is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted with the corresponding medium of the cells to prepare a test sample, and the final concentration of the compound ranges from 30 ⁇ M to 0.01 nM.
  • the tumor cells in the logarithmic growth phase were seeded at a density of 1000 cells/well into a 96-well cell culture plate, and after overnight at 37 ° C in a 5% CO 2 incubator, the test compound samples were added and the cells were further cultured for 48 hours.
  • Test Example 3 Effect of the compounds of the present application on human hERG ion channels stably expressed in HEK293 cells
  • hERG ion channel is stably expressed in HEK293 cells.
  • Patch clamp instrument patch clamp-505B
  • test compounds were prepared on the same day and re-dissolved in the extracellular fluid.
  • the extracellular fluid was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the intracellular fluid was: K Aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
  • the compounds were all perfused using a perfusion system using their own gravity. Test at least two cells per concentration. After the current is stable (or 5 minutes), the change in current magnitude before and after the compound is compared to calculate the blocking effect of the compound.
  • the positive control Cisapride concentration was selected based on its sensitivity to cell sensitivity, and the concentration of about 90% blocking rate was the optimal concentration of the positive control. When the Cisapride was tested at 100 nM, the blocking rate was about 90%, so the positive control Cisapride was set at 100 nM. The method is the same as the test compound.
  • the cells were transferred to a perfusion tank and perfused with extracellular fluid.
  • the intracellular fluid (mM) was: K Aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
  • the intracellular fluid was stored in small portions in a -80 degree refrigerator and thawed on the day of the experiment.
  • the electrodes were drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered using one-fifth of the sampling frequency.
  • the cells were clamped at –80 mV, then depolarized to 40 mV with a square wave lasting 4 seconds, and then hyperpolarized to -40 mV with a square wave for 2 seconds to obtain the hERG tail current (see Figure 1). This procedure is repeated every 20 seconds.
  • the hERG tail current is a pure hERG current.
  • the maximum current induced by the second square wave is detected.
  • the test compound is perfused, and when the reaction is stable, the blocking strength is calculated.
  • the specific IC 50 is shown in Table 3. See Figure 1 for details.
  • Table 3 Representative compounds of the present application IC 50 values of inhibition of the hERG potassium ion channel
  • Example 31 of the present application has less inhibitory activity on hERG potassium channel and lower cardiotoxicity than Avapritinib.
  • Test Example 4 This application represents a pharmacokinetic test of a compound
  • SD rats were used as test animals, and the drug concentration in plasma was determined by LC/MS/MS method after intragastric administration of Avapritinib, Example 2, Example 27 and Example 31.
  • 0.15 mL of blood was collected from the neck before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in a heparinized test tube at 5500 rpm. Centrifuge for 10 minutes, store at -20 ° C, and eat 4 hours after administration.
  • the sample to be administered was diluted with a mixed solvent of methanol and water (4:1, v/v) to a concentration of 1 ⁇ g ⁇ mL -1 , and 20 ⁇ L of the diluted sample and the internal standard solution (100 ng ⁇ mL -1 ) were added to 200 ⁇ L.
  • the acetonitrile solution (containing the IS solution) and 220 ⁇ L of water were then vortexed, and the supernatant of 3 ⁇ L of the mixed solution was taken to an LC-MS/MS system for analysis.
  • Test Example 5 Pharmacokinetics in beagle dogs
  • the Beagle dogs were used as test animals, and the drug concentration in plasma was determined by LC/MS/MS method after the administration of Avapritinib and the compound of Example 31 in the beagle dogs.
  • the representative compounds in the present application were studied in rats. Pharmacokinetic characteristics.
  • Oral administration solvent DMSO/0.5% CMC-Na (5:95, v/v)
  • the animal room is well ventilated, equipped with air conditioning, the temperature is maintained at 16-26 ° C, the humidity is maintained at 40% -70%.
  • the light and dark lighting is 12 hours each, and each dog is independently raised and can eat and drink freely.
  • the drug concentration was 0.6 mg/mL; 3 male beagle dogs in each group.

Abstract

Disclosed are a pyrrolotriazine derivative, a preparation method and use thereof. Specifically, disclosed are the pyrrolotriazine derivative of formula (I), a pharmaceutically acceptable salt thereof, a preparation method and use thereof as a therapeutic agent, particularly as a c-KIT inhibitor, wherein the definition of each substituent in the formula (I) is the same as defined in the description.

Description

吡咯并三嗪类衍生物、其制备方法及其用途Pyrrolotriazine derivative, preparation method thereof and use thereof 发明领域Field of invention
本申请涉及新型吡咯并三嗪类衍生物、其制备方法及包含该衍生物的药物组合物以及其作为治疗剂特别是作为c-KIT抑制剂的用途。The present application relates to novel pyrrolotriazine derivatives, processes for their preparation and pharmaceutical compositions comprising such derivatives and their use as therapeutic agents, in particular as c-KIT inhibitors.
发明背景Background of the invention
c-KIT(也称为KIT、CD117和干细胞因子受体)是充当III型受体的145kDa跨膜酪氨酸激酶蛋白。位于染色体4q11-21上的c-KIT原癌基因编码c-KIT受体，其配体是干细胞因子。所述受体具有酪氨酸蛋白激酶活性并且与配体SCF的结合导致c-KIT的自磷酸化和其与底物如磷脂酰肌醇3-激酶(PI3K)的缔合。蛋白质酪氨酸激酶对酪氨酸的磷酸化在细胞信号传导方面特别重要并且可以介导主要细胞过程例如增殖、存活、分化、凋亡、连接、侵袭和迁移的信号。c-KIT突变通常出现在编码近膜区结构域的DNA(外显子11)中。它们还以较低频率出现在外显子7、8、9、13、14、17和18中。突变使得c-KIT功能不依赖于由SCF激活，从而导致高细胞分裂速率和可能的基因组不稳定性。c-KIT基因的功能增加性突变和组成性磷酸化c-KIT的表达可见于大部分胃肠间质瘤(GIST)、肥大细胞增多症和急性髓性白血病中。其在不同的外显子处有不同位置的突变，第一代的c-KIT突变和相关药物主要为伊马替尼、舒尼替尼、达沙替尼和PKC412。c-KIT (also known as KIT, CD117 and stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that acts as a type III receptor. The c-KIT proto-oncogene located on chromosome 4q11-21 encodes the c-KIT receptor and its ligand is a stem cell factor. The receptor has tyrosine protein kinase activity and binding to the ligand SCF results in autophosphorylation of c-KIT and its association with a substrate such as phosphatidylinositol 3-kinase (PI3K). Phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signaling and can mediate signals of major cellular processes such as proliferation, survival, differentiation, apoptosis, ligation, invasion and migration. c-KIT mutations are commonly found in DNA encoding the membrane proximal domain (exon 11). They also appear in exons 7, 8, 9, 13, 14, 17 and 18 at a lower frequency. Mutations make c-KIT function independent of activation by SCF, resulting in high cell division rates and possible genomic instability. Functionally increased mutations in the c-KIT gene and expression of constitutive phosphorylation c-KIT can be found in most gastrointestinal stromal tumors (GIST), mastocytosis, and acute myeloid leukemia. It has mutations at different positions in different exons. The first generation of c-KIT mutations and related drugs are mainly imatinib, sunitinib, dasatinib and PKC412.
c-KIT已在胃肠道间质瘤、急性髓性白血病、系统性肥大细胞增生症、黑色素瘤、乳腺瘤、卵巢瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤、肥大细胞白血病等组织中被发现，其蛋白表达水平与肿瘤的发生发展有着密切的关系。其中胃肠间质瘤(gastrointestinal stromal tumor，GIST)是胃肠道最常见的间叶来源肿瘤，依照目前的GIST诊断标准，流行病学研究显示发病率为0.66-2.20/10万。GIST对传统化学治疗极不敏感，化疗药物有效率不足5％，进展期中位生存率仅约18个月。即使完整切除肿瘤，GIST的5年生存率也仅为35％-65％，2年内复发转移率为40％-50％，首诊时多达15％-50％的患者已存在转移。研究发现干细胞因子表面的跨膜酪氨酸激酶受体c-KIT和血小板源性生长因子受体PDGFRα基因的功能活化突变是GIST发生发展的关键。血小板源性生长因子受体(PDGF-R)是血小板源性生长因子(PDGF)家族成员的细胞表面酪氨酸激酶受体。PDGF亚基PDGF-A和PDGF-B是调控细胞增殖、细胞分化、细胞生长、发育和许多疾病包括癌症的重要调节因子。c-KIT has been used in gastrointestinal stromal tumors, acute myeloid leukemia, systemic mastocytosis, melanoma, breast adenoma, ovarian tumor, cervical cancer, seminoma, dysplasia, teratoma, hypertrophy It has been found in tissues such as cell leukemia, and its protein expression level is closely related to the occurrence and development of tumors. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal origin of the gastrointestinal tract. According to the current GIST diagnostic criteria, epidemiological studies show an incidence of 0.66-2.20/100,000. GIST is extremely insensitive to traditional chemotherapy, with less than 5% effective chemotherapy drugs and a median survival rate of only about 18 months. Even with complete tumor resection, the 5-year survival rate of GIST is only 35%-65%, and the recurrence and metastasis rate is 40%-50% within 2 years. Up to 15%-50% of patients in the first diagnosis have metastasis. It was found that the transmembrane tyrosine kinase receptor c-KIT on the surface of stem cell factor and the functional activating mutation of the platelet-derived growth factor receptor PDGFRα gene are the key to the development of GIST. The platelet-derived growth factor receptor (PDGF-R) is a cell surface tyrosine kinase receptor that is a member of the platelet-derived growth factor (PDGF) family. The PDGF subunits PDGF-A and PDGF-B are important regulators of cell proliferation, cell differentiation, cell growth, development, and many diseases including cancer.
随着第一代抑制剂伊马替尼(Imatinib)的临床应用，伊马替尼的获得性耐药问题逐渐成为该类抑制剂临床使用中面临的严重挑战。因此，迫切需要研究开发新的c-KIT抑制剂来满足市场需求。目前处于临床III期的c-KIT抑制剂药物包括Deciphera公司研发的ripretinib和Blueprint公司的Avapritinib。目前也已经公开了一系列的c-KIT抑制剂专利，其中包括WO2014039714、WO2014100620和WO2015134536A1等，c-KIT抑制剂的研究和应用已 取得一定的进展，但是提高的空间仍然巨大，仍有必要继续研究和开发新的c-KIT抑制剂。With the clinical application of the first-generation inhibitor, Imatinib, the acquired resistance of imatinib has become a serious challenge in the clinical use of such inhibitors. Therefore, there is an urgent need to research and develop new c-KIT inhibitors to meet market demand. Currently in clinical phase III c-KIT inhibitor drugs include ripretinib developed by Decifera and Avapritinib by Blueprint. A series of c-KIT inhibitor patents have also been published, including WO2014039714, WO2014100620 and WO2015134536A1. The research and application of c-KIT inhibitors have made some progress, but the room for improvement is still huge, and it is still necessary to continue. Research and development of new c-KIT inhibitors.
发明内容Summary of the invention
为了克服现有技术的不足，本申请的目的之一在于提供式(I)的新型吡咯并三嗪衍生物，或其立体异构体、互变异构体或其药学上可接受的盐。本申请的化合物同现有技术中公开的化合物具有较大的结构差异，且可以通过调节c-KIT活性来治疗或预防诸如胃肠道间质瘤和系统性肥大细胞增生等疾病。In order to overcome the deficiencies of the prior art, one of the objects of the present application is to provide a novel pyrrolotriazine derivative of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present application have large structural differences from the compounds disclosed in the prior art, and diseases such as gastrointestinal stromal tumors and systemic mastocytosis can be treated or prevented by modulating c-KIT activity.
式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐：a compound of the formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000001
Figure PCTCN2018100901-appb-000001
其中：among them:
E为氢原子或
Figure PCTCN2018100901-appb-000002
E is a hydrogen atom or
Figure PCTCN2018100901-appb-000002
环A选自环烷基、杂环基、芳基和/或杂芳基；优选为芳基；更优选为苯基；Ring A is selected from cycloalkyl, heterocyclyl, aryl and/or heteroaryl; preferably aryl; more preferably phenyl;
W和Q各自独立地选自C和/或N，但两者不同时为C；W和Q优选为N；W and Q are each independently selected from C and/or N, but the two are not simultaneously C; W and Q are preferably N;
D选自化学键、-(亚烷基)-、-(亚烯基)-、-(亚炔基)-、-(亚环烷基)-、-(亚杂环基)-、-C(O)-、-O-、-S-、-S(O)-、-SO 2-、-NR 6-、-O-(亚烷基)-、-(亚烷基)-O-、-NR 6-C(O)-、-C(O)-NR 6-、-(亚烷基)-NR 6-、-NR 6-(亚烷基)-、-NR 6-C(O)-(亚烷基)-、-C(O)-NR 6-(亚烷基)-、-NR 6-SO 2-、-SO 2-NR 6-、-NR 6-SO 2-(亚烷基)-和/或-SO 2-NR 6-(亚烷基)-；其中所述亚烷基、亚烯基、亚环烷基或亚杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7的取代基所取代； D is selected from a chemical bond, -(alkylene)-, -(alkenylene)-, -(alkynylene)-, -(cycloalkylene)-, -(heterocyclylene)-, -C( O)-, -O-, -S-, -S(O)-, -SO 2 -, -NR 6 -, -O-(alkylene)-, -(alkylene)-O-, - NR 6 -C(O)-, -C(O)-NR 6 -, -(alkylene)-NR 6 -, -NR 6 -(alkylene)-, -NR 6 -C(O)- (alkylene)-, -C(O)-NR 6 -(alkylene)-, -NR 6 -SO 2 -, -SO 2 -NR 6 -, -NR 6 -SO 2 -(alkylene And/or -SO 2 -NR 6 -(alkylene)-; wherein the alkylene, alkenylene, cycloalkylene or heterocyclylene group is further further selected from one or more selected from the group consisting of hydroxyl groups , halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C( Substituting the substituents of O) R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
R 1和R 3各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、羟基、氰基、硝基、卤素和/或-NR 6R 7，其中所述烷基、烷氧基、环烷基或杂环基任选进一步被一个或多个卤素所取代；R 1和R 3优选为氢原子； R 1 and R 3 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a hydroxyl group, a cyano group, a nitro group, a halogen, and/or —NR 6 R 7 , wherein the alkane a group, an alkoxy group, a cycloalkyl group or a heterocyclic group is optionally further substituted by one or more halogens; R 1 and R 3 are preferably a hydrogen atom;
R 2和R 5各自独立地选自氢原子、烷基、烷氧基、环烷基、羟基、氰基、硝基、卤素、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个 或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7的取代基所取代； R 2 and R 5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a hydroxyl group, a cyano group, a nitro group, a halogen group, a heterocyclic group, an aryl group, a heteroaryl group, and -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 , Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O)R 8 , -S Substituting (O) a substituent of p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
R 4选自烷基、环烷基、杂环基、芳基和/或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、-OR 8、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7的取代基所取代； R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further isolated by one or a plurality of selected from the group consisting of halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , Substituted with a substituent of -C(O)R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
R 6、R 7和R 8各自独立地选自氢原子、羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和/或杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) pNR 9R 10和/或-NR 9C(O)R 10的取代基所取代； R 6 , R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group. Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC Substituting (O) a substituent of R 11 , —S(O) p NR 9 R 10 and/or —NR 9 C(O)R 10 ;
或者，R 6和R 7与相连接的N原子一起形成4-8元杂环基，其中所述4-8元杂环内包含一个或多个N、O、S(O) p原子，并且所述4-8元杂环上任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) pNR 9R 10和/或-NR 9C(O)R 10的取代基所取代； Alternatively, R 6 and R 7 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) p atoms, and Optionally, the 4-8 membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , =O, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O) p Substituted by a substituent of NR 9 R 10 and/or -NR 9 C(O)R 10 ;
R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和/或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基和/或羧酸酯基的取代基所取代； R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, The aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and / or substituted with a substituent of a carboxylate group;
m选自1，2，3，4和/或5；m is selected from 1, 2, 3, 4 and/or 5;
n选自1，2，3和/或4；且n is selected from 1, 2, 3 and/or 4;
p选自0，1和/或2。p is selected from 0, 1 and/or 2.
根据本申请的优选的实施方案，式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：According to a preferred embodiment of the present application, the compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
D为-(亚烷基)-；优选为亚甲基；D is -(alkylene)-; preferably methylene;
其中所述亚烷基进一步被选自烷基、羟基、卤素和/或-NR 6R 7的取代基所取代；且 Wherein the alkylene group is further substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyl group, a halogen, and/or -NR 6 R 7 ;
R 6和R 7的定义如式(I)中所述。 R 6 and R 7 are as defined in formula (I).
根据本申请的优选的实施方案，对于式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：According to a preferred embodiment of the present application, the compound of the formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000003
Figure PCTCN2018100901-appb-000003
其中：among them:
R a为氢原子或烷基；优选为C 1-6烷基，更优选为甲基； R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
R b选自羟基、卤素和/或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
R 1-R 7、m和n的定义如式(I)中所述。 R 1 -R 7 , m and n are as defined in formula (I).
根据本申请的优选的实施方案，对于式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(III)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000004
Figure PCTCN2018100901-appb-000004
其中：among them:
R b选自羟基、卤素和/或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
R 1-R 7、m和n的定义如式(I)中所述。 R 1 -R 7 , m and n are as defined in formula (I).
根据本申请的优选的实施方案，对于式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(IV)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000005
Figure PCTCN2018100901-appb-000005
其中：among them:
R b选自羟基、卤素和/或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
R 1-R 7、m和n的定义如式(I)中所述。 R 1 -R 7 , m and n are as defined in formula (I).
根据本申请的优选的实施方案，对于式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000006
Figure PCTCN2018100901-appb-000006
其中：among them:
R b选自羟基、卤素和/或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
R 1-R 7、m和n的定义如式(I)中所述。 R 1 -R 7 , m and n are as defined in formula (I).
根据本申请的优选的实施方案，对于式(I)、(II)、(III)、(IV)或(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中各个R 2均为氢原子。 According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof An acceptable salt wherein each R 2 is a hydrogen atom.
根据本申请的优选的实施方案，对于式(I)、(II)、(III)、(IV)或(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:
R 4为杂芳基，优选为吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶基或吡啶基，更优选为吡唑基，其中所述的吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶基或吡啶基任选进一步被一个或多个选自C 1-6烷基、4-6元杂环基和/或-C(O)R 8的取代基所取代；且 R 4 is heteroaryl, preferably pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl, more preferably pyrazolyl, wherein said pyrrolyl Or pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl optionally further selected from one or more selected from C1-6 alkyl, 4-6 membered heterocyclyl and Substituted by a substituent of -C(O)R 8 ;
R 8为C 1-6烷基。 R 8 is a C 1-6 alkyl group.
根据本申请的优选的实施方案，对于式(I)、(II)、(III)、(IV)或(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:
R 4为四氢吡啶基，其中所述四氢吡啶基任选进一步被一个或多个选自C 1-6烷基、4-6元杂环基和/或-C(O)R 8的取代基所取代； R 4 is a tetrahydropyridinyl group, wherein the tetrahydropyridinyl group is further further selected from one or more selected from the group consisting of C 1-6 alkyl, 4-6 membered heterocyclic, and/or -C(O)R 8 Substituted by a substituent;
R 8为C 1-6烷基；且 R 8 is a C 1-6 alkyl group;
其中所述四氢吡啶基优选为
Figure PCTCN2018100901-appb-000007
Wherein the tetrahydropyridyl group is preferably
Figure PCTCN2018100901-appb-000007
根据本申请的优选的实施方案，对于式(I)、(II)、(III)、(IV)或(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:
R 5选自氢原子、卤素、烷基和/或烷氧基； R 5 is selected from a hydrogen atom, a halogen, an alkyl group and/or an alkoxy group;
所述卤素优选为F或Cl；The halogen is preferably F or Cl;
所述烷基优选为C 1-6烷基；更优选为甲基；且 The alkyl group is preferably a C 1-6 alkyl group; more preferably a methyl group;
所述烷氧基优选为C 1-6烷氧基；更优选为甲氧基。 The alkoxy group is preferably a C 1-6 alkoxy group; more preferably a methoxy group.
根据本申请的优选的实施方案，对于式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：According to a preferred embodiment of the present application, the compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R a为氢原子或烷基；优选为C 1-6烷基，更优选为甲基； R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
R b选自羟基、卤素和/或-NR 6R 7； R b is selected from the group consisting of hydroxyl, halogen and/or -NR 6 R 7 ;
R 1、R 2和R 3各自独立地为氢原子或C 1-6烷基； R 1 , R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group;
R 4为杂芳基或杂环基，其中所述杂芳基或杂环基任选进一步被一个或多个选自C 1-6烷基、3-8元环烷基、4-6元杂环基、6元芳基、5-6元杂芳基、-OR 8、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7的取代基所取代； R 4 is a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is further optionally further selected from one or more selected from C 1-6 alkyl, 3-8 membered cycloalkyl, 4-6 Heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O) Substituted by a substituent of R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
R 5选自氢原子、卤素、C 1-6烷基和/或C 1-6烷氧基； R 5 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and/or a C 1-6 alkoxy group;
R 6和R 7各自独立地为氢原子或C 1-6烷基； R 6 and R 7 are each independently a hydrogen atom or a C 1-6 alkyl group;
R 8为C 1-6烷基； R 8 is a C 1-6 alkyl group;
m选自1，2，3，4和/或5；m is selected from 1, 2, 3, 4 and/or 5;
n选自1，2，3和/或4；且n is selected from 1, 2, 3 and/or 4;
p选自0，1和/或2。p is selected from 0, 1 and/or 2.
本申请的具体化合物包括，但不限于：Specific compounds of the present application include, but are not limited to:
Figure PCTCN2018100901-appb-000008
Figure PCTCN2018100901-appb-000008
Figure PCTCN2018100901-appb-000009
Figure PCTCN2018100901-appb-000009
Figure PCTCN2018100901-appb-000010
Figure PCTCN2018100901-appb-000010
Figure PCTCN2018100901-appb-000011
Figure PCTCN2018100901-appb-000011
Figure PCTCN2018100901-appb-000012
Figure PCTCN2018100901-appb-000012
Figure PCTCN2018100901-appb-000013
Figure PCTCN2018100901-appb-000013
Figure PCTCN2018100901-appb-000014
Figure PCTCN2018100901-appb-000014
Figure PCTCN2018100901-appb-000015
Figure PCTCN2018100901-appb-000015
或其立体异构体、互变异构体或其药学上可接受的盐。Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.
本申请提供制备式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000016
Figure PCTCN2018100901-appb-000016
其中将式(IIA)的化合物或其盐与R 4取代的硼酸酯或硼酸反应，得到式(II)的化合物； Wherein the compound of the formula (IIA) or a salt thereof is reacted with an R 4 -substituted boronic acid ester or boric acid to obtain a compound of the formula (II);
其中：among them:
所述R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
Figure PCTCN2018100901-appb-000017
Figure PCTCN2018100901-appb-000017
X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
R 1-R 5、R a、R b、m和n的定义如式(II)中所述。 R 1 -R 5 , R a , R b , m and n are as defined in formula (II).
本申请进一步提供制备式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application further provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000018
Figure PCTCN2018100901-appb-000018
其中将式(IIB)的化合物或其盐与格氏试剂反应，得到式(II)的化合物；Wherein the compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to obtain a compound of the formula (II);
其中：among them:
所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
R a为烷基； R a is an alkyl group;
R b为羟基；且 R b is a hydroxyl group;
R 1-R 5、m和n的定义如式(II)中所述。 R 1 -R 5 , m and n are as defined in formula (II).
本申请提供另外的制备式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides an additional process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000019
Figure PCTCN2018100901-appb-000019
其中将式(IIC)的化合物在酸性条件下反应，得到式(II)的化合物；Wherein the compound of formula (IIC) is reacted under acidic conditions to provide a compound of formula (II);
其中：among them:
R a为烷基； R a is an alkyl group;
R b为-NR 6R 7； R b is -NR 6 R 7 ;
R 6和R 7为氢原子； R 6 and R 7 are a hydrogen atom;
R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 5、m和n的定义如式(II)中所述。 R 1 -R 5 , m and n are as defined in formula (II).
进一步，本申请提供制备式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：Further, the application provides the preparation of a compound of the formula (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000020
Figure PCTCN2018100901-appb-000020
其中：among them:
X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
R 1-R 3、R 5、R a、R b、m和n的定义如式(II)中所述。 R 1 -R 3 , R 5 , R a , R b , m and n are as defined in the formula (II).
根据本申请的优选的实施方案，其中对于式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(IIIA)、(IVA)或(VA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：According to a preferred embodiment of the present application, wherein the compound of the formula (IIA) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof is of the formula (IIIA), (IVA) Or a compound of (VA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000021
Figure PCTCN2018100901-appb-000021
其中：among them:
X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
R 1-R 3、R 5、R b、m和n的定义如式(II)中所述。 R 1 -R 3 , R 5 , R b , m and n are as defined in formula (II).
本申请式(IIA)的具体化合物包括，但不限于：Specific compounds of the formula (IIA) of the present application include, but are not limited to:
Figure PCTCN2018100901-appb-000022
Figure PCTCN2018100901-appb-000022
Figure PCTCN2018100901-appb-000023
Figure PCTCN2018100901-appb-000023
Figure PCTCN2018100901-appb-000024
Figure PCTCN2018100901-appb-000024
或其立体异构体、互变异构体或其药学上可接受的盐。Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.
本申请提供式(IIB)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The application provides a compound of the formula (IIB) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000025
Figure PCTCN2018100901-appb-000025
其中R 1-R 5、m和n的定义如式(II)中所述。 Wherein R 1 -R 5 , m and n are as defined in formula (II).
式(IIB)的化合物的具体化合物包括但不限于：Specific compounds of the compounds of formula (IIB) include, but are not limited to:
Figure PCTCN2018100901-appb-000026
Figure PCTCN2018100901-appb-000026
Figure PCTCN2018100901-appb-000027
Figure PCTCN2018100901-appb-000027
或其立体异构体、互变异构体或其药学上可接受的盐。Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.
本申请提供式(IIC)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The application provides a compound of the formula (IIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2018100901-appb-000028
Figure PCTCN2018100901-appb-000028
其中：among them:
R a为烷基； R a is an alkyl group;
R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 5、m和n的定义如式(II)中所述。 R 1 -R 5 , m and n are as defined in formula (II).
式(IIC)的化合物的具体化合物包括但不限于：Specific compounds of the compounds of formula (IIC) include, but are not limited to:
Figure PCTCN2018100901-appb-000029
Figure PCTCN2018100901-appb-000029
Figure PCTCN2018100901-appb-000030
Figure PCTCN2018100901-appb-000030
或其立体异构体、互变异构体或其药学上可接受的盐。Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.
本申请提供制备式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000031
Figure PCTCN2018100901-appb-000031
其中将式(IIj)的化合物或其盐与格氏试剂反应，得到式(IIA)的化合物；Wherein a compound of the formula (IIj) or a salt thereof is reacted with a Grignard reagent to give a compound of the formula (IIA);
其中：among them:
所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
R a为烷基； R a is an alkyl group;
R b为羟基； R b is a hydroxyl group;
X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
R 1-R 3、R 5、m和n的定义如式(IIA)中所述。 R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
本申请提供制备式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000032
Figure PCTCN2018100901-appb-000032
其中将式(IIj)的化合物与式(IIt)的化合物反应，其中式(IIt)的化合物的构型为(S)型或(R)型；优选为(S)型；得到式(IIk)的化合物；式(IIk)的化合物与格氏试剂反应，得到式(IIm)的化合物；式(IIm)的化合物在酸性条件下反应，得到式(IIA)的化合物；Wherein a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the (S) form or the (R) form; preferably the (S) form; and the formula (IIk) is obtained. a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm); a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);
其中：among them:
所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
R a为烷基； R a is an alkyl group;
R b为-NR 6R 7；R 6和R 7为氢原子； R b is -NR 6 R 7 ; R 6 and R 7 are a hydrogen atom;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 3、R 5、m和n的定义如式(IIA)中所述。 R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
本申请提供制备式(IIB)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides a process for the preparation of a compound of formula (IIB), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000033
Figure PCTCN2018100901-appb-000033
其中在碱性条件下，将式(IIp)的化合物与式(IIs)的化合物反应，得到式(IIB)的化合物；Wherein the compound of the formula (IIp) is reacted with a compound of the formula (IIs) under basic conditions to give a compound of the formula (IIB);
其中：among them:
X 2为卤素，优选为Cl或Br；且 X 2 is halogen, preferably Cl or Br;
R 1-R 5、m和n的定义如式(IIB)中所述。 R 1 -R 5 , m and n are as defined in formula (IIB).
本申请提供制备式(IIC)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：The present application provides a process for the preparation of a compound of formula (IIC), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:
Figure PCTCN2018100901-appb-000034
Figure PCTCN2018100901-appb-000034
将式(IIm)的化合物或其盐与R 4取代的硼酸酯或硼酸反应，得到式(IIC)的化合物； The compound of the formula (IIm) or a salt thereof is reacted with an R 4 -substituted boronic acid ester or boric acid to give a compound of the formula (IIC);
其中：among them:
所述R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
Figure PCTCN2018100901-appb-000035
Figure PCTCN2018100901-appb-000035
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
R a为烷基； R a is an alkyl group;
R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 5、m和n的定义如式(IIC)中所述。 R 1 -R 5 , m and n are as defined in formula (IIC).
更进一步，本申请提供药物组合物，所述药物组合物包含治疗有效量的式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，以及药学上可接受的载体、赋形剂或它们的组合。Further, the application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
本申请提供抑制c-KIT的方法，其包括将所述c-KIT受体与式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物相接触。The application provides a method of inhibiting c-KIT comprising the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.
本申请提供式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物在制备用于治疗由c-KIT或突变的c-KIT介导的疾病的药物中的用途，其中所述c-KIT或突变的c-KIT介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤和/或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症和/或急性髓性白血病，最优选为胃肠道间质瘤和系统性肥大细胞增生症；其中所述的突变c-KIT的突变位于外显子9、11、13、14、17和/或18处，和/或位于第816位氨基酸残基处，和/或第670位氨基酸残基处；其中所述第816位氨基酸残基处的突变优选为D816V或D816H，其中所述第670位氨基酸残基处的突变优选为T670I。The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof Use of a salt, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease mediated by c-KIT or a mutant c-KIT, wherein the c-KIT or mutant c-KIT mediated disease is preferably selected From gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia More preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation c- The mutation of KIT is at exon 9, 11, 13, 14, 17, and/or 18, and/or at amino acid residue 816, and/or at amino acid residue 670; wherein the 816th The mutation at the amino acid residue is preferably D816V or D816H, wherein the mutation at the amino acid residue at position 670 is preferably T670I.
本申请提供式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物在制备c-KIT抑制剂中的用途。The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof Use of a salt, or a pharmaceutical composition thereof, for the preparation of a c-KIT inhibitor.
本申请提供式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物在制备用于治疗由突变的或野生型的PDFGRα介导的疾病的药物中的用途，其中所述PDFGRα或突变的PDFGRα介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤和/或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症和/或急性髓性白血病，最优选为胃肠道间质瘤和系统性肥大细胞增生症；其中所述突变的PDFGRα的突变位于外显子18和/或第842位氨基酸残基处，其中所述第842位氨基酸残基处的突变优选为D842V突变。The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof Use of a salt, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease mediated by a mutant or wild-type PDFGRα, wherein the PDFGRα or mutant PDFGRα-mediated disease is preferably selected from the group consisting of a gastrointestinal tract Tumor, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; more preferably selected from the stomach Intestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGRα is located in exon 18 And/or at amino acid residue position 842, wherein the mutation at amino acid residue position 842 is preferably a D842V mutation.
本申请提供治疗由c-KIT或突变的c-KIT介导的疾病的方法，其包括给予患者治疗有效量的式(I)、式(II)、式(III)、式(IV)或式(V)的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物，其中所述c-KIT或突变的c-KIT介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤和/或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症和/或急性髓性白血病，最优选为胃肠道间质瘤和系统性肥大细胞增生症；其中所述突变的c-KIT的突变位于外显子9、11、13、14、17和/或18，和/或第816位氨基酸残基处，和/或第670位氨基酸残基处，其中所述第816位氨基酸残基处的突变优选为D816V或D816H；其中所述第670位氨基酸残基处的突变优选为T670I。The present application provides a method of treating a disease mediated by c-KIT or a mutant c-KIT comprising administering to a patient a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula a compound of (V), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein said c-KIT or mutated c-KIT mediated disease is preferably selected From gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia More preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation c- The mutation of KIT is located at exon 9, 11, 13, 14, 17, and/or 18, and/or at amino acid residue 816, and/or at amino acid residue 670, wherein the amino acid at position 816 The mutation at the residue is preferably D816V or D816H; wherein the mutation at the amino acid residue at position 670 is preferably T670I.
本申请提供治疗由PDFGRα或突变的PDFGRα介导的疾病的方法，其包括给予患者治疗有效剂量的式(I)、式(II)、式(III)、式(IV)或式(V)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其中所述PDFGRα或突变的PDFGRα介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤和/或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症和/或急性髓性白血病，最优选为胃肠道间质瘤和系统性肥大细胞增生症；其中所述突变的PDFGRα的突变位于外显子18和/或第842位氨基酸残基处；其中所述第842位氨基酸残基处的突变优选为D842V突变。The present application provides a method of treating a disease mediated by PDFGRα or a mutated PDFGRα comprising administering to a patient a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PDFGRα or mutated PDFGRα mediated disease is preferably selected from the group consisting of gastrointestinal stromal tumors , systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; more preferably selected from the gastrointestinal Teratoma, systemic mastocytosis, and/or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGRα is located in exon 18 and / or amino acid residue 842; wherein the mutation at amino acid residue position 842 is preferably a D842V mutation.
发明详述Detailed description of the invention
除非另有说明，否则本申请在说明书和权利要求书中所使用的部分术语定义如下：Unless otherwise stated, some of the terms used in this specification and claims are defined as follows:
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的饱和脂肪烃基团。例如，C 1-C 20是指包含1至20个碳原子，例如，可包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16 个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、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。烷基可以是取代或未取代的。 When "alkyl" as a group or part of a group is meant to include C 1 -C 20 linear or branched saturated aliphatic hydrocarbon groups having chain. For example, C 1 -C 20 means 1 to 20 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms , 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. The alkyl group can be substituted or unsubstituted.
“亚烷基”是二价的如上所定义的烷基。优选为C 1-C 10亚烷基，更优选为C 1-C 6亚烷基。例如，C 1-C 10是指包含1至10个碳原子，例如，可包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子。亚烷基基团的实施例包括但不限于亚甲基、亚乙基、
Figure PCTCN2018100901-appb-000036
亚正丙基等。亚烷基可以是取代或未取代的。 "Alkylene" is a divalent alkyl group as defined above. It is preferably a C 1 -C 10 alkylene group, more preferably a C 1 -C 6 alkylene group. For example, C 1 -C 10 means 1 to 10 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene,
Figure PCTCN2018100901-appb-000036
Acetylene and so on. The alkylene group may be substituted or unsubstituted.
“烯基”指包含至少两个碳原子和至少一个碳-碳双键的脂肪烃基团，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。烯基可以是任选取代的或未取代的。烯基可包含2至20个碳原子，例如，2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。"Alkenyl" refers to an aliphatic hydrocarbon group containing at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group can be optionally substituted or unsubstituted. The alkenyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.
“亚烯基”是指二价的如上所定义的烯基。例如，“亚乙烯基”表示基团-CH＝CH-。优选为C 2-C 10的亚烯基，更优选C 2-C 6亚烯基，最优选C 2-C 4亚烯基。亚烯基基团的实施例包括，但不限于亚乙烯基、亚2-丙烯基、亚1-、2-或3-丁烯基等。亚烯基可以是取代或未取代的。亚烯基可包含2至20个碳原子，例如，2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。 "Alkenylene" refers to a divalent alkenyl group as defined above. For example, "vinylidene" means the group -CH=CH-. Preferred is a C 2 -C 10 alkenylene group, more preferably a C 2 -C 6 alkenylene group, and most preferably a C 2 -C 4 alkenylene group. Examples of alkenylene groups include, but are not limited to, ethenylene, i2-propenyl, sub-1, 2- or 3-butenyl, and the like. The alkenylene group may be substituted or unsubstituted. The alkenylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.
“炔基”是指包含一个碳碳三键的脂肪烃基团，可为直链也可以带有支链。优先选择的是C 2-C 10的炔基，更优选C 2-C 6炔基，最优选C 2-C 4炔基。炔基基团的实施例包括，但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。炔基可包含2至20个碳原子，例如，2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。 "Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, either straight or branched. Preference is given to C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups, most preferably C 2 -C 4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted. An alkynyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.
“亚炔基”是指二价的如上所定义的炔基，优选为C 2-C 10的亚炔基，更优选C 2-C 6亚炔基，最优选C 2-C 4亚炔基。亚炔基基团的实施例包括，但不限于亚乙炔基、亚1-丙炔基、 亚2-丙炔基、亚1-、2-或3-丁炔基等。亚炔基可以是取代或未取代的。亚炔基可包含2至20个碳原子，例如，2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。 "Alkynylene" means a divalent alkynyl group as defined above, preferably a C 2 -C 10 alkynylene group, more preferably a C 2 -C 6 alkynylene group, most preferably a C 2 -C 4 alkynylene group . Examples of alkynylene groups include, but are not limited to, ethynylene, propylene-1-propynyl, 2-propynyl, sub-1, 2- or 3-butynyl, and the like. The alkynylene group may be substituted or unsubstituted. The alkynylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.
“环烷基”是指饱和(“环烷基”)或部分饱和的单环、稠环、桥环和螺环的碳环，但没有一个环具有完全共轭的π电子的芳香系统。优选为C 3-C 12环烷基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、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，优选环丙基、环己烯基。 "Cycloalkyl" refers to a saturated ("cycloalkyl") or partially saturated monocyclic, fused, bridged, and spiro carbon ring, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
“亚环烷基”是二价的如上所定义的环烷基。优选为C 3-C 12亚环烷基，更优选为C 3-C 8亚环烷基，最优选为C 3-C 6亚环烷基。亚环烷基基团的实施例包括但不限于亚环丙基、亚环丁基、亚环戊基等。亚环烷基可以是取代或未取代的。 "Cycloalkylene" is a divalent cycloalkyl group as defined above. It is preferably a C 3 -C 12 cycloalkylene group, more preferably a C 3 -C 8 cycloalkylene group, and most preferably a C 3 -C 6 cycloalkylene group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. A cycloalkylene group can be substituted or unsubstituted.
“螺环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，其一个或多个环可以含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。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、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。"Spirocyclyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), one or more of which may contain One or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
“稠环基”指5至18元，包含两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，其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电子的芳香系统，优选为6至12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、吡啶酮或多环稠环烷基，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”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。"Fused ring group" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures that share a carbon atom with each other, one or more of which may contain one or more double bonds, However, none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
“桥环基”指5至18元，包含两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，其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电子的芳香系统，优选为6至12元，更优选为7至10元。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、吡啶酮或多环桥环烷基，优选为双环、三环或吡啶酮，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环o[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。"Bridge ring group" means 5 to 18 members, containing two or more cyclic structures, sharing two carbon-polycyclic groups which are not directly bonded to each other, and one or more of the rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring o [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
环烷基的环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选 取代的或未取代的。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted.
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个成环的原子是杂原子，如氧、氮、硫原子等，包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2、3或4个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢吡喃基、1,1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。杂环基可包含3至14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个或14个)原子。"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl. The heterocyclic group may be substituted or unsubstituted. The heterocyclic group may contain 3 to 14 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) atoms.
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，其一个或多个环可以含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧和/或S(O) p(其中p选自0、1和/或2)的1，2、3或4个杂原子，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”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。螺杂环基可包含3至18个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个或18个)原子。 "Spiroheterocyclyl" means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and one or more of the rings may contain one or more a double bond, but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and/or S(O) p (where p is selected from 0, 1, and/or 2 1, 2, 3 or 4 heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl. Spiroheterocyclyl groups may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, 13, four, fifteen, fifteen , 16, 17, or 18) atoms.
“稠杂环基”指包含两个或两个以上环状结构彼此共用一对原子的全碳多环基团，其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电子的芳香系统，其中一个或多个环原子选自氮、氧和/或S(O) p(其中p选自0、1和/或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、吡啶酮或多环稠杂环基，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”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基、3-氮杂二环[3.1.0]己基、八氢苯并[b][1,4]二噁英(dioxine)。稠杂环基可包含3至18个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个或18个)原子。 "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more of which may contain one or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen and/or S(O) p (where p is selected from 0, 1 and/or 2) heteroatoms, the remaining ring atoms For carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine. The fused heterocyclic group may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, threeteen, fourteen, fifteen, 15 , 16, 17, or 18) atoms.
“桥杂环基”指5至14元，5至18元，包含两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，其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电子的芳香系统，其中一个或多个环原子选自氮、氧和/或S(O) p(其中p选自0、1和/或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、吡啶酮或多环桥杂环基，优选为双环、三环或吡啶酮，更有选为双环或三环。“稠杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1] 庚基，2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。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。杂环基可以是任选取代的或未取代的。桥杂环基可包含3至18个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个或18个)原子。 "Bridge heterocyclyl" refers to a polycyclic group of 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two atoms which are not directly bonded to each other, one or more rings thereof An aromatic system which may contain one or more double bonds, but none of which has a fully conjugated π-electron, wherein one or more ring atoms are selected from nitrogen, oxygen and/or S(O) p (where p is selected from 0 a hetero atom of 1, 1 and/or 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. The bridge heterocyclic group may contain 3 to 18 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, or 18) atoms.
“亚杂环基”是指二价的如上所述的杂环基。优选具有5至7元单环亚杂环基或7至10元双环杂环基或三环亚杂环基，其可以包含1，2、3或4个选自氮、氧和/或硫中的原子。亚杂环基可以是取代或未取代的。"Heterocyclylene" means a divalent heterocyclic group as described above. It preferably has a 5- to 7-membered monocyclic heterocyclic group or a 7 to 10 membered bicyclic heterocyclic group or a tricyclic heterocyclic group, which may contain 1, 2, 3 or 4 selected from nitrogen, oxygen and/or sulfur. The atom. The heterocyclylene group may be substituted or unsubstituted.
“芳基”是指包含一个、两个或更多个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可包含6至10个碳原子，例如，6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于： "Aryl" means a carbocyclic aromatic system comprising one, two or more rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group. The aryl group may contain from 6 to 10 carbon atoms, for example, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. The aryl group can be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
Figure PCTCN2018100901-appb-000037
Figure PCTCN2018100901-appb-000037
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，三唑基，四氮唑基，噻唑基，异噻唑基，1，2，3-噻二唑基，苯并间二氧杂环戊烯基，苯并咪唑基，吲哚基，异吲哚基，1，3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。杂芳基可包含6至10个(例如6个、7个、8个、9个或10个)原子。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，非限制性实施例包括但不限于："Heteroaryl" means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, oxazolyl, benzisothiazolyl, benzene And oxazolyl and benzoisoxazolyl. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can contain from 6 to 10 (eg, 6, 7, 8, 9, or 10) atoms. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
Figure PCTCN2018100901-appb-000038
Figure PCTCN2018100901-appb-000038
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。 "Alkoxy" means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C 1 -C 6 are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
“羟基”指-OH基团。"Hydroxy" refers to an -OH group.
“卤素”是指氟、氯、溴和碘。"Halogen" means fluoro, chloro, bromo and iodo.
“氨基”指-NH 2。 "Amino" means -NH 2 .
“氰基”指-CN。"Cyano" means -CN.
“硝基”指-NO 2。 "Nitro" means -NO 2 .
“苄基”指-CH 2-苯基。 "Benzyl" refers to -CH 2 - phenyl.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。"Carboxylic acid ester group" means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
“Boc”指叔丁氧基羰基。"Boc" refers to a tert-butoxycarbonyl group.
“DMSO”指二甲基亚砜。"DMSO" refers to dimethyl sulfoxide.
“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 by 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 will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-OR 8、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-S(O) pNR 6R 7和/或-NR 6C(O)R 7； As used herein, "substituted" or "substituted", unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy. , alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C (O) R 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 and/or -NR 6 C(O)R 7 ;
R 6、R 7和R 8各自独立地选自氢原子、羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和/或杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) PNR 9R 10和/或-NR 9C(O)R 10的取代基所取代； R 6 , R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group. Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC Substituting (O) a substituent of R 11 , -S(O) P NR 9 R 10 and/or -NR 9 C(O)R 10 ;
或者，R 6和R 7与相连接的N原子一起形成一个4-8元杂环基，其中4-8元杂环包含一个或多个N、O、S(O) p原子，并且4-8元杂环上进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) pNR 9R 10和/或-NR 9C(O)R 10的取代基所取代； Alternatively, R 6 and R 7 together with the attached N atom form a 4-8 membered heterocyclic group wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) p atoms, and 4 The 8-membered heterocyclic ring is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O) p NR 9 R 10 and / Or substituted with a substituent of -NR 9 C(O)R 10 ;
R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和/或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸和/或羧酸酯的取代基所取代； R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, The aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid And/or substituted with a substituent of a carboxylic acid ester;
p选自0，1和/或2。p is selected from 0, 1 and/or 2.
“药学上可接受的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的药学上可接受的盐可以为金属盐、与合适的酸形成的胺盐。"Pharmaceutically acceptable salt" refers to certain salts of the above compounds which retain their original biological activity and which are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt or an amine salt formed with a suitable acid.
“药物组合物”表示包含本申请的化合物或其生理学上可接受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上可接受的载体和赋形剂。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 comprising a compound of the present application, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
本发明化合物的合成方法Method for synthesizing the compound of the present invention
为了完成本申请的目的，本申请采用如下技术方案。In order to accomplish the object of the present application, the present application adopts the following technical solutions.
本申请式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的制备方法，包括以下步骤：The preparation method of the compound of the formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2018100901-appb-000039
Figure PCTCN2018100901-appb-000039
将式(IIA)的化合物或其盐与R 4取代的硼酸酯或硼酸反应，得到式(II)的化合物； Reaction of a compound of formula (IIA) or a salt thereof with an R 4 -substituted boronic acid ester or boric acid to provide a compound of formula (II);
其中：among them:
所述R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
Figure PCTCN2018100901-appb-000040
Figure PCTCN2018100901-appb-000040
X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
R 1-R 5、R a、R b、m和n的定义如式(II)中所述。 R 1 -R 5 , R a , R b , m and n are as defined in formula (II).
本申请式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的另外的制备方法，包括以下步骤：An additional method of preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, of the present application, comprising the steps of:
Figure PCTCN2018100901-appb-000041
Figure PCTCN2018100901-appb-000041
将式(IIB)的化合物或其盐与格氏试剂反应，得到式(II)的化合物；The compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to give a compound of the formula (II);
R a为烷基； R a is an alkyl group;
R b为羟基；且 R b is a hydroxyl group;
R 1-R 5、m和n的定义如式(II)中所述。 R 1 -R 5 , m and n are as defined in formula (II).
本申请式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的另一制备方法，包括以下步骤：Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprises the following steps:
Figure PCTCN2018100901-appb-000042
Figure PCTCN2018100901-appb-000042
将式(IIC)的化合物在酸性条件下反应，得到式(II)的化合物；The compound of the formula (IIC) is reacted under acidic conditions to give a compound of the formula (II);
其中：among them:
R a为烷基； R a is an alkyl group;
R b为氨基； R b is an amino group;
R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 5、m和n的定义如式(II)中所述。 R 1 -R 5 , m and n are as defined in formula (II).
本申请式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的制备方法，包括以下步骤：The preparation method of the compound of the formula (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2018100901-appb-000043
Figure PCTCN2018100901-appb-000043
Figure PCTCN2018100901-appb-000044
Figure PCTCN2018100901-appb-000044
式(IIa)的化合物与式(IIb)的化合物进行Suzuki偶联反应，得到式(IIc)的化合物；式(IIc)的化合物水解后得到式(IId)的化合物；在碱性条件下，式(IId)的化合物在缩合剂存在条件下进行缩合反应，得到式(IIe)的化合物；式(IIe)的化合物脱保护后得到式(IIf)的化合物；碱性条件下，式(IIf)的化合物与式(IIg)的化合物进行取代反应，得到式(IIh)的化合物；式(IIh)的化合物进一步与格氏试剂(IIi)反应，得到式(IIj)的化合物；式(IIj)的化合物与格氏试剂反应，得到式(IIA)的化合物；The compound of formula (IIa) is subjected to a Suzuki coupling reaction with a compound of formula (IIb) to give a compound of formula (IIc); the compound of formula (IIc) is hydrolyzed to give a compound of formula (IId); under basic conditions, The compound of (IId) is subjected to a condensation reaction in the presence of a condensing agent to obtain a compound of the formula (IIe); the compound of the formula (IIe) is deprotected to give a compound of the formula (IIf); and under basic conditions, the compound of the formula (IIf) The compound is subjected to a substitution reaction with a compound of the formula (IIg) to give a compound of the formula (IIh); the compound of the formula (IIh) is further reacted with a Grignard reagent (IIi) to give a compound of the formula (IIj); a compound of the formula (IIj) Reacting with a Grignard reagent to obtain a compound of formula (IIA);
其中：among them:
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
X 2-X 3各自独立为卤素，优选为Cl或Br； X 2 -X 3 are each independently halogen, preferably Cl or Br;
R a为烷基； R a is an alkyl group;
R b为羟基； R b is a hydroxyl group;
R c为氨基保护基，优选为叔丁氧基羰基； R c is an amino protecting group, preferably a tert-butoxycarbonyl group;
R d为烷基，优选甲基或乙基；且 R d is an alkyl group, preferably a methyl group or an ethyl group;
R 1-R 3、R 5、m和n的定义如式(IIA)中所述。 R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
本申请式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的另一制备方法，包括以下步骤：Another method for preparing a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to the present application, comprises the steps of:
Figure PCTCN2018100901-appb-000045
Figure PCTCN2018100901-appb-000045
Figure PCTCN2018100901-appb-000046
Figure PCTCN2018100901-appb-000046
式(IIe)的化合物与格氏试剂(IIi)反应，得到式(IIq)的化合物；式(IIq)的化合物脱保护后得到式(IIr)的化合物；碱性条件下，式(IIr)的化合物与式(IIg)的化合物进行取代反应，得到式(IIj)的化合物；式(IIj)的化合物与格氏试剂反应，得到式(IIA)的化合物；The compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIq); the compound of the formula (IIq) is deprotected to give a compound of the formula (IIr); under basic conditions, the formula (IIr) Substituting a compound with a compound of formula (IIg) to give a compound of formula (IIj); a compound of formula (IIj) is reacted with a Grignard reagent to provide a compound of formula (IIA);
其中：among them:
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
X 2为卤素，优选为Cl或Br； X 2 is halogen, preferably Cl or Br;
R a为烷基； R a is an alkyl group;
R b为羟基； R b is a hydroxyl group;
R c为氨基保护基，优选为叔丁氧基羰基；且 R c is an amino protecting group, preferably a tert-butoxycarbonyl group;
R 1-R 3、R 5、m和n的定义如式(IIA)中所述。 R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
本申请式(IIA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的另外的制备方法，包括以下步骤：An additional method of preparing a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, of the present application, comprising the steps of:
Figure PCTCN2018100901-appb-000047
Figure PCTCN2018100901-appb-000047
将式(IIj)的化合物与式(IIt)的化合物反应，其中式(IIt)的化合物的构型为(S)型或(R)型；优选为(S)型；得到式(IIk)的化合物；式(IIk)的化合物与格氏试剂反应，得到式(IIm)的化合物；式(IIm)的化合物在酸性条件下反应，得到式(IIA)的化合物；A compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the (S) form or the (R) form; preferably the (S) form; and the formula (IIk) is obtained. a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm); a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);
其中：among them:
所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
R a为烷基； R a is an alkyl group;
R b为-NR 6R 7； R b is -NR 6 R 7 ;
R 6和R 7为氢原子； R 6 and R 7 are a hydrogen atom;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 3、R 5、m和n的定义如式(IIA)中所述。 R 1 -R 3 , R 5 , m and n are as defined in the formula (IIA).
本申请式(IIB)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的制备方法，包括以下步骤：The preparation method of the compound of the formula (IIB) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2018100901-appb-000048
Figure PCTCN2018100901-appb-000048
式(IIe)的化合物与格氏试剂(IIi)反应，得到式(IIn)的化合物；式(IIn)的化合物脱保护后得到式(IIp)的化合物；碱性条件下，式(IIp)的化合物与式(IIs)的化合物进行取代反应，得到式(IIB)的化合物；The compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIn); the compound of the formula (IIn) is deprotected to give a compound of the formula (IIp); under basic conditions, the formula (IIp) Substituting a compound with a compound of formula (IIs) to give a compound of formula (IIB);
其中：among them:
X 2为卤素，优选为Cl或Br； X 2 is halogen, preferably Cl or Br;
R c为氨基保护基，优选为叔丁氧基羰基；且 R c is an amino protecting group, preferably a tert-butoxycarbonyl group;
R 1-R 5、m和n的定义如式(IIB)中所述。 R 1 -R 5 , m and n are as defined in formula (IIB).
本申请式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐的另一制备方法，包括以下步骤：Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprises the following steps:
Figure PCTCN2018100901-appb-000049
Figure PCTCN2018100901-appb-000049
将式(IIm)或其盐与R 4取代的硼酸酯或硼酸反应，得到式(IIC)的化合物；将式(IIC)在酸性条件下反应，得到式(II)的化合物； The compound of the formula (IIm) or a salt thereof is reacted with an R 4 -substituted boronic acid ester or boric acid to obtain a compound of the formula (IIC); and the compound of the formula (IIC) is reacted under acidic conditions to give a compound of the formula (II);
其中：among them:
所述的R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
Figure PCTCN2018100901-appb-000050
Figure PCTCN2018100901-appb-000050
X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
R a为烷基； R a is an alkyl group;
R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
R 1-R 5、m和n的定义如(IIC)中所述。 The definitions of R 1 -R 5 , m and n are as described in (IIC).
进一步，式(II)的化合物，当R b选自不同取代基时，基团之间可进行转换，具体地，由式(II-1)的化合物制备式(II-2)的化合物或其药学上可接受的盐的制备方法，包括以下步骤： Further, the compound of the formula (II), when R b is selected from different substituents, can be converted between the groups, in particular, the compound of the formula (II-2) or the compound of the formula (II-2) or A method of preparing a pharmaceutically acceptable salt, comprising the steps of:
Figure PCTCN2018100901-appb-000051
Figure PCTCN2018100901-appb-000051
将式(II-1)的化合物与N,N-二乙基-1,1,1-三氟-λ 4-磺胺反应，得到式(II-2)的化合物； Reaction of a compound of formula (II-1) with N,N-diethyl-1,1,1-trifluoro-λ 4 -sulfonamide to give a compound of formula (II-2);
其中：among them:
R b1为羟基； R b1 is a hydroxyl group;
R b2为F；且 R b2 is F;
R 1-R 5、R a、m和n的定义如式(II)中所述。 R 1 -R 5 , R a , m and n are as defined in formula (II).
上述制备方法中，碱性条件由有机碱或无机碱提供，有机碱选自二异丙基乙胺、吡啶、三乙胺、哌啶、N-甲基哌嗪和/或4-二甲氨吡啶，优选为二异丙基乙胺和三乙胺；无机碱选自碳酸钠、碳酸钾、碳酸铯、氢化钠和/或氢化钾，优选为碳酸铯和碳酸钾。In the above preparation method, the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and/or 4-dimethylamine. Pyridine, preferably diisopropylethylamine and triethylamine; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and/or potassium hydride, preferably cesium carbonate and potassium carbonate.
缩合试剂包括，但不限于：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、双(2-氧代-3-噁唑烷基)次磷酰氯、N,N-二环己基碳二亚胺、N,N-二异丙基碳二亚、o-苯并三氮唑-N,N,N’N’-四甲基脲硼酸酯(TBTU)，优选为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。Condensing reagents include, but are not limited to, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, bis(2-oxo-3- Oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, o-benzotriazole-N,N,N'N'- Tetramethylurea borate (TBTU), preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
偶联试剂包括，但不限于：[1,1’-双(二苯基膦基)二茂铁]二氯化钯、醋酸钯、四三苯基膦钯、三(二亚苄基丙酮)二钯或三叔丁基磷钯，优选为[1,1’-双(二苯基膦基)二茂铁]二氯化钯。Coupling reagents include, but are not limited to: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) Dipalladium or tri-tert-butylphosphine palladium is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁。The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide.
附图说明DRAWINGS
图1为测试例3中hERG钾离子通道测试中全细胞膜片钳的电压程序图。Figure 1 is a voltage program diagram of whole cell patch clamp in the hERG potassium ion channel test in Test Example 3.
具体实施方式Detailed ways
以下结合实施例用于进一步描述本发明，但这些实施例并非意在限制本发明的范围。The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
实施例Example
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。需要说明的是，下述实施例是用于说明本发明而不是对本发明的限制。The examples give the preparation of representative compounds represented by formula (I) and related structural identification data. It is to be noted that the following examples are intended to illustrate the invention and not to limit the invention.
1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准物(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。 The 1 H NMR spectrum was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, its unit is Hz.
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.2mm. The specification for thin layer chromatography separation and purification is 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。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
在下列实施例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH&Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等处购买。In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are either commercially available or synthesized according to known methods, and the commercially available materials and reagents are not further processed. Purification is used directly, unless otherwise indicated, and commercially available, including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd., etc.
CD 3OD：氘代甲醇。 CD 3 OD: Deuterated methanol.
CDCl 3：氘代氯仿。 CDCl 3 : deuterated chloroform.
DMSO-d 6：氘代二甲基亚砜。 DMSO-d 6 : deuterated dimethyl sulfoxide.
氩气氛是指反应瓶连接一个约1L容积的氩气气球。The argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
实施例中无特殊说明，反应中的溶液是指水溶液。There is no particular description in the examples, and the solution in the reaction means an aqueous solution.
对化合物进行纯化，采用硅胶柱层析洗脱剂体系和薄层色谱法，其中洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。The compound is purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Methyl chloride and ethyl acetate; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
实施例1Example 1
1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000052
Figure PCTCN2018100901-appb-000052
第一步first step
6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine
将6-溴吡咯并[2,1-f][1,2,4]三嗪-4(3H)-酮1a(4.8g,22.43mmol)溶于100mL三氯氧磷中，130℃下反应3小时。减压浓缩，向得到的残留物中加入100mL饱和冰碳酸氢钠水溶液，以二氯甲烷(100mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无 水硫酸钠干燥，减压浓缩，得到6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪1b(5.15g,棕色固体)，产率：98％。6-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1a (4.8 g, 22.43 mmol) was dissolved in 100 mL of phosphorus oxychloride and reacted at 130 ° C. 3 hours. The organic layer was extracted with dichloromethane (100 mL×3), and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. Drying and concentration under reduced pressure gave 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b (5.15 g, brown solid).
第二步Second step
2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸乙酯Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate
氩气保护下，将2-氯嘧啶-5-甲酸乙酯1c(1.9g，10.00mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1d(3.4g，11.00mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(1.5g，1.20mmol)、碳酸铯(6.6g，20.00mmol)溶于66mL 1,4-二氧六环/水(V/V＝10/1)中，60℃反应5小时。加入150mL乙酸乙酯稀释反应液，依次以水(30mL×2)、饱和氯化钠水溶液(30mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸乙酯1e(1.5g,白色固体)，产率：54.2％。Ethyl 2-chloropyrimidine-5-carboxylate 1c (1.9g, 10.00mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron under argon protection Heterocyclic pentane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1d (3.4 g, 11.00 mmol), [1,1'-bis(diphenylphosphino) Ferrocene] palladium dichloride (1.5 g, 1.20 mmol), cesium carbonate (6.6 g, 20.00 mmol) dissolved in 66 mL of 1,4-dioxane/water (V/V = 10/1), 60 The reaction was carried out at ° C for 5 hours. The reaction mixture was diluted with ethyl acetate (150 mL), EtOAc (EtOAc) Purification by the method (eluent: A system) to give ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e (1.5 g, white solid), Yield: 54.2%.
第三步third step
2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸2-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid
将2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸乙酯1e(1.5g，5.42mmol)溶于15mL四氢呋喃中，滴加10mL 1M的氢氧化钠水溶液，室温下反应5小时。减压浓缩除去四氢呋喃，加入20mL水，以1M的盐酸水溶液调节pH约为2-3,白色固体产物大量析出，过滤，干燥，得到粗品2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸1f(1.21g，淡黄色固体)，产率：89.6％。Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e (1.5 g, 5.42 mmol) was dissolved in 15 mL of THF. 10 mL of a 1 M aqueous sodium hydroxide solution was added dropwise, and the mixture was reacted at room temperature for 5 hours. The tetrahydrofuran was concentrated under reduced pressure, and 20 mL of water was added, and the pH was adjusted to about 2-3 with a 1 M aqueous hydrochloric acid solution, and a white solid product was precipitated in large portions, filtered and dried to give crude 2-(1-(tert-butoxycarbonyl)-1,2. , 3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f (1.21 g, pale yellow solid), yield: 89.6%.
第四步the fourth step
4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
将2-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酸1f(1.21g，4.86mmol)溶于50mL二氯甲烷中，依次加入N,N-二异丙基乙胺(3.13g，24.3mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(3.79g,9.72mmol)和N,O-二甲基羟胺盐酸盐酸盐(711mg,7.29mmol),室温下反应6小时。加入150mL二氯甲烷稀释反应液，依次以水(20mL×2)、1M的盐酸水溶液(20mL)、饱和碳酸氢钠水溶液(20mL)和饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(1.18g，白色固体)，产率：83.1％。2-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f (1.21 g, 4.86 mmol) was dissolved in 50 mL dichloromethane. N,N-diisopropylethylamine (3.13 g, 24.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoride were added in sequence. Phosphate (3.79 g, 9.72 mmol) and N,O-dimethylhydroxylamine hydrochloride (711 mg, 7.29 mmol) were reacted at room temperature for 6 hours. The reaction solution was diluted with 150 mL of dichloromethane, and washed with water (20 mL×2), 1M aqueous hydrochloric acid (20 mL), saturated aqueous sodium hydrogen carbonate (20 mL) and saturated aqueous sodium chloride (20 mL). Drying over sodium sulfate, EtOAc (EtOAc) 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.18 g, white solid), yield: 83.1%.
MS m/z(ESI)：292.9[M-55]MS m/z (ESI): 292.9 [M-55]
第五步the fifth step
4-(5-(4-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(4-Fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
氩气保护下，将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(1.18g,3.39mmol)溶于15mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加4-氟苯基溴化镁(13.6mL,1M/THF),室温下反应4小时。以饱和氯化铵水溶液淬灭反应， 加入100mL乙酸乙酯稀释反应液，依次以水(20mL×2)和饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(4-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1h(0.88g，白色固体)，产率：69.3％。1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.18) under argon g, 3.39 mmol) was dissolved in 15 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C with ice-water bath, and 4-fluorophenylmagnesium bromide (13.6 mL, 1 M/THF) was added dropwise, and reacted at room temperature for 4 hours. The reaction was quenched with aq. EtOAc EtOAc (EtOAc m. The residue obtained is purified by silica gel column chromatography (eluent: A system) to give 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate 1h (0.88 g, white solid), yield: 69.3%.
MS m/z(ESI)：327.9[M-55]MS m/z (ESI): 327.9 [M-55]
第六步Step 6
(4-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(4-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone
将4-(5-(4-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1h(880mg,2.36mmol)溶于10mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。减压浓缩，得到粗品(4-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮1i(667mg,褐色油状),直接用于下一步，产率：100％。4-(5-(4-Fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 h (880 mg, 2.36 mmol) was dissolved in 10 mL of dichloro To methane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 hours. Concentration under reduced pressure gave (4-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i (667 mg, brown oil) For the next step, yield: 100%.
MS m/z(ESI)：283.9[M+1]MS m/z (ESI): 283.9 [M+1]
第七步Seventh step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(4-fluorophenyl)methanone
将(4-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮1i(667mg,2.36mmol)溶于15mL二氯甲烷中，滴加N,N-二异丙基乙胺(1.2g,9.44mmol),室温下搅拌5分钟后加入6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪1b(657mg,2.83mmol),室温反应12小时。减压浓缩除去二氯甲烷，残留物中加入70mL乙酸乙酯稀释，依次以水(10mL)、1M的盐酸水溶液(10mL)和饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)甲酮1j(205mg,白色固体)，产率：17.7％。(4-Fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i (667 mg, 2.36 mmol) was dissolved in 15 mL dichloromethane N,N-diisopropylethylamine (1.2 g, 9.44 mmol) was added dropwise, and stirred at room temperature for 5 minutes, then 6-bromo-4-chloropyrrolo[2,1-f][1,2,4 was added. Triazine 1b (657 mg, 2.83 mmol) was reacted at room temperature for 12 hours. The organic layer was washed with anhydrous sodium sulfate, and the residue was evaporated to ethyl acetate (EtOAc) Drying, concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: A system) to give (2-(6-bromopyrrolo[2,1-f][1,2 ,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (205 mg, white solid) Yield: 17.7%.
MS m/z(ESI)：480.8[M+1]MS m/z (ESI): 480.8 [M+1]
第八步Eighth step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-基)-1-(4-氟苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- Base)-yl)-1-(4-fluorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)甲酮1j(200mg,0.42mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(4.2mL,1M/THF)，反应液室温下反应3小时。0℃下，加入10mL饱和氯化铵水溶液淬灭反应，减压蒸馏除去四氢呋喃，向残留物中加入50mL乙酸乙酯稀释反应液，分去水层，有机相依次以水(10mL×2)和饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(180mg,白色固体)，产率：87.1％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (200 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran. The reaction mixture was cooled to 0 ° C with ice-water bath, and methyl bromide was added dropwise. Magnesium (4.2 mL, 1 M / THF), and the reaction was allowed to react at room temperature for 3 hours. The reaction mixture was quenched by the addition of 10 mL of a saturated aqueous solution of ammonium chloride, and the mixture was evaporated to dryness. The residue was evaporated to dryness. The mixture was washed with aq. EtOAc (EtOAc m. 6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)- 1-(4-Fluorophenyl)ethan-1-ol 1k (180 mg, white solid), yield: 87.1%.
MS m/z(ESI)：494.8[M+1]MS m/z (ESI): 494.8 [M+1]
第九步Step 9
1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(180mg,0.36mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(151mg,0.73mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(51mg,0.07mmol)、碳酸钾(100mg,0.73mmol)溶于16.5mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应4小时。加入80mL乙酸乙酯稀释反应液，依次以水(10mL×2)和饱和氯化钠水溶液(30mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1(136.8mg,白色固体)，产率：92.4％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (180 mg, 0.36 mmol), 1-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (151 mg, 0.73 mmol), [1,1'-bis(diphenylphosphino) ) ferrocene] palladium dichloride (51 mg, 0.07 mmol), potassium carbonate (100 mg, 0.73 mmol) dissolved in 16.5 mL of 1,4-dioxane/water (V/V=10/1), 90 The reaction was carried out at ° C for 4 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Purification by the method (eluent: A system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrole) [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 1 (136.8 mg, white solid), Yield: 92.4%.
MS m/z(ESI)：496.9[M+1]MS m/z (ESI): 496.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.74(s,2H),7.90(s,1H),7.65(d,J＝9.0Hz,2H),7.58(s,1H),7.44-7.40(m,2H),7.32(s,1H),7.03(t,J＝8.0Hz,2H),6.85(s,1H),4.76(s,2H),4.20(d,J＝4.0Hz,2H),3.96(s,3H),2.96(s,2H),2.01(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H), 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 ( s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).
实施例2和实施例3Embodiment 2 and Embodiment 3
(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇2(S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 2
(R)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇3(R)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3
Figure PCTCN2018100901-appb-000053
Figure PCTCN2018100901-appb-000053
第一步first step
(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇2(S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 2
(R)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇3(R)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3
将1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1(136.8mg,0.27mmol)进一步通过采用超临界流体色谱(SFC)法，用高效液相制备色谱和手性柱对手性异构体进行拆分(手性柱ChiralPak AS,250×30mm I.D.,5μm；60mL/min；流动相A为CO 2且流动相 B为甲醇(0.1％NH 3.H 2O))进行拆分，得到(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇2(44.3mg,白色固体)，产率：32.4％，98.7％ee,保留时间：4.39min；(R)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇3(60.75mg,白色固体)，产率：44.4％，100.0％ee,保留时间：5.75min。 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2 , 4] triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 1 (136.8 mg, 0.27 mmol) further by using super Critical fluid chromatography (SFC) method, which was resolved by high performance liquid chromatography and chiral column chiral isomers (chiral Pak AS, 250×30 mm ID, 5 μm; 60 mL/min; mobile phase A was CO 2 ) And mobile phase B is methanol (0.1% NH 3 .H 2 O)) to obtain (S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-) Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- , pyrimidine-5-yl)ethan-1-ol 2 (44.3 mg, white solid), yield: 32.4%, 98.7% ee, retention time: 4.39 min; (R)-1-(4-fluorophenyl) -1(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl) -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3 (60.75 mg, white solid), yield: 44.4%, 100.0% ee, retention time : 5.75min.
化合物2Compound 2
MS m/z(ESI)：496.9[M+1]MS m/z (ESI): 496.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.74(s,2H),7.90(s,1H),7.65(d,J＝9.0Hz,2H),7.58(s,1H),7.44-7.40(m,2H),7.32(s,1H),7.03(t,J＝8.0Hz,2H),6.85(s,1H),4.76(s,2H),4.20(d,J＝4.0Hz,2H),3.96(s,3H),2.96(s,2H),2.01(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H), 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 ( s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).
化合物3Compound 3
MS m/z(ESI)：497.0[M+1]MS m/z (ESI): 497.0 [M+1]
1H NMR(400MHz,CDCl 3)δ8.74(s,2H),7.90(s,1H),7.65(d,J＝9.0Hz,2H),7.58(s,1H),7.44-7.40(m,2H),7.32(s,1H),7.03(t,J＝8.0Hz,2H),6.85(s,1H),4.76(s,2H),4.20(d,J＝4.0Hz,2H),3.96(s,3H),2.96(s,2H),2.01(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H), 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 ( s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).
实施例4Example 4
1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H) -yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one
Figure PCTCN2018100901-appb-000054
Figure PCTCN2018100901-appb-000054
Figure PCTCN2018100901-appb-000055
Figure PCTCN2018100901-appb-000055
第一步first step
1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H) -yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(200mg,0.40mmol)、1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮4a(201mg,0.80mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(59mg,0.08mmol)和碳酸钾(110mg,0.80mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应4小时。加入100mL乙酸乙酯稀释反应液，依次以水(20mL×2)和饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮4(123.8mg,白色固体)，产率：57.5％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (200 mg, 0.40 mmol), 1-(4-(4,4,5,5) -tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 4a (201 mg, 0.80 Ment), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59 mg, 0.08 mmol) and potassium carbonate (110 mg, 0.80 mmol) dissolved in 11 mL of 1,4-dioxane In the ring/water (V/V = 10/1), the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: A system) to give 1-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)- 3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1 (2H )-yl)ethan-1-one 4 (123.8 mg, white solid), yield: 57.5%.
MS m/z(ESI)：539.9[M+1]MS m/z (ESI): 539.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.66(s,2H),7.81(s,1H),7.54(d,J＝9.0Hz,1H),7.53-7.51(m,2H),7.34(s,1H),7.19(t,J＝4.0Hz,2H),6.74(s,1H),6.05-5.98(m,1H),5.23(s,2H),4.18-4.08(m,4H),3.77(s,1H),3.61(s,1H),2.88(s,2H),2.51-2.46(m,2H),2.08(d,J＝4.4Hz,3H),1.93(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0Hz, 1H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s, 2H), 4.18-4.08 (m, 4H), 3.77 (s) , 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).
实施例5和实施例6Example 5 and Example 6
(S)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮5(S)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1- Ketone 5
(R)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮6(R)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1- Ketone 6
Figure PCTCN2018100901-appb-000056
Figure PCTCN2018100901-appb-000056
Figure PCTCN2018100901-appb-000057
Figure PCTCN2018100901-appb-000057
第一步first step
(S)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮5(S)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1- Ketone 5
(R)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮6(R)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1- Ketone 6
将1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮4(123mg,0.23mmol)进一步通过采用超临界流体色谱(SFC)法，用高效液相制备色谱和手性柱对手性异构体进行拆分(手性柱ChiralPak AS,250×30mm I.D.,5μm；60mL/min；流动相A为CO 2且流动相B为甲醇(0.1％NH 3.H 2O))进行拆分，得到(S)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮5(47.77mg,白色固体)，产率：38.8％，100％ee，保留时间：7.45min；(R)-1-(4-(4-(4-(5-(1-(4-氟苯基)-1-羟乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)吡咯并[2,1-f][1,2,4]三嗪-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮6(55.06mg,白色固体)，产率：44.8％，100％ee，保留时间：11.83min。化合物5 1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 (2H) )-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 4 ( 123 mg, 0.23 mmol) was further resolved by high performance liquid chromatography and chiral column chiral isomers using supercritical fluid chromatography (SFC) method (chiral Pak AS, 250 x 30 mm ID, 5 μm; 60 mL) /min; mobile phase A is CO 2 and mobile phase B is methanol (0.1% NH 3 .H 2 O)), and (S)-1-(4-(4-(4-(5-( 1-(4-Fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1, 2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 5 (47.77 mg, white solid), yield: 38.8%, 100% ee , retention time: 7.45 min; (R)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3 ,6-Dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1 (2H) -yl)ethan-1-one 6 (55.06 mg, white solid), yield: 44.8%, 100% ee, retention time: 11.83 min. Compound 5
MS m/z(ESI)：539.9[M+1]MS m/z (ESI): 539.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.66(s,2H),7.81(s,1H),7.54(d,J＝9.0Hz,1H),7.53-7.51(m,2H),7.34(s,1H),7.19(t,J＝4.0Hz,2H),6.74(s,1H),6.05-5.98(m,1H),5.23(s,2H),4.18-4.08(m,4H),3.77(s,1H),3.61(s,1H),2.88(s,2H),2.51-2.46(m,2H),2.08(d,J＝4.4Hz,3H),1.93(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0Hz, 1H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s, 2H), 4.18-4.08 (m, 4H), 3.77 (s) , 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).
化合物6Compound 6
MS m/z(ESI)：539.9[M+1]MS m/z (ESI): 539.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.66(s,2H),7.81(s,1H),7.54(d,J＝9.0Hz,1H),7.53-7.51(m,2H),7.34(s,1H),7.19(t,J＝4.0Hz,2H),6.74(s,1H),6.05-5.98(m,1H),5.23(s,2H),4.18-4.08(m,4H),3.77(s,1H),3.61(s,1H),2.88(s,2H),2.51-2.46(m,2H),2.08(d,J＝4.4Hz,3H),1.93(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0Hz, 1H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s, 2H), 4.18-4.08 (m, 4H), 3.77 (s) , 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).
实施例7Example 7
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基) 嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol
Figure PCTCN2018100901-appb-000058
Figure PCTCN2018100901-appb-000058
第一步first step
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(494mg,0.30mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑7a(135mg,0.60mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(44mg,0.06mmol)和碳酸钾(83mg,0.60mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应4小时。加入80mL乙酸乙酯稀释反应液，依次以水(20mL×2)、饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇7(46mg,白色固体)，产率：9.3％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (494 mg, 0.30 mmol), 1-ethyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (135 mg, 0.60 mmol), [1,1'-bis(diphenylphosphine) Base) ferrocene] palladium dichloride (44 mg, 0.06 mmol) and potassium carbonate (83 mg, 0.60 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1), 90 The reaction was carried out at ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), EtOAc (EtOAc) Purification by the method (eluent: A system) gave 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 7 (46 mg, white solid), Yield: 9.3%.
MS m/z(ESI)：510.9[M+1]MS m/z (ESI): 510.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.66(s,2H),7.91(s,1H),7.63(d,J＝8.0Hz,2H),7.54(s,1H),7.35(q,J＝4.0Hz,2H),7.24(s,1H),6.98(t,J＝8.0Hz,2H),6.80(s,1H),4.69(s,2H),4.17-4.12(m,4H),2.90(s,2H),1.93(s,3H),1.47(d,J＝8.0Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.66 (s, 2H), 7.91 (s, 1H), 7.63 (d, J = 8.0Hz, 2H), 7.54 (s, 1H), 7.35 (q, J = 4.0 Hz, 2H), 7.24 (s, 1H), 6.98 (t, J = 8.0 Hz, 2H), 6.80 (s, 1H), 4.69 (s, 2H), 4.17 - 4.12 (m, 4H), 2.90 ( s, 2H), 1.93 (s, 3H), 1.47 (d, J = 8.0 Hz, 3H).
实施例8Example 8
1-(4-氯苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000059
Figure PCTCN2018100901-appb-000059
第一步first step
N-甲氧基-N-甲基-2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酰胺N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide
将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(14.0g,40.0mmol)溶于140mL的二氯甲烷中，加入36mL三氟乙酸，室温反应1h。减压浓缩，得到粗品N-甲氧基-N-甲基-2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酰胺8a(9.94g,棕色油状)，直接用于下一步反应，产率：100％。1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (14.0 g, 40.0 mmol) Dissolved in 140 mL of dichloromethane, added 36 mL of trifluoroacetic acid, and reacted at room temperature for 1 h. Concentration under reduced pressure gave crude N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide 8a (9.94 g, brown oil) , used directly in the next reaction, yield: 100%.
第二步Second step
2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)- N-methoxy-N-methylpyrimidine-5-carboxamide
将N-甲氧基-N-甲基-2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-甲酰胺8a(9.94g,40.1mmol)溶于100mL二氯甲烷中，滴加N,N-二异丙基乙胺(31.03g,240.5mmol)，室温下搅拌5min后加入6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪1b(9.72g,42.1mmol)，室温反应3小时。减压蒸除二氯甲烷，加入100mL异丙醇，放置过夜。产物析出，过滤，滤饼依次以异丙醇(50mL×2)、石油醚(50mL×2)洗涤，抽干，得到2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡 啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺8b(10.97g,乳白色固体)，产率：62％。N-Methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide 8a (9.94 g, 40.1 mmol) was dissolved in 100 mL of dichloro N,N-diisopropylethylamine (31.03 g, 240.5 mmol) was added dropwise to methane, and stirred at room temperature for 5 min, then 6-bromo-4-chloropyrrolo[2,1-f][1,2, 4] Triazine 1b (9.72 g, 42.1 mmol) was reacted at room temperature for 3 hours. Dichloromethane was evaporated under reduced pressure, and 100 mL of isopropyl alcohol was added and left overnight. The product was precipitated, filtered, and the filter cake was washed with isopropyl alcohol (50 mL×2) and petroleum ether (50 mL×2) and then dried to give 2-(1-(6-bromopyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (10.97 g, milky white solid), yield: 62%.
MS m/z(ESI)：443.1[M+1]MS m/z (ESI): 443.1 [M+1]
第三步third step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氯苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(4-chlorophenyl)methanone
氩气保护下，将2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺8b(1.8g,4.06mmol)溶于50mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加4-氯苯基溴化镁(20.2mL,1M/THF),室温下反应0.5小时。以50mL水淬灭反应，减压浓缩除去四氢呋喃，残留物中加入30mL水，然后用乙酸乙酯(50mL×2)萃取，合并有机相，以50mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氯苯基)甲酮8c(1.5g,淡黄色固体)，产率：75％。2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection -4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.8 g, 4.06 mmol) was dissolved in 50 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in ice water bath, and added dropwise 4 -Chlorophenylmagnesium bromide (20.2 mL, 1 M / THF) was reacted at room temperature for 0.5 hour. The reaction was quenched with 50 mL of EtOAc. EtOAc (EtOAc m. Drying over sodium sulfate and concentrating under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: C system) to give (2-(1-(6-bromopyrrolo[2,1-f][1 , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-chlorophenyl)methanone 8c (1.5 g, light Yellow solid), yield: 75%.
第四步the fourth step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氯苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- Pyrimidine-5-yl)-1-(4-chlorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氯苯基)甲酮8c(1.5g,3.02mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(24.2mL,1M/THF),室温下反应0.5小时。0℃下，加入50mL冰水淬灭反应，减压浓缩除去四氢呋喃，残留物以乙酸乙酯(60mL×3)萃取，合并有机相，以50mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氯苯基)乙-1-醇8d(1.2g,白色固体)，产率：76.8％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-chlorophenyl)methanone 8c (1.5 g, 3.02 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C with ice-water bath, and methyl ether was added dropwise. Magnesium bromide (24.2 mL, 1 M/THF) was reacted at room temperature for 0.5 h. The reaction was quenched by the addition of 50 mL of ice water, and the mixture was evaporated to dryness, and the residue was evaporated to ethyl acetate (60 mL×3), and the organic phase was washed with 50 mL of saturated aqueous sodium chloride. Drying with sodium and concentrating under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: C system) to give 1-(2-(6-bromopyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethyl-1- Alcohol 8d (1.2 g, white solid), yield: 76.8%.
第五步the fifth step
1-(4-氯苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氯苯基)乙-1-醇8d(600mg,1.17mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(366mg,1.76mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(171.3mg,0.23mmol)、碳酸钾(323mg,2.34mmol)溶于12mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应5小时。加入100mL乙酸乙酯稀释反应液，依次以水(30mL×2)、饱和氯化钠水溶液(40mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(4-氯苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇8(256mg,白色固体)，产率：42.7％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethan-1-ol 8d (600 mg, 1.17 mmol), 1-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (366 mg, 1.76 mmol), [1,1'-bis(diphenylphosphino) ) ferrocene] palladium dichloride (171.3 mg, 0.23 mmol), potassium carbonate (323 mg, 2.34 mmol) dissolved in 12 mL of 1,4-dioxane/water (V/V=10/1), 90 The reaction was carried out at ° C for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: C system) gave 1-(4-chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrole) [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 8 (256 mg, white solid), Yield: 42.7%.
MS m/z(ESI)：512.9[M+1]MS m/z (ESI): 512.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.73(s,2H),7.88(s,1H),7.65(d,J＝8.0Hz,2H),7.57(s,1H),7.45-7.28(m,5H),6.84(s,1H),4.74(s,2H),4.20(t,J＝8.0Hz,2H),3.94(s,3H),2.95(s,2H),2.00(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.73 (s, 2H), 7.88 (s, 1H), 7.65 (d, J = 8.0Hz, 2H), 7.57 (s, 1H), 7.45-7.28 (m, 5H), 6.84 (s, 1H), 4.74 (s, 2H), 4.20 (t, J = 8.0 Hz, 2H), 3.94 (s, 3H), 2.95 (s, 2H), 2.00 (s, 3H).
实施例9Example 9
1-(4-氯苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000060
Figure PCTCN2018100901-appb-000060
第一步first step
1-(4-氯苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氯苯基)乙-1-醇8d(200mg,0.39mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑7a(174mg,0.78mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(57.1mg,0.078mmol)和碳酸钾(108mg,0.78mmol)溶于11mL1,4-二氧六环/水(V/V＝10/1)中，90℃反应5小时。加入70mL乙酸乙酯稀释反应液，依次以水(25mL×2)、饱和氯化钠水溶液(30mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(4-氯苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇9(52mg,白色固体)，产率：25.4％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethan-1-ol 8d (200 mg, 0.39 mmol), 1-ethyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (174 mg, 0.78 mmol), [1,1'-bis(diphenylphosphino) ) ferrocene] palladium dichloride (57.1 mg, 0.078 mmol) and potassium carbonate (108 mg, 0.78 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1), 90 ° C Reaction for 5 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc). Purification by the method (eluent: C system) gave 1-(4-chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrole) [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 9 (52 mg, white solid), Yield: 25.4%.
MS m/z(ESI)：526.9[M+1]MS m/z (ESI): 526.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.74(s,2H),7.90(s,1H),7.71(s,1H),7.68(d,J＝1.6Hz,1H),7.62(s,1H),7.39-7.26(m,5H),6.85(s,1H),4.75(s,2H),4.25-4.20(m,4H),2.96(s,2H),2.00(s,3H),1.55(t,J＝7.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.74 (s, 2H), 7.90 (s, 1H), 7.71 (s, 1H), 7.68 (d, J = 1.6Hz, 1H), 7.62 (s, 1H) , 7.39-7.26 (m, 5H), 6.85 (s, 1H), 4.75 (s, 2H), 4.25-4.20 (m, 4H), 2.96 (s, 2H), 2.00 (s, 3H), 1.55 (t , J = 7.2 Hz, 3H).
实施例10Example 10
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol
Figure PCTCN2018100901-appb-000061
Figure PCTCN2018100901-appb-000061
第一步first step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(对甲苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(p-tolyl)methanone
氩气保护下，将2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺8b(800mg,1.8mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加4-甲基苯基溴化镁(7.2mL,1M/THF),室温下反应0.5小时。以5mL饱和氯化铵水溶液水淬灭反应，减压浓缩除去四氢呋喃，残留物中加入30mL水，以乙酸乙酯(30mL×2)萃取，合并有机相，以30mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(对甲苯基)甲酮10a(680mg,黄色固体)，产率：79％。2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection -4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (800 mg, 1.8 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. Methylphenylmagnesium bromide (7.2 mL, 1 M/THF) was reacted at room temperature for 0.5 h. The reaction was quenched with 5 mL of aq. EtOAc EtOAc EtOAc (EtOAc m. The residue was dried over anhydrous sodium sulfate (MgSO4)ielielielielielielielielielielielielielielielielielielielieliel f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(p-tolyl)methanone 10a (680 mg, Yellow solid), Yield: 79%.
第二步Second step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- Pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(对甲苯基)甲酮10a(680mg,1.43mmol)溶于15mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(14.4mL,1M/THF)，室温下反应0.5小时。0℃下，加入5mL饱和氯化铵淬灭反应，减压浓缩除去四氢呋喃，残留物中加入60mL水，以乙酸乙酯加(40 mL×3)萃取，合并有机相，以30mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇10b(401mg,黄色固体)，产率：56.9％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(p-tolyl)methanone 10a (680 mg, 1.43 mmol) was dissolved in 15 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in ice water bath, and methyl magnesium bromide was added dropwise. (14.4 mL, 1 M/THF), and allowed to react at room temperature for 0.5 hour. The reaction was quenched by the addition of 5 mL of saturated ammonium chloride. The residue was evaporated to dryness. The organic layer is washed with water and dried over anhydrous sodium sulfate. EtOAcjjjjjjjjjjjj And [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(pair Tolyl)ethan-1-ol 10b (401 mg, yellow solid), yield: 56.9%.
第三步third step
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol
氩气保护下，1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇10b(150mg,0.31mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(127.3mg,0.62mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(45.4mg,0.06mmol)和碳酸钾(85.6mg,0.62mmol)溶于11mL1,4-二氧六环/水(V/V＝10/1)中，90℃反应5小时。加入100mL乙酸乙酯稀释反应液，依次以水(40mL×2)、饱和氯化钠水溶液(40mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇10(18mg,白色固体)，产率：11.8％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10b (150 mg, 0.31 mmol), 1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (127.3 mg, 0.62 mmol), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (45.4 mg, 0.06 mmol) and potassium carbonate (85.6 mg, 0.62 mmol) were dissolved in 11 mL of 1,4-dioxane/water (V/V=10/1) at 90 °C. 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: C system) gave 1-(2-(1-(l-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10 (18 mg , white solid), Yield: 11.8%.
MS m/z(ESI)：493.0[M+1]MS m/z (ESI): 493.0 [M+1]
1H NMR(400MHz,CDCl 3)δ(s,2H),7.94(s,1H),7.72(s,2H),7.56(s,1H),7.31(d,J＝8.0Hz,3H),7.17(d,J＝8.0Hz,2H),6.92(s,1H),4.78(s,2H),4.24(s,2H),3.96(s,3H),3.00(s,2H),2.35(s,3H),2.00(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (s, 2H), 7.94 (s, 1H), 7.72 (s, 2H), 7.56 (s, 1H), 7.31 (d, J = 8.0Hz, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 4.78 (s, 2H), 4.24 (s, 2H), 3.96 (s, 3H), 3.00 (s, 2H), 2.35 (s, 3H), 2.00 (s, 3H).
实施例11Example 11
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol
Figure PCTCN2018100901-appb-000062
Figure PCTCN2018100901-appb-000062
Figure PCTCN2018100901-appb-000063
Figure PCTCN2018100901-appb-000063
第一步first step
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol
氩气保护下，1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇10b(150mg,0.31mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑7a(137.6mg,0.62mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(45.4mg,0.06mmol)和碳酸钾(85.6mg,0.62mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应5小时。加入100mL乙酸乙酯稀释反应液，依次以水(40mL×2)和饱和氯化钠水溶液(40mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(对甲苯基)乙-1-醇11(26mg,白色固体)，产率：16.5％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10b (150 mg, 0.31 mmol), 1-ethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (137.6 mg, 0.62 mmol), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (45.4 mg, 0.06 mmol) and potassium carbonate (85.6 mg, 0.62 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1), 90 ° C Reaction for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: C system) gave 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 11 (26 mg , white solid), Yield: 16.5%.
MS m/z(ESI)：507.0[M+1]MS m/z (ESI): 507.0 [M+1]
1H NMR(400MHz,CDCl 3)δ(s,2H),7.92(s,1H),7.71(d,J＝6.8Hz,2H),7.62(s,1H),7.31(d,J＝8.4Hz,3H),7.17(d,J＝8.0Hz,2H),6.88(s,1H),4.76(s,2H),4.25-4.19(m,4H),2.98(s,2H),2.35(s,3H),1.99(s,3H),1.54(t,J＝7.6Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (s, 2H), 7.92 (s, 1H), 7.71 (d, J = 6.8Hz, 2H), 7.62 (s, 1H), 7.31 (d, J = 8.4Hz , 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.88 (s, 1H), 4.76 (s, 2H), 4.25-4.19 (m, 4H), 2.98 (s, 2H), 2.35 (s, 3H), 1.99 (s, 3H), 1.54 (t, J = 7.6 Hz, 3H).
实施例12Example 12
1-(4-氟苯基)-1-(2-(1-(6-(1-丙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000064
Figure PCTCN2018100901-appb-000064
Figure PCTCN2018100901-appb-000065
Figure PCTCN2018100901-appb-000065
第一步first step
1-(4-氟苯基)-1-(2-(1-(6-(1-丙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(150mg,0.30mmol)、1-丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑12a(151mg,0.60mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(44mg,0.06mmol)和碳酸铯(195.6mg,0.60mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应4小时。加入50mL乙酸乙酯稀释反应液，依次以水(20mL×2)、饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(4-氟苯基)-1-(2-(1-(6-(1-丙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇12(30mg,白色固体)，产率：19.1％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-propyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 12a (151 mg, 0.60 mmol), [1,1'-bis(diphenylphosphino) ) ferrocene] palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1), 90 The reaction was carried out at ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (50 mL), EtOAc (EtOAc) Purification by the method (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)pyrrole) [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 12 (30 mg, white solid), Yield: 19.1%.
MS m/z(ESI)：525.0[M+1]MS m/z (ESI): 525.0 [M+1]
1H NMR(400MHz,CDCl 3)δ8.65(s,2H),7.76(s,1H),7.56(s,2H),7.50(s,1H),7.35-7.32(m,2H),7.20(s,1H),6.95(t,J＝8.4Hz,2H),6.75(s,1H),4.63(s,2H),4.09(t,J＝5.6Hz,2H),4.00(t,J＝6.8Hz,2H),2.85(s,2H),1.90(s,3H),1.83(q,J＝7.2Hz,2H),0.86(t,J＝7.6Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.65 (s, 2H), 7.76 (s, 1H), 7.56 (s, 2H), 7.50 (s, 1H), 7.35-7.32 (m, 2H), 7.20 ( s, 1H), 6.95 (t, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.63 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 4.00 (t, J = 6.8) Hz, 2H), 2.85 (s, 2H), 1.90 (s, 3H), 1.83 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.6 Hz, 3H).
实施例13Example 13
1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000066
Figure PCTCN2018100901-appb-000066
Figure PCTCN2018100901-appb-000067
Figure PCTCN2018100901-appb-000067
第一步first step
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(150mg,0.30mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2,3,6-四氢吡啶13a(135mg,0.60mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(44mg,0.06mmol)和碳酸铯(195.6mg,0.60mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，90℃反应4小时。加入50mL乙酸乙酯稀释反应液，依次以水(20mL×2)、饱和氯化钠水溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇13(25mg,灰色固体)，产率：16.3％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine 13a (135 mg, 0.60 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V In =10/1), the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (50 mL), EtOAc (EtOAc) Purification by the method (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridine) 4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl Ethyl-1-ol 13 (25 mg, gray solid), yield: 16.3%.
MS m/z(ESI)：512.0[M+1]MS m/z (ESI): 512.0 [M+1]
1H NMR(400MHz,DMSO)δ8.81(s,2H),7.83(d,J＝16.0Hz,2H),7.53-7.49(m,2H),7.26(s,1H),7.16(t,J＝8.4Hz,3H),6.23(s,1H),6.18(s,1H),4.72(s,2H),4.14(t,J＝5.6Hz,2H),3.01(s,2H),2.79(s,2H),2.57-2.56(m,2H),2.50-2.48(m,2H),2.28(s,3H),1.90(s,3H)。 1 H NMR (400MHz, DMSO) δ8.81 (s, 2H), 7.83 (d, J = 16.0Hz, 2H), 7.53-7.49 (m, 2H), 7.26 (s, 1H), 7.16 (t, J = 8.4 Hz, 3H), 6.23 (s, 1H), 6.18 (s, 1H), 4.72 (s, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.01 (s, 2H), 2.79 (s) , 2H), 2.57-2.56 (m, 2H), 2.50-2.48 (m, 2H), 2.28 (s, 3H), 1.90 (s, 3H).
实施例14Example 14
1-(4-氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000068
Figure PCTCN2018100901-appb-000068
Figure PCTCN2018100901-appb-000069
Figure PCTCN2018100901-appb-000069
第一步first step
(氧杂环丁烷-3-基)对甲基苯磺酸酯(oxetan-3-yl)p-toluenesulfonate
将氧杂环丁-3-醇14a(2.0g,27.0mmol)、三乙胺(10.9g,108.0mmol)和4-二甲氨基吡啶(330mg,2.7mmol)溶于20mL二氯甲烷中，加入对甲苯磺酸(10.3g,54.0mmol)，室温下反应12小时。减压浓缩，加入25mL水，以乙酸乙酯(50mL×2)萃取，合并有机相，依次以水(25mL×3)、饱和氯化钠水溶液(25mL×1)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(氧杂环丁烷-3-基)对甲基苯磺酸酯14b(3.2g,白色固体)，产率：51.9％。Oxetane-3-alcohol 14a (2.0 g, 27.0 mmol), triethylamine (10.9 g, 108.0 mmol) and 4-dimethylaminopyridine (330 mg, 2.7 mmol) were dissolved in 20 mL of dichloromethane and added p-Toluenesulfonic acid (10.3 g, 54.0 mmol) was reacted at room temperature for 12 hours. The organic layer was extracted with water (25 mL×3), saturated aqueous sodium chloride (25 mL×1), and the organic phase was anhydrous sulfuric acid. Drying with sodium and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (oxetane-3-yl)p-toluenesulfonate 14b (3.2 g , white solid), Yield: 51.9%.
第二步Second step
1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazole
将(氧杂环丁烷-3-基)对甲基苯磺酸酯14b(1.4g,6.1mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑14c(1.0g,5.2mmol)和碳酸铯(5.0g,15.5mmol)溶于20mL乙腈中，室温反应3小时。减压浓缩，加入30mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，依次以水(30mL×3)和饱和氯化钠水溶液(30mL×1)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑14d(482mg,白色固体),产率：37.4％。(Oxetane-3-yl)p-toluenesulfonate 14b (1.4 g, 6.1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-di Oxoborolan-2-yl)-1H-pyrazole 14c (1.0 g, 5.2 mmol) and cesium carbonate (5.0 g, 15.5 mmol) were dissolved in 20 mL of acetonitrile and allowed to react at room temperature for 3 hours. The organic layer was extracted with water (30 mL×3) and aqueous sodium chloride (30 mL×1) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: A) to give 1-(oxetane-3-yl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (482 mg, white solid), yield: 37.4%.
第三步third step
1-(4-氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-fluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-醇1k(150mg,0.30mmol)、1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑14d(150mg,0.60mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(44mg,0.06mmol)和碳酸铯(195.6mg,0.60mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃反应4.5小时。加入50mL乙酸乙酯稀释反应液，依次以水(10mL×2)、饱和氯化钠水溶液(20mL×1)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(4-氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H- 吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇14(10mg,白色固体)，产率：6.2％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-(oxetan-3-yl) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (150 mg, 0.60 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL of 1,4-dioxane/water ( In V/V = 10/1), the reaction was carried out at 100 ° C for 4.5 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with water (10 mL×2) and saturated aqueous sodium chloride (20 mL×1). Chromatography (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-(oxetane-3-yl))- 1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine -5-yl) Ethyl-1-ol 14 (10 mg, white solid), yield: 6.2%.
MS m/z(ESI)：538.9[M+1]MS m/z (ESI): 538.9 [M+1]
1H NMR(400MHz,DMSO)δ8.82(s,2H),8.34(s,1H),8.01(d,J＝11.2Hz,2H),7.88(s,1H),7.53-7.49(m,2H),7.32(s,1H),7.27(s,1H),7.15(t,J＝8.8Hz,2H),6.19(s,1H),5.58(t,J＝6.8Hz,1H),4.98-4.89(m,4H),4.74(s,2H),4.16(s,2H),2.82(s,2H),1.90(s,3H)。 1 H NMR (400MHz, DMSO) δ8.82 (s, 2H), 8.34 (s, 1H), 8.01 (d, J = 11.2Hz, 2H), 7.88 (s, 1H), 7.53-7.49 (m, 2H ), 7.32 (s, 1H), 7.27 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 6.19 (s, 1H), 5.58 (t, J = 6.8 Hz, 1H), 4.98-4.89 (m, 4H), 4.74 (s, 2H), 4.16 (s, 2H), 2.82 (s, 2H), 1.90 (s, 3H).
实施例15Example 15
1-(4-甲氧基苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-methoxyphenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000070
Figure PCTCN2018100901-appb-000070
第一步first step
(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-(3H)-酮(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-(3H)-one
氩气保护下，将6-溴吡咯并[2,1-F][1,2,4]三嗪-4(1H)-酮1a(8.00g,37.38mmol)、1-甲基 -4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(15.56g,74.76mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(2.74g,3.74mmol)和碳酸铯(36.54g,112.14mmol)溶于150mL1,4-二氧六环/乙醇/水(V/V/V＝10/4/1)中，120℃反应6小时。减压浓缩，加入50mL水，以乙酸乙酯(100mL×3)萃取，合并有机相，依次以水(100mL×3)、饱和氯化钠水溶液(100mL×1)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-(3H)-酮15a(3.23g,黄色固体)，产率：40.2％。6-Bromopyrrolo[2,1-F][1,2,4]triazin-4(1H)-one 1a (8.00 g, 37.38 mmol), 1-methyl-4- under argon (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (15.56 g, 74.76 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (2.74 g, 3.74 mmol) and cesium carbonate (36.54 g, 112.14 mmol) dissolved in 150 mL of 1,4-dioxane/ethanol/water (V/ In V/V = 10/4/1), the reaction was carried out at 120 ° C for 6 hours. The organic layer was extracted with water (100 mL×3), saturated aqueous sodium chloride (100 mL×1), and the organic phase was anhydrous sulfuric acid. Drying with sodium and concentrating under reduced pressure, the obtained residue was purified to silica gel column chromatography (eluent: A system) to give (1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-(3H)-one 15a (3.23 g, yellow solid), yield: 40.2%.
第二步Second step
4-氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine
将(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-(3H)-酮15a(3.23g,15.02mmol)溶于100mL三氯氧磷中，130℃下反应3小时。减压浓缩，得到的残留物中加入100mL冰水淬灭反应，以二氯甲烷(100mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到4-氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪15b(1.52g,黄色固体)，产率：43.2％。(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-(3H)-one 15a (3.23 g, 15.02 mmol) Dissolved in 100 mL of phosphorus oxychloride and reacted at 130 ° C for 3 hours. The organic layer was washed with 100 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: B system) to give 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2] , 1-f][1,2,4]triazine 15b (1.52 g, yellow solid), yield: 43.2%.
第三步third step
(4-甲氧基苯基)溴化镁(4-methoxyphenyl)magnesium bromide
氩气保护下，将镁屑(294mg,12.1mmol)和1粒碘溶于10mL四氢呋喃中，将1-溴-4-甲氧基苯15c(4.5g,24.2mmol)溶于2mL四氢呋喃中，取0.2mL滴加到上述反应液中，并且以电吹风吹反应瓶瓶底，引发反应，然后将剩余的1-溴-4-甲氧基苯溶液缓慢滴加到反应液中，并保持反应微微回流，加毕，室温下反应1小时。反应结束后，得到(4-甲氧基苯基)溴化镁15d(12mL,灰色溶液，1M/THF)，直接用于下一步，产率：100％。Under the protection of argon, magnesium swarf (294 mg, 12.1 mmol) and 1 iodine were dissolved in 10 mL of tetrahydrofuran, and 1-bromo-4-methoxybenzene 15c (4.5 g, 24.2 mmol) was dissolved in 2 mL of tetrahydrofuran. 0.2 mL was added dropwise to the above reaction solution, and the bottom of the reaction bottle was blown with a hair dryer to initiate a reaction, and then the remaining 1-bromo-4-methoxybenzene solution was slowly added dropwise to the reaction solution, and the reaction was kept slightly. The mixture was refluxed, added, and reacted at room temperature for 1 hour. After completion of the reaction, (4-methoxyphenyl)magnesium bromide 15d (12 mL, m.
第四步the fourth step
4-(5-(4-甲氧基苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(4-Methoxybenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
氩气保护下，将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(500mg,1.4mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加(4-甲氧基苯基)溴化镁15d(8.6mL,1M/THF)，室温下反应1小时。0℃下，以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(30mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(4-甲氧基苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯15e(228mg,白色固体)，产率：40％。4-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (500 mg under argon) , 1.4mmol) was dissolved in 10mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, (4-methoxyphenyl) magnesium bromide 15d (8.6mL, 1M / THF) was added dropwise, and reacted for 1 hour at room temperature. . The reaction mixture was quenched with EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: A) to give 4-(5-(4-methoxybenzoyl)pyrimidin-2-yl)-3,6- Hydropyridine-1(2H)-tert-butyl formate 15e (228 mg, white solid), yield: 40%.
第五步the fifth step
(4-甲氧基苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(4-methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone
将4-(5-(4-甲氧基苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯15e(169mg, 0.43mmol)溶于4mL二氯甲烷中，加入1mL三氟乙酸，室温下反应0.5小时。减压浓缩，得到(4-甲氧基苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮15f(126mg,棕色油状),产率：100％，直接用于下一步。Dissolve 4-(5-(4-methoxybenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 15e (169 mg, 0.43 mmol) in 4 mL Into dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (4-methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15f (126 mg, brown oil). Yield: 100%, used directly in the next step.
第六步Step 6
(4-甲氧基苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-12,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(4-methoxyphenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]3 Pyrazin-4-yl)-12,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)methanone
将(4-甲氧基苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮15f(126mg,0.43mmol)和4-氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪15b(100mg,0.43mmol)溶于5mL二氯甲烷中，然后加入N,N-二异丙基乙胺(332mg,2.57mmol)，室温下反应12小时。减压浓缩，加入15mL异丙醇搅拌10分钟，析出固体产物，过滤，滤饼以异丙醇(5mL×2)洗涤，抽干，得到(4-甲氧基苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-12,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮15g(180mg,白色固体)，产率：85％。(4-Methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15f (126 mg, 0.43 mmol) and 4-chloro- 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 15b (100 mg, 0.43 mmol) was dissolved in 5 mL dichloromethane. Then, N,N-diisopropylethylamine (332 mg, 2.57 mmol) was added, and the mixture was reacted at room temperature for 12 hours. The organic layer was concentrated under reduced pressure, and 15 mL of isopropyl alcohol was added and stirred for 10 minutes to precipitate a solid product, which was filtered, and the filter cake was washed with isopropyl alcohol (5 mL × 2) and dried to give (4-methoxyphenyl) (2-(1) -(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-12,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)methanone 15 g (180 mg, white solid), yield: 85%.
MS m/z(ESI)：492.9[M+1]MS m/z (ESI): 492.9 [M+1]
第七步Seventh step
1-(4-甲氧基苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-methoxyphenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将(4-甲氧基苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-12,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮15g(180mg,0.34mmol)，溶于8mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(2.9mL,1M/THF)，室温下反应0.5小时。0℃下，加入50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(4-甲氧基苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇15(31.9mg,淡黄色固体)，产率：18.7％。(4-methoxyphenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1] under argon , 2,4]triazin-4-yl)-12,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15 g (180 mg, 0.34 mmol), dissolved in 8 mL of tetrahydrofuran The reaction liquid was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (2.9 mL, 1 M / THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched by the addition of 50 mL of EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: A) to give 1-(4-methoxyphenyl)-1-(2-(1-(6-(1-) 1- -1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl Pyrimidine-5-yl)ethan-1-ol 15 (31.9 mg, pale yellow solid), yield: 18.7%.
MS m/z(ESI)：509.0[M+1]MS m/z (ESI): 509.0 [M+1]
1H NMR(400MHz,CDCl 3)δ8.74(s,2H),7.91(s,1H),7.70(d,J＝6.4Hz,2H),7.58(s,1H),7.35(d,J＝8.8Hz,2H),7.30(s,1H),6.89(s,1H),6.87(s,2H),4.76(s,2H),4.21(t,J＝1.4Hz,2H),3.95(s,3H),3.81(s,3H),2.97(s,2H),1.99(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.74 (s, 2H), 7.91 (s, 1H), 7.70 (d, J = 6.4Hz, 2H), 7.58 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.30 (s, 1H), 6.89 (s, 1H), 6.87 (s, 2H), 4.76 (s, 2H), 4.21 (t, J = 1.4 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 2.97 (s, 2H), 1.99 (s, 3H).
实施例16Example 16
1-(3,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000071
Figure PCTCN2018100901-appb-000071
第一步first step
(3,4-二氟苯基)溴化镁(3,4-difluorophenyl)magnesium bromide
氩气保护下，将镁屑(294mg,12.1mmol)和1粒碘溶于10mL四氢呋喃中，将4-溴-1,2-二氟苯16a(3.9g,20.4mmol)溶于2mL四氢呋喃中，取0.2mL滴加到上述反应液中，并且以电吹风吹反应瓶瓶底，引发反应，然后将剩余的4-溴-1,2-二氟苯溶液缓慢滴加到反应液中，并保持反应微微回流，加毕，室温下反应1小时。反应结束后，得到(3,4-二氟苯基)溴化镁16b(12mL,灰色溶液，1M/THF)，直接用于下一步，产率：100％。Under the protection of argon, magnesium swarf (294 mg, 12.1 mmol) and 1 iodine were dissolved in 10 mL of tetrahydrofuran, and 4-bromo-1,2-difluorobenzene 16a (3.9 g, 20.4 mmol) was dissolved in 2 mL of tetrahydrofuran. 0.2 mL was added dropwise to the above reaction solution, and the bottom of the reaction flask was blown with a hair dryer to initiate a reaction, and then the remaining 4-bromo-1,2-difluorobenzene solution was slowly added dropwise to the reaction solution, and kept. The reaction was slightly refluxed, and the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (3,4-difluorophenyl)magnesium bromide 16b (12 mL, m.p.
第二步Second step
4-(5-(3,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(3,4-Difluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
氩气保护下，将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔 丁酯1g(800mg,2.30mmol)溶于15mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加(3,4-二氟苯基)溴化镁16b(6.8mL,1M/THF)，室温下反应1小时。0℃下，以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(10mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(3,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯16c(670mg,白色固体)，产率：72.8％。1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (800 mg) under argon , 2.30 mmol) was dissolved in 15 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and (3,4-difluorophenyl)magnesium bromide 16b (6.8 mL, 1 M/THF) was added dropwise, and the reaction was carried out at room temperature. hour. The reaction mixture was quenched with EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: A) to give 4-(5-(3,4-difluorobenzoyl)pyrimidin-2-yl)-3,6- Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 16c (670 mg, white solid), yield: 72.8%.
MS m/z(ESI)：345.9[M-55]MS m/z (ESI): 345.9 [M-55]
第三步third step
(3,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(3,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone
将4-(5-(3,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯16c(570mg,1.43mmol)溶于12mL二氯甲烷中，加入3mL三氟乙酸，室温下反应0.5小时。减压浓缩，得到(3,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮16d(492mg,黄色油状),产率：100％，直接用于下一步。Dissolving 4-(5-(3,4-difluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 16c (570 mg, 1.43 mmol) In 12 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (3,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 16d (492 mg, m. , Yield: 100%, used directly in the next step.
第四步the fourth step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(3,4-二氟苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(3,4-difluorophenyl)methanone
将(3,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮16d(508mg,1.89mmol)和6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪甲酸甲酯1b(414mg,1.77mmol)溶于25mL二氯甲烷中，然后加入N,N-二异丙基乙胺(1.31mg,10.12mmol)，室温下反应4小时。减压浓缩，加入25mL异丙醇搅拌10分钟，析出固体产物，过滤，滤饼依次以异丙醇(10mL×2)和石油醚(10mL×2)洗涤，抽干，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(3,4-二氟苯基)甲酮16e(666mg,棕色固体)，产率：79.4％。(3,4-Difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 16d (508 mg, 1.89 mmol) and 6-bromo Methyl 4-chloropyrrolo[2,1-f][1,2,4]triazinecarboxylate 1b (414 mg, 1.77 mmol) was dissolved in 25 mL of dichloromethane then N,N-diisopropyl Ethylamine (1.31 mg, 10.12 mmol) was reacted at room temperature for 4 hours. The organic layer was concentrated under reduced pressure, and stirred for 15 minutes by adding 25 mL of isopropyl alcohol. The solid product was precipitated and filtered. The filter cake was washed with isopropyl alcohol (10 mL×2) and petroleum ether (10 mL×2), and dried to give (2-(1) -(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl (3,4-Difluorophenyl)methanone 16e (666 mg, brown solid), yield: 79.4%.
MS m/z(ESI)：496.7[M+1]MS m/z (ESI): 496.7 [M+1]
第五步the fifth step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(3,4-二氟苯基)乙-1-醇(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(3,4-二氟苯基)甲酮16e(666mg,1.34mmol)溶于25mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(10.7mL,1M/THF)，室温下反应0.5小时。0℃下，加入50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(3,4-二氟苯基)乙-1-醇16f(580mg,白色固体)，产率：85％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(3,4-difluorophenyl)methanone 16e (666 mg, 1.34 mmol) was dissolved in 25 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. Methylmagnesium bromide (10.7 mL, 1 M/THF) was reacted at room temperature for 0.5 h. The reaction was quenched by the addition of 50 mL of EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: A) to give (2-(1-(6-bromopyrrolo[2,1-f][1,2,4] Pyrazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (580 mg , white solid), Yield: 85%.
第六步Step 6
1-(3,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(3,4-二氟苯基)乙-1-醇16f(150mg,0.29mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(122mg,0.59mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(43mg,0.06mmol)和碳酸钾(121mg,0.88mmol)溶于6.6mL 1,4-二氧六环/水(V/V＝10/1)中，100℃反应4小时。加入80mL乙酸乙酯稀释反应液，依次以水(10mL×2)和饱和氯化钠水溶液(30mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(3,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇16(64.1mg,白色固体)，产率：42.5％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (150 mg, 0.29 mmol), 1-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (122 mg, 0.59 mmol), [1,1'-bis(diphenylphosphine) Base ferrocene] palladium dichloride (43 mg, 0.06 mmol) and potassium carbonate (121 mg, 0.88 mmol) dissolved in 6.6 mL of 1,4-dioxane/water (V/V = 10/1). The reaction was carried out at 100 ° C for 4 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Purification by the method (eluent: A system) to give 1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)ethyl-1 - Alcohol 16 (64.1 mg, white solid), yield: 42.5%.
MS m/z(ESI)：514.9[M+1]MS m/z (ESI): 514.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.37(s,2H),7.90(s,1H),7.70(s,1H),7.69(s,1H),7.58(s,1H),7.32-7.29(m,2H),7.16-7.13(m,2H),6.87(s,1H),4.76(s,2H),4.21(t,J＝1.4Hz,2H),3.95(s,3H),2.96(s,2H),2.00(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.37 (s, 2H), 7.90 (s, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.32-7.29 ( m, 2H), 7.16-7.13 (m, 2H), 6.87 (s, 1H), 4.76 (s, 2H), 4.21 (t, J = 1.4 Hz, 2H), 3.95 (s, 3H), 2.96 (s) , 2H), 2.00 (s, 3H).
实施例17Example 17
1-(3,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000072
Figure PCTCN2018100901-appb-000072
第一步first step
1-(3,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(3,4-二氟苯基)乙-1-醇16f(150mg,0.29mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑7a(130mg,0.59mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(43mg,0.06mmol)和碳酸钾(121mg,0.88mmol)溶于6.6mL 1,4-二氧六环/水(V/V＝10/1)中，100℃反应4小时。减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(3,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇17(12.0mg,淡黄色固体)，产率：8％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (150 mg, 0.29 mmol), 1-ethyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (130 mg, 0.59 mmol), [1,1'-bis(diphenylphosphine) Base ferrocene] palladium dichloride (43 mg, 0.06 mmol) and potassium carbonate (121 mg, 0.88 mmol) dissolved in 6.6 mL of 1,4-dioxane/water (V/V = 10/1). The reaction was carried out at 100 ° C for 4 hours. The residue was purified by silica gel column chromatography (eluent: A) to give 1-(3,4-difluorophenyl)-1-(2-(1-difluorophenyl)-1-(2-(1-(6-) 1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine- 4-yl)pyrimidin-5-yl)ethan-1-ol 17 (12.0 mg, pale yellow solid), yield: 8%.
MS m/z(ESI)：529.0[M+1]MS m/z (ESI): 529.0 [M+1]
1H NMR(400MHz,CDCl 3)8.66(s,2H),7.84(s,1H),7.63(d,J＝3.6Hz,2H),7.55(s,1H),7.26-7.24(m,2H),7.09-7.06(m,2H),6.81(m,1H),4.70(s,2H),4.18-4.12(m,\4H),2.90(s,2H),1.93(s,3H),1.47(t,J＝8.0Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) 8.66 (s, 2H), 7.84 (s, 1H), 7.63 (d, J = 3.6Hz, 2H), 7.55 (s, 1H), 7.26-7.24 (m, 2H) , 7.09-7.06 (m, 2H), 6.81 (m, 1H), 4.70 (s, 2H), 4.18-4.12 (m, \4H), 2.90 (s, 2H), 1.93 (s, 3H), 1.47 ( t, J = 8.0 Hz, 3H).
实施例18Example 18
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000073
Figure PCTCN2018100901-appb-000073
Figure PCTCN2018100901-appb-000074
Figure PCTCN2018100901-appb-000074
第一步first step
(2,4-二氟苯基)溴化镁(2,4-difluorophenyl)magnesium bromide
氩气保护下，将镁屑(374mg,15.6mmol)、一粒碘溶于10mL的干燥四氢呋喃中。将1-溴-2,4-二氟苯18a(2.3g,12.0mmol)溶于2mL的干燥四氢呋喃中，然后取0.4mL滴加到上述反应液中，并以吹风机加热反应瓶底，引发反应。缓慢加入剩余1-溴-2,4-二氟苯的四氢呋喃溶液，保持反应液微沸。滴毕，室温反应1小时。反应结束后，直接得到(2,4-二氟苯基)溴化镁18b(12mL,1M/THF,淡黄色液体)，产率：100％。Magnesium turnings (374 mg, 15.6 mmol) and one iodine were dissolved in 10 mL of dry tetrahydrofuran under argon. 1-Bromo-2,4-difluorobenzene 18a (2.3 g, 12.0 mmol) was dissolved in 2 mL of dry tetrahydrofuran, then 0.4 mL was added dropwise to the above reaction solution, and the bottom of the reaction flask was heated with a hair dryer to initiate a reaction. . The remaining 1-bromo-2,4-difluorobenzene in tetrahydrofuran was slowly added to keep the reaction solution slightly boiling. After the dropwise addition, the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (2,4-difluorophenyl)magnesium bromide 18b (12 mL, 1M/THF, pale yellow liquid) was obtained.
第二步Second step
4-(5-(2,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(2,4-Difluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
氩气保护下，将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(1.0g,2.87mmol)溶于10mL干燥四氢呋喃中，以冰水浴将反应液降温至0℃，缓慢滴加(2,4-二氟苯基)溴化镁18b(11.5mL,1M/THF)，30℃反应2小时。以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(2,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯18c(612mg,淡黄色固体)，产率：53％。1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.0) under argon g, 2.87 mmol) was dissolved in 10 mL of dry tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and (2,4-difluorophenyl)magnesium bromide 18b (11.5 mL, 1 M/THF) was slowly added dropwise, 30 The reaction was carried out at ° C for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc m. Purification by silica gel column chromatography (eluent: A system) gave 4-(5-(2,4-difluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 ( 2H)-tert-butyl formate 18c (612 mg, pale yellow solid), yield: 53%.
MS m/z(ESI)：345.9[M-55]MS m/z (ESI): 345.9 [M-55]
第三步third step
(2,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(2,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone
将4-(5-(2,4-二氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯18c(612mg,1.5mmol)溶于16mL二氯甲烷中，加入4mL三氟乙酸，室温下反应0.5小时。减压浓缩，得到(2,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮18d(461mg,黄色液体)，产率：100％。Dissolve 4-(5-(2,4-difluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 18c (612 mg, 1.5 mmol) In 16 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (2,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 18d (461 mg, yellow liquid) , Yield: 100%.
第四步the fourth step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(2,4-difluorophenyl)methanone
将(2,4-二氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮18d(461mg,1.53mmol)和 6-溴-4-氯吡咯并[2,1-f][1,2,4]三嗪1b(390mg,1.9mmol)溶于10mL二氯甲烷中，加入N,N-二异丙基乙胺(1.2g,9.2mmol)，室温下反应12小时。减压浓缩，加入20mL异丙醇，室温下搅拌10分钟，析出固体产物，过滤，滤饼依次以异丙醇(10mL×2)、石油醚(10mL×2)洗涤，抽干，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)甲酮18e(687mg,黄色固体)，产率：90.5％。(2,4-Difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 18d (461 mg, 1.53 mmol) and 6-bromo 4-Chloropyrrolo[2,1-f][1,2,4]triazine 1b (390 mg, 1.9 mmol) was dissolved in 10 mL of dichloromethane and N,N-diisopropylethylamine (1.2) g, 9.2 mmol), and reacted at room temperature for 12 hours. Concentrated under reduced pressure, 20 mL of isopropanol was added, and the mixture was stirred at room temperature for 10 minutes to precipitate a solid product, which was filtered, and the filter cake was washed with isopropyl alcohol (10 mL×2), petroleum ether (10 mL×2), and dried to give (2) -(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine- 5-yl)(2,4-difluorophenyl)methanone 18e (687 mg, yellow solid), yield: 90.5%.
MS m/z(ESI)：496.8[M+1]MS m/z (ESI): 496.8 [M+1]
第五步the fifth step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-4-基)-1-(2,4-二氟苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- 4-yl)-1-(2,4-difluorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)甲酮18e(320mg,0.65mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，缓慢滴加甲基溴化镁(5.2mL,1M/THF)，室温下反应0.5小时。以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-4-基)-1-(2,4-二氟苯基)乙-1-醇18f(310mg,白色固体)，产率：94％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (320mg, 0.65mmol) was dissolved in 10mL of tetrahydrofuran, the reaction solution was cooled to 0 °C in ice water bath, slowly drip Methylmagnesium bromide (5.2 mL, 1 M/THF) was added and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc EtOAc (EtOAc m. Purification by silica gel column chromatography (eluent: A) gave 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (310 mg, white solid) Yield: 94%.
MS m/z(ESI)：512.8[M+1]MS m/z (ESI): 512.8 [M+1]
第六步Step 6
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-4-基)-1-(2,4-二氟苯基)乙-1-醇18f(110mg,0.22mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑1l(89.4mg,0.43mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(32mg,0.043mmol)和碳酸铯(232mg,0.66mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，有机相以100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇18(22.1mg,白色固体)，产率：20％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-methyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (89.4 mg, 0.43 mmol), [1,1'-bis ( Diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (232 mg, 0.66 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V=10/1 In the reaction, the reaction was carried out at 100 ° C for 5 hours. The organic layer was combined with ethyl acetate (50 mL×3). Purification by eluent (eluent: A system) to give 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazole-4-) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)- 1-alcohol 18 (22.1 mg, white solid), yield: 20%.
MS m/z(ESI)：514.9[M+1]MS m/z (ESI): 514.9 [M+1]
1H NMR(400MHz,DMSO)δ8.75(s,2H),8.06(s,1H),7.99(s,1H),7.87(d,J＝5.4Hz,1H),7.86-7.75(m,2H),7.28(d,J＝7.5Hz,2H),7.20-7.09(m,2H),6.33(s,1H),4.75(s,2H),4.16(t,J＝5.3Hz,2H),3.86(s,3H),2.83(s,2H),1.92(s,3H)。 1 H NMR (400MHz, DMSO) δ8.75 (s, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.87 (d, J = 5.4Hz, 1H), 7.86-7.75 (m, 2H ), 7.28 (d, J = 7.5 Hz, 2H), 7.20-7.09 (m, 2H), 6.33 (s, 1H), 4.75 (s, 2H), 4.16 (t, J = 5.3 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 1.92 (s, 3H).
实施例19Example 19
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四 氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000075
Figure PCTCN2018100901-appb-000075
第一步first step
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-4-基)-1-(2,4-二氟苯基)乙-1-醇18f(110mg,0.22mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑7a(95mg,0.43mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(32mg,0.043mmol)和碳酸铯(210mg,0.65mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，有机相以100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇19(16.7mg,白色固体)，产率：15％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-ethyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (95 mg, 0.43 mmol), [1,1'-bis (two Phenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (210 mg, 0.65 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1) The reaction was carried out at 100 ° C for 5 hours. The organic layer was combined with ethyl acetate (50 mL×3). Purification by eluent (eluent: A system) to give 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazole-4-) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)- 1-alcohol 19 (16.7 mg, white solid), yield: 15%.
MS m/z(ESI)：529.3[M+1]MS m/z (ESI): 529.3 [M+1]
1H NMR(400MHz,CDCl 3)δ8.65(s,2H),7.84(s,1H),7.64-7.58(m,3H),7.55(s,1H),7.25(s,1H),6.91-6.86(m,1H),6.82-6.6.79(m,1H),6.74-6.69(m,1H),4.70(s,2H),4.18-4.14(m,4H),2.90(s,2H),1.95(s,3H),1.47(t,J＝4.0Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (s, 2H), 7.84 (s, 1H), 7.64 - 7.58 (m, 3H), 7.55 (s, 1H), 7.25 (s, 1H), 6.91 6.86(m,1H),6.82-6.6.79(m,1H),6.74-6.69(m,1H), 4.70(s,2H), 4.18-4.14(m,4H),2.90(s,2H), 1.95 (s, 3H), 1.47 (t, J = 4.0 Hz, 3H).
实施例20Example 20
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000076
Figure PCTCN2018100901-appb-000076
第一步first step
1-(2,4-二氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-4-基)-1-(2,4-二氟苯基)乙-1-醇18f(110mg,0.22mmol)、1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑14d(108mg,0.43mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(32mg,0.043mmol)和碳酸铯(210mg,0.65mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2,4-二氟苯基)-1-(2-(1-(6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇20(9.2mg,白色固体)，产率：8％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-(oxetan-3- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (108 mg, 0.43 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (210 mg, 0.65 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was concentrated under reduced pressure and purified to silicagel elutd (oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3 , 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 20 (9.2 mg, white solid), yield: 8%.
MS m/z(ESI)：556.9[M+1]MS m/z (ESI): 556.9 [M+1]
1H NMR(400MHz,CDCl 3)δ8.72(s,2H),7.90(s,1H),7.82(s,1H),7.81(s,1H),7.71-7.68(m,2H),7.32(s,1H),6.96(t,J＝6.8Hz,1H),6.87(s,1H),6.78(t,J＝4.8Hz,1H),5.48-5.52(m,1H),5.11(s,2H),5.10(s,2H),4.75(s,2H),4.21(s,2H),2.96(s,2H),2.02(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.72 (s, 2H), 7.90 (s, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.71-7.68 (m, 2H), 7.32 ( s, 1H), 6.96 (t, J = 6.8 Hz, 1H), 6.87 (s, 1H), 6.78 (t, J = 4.8 Hz, 1H), 5.48-5.52 (m, 1H), 5.11 (s, 2H) ), 5.10 (s, 2H), 4.75 (s, 2H), 4.21 (s, 2H), 2.96 (s, 2H), 2.02 (s, 3H).
实施例21Example 21
1-(4-氯-3-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-Chloro-3-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
Figure PCTCN2018100901-appb-000077
Figure PCTCN2018100901-appb-000077
第一步first step
(4-氯-3-氟苯基)溴化镁(4-chloro-3-fluorophenyl)magnesium bromide
氩气保护下，将镁屑(374mg,15.6mmol)、一粒碘溶于10mL干燥四氢呋喃中。将4-溴-1-氯-2-氟苯21a(2.5g,12.0mmol)溶于2mL的四氢呋喃中，然后取0.4mL滴加到上述反应液中，并以吹风机吹反应瓶底，加热引发反应。缓慢加入剩余4-溴-1-氯-2-氟苯的四氢呋喃溶液，保持反应液微沸。滴毕，室温反应1小时。反应结束后，直接得到(4-氯-3-氟苯基)溴化镁21b(12mL,1M/THF,褐色色液体)，产率：100％。Under the protection of argon, magnesium chips (374 mg, 15.6 mmol) and one iodine were dissolved in 10 mL of dry tetrahydrofuran. 4-Bromo-1-chloro-2-fluorobenzene 21a (2.5 g, 12.0 mmol) was dissolved in 2 mL of tetrahydrofuran, and then 0.4 mL was added dropwise to the above reaction solution, and the bottom of the reaction bottle was blown with a hair dryer, and the mixture was heated. reaction. The remaining 4-bromo-1-chloro-2-fluorobenzene in tetrahydrofuran solution was slowly added to keep the reaction solution slightly boiling. After the dropwise addition, the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (4-chloro-3-fluorophenyl)magnesium bromide 21b (12 mL, 1M / THF, brown liquid) was obtained.
第二步Second step
4-(5-(4-氯-3-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯4-(5-(4-Chloro-3-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
氩气保护下，将4-(5-(甲氧基(甲基)氨基甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯1g(1.0g,2.87mmol)溶于20mL干燥四氢呋喃中，以冰水浴将反应液降温至0℃，缓 慢滴加(4-氯-3-氟苯基)溴化镁21b(10.0mL,1M/THF)，室温反应0.5小时。以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到4-(5-(4-氯-3-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯21c(878mg,淡黄色固体)，产率：67％。1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.0) under argon g, 2.87 mmol) was dissolved in 20 mL of dry tetrahydrofuran, the reaction solution was cooled to 0 ° C in ice water bath, and (4-chloro-3-fluorophenyl)magnesium bromide 21b (10.0 mL, 1 M/THF) was slowly added dropwise. The reaction was carried out for 0.5 hour at room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc m. Purified by silica gel column chromatography (eluent: A system) to give 4-(5-(4-chloro-3-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 (2H)-tert-butyl formate 21c (878 mg, pale yellow solid), yield: 67%.
MS m/z(ESI)：361.9[M-55]MS m/z (ESI): 361.9 [M-55]
第三步third step
(4-氯-3-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(4-chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone
将4-(5-(4-氯-3-氟苯甲酰基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯21c(878mg,2.1mmol)溶于20mL二氯甲烷中，加入5mL三氟乙酸，室温下反应3小时。减压浓缩，得到(4-氯-3-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮21d(487mg,褐色液体)，产率：75％。Dissolving 4-(5-(4-chloro-3-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 21c (878 mg, 2.1 mmol) 5 mL of trifluoroacetic acid was added to 20 mL of dichloromethane, and the mixture was reacted at room temperature for 3 hours. Concentration under reduced pressure gave (4-chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21d (487 mg, brown liquid ), yield: 75%.
MS m/z(ESI)：317.9[M+1]MS m/z (ESI): 317.9 [M+1]
第四步the fourth step
(4-氯-3-氟苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮(4-chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4 Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)methanone
将(4-氯-3-氟苯基)(2-(1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮21d(487mg,0.77mmol)和4-氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪15b(98mg,0.43mmol)溶于20mL二氯甲烷中，加入N,N-二异丙基乙胺(3.9g,30.2mmol)，室温下反应12小时。减压浓缩，加入40mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(4-氯-3-氟苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮21e(128mg,褐色固体)，产率：57％。(4-Chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21d (487 mg, 0.77 mmol) and 4- Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 15b (98 mg, 0.43 mmol) was dissolved in dichloromethane (20 mL) N,N-diisopropylethylamine (3.9 g, 30.2 mmol) was added, and the mixture was reacted at room temperature for 12 hours. The organic layer was dried over anhydrous sodium sulfate (MgSO4). Purification by chromatography (eluent: A system) to give (4-chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrole) And [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21e (128 mg , brown solid), yield: 57%.
第五步the fifth step
1-(4-氯-3-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1-(4-Chloro-3-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol
氩气保护下，将(4-氯-3-氟苯基)(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)甲酮21e(128mg,0.24mmol)溶于10mL四氢呋喃中，以冰水浴将反应液降温至0℃，缓慢滴加甲基溴化镁(2.0mL,1M/THF)，室温下反应0.5小时。以50mL饱和氯化铵水溶液淬灭反应，减压浓缩除去四氢呋喃，残留物以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(4-氯-3-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇21(7mg,白色固体)，产率：6％。(4-Chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] under argon [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21e (128 mg, 0.24 mmol) dissolved in 10 mL of tetrahydrofuran The reaction solution was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (2.0 mL, 1 M / THF) was slowly added dropwise, and reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc (EtOAc m.) The organic layer was dried (MgSO4) (yield: EtOAc) to afford 1-(4-chloro-3-fluorophenyl)-1-(2-(1-(6-) (1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)pyrimidin-5-yl)ethan-1-ol 21 (7 mg, white solid), yield: 6%.
MS m/z(ESI)：530.9[M+1]MS m/z (ESI): 530.9 [M+1]
1H NMR(400MHz,DMSO)δ8.85(s,2H),8.06(s,1H),7.99(s,1H),7.88(s,1H),7.84(s,1H),7.57-7.51(m,2H),7.33(d,J＝7.2Hz,1H),7.27(s,2H),6.36(s,1H),4.74(s,2H),4.16(t,J＝7.2Hz,2H),3.86(s,3H),2.81(s,2H),1.92(s,3H)。 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.84 (s, 1H), 7.57-7.51 (m) , 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.27 (s, 2H), 6.36 (s, 1H), 4.74 (s, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.81 (s, 2H), 1.92 (s, 3H).
实施例22Example 22
(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine
Figure PCTCN2018100901-appb-000078
Figure PCTCN2018100901-appb-000078
第一步first step
(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(S)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5- 基)(4-氟苯基)甲酮1j(300mg,0.63mmol)、(S)-叔丁基亚磺酰胺22a(213mg,1.76mmol)和四乙氧基钛(317mg,1.39mmol)溶于10mL干燥四氢呋喃中，80℃下反应16小时。冷却至室温，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，有机相以100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺22b(133mg,黄色固体)，产率：36％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (300 mg, 0.63 mmol), (S)-tert-butylsulfinamide 22a (213 mg, 1.76 mmol) and tetraethoxy The base titanium (317 mg, 1.39 mmol) was dissolved in 10 mL of dry tetrahydrofuran and reacted at 80 ° C for 16 hours. After cooling to room temperature, 50 mL of water was added, and ethyl acetate (50 mL×3) was evaporated. The organic phase was combined, and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. Purification by eluent (eluent: A system) to give (S)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4) -yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 22b ( 133 mg, yellow solid), yield: 36%.
MS m/z(ESI)：581.8[M+1]MS m/z (ESI): 581.8 [M+1]
第二步Second step
N-((S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
氩气保护下，将(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(4-氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺22b(133mg,0.23mmol)溶于5mL四氢呋喃中，以冰水浴将反应液降温至0℃，缓慢滴加甲基溴化镁(1.6mL,1M/THF)，室温下反应0.5小时。以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到N-((S)1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺22c(100mg,黄色固体)，产率：73％。(S)-N-((2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 under argon protection ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 22b (133 mg, 0.23 mmol) In 5 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (1.6 mL, 1 M/THF) was slowly added dropwise, and reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc EtOAc (EtOAc m. Purified by silica gel column chromatography (eluent: A system) to give N-((S)1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4 Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane -2-sulfinamide 22c (100 mg, yellow solid), yield: 73%.
MS m/z(ESI)：597.8[M+1]MS m/z (ESI): 597.8 [M+1]
第三步third step
(S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-胺盐酸盐(S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride
将N-((S)1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺22c(100mg,0.17mmol)溶于1.5mL甲醇中，滴加盐酸甲醇溶液(1.5mL,4M)，室温下反应1小时。减压浓缩，得到(S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-胺盐酸盐粗产物22d(95mg,棕色固体)，产率：100％。N-((S)1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 22c (100 mg, 0.17 mmol) dissolved in 1.5 Methanol solution (1.5 mL, 4 M) was added dropwise to mL methanol, and the mixture was reacted at room temperature for 1 hour. Concentration under reduced pressure gave (S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3 ,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride crude product 22d (95 mg, brown solid), yield: 100% .
MS m/z(ESI)：493.8[M+1]MS m/z (ESI): 493.8 [M+1]
第四步the fourth step
(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine
氩气保护下，将(S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(4-氟苯基)乙-1-胺盐酸盐22d(95mg,0.17mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑1l(69mg,0.33mmol)、[1,1’-双(二苯基膦基)二茂铁] 二氯化钯(25mg,0.033mmol)和碳酸铯(272mg,0.84mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(S)-1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺22(28.6mg,土黄色固体)，产率：34％。Under the protection of argon, (S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride 22d (95 mg, 0.17 mmol), 1-methyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (69 mg, 0.33 mmol), [1,1 '-Bis(diphenylphosphino)ferrocene] palladium dichloride (25 mg, 0.033 mmol) and cesium carbonate (272 mg, 0.84 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V In =10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was concentrated under reduced pressure and purified to silicagel elute -methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)ethan-1-amine 22 (28.6 mg, yello solid). Yield: 34%.
MS m/z(ESI)：596.0[M+1]MS m/z (ESI): 596.0 [M+1]
1H NMR(400MHz,DMSO)δ9.40(s,2H),8.80(s,2H),8.07(s,1H),8.00(s,1H),7.89(s,1H),7.84(s,1H),7.49-7.45(m,2H),7.37-7.29(m,4H),4.77(s,2H),4.18(t,J＝4.0Hz,2H),3.86(s,3H),2.84(s,2H),2.51(s,3H)。 1 H NMR (400MHz, DMSO) δ9.40 (s, 2H), 8.80 (s, 2H), 8.07 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H ), 7.49-7.45 (m, 2H), 7.37-7.29 (m, 4H), 4.77 (s, 2H), 4.18 (t, J = 4.0 Hz, 2H), 3.86 (s, 3H), 2.84 (s, 2H), 2.51 (s, 3H).
实施例23Example 23
4-(4-(5-(1-氟-1-(4-氟苯基)乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪4-(4-(5-(1-fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine
Figure PCTCN2018100901-appb-000079
Figure PCTCN2018100901-appb-000079
第一步first step
4-(4-(5-(1-氟-1-(4-氟苯基)乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪4-(4-(5-(1-fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine
氩气保护下，将1-(4-氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇1(1.0g,2.0mmol)溶于20mL的四氢呋喃中，冷却至-78℃，加入N,N-二乙基-1,1,1-三氟-λ 4-磺胺23a(487.5mg,3.0mmol)，缓慢升温至0℃,0℃下反应2小时。-78℃下，加入50mL饱和氯化铵水溶液，将反应淬灭。加入100mL的二氯甲烷稀释反应，依次以水(30mL×3)和饱和氯化钠水溶液(20mL)洗涤，收集有机相，以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到4-(4-(5-(1- 氟-1-(4-氟苯基)乙基)嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪23(201mg,白色固体)，产率：36％。 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] under argon ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 1 (1.0 g, 2.0 mmol Dissolved in 20 mL of tetrahydrofuran, cooled to -78 ° C, added N,N-diethyl-1,1,1-trifluoro-λ 4 -sulfonamide 23a (487.5 mg, 3.0 mmol), slowly warmed to 0 ° C The reaction was carried out at 0 ° C for 2 hours. At -78 ° C, 50 mL of a saturated aqueous solution of ammonium chloride was added and the reaction was quenched. The reaction was diluted with aq. EtOAc (EtOAc) (EtOAc (EtOAc) Purification by the method (eluent: B system) gave 4-(4-(5-(1-fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydro Pyridine-1(2H)-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 23 (201 mg, white Solid), yield: 36%.
MS m/z(ESI)：499.3[M+1]MS m/z (ESI): 499.3 [M+1]
1H NMR(400MHz,DMSO)δ8.86(s,2H),8.05(s,1H),7.99(d,J＝1.3Hz,1H),7.88(s,1H),7.83(s,1H),7.51(dd,J＝8.8,5.4Hz,2H),7.33(s,1H),7.30-7.20(m,3H),4.76(s,2H),4.17(t,J＝5.6Hz,2H),3.86(s,3H),2.83(s,2H),2.14(d,J＝23.7Hz,3H)。 1 H NMR (400MHz, DMSO) δ8.86 (s, 2H), 8.05 (s, 1H), 7.99 (d, J = 1.3Hz, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.51 (dd, J=8.8, 5.4 Hz, 2H), 7.33 (s, 1H), 7.30-7.20 (m, 3H), 4.76 (s, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 2.14 (d, J = 23.7 Hz, 3H).
实施例24Example 24
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol
Figure PCTCN2018100901-appb-000080
Figure PCTCN2018100901-appb-000080
第一步first step
(2,6-二氟苯基)溴化镁(2,6-difluorophenyl)magnesium bromide
氩气保护下，将镁屑(520mg,22.0mmol)和1粒碘溶于15mL四氢呋喃中，加入1mL2-溴-1,3-二氟苯24a(3.86g,20.0mmol)溶于5mL四氢呋喃的溶液，加热引发反应，然后缓慢加入剩余的2-溴-1,3-二氟苯24a(2.0mL,16.89mmol)的四氢呋喃溶液，并保持反应微微回流，加毕，室温下反应1小时。反应结束后，得到(2,6-二氟苯基)溴化镁24b(20mL,浅棕色溶液,1.0M/THF)，直接用于下一步，产率：100％。Under argon protection, magnesium chips (520 mg, 22.0 mmol) and 1 iodine were dissolved in 15 mL of tetrahydrofuran, and 1 mL of 2-bromo-1,3-difluorobenzene 24a (3.86 g, 20.0 mmol) was dissolved in 5 mL of tetrahydrofuran. The reaction was initiated by heating, and then the remaining 2-bromo-1,3-difluorobenzene 24a (2.0 mL, 16.89 mmol) in tetrahydrofuran was slowly added, and the reaction was kept to reflux slightly, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, (2,6-difluorophenyl)magnesium bromide 24b (20 mL, light brown solution, 1.0 M/THF) was obtained.
第二步Second step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,6-二氟苯 基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(2,6-difluorophenyl)methanone
氩气保护下，将2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺8b(1.0g,2.26mmol)溶于20mL四氢呋喃中，滴加(2,6-二氟苯基)溴化镁24b(9.05mL,1.0M/THF)，室温下反应3小时。用5mL冰水淬灭反应，减压浓缩除去四氢呋喃，向残留物中加入40mL水，用乙酸乙酯(40mL×3)萃取，合并有机相，用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,6-二氟苯基)甲酮24c(168mg,黄色固体)，产率：15.6％。2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection 4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.0 g, 2.26 mmol) was dissolved in 20 mL of tetrahydrofuran, and (2,6-difluorophenyl) bromide was added dropwise. Magnesium 24b (9.05 mL, 1.0 M/THF) was reacted at room temperature for 3 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc) Drying, concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: A system) to give (2-(6-bromopyrrolo[2,1-f][1,2 ,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,6-difluorophenyl)methanone 24c (168 mg, yellow Solid), yield: 15.6%.
MS m/z(ESI)：496.8[M+1]MS m/z (ESI): 496.8 [M+1]
第三步third step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- Pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,6-二氟苯基)甲酮24c(180mg,0.36mmol)溶于5mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(0.72mL,1M/THF),室温下反应1小时。用5mL冰水淬灭反应，减压浓缩除去四氢呋喃，向残留物中加入20mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用15mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇24d(60mg,类白色固体)，产率：32.3％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,6-difluorophenyl)methanone 24c (180 mg, 0.36 mmol) was dissolved in 5 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. Methylmagnesium bromide (0.72 mL, 1 M/THF) was reacted at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The mixture was dried and concentrated under reduced pressure. EtOAcjjjjjjjjjj , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)- 1-alcohol 24d (60 mg, off-white solid), yield: 32.3%.
MS m/z(ESI)：512.8[M+1]MS m/z (ESI): 512.8 [M+1]
第四步the fourth step
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇24d(60mg,0.116mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(48mg,0.232mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(8.49mg,0.0012mmol)和碳酸铯(75.6mg,0.232mmol)溶于5.5mL 1,4-二氧六环中和水的混合溶剂(V/V＝10/1)中，加热至100℃反应4小时。反应液冷却至室温，加入50mL水，用乙酸乙酯(30mL×2)萃取，合并有机相，用饱和氯化钠水溶液(40mL)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,6-二氟苯基)乙-1-醇24(12.0mg,白色固体)，产率：20％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol 24d (60 mg, 0.116 mmol), 1-methyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (48 mg, 0.232 mmol), [1,1'-bis(diphenyl) a phosphinyl)ferrocene]palladium dichloride (8.49 mg, 0.0012 mmol) and cesium carbonate (75.6 mg, 0.232 mmol) dissolved in 5.5 mL of a mixture of 1,4-dioxane and water (V/ In V = 10/1), the mixture was heated to 100 ° C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc (3 mL, EtOAc) Purification by silica gel column chromatography (eluent: C system) afforded 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorobenzene Ethyl-1-alcohol 24 (12.0 mg, white solid), yield: 20%.
MS m/z(ESI)：514.9[M+1]MS m/z (ESI): 514.9 [M+1]
1H NMR(400MHz,DMSO)δ8.76(s,2H),8.05(s,1H),7.98(d,J＝1.4Hz,1H),7.87(s,1H),7.83(s,1H),7.40(t,J＝7.1Hz,1H),7.27(d,J＝8.2Hz,2H),7.06-7.00(m,2H),6.39(s,1H),4.74(s,2H),4.17(t,J＝5.3Hz,2H),3.86(s,3H),2.83(s,2H),1.96(s,3H)。 1 H NMR (400MHz, DMSO) δ8.76 (s, 2H), 8.05 (s, 1H), 7.98 (d, J = 1.4Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.06-7.00 (m, 2H), 6.39 (s, 1H), 4.74 (s, 2H), 4.17 (t , J = 5.3 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 1.96 (s, 3H).
实施例25Example 25
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol
Figure PCTCN2018100901-appb-000081
Figure PCTCN2018100901-appb-000081
第一步first step
(2,4,6-三氟苯基)溴化镁(2,4,6-trifluorophenyl)magnesium bromide
氩气保护下，将镁屑(541mg,22.54mmol)和1粒碘溶于20mL四氢呋喃中，向上述溶液中加入2-溴-1,3,5-三氟苯25a(0.67mL,5.65mmol)，并且以电吹风吹反应瓶瓶底，引发反应，然后缓慢加入2-溴-1,3,5-三氟苯25a(2.0mL,16.89mmol)，并保持反应微微回流，加毕，室温下反应1小时。反应结束后，得到(2,4,6-三氟苯基)溴化镁25b(22.6mL,淡黄色溶液,1.0M/THF)，直接用于下一步，产率：100％。Under the protection of argon, magnesium dust (541 mg, 22.54 mmol) and 1 iodine were dissolved in 20 mL of tetrahydrofuran, and 2-bromo-1,3,5-trifluorobenzene 25a (0.67 mL, 5.65 mmol) was added to the above solution. And the bottom of the reaction flask was blown with a hair dryer to initiate the reaction, then 2-bromo-1,3,5-trifluorobenzene 25a (2.0 mL, 16.89 mmol) was slowly added, and the reaction was kept at a slight reflux, and the temperature was increased. Reaction for 1 hour. After completion of the reaction, (2,4,6-trifluorophenyl)magnesium bromide 25b (22.6 mL, pale yellow solution, 1.0M/THF) was obtained.
第二步Second step
(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4,6-三氟苯基)甲酮(2-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl) Pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone
氩气保护下，将2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)-N-甲氧基-N-甲基嘧啶-5-甲酰胺8b(1.8g,4.06mmol)溶于50mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加(2,4,6-三氟苯基)溴化镁25b(16.2mL,1.0M/THF),室温下反应0.5小时。 以50mL水淬灭反应，以乙酸乙酯(100mL×3)萃取，合并有机相，以50mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4,6-三氟苯基)甲酮25c(708mg,淡黄色固体)，产率：35％。2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection -4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.8 g, 4.06 mmol) was dissolved in 50 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath, and added dropwise ( 2,4,6-Trifluorophenyl)magnesium bromide 25b (16.2 mL, 1.0 M/THF) was reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. Column chromatography (eluent: A system) was purified to give (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1 , 2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone 25c (708 mg, pale yellow solid), yield: 35%.
第三步third step
1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- Pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4,6-三氟苯基)甲酮25c(350mg,0.68mmol)溶于30mL四氢呋喃中，以冰水浴将反应液降温至0℃，滴加甲基溴化镁(7.0mL,1M/THF)，室温下反应0.5小时。0℃下，加入40mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(40mL×2)萃取，合并有机相，以50mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇25d(708mg,淡黄色固体)，产率：38.0％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone 25c (350 mg, 0.68 mmol) was dissolved in 30 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. Methylmagnesium bromide (7.0 mL, 1 M/THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched by the addition of 40 mL of EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: A) to give 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4 Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethyl-1- Alcohol 25d (708 mg, pale yellow solid), yield: 38.0%.
MS m/z(ESI)：530.9[M+1]MS m/z (ESI): 530.9 [M+1]
第四步the fourth step
1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇25d(90mg,0.169mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑1l(212.2mg,1.02mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.041mmol)和碳酸铯(300mg,0.921mmol)溶于20mL 1,4-二氧六环中(加0.1mL水)，100℃反应6小时。加入100mL乙酸乙酯稀释反应液，依次以水(30mL×2)和饱和氯化钠水溶液(40mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇25(15.8mg,白色固体)，产率：17.2％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol 25d (90 mg, 0.169 mmol), 1-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11 (212.2 mg, 1.02 mmol), [1,1'-double (Diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.041 mmol) and cesium carbonate (300 mg, 0.921 mmol) dissolved in 20 mL of 1,4-dioxane (plus 0.1 mL of water), 100 The reaction was carried out at ° C for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: A system) gave 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(2,4,6-trifluorophenyl) 1-Alcohol 25 (15.8 mg, white solid), Yield: 17.2%.
MS m/z(ESI)：532.8[M+1]MS m/z (ESI): 532.8 [M+1]
1H NMR(400MHz,DMSO)δ8.78(s,2H),8.06(s,1H),7.98(d,J＝1.2Hz,1H),7.86(d,J＝17.6Hz,2H),7.28(d,J＝8.8Hz,2H),7.13(t,J＝9.6Hz,2H),6.44(s,1H),4.75(s,2H),4.17(t,J＝5.5Hz,2H),3.86(s,3H),2.83(s,2H),1.94(s,3H)。 1 H NMR (400MHz, DMSO) δ8.78 (s, 2H), 8.06 (s, 1H), 7.98 (d, J = 1.2Hz, 1H), 7.86 (d, J = 17.6Hz, 2H), 7.28 ( d, J = 8.8 Hz, 2H), 7.13 (t, J = 9.6 Hz, 2H), 6.44 (s, 1H), 4.75 (s, 2H), 4.17 (t, J = 5.5 Hz, 2H), 3.86 ( s, 3H), 2.83 (s, 2H), 1.94 (s, 3H).
实施例26Example 26
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol
Figure PCTCN2018100901-appb-000082
Figure PCTCN2018100901-appb-000082
第一步first step
1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol
氩气保护下，将1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇25d(90mg,0.175mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑7a(250mg,1.13mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.041mmol)和碳酸铯(300mg,0.921mmol)溶于15.0mL 1,4-二氧六环中(加入0.5mL水)，100℃反应6小时。加入100mL乙酸乙酯稀释反应液，依次以水(30mL×2)和饱和氯化钠水溶液(40mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4,6-三氟苯基)乙-1-醇26(13.5mg,白色固体)，产率：15.2％。Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol 25d (90 mg, 0.175 mmol), 1-ethyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (250 mg, 1.13 mmol), [1,1'-double (diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.041 mmol) and cesium carbonate (300 mg, 0.921 mmol) dissolved in 15.0 mL of 1,4-dioxane (0.5 mL water). The reaction was carried out at 100 ° C for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL), EtOAc (EtOAc) Purification by the method (eluent: A system) gave 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(2,4,6-trifluorophenyl) 1-Alcohol 26 (13.5 mg, white solid), Yield: 15.2%.
MS m/z(ESI)：546.9[M+1]MS m/z (ESI): 546.9 [M+1]
1H NMR(400MHz,DMSO)δ8.78(s,2H),8.12(s,1H),7.99(d,J＝1.4Hz,1H),7.88(s,1H),7.84(s,1H),7.28(d,J＝6.8Hz,2H),7.13(t,J＝9.6Hz,2H),6.44(s,1H),4.75(s,2H),4.24-4.09(m,4H),2.84(s,2H),1.93(s,3H),1.41(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, DMSO) δ8.78 (s, 2H), 8.12 (s, 1H), 7.99 (d, J = 1.4Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.28 (d, J = 6.8 Hz, 2H), 7.13 (t, J = 9.6 Hz, 2H), 6.44 (s, 1H), 4.75 (s, 2H), 4.24 - 4.09 (m, 4H), 2.84 (s) , 2H), 1.93 (s, 3H), 1.41 (t, J = 7.4 Hz, 3H).
实施例27Example 27
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
Figure PCTCN2018100901-appb-000083
Figure PCTCN2018100901-appb-000083
第一步first step
(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(S)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methylene)-2-methylpropane-2-sulfinamide
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)甲酮18e(500mg,1.05mmol)、(S)-叔丁基亚磺酰胺22a(380mg,3.14mmol)和四乙氧基钛(0.55mL,2.63mmol,4.8M/THF)溶于15mL四氢呋喃中，80℃下反应16小时。冷却至室温，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，有机相以100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基) 嘧啶-5-基)(2,4-二氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺27a(492mg,黄色固体)，产率：78％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (500 mg, 1.05 mmol), (S)-tert-butylsulfinamide 22a (380 mg, 3.14 mmol) and Tetraethoxytitanium (0.55 mL, 2.63 mmol, 4.8 M/THF) was dissolved in 15 mL of tetrahydrofuran and reacted at 80 ° C for 16 hours. After cooling to room temperature, 50 mL of water was added, and ethyl acetate (50 mL×3) was evaporated. The organic phase was combined, and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. Purification by eluent (eluent: A system) to give (S)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4) -yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene)-2-methylpropane-2-sulfin Amide 27a (492 mg, yellow solid), yield: 78%.
MS m/z(ESI)：600.7[M+1]MS m/z (ESI): 600.7 [M+1]
第二步Second step
N-((R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺N-((R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
氩气保护下，将(S)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺27a(492mg,0.82mmol)溶于15mL四氢呋喃中，以冰水浴将反应液降温至0℃，缓慢滴加甲基溴化镁(4.1mL,1M/THF)，室温下反应40分钟。以50mL饱和氯化铵水溶液淬灭反应，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到N-((R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺27b(389mg,黄色固体)，产率：77％。(S)-N-((2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 under argon protection ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 27a (492 mg, 0.82 mmol Dissolved in 15 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (4.1 mL, 1 M / THF) was slowly added dropwise, and reacted at room temperature for 40 minutes. The reaction was quenched with EtOAc EtOAc (EtOAc m. Purification by silica gel column chromatography (eluent: A system) gave N-((()-(6-bromopyrrolo[2,1-f][1,2, 4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2 Methylpropane-2-sulfinamide 27b (389 mg, yellow solid), yield: 77%.
MS m/z(ESI)：616.8[M+1]MS m/z (ESI): 616.8 [M+1]
第三步third step
(R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺盐酸盐(R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride
将N-((R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺27b(389mg,0.63mmol)溶于6mL甲醇中，滴加盐酸甲醇溶液(6mL,4M)，室温下反应1小时。减压浓缩，得到(R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺盐酸盐27c(369mg,棕色固体)，产率：100％。N-((R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 27b (389 mg, 0.63 mmol It was dissolved in 6 mL of methanol, and a methanolic solution of hydrochloric acid (6 mL, 4 M) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Concentration under reduced pressure gave (R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3 ,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (369 mg, brown solid), yield: 100 %.
MS m/z(ESI)：511.8[M+1]MS m/z (ESI): 511.8 [M+1]
第四步the fourth step
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
氩气保护下，将(R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺盐酸盐27c(150mg,0.17mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑1l(122mg,0.586mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(43mg,0.0586mmol)和碳酸铯(477mg,1.465mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺 27(17.8mg,白色固体)，产率：12％。Under the protection of argon, (R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (150 mg, 0.17 mmol), 1-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (122 mg, 0.586 mmol), [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43 mg, 0.0586 mmol) and cesium carbonate (477 mg, 1.465 mmol) were dissolved in 11 mL of 1,4-dioxane/water ( In V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was dried over anhydrous sodium sulfate (MgSO4). Purification by chromatography (eluent: C system) gave (R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-) Pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5 Ethyl-1-amine 27 (17.8 mg, white solid), yield: 12%.
MS m/z(ESI)：513.9[M+1]MS m/z (ESI): 513.9 [M+1]
1H NMR(400MHz,DMSO)δ8.71(s,2H),8.06(s,1H),7.98(s,1H),7.91-7.77(m,3H),7.27(s,2H),7.13(dd,J＝23.8,9.0Hz,2H),4.74(s,2H),4.16(s,2H),3.86(s,3H),2.82(s,4H),1.79(s,3H)。 1 H NMR (400MHz, DMSO) δ8.71 (s, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.91-7.77 (m, 3H), 7.27 (s, 2H), 7.13 (dd , J = 23.8, 9.0 Hz, 2H), 4.74 (s, 2H), 4.16 (s, 2H), 3.86 (s, 3H), 2.82 (s, 4H), 1.79 (s, 3H).
实施例28Example 28
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
Figure PCTCN2018100901-appb-000084
Figure PCTCN2018100901-appb-000084
第一步first step
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
氩气保护下，将(R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺盐酸盐27c(120mg,0.235mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑7a(105mg,0.47mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.047mmol)和碳酸铯(383mg,1.17mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺28(9.8mg,淡黄色固体)，产率：8％。Under the protection of argon, (R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (120 mg, 0.235 mmol), 1-B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (105 mg, 0.47 mmol), [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35 mg, 0.047 mmol) and cesium carbonate (383 mg, 1.17 mmol) dissolved in 11 mL of 1,4-dioxane/water ( In V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was dried over anhydrous sodium sulfate (MgSO4). Purification by chromatography (eluent: C system) gave (R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-) Pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5 Ethyl-1-amine 28 (9.8 mg, pale yellow solid), yield: 8%.
MS m/z(ESI)：527.9[M+1]MS m/z (ESI): 527.9 [M+1]
1H NMR(400MHz,DMSO)δ8.71(s,2H),8.11(s,1H),7.98(d,J＝1.3Hz,1H),7.87(s,1H), 7.86-7.76(m,2H),7.27(s,2H),7.14(dt,J＝18.5,8.9Hz,2H),4.74(s,2H),4.26-4.03(m,4H),2.82(s,2H),2.67(s,2H),1.79(s,3H),1.41(dd,J＝9.9,4.7Hz,3H)。 1 H NMR (400MHz, DMSO) δ8.71 (s, 2H), 8.11 (s, 1H), 7.98 (d, J = 1.3Hz, 1H), 7.87 (s, 1H), 7.86-7.76 (m, 2H ), 7.27(s, 2H), 7.14 (dt, J = 18.5, 8.9 Hz, 2H), 4.74 (s, 2H), 4.26-4.03 (m, 4H), 2.82 (s, 2H), 2.67 (s, 2H), 1.79 (s, 3H), 1.41 (dd, J = 9.9, 4.7 Hz, 3H).
实施例29Example 29
(R)-1-(2-(1-(6-(1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺(R)-1-(2-(1-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1 ,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine
Figure PCTCN2018100901-appb-000085
Figure PCTCN2018100901-appb-000085
第一步first step
(R)-1-(2-(1-(6-(1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺(R)-1-(2-(1-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1 ,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine
氩气保护下，将(R)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺盐酸盐27c(140mg,0.274mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑29a(137mg,0.548mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(40mg,0.0548mmol)和碳酸铯(446mg,1.37mmol)溶于11mL 1,4-二氧六环/水(V/V＝10/1)中，100℃下反应5小时。减压浓缩，加入50mL水，以乙酸乙酯(50mL×3)萃取，合并有机相，以100mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(R)-1-(2-(1-(6-(1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙-1-胺29(20mg,白色固体)，产率：13％。Under the protection of argon, (R)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (140 mg, 0.274 mmol), 4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 29a (137 mg, 0.548 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.0548 mmol) and cesium carbonate (446 mg, 1.37 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V=10 In /1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was dried over anhydrous sodium sulfate (MgSO4). Chromatography (eluent: C system) to give (R)-1-(2-(1-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1 , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)- 1-amine 29 (20 mg, white solid), yield: 13%.
MS m/z(ESI)：500.3[M+1]MS m/z (ESI): 500.3 [M+1]
1H NMR(400MHz,DMSO)δ12.85(s,1H),8.71(s,2H),8.12(s,1H),8.01(s,1H),7.95-7.77(m,3H),7.28(d,J＝9.8Hz,2H),7.13(dd,J＝24.1,8.9Hz,2H),4.75(s,2H),4.17(s,2H),2.82(s,2H),2.71(s,2H),1.79(s,3H)。 1 H NMR (400MHz, DMSO) δ12.85 (s, 1H), 8.71 (s, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.95-7.77 (m, 3H), 7.28 (d , J = 9.8 Hz, 2H), 7.13 (dd, J = 24.1, 8.9 Hz, 2H), 4.75 (s, 2H), 4.17 (s, 2H), 2.82 (s, 2H), 2.71 (s, 2H) , 1.79 (s, 3H).
实施例30和实施例31Example 30 and Example 31
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇30(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 30
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇31(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31
Figure PCTCN2018100901-appb-000086
Figure PCTCN2018100901-appb-000086
第一步first step
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇30(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 30
(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇31(R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31
将1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇18(3.55g,6.8mmol)进一步通过采用超临界流体色谱(SFC)法，用高效液相制备色谱和手性柱对手性异构体进行拆分(手性柱ChiralPak IC,300×50mm I.D.,1μm；200mL/min；流动相A为CO 2且流动相B为EtOH(0.1％NH 3.H 2O)进行拆分，得到(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇30(1.53g,黄色固体)，产率：43.1％，98.1％ee，保留时间：7.99min；(R)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并 [2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-醇31(1.50g,黄色固体)，产率：42.3％，100％ee,保留时间：6.72min。 1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 18 (3.55 g, 6.8 mmol) further Resolution by high-performance liquid chromatography and chiral column chiral isomers by supercritical fluid chromatography (SFC) (chiral Pak IC, 300 × 50 mm ID, 1 μm; 200 mL/min; mobile phase A) Resolution was carried out for CO 2 and mobile phase B was EtOH (0.1% NH 3 .H 2 O) to give (S)-1-(2,4-difluorophenyl)-1-(2-(1-( 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 30 (1.53 g, yellow solid), yield: 43.1%, 98.1% ee, retention time: 7.99 min; (R)-1- 2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4]Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31 (1.50 g, yellow solid), yield: 42.3 %, 100% ee, retention time: 6.72 min.
化合物30Compound 30
MS m/z(ESI)：515.3[M+1]MS m/z (ESI): 515.3 [M+1]
1H NMR(400MHz,DMSO)δ8.74(s,2H),8.06(s,1H),7.98(d,J＝1.4Hz,1H),7.88(s,1H),7.83(d,J＝5.1Hz,2H),7.27(d,J＝7.1Hz,2H),7.18-7.10(m,2H),6.33(s,1H),4.74(s,2H),4.16(t,J＝5.5Hz,2H),3.86(s,3H),2.82(s,2H),1.91(s,3H)。 1 H NMR (400MHz, DMSO) δ8.74 (s, 2H), 8.06 (s, 1H), 7.98 (d, J = 1.4Hz, 1H), 7.88 (s, 1H), 7.83 (d, J = 5.1 Hz, 2H), 7.27 (d, J = 7.1 Hz, 2H), 7.18-7.10 (m, 2H), 6.33 (s, 1H), 4.74 (s, 2H), 4.16 (t, J = 5.5 Hz, 2H) ), 3.86 (s, 3H), 2.82 (s, 2H), 1.91 (s, 3H).
化合物31Compound 31
MS m/z(ESI)：515.3[M+1]MS m/z (ESI): 515.3 [M+1]
1H NMR(400MHz,DMSO)δ8.74(s,2H),8.05(s,1H),7.98(d,J＝1.5Hz,1H),7.88(s,1H),7.83(d,J＝5.0Hz,2H),7.31-7.25(m,2H),7.19-7.09(m,2H),6.33(s,1H),4.74(s,2H),4.16(t,J＝5.5Hz,2H),3.86(s,3H),2.82(s,2H),1.91(s,3H)。 1 H NMR (400MHz, DMSO) δ8.74 (s, 2H), 8.05 (s, 1H), 7.98 (d, J = 1.5Hz, 1H), 7.88 (s, 1H), 7.83 (d, J = 5.0 Hz, 2H), 7.31-7.25 (m, 2H), 7.19-7.09 (m, 2H), 6.33 (s, 1H), 4.74 (s, 2H), 4.16 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 2.82 (s, 2H), 1.91 (s, 3H).
实施例32Example 32
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
Figure PCTCN2018100901-appb-000087
Figure PCTCN2018100901-appb-000087
Figure PCTCN2018100901-appb-000088
Figure PCTCN2018100901-appb-000088
第一步first step
(R)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methylene)-2-methylpropane-2-sulfinamide
氩气保护下，将(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)甲酮18e(8g,16mmol)、(R)-叔丁基亚磺酰胺32a(4.5g,32mmol)和四乙氧基钛(9.2mL,43.8mmol,4.8M/THF)溶于60mL四氢呋喃中，80℃下反应10小时。冷却至室温，加入100mL水，以乙酸乙酯(100mL×3)萃取，合并有机相，有机相以100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺32b(4.7g,类白色固体)，产率：51％。Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (8 g, 16 mmol), (R)-tert-butylsulfinamide 32a (4.5 g, 32 mmol) and four Titanium ethoxide (9.2 mL, 43.8 mmol, 4.8 M/THF) was dissolved in 60 mL of tetrahydrofuran and reacted at 80 ° C for 10 hours. After cooling to room temperature, 100 mL of water was added, and ethyl acetate (100 mL×3) was added, and the organic phase was combined. The organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography (eluent: A system) gave (R)-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazine) 4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene-2-methylpropane-2- Sulfonamide 32b (4.7 g, off-white solid), yield: 51%.
MS m/z(ESI)：599.7[M+1]MS m/z (ESI): 599.7 [M+1]
第二步Second step
N-((S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
氩气保护下，将(R)-N-((2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)(2,4-二氟苯基)亚基)-2-甲基丙烷-2-亚磺酰胺32b(4.7g,8.1mmol)溶于15mL四氢呋喃中，将反应液降温至-40℃--50℃，缓慢滴加甲基溴化镁(24.3mL,1M/THF)，加毕， 反应液保持-40±5℃反应1.5小时。以200mL饱和氯化铵溶液淬灭反应，以乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到N-((S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺32c(3.33g,泡沫状固体)，产率：69％。(R)-N-((2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 under argon protection ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 32b (4.7 g, 8.1 Methyl) was dissolved in 15 mL of tetrahydrofuran, the reaction solution was cooled to -40 ° C -50 ° C, methyl magnesium bromide (24.3 mL, 1 M / THF) was added dropwise, and the reaction solution was kept at -40 ± 5 ° C. 1.5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc) :A system) purification to give N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-) 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 32c (3.33 g, foamy solid), yield: 69%.
MS m/z(ESI)：615.7[M+1]MS m/z (ESI): 615.7 [M+1]
第三步third step
N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺N-((S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2] ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methyl Propane-2-sulfinamide
将N-((S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺32c(1.23g,2.0mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑1l(832mg,4mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(146mg,0.2mmol)和碳酸铯(1.95g,6mmol)溶于13.2mL 1,4-二氧六环和水(V:V＝10:1)中，100℃下反应2.5小时。减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺32d(1g,黄色油状)，产率：81.3％。N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 32c (1.23 g, 2.0 Methyl), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (832mg , 4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.2 mmol) and cesium carbonate (1.95 g, 6 mmol) dissolved in 13.2 mL 1,4-two In the hexacyclohexane and water (V: V = 10:1), the reaction was carried out at 100 ° C for 2.5 hours. The organic layer was concentrated under reduced pressure and purified to silicagel eluting -(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide 32d (1 g, yellow oil), yield: 81.3%.
MS m/z(ESI)：618.0[M+1]MS m/z (ESI): 618.0 [M+1]
第四步the fourth step
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
将N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺32d(1g,1.62mmol)溶于20mL甲醇中，0℃下滴加浓盐酸(845mg,8.1mmol)，室温下反应2小时。以2N氢氧化钠溶液调节pH＝7，减压浓缩，再加入30mL水，调节pH＝10，以乙酸乙酯(70mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：C体系)纯化，得到(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺32(528mg,黄色固体)，产率：63.5％。N-((S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[ 2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-yl The propane-2-sulfinamide 32d (1 g, 1.62 mmol) was dissolved in 20 mL of methanol, and concentrated hydrochloric acid (845 mg, 8.1 mmol) was added dropwise at 0 ° C, and the mixture was reacted at room temperature for 2 hours. The pH was adjusted to 2 with a 2N sodium hydroxide solution, concentrated under reduced pressure, and then 30 mL of water was added to adjust pH=10, ethyl acetate (70 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. Concentration and purification of the residue by silica gel column chromatography (eluent: C system) to afford (S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-( 1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine- 4-yl)pyrimidin-5-yl)ethan-1-amine 32 (528 mg, yellow solid), yield: 63.5%.
MS m/z(ESI)：513.9[M+1]MS m/z (ESI): 513.9 [M+1]
1H NMR(400MHz,DMSO-d6)δ8.71(s,2H),8.06(s,1H),7.98(s,1H),7.90-7.80(m,3H),7.27(s,2H),7.20-7.07(m,2H),4.74(s,2H),4.16(t,J＝5.4Hz,2H),3.86(s,3H),2.82(s,2H),1.79(s,3H)。 1 H NMR (400MHz, DMSO- d6) δ8.71 (s, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.90-7.80 (m, 3H), 7.27 (s, 2H), 7.20 -7.07 (m, 2H), 4.74 (s, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.86 (s, 3H), 2.82 (s, 2H), 1.79 (s, 3H).
实施例33Example 33
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
Figure PCTCN2018100901-appb-000089
Figure PCTCN2018100901-appb-000089
第一步first step
N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺N-((S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2] ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methyl Propane-2-sulfinamide
将N-((S)-1-(2-(1-(6-溴吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)-1-(2,4-二氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺32c(1.23g,2.0mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑7a(890mg,4mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(146mg,0.2mmol)和碳酸铯(1.95g,6mmol)溶于13.2mL 1,4-二氧六环和水(V:V＝10:1)中，100℃下反应2.5小时。减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺33a(0.8g,黄色油状)，产率：63.5％。N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 32c (1.23 g, 2.0 Methyl), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (890 mg , 4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.2 mmol) and cesium carbonate (1.95 g, 6 mmol) dissolved in 13.2 mL 1,4-two In the hexacyclohexane and water (V: V = 10:1), the reaction was carried out at 100 ° C for 2.5 hours. The organic layer was concentrated under reduced pressure and purified to silicagel eluting -(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 Tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide 33a (0.8 g, yellow oil), yield: 63.5%.
MS m/z(ESI)：632.0[M+1]MS m/z (ESI): 632.0 [M+1]
第二步Second step
(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺(S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine
将N-((S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺33a(0.8g,1.27mmol)溶于16mL甲醇中，0℃下滴加浓盐酸(662mg,6.35mmol)，室温下反应2小时。以2N氢氧化钠溶液调节pH＝7，减压浓缩，再加入30mL水，调节pH＝10，以乙酸乙酯(70mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：C 体系)纯化，得到(S)-1-(2,4-二氟苯基)-1-(2-(1-(6-(1-乙基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)-1,2,3,6-四氢吡啶-4-基)嘧啶-5-基)乙-1-胺33(525mg,黄色固体)，产率：78.6％。N-((S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[ 2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-yl The propane-2-sulfinamide 33a (0.8 g, 1.27 mmol) was dissolved in 16 mL of methanol, and concentrated hydrochloric acid (662 mg, 6.35 mmol) was added dropwise at 0 ° C and allowed to react at room temperature for 2 hours. The pH was adjusted to 2 with a 2N sodium hydroxide solution, concentrated under reduced pressure, and then 30 mL of water was added to adjust pH=10, ethyl acetate (70 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: C) to afford (S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-) 1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine- 4-yl)pyrimidin-5-yl)ethan-1-amine 33 (525 mg, yellow solid), yield: 78.6%.
MS m/z(ESI)：527.9[M+1]MS m/z (ESI): 527.9 [M+1]
1H NMR(400MHz,DMSO-d6)δ8.71(s,2H),8.11(s,1H),7.89(s,1H),7.88-7.82(m,3H),7.27(s,2H),7.20-7.07(m,2H),4.74(s,2H),4.19-4.10(m,4H),2.82(s,2H),1.79(s,3H),1.41(t,J＝7.3Hz,3H)。 1 H NMR (400MHz, DMSO- d6) δ8.71 (s, 2H), 8.11 (s, 1H), 7.89 (s, 1H), 7.88-7.82 (m, 3H), 7.27 (s, 2H), 7.20 -7.07 (m, 2H), 4.74 (s, 2H), 4.19 - 4.10 (m, 4H), 2.82 (s, 2H), 1.79 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H).
生物学评价Biological evaluation
测试例1：本申请化合物对c-KIT[WT]、c-KIT[D816V]、PDGFRα[D842V]激酶活性测定Test Example 1: Determination of c-KIT [WT], c-KIT [D816V], PDGFRα [D842V] kinase activity by the compounds of the present application
以下方法用于测定本申请代表化合物在体外条件下对重组人源c-KIT[WT](野生型)、c-KIT[D816V](D816V突变)和PDGFRα[D842V](D842V突变)的激酶活性的抑制作用。The following method was used to determine the kinase activity of recombinant compounds of the present application against recombinant human c-KIT [WT] (wild type), c-KIT [D816V] (D816V mutation) and PDGFRα [D842V] (D842V mutation) under in vitro conditions. Inhibition.
本方法使用Cisbio公司的
Figure PCTCN2018100901-appb-000090
KinEASE-TK酪氨酸激酶试剂盒(货号62TK0PEB)，该试剂盒原理基于时间分辨荧光能量共振转移(TF-FRET)，通过测定蛋白介导的生物素化的多肽底物的磷酸化程度来反映化合物对蛋白激酶活性的抑制强弱。详细实验操作可参考试剂盒说明书。重组人源c-KIT[WT]、c-KIT[D816V]和PDGFRα[D842V]蛋白激酶购于Carna bioscience(日本，货号分别为c-KIT[WT]#08-156，c-KIT[D816V]#08-505，PDFGRα[D842V]#08-506)。 This method uses the company of Cisbio
Figure PCTCN2018100901-appb-000090
KinEASE-TK Tyrosine Kinase Kit (Cat. No. 62TK0PEB), the kit principle is based on time-resolved fluorescence energy resonance transfer (TF-FRET), which is reflected by measuring the degree of phosphorylation of protein-mediated biotinylated peptide substrates. Compounds inhibit the activity of protein kinases. For detailed experimental procedures, refer to the kit instructions. Recombinant human c-KIT [WT], c-KIT [D816V] and PDGFRα [D842V] protein kinases were purchased from Carna bioscience (Japan, item number c-KIT[WT]#08-156, c-KIT[D816V] #08-505, PDFGRα[D842V]#08-506).
将实验流程简述如下：受试化合物首先溶解于DMSO中制备为贮存液，随后以试剂盒中提供的缓冲液进行梯度稀释，受试化合物在反应体系中的终浓度范围为10μM-0.1nM。测试所用的ATP溶液(生工生物工程(上海)股份有限公司，#A600311)的浓度为预先测定的对应每个激酶的ATP Km值浓度，其中c-KIT[WT]、c-KIT[D816V]和PDGFRα[D842V]对应的ATP Km值浓度分别为100μM、30μM和30μM。反应在384孔微孔板中进行，首先向空孔中加入待测化合物和0.66ng受试蛋白，并在室温下孵育5分钟，然后向反应液中加入ATP溶液和生物素化的多肽底物溶液，并在室温下振荡孵育50分钟后，向反应中加入偶联有铕系元素化合物的抗磷酸化酪氨酸抗体和偶联有修饰化的别藻蓝蛋白XL665的链酶亲和素，并在室温下继续振荡孵育1小时。孵育结束后，在酶标仪以TF-FRET模式测定各孔在激发波长为304nm，发射波长为620nM和665nM的荧光强度值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较计算化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析，得到化合物的IC 50值，见表1-1和1-2。 The experimental procedure is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, followed by serial dilution with a buffer provided in the kit, and the final concentration of the test compound in the reaction system ranges from 10 μM to 0.1 nM. The concentration of the ATP solution used in the test (Biotech (Shanghai) Co., Ltd., #A600311) was determined by pre-determined ATP Km concentration for each kinase, where c-KIT[WT], c-KIT[D816V] The ATP Km values corresponding to PDGFRα [D842V] were 100 μM, 30 μM, and 30 μM, respectively. The reaction was carried out in a 384-well microplate. First, the test compound and 0.66 ng of the test protein were added to the well, and incubated at room temperature for 5 minutes, and then the ATP solution and the biotinylated polypeptide substrate were added to the reaction solution. After incubating for 50 minutes at room temperature with shaking at room temperature, an anti-phosphotyrosine antibody conjugated with a lanthanide compound and streptavidin coupled with modified allophycocyanin XL665 were added to the reaction. Incubate for 1 hour at room temperature with continued shaking. After the end of the incubation, the fluorescence intensity values of the respective wells at an excitation wavelength of 304 nm and emission wavelengths of 620 nM and 665 nM were measured in a TF-FRET mode by a microplate reader. The percentage inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the compound IC was obtained by nonlinear regression analysis of the compound concentration-inhibition rate by GraphPad Prism 5 software. 50 values, see Tables 1-1 and 1-2.
表1-1本申请代表化合物对c-KIT[D816V]抑制的IC 50值 Table 1-1 IC 50 values of compounds representing c-KIT [D816V] inhibition
实施例编号Example number IC 50(nM)/c-KIT[D816V] IC 50 (nM)/c-KIT[D816V]
伊马替尼Imatinib >5,000>5,000
AvapritinibAvapritinib 6060
44 99
77 1010
99 1111
1818 99
22twenty two 1212
2525 66
3131 44
结论：本申请的代表化合物对c-KIT[D816V]具有较好的抑制作用，且抑制作用优于Avapritinib。Conclusion: The representative compounds of the present application have a good inhibitory effect on c-KIT [D816V], and the inhibitory effect is superior to Avapritinib.
其中：Avapritinib的结构如下，根据公开专利申请WO 2015057873制备而得。Wherein: The structure of Avapritinib is as follows, and is prepared according to the published patent application WO 2015057873.
Figure PCTCN2018100901-appb-000091
Figure PCTCN2018100901-appb-000091
表1-2本申请代表化合物对c-KIT[WT]和PDGFRα[D842V]抑制的IC 50值 Table 50 value of the present application IC 1-2 Representative compounds of c-KIT [WT] and PDGFRα [D842V] inhibition
Figure PCTCN2018100901-appb-000092
Figure PCTCN2018100901-appb-000092
结论：本申请的代表化合物31对c-KIT[WT]和PDGFRα[D842V]均具有较好的抑制作用。Conclusion: Representative compound 31 of the present application has a good inhibitory effect on both c-KIT [WT] and PDGFRα [D842V].
测试例2：本申请化合物对小鼠肥大细胞瘤P815活性测定Test Example 2: Determination of P815 activity in mouse mastocytoma by the compound of the present application
以下方法用于测定本申请代表化合物对肿瘤细胞增殖的影响通过采用Cell Counting Kit-8试剂盒(Dojindo，东仁化学科技)来进行测定。针对c-KIT[D816V]，采用小鼠肥大细胞瘤P815(购于中国科学院上海生命科学研究院细胞资源中心)进行培养。The following method was used to determine the effect of the representative compound of the present application on tumor cell proliferation by using a Cell Counting Kit-8 kit (Dojindo, Toray Chemical). For c-KIT [D816V], mouse mastocytoma P815 (purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was used for culture.
实验方法简述如下：受试化合物首先溶解于DMSO中制备为贮存液，随后以对应细胞的培养基进行梯度稀释，配制成测试样品，化合物的终浓度范围在30μM-0.01nM。将处于对数生长期的肿瘤细胞以1000个/孔的密度接种至96孔细胞培养板中，在37℃，5％CO 2培养箱内过夜后，加入测试化合物样品后继续培养细胞48小时。培养结束后，向每孔加入10μL 的CCK-8检测液，并在37℃下孵育1-2小时，随后在酶标仪上读取样品各孔在450nM下的吸光度数值。通过与对照组(0.3％DMSO)的吸光度数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，得到化合物抑制细胞增殖的IC 50值，见表2。 The experimental method is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted with the corresponding medium of the cells to prepare a test sample, and the final concentration of the compound ranges from 30 μM to 0.01 nM. The tumor cells in the logarithmic growth phase were seeded at a density of 1000 cells/well into a 96-well cell culture plate, and after overnight at 37 ° C in a 5% CO 2 incubator, the test compound samples were added and the cells were further cultured for 48 hours. After the completion of the culture, 10 μL of CCK-8 test solution was added to each well, and incubated at 37 ° C for 1-2 hours, and then the absorbance values of the respective wells at 450 nM were read on a microplate reader. The percentage inhibition of the compound at each concentration point was calculated by comparison with the absorbance values of the control group (0.3% DMSO), followed by nonlinear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software to obtain compound inhibitory cells. The IC 50 values for proliferation are shown in Table 2.
表2本申请的代表化合物对小鼠肥大细胞瘤活性抑制的IC 50值 Table 2 Representative compounds of the present application mouse mast cell tumor inhibition activity IC 50 value
实施例编号Example number IC 50(nM)/P815 IC 50 (nM)/P815
伊马替尼Imatinib 32523252
1818 2828
3131 22twenty two
结论：本申请的代表化合物对小鼠肥大细胞瘤P815的增殖具有显著抑制作用。Conclusion: The representative compounds of the present application have a significant inhibitory effect on the proliferation of mouse mastocytoma P815.
测试例3：本申请的化合物对稳态表达于HEK293细胞的人类hERG离子通道的作用Test Example 3: Effect of the compounds of the present application on human hERG ion channels stably expressed in HEK293 cells
3.1细胞3.1 cells
hERG离子通道稳态表达的HEK293细胞。hERG ion channel is stably expressed in HEK293 cells.
3.2试验仪器3.2 Test equipment
膜片钳仪器：patch clamp-505BPatch clamp instrument: patch clamp-505B
微操控仪器：MP-225Micro-manipulation instrument: MP-225
拉制电极仪器：PC-10(Narishige，Japan)Drawn electrode instrument: PC-10 (Narishige, Japan)
3.3药物配制3.3 drug preparation
测试化合物的最终浓度均在当天配制，再溶于细胞外液。The final concentrations of the test compounds were prepared on the same day and re-dissolved in the extracellular fluid.
细胞外液(mM)为:NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。 The extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
细胞内液(mM)为：K Aspartate,130；MgCl 2,5；EGTA 5；HEPES,10；Tris-ATP 4；pH 7.2(KOH滴定)。 The intracellular fluid (mM) was: K Aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
3.4化合物的测试3.4 Compound test
化合物均采用利用自身重力的灌流系统进行灌流。每个浓度至少测试两个细胞。在电流稳定(或5分钟)后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。The compounds were all perfused using a perfusion system using their own gravity. Test at least two cells per concentration. After the current is stable (or 5 minutes), the change in current magnitude before and after the compound is compared to calculate the blocking effect of the compound.
3.5阳性对照3.5 positive control
阳性对照Cisapride浓度选择是根据它对细胞敏感性测试，阻断率90％左右的浓度为阳性对照最佳浓度。经测试Cisapride为100nM时，阻断率为90％左右，故阳性对照Cisapride定为100nM。方法和测试化合物一样。The positive control Cisapride concentration was selected based on its sensitivity to cell sensitivity, and the concentration of about 90% blocking rate was the optimal concentration of the positive control. When the Cisapride was tested at 100 nM, the blocking rate was about 90%, so the positive control Cisapride was set at 100 nM. The method is the same as the test compound.
3.6电生理3.6 Electrophysiology
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液(mM)为：K Aspartate,130；MgCl 2,5；EGTA 5；HEPES,10；Tris-ATP 4；pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱，实验当天融化。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音 用采样频率的五分之一进行过滤。 The cells were transferred to a perfusion tank and perfused with extracellular fluid. The intracellular fluid (mM) was: K Aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). The intracellular fluid was stored in small portions in a -80 degree refrigerator and thawed on the day of the experiment. The electrodes were drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered using one-fifth of the sampling frequency.
3.7测试过程和结果3.7 Test process and results
将细胞钳制在–80mV，然后用持续4秒方波去极化到40mV，再用持续2秒方波超极化到-40mV，以得到hERG尾电流(见附图1)。这一程序每20秒重复一次。hERG尾电流是纯hERG电流。检测第二个方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。具体IC 50见表3。具体见附图1。 The cells were clamped at –80 mV, then depolarized to 40 mV with a square wave lasting 4 seconds, and then hyperpolarized to -40 mV with a square wave for 2 seconds to obtain the hERG tail current (see Figure 1). This procedure is repeated every 20 seconds. The hERG tail current is a pure hERG current. The maximum current induced by the second square wave is detected. After it is stabilized, the test compound is perfused, and when the reaction is stable, the blocking strength is calculated. The specific IC 50 is shown in Table 3. See Figure 1 for details.
表3：本申请的代表化合物对hERG钾离子通道的抑制的IC 50值 Table 3: Representative compounds of the present application IC 50 values of inhibition of the hERG potassium ion channel
化合物编号Compound number hERG抑制溶度IC 50/μM hERG inhibition solubility IC 50 /μM
AvapritinibAvapritinib 55
3131 1313
结论：本申请实施例31化合物与Avapritinib相比，对hERG钾离子通道的抑制活性较小，具有较低的心脏毒性。Conclusion: The compound of Example 31 of the present application has less inhibitory activity on hERG potassium channel and lower cardiotoxicity than Avapritinib.
测试例4：本申请代表化合物的药代动力学测试Test Example 4: This application represents a pharmacokinetic test of a compound
1.概要1. Summary
以SD大鼠为受试动物，采用LC/MS/MS法测定大鼠灌胃给予Avapritinib、实施例2、实施例27和实施例31化合物后，测定其不同时刻血浆中的药物浓度，研究本申请化合物在大鼠体内的药代动力学特征。SD rats were used as test animals, and the drug concentration in plasma was determined by LC/MS/MS method after intragastric administration of Avapritinib, Example 2, Example 27 and Example 31. The pharmacokinetic profile of the claimed compound in rats.
2.实验方案2. Experimental protocol
2.1实验药品与动物2.1 Experimental drugs and animals
Avapritinib、实施例2、实施例27和实施例31化合物；Avapritinib, Example 2, Example 27 and Example 31 compounds;
健康成年SD雄性大鼠12只，分为4组，购自维通利华实验动物技术有限公司，生产许可证号：11400700109943。Twelve healthy male SD male rats were divided into 4 groups and purchased from Vitallihua Experimental Animal Technology Co., Ltd., production license number: 11400700109943.
2.2药物配置与给药2.2 drug configuration and drug delivery
称取适量的实验药品，加入0.5％CMC-Na，超声至溶液，用移液管吸取100μL用于浓度测定，配置溶液浓度为0.3mg/mL。Weigh an appropriate amount of the experimental drug, add 0.5% CMC-Na, sonicate to the solution, and pipette 100 μL for concentration determination. The concentration of the solution is 0.3 mg/mL.
健康成年SD雄性大鼠4只，分为12组，禁食过夜后分别灌胃给药，给药剂量为3mg/kg。Four healthy male Sprague-Dawley rats were divided into 12 groups. After fasting overnight, they were intragastrically administered at a dose of 3 mg/kg.
2.3样品采集2.3 sample collection
于给药前和给药后15分钟、30分钟、1小时、2小时、4小时、8小时、12小时和24小时颈部静脉采血0.15mL，置于肝素化试管中，5500转/分钟，离心10分钟，于-20℃保存，给药4小时后进食。0.15 mL of blood was collected from the neck before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in a heparinized test tube at 5500 rpm. Centrifuge for 10 minutes, store at -20 ° C, and eat 4 hours after administration.
2.4样品处理2.4 sample processing
血浆样品处理(For plasma samples)：For plasma samples:
取20μL样品，加入内标物(IS)(包含维拉帕米5ng·mL -1和格列本脲50ng·mL -1)的200 μL乙腈的溶液中，涡旋混合10分钟，以3700转/分的速度离心18分钟，然后取70μL上清液并将其加入到70μL水中，涡旋混合10分钟，取3μL混合液的上清液至LC-MS/MS系统中进行分析。 Take 20 μL of the sample, add a solution of internal standard (IS) (containing verapamil 5 ng·mL -1 and glibenclamide 50 ng·mL -1 ) in 200 μL of acetonitrile, and vortex for 10 minutes to 3700 rpm. Centrifuge at a speed of 18 minutes, then take 70 μL of the supernatant and add it to 70 μL of water, vortex for 10 minutes, and take 3 μL of the supernatant to the LC-MS/MS system for analysis.
给药样品处理(For dose sample)：For dose sample:
将给药样品用甲醇和水(4:1,v/v)的混合溶剂稀释至浓度为1μg·mL -1，取20μL稀释后的样品和内标物溶液(100ng·mL -1)加入200μL乙腈溶液(包含IS溶液)和220μL水，然后涡旋混合，取3μL混合液的上清液至LC-MS/MS系统中进行分析。 The sample to be administered was diluted with a mixed solvent of methanol and water (4:1, v/v) to a concentration of 1 μg·mL -1 , and 20 μL of the diluted sample and the internal standard solution (100 ng·mL -1 ) were added to 200 μL. The acetonitrile solution (containing the IS solution) and 220 μL of water were then vortexed, and the supernatant of 3 μL of the mixed solution was taken to an LC-MS/MS system for analysis.
3.药代动力学参数结果3. Pharmacokinetic parameter results
本申请的代表化合物的药代动力学参数如表4所示。The pharmacokinetic parameters of the representative compounds of the present application are shown in Table 4.
表4本申请代表化合物的大鼠药代动力学数据表Table 4 Rat pharmacokinetic data sheet representing the compound of the present application
Figure PCTCN2018100901-appb-000093
Figure PCTCN2018100901-appb-000093
结论：在大鼠药代动力学试验中，本申请代表化合物2、化合物27和化合物31化合物在体内的最高血药浓度均优于Avapritinib，具有较好的药代动力学性质。Conclusion: In the rat pharmacokinetic test, the present application represents the highest blood concentration of Compound 2, Compound 27 and Compound 31 in vivo, which is superior to Avapritinib and has good pharmacokinetic properties.
测试例5：比格犬体内药代动力学研究Test Example 5: Pharmacokinetics in beagle dogs
1.概要1. Summary
以比格犬为受试动物，采用LC/MS/MS法测定比格犬灌胃给予Avapritinib和实施例31化合物后，测定其不同时刻血浆中的药物浓度，研究本申请代表化合物在大鼠体内的药代动力学特征。The Beagle dogs were used as test animals, and the drug concentration in plasma was determined by LC/MS/MS method after the administration of Avapritinib and the compound of Example 31 in the beagle dogs. The representative compounds in the present application were studied in rats. Pharmacokinetic characteristics.
2.实验方案2. Experimental protocol
2.1实验药品2.1 experimental drugs
Avapritinib和化合物31；Avapritinib and compound 31;
口服给药溶媒：DMSO/0.5％CMC-Na(5:95，v/v)Oral administration solvent: DMSO/0.5% CMC-Na (5:95, v/v)
2.2动物2.2 Animals
取比格犬6只，动物房通风良好，装备空调，温度保持在16-26℃，湿度保持在40％-70％。明暗照明各12小时，每只犬独立饲养，可自由进食和饮水。Take the Beagle 6 animals, the animal room is well ventilated, equipped with air conditioning, the temperature is maintained at 16-26 ° C, the humidity is maintained at 40% -70%. The light and dark lighting is 12 hours each, and each dog is independently raised and can eat and drink freely.
2.3动物给药剂量2.3 Animal dose
灌胃给药，药物浓度0.6mg/mL；每组3只雄性比格犬。Administered by intragastric administration, the drug concentration was 0.6 mg/mL; 3 male beagle dogs in each group.
实验前一天，比格犬禁食过夜。实验当天，称量体重后，按以下公式计算每只犬的理论给药体积。给药试液应在实验当天现配现用。每只犬的实际给药量和血浆样品的采集时 间需详细记录在相应表格中。比格犬给药4h后可恢复进食，实验过程中可自由饮水。The day before the experiment, the Beagle was fasted overnight. On the day of the experiment, after weighing the body weight, the theoretical administration volume of each dog was calculated according to the following formula. The test solution should be ready for use on the day of the test. The actual dose of each dog and the collection time of the plasma sample are detailed in the corresponding table. Beagle dogs can resume eating after 4 hours of administration, and they can drink water freely during the experiment.
Figure PCTCN2018100901-appb-000094
Figure PCTCN2018100901-appb-000094
2.4样品采集与处理2.4 sample collection and processing
于给药前及给药后15分钟、30分钟、1小时、2小时、4小时、8小时、12小时和24小时，由颈静脉采血0.5mL，在4℃下离心5分钟从而分离血浆，于-20℃保存待测。Before the administration and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after the administration, 0.5 mL of blood was collected from the jugular vein, and centrifuged at 4 ° C for 5 minutes to separate the plasma. Store at -20 ° C for testing.
取比格犬血浆样品25ul，加入内标物25μl，甲醇225μl，涡旋混合2分钟，4℃12000rpm离心10分钟，取上清液用于LC-MS/MS分析。25 ul of Beagle plasma samples were taken, 25 μl of internal standard and 225 μl of methanol were added, vortexed for 2 minutes, centrifuged at 12,000 rpm for 10 minutes at 4 ° C, and the supernatant was taken for LC-MS/MS analysis.
2.5药物代谢动力学分析2.5 pharmacokinetic analysis
根据药物的血药浓度数据，运用Phoenix
Figure PCTCN2018100901-appb-000095
计算药代动力学参数，提供AUC inf、Cmax和T1/2参数及其平均值和标准差。 Use Phoenix based on blood drug concentration data
Figure PCTCN2018100901-appb-000095
Calculate pharmacokinetic parameters, provide AUC inf , Cmax and T1/2 parameters and their mean and standard deviation.
2.6药代动力学结果见表52.6 pharmacokinetic results are shown in Table 5.
表5：比格犬药代动力学参数Table 5: Beagle pharmacokinetic parameters
Figure PCTCN2018100901-appb-000096
Figure PCTCN2018100901-appb-000096
结论：在比格犬药代动力学试验中，同Avapritinib相比，本申请化合物31具有较大的最高血药浓度、药时曲线面积和较长的半衰期，具有较好的药代动力学性质。Conclusion: In the Beagle pharmacokinetic test, compared with Avapritinib, Compound 31 of this application has a larger maximum plasma concentration, a drug-time curve area and a longer half-life, and has better pharmacokinetic properties. .

Claims (30)

  1. 式(I)的化合物或其立体异构体、互变异构体或其药学上可接受的盐：a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100001
    Figure PCTCN2018100901-appb-100001
    其中：among them:
    E为氢原子或
    Figure PCTCN2018100901-appb-100002
    E is a hydrogen atom or
    Figure PCTCN2018100901-appb-100002
    环A选自环烷基、杂环基、芳基或杂芳基；优选为芳基；更优选为苯基；Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably aryl; more preferably phenyl;
    W和Q各自独立地选自C或N，但两者不同时为C；W和Q优选为N；W and Q are each independently selected from C or N, but are not simultaneously C; W and Q are preferably N;
    D选自化学键、-(亚烷基)-、-(亚烯基)-、-(亚炔基)-、-(亚环烷基)-、-(亚杂环基)-、-C(O)-、-O-、-S-、-S(O)-、-SO 2-、-NR 6-、-O-(亚烷基)-、-(亚烷基)-O-、-NR 6-C(O)-、-C(O)-NR 6-、-(亚烷基)-NR 6-、-NR 6-(亚烷基)-、-NR 6-C(O)-(亚烷基)-、-C(O)-NR 6-(亚烷基)-、-NR 6-SO 2-、-SO 2-NR 6-、-NR 6-SO 2-(亚烷基)-或-SO 2-NR 6-(亚烷基)-；其中所述亚烷基、亚烯基、亚环烷基或亚杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7或-NR 6C(O)R 7的取代基所取代； D is selected from a chemical bond, -(alkylene)-, -(alkenylene)-, -(alkynylene)-, -(cycloalkylene)-, -(heterocyclylene)-, -C( O)-, -O-, -S-, -S(O)-, -SO 2 -, -NR 6 -, -O-(alkylene)-, -(alkylene)-O-, - NR 6 -C(O)-, -C(O)-NR 6 -, -(alkylene)-NR 6 -, -NR 6 -(alkylene)-, -NR 6 -C(O)- (alkylene)-, -C(O)-NR 6 -(alkylene)-, -NR 6 -SO 2 -, -SO 2 -NR 6 -, -NR 6 -SO 2 -(alkylene Or -SO 2 -NR 6 -(alkylene)-; wherein the alkylene, alkenylene, cycloalkylene or heterocyclylene group is further further selected from one or more selected from the group consisting of hydroxyl groups, halogens , nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O) Substituted by a substituent of R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 or -NR 6 C(O)R 7 ;
    R 1和R 3各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、羟基、氰基、硝基、卤素或-NR 6R 7，其中所述烷基、烷氧基、环烷基或杂环基任选进一步被一个或多个卤素所取代；R 1和R 3优选为氢原子； R 1 and R 3 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a hydroxyl group, a cyano group, a nitro group, a halogen or -NR 6 R 7 , wherein the alkyl group, The alkoxy, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens; R 1 and R 3 are preferably a hydrogen atom;
    R 2和R 5各自独立地选自氢原子、烷基、烷氧基、环烷基、羟基、氰基、硝基、卤素、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7或-NR 6C(O)R 7，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7或-NR 6C(O)R 7的取代基所取代； R 2 and R 5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a hydroxyl group, a cyano group, a nitro group, a halogen group, a heterocyclic group, an aryl group, a heteroaryl group, and -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O)R 8 , -S(O) p NR 6 R 7 or -NR 6 C(O)R 7 , wherein The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, and a ring. Alkyl, heterocyclic, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O)R 8 , -S(O Substituting a substituent of p NR 6 R 7 or -NR 6 C(O)R 7 ;
    R 4选自烷基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、环烷基、杂环基、芳 基、杂芳基、-OR 8、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7或-NR 6C(O)R 7的取代基所取代； R 4 is selected from an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one or more Selected from halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C Substituting (O) a substituent of R 8 , —OC(O)R 8 , —S(O) p NR 6 R 7 or —NR 6 C(O)R 7 ;
    R 6、R 7和R 8各自独立地选自氢原子、羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) pNR 9R 10或-NR 9C(O)R 10的取代基所取代； R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, and a ring. Alkyl, heterocyclic, aryl, heteroaryl, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC(O Substituting a substituent of R 11 , -S(O) p NR 9 R 10 or -NR 9 C(O)R 10 ;
    或者，R 6和R 7与相连接的N原子一起形成4-8元杂环基，其中所述4-8元杂环包含一个或多个N、O、S(O) p原子，并且所述4-8元杂环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-NR 9R 10、-C(O)NR 9R 10、-C(O)R 11、-C(O)OR 11、-OC(O)R 11、-S(O) pNR 9R 10或-NR 9C(O)R 10的取代基所取代； Alternatively, R 6 and R 7 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) p atoms, and The 4-8 membered heterocyclic ring is optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -NR 9 R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O) p NR 9 Substituted by a substituent of R 10 or -NR 9 C(O)R 10 ;
    R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代； R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylic acid Substituted by a substituent of an ester group;
    m选自1，2，3，4或5；m is selected from 1, 2, 3, 4 or 5;
    n选自1，2，3或4；且n is selected from 1, 2, 3 or 4;
    p选自0，1或2。p is selected from 0, 1 or 2.
  2. 如权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：The compound of claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
    D为-(亚烷基)-；优选为亚甲基；D is -(alkylene)-; preferably methylene;
    其中所述亚烷基进一步被选自烷基、羟基、卤素或-NR 6R 7的取代基所取代；且 Wherein the alkylene group is further substituted with a substituent selected from an alkyl group, a hydroxyl group, a halogen or -NR 6 R 7 ;
    R 6和R 7的定义如权利要求1中所述。 The definitions of R 6 and R 7 are as set forth in claim 1.
  3. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a stereoisomer thereof, tautomerizable Or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100003
    Figure PCTCN2018100901-appb-100003
    其中：among them:
    R a为氢原子或烷基；优选为C 1-6烷基，更优选为甲基； R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
    R b选自羟基、卤素或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen or -NR 6 R 7 ;
    R 1-R 7、m和n的定义如权利要求1中所述。 R 1 -R 7 , m and n are as defined in claim 1.
  4. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(III)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a stereoisomer thereof, tautomerizable Or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100004
    Figure PCTCN2018100901-appb-100004
    其中：among them:
    R b选自羟基、卤素或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen or -NR 6 R 7 ;
    R 1-R 7、m和n的定义如权利要求1中所述。 R 1 -R 7 , m and n are as defined in claim 1.
  5. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(IV)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The compound of claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a stereoisomer thereof, tautomerize Or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100005
    Figure PCTCN2018100901-appb-100005
    其中：among them:
    R b选自羟基、卤素或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen or -NR 6 R 7 ;
    R 1-R 7、m和n的定义如权利要求1中所述。 R 1 -R 7 , m and n are as defined in claim 1.
  6. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(V)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：The compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (V) or a stereoisomer thereof, tautomerizable Or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100006
    Figure PCTCN2018100901-appb-100006
    其中：among them:
    R b选自羟基、卤素或-NR 6R 7；且 R b is selected from the group consisting of hydroxyl, halogen or -NR 6 R 7 ;
    R 1-R 7、m和n的定义如权利要求1中所述。 R 1 -R 7 , m and n are as defined in claim 1.
  7. 如权利要求1-6中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中各个R 2均为氢原子。 The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein each R 2 is a hydrogen atom.
  8. 如权利要求1-6中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：The compound of any one of claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
    R 4为杂芳基，优选为吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶基或吡啶基，更优选为吡唑基，其中所述吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶基或吡啶基任选进一步被一个或多个选自C 1-6烷基、4-6元杂环基或-C(O)R 8的取代基所取代；且 R 4 is a heteroaryl group, preferably pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl, more preferably pyrazolyl, wherein the pyrrolyl group, Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl is optionally further further selected from one or more selected from C1-6 alkyl, 4-6 membered heterocyclyl or Substituted by a substituent of C(O)R 8 ;
    R 8为C 1-6烷基。 R 8 is a C 1-6 alkyl group.
  9. 如权利要求1-6中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：The compound of any one of claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
    R 4为四氢吡啶基，其中所述四氢吡啶基任选进一步被一个或多个选自C 1-6烷基、4-6元杂环基或-C(O)R 8的取代基所取代； R 4 is a tetrahydropyridinyl group, wherein the tetrahydropyridinyl group is further optionally further substituted by one or more substituents selected from a C 1-6 alkyl group, a 4-6 membered heterocyclic group or -C(O)R 8 Replaced
    R 8为C 1-6烷基；且 R 8 is a C 1-6 alkyl group;
    其中所述四氢吡啶基优选为
    Figure PCTCN2018100901-appb-100007
    Wherein the tetrahydropyridyl group is preferably
    Figure PCTCN2018100901-appb-100007
  10. 如权利要求1-6中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：The compound of any one of claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
    R 5选自氢原子、卤素、烷基或烷氧基； R 5 is selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group;
    所述卤素优选为F或Cl；The halogen is preferably F or Cl;
    所述烷基优选为C 1-6烷基；更优选为甲基；且 The alkyl group is preferably a C 1-6 alkyl group; more preferably a methyl group;
    所述烷氧基优选为C 1-6烷氧基；更优选为甲氧基。 The alkoxy group is preferably a C 1-6 alkoxy group; more preferably a methoxy group.
  11. 如权利要求3所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中：A compound according to claim 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
    R a为氢原子或烷基；优选为C 1-6烷基，更优选为甲基； R a is a hydrogen atom or an alkyl group; preferably a C 1-6 alkyl group, more preferably a methyl group;
    R b选自羟基、卤素或-NR 6R 7； R b is selected from the group consisting of hydroxyl, halogen or -NR 6 R 7 ;
    R 1、R 2和R 3各自独立地为氢原子或C 1-6烷基； R 1 , R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group;
    R 4为杂芳基或杂环基，其中所述杂芳基或杂环基任选进一步被一个或多个选自C 1-6烷基、3-8元环烷基、4-6元杂环基、6元芳基、5-6元杂芳基、-OR 8、-NR 6R 7、-C(O)NR 6R 7、-C(O)R 8、-OC(O)R 8、-S(O) pNR 6R 7或-NR 6C(O)R 7的取代基所取代； R 4 is a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is further optionally further selected from one or more selected from C 1-6 alkyl, 3-8 membered cycloalkyl, 4-6 Heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, -OR 8 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -OC(O) Substituted by a substituent of R 8 , -S(O) p NR 6 R 7 or -NR 6 C(O)R 7 ;
    R 5选自氢原子、卤素、C 1-6烷基或C 1-6烷氧基； R 5 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group or a C 1-6 alkoxy group;
    R 6和R 7各自独立地为氢原子或C 1-6烷基； R 6 and R 7 are each independently a hydrogen atom or a C 1-6 alkyl group;
    R 8为C 1-6烷基； R 8 is a C 1-6 alkyl group;
    m选自1，2，3，4或5；m is selected from 1, 2, 3, 4 or 5;
    n选自1，2，3或4；且n is selected from 1, 2, 3 or 4;
    p选自0，1或2。p is selected from 0, 1 or 2.
  12. 如权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中所述化合物为：The compound of claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:
    Figure PCTCN2018100901-appb-100008
    Figure PCTCN2018100901-appb-100008
    Figure PCTCN2018100901-appb-100009
    Figure PCTCN2018100901-appb-100009
  13. 制备权利要求3所述的式(II)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100010
    Figure PCTCN2018100901-appb-100010
    其中将式(IIA)的化合物或其盐与R 4取代的硼酸酯或硼酸反应，得到式(II)的化合物； Wherein the compound of the formula (IIA) or a salt thereof is reacted with an R 4 -substituted boronic acid ester or boric acid to obtain a compound of the formula (II);
    其中：among them:
    所述R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
    Figure PCTCN2018100901-appb-100011
    Figure PCTCN2018100901-appb-100011
    X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
    R 1-R 5、R a、R b、m和n的定义如权利要求3中所述。 R 1 -R 5 , R a , R b , m and n are as defined in claim 3.
  14. 制备权利要求3所述的式(II)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100012
    Figure PCTCN2018100901-appb-100012
    其中将式(IIB)的化合物或其盐与格氏试剂反应，得到式(II)的化合物；Wherein the compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to obtain a compound of the formula (II);
    其中：among them:
    所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
    R a为烷基； R a is an alkyl group;
    R b为羟基；且 R b is a hydroxyl group;
    R 1-R 5、m和n的定义如权利要求3中所述。 R 1 -R 5 , m and n are as defined in claim 3.
  15. 制备权利要求3所述的式(II)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100013
    Figure PCTCN2018100901-appb-100013
    其中将式(IIC)的化合物在酸性条件下反应，得到式(II)的化合物；Wherein the compound of formula (IIC) is reacted under acidic conditions to provide a compound of formula (II);
    其中：among them:
    R a为烷基； R a is an alkyl group;
    R b为-NR 6R 7； R b is -NR 6 R 7 ;
    R 6和R 7为氢原子； R 6 and R 7 are a hydrogen atom;
    R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
    R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
    R 1-R 5、m和n的定义如权利要求3中所述。 R 1 -R 5 , m and n are as defined in claim 3.
  16. 式(IIA)的化合物或其立体异构体、互变异构体或其药学上可接受的盐：a compound of formula (IIA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100014
    Figure PCTCN2018100901-appb-100014
    其中：among them:
    X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
    R 1-R 3、R 5、R a、R b、m和n的定义如权利要求3中所述。 R 1 -R 3 , R 5 , R a , R b , m and n are as defined in claim 3.
  17. 根据权利要求16所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为式(IIIA)、(IVA)或(VA)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，The compound according to claim 16 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (IIIA), (IVA) or (VA) or a stereo Isomer, tautomer or pharmaceutically acceptable salt thereof,
    Figure PCTCN2018100901-appb-100015
    Figure PCTCN2018100901-appb-100015
    其中：among them:
    X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
    R 1-R 3、R 5、R b、m和n的定义如权利要求3中所述。 R 1 -R 3 , R 5 , R b , m and n are as defined in claim 3.
  18. 根据权利要求16所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中所述化合物为：The compound according to claim 16 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:
    Figure PCTCN2018100901-appb-100016
    Figure PCTCN2018100901-appb-100016
  19. 式(IIB)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：A compound of the formula (IIB): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100017
    Figure PCTCN2018100901-appb-100017
    其中R 1-R 5、m和n的定义如权利要求3中所述。 Wherein R 1 -R 5 , m and n are as defined in claim 3.
  20. 根据权利要求19所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，所述化合物为：The compound according to claim 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is:
    Figure PCTCN2018100901-appb-100018
    Figure PCTCN2018100901-appb-100018
  21. 式(IIC)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐：A compound of the formula (IIC): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2018100901-appb-100019
    Figure PCTCN2018100901-appb-100019
    其中：among them:
    R a为烷基； R a is an alkyl group;
    R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
    R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
    R 1-R 5、m和n的定义如权利要求3中所述。 R 1 -R 5 , m and n are as defined in claim 3.
  22. 根据权利要求21所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，所述化合物为：The compound according to claim 21, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is:
    Figure PCTCN2018100901-appb-100020
    Figure PCTCN2018100901-appb-100020
  23. 制备权利要求16所述的式(IIA)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to claim 16, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100021
    Figure PCTCN2018100901-appb-100021
    其中将式(IIj)的化合物或其盐与格氏试剂反应，得到式(IIA)的化合物；Wherein a compound of the formula (IIj) or a salt thereof is reacted with a Grignard reagent to give a compound of the formula (IIA);
    其中：among them:
    所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
    R a为烷基； R a is an alkyl group;
    R b为羟基； R b is a hydroxyl group;
    X 1为卤素，优选为Br；且 X 1 is halogen, preferably Br;
    R 1-R 3、R 5、m和n的定义如权利要求16中所述。 R 1 -R 3 , R 5 , m and n are as defined in claim 16.
  24. 制备权利要求16所述的式(IIA)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to claim 16, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100022
    Figure PCTCN2018100901-appb-100022
    其中将式(IIj)的化合物与式(IIt)的化合物反应，其中式(IIt)的化合物的构型为(S)型或(R)型；优选为(S)型；得到式(IIk)的化合物；式(IIk)的化合物与格氏试剂反应，得到式(IIm)的化合物；式(IIm)的化合物在酸性条件下反应，得到式(IIA)的化合物；Wherein a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the (S) form or the (R) form; preferably the (S) form; and the formula (IIk) is obtained. a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm); a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);
    其中：among them:
    所述格氏试剂优选为烷基溴化镁，更优选为甲基溴化镁；The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;
    X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
    R a为烷基； R a is an alkyl group;
    R b为-NR 6R 7； R b is -NR 6 R 7 ;
    R 6和R 7为氢原子； R 6 and R 7 are a hydrogen atom;
    R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
    R 1-R 3、R 5、m和n的定义如权利要求16中所述。 R 1 -R 3 , R 5 , m and n are as defined in claim 16.
  25. 制备权利要求19所述的式(IIB)的化合物或其立体异构体、互变异构体或其药学上可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of the formula (IIB), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 19, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100023
    Figure PCTCN2018100901-appb-100023
    其中在碱性条件下，将式(IIp)的化合物与式(IIs)的化合物反应，得到式(IIB)的化合物；Wherein the compound of the formula (IIp) is reacted with a compound of the formula (IIs) under basic conditions to give a compound of the formula (IIB);
    其中：among them:
    X 2为卤素，优选为Cl或Br；且 X 2 is halogen, preferably Cl or Br;
    R 1-R 5、m和n的定义的如权利要求19中所述。 The definitions of R 1 -R 5 , m and n are as set forth in claim 19.
  26. 制备权利要求21所述的式(IIC)的化合物或其立体异构体、互变异构体或其药学上 可接受的盐的方法，所述方法包括如下所示的反应：A process for the preparation of a compound of the formula (IIC), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 21, which comprises the reaction shown below:
    Figure PCTCN2018100901-appb-100024
    Figure PCTCN2018100901-appb-100024
    将式(IIm)的化合物或其盐与R 4取代的硼酸酯或硼酸反应，得到式(IIC)的化合物； The compound of the formula (IIm) or a salt thereof is reacted with an R 4 -substituted boronic acid ester or boric acid to give a compound of the formula (IIC);
    其中：among them:
    所述R 4取代的硼酸酯优选为： The R 4 substituted boronate is preferably:
    Figure PCTCN2018100901-appb-100025
    Figure PCTCN2018100901-appb-100025
    X 1为卤素，优选为Br； X 1 is halogen, preferably Br;
    R a为烷基； R a is an alkyl group;
    R f为-NH-S(O)R e； R f is -NH-S(O)R e ;
    R e为烷基，优选为叔丁基；且 R e is an alkyl group, preferably a tert-butyl group;
    R 1-R 5、m和n的定义如权利要求21中所述。 R 1 -R 5 , m and n are as defined in claim 21.
  27. 药物组合物，所述药物组合物包含治疗有效量的权利要求1-12中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，以及药学上可接受的载体、赋形剂或它们的组合。A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 12, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical Acceptable carriers, excipients or combinations thereof.
  28. 权利要求1-12中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或根据权利要求27所述的药物组合物在制备用于治疗由c-KIT或突变的c-KIT介导的疾病的药物中的用途，其中所述c-KIT或突变的c-KIT介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症或急性髓性白血病，最优选为胃肠道间质瘤或系统性肥大细胞增生症；其中所述突变的c-KIT的突变位于外显子9、11、13、14、17和/或18，或第816位氨基酸残基和/或第670位氨基酸残基处；其中所述第816位氨基酸残基处的突变优选为D816V或D816H，其中所述第670位氨基酸残基处的突变优选为T670I。A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the preparation of a medicament Use in a medicament for a disease mediated by c-KIT or a mutant c-KIT, wherein the c-KIT or mutant c-KIT mediated disease is preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mast cells Hyperplasia, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma or mast cell leukemia; more preferably selected from gastrointestinal stromal tumors, systemic Mast cell hyperplasia or acute myeloid leukemia, most preferably gastrointestinal stromal tumor or systemic mastocytosis; wherein the mutant c-KIT mutation is located in exons 9, 11, 13, 14, 17 And/or 18, or amino acid residue 816 and/or amino acid residue 670; wherein the mutation at amino acid residue 816 is preferably D816V or D816H, wherein the amino acid residue 670 The mutation at the site is preferably T670I.
  29. 权利要求1-12中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或根据权利要求27所述的药物组合物在制备c-KIT抑制剂中的用途。The compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, in the preparation of c-KIT Use in inhibitors.
  30. 权利要求1-12中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或根据根据权利要求27所述的药物组合物在制备用于治疗由突变的或野生型的PDFGRα介导的疾病的药物中的用途，其中所述PDFGRα或突变的PDFGRα介导的疾病优选选自胃肠道间质瘤、系统性肥大细胞增生症、急性髓性白血病、卵巢癌、乳腺癌、黑色素瘤、宫颈癌、精原细胞瘤、无性细胞瘤、畸胎瘤或肥大细胞白血病；更优选选自胃肠道间质瘤、系统性肥大细胞增生症或急性髓性白血病，最优选为胃肠道间质瘤和系统性肥大细胞增生症；其中所述突变的PDFGRα的突变位于外显子18和/或第842位氨基酸残基处，其中所述第842位氨基酸残基处的突变优选为D842V突变。A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, which is used in the preparation of Use of a medicament for treating a disease mediated by a mutant or wild-type PDFGRα, wherein the PDFGRα or mutant PDFGRα-mediated disease is preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis, acute marrow Leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma or mast cell leukemia; more preferably selected from gastrointestinal stromal tumors, systemic mastocytosis or Acute myeloid leukemia, most preferably gastrointestinal stromal tumor and systemic mastocytosis; wherein the mutant PDFGRα mutation is located at exon 18 and/or 842 amino acid residues, wherein said The mutation at amino acid residue position 842 is preferably a D842V mutation.
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