WO2018205916A1 - Fgfr4 inhibitor and preparation and use thereof - Google Patents

Fgfr4 inhibitor and preparation and use thereof Download PDF

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WO2018205916A1
WO2018205916A1 PCT/CN2018/085940 CN2018085940W WO2018205916A1 WO 2018205916 A1 WO2018205916 A1 WO 2018205916A1 CN 2018085940 W CN2018085940 W CN 2018085940W WO 2018205916 A1 WO2018205916 A1 WO 2018205916A1
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group
alkyl
compound
formula
alkoxy
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PCT/CN2018/085940
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French (fr)
Chinese (zh)
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王勇
赵立文
纪剑峰
戴鹏
郁壮壮
吕坤志
唐莹
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南京圣和药业股份有限公司
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Definitions

  • the invention belongs to the field of medical chemistry, and in particular relates to a novel class of FGFR4 inhibitors, a pharmaceutical composition containing the same, and the use of the inhibitor or the pharmaceutical composition as a tumor therapeutic drug.
  • FGFRs Fibroblast Growth Factor Receptors
  • FGFs Fibroblast Growth Factors
  • FGFR1, FGFR2, FGFR3, and FGFR4 The amino acid sequence between members of the FGFR family (FGFR1, FGFR2, FGFR3, and FGFR4) is highly conserved and differs in ligand affinity and tissue distribution. Due to gene amplification, mutation, fusion or ligand induction, FGFR members continue to activate, induce tumor cell proliferation, invasion, migration, promote angiogenesis, and promote tumor development. FGFRs are highly expressed and abnormally activated in a variety of tumors, and are closely related to the poor prognosis of cancer patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer.
  • cancer patients such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer.
  • Fibroblast growth factor receptor 4 is a member of the fibroblast growth factor receptor family and is encoded by the FGFR4 gene, which contains 18 exons. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors, indicating inappropriate calcium and phosphorus deposition in soft tissues (Brown, AP et al. (2005), Toxicol. Pathol, pp. 449-455). This suggests that it is desirable to selectively inhibit FGFR4 to avoid certain toxicity. The study found that FGFR4 is the only receptor that shows specificity of FGF19 (a physiological ligand of FGFR4).
  • FGF19 can cause activation of the FGF19-FGFR4 pathway, causing certain sarcoma, renal cell carcinoma, breast cancer and liver cancer.
  • FGFR4 inhibitor treatment is effective for tumors with FGF19 gene amplification. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors, characterized by inappropriate calcium and phosphorus deposition in soft tissues (Brown, AP et al. (2005), Toxicol. Pathol, pp. 449-455). This suggests that selective inhibition of FGFR4 without inhibiting other subtypes of FGFR such as FGFR1 may avoid certain toxic side effects of the drug.
  • the present invention provides a fibroblast growth factor receptor inhibitor of the formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which exhibits good FGFR inhibitory activity, particularly selective inhibition of FGFR4 activity,
  • a warhead is a portion that forms a covalent bond with a nucleophile
  • X, G are each independently selected from CH and N;
  • R 1 and R 2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, An alkyl acylalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, nitro group, cyano group, hydroxyl group, amino group, hydroxyalkane group Alkyl, alkoxyalkyl, aminoalkyl, alkylacylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one or more selected from the group consisting of alkyl, halo, haloalkyl Substituted with a substituent of a halo
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a saturated or unsaturated monoheterocyclic group, a spiroheterocyclic group, a fused heterocyclic group or a bridged heterocyclic group, wherein said monoheterocyclic group, spirohetero
  • the cyclo, fused or heterocyclic heterocyclic group is optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, Substituted with a substituent of an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkyl acyl group, an alkyl acylalkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
  • R 3 , R 4 , R 5 are each independently selected from halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, alkyl acylalkyl , hydroxyalkyl, alkoxy, aminoalkyl, aryl, heteroaryl and heterocycloalkyl, wherein n is selected from 0, 1 and 2, p is selected from 0, 1 and 2, and q is selected from 0, 1, 2, 3, 4 and 5;
  • R 6 is selected from H and optionally substituted alkyl; or R 6 and an adjacent aromatic or aromatic heterocyclic ring together with the amino group to which they are attached form an 8-12 membered heterocyclic group;
  • R 7 is selected from H and an optionally substituted alkyl group.
  • a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof wherein R 1 , R 2 are each independently H, C 1- 6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, hydroxy C 1-6 alkyl, alkane Oxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkyl acyl C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, aryl and a heteroaryl group, wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, nitro group, cyano group, hydroxyl group, amino group, carboxyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, alkyl group
  • the alkyl group is independently H, C 1- 6 al
  • a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof wherein R 1 , R 2 are each independently selected from C 1- 3 alkyl, amino C 1-3 alkyl, C 1-3 alkylamino C 1-3 alkyl.
  • R 1 , R 2 are each independently selected from C 1- 3 alkyl, amino C 1-3 alkyl, C 1-3 alkylamino C 1-3 alkyl.
  • the compounds of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrugs thereof wherein R 1 is methyl, R 2 is dimethylaminoethyl base.
  • the compounds of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof wherein R 7 is selected from H and alkyl, wherein said alkyl group is Selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, Substituent substitution of alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
  • warhead X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in Formula I;
  • Ring A is a nitrogen heterocyclic group, wherein the nitrogen heterocyclic group is optionally further selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, Substituents such as amino, carboxyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylacyl, alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are substituted.
  • the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof wherein Ring A is 3 to 8 members a nitrogen monoheterocyclic group; further preferably a 5- or 6-membered nitrogen monoheterocyclic group; non-limiting examples of the ring A include a substituted or unsubstituted pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group Oryl or tetrahydrofuranyl.
  • the n-nitropolycyclic heterocyclic group is more preferably a 7- to 15-membered nitrogen spiroheterocyclyl group, a nitrogen fused heterocyclic group and a nitrogen bridged heterocyclic group, and further preferably a 7- to 12-membered nitrogen monospiroheterocyclic group and nitrogen.
  • a bridged heterocyclic group wherein said nitrogen polycyclic heterocyclic group, a nitrogen spiroheterocyclyl group, a nitrogen fused heterocyclic group or a nitrogen bridged heterocyclic group is optionally selected from one or more selected from the group consisting of halogen and C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C Substituted by a substituent of a 3-8 cycloalkyl group and a C 3-8 heterocyclic group.
  • Ring A is selected from 7 to a 15-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocycl
  • Ring A is selected from 7 to a 12-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl, and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocycl
  • Ring A is selected from 7 to a 12-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl, and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocycl
  • the compound of Formula II above or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from the group consisting of the following bridged heterocyclic groups :
  • these groups being optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, halo C 1 - 6 alkyl, C1 -6 alkoxy, halo C 1-6 alkoxy, nitro Base, cyano group, hydroxyl group, amino group, carboxyl group, amino C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkyl acyl group, C Substituents of 1-6 alkylacyl C 1-6 alkyl, 3-8 membered aryl, 3-8 membered heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocyclyl are substituted.
  • the compound of Formula II above or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from the group consisting of the following bridged heterocyclic groups :
  • these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, Substituents of a C 1-6 alkyl acyl C 1-6 alkyl group, a 3-8 membered aryl group, a 3-8 membered heteroaryl group, a C 3-8 cycloalkyl group and a C 3-8 heterocyclic group are substituted.
  • the warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in Formula I;
  • n and d are each independently selected from 1, 2, 3 and 4;
  • Ring B is selected from the group consisting of a cycloalkyl group and a heterocyclic group, wherein said cycloalkyl group and heterocyclic group are optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and nitrate.
  • Base cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, alkyl acylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclic Substituted by a substituent.
  • Ring B is selected from 3-8 members a cycloalkyl group and a heterocyclic group, preferably, ring B is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 azacycloalkyl, C 3-8 oxacycloalkyl, C 3-8 nitrox a cycloalkyl group and a C 3-8 thiacycloalkyl group, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 Alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl
  • Ring B examples include cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl or tetrahydrofuranyl, wherein these groups are optional One or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, Hydroxy, amino, carboxyl, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl Substituted by a substituent of the acyl C 1-6 alkyl group.
  • a compound of Formula III or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein
  • the warhead is selected from the following groups:
  • R a , R b , R c are each independently selected from H, alkyl, cycloalkyl, cyano, wherein the alkyl or cycloalkyl is optionally selected from a plurality selected from halogen, alkyl, haloalkyl Substituted by a group of alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acylalkyl, Xa is selected from halogen and a triflate; preferably, R a , R b , R c are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, cyano, wherein the alkyl or ring
  • the alkyl group is optionally selected from a plurality of halogens, C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, C 1-6 alkoxy
  • the warhead is selected from the group consisting of acryloyl, methacryloyl and propargyl.
  • a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof each of which R 3 and R 4 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy; preferably C 1-3 alkyl, C 1-3 alkoxy; more preferably selected from methyl, B Base, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, wherein n is selected from 0, 1 and 2 and p is selected from 0, 1 and 2.
  • the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof wherein R 5 is selected From halogen, C 1-6 alkoxy; preferably selected from halogen, C 1-3 alkoxy; non-limiting examples of R 4 include fluoro, chloro, methoxy, ethoxy, propoxy, isopropyl An oxy group, wherein q is selected from the group consisting of 0, 1, 2, 3, 4 and 5; in some specific embodiments, each R 5 is selected from the group consisting of fluorine, chlorine, methoxy, ethoxy, propoxy, isopropyl Oxy group, q is 4.
  • G is selected from CH and N;
  • X is selected from CH and N;
  • R 3 is selected from C 1-3 alkoxy and C 1-3 alkyl, and n is 1;
  • R 5 is selected from halogen and C 1-3 alkoxy, and q is 4;
  • R 6 is selected from the group consisting of H and C 1-6 alkyl
  • R 7 is selected from the group consisting of H and C 1-6 alkyl groups.
  • the salt is preferably a phosphate, a sulfate, a hydrochloride, a hydrobromide, a citrate, a maleate, a malonate, a mandelate, a succinate, a fumarate, an acetate, or a milk.
  • the acid salt, nitrate, sulfonate, p-toluenesulfonate, malate or methanesulfonate is more preferably a methanesulfonate.
  • the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof Restricted examples include:
  • the invention provides a process for the preparation of a compound of formula I, which process comprises the steps of:
  • a compound of formula i is reacted with a compound of formula ii by palladium mediated coupling to give a compound of formula iii;
  • warhead X, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q have the definitions as defined in Formula I;
  • LG1, LG2 represents a leaving group, may be the same or different, preferably a halogen or sulfonyloxy group, more preferably Cl, Br, I;
  • M may be -B(OR 11 ) 2 , -Sn(alkyl) or -Zn-halogen-, wherein R 11 is H or an alkyl group, preferably a methyl group.
  • the reduction of the nitro compound into an aromatic primary amine can be carried out by a conventional reduction reaction.
  • the commonly used reagents are metal plus acid, metal with iron, zinc or tin, acid with hydrochloric acid, sulfuric acid or acetic acid;
  • the nitro group can also be reduced by catalytic hydrogenation.
  • the usual catalysts are Ni, Pt, Pd, etc., and the reaction can be carried out under neutral conditions.
  • the invention provides a method of making a compound of Formula II of the invention, the method comprising the steps of:
  • ring A, warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q have the definitions in formula II;
  • LG1, LG2 represents a leaving group, may be the same or different, preferably a halogen or sulfonyloxy group, more preferably Cl, Br, I;
  • M may be -B(OR 11 ) 2 , -Sn(alkyl) or -Zn-halogen-, wherein R 11 is H or an alkyl group, preferably a methyl group.
  • the reduction of the nitro compound into an aromatic primary amine can be carried out by a conventional reduction reaction.
  • the commonly used reagents are metal plus acid, metal with iron, zinc or tin, acid with hydrochloric acid, sulfuric acid or acetic acid;
  • the nitro group can also be reduced by catalytic hydrogenation.
  • the usual catalysts are Ni, Pt, Pd, etc., and the reaction can be carried out under neutral conditions.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula I, Formula II or Formula III of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof A pharmaceutically acceptable carrier.
  • the compound of the formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, may be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation.
  • a pharmaceutically acceptable carrier Suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulation can be prepared by methods known in the art and comprises a carrier conventionally used in the field of pharmaceutical formulations.
  • the present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention, and And/or a method for preventing tumors and for use in the preparation of a medicament for treating and/or preventing tumors, comprising administering a compound of the formula I, formula II or formula III of the present invention to a tumor-prone population or a tumor patient, isomerization a drug, a solvate, a crystal or a prodrug or a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the formula I, formula II or formula III of the present invention to effectively reduce tumors Incidence, prolong the life of cancer patients.
  • the present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention for use in therapy and/or A method of preventing a disease or condition mediated by FGFR-4 or FGF19 and for use in the manufacture of a medicament for treating and/or preventing a disease or condition mediated by FGFR-4 or FGF19, characterized by FGFR-4 or FGF19 overexpression, FGFR4 or FGF19 amplification.
  • a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor and a use thereof in the manufacture of a medicament for the treatment and/or prevention of a tumor, wherein the tumor is mediated by FGFR4.
  • a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor, and a method for the preparation of a medicament for treating and/or preventing a tumor, wherein the tumor is selected from the group consisting of liver cancer, rhabdomyosarcoma, malignant lung adenocarcinoma, glioblastoma, esophageal squamous cell carcinoma Malignant peripheral nerve sheath tumor, breast cancer, prostate cancer, ovarian cancer, gastric cancer, pancreatic cancer, colon cancer and renal cell carcinoma.
  • a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor of a composition and use in the manufacture of a medicament for the treatment and/or prevention of a tumor, wherein said tumor is selected from a preferred embodiment, one having the general formula I, the general formula II or A method of treating and/or preventing a tumor of a compound of formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the invention, and a medicament for the treatment and/or prevention of a tumor
  • the use of the tumor is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, liver cancer, and sarcoma.
  • the liver cancer is hepatocellular carcinoma.
  • a decrease in the level of FGF19 promotes bile acid synthesis, and thus a compound that lowers the level of FGF19 can be used to treat hyperlipidemia.
  • the present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the present invention A method of treating and/or preventing hyperlipidemia of a composition and use in the preparation of a medicament for treating and/or preventing hyperlipidemia.
  • “Isomers” of the present invention include cis-trans isomers of the cis or trans configuration, as well as enantiomers and diastereomers derived from chiral carbons.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, and the acid may be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid and the like.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into the invention by oxidation, reduction, hydrolysis or the like of the enzyme and/or A compound which is converted into a compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • a "pharmaceutical composition” is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the "warhead" of the present invention is a moiety that forms a covalent bond with a nucleophile which is formed between the warhead of the inhibitor and the cysteine residue of FGFR4.
  • the warhead includes, but is not limited to, alkyl halides, alkyl sulfonates, heteroaryl halides, epoxides, haloacetamides, maleimides, sulfonates, alpha-beta unsaturation Ketone, ⁇ - ⁇ unsaturated ester, vinyl sulfone, propargyl group, acryloyl group.
  • the structure of an exemplary warhead is as follows:
  • Xa represents a leaving group and may be a halogen or an activated hydroxyl moiety (e.g., a triflate); R a , R b , R c are each independently selected from H, optionally substituted or unsubstituted.
  • alkyl group an optionally substituted or unsubstituted cycloalkyl group, a cyano group or the like, wherein the substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyanide A group, a hydroxyl group, an amino group, a carboxyl group, an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group or an alkylacylalkyl group.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising from 3 to 20 carbon atoms, preferably from 4 to 13 carbon atoms.
  • Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl
  • a cyclooctyl group or the like is preferably a cyclopentyl group or a cyclohexyl group.
  • Polycycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the "spirocycloalkyl group” of the present invention means a polycyclic group of 5-20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings, and the spirocycloalkyl group may contain one or more double bonds, preferably 5-14 yuan, more preferably 7-10 yuan.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group or a bispirocycloalkyl group, depending on the number of spiro atoms shared between the ring and the ring. .
  • spiro rings include
  • fused cycloalkyl means 5-20 members, and each ring in the system shares a polycyclic alkyl group of a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may be Containing one or more double bonds, preferably 6-14 yuan, more preferably 7-10 yuan, depending on the number of constituent rings, can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, preferably bicyclic or The tricyclic ring is more preferably a 5-member/5-membered or a 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl groups are:
  • bridged cycloalkyl group of the present invention means an all-carbon polycyclic group of 5 to 20 members in which any two rings share two carbon atoms which are not directly bonded, and these may contain one or more double bonds. It is preferably 6-14 yuan, more preferably 7-10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include
  • the cycloalkyl group of the present invention may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, Hydroxy, mercapto, cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, Aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of N, O and S ( O) a hetero atom of e (where e is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • the heterocyclic group preferably includes 3 to 12 ring atoms containing 1 to 4 hetero atoms; more preferably, the heterocyclic group contains 5 to 11 ring atoms, of which 1 to 2 are hetero atoms.
  • Heterocycloalkyl as used in the present invention means a saturated or unsaturated, non-aromatic monocyclic, fused ring, spiro or bridged ring containing from 3 to 20 carbon atoms and containing a hetero atom such as N, O or S. Replace one or more C atoms.
  • heterocycloalkyl groups include tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indanyl, Isoindoline, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, Thiomorpholyl-S,S-dioxide, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, homothiomorpholinyl-S, S-dioxide, oxazolidinyl, di Hydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidin
  • “Spiroheterocyclyl” means a 5 to 20 membered polycyclic heterocyclic group in which one atom (spiro atom) is shared between the individual rings, wherein one or more ring atoms are selected from the group consisting of N, O and S(O) e
  • the hetero atom (wherein e is an integer from 0 to 2), the remaining ring atoms are carbon, and the spiroheterocycloalkyl group may contain one or more double bonds, preferably 6-14 members, more preferably 7-12 members.
  • a nitrogen spiro heterocyclic group When it is a spiroheterocyclic group containing one or more nitrogen atoms, it is abbreviated as "a nitrogen spiro heterocyclic group”.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group or a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring.
  • spiroheterocyclyl groups include
  • the "fused heterocyclic group" of the present invention means 5-20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, wherein one or more rings may contain One or more double bonds, wherein one or more ring atoms are selected from heteroatoms of N, O or S(O) e (wherein e is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6-14 yuan, more preferably 7-12 yuan.
  • a fused heterocyclic group containing one or more nitrogen atoms abbreviated as "a nitrogen fused heterocyclic group”.
  • fused ring heterocyclic groups include
  • the "bridge heterocyclic group” of the present invention means a 5 to 14 membered member, and any two rings share two polycyclic heterocyclic groups of atoms which are not directly bonded, and these may contain one or more double bonds, one or more of which
  • the ring atoms are selected from heteroatoms of N, O or S(O) e (wherein e is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6-14 yuan, more preferably 7-12 yuan. When it is a bridged heterocyclic group containing one or more nitrogen atoms, it is abbreviated as "a nitrogen bridged heterocyclic group”.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups preferably bicyclic, tricyclic or tetracyclic, non-limiting examples of bridged heterocyclic groups.
  • bridge heterocyclic groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl Substituted by a C 1-6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group.
  • the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, fluorenyl. , cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, Aryloxy, arylthio, heteroaryl, heteroaryloxy.
  • the invention refers to a heterocyclic group containing one or more nitrogen atoms, abbreviated as "a nitrogen heterocyclic group".
  • the heterocyclic group may also contain one or more other heteroatoms such as O or S(O) e (wherein e is an integer from 0 to 2).
  • a nitrogen monoheterocyclic group When ring A is a single heterocyclic ring, the present invention refers to it as "a nitrogen monoheterocyclic group"; when ring A is a polyheterocyclic ring, the present invention refers to it as a "nitropolyheterocyclic group"; When ring A is a monospiroheterocyclic group, the present invention refers to it as "a nitrogen monospiroheterocyclic group”.
  • aryl group of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 One carbon atom, preferably from about 6 to about 14 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, Cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, aryl Alkoxy, arylthio, heteroaryl, heteroaryloxy.
  • heteroaryl of the present invention means an aromatic monocyclic or polycondensed ring such as an aromatic group in which at least one carbon atom of a bicyclic or tricyclic ring is replaced by a hetero atom, and the hetero atom is O, S, N.
  • Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
  • the heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, hydroxy, decyl. , cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, Aryloxy, arylthio, heteroaryl, heteroaryloxy.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • the sulfur atom is replaced by an oxo group
  • the sulfur atom is replaced by two oxo groups
  • alkyl group of the present invention means a linear or branched saturated hydrocarbon group, preferably a C 1-8 alkyl group, more preferably a C 1-6 alkyl group.
  • alkyl groups include phenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, Cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, aryl Alkoxy, arylthio, heteroaryl, heteroaryloxy.
  • alkoxy group of the present invention means an -O-alkyl group.
  • haloalkoxy group of the present invention means an alkoxy group substituted with at least one halogen, preferably a C 1-6 alkoxy group substituted with at least one halogen, and further preferably a C 1-3 alkane substituted with at least one halogen.
  • Oxyl, a suitable halogenated C 1-3 alkoxy group is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; Chloroethoxy, difluoroethoxy, trichloroethoxy, trifluoroethoxy.
  • the "nitro group" of the present invention means -NO 2 .
  • the "cyano group" of the present invention means -CN.
  • the "hydroxyl group" of the present invention means -OH.
  • hydroxyalkyl group of the present invention means OH-alkyl-.
  • alkyl acylalkyl group of the present invention means an alkyl-C(O)-alkyl group-
  • Aminoalkyl refers to the present invention is NH 2 - alkyl -, (alkyl) NH- alkyl - or (alkyl) (alkyl) N- alkyl -.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted 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.
  • Haldrogen and “carbon” in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers, such as isotopes of hydrogen including lanthanum and cerium, and isotopes of carbon including 13 C and 14 C.
  • Step 2 Preparation of ethyl 6-chloro-4-ethylaminonicotinate
  • Step 5 Preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 6 Preparation of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 9 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(4-methylpiperazin-1-yl)-3- Preparation of nitrophenyl)-1,6-naphthyridin-2(1H)-one
  • Step 10 7-(3-Amino-4-(4-methylpiperazin-1-yl)phenyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Preparation of 1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 11 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
  • Step 1 Preparation of 6-chloro-4-(isopropylamino)nicotinic acid ethyl ester
  • 6-Chloro-4-(isopropylamino)nicotinic acid ethyl ester (10 g, 41.32 mmol) was dissolved in 100 ml of tetrahydrofuran, and LiAlH 4 (3.14 g, 82.64 mmol) was slowly added at room temperature, stirred at room temperature for 3 h, with hydr The reaction was quenched with EtOAc (EtOAc)EtOAc. ESI-MS m/z: 201 [M+H] + .
  • Step 3 Preparation of 6-chloro-4-(isopropylamino) nicotinaldehyde
  • Step 4 Preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
  • Step 5 Preparation of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
  • Step 7 1-Ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of alk-2-yl)phenyl)piperazine
  • Step 8 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(4-ethylpiperazin-1-yl)-2-methoxy-5 Of -nitrophenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
  • Step 9 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-isopropyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  • 6-Methoxy-3-nitropyridin-2-amine (7.8 g, 46 mmol) was dissolved in 150 mL of DMF and N-bromosuccinimide (NBS) (9 g, 51 mmol) was added and stirred at room temperature for 1 hour.
  • NSS N-bromosuccinimide
  • Step 4 1-Ethyl-4-(6-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of alk-2-yl)pyridin-2-yl)piperazine
  • Step 5 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(-4-ethylpiperazin-1-yl)-6-methoxypyridin-3-yl)acrylamide
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material in the step 9 is 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above-mentioned step 4, 1-ethyl-4-(6-methoxy-3-nitro- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine.
  • Example 5 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-2-(4-ethyl-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  • Step 4 (2S,6R)-1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-di Preparation of oxaborolan-2-yl)phenyl)-2,6-dimethylpiperazine
  • the preparation method is the same as that in the first step of the first embodiment except that the starting material 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine is replaced by the above step 3 (2S, 6R)-4- (4-Bromo-5-methoxy-2-nitrophenyl)-1-ethyl-2,6-dimethylpiperazine, the title compound was synthesized.
  • Step 5 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-ethyl-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)phenyl)piperazine was replaced by the above step 4 (2S,6R)-1-ethyl-4-(5-methoxy-2-nitro 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylpiperazine.
  • Step 1 1-(4-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Of -phenyl)piperazin-1-yl)ethanone
  • the preparation was similar to the procedure of steps 2 and 7 of Example 2, replacing 1-ethylpiperazine in step 6 with 1-acetylpiperazine.
  • Step 2 N-(2-(4-Acetylpiperazin-1-yl)-5-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl Preparation of -2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-4-methoxyphenyl)acrylamide
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above 1-step product 1-(4-(5-methoxy-2-nitro-4-(4,4) , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethanone.
  • Step 1 3-Fluoro-1-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)phenyl)pyrrolidine
  • Step 2 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(3-fluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above-mentioned step 1, 3-fluoro-1-(5-methoxy-2-nitro-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine.
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the product of Step 2 of Example 2, 1-ethyl-4-(5-methoxy-2-nitro-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine.
  • Example 9 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]indol-2-yl)phenyl)acrylamide
  • Step 2 2-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of phenyl)-8-oxa-2-azaspiro[4.5]decane
  • Step 3 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]indol-2-yl)phenyl)acrylamide
  • the preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the above 2-step product 2-(5-methoxy-2-nitro-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-oxa-2-azaspiro[4.5]decane.
  • Example 10 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)acrylamide
  • Step 1 Preparation of 7-(4-bromo-5-methoxy-2-nitrophenyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid tert-butyl ester
  • Step 4 2-Ethyl-7-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Preparation of 2-yl)phenyl)-2,7-diazaspiro[4.4]decane
  • Step 5 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(7-ethyl-2,7-diazaspiro[ Preparation of 4.4]decane-2-yl)-2-methoxy-5-nitrophenyl)-1,6-naphthyridin-2(1H)-one
  • Step 6 7-(5-Amino-4-(7-ethyl-2,7-diazaspiro[4.4]decan-2-yl)-2-methoxyphenyl)-3-(2 Of 6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 7 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)acrylamide
  • Example 11 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-4-methoxyphenyl)acrylamide
  • Step 3 (2R,6S)-4-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of tert-butyl ester of alk-2-yl)phenyl)-2,6-dimethylpiperidine-1-carboxylate
  • Step 4 (2R,6S)-4-(4-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2 -dihydro-1,6-naphthyridin-4-yl)-7-yl)-5-methoxy-2-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylic acid
  • Step 5 (2R,6S)-4-(2-Amino-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo Of tert-butyl-1,2-dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylate
  • Step 6 (2R,6S)-4-(2-Acrylamide-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2- Preparation of oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
  • Step 7 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  • Example 12 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydroxy-1, 6-(naphthylpyridine-7-alkenyl)-2(4-ethylpiperazin-1-enyl)-4-methoxyphenyl)-butyl-2-ynylamide
  • Step 1 7-(5-Amino-4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-3-(2,6-dichloro-3,5-dimethyl Preparation of oxyphenyl)-1-ethyl-1,6-naphthyridine 2(1H)-one
  • the preparation method is similar to the steps 9 and 10 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2) - Dioxaborolan-2-yl)phenyl)piperazine was replaced with the product obtained in Step 7 of Example 2.
  • 2-butynoic acid 100 g, 1.20 mol was added to a 3000 mL three-necked flask, 1.98 L of dichloromethane, 30 mL of N,N-dimethylformamide was added, and the mixture was stirred at -5 ° C for 10 min, then oxalyl chloride (151.2 g) was added dropwise. , 1.20 mol), stirring at -5 ° C for 20 min, then moving to room temperature for 1.5 h and then set aside.
  • Step 3 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)-butyl-2-ynylamide
  • Example 13 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)but-2-ynamide preparation
  • the preparation method was similar to that in Example 12, except that the starting material 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3)
  • the 2-dioxaborolan-2-yl)phenyl)piperazine was replaced with the product obtained in Step 2 of Example 9 above.
  • Step 1 Preparation of ethyl 4-ethylamino-2-(methylthio)-pyrimidine-5-carboxylate
  • Step 7 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-hydroxypyridine [2,3-d]pyrimidin-7(8H)-one preparation
  • Step 8 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-chloropyridine [2,3-d]pyrimidin-7(8H)-one preparation
  • Step 9 N 1 -(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Of phenyl)-phenyl)-N 1 ,N 2 ,N 2 -trimethylethyl-1,2-diamine
  • the preparation method was similar to the steps 6 and 7 in Example 2, except that 1-ethylpiperazine in the starting material was replaced with N,N,N'-trimethylethylenediamine.
  • Step 10 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl)(amino)-2-yl) Preparation of oxy-5-nitrophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one
  • Step 11 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl)(amino)-2-yl) Preparation of oxy-5-aminophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one
  • Step 12 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2 ,3-d]pyrimidin-2-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
  • Step 1 Preparation of ethyl 2-chloro-4-(ethylamino)pyrimidine-5-carboxylate
  • Step 5 6-(3,5-Dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy-5-nitrate Preparation of phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • the compound obtained in the step 7 of Example 2 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolane-2-yl)phenyl)piperazine (476 mg), the product of the above step 4, 2-chloro-6-(3,5-dimethoxyphenyl)-8-ethylpyridine [2,3-d]pyrimidin-7(8H)-one (350 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (74 mg) and potassium acetate (298 mg) After 15 mL of 1,4-dioxane and 8 mL of water were added, and the reaction mixture was refluxed for 2h, the reaction mixture was filtered. ESI-MS m/z: 575[M+H] +
  • Step 6 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2- Preparation of methoxy-5-nitrophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 7 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2- Preparation of methoxy-5-aminophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 8 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridyl[ Preparation of 2,3-d]pyrimidin-2-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  • 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy 5-Aminophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one 200 mg was dissolved in 10 mL of tetrahydrofuran and added N,N-diisopropylethylamine (212 mg), ice The acryloyl chloride (39 ul) was added dropwise to the residue.
  • the preparation method was similar to that of Example 14, Steps 5, 6, 7, and 8, except that the compound of the starting material in Step 5 of Example 14 was 1-ethyl-4-(5-methoxy-2-nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the 1-methyl ester obtained in Step 1 of Example 1.
  • Step 2 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[ 2,3-d]piperazin-2-yl)-2-(4-ethylpiperazin-1-yl)-phenyl]acrylamide
  • the preparation method was similar to that of Example 15, except that the compound of the starting material in Step 5 of Example 15 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5). -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the compound 1-ethyl-4-(2-nitro) obtained in the above step 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine.
  • the preparation method is similar to that of Example 5, except that the starting compound 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1 in the step 4 is used. , 6-naphthyridine-2(1H)-one was replaced by the compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2- which was obtained in the step 8 of Example 14. Chloropyridine [2,3-d]pyrimidin-7(8H)-one.
  • Step 2 5-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane
  • Step 3 N-(2-(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-(6-(2,6-dichloro-3,5-di Methoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-4-methoxyphenyl)acrylamide preparation
  • the preparation method was similar to that of Example 15, except that the compound in Step 5 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the compound 5-(5-methoxy-2-nitro-4-() obtained in the above step 2 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]g alkyl.
  • Step 1 3,3-Difluoro-1-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxole) Preparation of borane-2-yl)phenyl)pyrrolidine
  • the synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 3,3-difluoropyrrole.
  • Step 2 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[ Preparation of 2,3-d]pyrimidin-2-yl)-2-(3,3-difluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
  • the preparation method was similar to that of Example 15, except that the compound in Step 5 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the above step 1 product 3,3-difluoro-1-(5-methoxy-2- Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine.
  • the preparation method was similar to that of Example 15, except that the starting compound 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl) in Step 5 was prepared.
  • Base-1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the product of Step 1 of Example 6 1-(4-(5-methoxy-2-nitrate) Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethanone Compound.
  • the synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 2-oxa-7- Oxalate of azaspiro[3.5]decane.
  • the synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 7-oxa-2- Oxalate of azaspiro[3.5]decane.
  • the synthesis method is the same as in Steps 2 and 2 of Example 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in Step 1 is replaced by 3-methoxy-pyrrole.
  • the hydrochloride salt of the alkane is replaced by 3-methoxy-pyrrole.
  • the synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced by 1-oxa-8-. Azaspiro[4.5]decane.
  • Example 27 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)but-2- Preparation of alkyne amide
  • Step 1 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(2-methoxy-5-nitro-4-(8-oxygen) Preparation of hetero-2-azaspiro[4.5]decane-2-yl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • the preparation method is similar to the steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of Example 14, except that the starting material in the step 10 is N 1 -(5-methoxy-2-nitro 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N 1 ,N 2 ,N 2 -trimethylethane -1,2-diamine was replaced by the compound 2-step 5-(2-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3) prepared in the second step of Example 9. , 2-dioxaborolan-2-yl)phenyl)-8-oxa-2-azaspiro[4.5]decane.
  • Step 2 2-(5-Amino-2-methoxy-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)-6-(2,6- Preparation of dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 3 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridyl[ 2,3-d]pyrimidin-2-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)but-2-yne
  • amide N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridyl[ 2,3-d]pyrimidin-2-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)but-2-yne
  • Example 28 N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)propene Preparation of amide
  • the preparation method is similar to that of Example 14, except that the starting compound N 1 -(5-methoxy-2-nitro 4-(4,4,5,5-tetramethyl-1,3) in Step 10 is prepared.
  • ,2-dioxaborolan-2-yl)phenyl)-N 1 ,N 2 ,N 2 -trimethylethane-1,2-diamine is the product of step 4 of Example 10 2-B 7-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base)-2,7-diazaspiro[4.4]decane.
  • Example 29 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridinyl-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide
  • Example 30 N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
  • Examples 31-53 were synthesized according to the synthesis method of Examples 1-30 of the present invention using different raw materials, and the characterization parameters of Examples 31-53 are shown in Table 1:
  • Step 1 7-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxy-5-nitrophenyl)-3-(2, Preparation of 6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 2 7-(5-Amino-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxyphenyl)-3-(2,6 Of 2-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
  • Step 3 N-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-(3-(2,6-dichloro-3,5-dimethyl) Oxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-diazaphthalen-7-yl)-4-methoxyphenyl)but-2-yne
  • amide 2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-(3-(2,6-dichloro-3,5-dimethyl)
  • Comparative Example 1 Compound A
  • Comparative Example 2 Compound B
  • the compound name is N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (BLU-554), prepared by the synthesis method of Compound 40 compound in WO2015/061572, and identified by hydrogen spectrum and mass spectrometry.
  • the inhibitory activities of Compound A, Compound B and Compound C against FGFR4 kinase and FGFR1 kinase, and the inhibitory activities against human hepatoma cell lines Hep3B and HUH-7 cells, and small were tested using the following Experimental Examples 1, 2 and 3. Pharmacokinetic characteristics in mice.
  • the results of the experiment showed that the selectivity of Compound A, Compound B and Compound C to FGFR4 kinase and FGFR1 kinase was significantly lower than that of the present invention, and the inhibitory activity against human hepatoma cell line Hep3B cells and HUH-7 cells was significantly weaker than that of the present invention.
  • the compounds, as well as the half-life and AUC, are also inferior to the compounds of the invention.
  • FGFR1 purchased from Carna, catalog number 08-133;
  • FGFR4 purchased from Carna, catalog number 08-136;
  • Staurosporine 9 purchased from Sigma, catalog number S4400-1MG;
  • A.1 ⁇ Kinase Buffer basis 20mM HEPES, pH 7.5,0.01% Triton X-100,10mM MgCl 2, 2mM DTT.
  • Stop buffer 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.
  • the assay plate contained 5 ⁇ L of compound (10% DMSO).
  • Inhibition rate % (maximum conversion value - actual conversion value) / (maximum conversion value - minimum conversion value) ⁇ 100, where "maximum conversion value” represents a DMSO vehicle control with no compound, and “minimum conversion value” represents no kinase No compound control.
  • the compounds of the invention are potent kinase inhibitors that are selective for FGFR4, are useful in the treatment of diseases associated with FGFR4 kinase, and may reduce the side effects caused by inhibition of FGFR1 kinase.
  • FBS FBS
  • DMEM medium purchased from GIBCO
  • CellTiter Glo purchased from Promega.
  • Day-1 cells were added to 96 wells at a density of 3 ⁇ 10 3 cells/well, 100 ⁇ l per well;
  • the experimental results show that the compound of the present invention has a very good inhibitory activity on the proliferation of human hepatoma cell lines HePB and HuH-7 expanded by FGFR4 DNA, and some compounds are far superior to the reference compound and are effective FGFR4 selective inhibitors. .
  • Oral drug formula is 10% ethanol, 10% solutol, 80% physiological saline dissolved, made 0.5mg/ml clear solution
  • intravenous drug formula is 2% ethanol, 2% solutol, 96% normal saline, made 0.1mg/ml Clarify the solution.
  • mice Male BALB/c mice, 3 in each group, weighing 18-22, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • mice were fasted but allowed to drink water for 12 hours, and the blank plasma was taken at 0 o'clock;
  • step 1) intragastric administration (IG) were administered with the compound of the examples of the present invention and the reference compound 10 mg/kg; the compound of the present invention and the reference compound 1 mg were administered intravenously (IV). /kg;

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Abstract

The present invention falls within the field of medical chemistry, and in particular relates to an FGFR4 inhibitor as shown in formula II, a preparation method thereof, a pharmaceutical composition comprising the inhibitor, and the use of the inhibitor or the pharmaceutical composition as a therapeutic drug for tumours.

Description

FGFR4抑制剂及其制备与应用FGFR4 inhibitor and its preparation and application 技术领域Technical field
本发明属于医药化学领域，具体涉及一类新型的FGFR4抑制剂、含有该抑制剂的药物组合物，以及所述抑制剂或药物组合物作为肿瘤治疗药物的用途。The invention belongs to the field of medical chemistry, and in particular relates to a novel class of FGFR4 inhibitors, a pharmaceutical composition containing the same, and the use of the inhibitor or the pharmaceutical composition as a tumor therapeutic drug.
背景技术Background technique
受体酪氨酸激酶由于其异常表达激活或基因突变，在肿瘤发生发展、侵袭转移、药物抗性等各个环节均发挥关键作用，已成为抗肿瘤药物研发的重要靶点。成纤维细胞生长因子受体(Fibroblast Growth Factor Receptors,FGFRs)是受体酪氨酸激酶家族的重要成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。其配体是成纤维细胞生长因子(Fibroblast Growth Factors,FGFs)。这些受体通过与FGFs和硫酸乙酰肝素蛋白多糖(Heparan-SulfateProteoglycans，HSPGs)形成三元复合物，进而引发一系列的信号传导，参与调节生物体内的多种生理、病理过程。Receptor tyrosine kinase plays a key role in tumor development, invasion and metastasis, drug resistance and other factors due to its abnormal expression activation or gene mutation, and has become an important target for the development of anti-tumor drugs. Fibroblast Growth Factor Receptors (FGFRs) are important members of the receptor tyrosine kinase family, including four subtypes of FGFR1, FGFR2, FGFR3 and FGFR4. Its ligand is Fibroblast Growth Factors (FGFs). These receptors form a ternary complex with FGFs and Heparan-Sulfate Proteoglycans (HSPGs), which in turn trigger a series of signaling and participate in the regulation of various physiological and pathological processes in the organism.
FGFR家族成员(FGFR1、FGFR2、FGFR3和FGFR4)之间的氨基酸序列是高度保守的，在配体亲和力及组织分布等方面表现不同。由于基因扩增、突变、融合或配体诱导等原因，FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭、迁移，促进血管生成，促进肿瘤的发生发展。FGFRs在多种肿瘤中高表达并异常激活，与肿瘤病人的不良预后密切相关，如非小细胞肺癌、乳腺癌、胃癌、膀胱癌、子宫内膜癌、***癌、***、结肠癌、食管癌、角质母细胞瘤、骨髓瘤、横纹肌肉瘤等。成纤维细胞生长因子受体4(FGFR4)是成纤维细胞生长因子受体家族中的成员，由FGFR4基因编码，FGFR4基因组结构含有18个外显子。在用FGFR1抑制剂处理过的大鼠体内观测到异位矿化，显示在软组织中有不当的钙磷沉积(Brown,AP等(2005),Toxicol.Pathol,第449-455页)。这表明选择性的抑制FGFR4来避免某些毒性是可取的。研究发现，FGFR4是FGF19(FGFR4的生理配体)唯一显示有特异性的受体，FGF19过表达可引起FGF19-FGFR4通路激活，从而引起某些肉瘤、肾细胞癌、乳癌及肝癌等癌症。对于具有FGF19基因扩增的肿瘤，FGFR4抑制剂治疗是有效的。在用FGFR1抑制剂治疗的大鼠体内观测到异位矿化，其特征是在软组织中有不当的钙磷沉积(Brown,AP等(2005),Toxicol.Pathol,第449-455页)。这表明选择性的抑制FGFR4，而不抑制FGFR的其它亚型例如FGFR1可避免药物的某些毒副作用。目前，公开了一系列FGFR4抑制剂，包括WO2015/108992、WO2015/059668、WO2015/061572等中公开的化合物。但仍需开发具有更好药效，毒性更小，选择性更高的化合物。The amino acid sequence between members of the FGFR family (FGFR1, FGFR2, FGFR3, and FGFR4) is highly conserved and differs in ligand affinity and tissue distribution. Due to gene amplification, mutation, fusion or ligand induction, FGFR members continue to activate, induce tumor cell proliferation, invasion, migration, promote angiogenesis, and promote tumor development. FGFRs are highly expressed and abnormally activated in a variety of tumors, and are closely related to the poor prognosis of cancer patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer. , keratinoma, myeloma, rhabdomyosarcoma, etc. Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family and is encoded by the FGFR4 gene, which contains 18 exons. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors, indicating inappropriate calcium and phosphorus deposition in soft tissues (Brown, AP et al. (2005), Toxicol. Pathol, pp. 449-455). This suggests that it is desirable to selectively inhibit FGFR4 to avoid certain toxicity. The study found that FGFR4 is the only receptor that shows specificity of FGF19 (a physiological ligand of FGFR4). Overexpression of FGF19 can cause activation of the FGF19-FGFR4 pathway, causing certain sarcoma, renal cell carcinoma, breast cancer and liver cancer. For tumors with FGF19 gene amplification, FGFR4 inhibitor treatment is effective. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors, characterized by inappropriate calcium and phosphorus deposition in soft tissues (Brown, AP et al. (2005), Toxicol. Pathol, pp. 449-455). This suggests that selective inhibition of FGFR4 without inhibiting other subtypes of FGFR such as FGFR1 may avoid certain toxic side effects of the drug. Currently, a series of FGFR4 inhibitors are disclosed, including the compounds disclosed in WO 2015/108992, WO 2015/059668, WO 2015/061572, and the like. However, there is still a need to develop compounds that are more potent, less toxic, and more selective.
发明内容Summary of the invention
第一方面，本发明提供一种具有通式I的成纤维细胞生长因子受体抑制剂或其药学可接 受的盐、异构体、溶剂合物、结晶或前药，该类化合物表现出良好的FGFR抑制活性，尤其选择性的抑制FGFR4的活性，In a first aspect, the present invention provides a fibroblast growth factor receptor inhibitor of the formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which exhibits good FGFR inhibitory activity, particularly selective inhibition of FGFR4 activity,
Figure PCTCN2018085940-appb-000001
Figure PCTCN2018085940-appb-000001
其中：among them:
弹头是能与亲核试剂形成共价键的部分；A warhead is a portion that forms a covalent bond with a nucleophile;
X、G各自独立地选自CH和N；X, G are each independently selected from CH and N;
R 1、R 2各自独立地选自H、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羟基烷基、烷氧基烷基、氨基烷基、烷基酰基烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羟基烷基、烷氧基烷基、氨基烷基、烷基酰基烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、卤素、卤代烷基、卤代烷氧基、羟基、硝基、氨基、羧基、羟基烷基、烷氧基的取代基所取代；或者 R 1 and R 2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, An alkyl acylalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, nitro group, cyano group, hydroxyl group, amino group, hydroxyalkane group Alkyl, alkoxyalkyl, aminoalkyl, alkylacylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one or more selected from the group consisting of alkyl, halo, haloalkyl Substituted with a substituent of a haloalkoxy group, a hydroxyl group, a nitro group, an amino group, a carboxyl group, a hydroxyalkyl group, or an alkoxy group; or
R 1和R 2与它们所连接的氮原子一起形成饱和或不饱和的单杂环基、螺杂环基、稠杂环基或桥杂环基，其中所述的单杂环基、螺杂环基、稠杂环基或桥杂环基任选地被一个或多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基所取代； R 1 and R 2 together with the nitrogen atom to which they are attached form a saturated or unsaturated monoheterocyclic group, a spiroheterocyclic group, a fused heterocyclic group or a bridged heterocyclic group, wherein said monoheterocyclic group, spirohetero The cyclo, fused or heterocyclic heterocyclic group is optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, Substituted with a substituent of an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkyl acyl group, an alkyl acylalkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
R 3、R 4、R 5各自独立地选自卤素、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、烷基酰基烷基、羟基烷基、烷氧基、氨基烷基、芳基、杂芳基和杂环烷基，其中n选自0、1和2，p选自0、1和2，以及q选自0、1、2、3、4和5； R 3 , R 4 , R 5 are each independently selected from halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, alkyl acylalkyl , hydroxyalkyl, alkoxy, aminoalkyl, aryl, heteroaryl and heterocycloalkyl, wherein n is selected from 0, 1 and 2, p is selected from 0, 1 and 2, and q is selected from 0, 1, 2, 3, 4 and 5;
R 6选自H和任选取代的烷基；或者R 6和相邻的芳环或芳杂环与它们共同连接的氨基一起形成8-12元杂环基；和 R 6 is selected from H and optionally substituted alkyl; or R 6 and an adjacent aromatic or aromatic heterocyclic ring together with the amino group to which they are attached form an 8-12 membered heterocyclic group;
R 7选自H和任选取代的烷基。 R 7 is selected from H and an optionally substituted alkyl group.
在本发明的一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 1、R 2各自独立地H、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羟基C 1-6烷基、烷氧基C 1-6烷基、氨基C 1-6烷基、C 1-6烷基酰基C 1-6烷基、C 3-8环烷基、C 3-8杂环基、芳基和杂芳基，其中所述烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、羟基烷基、烷氧基烷基、氨基烷基、烷基酰基烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个选自C 1-6烷基、卤素、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、硝基、氨基、羟基C 1-6烷基、C 1-6烷氧基的取代基所取代。在本发明的一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 1、R 2各自独立地选自C 1-3 烷基、氨基C 1-3烷基、C 1-3烷基氨基C 1-3烷基。在一个具体的实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 1为甲基，R 2为二甲基氨基乙基。 In some embodiments of the invention, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 , R 2 are each independently H, C 1- 6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, hydroxy C 1-6 alkyl, alkane Oxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkyl acyl C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, aryl and a heteroaryl group, wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, nitro group, cyano group, hydroxyl group, amino group, carboxyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, alkyl group The alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally one or more selected from C 1-6 alkyl, halogen, halogenated C 1-6 alkyl, halogenated C Substituents of 1-6 alkoxy, hydroxy, nitro, amino, hydroxy C 1-6 alkyl, and C 1-6 alkoxy are substituted. In some embodiments of the invention, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 , R 2 are each independently selected from C 1- 3 alkyl, amino C 1-3 alkyl, C 1-3 alkylamino C 1-3 alkyl. In a specific embodiment, the compounds of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrugs thereof, wherein R 1 is methyl, R 2 is dimethylaminoethyl base.
在另一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 1和R 2与它们所连接的氮原子一起形成饱和或不饱和的3-12元单环氮杂环烷基、单环二氮杂环烷基、单环氮氧杂环烷基、氮杂螺环烷基、二氮杂螺环烷基、氮氧杂螺环烷基、氮杂稠环烷基、二氮杂稠环烷基、氮氧杂稠环烷基、氮杂桥环烷基、二氮杂桥环烷基和氮氧杂桥环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In other embodiments, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a saturation Or unsaturated 3-12 membered monocyclic azacycloalkyl, monocyclic diazacycloalkyl, monocyclic oxacycloalkyl, azaspirocycloalkyl, diazaspirocycloalkyl, nitrogen Oxospirocycloalkyl, aza fused cycloalkyl, diaza fused cycloalkyl, oxacyclobutadiene, aza bridged alkyl, diazabicycloalkyl and nitrox bridge An alkyl group, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxyl, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkane Substituents of a acyl group, a C 1-6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group are substituted.
在另一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 1和R 2与它们所连接的氮原子一起形成饱和或不饱和的氮杂桥环烷基、二氮杂桥环烷基和氮氧杂桥环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In other embodiments, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a saturation Or an unsaturated aza-bridged cycloalkyl, diazabicycloalkyl and oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, Halogen C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1 -6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3 Substituted by a substituent of -8 cycloalkyl and C 3-8 heterocyclic.
在另一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 6选自H和烷基，其中所述烷基任选被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基取代。 In other embodiments, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 6 is selected from H and alkyl, wherein said alkyl is Selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, Substituent substitution of alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
在另一些实施方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 7选自H和烷基，其中所述烷基任选被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基取代。 In other embodiments, the compounds of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 7 is selected from H and alkyl, wherein said alkyl group is Selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, Substituent substitution of alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
在本发明的另一些优选方案中，根据通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中通式I具有以下通式II所示的结构，In a further preferred embodiment of the invention, a compound according to formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein formula I has the structure of formula II below ,
Figure PCTCN2018085940-appb-000002
Figure PCTCN2018085940-appb-000002
其中弹头、X、G、R 3、R 4、R 5、R 6、R 7、n、p、q的定义如通式I所述； Wherein the warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in Formula I;
环A为氮杂环基，其中所述的氮杂环基任选进一步被一个或多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基所取代。Ring A is a nitrogen heterocyclic group, wherein the nitrogen heterocyclic group is optionally further selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, Substituents such as amino, carboxyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylacyl, alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are substituted.
在本发明的另一些优选实施方案中，根据通式II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为3元-8元的氮单杂环基；再优选为5元或6元氮单杂环基；环A的非限制性实例包括取代或未取代的吡咯烷基、哌啶基、哌嗪基、吗啉基、吡喃基或四氢呋喃基。In another preferred embodiment of the present invention, the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is 3 to 8 members a nitrogen monoheterocyclic group; further preferably a 5- or 6-membered nitrogen monoheterocyclic group; non-limiting examples of the ring A include a substituted or unsubstituted pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group Oryl or tetrahydrofuranyl.
在本发明的另一些优选的实施方案中，根据通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为7元至15元氮多环杂环基，更优选为7元至15元氮螺杂环基、氮稠杂环基和氮桥杂环基，再优选为7元至12元氮单螺杂环基和氮桥杂环基，其中所述氮多环杂环基、氮螺杂环基、氮稠杂环基或氮桥杂环基任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In another preferred embodiment of the present invention, the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is from 7 to 15 The n-nitropolycyclic heterocyclic group is more preferably a 7- to 15-membered nitrogen spiroheterocyclyl group, a nitrogen fused heterocyclic group and a nitrogen bridged heterocyclic group, and further preferably a 7- to 12-membered nitrogen monospiroheterocyclic group and nitrogen. A bridged heterocyclic group, wherein said nitrogen polycyclic heterocyclic group, a nitrogen spiroheterocyclyl group, a nitrogen fused heterocyclic group or a nitrogen bridged heterocyclic group is optionally selected from one or more selected from the group consisting of halogen and C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C Substituted by a substituent of a 3-8 cycloalkyl group and a C 3-8 heterocyclic group.
在本发明的另一些优选的实施方案中，根据通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自7元至15元氮杂桥环烷基、二氮杂桥环烷基和氮氧杂桥环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In another preferred embodiment of the present invention, according to the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from 7 to a 15-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocyclyl are substituted.
在本发明的另一些优选的实施方案中，根据通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自7元至12元氮杂桥环烷基、二氮杂桥环烷基和氮氧杂桥环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In another preferred embodiment of the present invention, according to the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from 7 to a 12-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl, and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocyclyl are substituted.
在本发明的另一些优选的实施方案中，根据通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自7元至12元氮杂桥环烷基、二氮杂桥环烷基和氮氧杂桥环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 In another preferred embodiment of the present invention, according to the compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from 7 to a 12-membered aza-bridged cycloalkyl, a diazetane-cycloalkyl, and an oxa-halocycloalkyl, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 Substituents of cycloalkyl and C 3-8 heterocyclyl are substituted.
在本发明的一些实施方案中，根据以上通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自以下桥杂环基：In some embodiments of the invention, the compound of Formula II above, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from the group consisting of the following bridged heterocyclic groups :
Figure PCTCN2018085940-appb-000003
其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1- 6烷基、C1 -6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、3-8元芳基、3-8元杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。
Figure PCTCN2018085940-appb-000003
Wherein these groups being optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, halo C 1 - 6 alkyl, C1 -6 alkoxy, halo C 1-6 alkoxy, nitro Base, cyano group, hydroxyl group, amino group, carboxyl group, amino C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 alkyl acyl group, C Substituents of 1-6 alkylacyl C 1-6 alkyl, 3-8 membered aryl, 3-8 membered heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocyclyl are substituted.
在本发明的一些实施方案中，根据以上通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自以下桥杂环基：In some embodiments of the invention, the compound of Formula II above, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is selected from the group consisting of the following bridged heterocyclic groups :
Figure PCTCN2018085940-appb-000004
其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、3-8元芳基、3-8元杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。
Figure PCTCN2018085940-appb-000004
Wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, Substituents of a C 1-6 alkyl acyl C 1-6 alkyl group, a 3-8 membered aryl group, a 3-8 membered heteroaryl group, a C 3-8 cycloalkyl group and a C 3-8 heterocyclic group are substituted.
在本发明的另一些优选实施方案中，根据通式I或通式II的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所示的通式I或通式II具有以下通式III所示的结构：In a further preferred embodiment of the invention, a compound according to formula I or formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein formula I or Formula II has the structure shown in Formula III below:
Figure PCTCN2018085940-appb-000005
Figure PCTCN2018085940-appb-000005
其中：弹头、X、G、R 3、R 4、R 5、R 6、R 7、n、p、q的定义如通式I所述； Wherein: the warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in Formula I;
m和d各自独立地选自1、2、3和4；m and d are each independently selected from 1, 2, 3 and 4;
环B选自环烷基和杂环基，其中所述的环烷基和杂环基任选地被一个或多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基所取代。Ring B is selected from the group consisting of a cycloalkyl group and a heterocyclic group, wherein said cycloalkyl group and heterocyclic group are optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and nitrate. Base, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, alkyl acylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclic Substituted by a substituent.
在本发明的另一些优选的实施方案中，根据通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环B选自3-8元环烷基和杂环基，优选地，环B选自C 3-8环烷基、C 3-8氮杂环烷基、C 3-8氧杂环烷基、C 3-8氮氧杂环烷基和C 3-8硫杂环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。在一些实施方案中，环B的非限制性实例包括环戊基、环己基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡喃基或四氢呋喃基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基的取代基所取代。 In another preferred embodiment of the present invention, the compound of Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring B is selected from 3-8 members a cycloalkyl group and a heterocyclic group, preferably, ring B is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 azacycloalkyl, C 3-8 oxacycloalkyl, C 3-8 nitrox a cycloalkyl group and a C 3-8 thiacycloalkyl group, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 Alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocyclic Substituted by a substituent. In some embodiments, non-limiting examples of Ring B include cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl or tetrahydrofuranyl, wherein these groups are optional One or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, Hydroxy, amino, carboxyl, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl Substituted by a substituent of the acyl C 1-6 alkyl group.
在本发明的一些具体实施方案中，根据通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中In some specific embodiments of the invention, a compound of Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein
基团
Figure PCTCN2018085940-appb-000006
选自
Figure PCTCN2018085940-appb-000007
Figure PCTCN2018085940-appb-000008
其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基的取代基所取代。 Group
Figure PCTCN2018085940-appb-000006
Selected from
Figure PCTCN2018085940-appb-000007
Figure PCTCN2018085940-appb-000008
Wherein these groups being optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, halo C 1- 6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, Substituted by a substituent of a C 1-6 alkyl acyl C 1-6 alkyl group.
在本发明的另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中弹头选自以下基团：In another preferred embodiment of the invention, a compound according to formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein The warhead is selected from the following groups:
Figure PCTCN2018085940-appb-000009
Figure PCTCN2018085940-appb-000009
其中R a、R b、R c各自独立地选自H、烷基、环烷基、氰基，其中所述烷基或环烷基任选被一个多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基烷基的基团取代，Xa选自卤素和三氟甲磺酸酯；优选地，R a、R b、R c各自独立地选自H、C 1-6烷基、C 3-8环烷基、氰基，其中所述烷基或环烷基任选被一个多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、烷氧基C 1-6烷基、C 1-6烷基酰基C 1-6烷基的基团取代。 Wherein R a , R b , R c are each independently selected from H, alkyl, cycloalkyl, cyano, wherein the alkyl or cycloalkyl is optionally selected from a plurality selected from halogen, alkyl, haloalkyl Substituted by a group of alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acylalkyl, Xa is selected from halogen and a triflate; preferably, R a , R b , R c are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, cyano, wherein the alkyl or ring The alkyl group is optionally selected from a plurality of halogens, C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, C 1-6 alkoxy groups, halogenated C 1-6 alkoxy groups, nitro groups, cyanogens. a group of a hydroxyl group, a hydroxyl group, an amino group, a carboxyl group, an amino C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an alkoxy C 1-6 alkyl group, a C 1-6 alkyl acyl C 1-6 alkyl group Replace.
在本发明的另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中弹头选自丙烯酰基、甲基丙烯酰基和炔丙基酰基。In another preferred embodiment of the invention, a compound according to formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein The warhead is selected from the group consisting of acryloyl, methacryloyl and propargyl.
在本发明另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中各R 3、R 4各自独立地选自C 1-6烷基、C 1-6烷氧基；优选为C 1-3烷基、C 1-3烷氧基；更优选选自甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基，其中n选自0、1和2和p选自0、1和2。 In another preferred embodiment of the invention, a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, each of which R 3 and R 4 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy; preferably C 1-3 alkyl, C 1-3 alkoxy; more preferably selected from methyl, B Base, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, wherein n is selected from 0, 1 and 2 and p is selected from 0, 1 and 2.
在另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 5选自卤素、C 1-6烷氧基；优选选自卤素、C 1-3烷氧基；R 4的非限制性实例包括氟、氯、甲氧基、乙氧基、丙氧基、异丙氧基，其中q选自0、1、2、3、4和5；在一些具体的实施方案中，各R 5选自氟、氯、甲氧基、乙氧基、丙氧基、异丙氧基，q为4。 In other preferred embodiments, the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 5 is selected From halogen, C 1-6 alkoxy; preferably selected from halogen, C 1-3 alkoxy; non-limiting examples of R 4 include fluoro, chloro, methoxy, ethoxy, propoxy, isopropyl An oxy group, wherein q is selected from the group consisting of 0, 1, 2, 3, 4 and 5; in some specific embodiments, each R 5 is selected from the group consisting of fluorine, chlorine, methoxy, ethoxy, propoxy, isopropyl Oxy group, q is 4.
在另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可 接受的盐、异构体、溶剂合物、结晶或前药，其中R 6选自为H和C 1-6烷基。 In other preferred embodiments, the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 6 is selected From H and C 1-6 alkyl.
在另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R 7选自H和C 1-6烷基，优选为C 1-3烷基，更优选选自甲基、乙基和异丙基。 In other preferred embodiments, the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 7 is selected From H and C 1-6 alkyl, preferably C 1-3 alkyl, more preferably selected from the group consisting of methyl, ethyl and isopropyl.
在一些实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：In some embodiments, a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:
G选自CH和N；G is selected from CH and N;
X选自CH和N；X is selected from CH and N;
R 3选自C 1-3烷氧基和C 1-3烷基，n为1； R 3 is selected from C 1-3 alkoxy and C 1-3 alkyl, and n is 1;
p为0；p is 0;
R 5选自卤素和C 1-3烷氧基，q为4； R 5 is selected from halogen and C 1-3 alkoxy, and q is 4;
R 6选自为H和C 1-6烷基； R 6 is selected from the group consisting of H and C 1-6 alkyl;
R 7选自为H和C 1-6烷基。 R 7 is selected from the group consisting of H and C 1-6 alkyl groups.
在另一些优选的实施方案中，根据通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述的盐优选为磷酸盐、硫酸盐、盐酸盐、氢溴酸盐、柠檬酸盐、马来酸盐、丙二酸盐、扁桃酸盐、琥珀酸盐、富马酸盐、醋酸盐、乳酸盐、硝酸盐、磺酸盐、对甲苯磺酸盐、苹果酸盐或甲磺酸盐，更优选为甲磺酸盐。In other preferred embodiments, the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein The salt is preferably a phosphate, a sulfate, a hydrochloride, a hydrobromide, a citrate, a maleate, a malonate, a mandelate, a succinate, a fumarate, an acetate, or a milk. The acid salt, nitrate, sulfonate, p-toluenesulfonate, malate or methanesulfonate is more preferably a methanesulfonate.
在本发明的一些具体实施方案中，所述的通式I、通式II或通式III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的非限制性实例包括：In some embodiments of the invention, the compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof Restricted examples include:
Figure PCTCN2018085940-appb-000010
Figure PCTCN2018085940-appb-000010
Figure PCTCN2018085940-appb-000011
Figure PCTCN2018085940-appb-000011
Figure PCTCN2018085940-appb-000012
Figure PCTCN2018085940-appb-000012
第二方面，本发明提供通式I的化合物的制备方法，该方法包括以下步骤：In a second aspect, the invention provides a process for the preparation of a compound of formula I, which process comprises the steps of:
Figure PCTCN2018085940-appb-000013
Figure PCTCN2018085940-appb-000013
(1)、式i化合物与式ii化合物通过钯介导的耦合反应得到式iii化合物；(1), a compound of formula i is reacted with a compound of formula ii by palladium mediated coupling to give a compound of formula iii;
(2)、将式iii化合物的芳环或芳杂环上的硝基还原为氨基，得到式iv化合物；(2) reducing the nitro group on the aromatic ring or the aromatic heterocyclic ring of the compound of formula iii to an amino group to obtain a compound of the formula iv;
(3)、式iv化合物与弹头-LG2通过酰胺偶联反应得到式I化合物；(3), the compound of the formula iv and the warhead-LG2 are coupled by an amide to obtain a compound of the formula I;
其中弹头、X、G、R 1、R 2、R 3、R 4、R 5、R 6、R 7、n、p、q具有如通式I中的定义； Wherein the warhead, X, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q have the definitions as defined in Formula I;
LG1、LG2代表离去基团，可以相同也可以不同，优选为卤素或磺酰氧基，更优选为Cl、Br、I；LG1, LG2 represents a leaving group, may be the same or different, preferably a halogen or sulfonyloxy group, more preferably Cl, Br, I;
M可以为-B(OR 11) 2、-Sn(烷基)或者-Zn-卤素-，其中R 11为H或烷基，优选为甲基。 M may be -B(OR 11 ) 2 , -Sn(alkyl) or -Zn-halogen-, wherein R 11 is H or an alkyl group, preferably a methyl group.
将硝基化合物还原制成芳香一级胺可采用常规的还原反应，常用的试剂有金属加酸，金属用铁、锌或锡，酸用盐酸、硫酸或醋酸等；The reduction of the nitro compound into an aromatic primary amine can be carried out by a conventional reduction reaction. The commonly used reagents are metal plus acid, metal with iron, zinc or tin, acid with hydrochloric acid, sulfuric acid or acetic acid;
也可用催化氢化法还原硝基，常用催化剂有Ni、Pt、Pd等，反应在中性条件下即可进行。The nitro group can also be reduced by catalytic hydrogenation. The usual catalysts are Ni, Pt, Pd, etc., and the reaction can be carried out under neutral conditions.
在本发明提供的通式I化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的制备方法的基础上，本领域技术人员选用常规的原料即可得到通式II或通式III化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药。Based on the preparation method of the compound of the general formula I provided by the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, those skilled in the art can obtain the general formula II by using a conventional raw material. Or a compound of formula III or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
在一些实施方案中，本发明提供本发明的通式II的化合物的制备方法，该方法包括以下步骤：In some embodiments, the invention provides a method of making a compound of Formula II of the invention, the method comprising the steps of:
Figure PCTCN2018085940-appb-000014
Figure PCTCN2018085940-appb-000014
(1)、式1化合物与式2化合物通过钯介导的耦合反应得到式3化合物；(1), a compound of formula 1 and a compound of formula 2 are palladium mediated coupling reaction to give a compound of formula 3;
(2)、将式3化合物的芳环或芳杂环上的硝基还原为氨基，得到式4化合物；(2) reducing the nitro group on the aromatic ring or the aromatic heterocyclic ring of the compound of formula 3 to an amino group to obtain a compound of formula 4;
(3)、式4化合物与弹头-LG2通过酰胺偶联反应得到式II化合物；(3), the compound of formula 4 and the warhead-LG2 are coupled by an amide to obtain a compound of formula II;
其中环A、弹头、X、G、R 3、R 4、R 5、R 6、R 7、n、p、q具有如通式II中的定义； Wherein ring A, warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q have the definitions in formula II;
LG1、LG2代表离去基团，可以相同也可以不同，优选为卤素或磺酰氧基，更优选为Cl、Br、I；LG1, LG2 represents a leaving group, may be the same or different, preferably a halogen or sulfonyloxy group, more preferably Cl, Br, I;
M可以为-B(OR 11) 2、-Sn(烷基)或者-Zn-卤素-，其中R 11为H或烷基，优选为甲基。 M may be -B(OR 11 ) 2 , -Sn(alkyl) or -Zn-halogen-, wherein R 11 is H or an alkyl group, preferably a methyl group.
将硝基化合物还原制成芳香一级胺可采用常规的还原反应，常用的试剂有金属加酸，金属用铁、锌或锡，酸用盐酸、硫酸或醋酸等；The reduction of the nitro compound into an aromatic primary amine can be carried out by a conventional reduction reaction. The commonly used reagents are metal plus acid, metal with iron, zinc or tin, acid with hydrochloric acid, sulfuric acid or acetic acid;
也可用催化氢化法还原硝基，常用催化剂有Ni、Pt、Pd等，反应在中性条件下即可进行。The nitro group can also be reduced by catalytic hydrogenation. The usual catalysts are Ni, Pt, Pd, etc., and the reaction can be carried out under neutral conditions.
第三方面，本发明提供药物组合物，其包含本发明通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体。In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the formula I, Formula II or Formula III of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof A pharmaceutically acceptable carrier.
可以将通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药与药学上可接受的载体混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体。The compound of the formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, may be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation. Suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulation can be prepared by methods known in the art and comprises a carrier conventionally used in the field of pharmaceutical formulations.
第四方面，本发明提供通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，包括向肿瘤易发人群或肿瘤患者施用本发明通式I、通式II或通式III所示的化合物、异构体、溶剂合物、结晶或前药或者包含本发明通式I、通式II或通式III所示化合物、异构体、溶剂合物、结晶或前药的药物组合物，以有效降低肿瘤发生率、延长肿瘤患者生命。In a fourth aspect, the present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention, and And/or a method for preventing tumors and for use in the preparation of a medicament for treating and/or preventing tumors, comprising administering a compound of the formula I, formula II or formula III of the present invention to a tumor-prone population or a tumor patient, isomerization a drug, a solvate, a crystal or a prodrug or a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the formula I, formula II or formula III of the present invention to effectively reduce tumors Incidence, prolong the life of cancer patients.
本发明提供通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物用于治疗和/或预防由FGFR-4或FGF19介导的疾病或病症的方法以及在制备治疗和/或预防由FGFR-4或FGF19介导的疾病或病症的药物中的应用，其特征在于个体中FGFR-4或FGF19过度表达、FGFR4或FGF19扩增。在一个优选的实施方案中，一种具有通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，其中所述肿瘤由FGFR4介导。在一个优选的实施方案中，一种具有通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，其中所述肿瘤选自肝癌、横纹肌肉瘤、恶性肺腺癌、恶性胶质瘤、食管鳞状细胞癌、恶性外周神经鞘膜瘤、乳腺癌、***癌、卵巢癌、胃癌、胰腺癌、结肠癌和肾细胞癌。在一个优选的实施方案中，一种具有通式I、通式II或通式III所示化合物或其药学可接受的 盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，其中所述肿瘤选自在一个优选的实施方案中，一种具有通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，其中所述肿瘤选自乳腺癌、卵巢癌、肺癌、肝癌和肉瘤。在一个具体的实施方案中，所述肝癌为肝细胞癌。FGF19水平的降低可促进胆汁酸合成，因此降低FGF19水平的化合物可用于治疗高脂血症。在一个具体的实施方案中，本发明提供通式I、通式II或通式III所示化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防高脂血症的方法和在制备治疗和/或预防高脂血症的药物中的应用。The present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the present invention for use in therapy and/or A method of preventing a disease or condition mediated by FGFR-4 or FGF19 and for use in the manufacture of a medicament for treating and/or preventing a disease or condition mediated by FGFR-4 or FGF19, characterized by FGFR-4 or FGF19 overexpression, FGFR4 or FGF19 amplification. In a preferred embodiment, a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor and a use thereof in the manufacture of a medicament for the treatment and/or prevention of a tumor, wherein the tumor is mediated by FGFR4. In a preferred embodiment, a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor, and a method for the preparation of a medicament for treating and/or preventing a tumor, wherein the tumor is selected from the group consisting of liver cancer, rhabdomyosarcoma, malignant lung adenocarcinoma, glioblastoma, esophageal squamous cell carcinoma Malignant peripheral nerve sheath tumor, breast cancer, prostate cancer, ovarian cancer, gastric cancer, pancreatic cancer, colon cancer and renal cell carcinoma. In a preferred embodiment, a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the invention A method of treating and/or preventing a tumor of a composition and use in the manufacture of a medicament for the treatment and/or prevention of a tumor, wherein said tumor is selected from a preferred embodiment, one having the general formula I, the general formula II or A method of treating and/or preventing a tumor of a compound of formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of the invention, and a medicament for the treatment and/or prevention of a tumor The use of the tumor is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, liver cancer, and sarcoma. In a specific embodiment, the liver cancer is hepatocellular carcinoma. A decrease in the level of FGF19 promotes bile acid synthesis, and thus a compound that lowers the level of FGF19 can be used to treat hyperlipidemia. In a specific embodiment, the present invention provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a medicament of the present invention A method of treating and/or preventing hyperlipidemia of a composition and use in the preparation of a medicament for treating and/or preventing hyperlipidemia.
术语说明：Explanation of terms:
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning
本发明的“异构体”包括顺式或反式构型的顺反异构体，也包括手性碳产生的对映异构体和非对映异构体。"Isomers" of the present invention include cis-trans isomers of the cis or trans configuration, as well as enantiomers and diastereomers derived from chiral carbons.
本发明的“药学可接受的盐”是指本发明所述的化合物与酸形成的药学上可接受的盐，所述的酸可选自：磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲磺酸等。The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, and the acid may be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid and the like.
本发明的“溶剂合物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂合物的特殊形式，其中与水发生配位。在本发明范围内，溶剂合物优选是水合物。The "solvate" of the present invention means a form of the compound of the present invention which forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the invention, the solvate is preferably a hydrate.
本发明的“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。"Crystalline" as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
本发明的“前药”是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物和/或通过胃酸等的水解反应等转化成本发明的化合物的化合物。The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into the invention by oxidation, reduction, hydrolysis or the like of the enzyme and/or A compound which is converted into a compound of the invention by a hydrolysis reaction such as gastric acid or the like.
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。A "pharmaceutical composition" according to the invention is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
本发明的“弹头”是与亲核试剂形成共价键的部分，所述共价键是在抑制剂的弹头与FGFR4的半胱胺酸残基之间形成。所述弹头包括但不限于，烷基卤化物、磺酸烷酯、杂芳基卤化物、环氧化物、卤基乙酰胺、顺丁烯二酰亚胺、磺酸酯、α-β不饱和酮、α-β不饱和酯、乙烯基砜、炔丙基酰基、丙烯酰基。示例性弹头的结构如下所示：The "warhead" of the present invention is a moiety that forms a covalent bond with a nucleophile which is formed between the warhead of the inhibitor and the cysteine residue of FGFR4. The warhead includes, but is not limited to, alkyl halides, alkyl sulfonates, heteroaryl halides, epoxides, haloacetamides, maleimides, sulfonates, alpha-beta unsaturation Ketone, α-β unsaturated ester, vinyl sulfone, propargyl group, acryloyl group. The structure of an exemplary warhead is as follows:
Figure PCTCN2018085940-appb-000015
Figure PCTCN2018085940-appb-000015
其中Xa代表离去基团，可以为卤素或经活化的羟基部分(例如三氟甲磺酸酯)；R a、R b、R c各自独立地选自H、任选的取代或未取代的烷基、任选的取代或未取代的环烷基、氰基等，其中所述取代基选自一个或多个卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基烷基。 Wherein Xa represents a leaving group and may be a halogen or an activated hydroxyl moiety (e.g., a triflate); R a , R b , R c are each independently selected from H, optionally substituted or unsubstituted. An alkyl group, an optionally substituted or unsubstituted cycloalkyl group, a cyano group or the like, wherein the substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyanide A group, a hydroxyl group, an amino group, a carboxyl group, an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group or an alkylacylalkyl group.
本发明的“环烷基”是指饱和或者部分不饱和单环或多环取代基，其包括3-20个碳原子，优选4-13个碳原子。单环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选为环戊基、环己基。多环烷基包括螺环、稠环和桥环的环烷基。"Cycloalkyl" as used in the present invention refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising from 3 to 20 carbon atoms, preferably from 4 to 13 carbon atoms. Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl A cyclooctyl group or the like is preferably a cyclopentyl group or a cyclohexyl group. Polycycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
本发明的“螺环烷基”是指5-20元，单环之间共用一个碳原子(称螺原子)的多环基团，螺环烷基可以含有一个或多个双键，优选为5-14元，更优选为7-10元。根据环与环之间共用的螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基或双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元单螺环烷基。螺环的非限制性实例包括The "spirocycloalkyl group" of the present invention means a polycyclic group of 5-20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings, and the spirocycloalkyl group may contain one or more double bonds, preferably 5-14 yuan, more preferably 7-10 yuan. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group or a bispirocycloalkyl group, depending on the number of spiro atoms shared between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spiro rings include
Figure PCTCN2018085940-appb-000016
Figure PCTCN2018085940-appb-000016
本发明的“稠环烷基”是指5-20元，体系中的每个环与体系中的其他环共享毗邻的一对碳原子的多环烷基基团，其中一个或多个环可以含有一个或多个双键，优选为6-14元，更优选为7-10元，根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例为：The "fused cycloalkyl" of the present invention means 5-20 members, and each ring in the system shares a polycyclic alkyl group of a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may be Containing one or more double bonds, preferably 6-14 yuan, more preferably 7-10 yuan, depending on the number of constituent rings, can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, preferably bicyclic or The tricyclic ring is more preferably a 5-member/5-membered or a 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups are:
Figure PCTCN2018085940-appb-000017
Figure PCTCN2018085940-appb-000017
本发明的“桥环烷基”是指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键。优选为6-14元，更优选为7-10元。根据组成环的数目可以分为双环、三环、四环或多环环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包含The "bridged cycloalkyl group" of the present invention means an all-carbon polycyclic group of 5 to 20 members in which any two rings share two carbon atoms which are not directly bonded, and these may contain one or more double bonds. It is preferably 6-14 yuan, more preferably 7-10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include
Figure PCTCN2018085940-appb-000018
Figure PCTCN2018085940-appb-000018
本发明的环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、烷基、链烯基、链炔基、环烷基、杂环基、杂环基氧基、杂环基氨基、杂环基硫基、芳基、芳基氧基、芳基硫基、杂芳基、杂芳基氧基。The cycloalkyl group of the present invention may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, Hydroxy, mercapto, cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, Aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy.
本发明的“杂环基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3-20个环原子，其中一个或多个环原子选自N、O和S(O) e(其中e是0至2的整数)的杂原子，其余环原子为碳。其中杂环基优选包括3-12个环原子，其中含有1-4个杂原子；更优选为杂环基包含5-11个环原子，其中1-2个是杂原子。 The "heterocyclyl" of the present invention refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of N, O and S ( O) a hetero atom of e (where e is an integer from 0 to 2), and the remaining ring atoms are carbon. Wherein the heterocyclic group preferably includes 3 to 12 ring atoms containing 1 to 4 hetero atoms; more preferably, the heterocyclic group contains 5 to 11 ring atoms, of which 1 to 2 are hetero atoms.
本发明的“杂环烷基”是指饱和或不饱和、非芳香族单环、稠环、螺环或桥环，其含有3-20个碳原子且含有杂原子例如N、O或S以替代一个或多个C原子。杂环烷基的实例包括四氢呋喃基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、二氢吲哚基、异二氢吲哚基、吗啉基、硫代吗啉基、高吗啉基、高哌啶基、高哌嗪基、高硫代吗啉基、硫代吗啉基-S-氧化物、硫代吗啉基-S,S-二氧化物、吡喃基、四氢吡喃基、四氢噻吩基、高硫代吗啉基-S,S-二氧化物、噁唑烷基、二氢吡唑基、二氢吡咯基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢呋喃基、二氢吡喃基、四氢噻吩基-S-氧化物、四氢噻吩基-S,S-二氧化物、高硫代吗啉基-S-氧化物、2-氧杂-5-氮杂双环[2.2.1]庚烷、8-氧杂-3-氮杂双环[3.2.1]辛烷、3，8-二氮杂双环[3.2.1]辛烷、2,5-二氮杂双环[2.2.1]庚烷、3,8-二氮杂双环[3.2.1]辛烷、3,9-二氮杂双环[4.2.1]壬烷和2,6-二氮杂双环[3.2.2]壬烷。"Heterocycloalkyl" as used in the present invention means a saturated or unsaturated, non-aromatic monocyclic, fused ring, spiro or bridged ring containing from 3 to 20 carbon atoms and containing a hetero atom such as N, O or S. Replace one or more C atoms. Examples of heterocycloalkyl groups include tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indanyl, Isoindoline, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, Thiomorpholyl-S,S-dioxide, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, homothiomorpholinyl-S, S-dioxide, oxazolidinyl, di Hydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophene s-S,S-dioxide, high thiomorpholino-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo [3.2.1] Octane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2 .1] Octane, 3,9-diazabicyclo[4.2.1]nonane and 2,6-diazabicyclo[3.2.2]nonane.
“螺杂环基”是指5-20元，单环之间共用一个原子(螺原子)的多环杂环基团，其中一个或多个环原子选自N、O和S(O) e(其中e是0至2的整数)的杂原子，其余环原子为碳，螺杂环烷基可以含有一个或多个双键，优选6-14元，更优选为7-12元。当含有一个或多个氮原子的螺杂环基，简称“氮螺杂环基”。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基或双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元单螺杂环基。螺杂环基的非限制性实例包含 "Spiroheterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which one atom (spiro atom) is shared between the individual rings, wherein one or more ring atoms are selected from the group consisting of N, O and S(O) e The hetero atom (wherein e is an integer from 0 to 2), the remaining ring atoms are carbon, and the spiroheterocycloalkyl group may contain one or more double bonds, preferably 6-14 members, more preferably 7-12 members. When it is a spiroheterocyclic group containing one or more nitrogen atoms, it is abbreviated as "a nitrogen spiro heterocyclic group". The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group or a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 6 yuan single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include
Figure PCTCN2018085940-appb-000019
Figure PCTCN2018085940-appb-000019
本发明的“稠杂环基”是指5-20元，体系中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，其中一个或多个环可以含有一个或多个双键，其中一个或多个环原子选自N、O或S(O) e(其中e是0至2的整数)的杂原子，其余环原子为碳。优选为6-14元，更优选为7-12元。当含有一个或多个氮原子的稠杂环基，简称“氮稠杂环基”。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为更优选为5元/5元或5元/6元双环烷基。稠环杂环基的非限制性实例包含 The "fused heterocyclic group" of the present invention means 5-20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, wherein one or more rings may contain One or more double bonds, wherein one or more ring atoms are selected from heteroatoms of N, O or S(O) e (wherein e is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6-14 yuan, more preferably 7-12 yuan. A fused heterocyclic group containing one or more nitrogen atoms, abbreviated as "a nitrogen fused heterocyclic group". It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group depending on the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably more preferably a 5 member/5 member or a 5 member/6 member bicycloalkyl group. . Non-limiting examples of fused ring heterocyclic groups include
Figure PCTCN2018085940-appb-000020
Figure PCTCN2018085940-appb-000020
本发明的“桥杂环基”是指5-14元，任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，其中一个或多个环原子选自N、O或S(O) e(其中e是0至2的整数)的杂原子，其余环原子为碳。优选为6-14元，更优选为7-12元。当含有一个或多个氮原子的桥杂环基，简称“氮桥杂环基”。根据组成环的数目可以分为双环、三环、四环或多环桥环基，优选为双环、三环或四环，桥环杂环基的非限制性实例包含 The "bridge heterocyclic group" of the present invention means a 5 to 14 membered member, and any two rings share two polycyclic heterocyclic groups of atoms which are not directly bonded, and these may contain one or more double bonds, one or more of which The ring atoms are selected from heteroatoms of N, O or S(O) e (wherein e is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6-14 yuan, more preferably 7-12 yuan. When it is a bridged heterocyclic group containing one or more nitrogen atoms, it is abbreviated as "a nitrogen bridged heterocyclic group". Depending on the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic, non-limiting examples of bridged heterocyclic groups.
Figure PCTCN2018085940-appb-000021
这些桥杂环基任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。
Figure PCTCN2018085940-appb-000021
These bridge heterocyclic groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl Substituted by a C 1-6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group.
杂环基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、烷基、链烯基、链炔基、环烷基、杂环基、杂环基氧基、杂环基氨基、杂环基硫基、 芳基、芳基氧基、芳基硫基、杂芳基、杂芳基氧基。The heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, fluorenyl. , cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, Aryloxy, arylthio, heteroaryl, heteroaryloxy.
本发明的
Figure PCTCN2018085940-appb-000022
是指含有一个或多个氮原子的杂环基，简称“氮杂环基”。所述杂环基也可以含有一个或多个其他杂原子，例如O或S(O) e(其中e是0至2的整数)。当环A为单杂环时，本发明将其称为“氮单杂环基”；当环A为多杂环时，本发明将其称为“氮多杂环基”；依次列推，当环A为单螺杂环基，本发明将其称为“氮单螺杂环基”。 The invention
Figure PCTCN2018085940-appb-000022
It refers to a heterocyclic group containing one or more nitrogen atoms, abbreviated as "a nitrogen heterocyclic group". The heterocyclic group may also contain one or more other heteroatoms such as O or S(O) e (wherein e is an integer from 0 to 2). When ring A is a single heterocyclic ring, the present invention refers to it as "a nitrogen monoheterocyclic group"; when ring A is a polyheterocyclic ring, the present invention refers to it as a "nitropolyheterocyclic group"; When ring A is a monospiroheterocyclic group, the present invention refers to it as "a nitrogen monospiroheterocyclic group".
本发明的“芳基”是指可以包含单环或多稠环例如二环或三环的芳香环的芳香系，其中至少稠合的环的一部分形成共轭的芳香系，其含有5至50个碳原子，优选约6至约14个碳原子。合适的芳基包括但不限于苯基、萘基、联苯基、蒽基、四氢萘基、芴基、茚满基、亚联苯基和苊基。The "aryl group" of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 One carbon atom, preferably from about 6 to about 14 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl.
芳基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、烷基、链烯基、链炔基、环烷基、杂环基、杂环基氧基、杂环基氨基、杂环基硫基、芳基、芳基氧基、芳基硫基、杂芳基、杂芳基氧基。The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, Cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, aryl Alkoxy, arylthio, heteroaryl, heteroaryloxy.
本发明的“杂芳基”是指芳族单环或多稠环如二环或三环的至少有一个碳原子被杂原子替代的芳香性基团，所述的杂原子为O、S、N。合适的杂芳基包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、***基等。The "heteroaryl" of the present invention means an aromatic monocyclic or polycondensed ring such as an aromatic group in which at least one carbon atom of a bicyclic or tricyclic ring is replaced by a hetero atom, and the hetero atom is O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
杂芳基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、烷基、链烯基、链炔基、环烷基、杂环基、杂环基氧基、杂环基氨基、杂环基硫基、芳基、芳基氧基、芳基硫基、杂芳基、杂芳基氧基。The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, hydroxy, decyl. , cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, Aryloxy, arylthio, heteroaryl, heteroaryloxy.
本发明的“卤素“是指氟、氯、溴或碘。The "halogen" of the present invention means fluorine, chlorine, bromine or iodine.
本发明的“氧代”是指O＝，例如碳原子被氧代基团取代形成
Figure PCTCN2018085940-appb-000023
硫原子被一个氧代基团取代形成
Figure PCTCN2018085940-appb-000024
硫原子被两个氧代基团取代形成
Figure PCTCN2018085940-appb-000025
The "oxo" of the present invention means O =, for example, a carbon atom is substituted by an oxo group.
Figure PCTCN2018085940-appb-000023
The sulfur atom is replaced by an oxo group
Figure PCTCN2018085940-appb-000024
The sulfur atom is replaced by two oxo groups
Figure PCTCN2018085940-appb-000025
本发明的“烷基”是指直链或支链的饱和烃基，优选为C 1-8烷基，更优选C 1-6烷基。烷基的非限制性实例包括基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基。 The "alkyl group" of the present invention means a linear or branched saturated hydrocarbon group, preferably a C 1-8 alkyl group, more preferably a C 1-6 alkyl group. Non-limiting examples of alkyl groups include phenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl.
烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、烷基、链烯基、链炔基、环烷基、杂环基、杂环基氧基、杂环基氨基、杂环基硫基、芳基、芳基氧基、芳基硫基、杂芳基、杂芳基氧基。The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, Cyano, nitro, azide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, aryl, aryl Alkoxy, arylthio, heteroaryl, heteroaryloxy.
本发明的“卤代烷基”是指至少被一个卤素原子取代的烷基。The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen atom.
本发明的“烷氧基”是指-O-烷基。The "alkoxy group" of the present invention means an -O-alkyl group.
本发明的“卤代烷氧基”是指至少被一个卤素取代的烷氧基，优选为至少被一个卤素取代的C 1-6烷氧基，进一步优选为至少被一个卤素取代的C 1-3烷氧基，合适的卤代C 1-3烷氧基为氯甲氧基、氟甲氧基、二氯甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基；二氯乙氧基、二氟乙氧基、三氯乙氧基、三氟乙氧基。 The "haloalkoxy group" of the present invention means an alkoxy group substituted with at least one halogen, preferably a C 1-6 alkoxy group substituted with at least one halogen, and further preferably a C 1-3 alkane substituted with at least one halogen. Oxyl, a suitable halogenated C 1-3 alkoxy group is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; Chloroethoxy, difluoroethoxy, trichloroethoxy, trifluoroethoxy.
本发明的“硝基”是指-NO 2。 The "nitro group" of the present invention means -NO 2 .
本发明的“氰基”是指-CN。The "cyano group" of the present invention means -CN.
本发明的“羟基”是指-OH。The "hydroxyl group" of the present invention means -OH.
本发明的“羟基烷基”是指OH-烷基-。The "hydroxyalkyl group" of the present invention means OH-alkyl-.
本发明的“烷基酰基烷基”是指烷基-C(O)-烷基-The "alkyl acylalkyl group" of the present invention means an alkyl-C(O)-alkyl group-
本发明的“氨基”指-NH 2、-NH-(烷基)或-N(烷基)(烷基)。 The "amino group" of the present invention means -NH 2 , -NH-(alkyl) or -N(alkyl)(alkyl).
本发明的“氨基烷基”是指NH 2-烷基-、(烷基)NH-烷基-或(烷基)(烷基)N-烷基-。 "Aminoalkyl" refers to the present invention is NH 2 - alkyl -, (alkyl) NH- alkyl - or (alkyl) (alkyl) N- alkyl -.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted 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.
本发明化合物中的“氢”、“碳”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子，例如氢的同位素包括氚和氘，碳的同位素包括 13C和 14C。 "Hydrogen" and "carbon" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers, such as isotopes of hydrogen including lanthanum and cerium, and isotopes of carbon including 13 C and 14 C.
具体实施方式detailed description
以下结合实施例进一步描述、解释本发明，但这些实施例并非意味着限制本发明的范围。以下实施例中使用的材料如无特殊说明均为商购获得。The invention is further described and illustrated in the following examples, but these examples are not intended to limit the scope of the invention. The materials used in the following examples are commercially available unless otherwise specified.
实施例1：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺的制备Example 1: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000026
Figure PCTCN2018085940-appb-000026
步骤1：3,5-二甲氧基苯乙酸甲酯的制备Step 1: Preparation of methyl 3,5-dimethoxyphenylacetate
Figure PCTCN2018085940-appb-000027
Figure PCTCN2018085940-appb-000027
在单颈瓶中加入3,5-二甲氧基苯乙酸(20g，100mmol)、DMF(0.15mL)和甲醇(300mL)，室温下缓慢加入氯化亚砜(22mL,300mmol)，室温搅拌过夜。TLC(EA：PE＝1:1)显示反应完全。减压旋蒸除去溶剂，残留物经碳酸氢钠水溶液中和，乙酸乙酯(250×3mL)萃取，有机相经无水硫酸钠干燥、浓缩，得黄色油状物23g，收率100％。ESI-MS m/z:211.2[M+H] +. 3,5-Dimethoxyphenylacetic acid (20 g, 100 mmol), DMF (0.15 mL) and methanol (300 mL) were added to a single-necked flask, and thionyl chloride (22 mL, 300 mmol) was slowly added at room temperature overnight. . TLC (EA: PE = 1:1) showed the reaction was completed. The solvent was evaporated under reduced pressure. EtOAc m. ESI-MS m/z: 211.2 [M+H] + .
步骤2：6-氯-4-乙氨基烟酸乙酯的制备Step 2: Preparation of ethyl 6-chloro-4-ethylaminonicotinate
Figure PCTCN2018085940-appb-000028
Figure PCTCN2018085940-appb-000028
在单颈瓶中加入4,6-二氯烟酸乙酯(25g，100mmol)、DIPEA(25.8g，200mmol)和乙腈(200mL)，室温下加入乙胺醇溶液(5.4g,120mmol)，70℃搅拌过夜。TLC(EA：PE＝1:2)显示反应完全。减压旋蒸除去溶剂，加水300mL，乙酸乙酯(250×3mL)萃取，有机相经无水硫酸钠干燥、浓缩，得黄色油状物20g，收率90％。ESI-MS m/z：229.2[M+H] +. 4,6-Dichloronicotinate ethyl ester (25 g, 100 mmol), DIPEA (25.8 g, 200 mmol) and acetonitrile (200 mL) were added to a single-necked flask, and ethylamine solution (5.4 g, 120 mmol) was added at room temperature, 70 Stir at °C overnight. TLC (EA: PE = 1:2) showed the reaction was complete. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. ESI-MS m/z: 229.2 [M+H] + .
步骤3：6-氯-4-乙氨基烟醇的制备Step 3: Preparation of 6-chloro-4-ethylaminonicotinol
Figure PCTCN2018085940-appb-000029
Figure PCTCN2018085940-appb-000029
在单颈瓶中加入6-氯-4-乙氨基烟酸乙酯(20g，90mmol)和THF(200mL)，室温下缓慢加入LiAlH 4(8g,200mmol)，室温搅拌3h。TLC(EA：PE＝1:2)显示反应完全。氢氧化钠水溶液(1N，20mL)淬灭，过滤，滤液中加水300mL，乙酸乙酯(250×3mL)萃取，有机相经无水硫酸钠干燥、浓缩，得黄色油状物20g，收率100％。ESI-MS m/z：187.2[M+H] +. Was added 6-chloro-4-ethylamino-nicotinic acid ethyl ester (20g, 90mmol) in a single neck flask and THF (200mL), at room temperature was slowly added LiAlH 4 (8g, 200mmol), at room temperature stirred for 3h. TLC (EA: PE = 1:2) showed the reaction was complete. The aqueous solution of sodium hydroxide (1N, 20 mL) was evaporated, filtered, evaporated, evaporated, evaporated, evaporated. . ESI-MS m/z: 187.2 [M+H] + .
步骤4：6-氯-4-乙氨基烟醛的制备Step 4: Preparation of 6-chloro-4-ethylaminonicotin
Figure PCTCN2018085940-appb-000030
Figure PCTCN2018085940-appb-000030
在单颈瓶中加入6-氯-4-乙氨基烟醇(15g，80mmol)、二氧化锰(104g，1196mmol)和DCM(300mL)，室温搅拌过夜。TLC(EA：PE＝1:2)显示反应完全。过滤，DCM(100×3mL)洗涤，滤液浓缩，得黄色油状物15g，收率100％。ESI-MS m/z:185.2[M+H] +. To a single-necked flask were added 6-chloro-4-ethylaminonicotinol (15 g, 80 mmol), manganese dioxide (104 g, 1196 mmol) and DCM (300 mL). TLC (EA: PE = 1:2) showed the reaction was complete. Filtration, washing with DCM (100×3 mL). ESI-MS m/z: 185.2 [M+H] + .
步骤5：7-氯-3-(3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 5: Preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000031
Figure PCTCN2018085940-appb-000031
在单颈瓶中加入6-氯-4-乙氨基烟醛(10g，54.3mmol)、3,5-二甲氧基苯乙酸甲酯(11.55g， 55mmol)、碳酸钾(13.8g，100mmol)和DMF(30mL)，氩气保护，105℃搅拌3小时。LC-MS显示反应完全。过滤，乙酸乙酯(50×3mL)洗涤，滤液中加水100mL，乙酸乙酯(150×3mL)萃取，有机相经无水硫酸钠干燥、浓缩，得棕色油状物12g，直接用于下一步反应，收率64％。ESI-MS m/z:345.1[M+H] +. Add 6-chloro-4-ethylaminonicotin (10 g, 54.3 mmol), methyl 3,5-dimethoxyphenylacetate (11.55 g, 55 mmol), potassium carbonate (13.8 g, 100 mmol) to a single-neck flask. And DMF (30 mL), argon-protected, stirred at 105 ° C for 3 hours. LC-MS showed the reaction was complete. Filtration, ethyl acetate (50×3 mL), EtOAc (EtOAc) (EtOAc) The yield is 64%. ESI-MS m/z: 345.1 [M+H] + .
步骤6：7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 6: Preparation of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000032
Figure PCTCN2018085940-appb-000032
在单颈瓶中加入7-氯-3-(3,5-二甲氧基苯基)-乙基-1,6-萘啶-2(1H)-酮(10g，28mmol)和乙腈(300mmol)，冰浴下滴加磺酰氯(4.8mL，60mmol)，继续搅拌1小时。LC-MS显示反应完全。过滤，滤饼用乙腈(20×2mL)洗涤，得白色固体10g，直接用于下一步反应，收率84％。ESI-MS m/z:413.1[M+H] +. Add 7-chloro-3-(3,5-dimethoxyphenyl)-ethyl-1,6-naphthyridin-2(1H)-one (10 g, 28 mmol) and acetonitrile (300 mmol) to a single-neck flask. The sulfonyl chloride (4.8 mL, 60 mmol) was added dropwise under ice-cooling and stirring was continued for one hour. LC-MS showed the reaction was complete. Filtration and washing of the cake with acetonitrile (20.times.2 mL) gave 10 g of white solid. ESI-MS m/z: 413.1 [M+H] + .
步骤7：1-(4-溴-2-硝基苯基)-4-甲基哌嗪的制备Step 7: Preparation of 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine
Figure PCTCN2018085940-appb-000033
Figure PCTCN2018085940-appb-000033
在单颈瓶中加入4-氟-1-溴-2-硝基苯(2.2g，10mmol)、甲基哌嗪(1.2g，12mmol)、DIPEA(2.6g，20mmol)和THF(30mmol)，70℃搅拌1h。LC-MS显示反应完全。旋转蒸发浓缩得黄色油状物3g，收率100％。ESI-MS m/z:300.0[M+H] +. 4-Fluoro-1-bromo-2-nitrobenzene (2.2 g, 10 mmol), methylpiperazine (1.2 g, 12 mmol), DIPEA (2.6 g, 20 mmol) and THF (30 mmol) were added to a single flask. Stir at 70 ° C for 1 h. LC-MS showed the reaction was complete. Concentration by rotary evaporation gave 3 g of a yellow oil, yield 100%. ESI-MS m/z: 300.0 [M+H] + .
步骤8：1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪的制备Step 8: 1-Methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Preparation of piperazine
Figure PCTCN2018085940-appb-000034
Figure PCTCN2018085940-appb-000034
在单颈瓶中加入1-(4-溴-2-硝基苯基)-4-甲基哌嗪(3g，10mmol)、联硼酸频哪醇酯(5g，20mmol)、醋酸钾(3g，30mmol)、二(三苯基膦)合氯化钯(0.7g，1mmol)和1,4-二氧六环(30mL)，氩气保护，80℃搅拌过夜。LC-MS显示反应完全。除去溶剂，残留物经硅胶柱层析，得黄色油状物2g。ESI-MS m/z:348.2[M+H] +. Add 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine (3 g, 10 mmol), diboronic acid pinacol ester (5 g, 20 mmol), potassium acetate (3 g, in a single-necked flask). 30 mmol), bis(triphenylphosphine)palladium chloride (0.7 g, 1 mmol) and 1,4-dioxane (30 mL) were argon-protected and stirred at 80 ° C overnight. LC-MS showed the reaction was complete. The solvent was removed and the residue was purifiedjjjjjjjj ESI-MS m/z: 348.2 [M+H] + .
步骤9：3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-7-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1,6-萘啶-2(1H)-酮的制备Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(4-methylpiperazin-1-yl)-3- Preparation of nitrophenyl)-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000035
Figure PCTCN2018085940-appb-000035
将7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(1g，2.4mmol)、1-甲 基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪(0.84g，2.4mmol)、四(三苯基膦)钯(277mg，0.24mmol)、碳酸钠(5g，4.8mmol)、1,4-二氧六环(40mL)和水(10mL)置于圆底烧瓶中，氩气置换出体系中的空气，80℃反应5h，反应完毕后，蒸除其中的1,4-二氧六环,柱层析得黄色固体440mg，产率46％。ESI-MS m/z:598.1[M+H] +. 7-Chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (1 g, 2.4 mmol , 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Piperazine (0.84 g, 2.4 mmol), tetrakis(triphenylphosphine)palladium (277 mg, 0.24 mmol), sodium carbonate (5 g, 4.8 mmol), 1,4-dioxane (40 mL) and water (10 mL) Placed in a round bottom flask, argon gas is used to displace the air in the system, and reacted at 80 ° C for 5 h. After the reaction is completed, the 1,4-dioxane is distilled off, and column chromatography yields 440 mg of a yellow solid. Yield 46 %. ESI-MS m/z: 598.1 [M+H] + .
步骤10：7-(3-氨基-4-(4-甲基哌嗪-1-基)苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 10: 7-(3-Amino-4-(4-methylpiperazin-1-yl)phenyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Preparation of 1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000036
Figure PCTCN2018085940-appb-000036
将3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-7-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1,6-萘啶-2(1H)-酮(440mg，0.6mmol)溶于乙醇(10ml)中，加入氯化铵(168mg，3mmol)、铁粉(200mg，3.6mmol)、H 2O(2ml)后，80℃反应1h。反应完成后，过滤除去不溶物，收集滤液，DCM萃取，饱和NaCl溶液洗涤，干燥DCM层，无水Na 2SO 4干燥，旋蒸，得黄色固体400mg，收率89.5％。ESI-MS m/z:568.1[M+H] +. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(4-methylpiperazin-1-yl)-3-nitro Phenyl)-1,6-naphthyridin-2(1H)-one (440 mg, 0.6 mmol) was dissolved in ethanol (10 ml), ammonium chloride (168 mg, 3 mmol), iron powder (200 mg, 3.6 mmol), After H 2 O (2 ml), it was reacted at 80 ° C for 1 h. After the completion of the reaction, the insoluble material was filtered, and the filtrate was collected, washed with DCM, washed with saturated NaCI solution, dried DCM layer, dried over anhydrous Na 2 SO 4 and evaporated to give a yellow solid 400 mg. ESI-MS m/z: 568.1 [M+H] + .
步骤11：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺的制备Step 11: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000037
Figure PCTCN2018085940-appb-000037
在单颈瓶中加入3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-7-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1,6-萘啶-2(1H)-酮(400mg，0.7mmol)、DIPEA(1mL)和无水THF(20mL)，-10℃下搅拌下加入丙烯酰氯(50μl，0.7mmol)，继续搅拌20min。LC-MS显示反应完全。加入0.1mL水粹灭，二氯甲烷萃取，柱层析得淡黄色固体200mg，收率52.4％。 1H-NMR(500MHz,CDCl 3):δ1.45(s,3H),2.44(s,3H),2.68(m,4H),3.02(t,4H),3.98(s,6H),4.48(q,2H),5.85(d,1H),6.38(d,1H),6.48(d,1H),6.67(s,1H),7.36(d,1H),7.66(s,1H),7.72(s,1H),7.91(dd,1H),8.69(s,1H),8.88(s,1H),9.16(s,1H).ESI-MS m/z:622.1[M+H] +. Add 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(4-methylpiperazin-1-yl) to a single-necked flask 3-Nitrophenyl)-1,6-naphthyridin-2(1H)-one (400 mg, 0.7 mmol), DIPEA (1 mL) and dry THF (20 mL). (50 μl, 0.7 mmol), stirring was continued for 20 min. LC-MS showed the reaction was complete. After adding 0.1 mL of water, it was extracted with dichloromethane, and then purified by column chromatography to give a pale yellow solid (yield: 22.4%). 1 H-NMR (500MHz, CDCl 3): δ1.45 (s, 3H), 2.44 (s, 3H), 2.68 (m, 4H), 3.02 (t, 4H), 3.98 (s, 6H), 4.48 ( q, 2H), 5.85 (d, 1H), 6.38 (d, 1H), 6.48 (d, 1H), 6.67 (s, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.72 (s) , 1H), 7.91 (dd, 1H), 8.69 (s, 1H), 8.88 (s, 1H), 9.16 (s, 1H). ESI-MS m/z: 622.1 [M+H] + .
实施例2：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-异丙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 2: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-isopropyl-2-oxo-1,2-dihydro- Preparation of 1,6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000038
Figure PCTCN2018085940-appb-000038
步骤1：6-氯-4-(异丙基氨基)烟酸乙酯的制备Step 1: Preparation of 6-chloro-4-(isopropylamino)nicotinic acid ethyl ester
Figure PCTCN2018085940-appb-000039
Figure PCTCN2018085940-appb-000039
将4,6-二氯烟酸乙酯(10g,45.45mmol)溶于100mL乙腈中，加入DIPEA(6.2g,47.73mmol)，-5℃下缓慢滴加异丙胺(2.82g,47.73mmol)，70℃搅拌过夜，在反应液中加入大量水，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:243[M+H] + Ethyl 4,6-dichloronicotinate (10 g, 45.45 mmol) was dissolved in 100 mL of acetonitrile, DIPEA (6.2 g, 47.73 mmol) was added, and isopropylamine (2.82 g, 47.73 mmol) was slowly added dropwise at -5 °C. After stirring at 70 ° C overnight, a large amount of water was added to the mixture, ethyl acetate was evaporated, ESI-MS m/z: 243[M+H] +
步骤2：(6-氯-4-(异丙基氨基)吡啶-3-基)甲醇的制备Step 2: Preparation of (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol
Figure PCTCN2018085940-appb-000040
Figure PCTCN2018085940-appb-000040
将6-氯-4-(异丙基氨基)烟酸乙酯(10g,41.32mmol)溶于100ml四氢呋喃中，室温下缓慢加入LiAlH 4(3.14g,82.64mmol)，室温搅拌3h，用氢氧化钠水溶液(1N，16mL)淬灭反应，过滤，滤液用乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:201[M+H] +. 6-Chloro-4-(isopropylamino)nicotinic acid ethyl ester (10 g, 41.32 mmol) was dissolved in 100 ml of tetrahydrofuran, and LiAlH 4 (3.14 g, 82.64 mmol) was slowly added at room temperature, stirred at room temperature for 3 h, with hydr The reaction was quenched with EtOAc (EtOAc)EtOAc. ESI-MS m/z: 201 [M+H] + .
步骤3：6-氯-4-(异丙基氨基)烟醛的制备Step 3: Preparation of 6-chloro-4-(isopropylamino) nicotinaldehyde
Figure PCTCN2018085940-appb-000041
Figure PCTCN2018085940-appb-000041
将(6-氯-4-(异丙基氨基)吡啶-3-基)甲醇(8g,40mmol)溶于20mL二氯甲烷中，室温下缓慢加入二氧化锰(34.78g,400mmol)，室温搅拌过夜，过滤，旋干得标题化合物。ESI-MS m/z:199[M+H] + (6-Chloro-4-(isopropylamino)pyridin-3-yl)methanol (8 g, 40 mmol) was dissolved in dichloromethane (20 mL), and then, then,,,,,,,,,,,,,,,,,,, Over the night, filter and spin dry to give the title compound. ESI-MS m/z: 199[M+H] +
步骤4：7-氯-3-(3,5-二甲氧基苯基)-1-异丙基-1,6-萘啶-2(1H)-酮的制备Step 4: Preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000042
Figure PCTCN2018085940-appb-000042
将6-氯-4-(异丙基氨基)烟醛(2g,10.1mmol)，2-(3,5-二甲氧基苯基)乙酸甲酯(4.24g,20.2mmol)和碳酸钾(4.18g,30.3mmol)溶于10mL DMF中，氩气保护，110℃下反应7h，将反应液用饱和氯化钠溶液稀释，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:359[M+H] + 6-Chloro-4-(isopropylamino)nicaldaldehyde (2 g, 10.1 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.24 g, 20.2 mmol) and potassium carbonate ( 4.18g, 30.3mmol) was dissolved in 10 mL of DMF, EtOAc (EtOAc) EtOAc. ESI-MS m/z: 359[M+H] +
步骤5：7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-异丙基-1,6-萘啶-2(1H)-酮的制备Step 5: Preparation of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000043
Figure PCTCN2018085940-appb-000043
7-氯-3-(3,5-二甲氧基苯基)-1-异丙基-1,6-萘啶-2(1H)-酮(358mg,1mmol)溶于10mLTHF中，冰浴下滴加磺酰氯(400ul)，室温搅拌30min，将反应液用饱和碳酸氢钠溶液淬灭，乙 酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:427[M+H] + 7-Chloro-3-(3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (358 mg, 1 mmol) dissolved in 10 mL THF, ice bath The sulfonyl chloride (400 ul) was added dropwise, and the title compound was obtained. ESI-MS m/z: 427[M+H] +
步骤6：1-(4-溴-5-甲氧基-2-硝基苯基)-4-乙基哌嗪的制备Step 6: Preparation of 1-(4-bromo-5-methoxy-2-nitrophenyl)-4-ethylpiperazine
Figure PCTCN2018085940-appb-000044
Figure PCTCN2018085940-appb-000044
将1-溴-4-氟-2-甲氧基-5-硝基苯(1.3g)溶于10mL 1-乙基哌嗪中，70℃下搅拌2h，将反应液加水稀释，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:344[M+H] +. 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (1.3 g) was dissolved in 10 mL of 1-ethylpiperazine, stirred at 70 ° C for 2 h, and the reaction solution was diluted with water, ethyl acetate Extract, dry and spin dry to give the title compound. ESI-MS m/z: 344 [M+H] + .
步骤7：1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪的制备Step 7: 1-Ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of alk-2-yl)phenyl)piperazine
Figure PCTCN2018085940-appb-000045
Figure PCTCN2018085940-appb-000045
将1-(4-溴-5-甲氧基-2-硝基苯基)-4-乙基哌嗪(1g,2.92mmol)、联硼酸频那醇酯(0.811g,3.21mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.214g,0.292mmol)和醋酸钾(0.858g,8.76mmol)依次加入10mL1,4-二氧六环中，氩气保护，95℃反应2h，将反应液过滤，滤液用饱和NaCl溶液洗涤，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:391[M+H] +. 1-(4-Bromo-5-methoxy-2-nitrophenyl)-4-ethylpiperazine (1 g, 2.92 mmol), boranoic acid pinacol ester (0.811 g, 3.21 mmol), [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.214 g, 0.292 mmol) and potassium acetate (0.858 g, 8.76 mmol) were sequentially added to 10 mL of 1,4-dioxane. The reaction was argon-protected, and the reaction mixture was filtered, and then filtered. ESI-MS m/z: 391 [M+H] + .
步骤8：3-(2,6-二氯-3,5-二甲氧基苯基)-7-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-硝基苯基)-1-异丙基-1,6-萘啶-2(1H)-酮的制备Step 8: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(4-ethylpiperazin-1-yl)-2-methoxy-5 Of -nitrophenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000046
Figure PCTCN2018085940-appb-000046
将1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪(700mg)，7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-异丙基-1,6-萘啶-2(1H)-酮(300mg)，二(三苯基膦)二氯化钯(25mg)，碳酸钾(290mg)依次加入15mL1,4-二氧六环和8mL水中，氩气保护，回流反应2h，将反应液过滤，滤液用饱和NaCl溶液洗涤，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:656[M+H] + 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)phenyl)piperazine (700 mg), 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-isopropyl-1,6-naphthyridine -2(1H)-one (300mg), bis(triphenylphosphine)palladium dichloride (25mg), potassium carbonate (290mg) was added to 15mL of 1,4-dioxane and 8mL of water, argon gas protection, reflux After the reaction was carried out for 2 h, the title compound was evaporated. ESI-MS m/z: 656[M+H] +
步骤9：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-异丙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 9: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-isopropyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000047
Figure PCTCN2018085940-appb-000047
制备方法类似于实施例1步骤10、11。 1H-NMR(400MHz,CDCl 3):δ1.23(t,3H),1.71(d,6H),2.63(q,2H),2.78(s,4H),3.08-3.14(m,5H),3.91(s,3H),3.98(s,6H),5.79(d,1H),6.28-6.34(m,1H),6.43(d,1H),6.66(s,1H),6.91(s,1H),7.65(s,1H),8.08(s,1H),8.28(s,1H),8.86(s,1H),8.96(s,1H).ESI-MSm/z:680.3[M+H] + . The preparation method is similar to the steps 10 and 11 of Example 1. 1 H-NMR (400MHz, CDCl 3): δ1.23 (t, 3H), 1.71 (d, 6H), 2.63 (q, 2H), 2.78 (s, 4H), 3.08-3.14 (m, 5H), 3.91(s,3H), 3.98(s,6H), 5.79(d,1H), 6.28-6.34(m,1H),6.43(d,1H),6.66(s,1H),6.91(s,1H) , 7.65 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.86 (s, 1H), 8.96 (s, 1H). ESI-MS m/z: 680.3 [M+H] + .
实施例3：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(-4-乙基哌嗪-1-基)-6-甲氧基吡啶-3-基)丙烯酰胺的制备Example 3: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(-4-ethylpiperazin-1-yl)-6-methoxypyridin-3-yl)acrylamide
Figure PCTCN2018085940-appb-000048
Figure PCTCN2018085940-appb-000048
步骤1：5-溴-6-甲氧基-3-硝基吡啶-2-胺的制备Step 1: Preparation of 5-bromo-6-methoxy-3-nitropyridin-2-amine
Figure PCTCN2018085940-appb-000049
Figure PCTCN2018085940-appb-000049
将6-甲氧基-3-硝基吡啶-2-胺(7.8g,46mmol)溶于150mL DMF,加入N-溴代丁二酰亚胺(NBS)(9g,51mmol),室温搅拌1小时，加入饱和NaCl溶液，乙酸乙酯萃取干燥柱层析得标题化合物。ESI-MS m/z:248.0[M+H] +. 6-Methoxy-3-nitropyridin-2-amine (7.8 g, 46 mmol) was dissolved in 150 mL of DMF and N-bromosuccinimide (NBS) (9 g, 51 mmol) was added and stirred at room temperature for 1 hour. The title compound was obtained by the addition of aq. ESI-MS m/z: 248.0 [M+H] + .
步骤2：3-溴-6-氟-2-甲氧基-5-硝基吡啶的制备Step 2: Preparation of 3-bromo-6-fluoro-2-methoxy-5-nitropyridine
Figure PCTCN2018085940-appb-000050
Figure PCTCN2018085940-appb-000050
将5-溴-6-甲氧基-3-硝基吡啶-2-胺(1.85g,7.5mmol)溶于30mL氟化氢的吡啶溶液，降温至-78℃，分批加入亚硝酸钠(570mg,8.25mmol)，搅拌30min后升至0℃搅拌30min，然后升至60℃搅拌30min，冰水淬灭，1N氢氧化钠水溶液中和，乙酸乙酯萃取干燥旋干得标题化合物。ESI-MS m/z：250.9[M+H] +. 5-Bromo-6-methoxy-3-nitropyridin-2-amine (1.85 g, 7.5 mmol) was dissolved in 30 mL of a solution of hydrogen fluoride in pyridine, cooled to -78 ° C, and sodium nitrite (570 mg, 8.25 mmol), stirred for 30 min, then stirred at 0<0>C for 30 min, then EtOAc (EtOAc) ESI-MS m/z: 250.9 [M+H] + .
步骤3：1-(5-溴-6-甲氧基-3-硝基吡啶-2-基)-4-乙基哌嗪的制备Step 3: Preparation of 1-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-4-ethylpiperazine
Figure PCTCN2018085940-appb-000051
Figure PCTCN2018085940-appb-000051
将3-溴-6-氟-2-甲氧基-5-硝基吡啶(1.6g)溶于5mL N-乙基哌嗪，90℃加热搅拌1小时，加入饱和NaCl溶液，乙酸乙酯萃取，干燥旋干即得标题化合物。ESI-MS m/z：345.1[M+H] +. Dissolve 3-bromo-6-fluoro-2-methoxy-5-nitropyridine (1.6 g) in 5 mL of N-ethylpiperazine, stir at 90 °C for 1 hour, add saturated NaCl solution, and extract with ethyl acetate. Dry and spin dry to give the title compound. ESI-MS m/z: 345.1 [M+H] + .
步骤4：1-乙基-4-(6-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)哌嗪的制备Step 4: 1-Ethyl-4-(6-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of alk-2-yl)pyridin-2-yl)piperazine
Figure PCTCN2018085940-appb-000052
Figure PCTCN2018085940-appb-000052
将1-(5-溴-6-甲氧基-3-硝基吡啶-2-基)-4-乙基哌嗪(1.3g)溶于20mL 1,4-二氧六环，加入联硼酸频那醇酯(1.9g)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.25g)和醋酸钾(1.11g)，氮气保护，100℃加热搅拌3小时，过滤，旋干，乙酸乙酯溶解，饱和NaCl溶液洗涤，旋干，石油醚洗涤，旋干即得标题化合物。ESI-MS m/z:393.3[M+H] +. 1-(5-Bromo-6-methoxy-3-nitropyridin-2-yl)-4-ethylpiperazine (1.3 g) was dissolved in 20 mL of 1,4-dioxane, and diboronic acid was added. Finacol ester (1.9g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.25g) and potassium acetate (1.11g), protected by nitrogen, heated and stirred at 100 °C After 3 hours, it was filtered, dried, evaporated, evaporated, evaporated ESI-MS m/z: 393.3 [M+H] + .
步骤5：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(-4-乙基哌嗪-1-基)-6-甲氧基吡啶-3-基)丙烯酰胺的制备Step 5: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(-4-ethylpiperazin-1-yl)-6-methoxypyridin-3-yl)acrylamide
Figure PCTCN2018085940-appb-000053
Figure PCTCN2018085940-appb-000053
制备方法类似于实施例1步骤9、10、11，不同的是将步骤9中的原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为上述步骤4所得物1-乙基-4-(6-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)哌嗪。 1H-NMR(400MHz,DMSO-d6):δ1.04(t，3H)，1.32(t，3H),2.34(q，2H)，2.46-2.61(m，4H),3.37-3.46(m,4H),3.94(s，6H),4.00(s，3H),4.29(q，2H)，5.77(d，1H),6.25(d，1H)，6.44-6.52(m，1H),7.02(s,1H),8.01(s，1H)，8.18(s，1H),8.50(s，1H)，8.95(s，1H),9.56(s，1H).ESI-MS m/z:667.4[M+H] +. The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material in the step 9 is 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above-mentioned step 4, 1-ethyl-4-(6-methoxy-3-nitro- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine. 1 H-NMR (400MHz, DMSO -d6): δ1.04 (t, 3H), 1.32 (t, 3H), 2.34 (q, 2H), 2.46-2.61 (m, 4H), 3.37-3.46 (m, 4H), 3.94(s,6H), 4.00(s,3H), 4.29(q,2H), 5.77(d,1H),6.25(d,1H),6.44-6.52(m,1H),7.02(s , 1H), 8.01 (s, 1H), 8.18 (s, 1H), 8.50 (s, 1H), 8.95 (s, 1H), 9.56 (s, 1H). ESI-MS m/z: 667.4 [M+ H] + .
实施例4：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-乙基哌嗪-1-基)苯基)丙烯酰胺的制备Example 4: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000054
Figure PCTCN2018085940-appb-000054
制备方法类似实施例1，不同的是将步骤7中的原料甲基哌嗪替换为1-乙基哌嗪。 1H-NMR(400MHZ.CDCl 3):δ1.19(t,3H),1.47(t,3H),2.55(q,2H),2.62-2.80(m,4H),3.03(t,4H),3.98(s,6H),4.47(q,2H),5.84(d,1H),6.32-6.38(m,1H),6.45(d,1H),6.67(s,1H),7.35(d,1H),7.66(s,1H),7.71(s,1H),7.90(d,1H),8.71(s,1H),8.88(s,1H),9.16(s,1H).ESI-MSm/z:636.2[M+H] + The preparation method was similar to that of Example 1, except that the starting material methylpiperazine in Step 7 was replaced with 1-ethylpiperazine. 1 H-NMR (400MHZ.CDCl 3 ): δ 1.19 (t, 3H), 1.47 (t, 3H), 2.55 (q, 2H), 2.62-2.80 (m, 4H), 3.03 (t, 4H), 3.98(s,6H),4.47(q,2H),5.84(d,1H),6.32-6.38(m,1H),6.45(d,1H),6.67(s,1H),7.35(d,1H) , 7.66(s,1H), 7.71(s,1H), 7.90(d,1H),8.71(s,1H),8.88(s,1H),9.16(s,1H).ESI-MSm/z:636.2 [M+H] +
实施例5：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7- 基)-2-(-4-乙基-3,5-二甲基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 5: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-2-(4-ethyl-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000055
Figure PCTCN2018085940-appb-000055
步骤1：(3S,5R)-1-(4-溴-5-甲氧基-2-硝基苯基)-3,5-二甲基哌嗪的制备Step 1: Preparation of (3S,5R)-1-(4-bromo-5-methoxy-2-nitrophenyl)-3,5-dimethylpiperazine
Figure PCTCN2018085940-appb-000056
Figure PCTCN2018085940-appb-000056
以实施例1步骤7的方法，以1-溴-4-氟-2-甲氧基-5-硝基苯和顺-2,6-二甲基哌嗪为原料，合成标题化合物。ESI-MS m/z:344.0[M+H] +. The title compound was synthesized by the procedure of Step 7 of Example 1 using 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene and cis-2,6-dimethylpiperazine as starting materials. ESI-MS m/z: 344.0 [M+H] + .
步骤2：(3R,5S)-1-(4-溴-5-甲氧基-2-硝基苯基)-3,5-二甲基哌嗪的制备Step 2: Preparation of (3R,5S)-1-(4-bromo-5-methoxy-2-nitrophenyl)-3,5-dimethylpiperazine
Figure PCTCN2018085940-appb-000057
Figure PCTCN2018085940-appb-000057
将1-溴-4-氟-2-甲氧基-5-硝基苯(1g)溶于10mL N-甲基吡咯烷酮，加入顺-2,6-二甲基哌嗪(1.38g)，100℃加热搅拌2小时，将反应液倒入100mL饱和食盐水中,乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，干燥旋干得1.3g标题化合物。ESI-MS m/z:344.0[M+H] +. 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (1 g) was dissolved in 10 mL of N-methylpyrrolidone, and cis-2,6-dimethylpiperazine (1.38 g) was added, 100 The mixture was heated and stirred for 2 hours, and the reaction mixture was poured into 100 mL of brine, and ethyl acetate was evaporated. ESI-MS m/z: 344.0 [M+H] + .
步骤3：(2S,6R)-4-(4-溴-5-甲氧基-2-硝基苯基)-1-乙基-2,6-二甲基哌嗪的制备Step 3: Preparation of (2S,6R)-4-(4-bromo-5-methoxy-2-nitrophenyl)-1-ethyl-2,6-dimethylpiperazine
Figure PCTCN2018085940-appb-000058
Figure PCTCN2018085940-appb-000058
在100mL单颈瓶中加入(3S,5R)-1-(4-溴-5-甲氧基-2-硝基苯基)-3,5-二甲基哌嗪(1g，3mmol)、碘乙烷(1g，6mmol)、碳酸钾(1.2g，9mmol)和DMF(10mL)。氩气保护，室温搅拌3h。LC-MS显示反应完全。DCM萃取，饱和NaCl溶液洗涤，干燥DCM层，无水Na 2SO 4干燥，旋蒸，得黄色油状物800mg，收率89.5％。ESI-MS m/z:372.0[M+H] +. Add (3S,5R)-1-(4-bromo-5-methoxy-2-nitrophenyl)-3,5-dimethylpiperazine (1 g, 3 mmol), iodine to a 100 mL single-necked flask Ethane (1 g, 6 mmol), potassium carbonate (1.2 g, 9 mmol) and DMF (10 mL). Argon protection, stirring at room temperature for 3 h. LC-MS showed the reaction was complete. Extracted with DCM, washed with saturated NaCl solution, dried DCM layer was dried over anhydrous Na 2 SO 4, and rotary evaporated to give a yellow oil 800mg, yield 89.5%. ESI-MS m/z: 372.0 [M+H] + .
步骤4：(2S,6R)-1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-2,6-二甲基哌嗪的制备Step 4: (2S,6R)-1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-di Preparation of oxaborolan-2-yl)phenyl)-2,6-dimethylpiperazine
Figure PCTCN2018085940-appb-000059
Figure PCTCN2018085940-appb-000059
制备方法同实施例1步骤8，不同的是将原料1-(4-溴-2-硝基苯基)-4-甲基哌嗪替换成 上述步骤3所得物(2S,6R)-4-(4-溴-5-甲氧基-2-硝基苯基)-1-乙基-2,6-二甲基哌嗪，合成标题化合物。ESI-MS m/z:350.2[M+H] +. The preparation method is the same as that in the first step of the first embodiment except that the starting material 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine is replaced by the above step 3 (2S, 6R)-4- (4-Bromo-5-methoxy-2-nitrophenyl)-1-ethyl-2,6-dimethylpiperazine, the title compound was synthesized. ESI-MS m/z: 350.2 [M+H] + .
步骤5：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(-4-乙基-3,5-二甲基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 5: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-ethyl-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000060
Figure PCTCN2018085940-appb-000060
制备方法类似实施例1步骤9、10、11，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为上述步骤4所得物(2S,6R)-1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-2,6-二甲基哌嗪。 1H-NMR(500MHz,DMSO-d 6):δ1.03(t,3H),1.19(d,6H),1.44(t,3H),2.70(m,2H),2.87-2.94(m,4H),3.03(dd,2H),3.90(s,3H),3.98(s,6H),4.42(q,2H),5.79(d,1H),6.38(d,1H),6.44(d,1H),6.67(s,1H),6.86(s,1H),7.71(s,1H),7.84(s,1H),8.33(s,1H),8.89(s,1H),8.96(s,1H).ESI-MS m/z:694.2[M+H] +. The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)phenyl)piperazine was replaced by the above step 4 (2S,6R)-1-ethyl-4-(5-methoxy-2-nitro 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylpiperazine. 1 H-NMR (500MHz, DMSO-d 6 ): δ 1.03 (t, 3H), 1.19 (d, 6H), 1.44 (t, 3H), 2.70 (m, 2H), 2.87-2.94 (m, 4H) ), 3.03 (dd, 2H), 3.90 (s, 3H), 3.98 (s, 6H), 4.42 (q, 2H), 5.79 (d, 1H), 6.38 (d, 1H), 6.44 (d, 1H) , 6.67 (s, 1H), 6.86 (s, 1H), 7.71 (s, 1H), 7.84 (s, 1H), 8.33 (s, 1H), 8.89 (s, 1H), 8.96 (s, 1H). ESI-MS m/z: 694.2 [M+H] + .
实施例6：N-(2-(4-乙酰基哌嗪-1-基)-5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-4-甲氧基苯基)丙烯酰胺的制备Example 6: N-(2-(4-Acetylpiperazin-1-yl)-5-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-B Preparation of keto-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000061
Figure PCTCN2018085940-appb-000061
步骤1:1-(4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪-1-基)乙酮的制备Step 1: 1-(4-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Of -phenyl)piperazin-1-yl)ethanone
Figure PCTCN2018085940-appb-000062
Figure PCTCN2018085940-appb-000062
制备方法类似于实施例2步骤6、7，将步骤6中的1-乙基哌嗪替换为1-乙酰基哌嗪。The preparation was similar to the procedure of steps 2 and 7 of Example 2, replacing 1-ethylpiperazine in step 6 with 1-acetylpiperazine.
步骤2：N-(2-(4-乙酰基哌嗪-1-基)-5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-4-甲氧基苯基)丙烯酰胺的制备Step 2: N-(2-(4-Acetylpiperazin-1-yl)-5-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl Preparation of -2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000063
Figure PCTCN2018085940-appb-000063
制备方法类似于实施例1步骤9、10、11，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为上述步骤1所得物1-(4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪-1-基)乙酮。 1H-NMR(500MHz,DMSO-d 6):δ1.30(t,3H),2.07(s,3H),2.95(m,4H),3.67(t,4H),3.96(s,9H),4.31(dd,2H),5.76(d,1H),6.26(d,1H),6.68(m,1H),6.91(s,1H,ArH),7.02(s,1H),8.02(s,1H),8.04(s,1H),8.45(s,1H),8.98(s,1H),9.22(s,1H).ESI-MS m/z:680.2[M+H] +. The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above 1-step product 1-(4-(5-methoxy-2-nitro-4-(4,4) , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethanone. 1 H-NMR (500MHz, DMSO -d 6): δ1.30 (t, 3H), 2.07 (s, 3H), 2.95 (m, 4H), 3.67 (t, 4H), 3.96 (s, 9H), 4.31 (dd, 2H), 5.76 (d, 1H), 6.26 (d, 1H), 6.68 (m, 1H), 6.91 (s, 1H, ArH), 7.02 (s, 1H), 8.02 (s, 1H) , 8.04 (s, 1H), 8.45 (s, 1H), 8.98 (s, 1H), 9.22 (s, 1H). ESI-MS m/z: 680.2 [M+H] + .
实施例7：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(3-氟吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 7: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(3-fluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000064
Figure PCTCN2018085940-appb-000064
步骤1：3-氟-1-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)吡咯烷的制备Step 1: 3-Fluoro-1-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)phenyl)pyrrolidine
Figure PCTCN2018085940-appb-000065
Figure PCTCN2018085940-appb-000065
制备方法类似于实施例2步骤6、7，不同的是将步骤6中的1-乙基哌嗪替换为3-氟吡咯烷。ESI-MSm/z:366[M+H] + The preparation method was similar to that of Example 2, Steps 6, 7 except that the 1-ethylpiperazine in Step 6 was replaced with 3-fluoropyrrolidine. ESI-MSm/z: 366[M+H] +
步骤2：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(3-氟吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 2: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(3-fluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000066
Figure PCTCN2018085940-appb-000066
制备方法类似于实施例1步骤9、10、11，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为上述步骤1所得物3-氟-1-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)吡咯烷。 1H-NMR(400MHz,CDCl 3):δ1.42(t,3H),2.26-2.31(m,2H),3.23-3.35(m,1H),3.48-3.55(m,4H),3.91(s,3H),3.95(s,6H), 4.40(q,2H),5.74(d,1H),6.28(d,1H),6.38-6.43(m,1H),6.61(s,1H),6.64(s,1H),7.63(s,1H),7.66(s,1H),7.87(s,1H),8.40(s,1H),8.83(s,1H).ESI-MSm/z:641.2[M+H] + The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the above-mentioned step 1, 3-fluoro-1-(5-methoxy-2-nitro-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine. 1 H-NMR (400MHz, CDCl 3 ): δ 1.42 (t, 3H), 2.26-2.31 (m, 2H), 3.23-3.35 (m, 1H), 3.48-3.55 (m, 4H), 3.91 (s) , 3H), 3.95 (s, 6H), 4.40 (q, 2H), 5.74 (d, 1H), 6.28 (d, 1H), 6.38-6.43 (m, 1H), 6.61 (s, 1H), 6.64 ( s, 1H), 7.63 (s, 1H), 7.66 (s, 1H), 7.87 (s, 1H), 8.40 (s, 1H), 8.83 (s, 1H). ESI-MS m/z: 641.2 [M+ H] +
实施例8：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 8: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000067
Figure PCTCN2018085940-appb-000067
制备方法类似于实施例1步骤9、10、11，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为实施例2步骤7所得物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪。 1H-NMR(400MHz,DMSO-d 6):δ9.13(s,1H),8.97(s,1H),8.35(s,1H),8.04-8.02(m,2H),7.02(s,1H),6.88(s,1H),6.66-6.60(m,1H),6.23(d,1H),5.74(d,1H),4.32-4.31(m,2H),3.98(s,6H),3.94(s,3H),2.99(m,4H),2.61(m,4H),2.44-2.42(m,2H),1.30(t,3H),1.05(t,3H).ESI-MSm/z:666.2[M+H] + The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the product of Step 2 of Example 2, 1-ethyl-4-(5-methoxy-2-nitro-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. 1 H-NMR (400MHz, DMSO -d 6): δ9.13 (s, 1H), 8.97 (s, 1H), 8.35 (s, 1H), 8.04-8.02 (m, 2H), 7.02 (s, 1H ), 6.88 (s, 1H), 6.66-6.60 (m, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 4.32-4.31 (m, 2H), 3.98 (s, 6H), 3.94 ( s, 3H), 2.99 (m, 4H), 2.61 (m, 4H), 2.44-2.42 (m, 2H), 1.30 (t, 3H), 1.05 (t, 3H). ESI-MS m/z: 666.2 [ M+H] +
实施例9：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸-2-基)苯基)丙烯酰胺的制备Example 9: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]indol-2-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000068
Figure PCTCN2018085940-appb-000068
步骤1：2-(4-溴-5-甲氧基-2-硝基苯基)-8-氧杂-2-氮杂螺[4.5]癸烷的制备Step 1: Preparation of 2-(4-bromo-5-methoxy-2-nitrophenyl)-8-oxa-2-azaspiro[4.5]decane
Figure PCTCN2018085940-appb-000069
Figure PCTCN2018085940-appb-000069
将8-氧杂-2-氮杂螺[4.5](1.07g)以及1-溴-4-氟-2-甲氧基-5-硝基苯(1mg)溶于14mLN,N-二甲基甲酰胺中，加入碳酸钾(2.78g)，100℃搅拌2.5h，LCMS检测反应完成后，加入大量水洗去N,N-二甲基甲酰胺，乙酸乙酯萃取，分液、干燥、旋干乙酸乙酯层，得标题化合物。ESI-MS m/z:371[M+H] + 8-oxa-2-azaspiro[4.5] (1.07 g) and 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene (1 mg) were dissolved in 14 mL of N,N-dimethyl To the formamide, potassium carbonate (2.78g) was added and stirred at 100 ° C for 2.5 h. After the LCMS reaction was completed, a large amount of water was added to remove N,N-dimethylformamide, and ethyl acetate was extracted, and the mixture was separated, dried and dried. The ethyl acetate layer gave the title compound. ESI-MS m/z: 371[M+H] +
步骤2：2-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-8-氧杂-2-氮杂螺[4.5]癸烷的制备Step 2: 2-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of phenyl)-8-oxa-2-azaspiro[4.5]decane
Figure PCTCN2018085940-appb-000070
Figure PCTCN2018085940-appb-000070
将步骤1制得的2-(4-溴-5-甲氧基-2-硝基苯基)-8-氧杂-2-氮杂螺[4.5]癸烷(1.38g)、联硼酸频那醇酯(2.37g)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(273.6mg)和醋酸钾(1.10g)依次加入15mL1,4-二氧六环中，氩气环境下90℃反应12h，将反应液过滤，滤液用饱和氯化钠溶液洗涤，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:418[M+H] + 2-(4-Bromo-5-methoxy-2-nitrophenyl)-8-oxa-2-azaspiro[4.5]decane (1.38 g) obtained in Step 1, boronic acid frequency That alcohol ester (2.37g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (273.6mg) and potassium acetate (1.10g) were sequentially added to 15mL of 1,4-dioxane. The mixture was reacted at 90 ° C for 12 h under argon. The reaction mixture was filtered. ESI-MS m/z: 418[M+H] +
步骤3：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸-2-基)苯基)丙烯酰胺的制备Step 3: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]indol-2-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000071
Figure PCTCN2018085940-appb-000071
制备方法类似于实施例1步骤9、10、11，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为上述步骤3所得物2-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-8-氧杂-2-氮杂螺[4.5]癸烷。 1H-NMR(400MHz,DMSO-d 6):δ1.31(t,3H),1.48-1.61(m,4H),1.81(t,2H,),3.29(s,2H),3.44(t,2H),3.52-3.69(m,4H),3.98(s,9H),4.29(q,2H),5.71(d,1H),6.23(d,1H),6.43-6.48(m,2H),7.01(s,1H),7.85(s,1H),7.96(s,1H),8.07(s,1H),8.89(s,1H),9.50(s,1H).ESI-MS m/z：693.2[M+H] +. The preparation method is similar to the steps 9, 10 and 11 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the above 2-step product 2-(5-methoxy-2-nitro-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-oxa-2-azaspiro[4.5]decane. 1 H-NMR (400MHz, DMSO -d 6): δ1.31 (t, 3H), 1.48-1.61 (m, 4H), 1.81 (t, 2H,), 3.29 (s, 2H), 3.44 (t, 2H), 3.52-3.69 (m, 4H), 3.98 (s, 9H), 4.29 (q, 2H), 5.71 (d, 1H), 6.23 (d, 1H), 6.43-6.48 (m, 2H), 7.01 (s, 1H), 7.85 (s, 1H), 7.96 (s, 1H), 8.07 (s, 1H), 8.89 (s, 1H), 9.50 (s, 1H). ESI-MS m/z: 693.2 [ M+H] + .
实施例10：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-4-甲氧基苯基)丙烯酰胺的制备Example 10: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-Naphthyridin-7-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000072
Figure PCTCN2018085940-appb-000072
步骤1：7-(4-溴-5-甲氧基-2-硝基苯基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯的制备Step 1: Preparation of 7-(4-bromo-5-methoxy-2-nitrophenyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid tert-butyl ester
Figure PCTCN2018085940-appb-000073
Figure PCTCN2018085940-appb-000073
将1-溴-4-氟-2-甲氧基-5-硝基苯(700mg)溶于8mLN-甲基吡咯烷酮，加入2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(765mg)，100℃加热搅拌2小时，将反应液倒入100mL饱和食盐水 中，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，干燥旋干得1.1g标题化合物。ESI-MS m/z:456.1[M+H] + 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (700 mg) was dissolved in 8 mL of N-methylpyrrolidone and 2,7-diazaspiro[4.4]nonane-2-carboxylic acid was added. The tert-butyl ester (765 mg) was stirred and heated at 100 ° C for 2 hours. The reaction mixture was poured into 100 mL of EtOAc. ESI-MS m/z: 456.1 [M+H] +
步骤2：(4-溴-5-甲氧基-2-硝基苯基)-2,7-二氮杂螺[4.4]壬烷的制备Step 2: Preparation of (4-bromo-5-methoxy-2-nitrophenyl)-2,7-diazaspiro[4.4]decane
Figure PCTCN2018085940-appb-000074
Figure PCTCN2018085940-appb-000074
将7-(4-溴-5-甲氧基-2-硝基苯基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1.1g)溶于20mL二氯甲烷，加入三氟乙酸(11g)，室温搅拌2小时，将反应液用饱和碳酸氢钠水溶液中和，二氯甲烷萃取，合并有机相，干燥旋干得800mg标题化合物。ESI-MS m/z:356.1[M+H] + Dissolve tert-butyl 7-(4-bromo-5-methoxy-2-nitrophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (1.1 g) in 20 mL Dichloromethane, trifluoroacetic acid (11 g) was added, and the mixture was stirred at room temperature for 2 hr. ESI-MS m/z: 356.1 [M+H] +
步骤3：2-(4-溴-5-甲氧基-2-硝基苯基)-7-乙基-2,7-二氮杂螺[4.4]壬烷的制备Step 3: Preparation of 2-(4-bromo-5-methoxy-2-nitrophenyl)-7-ethyl-2,7-diazaspiro[4.4]decane
Figure PCTCN2018085940-appb-000075
Figure PCTCN2018085940-appb-000075
将(4-溴-5-甲氧基-2-硝基苯基)-2,7-二氮杂螺[4.4]壬烷(600mg)溶于10mL无水N,N-二甲基甲酰胺，-10℃搅拌下加入60％NaH(82mg),继续搅拌1小时后滴加碘乙烷(176微升)，30min后加入饱和食盐水淬灭，乙酸乙酯萃取干燥旋干得550mg标题化合物。ESI-MS m/z:(4-Bromo-5-methoxy-2-nitrophenyl)-2,7-diazaspiro[4.4]nonane (600 mg) was dissolved in 10 mL of anhydrous N,N-dimethylformamide After stirring at -10 ° C, 60% NaH (82 mg) was added, and stirring was continued for 1 hour, then ethyl iodide (176 μl) was added dropwise. After 30 min, it was quenched with saturated brine. . ESI-MS m/z:
384.1[M+H] + 384.1[M+H] +
步骤4：2-乙基-7-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-2,7-二氮杂螺[4.4]壬烷的制备Step 4: 2-Ethyl-7-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Preparation of 2-yl)phenyl)-2,7-diazaspiro[4.4]decane
Figure PCTCN2018085940-appb-000076
Figure PCTCN2018085940-appb-000076
将2-(4-溴-5-甲氧基-2-硝基苯基)-7-乙基-2,7-二氮杂螺[4.4]壬烷(500mg)溶于20mL 1,4-二氧六环，加入联硼酸频那醇酯(440mg)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(100mg)和醋酸钾(400mg)，氮气保护，100℃加热搅拌过夜，柱层析得380mg标题化合物。ESI-MS m/z:432.3[M+H] + 2-(4-Bromo-5-methoxy-2-nitrophenyl)-7-ethyl-2,7-diazaspiro[4.4]decane (500 mg) was dissolved in 20 mL of 1,4- Dioxane, addition of pinacol borate (440 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg) and potassium acetate (400 mg), nitrogen protection The mixture was stirred with heating at 100 ° C overnight, and the title compound was obtained. ESI-MS m/z: 432.3 [M+H] +
步骤5：3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-7-(4-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-2-甲氧基-5-硝基苯基)-1,6-萘啶-2(1H)-酮的制备Step 5: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(7-ethyl-2,7-diazaspiro[ Preparation of 4.4]decane-2-yl)-2-methoxy-5-nitrophenyl)-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000077
Figure PCTCN2018085940-appb-000077
将化合物7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(181mg)溶于 10mL 1,4-二氧六环，3mL水，加入上述步骤4所得化合物2-乙基-7-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-2,7-二氮杂螺[4.4]壬烷(380mg)，四三苯基磷钯(102mg)，碳酸钠(140mg)，氮气保护，100℃加热搅拌1小时，过滤，旋干，柱层析得190mg标题化合物。ESI-MS m/z:682.2[M+H] + Dissolve the compound 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (181 mg) In 10 mL of 1,4-dioxane, 3 mL of water, the compound obtained in the above step 4 was added 2-ethyl-7-(5-methoxy-2-nitro-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-diazaspiro[4.4]decane (380 mg), tetrakistriphenylphosphine palladium ( 102 mg), sodium carbonate (140 mg), m.p. ESI-MS m/z: 682.2 [M+H] +
步骤6：7-(5-氨基-4-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-2-甲氧基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 6: 7-(5-Amino-4-(7-ethyl-2,7-diazaspiro[4.4]decan-2-yl)-2-methoxyphenyl)-3-(2 Of 6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000078
Figure PCTCN2018085940-appb-000078
将3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-7-(4-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-2-甲氧基-5-硝基苯基)-1,6-萘啶-2(1H)-酮(190mg)溶于20mL甲醇，加入10％钯碳(30mg)，通氢气，30℃加热搅拌3小时，过滤除去钯碳，旋干得120mg标题化合物。ESI-MS m/z:652.3[M+H] +. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-(7-ethyl-2,7-diazaspiro[4.4] Cycloalkyl-2-yl)-2-methoxy-5-nitrophenyl)-1,6-naphthyridin-2(1H)-one (190 mg) dissolved in 20 mL of methanol, 10% palladium carbon (30 mg) The mixture was stirred with hydrogen at 30 ° C for 3 hours, and the palladium carbon was removed by filtration and dried to give 120 mg of the title compound. ESI-MS m/z: 652.3 [M+H] + .
步骤7：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-4-甲氧基苯基)丙烯酰胺的制备Step 7: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000079
Figure PCTCN2018085940-appb-000079
将7-(5-氨基-4-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-2-甲氧基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(120mg)溶于10mL二氯甲烷,加入二异丙基乙基胺(96mg),-5℃搅拌下滴入丙烯酰氯(22μL)，搅拌30分钟，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机相，干燥旋干制备分离得标题化合物。 1H-NMR(400MHZ,DMSO-d 6):δ1.00(t,3H),1.28(t,3H),1.72-1.88(m,4H),2.35-2.67(m,4H),3.26-3.45(m,4H),3.27(q,2H),3.96-3.97(m,9H),4.27(q,2H),5.72(dd,1H),6.21(dd,1H),6.40-6.48(m,2H),7.01(s,1H),7.84(s,1H),7.97(s,1H),8.07(s,1H),8.89(s,1H),9.51(s,1H).ESI-MS m/z:706.3[M+H] + 7-(5-Amino-4-(7-ethyl-2,7-diazaspiro[4.4]decan-2-yl)-2-methoxyphenyl)-3-(2,6 -Dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (120 mg) was dissolved in 10 mL of dichloromethane and diisopropyl The amide (96 mg) was added dropwise with acryloyl chloride (22 μL), and the mixture was stirred for 30 min. 1 H-NMR (400 MHZ, DMSO-d 6 ): δ 1.00 (t, 3H), 1.28 (t, 3H), 1.72-1.88 (m, 4H), 2.35-2.67 (m, 4H), 3.26-3. (m, 4H), 3.27 (q, 2H), 3.96-3.97 (m, 9H), 4.27 (q, 2H), 5.72 (dd, 1H), 6.21 (dd, 1H), 6.40-6.48 (m, 2H) ), 7.01 (s, 1H), 7.84 (s, 1H), 7.97 (s, 1H), 8.07 (s, 1H), 8.89 (s, 1H), 9.51 (s, 1H). ESI-MS m/z :706.3[M+H] +
实施例11：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-((3R,5S)-3,5-二甲基哌啶-1-基)-4-甲氧基苯基)丙烯酰胺Example 11: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000080
Figure PCTCN2018085940-appb-000080
步骤1：(3R,5S)-1-(4-溴-5-甲氧基-2-硝基苯基)-3,5-二甲基哌嗪的制备Step 1: Preparation of (3R,5S)-1-(4-bromo-5-methoxy-2-nitrophenyl)-3,5-dimethylpiperazine
Figure PCTCN2018085940-appb-000081
Figure PCTCN2018085940-appb-000081
将1-溴-4-氟-2-甲氧基-5-硝基苯(1g)溶于10mL N-甲基吡咯烷酮，加入顺-2,6-二甲基哌嗪(1.38g),100℃加热搅拌2小时，将反应液倒入100mL饱和食盐水中,乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，干燥旋干得1.3g标题化合物。ESI-MS m/z:344.1[M+H] +. 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (1 g) was dissolved in 10 mL of N-methylpyrrolidone, and cis-2,6-dimethylpiperazine (1.38 g) was added, 100 The mixture was heated and stirred for 2 hours, and the reaction mixture was poured into 100 mL of brine, and ethyl acetate was evaporated. ESI-MS m/z: 344.1 [M+H] + .
步骤2：(2R，6S)-4-(4-溴-5-甲氧基-2-硝基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯的制备Step 2: Preparation of (2R,6S)-4-(4-bromo-5-methoxy-2-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2018085940-appb-000082
Figure PCTCN2018085940-appb-000082
将(3R,5S)-1-(4-溴-5-甲氧基-2-硝基苯基)-3,5-二甲基哌嗪(600mg)溶于20mL二氯甲烷，加入1N NaOH(3.5mL)，室温搅拌下加入二碳酸二叔丁酯(420mg)，搅拌过夜，用二氯甲烷萃取,干燥,旋干,柱层析得800mg标题化合物。ESI-MS m/z:444.1[M+H] +. (3R,5S)-1-(4-Bromo-5-methoxy-2-nitrophenyl)-3,5-dimethylpiperazine (600 mg) was dissolved in 20 mL of dichloromethane and 1N NaOH was added. (3.5 mL), di-tert-butyl dicarbonate (420 mg) was added at room temperature, stirred overnight, extracted with dichloromethane. ESI-MS m/z: 444.1 [M+H] + .
步骤3：(2R,6S)-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2,6-二甲基哌啶-1-羧酸叔丁酯的制备Step 3: (2R,6S)-4-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of tert-butyl ester of alk-2-yl)phenyl)-2,6-dimethylpiperidine-1-carboxylate
Figure PCTCN2018085940-appb-000083
Figure PCTCN2018085940-appb-000083
将(2R,6S)-4-(4-溴-5-甲氧基-2-硝基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁酯(750mg)溶于20mL 1,4-二氧六环，加入联硼酸频那醇酯(471mg)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg)，醋酸钾(496mg)，氮气保护，100℃加热搅拌过夜，柱层析得531mg标题化合物。ESI-MS m/z:492.2[M+H] +. (2R,6S)-4-(4-Bromo-5-methoxy-2-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (750 mg) was dissolved in 20 mL 1,4-dioxane, added boranoic acid pinacol ester (471 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg), potassium acetate (496 mg) ), nitrogen-protected, stirred with heating at 100 ° C overnight, and then purified by column chromatography. ESI-MS m/z: 492.2 [M+H] + .
步骤4：(2R,6S)-4-(4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-4-基)-7-基)-5-甲氧基-2-硝基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯的制备Step 4: (2R,6S)-4-(4-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2 -dihydro-1,6-naphthyridin-4-yl)-7-yl)-5-methoxy-2-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylic acid Preparation of butyl ester
Figure PCTCN2018085940-appb-000084
Figure PCTCN2018085940-appb-000084
将化合物7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(531mg)溶于 10mL 1,4-二氧六环和3mL水中，加入上述步骤3所得化合物(2R,6S)-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2,6-二甲基哌啶-1-羧酸叔丁酯(950mg)、四三苯基磷钯(300mg)和碳酸钠(410mg)，氮气保护，100℃加热搅拌1小时，过滤、旋干、柱层析，得500mg标题化合物。ESI-MS m/z:742.2[M+H] +. Dissolve the compound 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (531 mg) The compound (2R,6S)-4-(5-methoxy-2-nitro-4-(4,4,5,5) obtained in the above step 3 was added to 10 mL of 1,4-dioxane and 3 mL of water. -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylpiperidine-1-carboxylic acid tert-butyl ester (950 mg), four or three Phenylphosphorus palladium (300 mg) and sodium carbonate (410 mg) were evaporated under nitrogen, and stirred at 100 ° C for 1 hour. ESI-MS m/z: 742.2 [M+H] + .
步骤5：(2R,6S)-4-(2-氨基-4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-5-甲氧基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯的制备Step 5: (2R,6S)-4-(2-Amino-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo Of tert-butyl-1,2-dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylate
Figure PCTCN2018085940-appb-000085
Figure PCTCN2018085940-appb-000085
将(2R,6S)-4-(4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-4-基)-7-基)-5-甲氧基-2-硝基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯(450mg)溶于20mL甲醇，加入10％钯碳(70mg)，通氢气，30℃加热搅拌3小时，过滤除去钯碳，旋干得340mg标题化合物。ESI-MS m/z:712.2[M+H] +. (2R,6S)-4-(4-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-di Hydrogen-1,6-naphthyridin-4-yl)-7-yl)-5-methoxy-2-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (450 mg) was dissolved in 20 mL of methanol, and 10% palladium carbon (70 mg) was added thereto, and hydrogen gas was added thereto, and the mixture was stirred under heating at 30 ° C for 3 hours, and the palladium carbon was removed by filtration to give 340 mg of the title compound. ESI-MS m/z: 712.2 [M+H] + .
步骤6：(2R,6S)-4-(2-丙烯酰胺基-4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-5-甲氧基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯的制备Step 6: (2R,6S)-4-(2-Acrylamide-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2- Preparation of oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2018085940-appb-000086
Figure PCTCN2018085940-appb-000086
将(2R,6S)-4-(2-氨基-4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-5-甲氧基苯基)-2,6-二甲基哌嗪-1-羧酸叔丁酯(290mg)溶于10mL二氯甲烷，加入二异丙基乙基胺(213mg)，-5℃搅拌下滴入烯丙基酰氯(47微升)，搅拌30分钟，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机相，干燥旋干制备分离得300mg标题化合物。ESI-MS m/z:766.3[M+H] +. (2R,6S)-4-(2-Amino-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (290 mg) dissolved in 10 mL Dichloromethane, diisopropylethylamine (213 mg) was added, and allylic acid chloride (47 μl) was added dropwise with stirring at -5 ° C, stirred for 30 minutes, added with saturated aqueous sodium hydrogencarbonate, and extracted with dichloromethane. The organic phase was dried and dried to give the title compound. ESI-MS m/z: 766.3 [M+H] + .
步骤7：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-((3R,5S)-3,5-二甲基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 7: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000087
Figure PCTCN2018085940-appb-000087
将(2R,6S)-4-(2-丙烯酰胺基-4-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-5-甲氧基苯基)-2,6-二甲基哌嗪-1-甲酸叔丁酯(300mg)溶于20mL二氯甲烷，加入三氟乙酸(1.4g),室温搅拌2小时，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，干燥， 旋干制备得20mg。 1H-NMR(400MHZ,DMSO-d 6):0.97(d,6H),1.28(t,3H),2.25-2.33(m,2H),3.00(d,4H),3.92(s,3H),3.95(s,6H),4.30(q,2H),5.75(d,1H),6.25(d,1H,),6.51-6.59(m,1H),6.8(s,1H),6.98(s,1H),7.99(s,1H),8.02(s,1H),8.27(s,1H),8.96(s,1H),9.12(s,1H).ESI-MS m/z:666.1[M+H] +. (2R,6S)-4-(2-acrylamido-4-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo -1,2-Dihydro-1,6-naphthyridin-7-yl)-5-methoxyphenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (300 mg) was dissolved 20 mL of dichloromethane, trifluoroacetic acid (1.4 g) was added, and the mixture was stirred at room temperature for 2 hr, then aq. 1 H-NMR (400 MHZ, DMSO-d 6 ): 0.97 (d, 6H), 1.28 (t, 3H), 2.25-2.33 (m, 2H), 3.00 (d, 4H), 3.92 (s, 3H), 3.95 (s, 6H), 4.30 (q, 2H), 5.75 (d, 1H), 6.25 (d, 1H,), 6.51-6.59 (m, 1H), 6.8 (s, 1H), 6.98 (s, 1H) ), 7.99 (s, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 8.96 (s, 1H), 9.12 (s, 1H). ESI-MS m/z: 666.1 [M+H] + .
实施例12：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧-1,2-二羟基-1,6-(萘基吡啶-7-烯基)-2(4-乙基哌嗪-1-烯基)-4-甲氧基苯基)-丁基-2-炔酰胺Example 12: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydroxy-1, 6-(naphthylpyridine-7-alkenyl)-2(4-ethylpiperazin-1-enyl)-4-methoxyphenyl)-butyl-2-ynylamide
Figure PCTCN2018085940-appb-000088
Figure PCTCN2018085940-appb-000088
步骤1：7-(5-氨基-4-(4-乙基哌嗪-1-基)-2-甲氧基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶2(1H)-酮的制备Step 1: 7-(5-Amino-4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-3-(2,6-dichloro-3,5-dimethyl Preparation of oxyphenyl)-1-ethyl-1,6-naphthyridine 2(1H)-one
Figure PCTCN2018085940-appb-000089
Figure PCTCN2018085940-appb-000089
制备方法类似于实施例1步骤9、10，不同的是将原料1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪替换为实施2中步骤7所得物。ESI-MS m/z:642.2[M+H] +. The preparation method is similar to the steps 9 and 10 of the embodiment 1, except that the starting material 1-methyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2) - Dioxaborolan-2-yl)phenyl)piperazine was replaced with the product obtained in Step 7 of Example 2. ESI-MS m/z: 642.2 [M+H] + .
步骤2：2-炔基丁酰氯的制备Step 2: Preparation of 2-alkynylbutyryl chloride
Figure PCTCN2018085940-appb-000090
Figure PCTCN2018085940-appb-000090
将2-丁炔酸(100g，1.20mol)加入3000mL三颈瓶中，加入1.98L二氯甲烷，30mL N,N-二甲基甲酰胺，-5℃搅拌10min后滴加草酰氯(151.2g，1.20mol)，继续-5℃搅拌20min后，移至室温反应1.5h后备用。2-butynoic acid (100 g, 1.20 mol) was added to a 3000 mL three-necked flask, 1.98 L of dichloromethane, 30 mL of N,N-dimethylformamide was added, and the mixture was stirred at -5 ° C for 10 min, then oxalyl chloride (151.2 g) was added dropwise. , 1.20 mol), stirring at -5 ° C for 20 min, then moving to room temperature for 1.5 h and then set aside.
步骤3：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)-丁基-2-炔酰胺的制备Step 3: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1, Preparation of 6-naphthyridin-7-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)-butyl-2-ynylamide
Figure PCTCN2018085940-appb-000091
Figure PCTCN2018085940-appb-000091
将步骤1制备的7-(5-氨基-4-(4-乙基哌嗪-1-基)-2-甲氧基苯基)-3-(2,6二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(300mg)溶于N-甲基吡咯烷酮，冰浴下缓慢滴加2-炔基丁酰氯(0.8mL)，搅拌2h，加入饱和碳酸钠溶液淬灭，二氯甲烷萃取，旋干，制备分离。 1H-NMR(400MHz,DMSO-d 6):δ1.05(t,3H)，1.29(t,3H)，2.06(s,3H)，2.39(q,2H)，2.57(t,4H),2.99(t,4H)，3.93(s,3H)，3.98(s,6H)，4.30(q,2H)，6.86(s,1H)，7.02(s,1H)，8.01(s,1H)，8.02(s,1H)，8.12(s,1H)，8.97(s,1H)，9.41(s,1H).ESI-MS m/z：678.3[M+H] +. 7-(5-Amino-4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-3-(2,6-dichloro-3,5-di prepared in Step 1 Methoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (300 mg) was dissolved in N-methylpyrrolidone, and 2-alkynylbutyryl chloride (0.8) was slowly added dropwise in an ice bath. (mL), stirred for 2 h, quenched by the addition of saturated sodium carbonate solution, extracted with dichloromethane, dried and dried. 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.05 (t, 3H), 1.29 (t, 3H), 2.06 (s, 3H), 2.39 (q, 2H), 2.57 (t, 4H), 2.99(t,4H),3.93(s,3H),3.98(s,6H),4.30(q,2H),6.86(s,1H),7.02(s,1H),8.01(s,1H),8.02 (s, 1H), 8.12 (s, 1H), 8.97 (s, 1H), 9.41 (s, 1H). ESI-MS m/z: 678.3 [M+H] + .
实施例13：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)丁-2-炔酰胺的制备Example 13: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)but-2-ynamide preparation
Figure PCTCN2018085940-appb-000092
Figure PCTCN2018085940-appb-000092
制备方法类似于实施例12，不同的是将原料1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪替换成上述实施例9步骤2所得物。 1H-NMR(400MHz,DMSO-d 6):δ1.30(t,3H),1.56(t,4H),1.84(t,2H),2.03(s,3H),3.31(s,2H),3.48(t,2H),3.58-3.68(m,4H),3.95(s,9H),4.30(q,2H),6.36(s,1H,),7.01(s,1H),7.74(s,1H),7.97(s,1H),8.04(s,1H),8.89(s,1H),8.93(s,1H).ESI-MS m/z:705.3[M+H] +. The preparation method was similar to that in Example 12, except that the starting material 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3) The 2-dioxaborolan-2-yl)phenyl)piperazine was replaced with the product obtained in Step 2 of Example 9 above. 1 H-NMR (400MHz, DMSO -d 6): δ1.30 (t, 3H), 1.56 (t, 4H), 1.84 (t, 2H), 2.03 (s, 3H), 3.31 (s, 2H), 3.48 (t, 2H), 3.58-3.68 (m, 4H), 3.95 (s, 9H), 4.30 (q, 2H), 6.36 (s, 1H,), 7.01 (s, 1H), 7.74 (s, 1H) ), 7.97 (s, 1H), 8.04 (s, 1H), 8.89 (s, 1H), 8.93 (s, 1H). ESI-MS m/z: 705.3 [M+H] + .
实施例14：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶[2,3-d]嘧啶-2-基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Example 14: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [ Preparation of 2,3-d]pyrimidin-2-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000093
Figure PCTCN2018085940-appb-000093
步骤1：4-乙氨基-2-(甲硫基)-嘧啶-5-甲酸乙酯的制备Step 1: Preparation of ethyl 4-ethylamino-2-(methylthio)-pyrimidine-5-carboxylate
Figure PCTCN2018085940-appb-000094
Figure PCTCN2018085940-appb-000094
在500ml单颈瓶中加入4-氯-2-(甲硫基)-嘧啶-5-甲酸乙酯(23.2g，100mmol)、乙胺甲醇溶液(30g，200mmol)和四氢呋喃(200mL)。室温搅拌1小时。TLC(PE：EA＝20:1)显示反应完全。减压旋蒸除去溶剂，残留物中加入饱和碳酸氢纳水溶液至PH＝7。乙酸乙酯(200×3ml)萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得黄色油状物25g。收率100％。ESI-MS m/z：242.1[M+H] +. To a 500 ml one-necked flask was added 4-chloro-2-(methylthio)-pyrimidine-5-carboxylic acid ethyl ester (23.2 g, 100 mmol), ethylamine in methanol (30 g, 200 mmol) and tetrahydrofuran (200 mL). Stir at room temperature for 1 hour. TLC (PE: EA = 20:1) showed the reaction was complete. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to pH = 7. Ethyl acetate (200×3 ml) was evaporated and evaporated. The yield is 100%. ESI-MS m/z: 242.1 [M+H] + .
步骤2：4-乙氨基-2-(甲硫基)-嘧啶-5-乙醇的制备Step 2: Preparation of 4-ethylamino-2-(methylthio)-pyrimidine-5-ethanol
Figure PCTCN2018085940-appb-000095
Figure PCTCN2018085940-appb-000095
在500ml单颈瓶中加入4-乙氨基-2-(甲硫基)-嘧啶-5-甲酸乙酯(25g，100mmol)和四氢呋喃(200mL)。室温下缓慢加入LAH(7.6g，200mmol)。室温下继续搅拌1小时。TLC(PE：EA＝2:1)显示反应完全。反应体系中缓慢、依次加入水(7.6g)、15％氢氧化钠水溶液(23g)、水(7.6g)和无水硫酸钠(100g)。室温下搅拌0.5小时后，过滤。滤饼经乙酸乙酯(100×3ml) 洗涤，滤液浓缩得黄色固体14g。收率：75％。ESI-MS m/z：200.1[M+H] +. To a 500 ml one-necked flask was added ethyl 4-ethylamino-2-(methylthio)-pyrimidine-5-carboxylate (25 g, 100 mmol) and tetrahydrofuran (200 mL). LAH (7.6 g, 200 mmol) was slowly added at room temperature. Stirring was continued for 1 hour at room temperature. TLC (PE: EA = 2:1) showed the reaction was complete. In the reaction system, water (7.6 g), 15% aqueous sodium hydroxide solution (23 g), water (7.6 g) and anhydrous sodium sulfate (100 g) were added slowly. After stirring at room temperature for 0.5 hour, it was filtered. The filter cake was washed with ethyl acetate (100×3 mL). Yield: 75%. ESI-MS m/z: 200.1 [M+H] + .
步骤3：4-乙氨基-2-(甲硫基)嘧啶-5-甲醛的制备Step 3: Preparation of 4-ethylamino-2-(methylthio)pyrimidine-5-carboxaldehyde
Figure PCTCN2018085940-appb-000096
Figure PCTCN2018085940-appb-000096
在500ml单颈瓶中加入4-乙氨基-2-(甲硫基)嘧啶-5-乙醇(14g，70mmol)、二氧化锰(33g，375mmol)和二氯甲烷(300mL)。室温搅拌过夜。TLC(PE：EA＝2:1)显示反应完全。过滤，滤饼经二氯甲烷(100×3mL)洗涤，滤液浓缩得黄色固体12.5g。收率：90％。ESI-MS m/z:198.1[M+H] +. To a 500 ml one-necked flask was added 4-ethylamino-2-(methylthio)pyrimidine-5-ethanol (14 g, 70 mmol), manganese dioxide (33 g, 375 mmol) and dichloromethane (300 mL). Stir at room temperature overnight. TLC (PE: EA = 2:1) showed the reaction was complete. Filtration, the filter cake was washed with dichloromethane (100×3 mL). Yield: 90%. ESI-MS m/z: 198.1 [M+H] + .
步骤4：6-(3,5-二甲氧基苯基)-8-乙基-2-(甲硫基)吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 4: Preparation of 6-(3,5-dimethoxyphenyl)-8-ethyl-2-(methylthio)pyridine [2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000097
Figure PCTCN2018085940-appb-000097
在250mL单颈瓶中加入4-乙氨基-2-(甲硫基)嘧啶-5-甲醛(12g，60mmol)、3,5-二甲氧基苯乙酸乙酯(12.6g，60mmol)、碳酸钾(16.5g，120mmol)和DMF(40mL)。加热至110℃反应3小时。TLC(PE：EA＝2:1)显示反应完全。反应体系冷却至室温后，加水500mL，乙酸乙酯(200×3mL)萃取，水(200×3mL)和饱和食盐水(200mL)洗涤。有机相经无水硫酸钠干燥、浓缩得黄色固体16g，收率:74.5％。ESI-MS m/z:358.1[M+H] +. 4-ethylamino-2-(methylthio)pyrimidine-5-carboxaldehyde (12 g, 60 mmol), ethyl 3,5-dimethoxyphenylacetate (12.6 g, 60 mmol), carbonic acid in a 250 mL one-neck flask Potassium (16.5 g, 120 mmol) and DMF (40 mL). The mixture was heated to 110 ° C for 3 hours. TLC (PE: EA = 2:1) showed the reaction was complete. After the reaction system was cooled to room temperature, water (500 mL), ethyl acetate (200×3 mL), and water (200×3 mL) and brine (200 mL) were washed. The organic phase was dried over anhydrous sodium sulfate and evaporated. ESI-MS m/z: 358.1 [M+H] + .
步骤5：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(甲硫基)吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 5: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(methylthio)pyridine [2,3-d]pyrimidine-7 (8H )- Preparation of ketone
Figure PCTCN2018085940-appb-000098
Figure PCTCN2018085940-appb-000098
在250mL单颈瓶中加入6-(3,5-二甲氧基苯基)-8-乙基-2-(甲硫基)吡啶[2,3-d]嘧啶-7(8H)-酮(7g，20mmol)和四氢呋喃(200mL)。冰浴下缓慢滴加磺酰氯(4.85mL，60mmol)。5分钟后滴毕，继续搅拌1小时。LC-MS显示反应完全。加水1mL粹灭反应，减压旋蒸除去溶剂。残留物中加入乙腈(100mL)，过滤，乙腈(10×3mL)洗涤，得黄色固体5.5g，收率：64.7％。ESI-MS m/z:426.0[M+H] +. Add 6-(3,5-dimethoxyphenyl)-8-ethyl-2-(methylthio)pyridine [2,3-d]pyrimidin-7(8H)-one to a 250 mL single-necked flask (7 g, 20 mmol) and tetrahydrofuran (200 mL). Sulfonyl chloride (4.85 mL, 60 mmol) was slowly added dropwise under ice bath. After 5 minutes, the mixture was continuously stirred for 1 hour. LC-MS showed the reaction was complete. 1 mL of water was added to quench the reaction, and the solvent was evaporated under reduced pressure. Acetonitrile (100 mL) was added to the residue, which was filtered and washed with acetonitrile (10×3mL) ESI-MS m/z: 426.0 [M+H] + .
步骤6：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(甲砜基)吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(methylsulfonyl)pyridine [2,3-d]pyrimidine-7 (8H )- Preparation of ketone
Figure PCTCN2018085940-appb-000099
Figure PCTCN2018085940-appb-000099
在250mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(甲硫基)吡啶[2,3-d]嘧啶-7(8H)-酮(5g，11.7mmol)和二氯甲烷(150mL)，室温下加入间氯过氧苯甲酸(4g，23.4mmol)，室温搅拌1小时。TLC(PE：EA＝1:2)显示反应完全。反应体系中加入饱和碳酸氢 纳水溶液200mL，加水100mL，二氯甲烷(200×3mL)萃取，有机相经无水硫酸钠干燥，浓缩，得黄色固体3.2g，收率：69.8％。ESI-MS m/z:458.0[M+H] +. Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(methylthio)pyridine [2,3-d]pyrimidine to a 250 mL single-necked flask -7(8H)-one (5 g, 11.7 mmol) and dichloromethane (150 mL), m. m. TLC (PE: EA = 1:2) showed the reaction was complete. To the reaction system, 200 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and 100 mL of water was added, and dichloromethane (200×3 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid (3.2 g, yield: 69.8%). ESI-MS m/z: 458.0 [M+H] + .
步骤7：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-羟基吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 7: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-hydroxypyridine [2,3-d]pyrimidin-7(8H)-one preparation
Figure PCTCN2018085940-appb-000100
Figure PCTCN2018085940-appb-000100
在100mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(甲砜基)吡啶[2,3-d]嘧啶-7(8H)-酮(2.5g，5.46mmol)和四氢呋喃(20mL)，室温下加入氢氧化钾水溶液(1.5g，27mmol，溶于20mL水中)，室温下搅拌3小时。TLC(EA：PE＝2:1)显示反应完全。减压旋蒸除去溶剂，反应体系中加入浓盐酸调节PH至2，过滤，乙腈(2×2mL)洗涤，得黄色固体1.8g，收率：83.2％。ESI-MS m/z:396.0[M+H] +. Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(methylsulfonyl)pyridine [2,3-d]pyrimidine to a 100 mL single-necked flask -7(8H)-one (2.5g, 5.46mmol) and tetrahydrofuran (20mL) were added to a solution of potassium hydroxide (1.5g, 27mmol, dissolved in 20mL of water) at room temperature and stirred for 3 hours at room temperature. TLC (EA: PE = 2:1) showed the reaction was completed. The solvent was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc) ESI-MS m/z: 396.0 [M+H] + .
步骤8：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-氯吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 8: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-chloropyridine [2,3-d]pyrimidin-7(8H)-one preparation
Figure PCTCN2018085940-appb-000101
Figure PCTCN2018085940-appb-000101
在100mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-羟基吡啶[2,3-d]嘧啶-7(8H)-酮(1.8g，4.5mmol)和乙腈(10mL)，室温下加入三氯氧磷(10mL)，加热至90℃，反应3小时。TLC(EA：PE＝1:1)显示反应完全。减压旋蒸除去溶剂，残留物中加入水(5mL)，抽滤，乙腈(1×2mL)洗涤两次，得黄色固体2.0g，收率：100％。ESI-MS m/z:414.0[M+H] +. Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-hydroxypyridine [2,3-d]pyrimidine-7 (8H) to a 100 mL single-necked flask --ketone (1.8 g, 4.5 mmol) and acetonitrile (10 mL), phosphorus oxychloride (10 mL) was added at room temperature, and heated to 90 ° C for 3 hours. TLC (EA: PE = 1:1) showed the reaction was completed. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. ESI-MS m/z: 414.0 [M+H] + .
步骤9：N 1-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-N 1，N 2，N 2-三甲基乙基-1,2-二胺的制备 Step 9: N 1 -(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Of phenyl)-phenyl)-N 1 ,N 2 ,N 2 -trimethylethyl-1,2-diamine
Figure PCTCN2018085940-appb-000102
Figure PCTCN2018085940-appb-000102
制备方法类似于实施例2中的步骤6、7，不同的是将原料中的1-乙基哌嗪替换为N,N,N’-三甲基乙二胺。ESI-MS m/z:380.2[M+H] +. The preparation method was similar to the steps 6 and 7 in Example 2, except that 1-ethylpiperazine in the starting material was replaced with N,N,N'-trimethylethylenediamine. ESI-MS m/z: 380.2 [M+H] + .
步骤10：6-(2,6-二氯-3,5-二甲氧基苯基)-2-(4-((2-(二甲基氨基)乙基)(氨基)-2-甲氧基-5-硝基苯基)-8-乙基)吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 10: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl)(amino)-2-yl) Preparation of oxy-5-nitrophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000103
Figure PCTCN2018085940-appb-000103
在100mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-氯吡啶[2,3-d]嘧啶-7(8H)-酮(500mg，1.2mmol)，碳酸钾(414mg，3.0mmol)、双三苯基膦二氯化钯(35.6mg，0.05mmol)、N 1-(5-甲氧基-2-硝基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-N 1，N 2，N 2-三甲基乙烷-1,2-二胺(570mg，1.5mmol)、水(5mL)和二氧六环(20mL)，氩气保护，80℃ 反应2小时。LC-MS显示反应完全。待反应体系冷却至室温后，反应体系中加入水100mL，乙酸乙酯(200×3mL)萃取，有机相经饱和食盐水(100×3mL)洗涤、浓缩，得黄色固体400mg，收率：52.8％。ESI-MS m/z:631.1[M+H] +. Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-chloropyridine [2,3-d]pyrimidine-7 (8H) to a 100 mL single-necked flask )-ketone (500 mg, 1.2 mmol), potassium carbonate (414 mg, 3.0 mmol), bistriphenylphosphine palladium dichloride (35.6 mg, 0.05 mmol), N 1 -(5-methoxy-2-nitro 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N 1 ,N 2 ,N 2 -trimethylethane -1,2-Diamine (570 mg, 1.5 mmol), water (5 mL) and dioxane (20 mL), argon gas, and reacted at 80 ° C for 2 hours. LC-MS showed the reaction was complete. After the reaction system was cooled to room temperature, 100 mL of water was added to the reaction system, and ethyl acetate (200×3 mL) was added, and the organic phase was washed with saturated brine (100×3 mL) and concentrated to give a white solid (400 mg, yield: 52.8%) . ESI-MS m/z: 631.1 [M+H] + .
步骤11：6-(2,6-二氯-3,5-二甲氧基苯基)-2-(4-((2-(二甲基氨基)乙基)(氨基)-2-甲氧基-5-胺基苯基)-8-乙基)吡啶[2,3-d]嘧啶-7(8H)-酮的制备Step 11: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl)(amino)-2-yl) Preparation of oxy-5-aminophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000104
Figure PCTCN2018085940-appb-000104
在100mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-2-(4-((2-(二甲基氨基)乙基)(氨基)-2-甲氧基-5-硝基苯基)-8-乙基)吡啶[2,3-d]嘧啶-7(8H)-酮(400mg，0.63mmol)，氯化亚锡(414mg，3.0mmol)和乙醇(20mL)，80℃反应2小时。LC-MS显示反应完全。减压旋蒸除去溶剂，残留物中加入饱和碳酸氢纳水溶液100mL，乙酸乙酯(200×3mL)萃取，有机相经浓缩，得黄色固体300mg，收率：79.3％。ESI-MS m/z:601.1[M+H] +. Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl))amino) to a 100 mL single-necked flask 2-methoxy-5-nitrophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one (400 mg, 0.63 mmol), stannous chloride (414 mg, 3.0 mmol) and ethanol (20 mL) were reacted at 80 ° C for 2 hours. LC-MS showed the reaction was complete. The solvent was evaporated under reduced pressure. EtOAc EtOAc (EtOAc) ESI-MS m/z: 601.1 [M+H] + .
步骤12：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶[2,3-d]嘧啶-2-基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Step 12: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2 ,3-d]pyrimidin-2-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000105
Figure PCTCN2018085940-appb-000105
在100mL单颈瓶中加入6-(2,6-二氯-3,5-二甲氧基苯基)-2-(4-((2-(二甲基氨基)乙基)(氨基)-2-甲氧基-5-胺基苯基)-8-乙基)吡啶[2,3-d]嘧啶-7(8H)-酮(300mg，0.5mmol)、DIPEA(129mg，1.0mmol)和无水四氢呋喃(20mL)。-10℃下缓慢滴加丙烯酰氯(40μl，0.5mmol，溶于0.5mL四氢呋喃中)，滴毕，继续搅拌10min。LC-MS显示反应完全。减压旋蒸除去溶剂，prep-HPLC(CH 3CN/H 2O，0.1％TEA)，得黄色固体30mg，收率：9.2％。 1H-NMR(400MHz,CDCl 3)：δ10.08(s,1H),9.13(s,1H),8.96(s,1H),7.63(s,1H),6.91(s,1H),6.65(s,1H),6.46-6.42(d,1H),6.37-6.30(m,1H),5.71-5.69(d,1H),4.68-4.62(m,2H),3.96(s,6H),3.90(s,3H),2.95(m,2H),2.80(s,3H),2.48(m,2H),2.32(s,6H),1.45-1.38(m,3H).ESI-MSm/z:655.2[M+H] + Add 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(4-((2-(dimethylamino)ethyl))amino) to a 100 mL single-necked flask 2-methoxy-5-aminophenyl)-8-ethyl)pyridine [2,3-d]pyrimidin-7(8H)-one (300 mg, 0.5 mmol), DIPEA (129 mg, 1.0 mmol) And anhydrous tetrahydrofuran (20 mL). Acryloyl chloride (40 μl, 0.5 mmol, dissolved in 0.5 mL of tetrahydrofuran) was slowly added dropwise at -10 ° C, and the mixture was stirred for 10 min. LC-MS showed the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure, prep-HPLC (CH 3 CN / H 2 O, 0.1% TEA), to give a yellow solid 30mg, Yield: 9.2%. 1 H-NMR (400MHz, CDCl 3): δ10.08 (s, 1H), 9.13 (s, 1H), 8.96 (s, 1H), 7.63 (s, 1H), 6.91 (s, 1H), 6.65 ( s, 1H), 6.46-6.42 (d, 1H), 6.37-6.30 (m, 1H), 5.71-5.69 (d, 1H), 4.68-4.62 (m, 2H), 3.96 (s, 6H), 3.90 ( s, 3H), 2.95 (m, 2H), 2.80 (s, 3H), 2.48 (m, 2H), 2.32 (s, 6H), 1.45-1.38 (m, 3H). ESI-MSm/z: 655.2 [ M+H] +
实施例15：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 15: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000106
Figure PCTCN2018085940-appb-000106
步骤1：2-氯-4-(乙基氨基)嘧啶-5-甲酸乙酯的制备Step 1: Preparation of ethyl 2-chloro-4-(ethylamino)pyrimidine-5-carboxylate
Figure PCTCN2018085940-appb-000107
Figure PCTCN2018085940-appb-000107
将2,4-二氯-5-嘧啶甲酸乙酯(10g)溶于100mLTHF中，加入N,N-二异丙基乙胺(11.76g)，-5℃下缓慢滴加乙胺醇溶液(8.2g)，室温搅拌过夜，将反应液中加入大量水，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:230[M+H] + Ethyl 2,4-dichloro-5-pyrimidinecarboxylate (10 g) was dissolved in 100 mL of THF, and N,N-diisopropylethylamine (11.76 g) was added thereto, and an ethylamine solution was slowly added dropwise at -5 °C. 8.2 g), stirred at room temperature overnight, aq. ESI-MS m/z: 230 [M+H] +
步骤2：(2-氯-4-(乙基氨基)嘧啶-5-基)甲醇的制备Step 2: Preparation of (2-chloro-4-(ethylamino)pyrimidin-5-yl)methanol
Figure PCTCN2018085940-appb-000108
Figure PCTCN2018085940-appb-000108
将2-氯-4-(乙基氨基)嘧啶-5-甲酸乙酯(2g)溶于20mL四氢呋喃中，室温下缓慢加入LiAlH 4(0.736g)，室温搅拌3h，用水(1mL)和氢氧化钠水溶液(2N，1mL)淬灭反应，过滤，滤液用乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:188[M+H] + Ethyl 2-chloro-4-(ethylamino)pyrimidine-5-carboxylate (2 g) was dissolved in 20 mL of tetrahydrofuran. LiAlH 4 (0.736 g) was slowly added at room temperature, stirred at room temperature for 3 h, water (1 mL) and EtOAc The reaction was quenched with EtOAc (EtOAc)EtOAc. ESI-MS m/z: 188 [M+H] +
步骤3：2-氯-4-(乙基氨基)嘧啶-5-甲醛的制备Step 3: Preparation of 2-chloro-4-(ethylamino)pyrimidine-5-carboxaldehyde
Figure PCTCN2018085940-appb-000109
Figure PCTCN2018085940-appb-000109
将(2-氯-4-(乙基氨基)嘧啶-5-基)甲醇(1g)溶于20mL二氯甲烷中，室温下缓慢加入二氧化锰(7g)，室温搅拌过夜，过滤，旋干得标题化合物。ESI-MS m/z:186[M+H] + (2-Chloro-4-(ethylamino)pyrimidin-5-yl)methanol (1 g) was dissolved in 20 mL of dichloromethane. Manganese dioxide (7 g) was slowly added at room temperature, stirred at room temperature overnight, filtered and dried The title compound was obtained. ESI-MS m/z: 186[M+H] +
步骤4：2-氯-6-(3,5-二甲氧基苯基)-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 4: Preparation of 2-chloro-6-(3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000110
Figure PCTCN2018085940-appb-000110
将2-氯-4-(乙基氨基)嘧啶-5-甲醛(0.5g)和2-(3,5-二甲氧基苯基)乙酸甲酯(0.681g)溶于10mL N,N-二甲基甲酰胺中，100℃下反应2h，将反应液用饱和氯化钠溶液稀释，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:346[M+H] + 2-Chloro-4-(ethylamino)pyrimidine-5-carbaldehyde (0.5 g) and methyl 2-(3,5-dimethoxyphenyl)acetate (0.681 g) were dissolved in 10 mL of N,N- In dimethylformamide, the reaction was carried out at 100 ° C for 2 h. ESI-MS m/z: 346[M+H] +
步骤5：6-(3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-硝基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 5: 6-(3,5-Dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy-5-nitrate Preparation of phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000111
Figure PCTCN2018085940-appb-000111
将实施例2步骤7所得化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪(476mg)、上述步骤4所得物2-氯-6-(3,5-二甲氧基苯基)-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮(350mg)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(74mg)和醋酸钾(298mg)依次加入15mL1,4-二氧六环和8mL水中，回流反应2h，将反应液过滤，滤液用 饱和氯化钠溶液洗涤，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:575[M+H] + The compound obtained in the step 7 of Example 2 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolane-2-yl)phenyl)piperazine (476 mg), the product of the above step 4, 2-chloro-6-(3,5-dimethoxyphenyl)-8-ethylpyridine [2,3-d]pyrimidin-7(8H)-one (350 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (74 mg) and potassium acetate (298 mg) After 15 mL of 1,4-dioxane and 8 mL of water were added, and the reaction mixture was refluxed for 2h, the reaction mixture was filtered. ESI-MS m/z: 575[M+H] +
步骤6：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-硝基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2- Preparation of methoxy-5-nitrophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000112
Figure PCTCN2018085940-appb-000112
将6-(3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-硝基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(220mg)溶于10mL乙腈中，冰浴下滴加磺酰氯(62ul)，室温搅拌30min，将反应液用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，干燥，旋干得标题化合物。ESI-MS m/z:643[M+H] + 6-(3,5-Dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy-5-nitrobenzene Pyridyl[2,3-d]pyrimidin-7(8H)-one (220mg) was dissolved in 10mL of acetonitrile, sulfonyl chloride (62ul) was added dropwise in an ice bath, stirred at room temperature for 30min, and the reaction solution was saturated with hydrogen carbonate. The sodium solution was quenched, EtOAc (EtOAc) ESI-MS m/z: 643[M+H] +
步骤7：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-氨基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 7: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2- Preparation of methoxy-5-aminophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000113
Figure PCTCN2018085940-appb-000113
将6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-硝基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(200mg)溶于10mL甲醇中，加入钯碳(70mg)，套上氢气，室温搅拌1h，将反应液过滤，滤液旋干得标题化合物。ESI-MS m/z:613[M+H] + 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy 5--5-nitrophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg) was dissolved in 10 mL of methanol, palladium carbon (70 mg) was added, and hydrogen was stirred at room temperature for 1 h. The reaction mixture was filtered, and the title compound ESI-MS m/z: 613[M+H] +
步骤8：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 8: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridyl[ Preparation of 2,3-d]pyrimidin-2-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000114
Figure PCTCN2018085940-appb-000114
将6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(4-(4-乙基哌嗪-1-基)-2-甲氧基-5-氨基苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(200mg)溶于10mL四氢呋喃中，加入N,N-二异丙基乙胺(212mg)，冰浴下滴加丙烯酰氯(39ul)，室温搅拌30min，将反应液用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，干燥，旋干，制备得标题化合物。 1H-NMR(400MHz,DMSO-d 6):δ1.05(t,3H),1.29(t,3H),2.42(q,2H),2.59(s,4H),3.00(s,4H),3.89(s,3H),3.98(s,6H),4.44(q,2H),5.73(d,1H),6.24(d,1H),6.63(q,1H),6.86(s,1H),7.03(s,1H),8.04(s,1H),8.29(s,1H),9.18(s,1H),9.17(s,1H).ESI-MSm/z:667.2[M+H] + 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(4-(4-ethylpiperazin-1-yl)-2-methoxy 5-Aminophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg) was dissolved in 10 mL of tetrahydrofuran and added N,N-diisopropylethylamine (212 mg), ice The acryloyl chloride (39 ul) was added dropwise to the residue. 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.05 (t, 3H), 1.29 (t, 3H), 2.42 (q, 2H), 2.59 (s, 4H), 3.00 (s, 4H), 3.89 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H), 5.73 (d, 1H), 6.24 (d, 1H), 6.63 (q, 1H), 6.86 (s, 1H), 7.03 (s, 1H), 8.04 (s, 1H), 8.29 (s, 1H), 9.18 (s, 1H), 9.17 (s, 1H). ESI-MS m/z: 667.2 [M+H] +
实施例16：N-[5-[6-(2,6-二氯-3,5-二甲氧基-苯)-8-乙基-7-氧代-7,8-二氢-吡啶并[2,3-d] 哌嗪-1-基]-2-(4-甲基-哌嗪-1-基)-苯基]-丙烯酰胺的制备Example 16: N-[5-[6-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-ethyl-7-oxo-7,8-dihydro-pyridine And [2,3-d] Preparation of piperazin-1-yl]-2-(4-methyl-piperazin-1-yl)-phenyl]-acrylamide
Figure PCTCN2018085940-appb-000115
Figure PCTCN2018085940-appb-000115
制备方法类似于实施例14步骤5、6、7、8，不同的是将实施例14步骤5中原料的化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪替换为实施例1步骤8所得物1-甲基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪。 1H-NMR(400MHZ,CDCl 3):δ1.46(t,3H),1.62(s,4H),2.41(s,3H),2.65(s,4H),3.96(s,6H),4.70(q,2H),5.82(dd,1H),6.33(dd,1H),6.47(dd,1H),6.65(s,1H),7.31(d,1H),7.60(dd,1H),8.31(m,1H),8.56(d,1H),8.94(d,1H),9.63(s,1H).ESI-MS m/z:623.3[M+H] + The preparation method was similar to that of Example 14, Steps 5, 6, 7, and 8, except that the compound of the starting material in Step 5 of Example 14 was 1-ethyl-4-(5-methoxy-2-nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the 1-methyl ester obtained in Step 1 of Example 1. 4-(2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. 1 H-NMR (400 MHZ, CDCl 3 ): δ 1.46 (t, 3H), 1.62 (s, 4H), 2.41 (s, 3H), 2.65 (s, 4H), 3.96 (s, 6H), 4.70 ( q, 2H), 5.82 (dd, 1H), 6.33 (dd, 1H), 6.47 (dd, 1H), 6.65 (s, 1H), 7.31 (d, 1H), 7.60 (dd, 1H), 8.31 (m) ,1H), 8.56(d,1H), 8.94(d,1H), 9.63(s,1H).ESI-MS m/z:623.3[M+H] +
实施例17：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]哌嗪-2-基)-2-(4-乙基哌嗪-1-基)-苯基]丙烯酰胺的制备Example 17: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]piperazin-2-yl)-2-(4-ethylpiperazin-1-yl)-phenyl]acrylamide
Figure PCTCN2018085940-appb-000116
Figure PCTCN2018085940-appb-000116
步骤1：1-乙基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪的制备Step 1:1-ethyl-4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Preparation of piperazine
Figure PCTCN2018085940-appb-000117
Figure PCTCN2018085940-appb-000117
制备方法类似于实施例1步骤7、8，不同的是将实施例1步骤7中的原料甲基哌嗪替换为1-乙基哌嗪。ESI-MS m/z:360.2[M+H] + The preparation method was similar to that of Example 1, Steps 7 and 8, except that the starting material methylpiperazine in Step 7 of Example 1 was replaced with 1-ethylpiperazine. ESI-MS m/z: 360.2 [M+H] +
步骤2：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]哌嗪-2-基)-2-(4-乙基哌嗪-1-基)-苯基]丙烯酰胺Step 2: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[ 2,3-d]piperazin-2-yl)-2-(4-ethylpiperazin-1-yl)-phenyl]acrylamide
Figure PCTCN2018085940-appb-000118
Figure PCTCN2018085940-appb-000118
制备方法类似于实施例15，不同的是将实施例15步骤5中原料的化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪替换成上述步骤1制得的化合物1-乙基-4-(2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪。 1H-NMR(400MHZ,CDCl 3):δ1.11-1.21(m,3H),1.47(s,3H),2.54(q,2H),2.62(s,2H),2.73(d,2H),3.03(t,4H),3.96(s,6H),4.70(q,2H),5.79-5.87(m,1H),6.33(dd,1H),6.47(d,1H), 6.65(s,1H),7.32(d,1H),7.62(s,1H),8.31(dd,1H),8.56(d,1H),8.94(d,1H),9.63(s,1H).ESI-MS m/z:637.2[M+H] + The preparation method was similar to that of Example 15, except that the compound of the starting material in Step 5 of Example 15 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5). -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the compound 1-ethyl-4-(2-nitro) obtained in the above step 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. 1 H-NMR (400 MHZ, CDCl 3 ): δ 1.11-1.21 (m, 3H), 1.47 (s, 3H), 2.54 (q, 2H), 2.62 (s, 2H), 2.73 (d, 2H), 3.03(t,4H),3.96(s,6H), 4.70(q,2H), 5.79-5.87(m,1H),6.33(dd,1H),6.47(d,1H), 6.65(s,1H) , 7.32 (d, 1H), 7.62 (s, 1H), 8.31 (dd, 1H), 8.56 (d, 1H), 8.94 (d, 1H), 9.63 (s, 1H). ESI-MS m/z: 637.2[M+H] +
实施例18：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)甲基丙烯酰胺的制备Example 18: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)methacrylamide
Figure PCTCN2018085940-appb-000119
Figure PCTCN2018085940-appb-000119
制备方法类似于实施例15，不同的是将实施例15步骤8中的原料丙烯酰氯替换成甲基丙烯酰氯。 1H-NMR(400MHz,CDCl 3):δ1.11(t,3H),1.35(t,3H),2.05(s,3H),2.48(m,2H),2.54-2.80(m,4H),2.93-3.05(s,4H),3.81(s,3H),3.89(s,6H),4.56(q,2H),5.41(d,1H),5.84(d,1H),6.57(s,1H),6.85(s,1H),7.56(s,1H),8.64(s,1H),8.89(s,1H),8.96(s,1H).ESI-MSm/z:681.3[M+H] + The preparation method was similar to that of Example 15, except that the starting material acryloyl chloride in the step 8 of Example 15 was replaced with methacryloyl chloride. 1 H-NMR (400MHz, CDCl 3 ): δ 1.11 (t, 3H), 1.35 (t, 3H), 2.05 (s, 3H), 2.48 (m, 2H), 2.54-2.80 (m, 4H), 2.93-3.05(s,4H),3.81(s,3H),3.89(s,6H),4.56(q,2H),5.41(d,1H),5.84(d,1H),6.57(s,1H) , 6.85(s,1H), 7.56(s,1H), 8.64(s,1H),8.89(s,1H),8.96(s,1H).ESI-MSm/z:681.3[M+H] +
实施例19：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-((3S，5R)-4-乙基-3,5-二甲基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 19: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl)-2-((3S,5R)-4-ethyl-3,5-dimethylpiperazin-1-yl)-4-methoxyphenyl Preparation of acrylamide
Figure PCTCN2018085940-appb-000120
Figure PCTCN2018085940-appb-000120
制备方法类似于实施例5，不同的是将步骤4中的原料化合物7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮替换为实施例14步骤8所得化合物6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-氯吡啶[2,3-d]嘧啶-7(8H)-酮。 1H-NMR(400MHz,DMSO-d 6):δ0.92(t,3H),1.03(d,6H),1.29(t,3H),2.48-2.53(m,2H,),2.84-2.87(m,4H),3.08-3.11(m,2H),3.89(s,3H),3.98(s,6H),4.45(q,2H),5.79(d,1H),6.38(d,1H),6.59-6.66(m,1H),6.79(s,1H),7.03(s,1H),8.03(s,1H),8.27(s,1H),9.17(s,2H).ESI-MSm/z:695.3[M+H] + The preparation method is similar to that of Example 5, except that the starting compound 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1 in the step 4 is used. , 6-naphthyridine-2(1H)-one was replaced by the compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2- which was obtained in the step 8 of Example 14. Chloropyridine [2,3-d]pyrimidin-7(8H)-one. 1 H-NMR (400 MHz, DMSO-d 6 ): δ 0.92 (t, 3H), 1.03 (d, 6H), 1.29 (t, 3H), 2.48-2.53 (m, 2H,), 2.84. m, 4H), 3.08-3.11 (m, 2H), 3.89 (s, 3H), 3.98 (s, 6H), 4.45 (q, 2H), 5.79 (d, 1H), 6.38 (d, 1H), 6.59 -6.66(m,1H), 6.79(s,1H), 7.03(s,1H),8.03(s,1H), 8.27(s,1H),9.17(s,2H).ESI-MSm/z:695.3 [M+H] +
实施例20：N-(2-(2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基苯基)丙烯酰胺的制备Example 20: N-(2-(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-(6-(2,6-dichloro-3,5- Dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-4-methoxyphenyl)acrylamide Preparation
Figure PCTCN2018085940-appb-000121
Figure PCTCN2018085940-appb-000121
步骤1：5-(4-溴-5-甲氧基-2-硝基苯基)-2-氧杂-5-氮杂双环[2.2.1]庚烷的制备Step 1: Preparation of 5-(4-bromo-5-methoxy-2-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane
Figure PCTCN2018085940-appb-000122
Figure PCTCN2018085940-appb-000122
在50mL单颈瓶中加入1-溴-4-氟-2-甲氧基-5-硝基苯(800mg，3.23mmol)、2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐(658mg,4.84mm),碳酸钾(1.4g,9.69mmol),20mL N,N-二甲基甲酰胺，90℃搅拌2h。TLC(EA：PE＝1:2)显示反应完全。加水100mL，乙酸乙酯(50×3mL)萃取，有机相经无水硫酸钠干燥、浓缩，得标题化合物。ESI-MS m/z:329.09[M+H] +. Add 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene (800 mg, 3.23 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane to a 50 mL single-necked flask. Hydrochloride (658 mg, 4.84 mm), potassium carbonate (1.4 g, 9.69 mmol), 20 mL of N,N-dimethylformamide, stirred at 90 ° C for 2 h. TLC (EA: PE = 1:2) showed the reaction was complete. The mixture was extracted with EtOAc (EtOAc)EtOAc. ESI-MS m/z: 329.09 [M+H] + .
步骤2：5-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2-氧杂-5-氮杂双环[2.2.1]庚烷的制备Step 2: 5-(5-Methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane
Figure PCTCN2018085940-appb-000123
Figure PCTCN2018085940-appb-000123
在100mL单颈瓶中加入5-(4-溴-5-甲氧基-2-硝基苯基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(1.1g,3.35mmol)、联硼酸频哪醇酯(1.69g,6.7mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.22g,0.34mmol)、醋酸钾(0.99g，10mmol)和20mL 1,4-二氧六环，氮气保护，100℃加热搅拌过夜，过滤，旋干，乙酸乙酯溶解，饱和食盐水洗涤，无水硫酸钠干燥，旋干得标题化合物。ESI-MS m/z:377.14[M+H] +. Add 5-(4-bromo-5-methoxy-2-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.1 g, 3.35) to a 100 mL single-necked flask. Ment), bis-boronic acid pinacol ester (1.69 g, 6.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22 g, 0.34 mmol), potassium acetate ( 0.99g, 10mmol), and 20mL 1,4-dioxane, protected with nitrogen, stirred at 100 ° C overnight, filtered, dried, evaporated ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate Compound. ESI-MS m/z: 377.14 [M+H] + .
步骤3：N-(2-(2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基苯基)丙烯酰胺的制备Step 3: N-(2-(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-(6-(2,6-dichloro-3,5-di Methoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-4-methoxyphenyl)acrylamide preparation
Figure PCTCN2018085940-appb-000124
Figure PCTCN2018085940-appb-000124
制备方法类似于实施例15，不同的是将步骤5中的化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)哌嗪替换为上述步骤2制得的化合物5-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2-氧杂-5-氮杂双环[2.2.1]庚烷。 1H-NMR(400MHz,DMSO-d 6):δ1.24(t,3H),1.83-1.95(m,2H),2.97-2.99(m,1H),3.57-3.59(m,1H),3.79-3.84(m,2H),3.93(s,3H),4.01(s,6H),4.41(q,2H),4.56(d,2H),5.61(s,1H),5.73(d,1H),6.20(d,1H),6.39(t,1H),6.94(s,1H),7.74(s,1H),7.92(s,1H),9.06(s,1H),9.59(s,1H).ESI-MS m/z:652.2[M+H] + The preparation method was similar to that of Example 15, except that the compound in Step 5 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the compound 5-(5-methoxy-2-nitro-4-() obtained in the above step 2 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]g alkyl. 1 H-NMR (400MHz, DMSO -d 6): δ1.24 (t, 3H), 1.83-1.95 (m, 2H), 2.97-2.99 (m, 1H), 3.57-3.59 (m, 1H), 3.79 -3.84 (m, 2H), 3.93 (s, 3H), 4.01 (s, 6H), 4.41 (q, 2H), 4.56 (d, 2H), 5.61 (s, 1H), 5.73 (d, 1H), 6.20(d,1H), 6.39(t,1H), 6.94(s,1H), 7.74(s,1H), 7.92(s,1H),9.06(s,1H),9.59(s,1H).ESI -MS m/z: 652.2 [M+H] +
实施例21：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(3,3-二氟吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备Example 21: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-2-(3,3-difluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000125
Figure PCTCN2018085940-appb-000125
步骤1：3,3-二氟-1-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)吡咯烷的制备Step 1: 3,3-Difluoro-1-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxole) Preparation of borane-2-yl)phenyl)pyrrolidine
Figure PCTCN2018085940-appb-000126
Figure PCTCN2018085940-appb-000126
合成方法同实施例20步骤1、2，不同的是将步骤1中的原料2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐替换成3,3-二氟吡咯烷的盐酸盐。ESI-MS m/z:385.2[M+H] + The synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 3,3-difluoropyrrole. The hydrochloride salt of the alkane. ESI-MS m/z: 385.2 [M+H] +
步骤2：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(3,3-二氟吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备Step 2: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[ Preparation of 2,3-d]pyrimidin-2-yl)-2-(3,3-difluoropyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000127
Figure PCTCN2018085940-appb-000127
制备方法类似于实施例15，不同的是将步骤5中的化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪替换为上述步骤1所得物3,3-二氟-1-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)吡咯烷。 1H-NMR(400MHz,DMSO-d 6):δ1.29(t,3H),2.00(t,2H),3.63(t,2H),3.79(t,2H),3.92(s,3H),3.98(s,6H),4.45(q,2H),5.74(d,1H),6.24(d,1H),6.49(t,1H),7.03(s,1H),7.74(s,1H),7.86(s,1H),7.99(s,1H),9.12(s,1H),9.60(s,1H),ESI-MS m/z:660.19[M+H] + The preparation method was similar to that of Example 15, except that the compound in Step 5 was 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl). -1,3,2-dioxaborolan-2-yl)phenyl)piperazine is replaced by the above step 1 product 3,3-difluoro-1-(5-methoxy-2- Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine. 1 H-NMR (400MHz, DMSO -d 6): δ1.29 (t, 3H), 2.00 (t, 2H), 3.63 (t, 2H), 3.79 (t, 2H), 3.92 (s, 3H), 3.98(s,6H), 4.45(q,2H), 5.74(d,1H), 6.24(d,1H), 6.49(t,1H),7.03(s,1H),7.74(s,1H),7.86 (s, 1H), 7.99 ( s, 1H), 9.12 (s, 1H), 9.60 (s, 1H), ESI-MS m / z: 660.19 [m + H] +
实施例22：N-(2-(4-乙酰基哌嗪-1-基)-5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[d]嘧啶-2-基)-4-甲氧基苯基)丙烯酰胺Example 22: N-(2-(4-Acetylpiperazin-1-yl)-5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-B 7-oxo-7,8-dihydropyrido[d]pyrimidin-2-yl)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000128
Figure PCTCN2018085940-appb-000128
制备方法类似于实施例15，不同的是将步骤5中的原料化合物1-乙基-4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪替换为实施例6步骤1所得物1-(4-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)哌嗪-1-基)乙酮制备得到标题化合物。 1H-NMR(400MHz,DMSO-d 6):δ1.29(s,3H),2.07(s,3H),2.95-2.98(m,4H),3.67(t,4H),3.75(s,3H),3.90(s,6H),4.44(q,2H),5.76(d,1H),6.26(d,1H),6.64-6.71(m,1H),6.89(s,1H),7.04(s,1H),8.04(s,1H),8.40(s,1H),9.19(s,1H),9.23(s,1H),ESI-MS m/z:681.1[M+H] + The preparation method was similar to that of Example 15, except that the starting compound 1-ethyl-4-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl) in Step 5 was prepared. Base-1,3,2-dioxaborolan-2-yl)phenyl)piperazine was replaced by the product of Step 1 of Example 6 1-(4-(5-methoxy-2-nitrate) Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethanone Compound. 1 H-NMR (400MHz, DMSO -d 6): δ1.29 (s, 3H), 2.07 (s, 3H), 2.95-2.98 (m, 4H), 3.67 (t, 4H), 3.75 (s, 3H ), 3.90 (s, 6H), 4.44 (q, 2H), 5.76 (d, 1H), 6.26 (d, 1H), 6.64-6.71 (m, 1H), 6.89 (s, 1H), 7.04 (s, 1H), 8.04 (s, 1H), 8.40 (s, 1H), 9.19 (s, 1H), 9.23 (s, 1H), ESI-MS m/z: 681.1 [M+H] +
实施例23：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)苯基)丙烯酰胺的制备Example 23: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(2-oxa-7-azaspiro[3.5]decane-7-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000129
Figure PCTCN2018085940-appb-000129
合成方法同实施例20步骤1、2，不同的是将步骤1中的原料2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐替换成2-氧杂-7-氮杂螺[3.5]壬烷的草酸盐。 1H-NMR(400MHz,DMSO-d 6):δ1.28(t,3H),2.01(t,4H),2.87(t,4H),3.87(s,3H),3.98(s,6H),4.39(s,4H),4.44(q,2H),5.74(d,1H),6.24(d,1H),6.62(t,1H),6.84(s,1H),7.04(s,1H),8.03(s,1H),8.35(s,1H),9.11(s,1H),9.18(s,1H),ESI-MS m/z:680.2[M+H] + The synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 2-oxa-7- Oxalate of azaspiro[3.5]decane. 1 H-NMR (400MHz, DMSO -d 6): δ1.28 (t, 3H), 2.01 (t, 4H), 2.87 (t, 4H), 3.87 (s, 3H), 3.98 (s, 6H), 4.39(s,4H), 4.44(q,2H), 5.74(d,1H), 6.24(d,1H), 6.62(t,1H), 6.84(s,1H),7.04(s,1H),8.03 (s, 1H), 8.35 (s, 1H), 9.11 (s, 1H), 9.18 (s, 1H), ESI-MS m/z: 680.2 [M+H] +
实施例24：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)苯基)丙烯酰胺的制备Example 24: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(7-oxa-2-azaspiro[3.5]decane-2-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000130
Figure PCTCN2018085940-appb-000130
合成方法同实施例20步骤1、2，不同的是将步骤1中的原料2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐替换成7-氧杂-2-氮杂螺[3.5]壬烷的乙二酸盐. 1H-NMR(400MHz,DMSO-d 6):δ1.29(t,3H),1.74(t,4H),3.55(t,4H),3.79(s,4H),3.88(s,3H),3.98(s,6H),4.44(q,2H),5.72(d,1H),6.15(s,1H),6.24(d,1H),6.41-6.47(m,1H),7.02(s,1H),7.80(s,1H),7.96(s,1H),9.08(s,1H),9.40(s,1H),ESI-MS m/z:680.2[M+H] + The synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced with 7-oxa-2- Oxalate of azaspiro[3.5]decane. 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.29 (t, 3H), 1.74 (t, 4H), 3.55 (t, 4H), 3.79 (s, 4H), 3.88 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H), 5.72 (d, 1H), 6.15 (s, 1H), 6.24 (d, 1H), 6.41 - 6.47 (m, 1H), 7.02 (s, 1H), 7.80 (s, 1H), 7.96 (s, 1H), 9.08 (s, 1H), 9.40 (s, 1H), ESI-MS m/z: 680.2[M+H] +
实施例25：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(3-甲氧基吡咯烷-1-基)苯基)丙烯酰胺的制备Example 25: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(3-methoxypyrrolidin-1-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000131
Figure PCTCN2018085940-appb-000131
合成方法同实施例20步骤1、2，不同的是将步骤1中的原料2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐替换成3-甲氧基-吡咯烷的盐酸盐。 1H-NMR(400MHz,DMSO-d 6):δ1.29(t,3H),1.93-2.03(m,2H),3.25(s,3H),3.39(d,2H),3.48-3.61(m,2H),3.90(s,3H),3.97(s,6H),4.02-4.05(m,1H),4.46(m,2H),5.74(d,1H),6.24(m,1H),6.38(m,1H),6.44(s,1H),7.02(s,1H),7.83(s,1H),7.96(s,1H),9.08(s,1H),9.57(s,1H).ESI-MS m/z:654.2[M+H] + The synthesis method is the same as in Steps 2 and 2 of Example 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in Step 1 is replaced by 3-methoxy-pyrrole. The hydrochloride salt of the alkane. 1 H-NMR (400MHz, DMSO -d 6): δ1.29 (t, 3H), 1.93-2.03 (m, 2H), 3.25 (s, 3H), 3.39 (d, 2H), 3.48-3.61 (m , 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.02-4.05 (m, 1H), 4.46 (m, 2H), 5.74 (d, 1H), 6.24 (m, 1H), 6.38 ( m,1H), 6.44 (s, 1H), 7.02 (s, 1H), 7.83 (s, 1H), 7.96 (s, 1H), 9.08 (s, 1H), 9.57 (s, 1H). ESI-MS m/z: 654.2 [M+H] +
实施例26:N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(1-氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)丙烯酰胺的制备Example 26: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(1-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)acrylamide
Figure PCTCN2018085940-appb-000132
Figure PCTCN2018085940-appb-000132
合成方法同实施例20步骤1、2，不同的是将步骤1中的原料2-氧杂-5-氮杂双环[2.2.1]庚烷的盐酸盐替换成1-氧杂-8-氮杂螺[4.5]癸烷。 1H-NMR(400MHz,CDCl 3):δ1.26(t,3H),1.43(t,4H),1.78-1.88(m,4H),2.87-2.91(m,2H),3.08-3.13(m,2H),3.89(s,3H),3.93(m,2H),3.96(s,6H),4.63(q,2H),5.75(d,1H),6.30(d,1H),6.37-6.41(m,1H),6.65(s,1H),6.90(s,1H),7.63(s,1H),8.31(s,1H),8.96(s,1H),9.00(s,1H).ESI-MSm/z:694.2[M+H] +. The synthesis method is the same as that in the steps 2 and 2 of the embodiment 20, except that the hydrochloride of the starting material 2-oxa-5-azabicyclo[2.2.1]heptane in the step 1 is replaced by 1-oxa-8-. Azaspiro[4.5]decane. 1 H-NMR (400MHz, CDCl 3): δ1.26 (t, 3H), 1.43 (t, 4H), 1.78-1.88 (m, 4H), 2.87-2.91 (m, 2H), 3.08-3.13 (m , 2H), 3.89 (s, 3H), 3.93 (m, 2H), 3.96 (s, 6H), 4.63 (q, 2H), 5.75 (d, 1H), 6.30 (d, 1H), 6.37-6.41 ( m,1H), 6.65(s,1H), 6.90(s,1H), 7.63(s,1H), 8.31(s,1H),8.96(s,1H),9.00(s,1H).ESI-MSm /z:694.2[M+H] + .
实施例27:N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)丁-2-炔酰胺的制备Example 27: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)but-2- Preparation of alkyne amide
Figure PCTCN2018085940-appb-000133
Figure PCTCN2018085940-appb-000133
步骤1：6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(2-甲氧基-5-硝基-4-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 1: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(2-methoxy-5-nitro-4-(8-oxygen) Preparation of hetero-2-azaspiro[4.5]decane-2-yl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000134
Figure PCTCN2018085940-appb-000134
制备方法类似实施例14步骤1、2、3、4、5、6、7、8、9、10，不同的是将步骤10中的原料N 1-(5-甲氧基-2-硝基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-N 1，N 2，N 2-三甲基乙烷-1,2-二胺替换为实施例9步骤2制备得到的化合物2-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-8-氧杂-2-氮杂螺[4.5]癸烷。ESI-MS m/z:670.2[M+H] + The preparation method is similar to the steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of Example 14, except that the starting material in the step 10 is N 1 -(5-methoxy-2-nitro 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N 1 ,N 2 ,N 2 -trimethylethane -1,2-diamine was replaced by the compound 2-step 5-(2-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3) prepared in the second step of Example 9. , 2-dioxaborolan-2-yl)phenyl)-8-oxa-2-azaspiro[4.5]decane. ESI-MS m/z: 670.2 [M+H] +
步骤2：2-(5-氨基-2-甲氧基-4-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮的制备Step 2: 2-(5-Amino-2-methoxy-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)-6-(2,6- Preparation of dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one
Figure PCTCN2018085940-appb-000135
Figure PCTCN2018085940-appb-000135
将步骤1制得的6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-2-(2-甲氧基-5-硝基-4-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(140mg)溶于乙醇(9mL)和水(3mL)，加入还原铁粉(90.9mg)，氯化铵(86.8mg)，LCMS检测反应完成后，旋蒸除去乙醇，加入饱和碳酸氢钠水溶液调至中性，EA萃取，干燥，旋干得标题化合物。ESI-MS m/z: 640.2[M+H] + 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(2-methoxy-5-nitro-4-() prepared in the first step 8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (140 mg) was dissolved in ethanol (9 mL) and Water (3mL), reduced iron powder (90.9mg), ammonium chloride (86.8mg), after LCMS detection reaction, the ethanol was removed by rotary evaporation, neutralized with saturated aqueous sodium hydrogencarbonate solution, extracted with EA, dried, and spun The title compound was dried. ESI-MS m/z: 640.2[M+H] +
步骤3：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)丁-2-炔酰胺的制备Step 3: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridyl[ 2,3-d]pyrimidin-2-yl)-4-methoxy-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)but-2-yne Preparation of amide
Figure PCTCN2018085940-appb-000136
Figure PCTCN2018085940-appb-000136
将步骤2制得的2-(5-氨基-2-甲氧基-4-(8-氧杂-2-氮杂螺[4.5]癸烷-2-基)苯基)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮(70mg)溶于2mLN-甲基吡咯烷酮中，加入N,N-二异丙基乙基胺(54.6mg)，0℃搅拌下加入2-炔基丁酰氯(0.3mol/mL,1mL)，继续反应0.5小时，将反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，干燥，旋干，制备分离得标题化合物。 1H-NMR(400MHz,CDCl 3):δ1.26(m,3H),1.41(m,4H),1.92(t,2H),2.02(s,3H),3.25(s,2H),3.47(t,2H),3.72(m,4H),3.94(s,3H),3.96(s,6H),4.61(q,2H),6.48(s,1H),6.64(s,1H),7.32(s,1H),7.59(s,1H),8.22(s,1H),8.91(s,1H).ESI-MS m/z:706.2[M+H] + 2-(5-Amino-2-methoxy-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)phenyl)-6-(2) prepared in Step 2 ,6-Dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (70 mg) was dissolved in 2 mL of N-methylpyrrolidone Add N,N-diisopropylethylamine (54.6 mg), add 2-alkynylbutyryl chloride (0.3 mol/mL, 1 mL) with stirring at 0 ° C, continue the reaction for 0.5 hours, and use saturated hydrogen carbonate in the reaction solution. The sodium aqueous solution was quenched, extracted with ethyl acetate. 1 H-NMR (400MHz, CDCl 3): δ1.26 (m, 3H), 1.41 (m, 4H), 1.92 (t, 2H), 2.02 (s, 3H), 3.25 (s, 2H), 3.47 ( t, 2H), 3.72 (m, 4H), 3.94 (s, 3H), 3.96 (s, 6H), 4.61 (q, 2H), 6.48 (s, 1H), 6.64 (s, 1H), 7.32 (s) , 1H), 7.59 (s, 1H), 8.22 (s, 1H), 8.91 (s, 1H). ESI-MS m/z: 706.2 [M+H] +
实施例28：N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)-2-(7-乙基-2,7-二氮杂螺[4.4]壬烷-2-基)-4-甲氧基苯基)丙烯酰胺的制备Example 28: N-(5-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl)-2-(7-ethyl-2,7-diazaspiro[4.4]decane-2-yl)-4-methoxyphenyl)propene Preparation of amide
Figure PCTCN2018085940-appb-000137
Figure PCTCN2018085940-appb-000137
制备方法类似于实施例14，不同的是将步骤10中的原料化合物N 1-(5-甲氧基-2-硝基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-N 1，N 2，N 2-三甲基乙烷-1,2-二胺为实施例10步骤4所得物2-乙基-7-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-2,7-二氮杂螺[4.4]壬烷。 The preparation method is similar to that of Example 14, except that the starting compound N 1 -(5-methoxy-2-nitro 4-(4,4,5,5-tetramethyl-1,3) in Step 10 is prepared. ,2-dioxaborolan-2-yl)phenyl)-N 1 ,N 2 ,N 2 -trimethylethane-1,2-diamine is the product of step 4 of Example 10 2-B 7-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base)-2,7-diazaspiro[4.4]decane.
1H-NMR(400MHz,DMSO-d 6):δ1.03(t,3H),1.29(t,3H),1.74-1.90(m,4H),2.50-2.67(m,4H),3.26-3.45(m,4H),3.44(q,2H),3.89(s,3H),3.97(s,6H),4.46(q,2H),5.70(d,1H),6.19(d,1H),6.22(m,1H),6.23-6.47(m,1H),7.02(s,1H),7.82(s,1H),7.96(s,1H),9.07(s,1H),9.52(s,1H).ESI-MS m/z:707.2[M+H] + 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.03 (t, 3H), 1.29 (t, 3H), 1.74-1.90 (m, 4H), 2.50 - 2.67 (m, 4H), 3.26 - 3.45 (m, 4H), 3.44 (q, 2H), 3.89 (s, 3H), 3.97 (s, 6H), 4.46 (q, 2H), 5.70 (d, 1H), 6.19 (d, 1H), 6.22 ( m,1H), 6.23-6.47 (m, 1H), 7.02 (s, 1H), 7.82 (s, 1H), 7.96 (s, 1H), 9.07 (s, 1H), 9.52 (s, 1H). -MS m/z: 707.2 [M+H] +
实施例29：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶基-7-基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)丙烯酰胺的制备Example 29: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridinyl-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide
Figure PCTCN2018085940-appb-000138
Figure PCTCN2018085940-appb-000138
制备方法同实施例1，不同的是将原料N-甲基哌嗪替换为N,N,N'-三甲基乙二胺制得标题化合物。 1H-NMR(500MHz,CDCl 3-d 6):δ1.46(s,3H),1.73(s,6H),2.41(t,2H),2.80(s,3H),2.94(t,2H),3.98(s,6H),4.49(dd,2H),5.79(d,1H),6.46(m,1H),6.52(d,1H),6.67(s,1H,ArH),7.39(d,1H,ArH),7.68(s,1H,ArH),7.72(s,1H,ArH),7.87(d,1H,ArH),8.88(s,1H,ArH),9.27(s,1H,ArH),10.34(s,1H,NH).ESI-MS m/z:624.2[M+H] +. The preparation method was the same as in Example 1, except that the starting material N-methylpiperazine was replaced with N,N,N'-trimethylethylenediamine to give the title compound. 1 H-NMR (500MHz, CDCl 3 -d 6 ): δ 1.46 (s, 3H), 1.73 (s, 6H), 2.41 (t, 2H), 2.80 (s, 3H), 2.94 (t, 2H) , 3.98 (s, 6H), 4.49 (dd, 2H), 5.79 (d, 1H), 6.46 (m, 1H), 6.52 (d, 1H), 6.67 (s, 1H, ArH), 7.39 (d, 1H) , ArH), 7.68 (s, 1H, ArH), 7.72 (s, 1H, ArH), 7.87 (d, 1H, ArH), 8.88 (s, 1H, ArH), 9.27 (s, 1H, ArH), 10.34 (s, 1H, NH). ESI-MS m/z: 624.2 [M+H] + .
实施例30：N-(5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-萘啶-7-基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备Example 30: N-(5-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1 Of 6-naphthyridin-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide
Figure PCTCN2018085940-appb-000139
Figure PCTCN2018085940-appb-000139
制备方法同实施例6，不同的是将原料乙酰基哌嗪替换成N,N,N’-三甲基乙二胺。 1H-NMR(400MHz，CDCl 3)：δ10.13(s,1H),9.00(s,1H),8.87(s,1H),7.82(s,1H),7.76(s,1H),6.90(s,1H),6.65(s,1H),6.42-6.42(m,1H),6.35-6.28(m,1H),5.71-5.68(m,1H),4.42-4.14(m,2H),3.96(s,6H),3.91(s,3H),2.94(s,2H),2.79(s,3H),2.39(s,2H),2.79(s,6H),1.42(t,3H).ESI-MS m/z:654.2[M+H] + . The preparation method was the same as in Example 6, except that the starting material acetylpiperazine was replaced with N,N,N'-trimethylethylenediamine. 1 H-NMR (400MHz, CDCl 3): δ10.13 (s, 1H), 9.00 (s, 1H), 8.87 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 6.90 ( s, 1H), 6.65 (s, 1H), 6.42-6.42 (m, 1H), 6.35-6.28 (m, 1H), 5.71-5.68 (m, 1H), 4.42-4.14 (m, 2H), 3.96 ( s, 6H), 3.91 (s, 3H), 2.94 (s, 2H), 2.79 (s, 3H), 2.39 (s, 2H), 2.79 (s, 6H), 1.42 (t, 3H). ESI-MS m/z: 654.2 [M+H] + .
利用不同的原料按照本发明实施例1-30的合成方法合成实施例31-53，实施例31-53的表征参数如表1所示：Examples 31-53 were synthesized according to the synthesis method of Examples 1-30 of the present invention using different raw materials, and the characterization parameters of Examples 31-53 are shown in Table 1:
表1：Table 1:
Figure PCTCN2018085940-appb-000140
Figure PCTCN2018085940-appb-000140
Figure PCTCN2018085940-appb-000141
Figure PCTCN2018085940-appb-000141
Figure PCTCN2018085940-appb-000142
Figure PCTCN2018085940-appb-000142
Figure PCTCN2018085940-appb-000143
Figure PCTCN2018085940-appb-000143
实施例49：N-(2-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-二氮杂萘-7-基)-4-甲氧基苯基)丁-2-炔酰胺的制备Example 49: N-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-(3-(2,6-dichloro-3,5-di) Methoxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-diazaphthalen-7-yl)-4-methoxyphenyl)but-2- Preparation of alkyne amide
Figure PCTCN2018085940-appb-000144
Figure PCTCN2018085940-appb-000144
步骤1：7-(4-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-2-甲氧基-5-硝基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 1: 7-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxy-5-nitrophenyl)-3-(2, Preparation of 6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000145
Figure PCTCN2018085940-appb-000145
将7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(170mg，0.41mmol)溶于3.4mL 1,4-二氧六环和0.85mL水中，加入5-(5-甲氧基-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(170mg，0.45mmol)，四三苯基磷钯(47.7mg，0.04mmol)，碳酸钠(143mg，1.36mmol)，氩气保护，100℃加热搅拌2小时后，反应完成。冷却放置过夜，次日过滤得到黄色固体，并溶于二氯甲烷后，水洗，旋干后加入乙酸乙酯打浆后过滤，得标题化合物。ESI-MS m/z:627.26[M+H] +. 7-Chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (170 mg, 0.41 mmol) Dissolved in 3.4 mL of 1,4-dioxane and 0.85 mL of water, and added 5-(5-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (170 mg, 0.45 mmol), tetratriphenylphosphine palladium (47.7 mg, 0.04 mmol), sodium carbonate (143 mg, 1.36 mmol), argon gas, and stirred at 100 ° C for 2 hours, the reaction was completed. After cooling, it was allowed to stand overnight. The title compound was obtained. ESI-MS m/z: 627.26 [M+H] + .
步骤2：7-(5-氨基-4-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-2-甲氧基苯基)-3-(2,6-二氯-3,5- 二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮的制备Step 2: 7-(5-Amino-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxyphenyl)-3-(2,6 Of 2-dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2018085940-appb-000146
Figure PCTCN2018085940-appb-000146
将7-(4-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-2-甲氧基-5-硝基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(124.2mg，0.198mmol)溶于2.48mL乙醇和0.62mL水中，加入铁粉(111mg，1.98mmol)和氯化铵(105mg，1.98mmol)，100℃下回流反应2h。反应完成后，放置室温冷却，向反应液中加入饱和碳酸氢钠水溶液中和，然后加入20ml二氯甲烷，过滤，取有机层干燥旋干后加入乙酸乙酯打浆后过滤得标题化合物。ESI-MS m/z:597.20[M+H] +. 7-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxy-5-nitrophenyl)-3-(2,6- Dichloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (124.2 mg, 0.198 mmol) was dissolved in 2.48 mL of ethanol and 0.62 mL of water. Iron powder (111 mg, 1.98 mmol) and ammonium chloride (105 mg, 1.98 mmol) were added, and the mixture was refluxed at 100 ° C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated. ESI-MS m/z: 597.20 [M+H] + .
步骤3：N-(2-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-5-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-2-氧代-1,2-二氢-1,6-二氮杂萘-7-基)-4-甲氧基苯基)丁-2-炔酰胺的制备Step 3: N-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-(3-(2,6-dichloro-3,5-dimethyl) Oxyphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-diazaphthalen-7-yl)-4-methoxyphenyl)but-2-yne Preparation of amide
Figure PCTCN2018085940-appb-000147
Figure PCTCN2018085940-appb-000147
将7-(5-氨基-4-(2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-2-甲氧基苯基)-3-(2,6-二氯-3,5-二甲氧基苯基)-1-乙基-1,6-萘啶-2(1H)-酮(94.5mg，0.158mmol)溶于1.6mL二氯甲烷，加入二异丙基乙基胺(61.5mg，0.476mmol)，-5℃搅拌下滴入2-炔基丁酰氯0.4mL(0.6mol/L，0.238mmol)，搅拌15分钟，加入20mL饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机相，干燥旋干柱层析得标题化合物。 1H-NMR(400MHz,DMSO-d 6):δ1.30(t,3H),1.87(s,2H),2.02(s,3H),3.05(d,1H),3.65(d,1H),3.80(d,1H),3.91(d,1H),3.95(s,3H),3.97(s,6H),4.30(q,2H),4.61(s,1H),4.65(s,1H),6.42(s,1H),7.01(s,1H),7.74(s,1H),7.97(s,1H),8.04(s,1H),8.91(s,1H),9.86(s,1H).ESI-MS m/z:663.2[M+H] +. 7-(5-Amino-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-methoxyphenyl)-3-(2,6-di Chloro-3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (94.5 mg, 0.158 mmol) was dissolved in 1.6 mL of dichloromethane. Propylethylamine (61.5 mg, 0.476 mmol), 0.4 mL (0.6 mol/L, 0.238 mmol) of 2-alkynylbutanoyl chloride was added dropwise with stirring at -5 ° C, stirred for 15 minutes, and 20 mL of saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with dichloromethane, and the combined organic layers were evaporated to dry 1 H-NMR (400MHz, DMSO -d 6): δ1.30 (t, 3H), 1.87 (s, 2H), 2.02 (s, 3H), 3.05 (d, 1H), 3.65 (d, 1H), 3.80 (d, 1H), 3.91 (d, 1H), 3.95 (s, 3H), 3.97 (s, 6H), 4.30 (q, 2H), 4.61 (s, 1H), 4.65 (s, 1H), 6.42 (s, 1H), 7.01 (s, 1H), 7.74 (s, 1H), 7.97 (s, 1H), 8.04 (s, 1H), 8.91 (s, 1H), 9.86 (s, 1H). MS m/z: 663.2 [M+H] + .
比较例1和比较例2Comparative Example 1 and Comparative Example 2
Figure PCTCN2018085940-appb-000148
Figure PCTCN2018085940-appb-000148
参照专利申请WO2015/4108992中关于Compound Numbers 19和27描述的方法制备比较例1(化合物A)和比较例2(化合物B)的化合物，并通过氢谱和质谱鉴定。Compounds of Comparative Example 1 (Compound A) and Comparative Example 2 (Compound B) were prepared by the methods described in Compound No. WO 2015/4108992 for Compound Numbers 19 and 27, and identified by hydrogen spectroscopy and mass spectrometry.
比较例3Comparative example 3
Figure PCTCN2018085940-appb-000149
Figure PCTCN2018085940-appb-000149
化合物名称为N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide(BLU-554)，参照WO2015/061572中Compound 40化合物的合成方法制备，并通过氢谱和质谱鉴定。The compound name is N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (BLU-554), prepared by the synthesis method of Compound 40 compound in WO2015/061572, and identified by hydrogen spectrum and mass spectrometry.
使用以下实验例1、2和3的方法测试了化合物A、化合物B和化合物C对FGFR4激酶和FGFR1激酶的抑制活性，对人肝癌细胞株Hep3B细胞和HUH-7细胞的抑制活性，以及在小鼠中的药代动力学特征。实验结果显示，化合物A、化合物B、化合物C对FGFR4激酶和FGFR1激酶的选择性明显低于本发明的化合物，对人肝癌细胞株Hep3B细胞和HUH-7细胞的抑制活性明显弱于本发明的化合物，以及半衰期和AUC也差于本发明的化合物。The inhibitory activities of Compound A, Compound B and Compound C against FGFR4 kinase and FGFR1 kinase, and the inhibitory activities against human hepatoma cell lines Hep3B and HUH-7 cells, and small were tested using the following Experimental Examples 1, 2 and 3. Pharmacokinetic characteristics in mice. The results of the experiment showed that the selectivity of Compound A, Compound B and Compound C to FGFR4 kinase and FGFR1 kinase was significantly lower than that of the present invention, and the inhibitory activity against human hepatoma cell line Hep3B cells and HUH-7 cells was significantly weaker than that of the present invention. The compounds, as well as the half-life and AUC, are also inferior to the compounds of the invention.
实验例1体外激酶活性评价Experimental Example 1 Evaluation of in vitro kinase activity
1实验材料1 experimental material
FGFR1，购自Carna，商品目录号08-133；FGFR1, purchased from Carna, catalog number 08-133;
FGFR4，购自Carna，商品目录号08-136；FGFR4, purchased from Carna, catalog number 08-136;
P22peptide，购自GL Biochem，商品目录号112393；P22peptide, available from GL Biochem, catalog number 112393;
Staurosporine9，购自Sigma，商品目录号S4400-1MG；Staurosporine 9, purchased from Sigma, catalog number S4400-1MG;
2实验方法2 experimental methods
1)准备1×激酶基础缓冲液和终止缓冲液1) Prepare 1× Kinase Base Buffer and Stop Buffer
A.1×激酶基础缓冲液：20mM HEPES、pH 7.5，0.01％Triton X-100，10mM MgCl 2，2mM DTT。 A.1 × Kinase Buffer basis: 20mM HEPES, pH 7.5,0.01% Triton X-100,10mM MgCl 2, 2mM DTT.
B.终止缓冲液：100mM HEPES、pH7.5，0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA。B. Stop buffer: 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.
2)准备化合物2) Preparing compounds
A.配制本发明实施例的化合物以及参照化合物A、化合物B、化合物C的10mM储备液。A. A 10 mM stock solution of the compound of the examples of the invention and reference compound A, compound B, and compound C was prepared.
B.准备50×化合物溶液：以上本发明实施例的化合物和参照化合物从500μM开始，用DMSO依次3倍稀释，共10个浓度。B. Preparation of 50× compound solution: The above compounds of the examples of the present invention and the reference compound were diluted from 500 μM in three-fold dilutions with DMSO for a total of 10 concentrations.
C.在同一块96孔板的2个空的孔中各加入100μL 100％DMSO作为无化合物和无激酶对照。标记此96孔板为来源板。C. 100 μL of 100% DMSO was added to each of the 2 empty wells of the same 96-well plate as a no-compound and no kinase control. Mark this 96-well plate as the source plate.
D.准备中间板：从来源板中转移10μL化合物到新的96孔板中，作为中间板；在中间板每孔中加入90μL 1×激酶缓冲液；振荡混匀10min。D. Preparation of the intermediate plate: Transfer 10 μL of the compound from the source plate to a new 96-well plate as an intermediate plate; add 90 μL of 1×kinase buffer to each well of the middle plate; mix by shaking for 10 min.
3)准备实验板：从96孔中间板中，每孔转移5μL到384孔板中，2复孔。3) Prepare the experimental plate: Transfer 5 μL to 384-well plate per well from the 96-well intermediate plate, 2 duplicate wells.
4)激酶反应4) Kinase reaction
A.准备2.5×激酶溶液：将激酶分别加入到1×基础缓冲液中。A. Preparation of a 2.5X Kinase Solution: The kinases were separately added to 1X base buffer.
B.准备2.5×多肽溶液：将FAM标记的多肽和ATP加到1×基础缓冲液中。B. Preparation of 2.5 x polypeptide solution: The FAM-labeled polypeptide and ATP were added to 1 x basal buffer.
C.实验板中已含5μL化合物(10％DMSO)。C. The assay plate contained 5 μL of compound (10% DMSO).
D.转移2.5×激酶溶液到实验板中：加10μL 2.5×激酶溶液到384孔实验板的各孔中。D. Transfer the 2.5X kinase solution to the assay plate: Add 10 μL of 2.5× kinase solution to each well of a 384-well assay plate.
E.室温孵育10min。E. Incubate for 10 min at room temperature.
F.转移2.5×多肽溶液到实验板中：加10μL 2.5×多肽溶液到384孔实验板的各孔中。F. Transfer the 2.5 x polypeptide solution to the assay plate: Add 10 μL of 2.5 x polypeptide solution to each well of a 384-well assay plate.
G.激酶反应和终止：在28℃条件下孵育一定的时间；加入25μL终止缓冲液终止反应。G. Kinase reaction and termination: Incubate at 28 °C for a certain period of time; stop the reaction by adding 25 μL of Stop Buffer.
5)Caliper仪器读数：在Caliper仪器上读取数据。5) Caliper instrument reading: Read data on the Caliper instrument.
6)拟合曲线6) Fitting curve
A.从Caliper程序中获得转化值数据。A. Obtain conversion value data from the Caliper program.
B.将转化值转换成抑制率。B. Convert the conversion value to inhibition rate.
抑制率％＝(最大转化值–实际转化值)/(最大转化值–最小转化值)×100，其中“最大转化值”代表有激酶无化合物的DMSO溶媒对照，“最小转化值”代表无激酶无化合物对照。Inhibition rate % = (maximum conversion value - actual conversion value) / (maximum conversion value - minimum conversion value) × 100, where "maximum conversion value" represents a DMSO vehicle control with no compound, and "minimum conversion value" represents no kinase No compound control.
C.采用Xlfit excel add-in 4.3.1数据处理软件计算IC 50值。计算公式：Y＝Bottom+(Top–Bottom)/(1+LogIC 50/X)×HillSlope)，结果见表2： C. IC 50 values were calculated using Xlfit excel add-in 4.3.1 data processing software. Calculate the formula: Y=Bottom+(Top–Bottom)/(1+LogIC 50 /X)×HillSlope), the results are shown in Table 2:
表2Table 2
化合物编号Compound number FGFR4激酶IC 50(nM) FGFR4 kinase IC 50 (nM) FGFR1激酶IC 50(nM) FGFR1 kinase IC 50 (nM)
化合物ACompound A 3434 200200
化合物BCompound B 8585 --
实施例6Example 6 3.63.6 >5000>5000
实施例8Example 8 3.33.3 31433143
实施例9Example 9 1212 40414041
实施例10Example 10 1010 983983
实施例12Example 12 3.23.2 527527
实施例13Example 13 2727 10341034
实施例15Example 15 6.36.3 18141814
实施例19Example 19 8.38.3 413413
实施例20Example 20 4040 39153915
实施例22Example 22 6.86.8 >5000>5000
实施例23Example 23 23twenty three 1077210772
实施例27Example 27 1515 34203420
实施例30Example 30 4.04.0 27992799
化合物编号Compound number FGFR4激酶IC 50(nM) FGFR4 kinase IC 50 (nM) FGFR1激酶IC 50(nM) FGFR1 kinase IC 50 (nM)
实施例31Example 31 0.370.37 593.13593.13
实施例32Example 32 4.24.2 42844284
实施例34Example 34 1818 25312531
实施例35Example 35 6.36.3 >5000>5000
实施例40Example 40 7.67.6 15161516
实施例43Example 43 7.87.8 >5000>5000
实施例44Example 44 7.77.7 >5000>5000
实施例45Example 45 9.49.4 31723172
实施例48Example 48 4.84.8 779779
实施例49Example 49 5.55.5 21492149
实施例50Example 50 7.77.7 >5000>5000
实施例51Example 51 0.820.82 585.38585.38
实施例52Example 52 0.960.96 127.56127.56
实施例53Example 53 0.780.78 840.79840.79
实施例59Example 59 6.66.6 275275
化合物CCompound C 1313 653653
实验结果表明，本发明的化合物对FGFR4激酶具有强的抑制活性，对FGFR1激酶的抑制活性低，对FGFR4激酶和FGFR1激酶的选择性明显优于参照化合物。因此，本发明的化合物是选择性针对FGFR4的有活性优势的激酶抑制剂，可用于治疗与FGFR4激酶相关的疾病，并可能降低因对FGFR1激酶的抑制而导致的副作用。The experimental results show that the compound of the present invention has strong inhibitory activity against FGFR4 kinase, low inhibitory activity against FGFR1 kinase, and selectivity to FGFR4 kinase and FGFR1 kinase is significantly superior to that of the reference compound. Thus, the compounds of the invention are potent kinase inhibitors that are selective for FGFR4, are useful in the treatment of diseases associated with FGFR4 kinase, and may reduce the side effects caused by inhibition of FGFR1 kinase.
实验例2细胞增殖抑制实验Experimental Example 2 Cell proliferation inhibition experiment
1实验材料1 experimental material
1.1化合物：使用本发明实施例的化合物、化合物A、化合物C进行该实验。1.1 Compound: This experiment was carried out using the compound of the examples of the present invention, Compound A, and Compound C.
1.2细胞：Hep3B细胞、HUH-7细胞，由上海药明康德新药开发有限公司提供。1.2 Cells: Hep3B cells, HUH-7 cells, provided by Shanghai WuXi PharmaTech Development Co., Ltd.
1.3试剂：FBS、DMEM，培养基购于GIBCO公司；CellTiter Glo，购于Promega公司。1.3 Reagents: FBS, DMEM, medium purchased from GIBCO; CellTiter Glo, purchased from Promega.
1.4仪器Tecan D300e快速移液器；Biotek荧光检测仪1.4 instrument Tecan D300e fast pipette; Biotek fluorescence detector
2实验方法2 experimental methods
所有化合物溶于DMSO后储存于-20℃冰箱中。All compounds were dissolved in DMSO and stored in a -20 ° C freezer.
Day-1：按3X10 3个细胞/孔的密度将细胞加入96孔内，每孔100μl； Day-1: cells were added to 96 wells at a density of 3 ×10 3 cells/well, 100 μl per well;
空白对照加入每孔100μl的培养基；其余不测试的边缘孔加入100μl的PBS；Add 100 μl of medium per well to the blank control; add 100 μl of PBS to the remaining unmeasured edge wells;
Day 0：设置化合物加样程序，并使用Tecan D300e自动加样；测试化合物的起始浓度为10μM，3倍稀释，9浓度，复孔；阳性参照Staurosporine起始浓度为1μM，3倍稀释，9个浓度，复孔；Day 0: Set the compound loading procedure and auto-load using Tecan D300e; the starting concentration of the test compound is 10 μM, 3-fold dilution, 9 concentration, duplicate well; positive reference Staurosporine initial concentration is 1 μM, 3-fold dilution, 9 Concentration
Day 3:将实验96孔板室温平衡30分钟；在加入CTG前观察化合物溶解性和细胞状态；每孔加入50μl CellTiter Glo试剂，10分钟后用BioTec(Luminescence)检测信号。Day 3: The experimental 96-well plates were equilibrated at room temperature for 30 minutes; compound solubility and cell status were observed before addition of CTG; 50 μl of CellTiter Glo reagent was added to each well, and signal was detected with BioTec (Luminescence) 10 minutes later.
3数据分析：3 data analysis:
XL-fit软件分析数据(供应商：ID Business Solution Ltd.,版本：XL fit 5.0)XL-fit software analysis data (supplier: ID Business Solution Ltd., version: XL fit 5.0)
计算公式：R(％)＝{1-RLU 化合物-RLU 空白}/{RLU 对照-RLU 空白}×100％ Calculation formula: R (%) = {1-RLU compound - RLU blank } / {RLU control - RLU blank } × 100%
结果见表3：The results are shown in Table 3:
表3table 3
Figure PCTCN2018085940-appb-000150
Figure PCTCN2018085940-appb-000150
“-”表示未测"-" means untested
实验结果显示，本发明的化合物对FGFR4DNA扩增的人肝癌细胞株HePB和HuH-7细胞的增殖具有非常好的抑制活性，部分化合物的活性远优于参照化合物，是有效的FGFR4选择性抑制剂。The experimental results show that the compound of the present invention has a very good inhibitory activity on the proliferation of human hepatoma cell lines HePB and HuH-7 expanded by FGFR4 DNA, and some compounds are far superior to the reference compound and are effective FGFR4 selective inhibitors. .
实验例3药物代谢实验Experimental Example 3 Drug Metabolism Experiment
1实验材料1 experimental material
1.1化合物1.1 compound
使用本发明实施例的化合物以及参照化合物A、化合物B和化合物C进行该实验。口服药物配方为10％乙醇，10％solutol，80％生理盐水溶解，制成0.5mg/ml澄清溶液，静脉药物配方为2％乙醇，2％solutol，96％生理盐水，制成0.1mg/ml澄清溶液。This experiment was carried out using the compound of the examples of the present invention and the reference compound A, compound B and compound C. Oral drug formula is 10% ethanol, 10% solutol, 80% physiological saline dissolved, made 0.5mg/ml clear solution, intravenous drug formula is 2% ethanol, 2% solutol, 96% normal saline, made 0.1mg/ml Clarify the solution.
1.2动物1.2 animals
雄性BALB/c小鼠，每组各3只，体重18-22，上海西普尔-必凯实验动物有限公司提供。受试小鼠实验前给予2～4天的环境适应期，给药前禁食8-12h，给药2h后给水，4h后给食。Male BALB/c mice, 3 in each group, weighing 18-22, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
1.3试剂1.3 reagent
甲醇(色谱纯)：Spectrum公司生产；乙腈(色谱纯)：Spectrum公司生产；Methanol (chromatographically pure): produced by Spectrum; acetonitrile (chromatographically pure): produced by Spectrum;
其余试剂均为市售分析纯。The remaining reagents were all commercially available analytical grades.
1.4仪器1.4 Instrument
美国AB公司API4500型三重四级杆液质联用仪，配有电喷雾离子源(ESI)，LC-30AD双泵；SIL-30AC自动进样器；CTO-30AC柱温箱；DGU-20A3R脱气机；AnalystQSA01.01色谱工作站；Milli-Q超纯水器(Millipore Inc)；QilinbeierVortex-5振荡器；HITACHI CF16RⅩⅡ台式高速冷冻离心机。American AB company API4500 triple quadrupole liquid-mass instrument with electrospray ion source (ESI), LC-30AD double pump; SIL-30AC autosampler; CTO-30AC column thermostat; DGU-20A3R off Gas machine; AnalystQSA01.01 chromatography workstation; Milli-Q ultrapure water (Millipore Inc); QilinbeierVortex-5 oscillator; HITACHI CF16RXII desktop high speed refrigerated centrifuge.
2实验方法2 experimental methods
1)小鼠禁食但可自由饮水12小时后，采取0时刻空白血浆；1) The mice were fasted but allowed to drink water for 12 hours, and the blank plasma was taken at 0 o'clock;
2)取步骤1)中的小鼠3只，灌胃(intragastric administration,I.G.)给予本发明实施例的化合物以及参照化合物10mg/kg；静脉(I.V.)给予本发明实施例的化合物以及参照化合物1mg/kg；2) 3 mice in step 1), intragastric administration (IG) were administered with the compound of the examples of the present invention and the reference compound 10 mg/kg; the compound of the present invention and the reference compound 1 mg were administered intravenously (IV). /kg;
3)于灌胃后5min，15min，30min，1h，2h，4h，8h，10h，24h，从眼底静脉丛连续取血置于分布有肝素的EP管中，8000rpm/min离心5min后取上层血浆，-20℃冻存，待LC-MS/MS分析；3) 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, 24 h after intragastric administration, continuous blood was taken from the fundus venous plexus in an EP tube with heparin distributed, and centrifuged at 8000 rpm/min for 5 min. , frozen at -20 ° C, to be analyzed by LC-MS/MS;
4)根据步骤3)所得的血药浓度-时间数据，采用WinNonlin软件求算药代动力学参数，结果见表4。4) According to the plasma concentration-time data obtained in step 3), the pharmacokinetic parameters were calculated using WinNonlin software, and the results are shown in Table 4.
表4Table 4
Figure PCTCN2018085940-appb-000151
Figure PCTCN2018085940-appb-000151
Figure PCTCN2018085940-appb-000152
Figure PCTCN2018085940-appb-000152
实验表明，小鼠对本发明化合物的口服吸收暴露量明显高于参照化合物，半衰期长于参照化合物，可保证化合物在小鼠体内存在着更长时间的有效血药浓度。Experiments have shown that the oral absorption of the compound of the present invention by the mouse is significantly higher than that of the reference compound, and the half-life is longer than that of the reference compound, which ensures that the compound has a longer effective blood concentration in the mouse.
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims (10)

  1. 一种通式II所示的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，a compound of the formula II or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
    Figure PCTCN2018085940-appb-100001
    Figure PCTCN2018085940-appb-100001
    其中：among them:
    弹头是能与亲核试剂形成共价键的部分；A warhead is a portion that forms a covalent bond with a nucleophile;
    X、G各自独立地选自CH和N；X, G are each independently selected from CH and N;
    环A选自氮杂环基，所述氮杂环基任选地被一个或多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基所取代；Ring A is selected from a nitrogen heterocyclic group, which is optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino Substituted with a substituent of a carboxy group, an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkyl acyl group, an alkyl acylalkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;
    各R 3、R 4、R 5各自独立地选自卤素、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、烷基酰基烷基、羟基烷基、烷氧基、氨基烷基、芳基、杂芳基和杂环烷基，其中n选自0、1和2，p选自0、1和2，以及q选自0、1、2、3、4和5； Each of R 3 , R 4 , and R 5 is independently selected from the group consisting of halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, alkyl acyl a group, a hydroxyalkyl group, an alkoxy group, an aminoalkyl group, an aryl group, a heteroaryl group and a heterocycloalkyl group, wherein n is selected from 0, 1 and 2, p is selected from 0, 1 and 2, and q is selected from 0. 1, 2, 3, 4 and 5;
    R 6选自H和任选取代的烷基；或者R 6和相邻的芳环或芳杂环与它们共同连接的氨基一起形成8-12元杂环基；和 R 6 is selected from H and optionally substituted alkyl; or R 6 and an adjacent aromatic or aromatic heterocyclic ring together with the amino group to which they are attached form an 8-12 membered heterocyclic group;
    R 7选自H和任选取代的烷基。 R 7 is selected from H and an optionally substituted alkyl group.
  2. 根据权利要求1所述的通式II的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自7元至15元氮桥杂环基，其任选地被一个或多个选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、羧基、氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、烷基酰基烷基、芳基、杂芳基、环烷基和杂环基的取代基所取代。The compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, according to Claim 1, wherein Ring A is selected from a 7- to 15-membered nitrogen bridged heterocyclic group, It is optionally selected from one or more selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, carboxy, aminoalkyl, hydroxyalkyl, alkoxy Substituents of alkyl, alkylacyl, alkylacylalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are substituted.
  3. 根据权利要求2所述的通式II的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自7元至12元氮桥杂环基，其任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。 A compound of formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, according to claim 2, wherein ring A is selected from the group consisting of 7- to 12-membered nitrogen bridged heterocyclic groups, It is optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, Cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1- Substituents of a 6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group are substituted.
  4. 根据权利要求3所述的通式II的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中环A选自以下桥杂环基：A compound of formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, according to claim 3, wherein ring A is selected from the group consisting of the following bridged heterocyclic groups:
    Figure PCTCN2018085940-appb-100002
    其任选地被一个或多个选自 卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代。
    Figure PCTCN2018085940-appb-100002
    It is optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, Cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1- Substituents of a 6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group are substituted.
  5. 根据权利要求1所述的通式II的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药，其中所述的通式II具有以下通式III的结构：A compound of formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, according to claim 1, wherein said formula II has the structure of formula III:
    Figure PCTCN2018085940-appb-100003
    Figure PCTCN2018085940-appb-100003
    其中弹头、X、G、R 3、R 4、R 5、R 6、R 7、n、p、q的定义如权利要求1所述； Wherein the warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in claim 1;
    m和d各自独立地选自1、2、3和4；m and d are each independently selected from 1, 2, 3 and 4;
    环B选自C 3-8环烷基、C 3-8氮杂环烷基、C 3-8氧杂环烷基、C 3-8氮氧杂环烷基和C 3-8硫杂环烷基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基、芳基、杂芳基、C 3-8环烷基和C 3-8杂环基的取代基所取代； Ring B is selected from C 3-8 cycloalkyl, C 3-8 azacycloalkyl, C 3-8 oxacycloalkyl group, C 3-8 nitrogen oxygen and C 3-8 heterocycloalkyl thietan An alkyl group, wherein these groups are optionally selected from one or more selected from the group consisting of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxyl, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkane Substituted with a substituent of a acyl group, a C 1-6 alkyl acyl C 1-6 alkyl group, an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, and a C 3-8 heterocyclic group;
    优选地，环B选自环戊基、环己基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡喃基和四氢呋喃基，其中这些基团任选地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、硝基、氰基、羟基、氨基、羧基、氨基C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷基酰基、C 1-6烷基酰基C 1-6烷基的取代基所取代。 Preferably, ring B is selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl and tetrahydrofuranyl, wherein these groups are optionally selected by one or more From halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, carboxy, amino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, C 1-6 alkyl acyl C 1-6 alkyl Substituted by a substituent.
  6. 根据权利要求1所述的通式II的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物选自：A compound of formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, according to claim 1, wherein said compound is selected from the group consisting of:
    Figure PCTCN2018085940-appb-100004
    Figure PCTCN2018085940-appb-100004
    Figure PCTCN2018085940-appb-100005
    Figure PCTCN2018085940-appb-100005
    Figure PCTCN2018085940-appb-100006
    Figure PCTCN2018085940-appb-100006
  7. 一种制备根据权利要求1所述的通式II的化合物或其药学上可接受的盐、异构体、溶剂合物、结晶或前药的制备方法，所述方法包括以下步骤：A process for the preparation of a compound of formula II according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, the process comprising the steps of:
    Figure PCTCN2018085940-appb-100007
    Figure PCTCN2018085940-appb-100007
    (1)、式1化合物与式2化合物通过钯介导的耦合反应得到式3化合物；(1), a compound of formula 1 and a compound of formula 2 are palladium mediated coupling reaction to give a compound of formula 3;
    (2)、将式3化合物的芳环或芳杂环上的硝基还原为氨基，得到式4化合物；(2) reducing the nitro group on the aromatic ring or the aromatic heterocyclic ring of the compound of formula 3 to an amino group to obtain a compound of formula 4;
    (3)、式4化合物与弹头-LG2通过酰胺偶联反应得到式II化合物；(3), the compound of formula 4 and the warhead-LG2 are coupled by an amide to obtain a compound of formula II;
    其中环A、弹头、X、G、R 3、R 4、R 5、R 6、R 7、n、p、q的定义如权利要求1所述； Wherein ring A, warhead, X, G, R 3 , R 4 , R 5 , R 6 , R 7 , n, p, q are as defined in claim 1;
    LG1、LG2代表离去基团，可以相同也可以不同，优选为卤素或磺酰氧基；LG1, LG2 represents a leaving group, which may be the same or different, preferably a halogen or a sulfonyloxy group;
    M可以为-B(OR 11) 2、-Sn(烷基)或者-Zn-卤素-，其中R 11为H或烷基，优选为甲基。 M may be -B(OR 11 ) 2 , -Sn(alkyl) or -Zn-halogen-, wherein R 11 is H or an alkyl group, preferably a methyl group.
  8. 一种药物组合物，其包含权利要求1-6之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体。A pharmaceutical composition comprising a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
  9. 根据权利要求1-6任一项所述的化合物或根据权利要求8所述的组合物在制备用于预防和/或***药物中的应用，优选地，所述肿瘤由FGFR4激酶介导。The use of a compound according to any one of claims 1 to 6 or a composition according to claim 8 for the preparation of a medicament for the prevention and/or treatment of a tumor, preferably the tumor is mediated by FGFR4 kinase.
  10. 根据权利要求9所述的应用，其中所述的肿瘤选自肝癌、乳腺癌、卵巢癌、肺癌和肉瘤。The use according to claim 9, wherein the tumor is selected from the group consisting of liver cancer, breast cancer, ovarian cancer, lung cancer and sarcoma.
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