WO2019034128A1 - Dérivé de pyrrolotriazine, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrrolotriazine, son procédé de préparation et son utilisation 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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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/zh
Publication of WO2019034128A1 publication Critical patent/WO2019034128A1/fr

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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

L'invention concerne un dérivé de pyrrolotriazine, son procédé de préparation et son utilisation. L'invention concerne particulièrement le dérivé de pyrrolotriazine de formule (I), un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation et une utilisation de celui-ci en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de c-KIT, la définition de chaque substituant dans la formule (I) étant la même que celle définie dans la description.
PCT/CN2018/100901 2017-08-18 2018-08-16 Dérivé de pyrrolotriazine, son procédé de préparation et son utilisation WO2019034128A1 (fr)

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WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
US10807985B2 (en) 2013-10-17 2020-10-20 Blueprint Medicines Corporation Compositions useful for treating disorders related to kit
US10829493B2 (en) 2019-04-12 2020-11-10 Blueprint Medicines Corporation Compositions and methods for treating KIT- and PDGFRA-mediated diseases
CN112480116A (zh) * 2019-09-11 2021-03-12 南京正大天晴制药有限公司 Pkb抑制剂
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
US11040979B2 (en) 2017-03-31 2021-06-22 Blueprint Medicines Corporation Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022081627A1 (fr) 2020-10-14 2022-04-21 Blueprint Medicines Corporation Compositions et méthodes de traitement de maladies à médiation par kit et pdgfra
US11964980B2 (en) 2019-04-12 2024-04-23 Blueprint Medicines Corporation Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making

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Cited By (11)

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Publication number Priority date Publication date Assignee Title
US10807985B2 (en) 2013-10-17 2020-10-20 Blueprint Medicines Corporation Compositions useful for treating disorders related to kit
US11827642B2 (en) 2013-10-17 2023-11-28 Blueprint Medicines Corporation Compositions useful for treating disorders related to KIT
US11040979B2 (en) 2017-03-31 2021-06-22 Blueprint Medicines Corporation Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
US10829493B2 (en) 2019-04-12 2020-11-10 Blueprint Medicines Corporation Compositions and methods for treating KIT- and PDGFRA-mediated diseases
US11964980B2 (en) 2019-04-12 2024-04-23 Blueprint Medicines Corporation Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
CN112480116A (zh) * 2019-09-11 2021-03-12 南京正大天晴制药有限公司 Pkb抑制剂
CN112480116B (zh) * 2019-09-11 2024-03-29 南京正大天晴制药有限公司 Pkb抑制剂
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022081627A1 (fr) 2020-10-14 2022-04-21 Blueprint Medicines Corporation Compositions et méthodes de traitement de maladies à médiation par kit et pdgfra

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