WO2017202343A1 - 五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用 - Google Patents

五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用 Download PDF

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WO2017202343A1
WO2017202343A1 PCT/CN2017/085765 CN2017085765W WO2017202343A1 WO 2017202343 A1 WO2017202343 A1 WO 2017202343A1 CN 2017085765 W CN2017085765 W CN 2017085765W WO 2017202343 A1 WO2017202343 A1 WO 2017202343A1
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group
substituted
unsubstituted
compound
alkyl
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PCT/CN2017/085765
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English (en)
French (fr)
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蒋华良
柳红
耿美玉
郑明月
艾菁
王玉兰
吴小伟
李双杰
彭霞
李淳朴
陈凯先
Original Assignee
中国科学院上海药物研究所
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Priority claimed from CN201710060243.8A external-priority patent/CN107417687A/zh
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Priority to EP17802189.5A priority Critical patent/EP3470415A4/en
Priority to CN201780032658.2A priority patent/CN109641908B/zh
Priority to US16/304,508 priority patent/US20190135818A1/en
Priority to JP2018561990A priority patent/JP2019519534A/ja
Priority to AU2017269462A priority patent/AU2017269462A1/en
Publication of WO2017202343A1 publication Critical patent/WO2017202343A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/535—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a class of five-membered heterocyclic [3,4-d]pyridazinone compounds, a preparation method thereof, a pharmaceutical combination and application thereof, which have FGFR kinase inhibitory activity and can be used for treatment with FGFR enzymes.
  • Targeted therapy is a drug therapy that interferes with these signaling pathways to prevent cancer cell growth. Compared with traditional chemotherapy methods, targeted therapy can more specifically act on carcinogenic sites, inhibit tumor cell growth, and reduce Damage to normal tissue cells. So far, the FDA has approved the marketing of 26 small molecule targeted drugs, for example, imatinib, an anticancer drug based on ABL tyrosine kinase, and EGFR-based, HER2/4 tyrosine kinase.
  • Targeted therapy has a significant impact on cancer treatment, such as Afatinib and Trametinib based on MEK tyrosine kinase (Nature Reviews Clinical Oncology (2015) doi:10.1038/nrclinonc.2015.213 ).
  • FGFR fibroblast growth factor receptors
  • RTKs receptor tyrosine protein kinases
  • FGFR1, FGFR2, FGFR3, and FGFR4 receptor tyrosine protein kinases
  • FGFR1, FGFR2, FGFR3, and FGFR4 receptor subtypes
  • fibroblast growth factor binds to the FGFR receptor, induces FGFR dimerization and phosphorylates tyrosine at the end of the cytoplasmic structure of FGFR, and activates downstream FRS2-Ras-MAPK, PLC ⁇ , and PI3K- AKT/PKB signaling pathway.
  • FGFR signaling pathway is involved in the regulation of embryonic development, cell proliferation and migration, and neovascularization (Cytokine & Growth Factor Reviews 16 (2005) 233–247).
  • Activation or high expression of FGFR mutations is closely related to the development of human tumors.
  • Activation or overexpression of FGFR in cells leads to the persistence and overactivation of the FGFR signaling pathway, allowing cells to acquire carcinogenic functions such as hyperproliferation and apoptosis.
  • the study found abnormal expression of FGFR in various cancer cells, such as breast cancer, lung cancer, ovarian cancer, gastric cancer, uterine tumor, glioblastoma, bladder cancer, liver cancer, solid tumor, etc.
  • FGFR is recognized as an important target for the development of anti-tumor drugs and is one of the most popular targets for drug development.
  • carcinoma eg bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, Lung cancer, ovarian cancer, prostate cancer
  • hematopoietic malignancies eg multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, myeloproliferative neoplasms and Walden Trent's macroglobulinemia
  • other neoplasms eg, glioblastoma, melanoma, and rhabdomyosarcoma
  • FGFR activation is also implicated in bone and chondrocyte disorders including, but not limited to, achondroplasia and craniosynostosis
  • the present invention provides a novel and effective five-membered heterocyclic [3,4-d]pyridazinone FGFR small molecule inhibition structure. Agent.
  • X 1 is selected from CH, C, N; preferably CH or C;
  • X 2 and X 3 are each independently selected from CH, C, NH, N, O or S; preferably NH, N, CH or C;
  • X 4 and X 5 are C;
  • Q is selected from: a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 8-10 membered bicyclic heteroaryl group;
  • Or Q is selected from -LA, wherein L is a substituted or unsubstituted C1-C4 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a C2-C4 alkynylene group, a C1-C4 alkylene oxide group.
  • Base -(C1-C4 alkyl)-NH-, -CO-NH-, -NH-CO-;
  • A is selected from substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-8 member a cycloheteroaryl, substituted or unsubstituted 8-10 membered bicyclic heteroaryl;
  • k is selected from 0, 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4;
  • L3 is a free, or substituted or unsubstituted C1-C4 alkylene group
  • R1, R3 and R4 are each independently selected from: hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group , -(C1-C6 alkyl)-N(C1-C6 alkyl)(C1-C6 alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), or substituted or unsubstituted Phenyl group;
  • R2 is selected from hydrogen or a C1-C4 alkyl group
  • R 2 and R 3 , R 2 and R 4 together with the attached nitrogen atom constitute a substituted or unsubstituted 4-7 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, O, S, and At least one hetero atom is N;
  • R5 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, formyl, C1-C4 alkylcarbonyl, or C1-C4 alkoxycarbonyl;
  • the C1-C6 alkoxy group, a C1-C6 alkyl group, and a C1-C6 alkylamino group include a straight chain or a branched chain;
  • the C3-C6 cycloalkyl group is optionally substituted by 1 to 2 each independently selected from a C1-C4 alkyl group, a hydroxyl group, a halogen, or an amino group.
  • the 4-7 membered heterocyclic group is independently selected from 1 to 2 independently from a C1-C4 alkyl group, a C1-C4 alkoxy group, a hydroxyl group, an amino group, an oxo group, Substituted by a group in CONH 2 ;
  • the phenyl selectivity is independently selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkyl , C1-C4 alkoxy substituted.
  • the substitution refers to a hydroxyl group selected from the group consisting of a hydroxyl group, a halogen, a cyano group, a nitro group, an amino group, a carboxyl group, a —CH 2 OH, a —CONH 2 , a substituted or unsubstituted C1-C6 alkane.
  • the C1-C6 alkyl substituent is independently 1-3 selected from oxo, halogen, cyano, cyclopropyl, hydroxy, amino, -N(C1-C6 alkane) a (C1-C6 alkyl) group;
  • the substituent on the 5-10 membered heteroaryl group is selected from the group consisting of C1-C6 alkyl, -(C1-C6 alkyl)-N(C1-C6 alkyl) (C1- C6 alkyl);
  • the G is not an unsubstituted phenyl group.
  • the G is not an unsubstituted phenyl group.
  • G when G is at X 2 and Q is In the meantime, the G is not an unsubstituted phenyl group.
  • At least one of Lx 1 , Lx 2 , Lx 3 , Lx 4 and Lx 5 is -NH-.
  • At least one of Lx 1 , Lx 2 , Lx 3 , Lx 4 and Lx 5 is -C ⁇ C-.
  • Q is selected from the group consisting of a substituted or unsubstituted group: a naphthyl group, a benzo 5-6 membered monocyclic heteroaryl group, a 5-6 membered monocyclic heteroaryl group, and a 5-6 membered list.
  • a substituted or unsubstituted group a naphthyl group, a benzo 5-6 membered monocyclic heteroaryl group, a 5-6 membered monocyclic heteroaryl group, and a 5-6 membered list.
  • Or Q is selected from -LA, wherein L is unsubstituted or halogen-substituted C1-C4 alkylene, unsubstituted or halogen-substituted C2-C4 alkenylene, C2-C4 alkynylene, C1-C4 sub Alkoxy, -(C1-C4 alkyl)-NH-, -CO-NH-, -NH-CO-; A is selected from substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-6 Mono-monoheteroaryl.
  • the Q is selected from the group consisting of a substituted or unsubstituted group: naphthalene, anthracene, oxazole, isoindole, benzimidazole, benzofuran, benzothiophene, benzothiazole, Quinoline, isoquinoline, benzopyrimidine or benzopyran;
  • the L is selected from the group consisting of unsubstituted or halogen-substituted C1-C3 straight or branched alkylene, unsubstituted or halogen-substituted C2-C4 straight or branched Alkenyl, unsubstituted or halogen-substituted C2-C4 straight or branched alkynyl, -CO-NH-, -NH-CO-.
  • the A is selected from the group consisting of a substituted or unsubstituted group: pyrrolyl, furyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, phenyl, pyridyl , pyrimidinyl, pyridazinyl, pyrazinyl;
  • R1, R3, and R4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-7 membered heterocyclic group. a substituted or unsubstituted phenyl group;
  • R 2 and R 3 , R 2 and R 4 together with the attached nitrogen atom constitute a substituted or unsubstituted 4-7 membered saturated heterocyclic ring, and the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O and S, And at least one hetero atom is N;
  • R5 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, formyl, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl.
  • X 1 is C, and X 2 and X 3 are both N; or X 1 is C, X 2 is CH and X 3 is N; or X 1 is C, X 2 is C and X 3 is N.
  • X 1 , X 2 , X 3 , X 4 , X 5 , Q, G, -Lx 1 - Lx 2 - Lx 3 - Lx 4 - Lx 5 - M, A, m, L1 L3, R 1 , R 2 , R 3 and R 4 are each independently a group corresponding to each compound in the examples.
  • the compound is selected from the group consisting of compounds A1-A92.
  • X 1 , X 2 , X 3 , X 4 , X 5 , Q and G have the same definitions as described above;
  • R x is selected from C 1 -C 6 alkyl;
  • the compound of formula (I)-1 is cyclized with hydrazine hydrate to give a compound of formula (I).
  • Rx is methyl or ethyl.
  • a third aspect of the invention provides a use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for:
  • the disease associated with FGFR activity or expression is selected from the group consisting of a carcinoma, a hematopoietic malignant disease, other neoplasms, bone and chondrocyte disorders, hypophosphatemia, fibrotic diseases, psoriasis , plaque tumor, bullous skin disease, atherosclerosis, restenosis, mesangial cell proliferation disease, glomerular disease, diabetic nephropathy, nephropathy and benign prostatic hyperplasia, eye disease, and craniosynostosis
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer , esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, multiple mye
  • the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, or a combination thereof; and/or
  • the tumor cells are a gastric cancer cell line, a lung cancer cell line, a leukemia cell line, a bladder cancer cell line, and a liver cancer cell line.
  • the disease associated with FGFR kinase activity or expression is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, and renal cancer.
  • the patented compound is useful for preventing or inhibiting metastasis of a general tumor.
  • a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) pharmaceutically acceptable a.
  • the effective amount means a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.9%.
  • the pharmaceutical composition is for inhibiting FGFR kinase activity.
  • the pharmaceutical combination is for treating a disease associated with FGFR kinase activity or expression.
  • a fifth aspect of the invention provides a method of inhibiting FGFR kinase activity, comprising the steps of: administering to a subject, an inhibitory effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable compound thereof The salt is accepted, or an inhibitory effective amount of the pharmaceutical composition according to the fourth aspect of the invention is administered to the subject.
  • the inhibition is inhibition in vivo or inhibition in vitro.
  • FIG. 1 A26 inhibits the growth of human lung cancer NCI-H1581 nude mice xenografts
  • FIG. 1 Growth pattern of human lung cancer NCI-H1581 nude mice transplanted with Somcl-15-290.
  • the present inventors prepared a class of compounds having the structure shown in Formula I based on long-term and intensive research and found that they have FGFR kinase inhibitory activity. And the compound can inhibit the activity of FGFR kinase activity or expression at a very low concentration (as low as ⁇ 100nmol/L), that is, an inhibitory effect on a series of FGFR kinases, and the inhibitory activity is quite excellent. Such as tumors. Based on the above findings, the inventors completed the present invention.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl, or the like.
  • the definition of "C1-C6 alkyl” includes “C1-C4 alkyl”.
  • C1-C6 alkylene group means a group formed after the loss of a hydrogen atom a C1-C6 alkyl group, e.g. -CH 2 -, - CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 - and -CH 2 -CH(CH 3 )-CH 2 -, or a similar group.
  • C1-C6 alkylene includes "C1-C4 alkylene".
  • C2-C6 alkenyl refers to a straight or branched chain group having 1-3 double bonds and 2 to 6 carbon atoms, such as ethenyl, propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, a 2-methyl-1-propenyl group, a 1,3-butadienyl group, a 1,3,5-hexanetrienyl group, or the like.
  • the definition of "C2-C6 alkenyl” includes “C2-C4 alkenyl”.
  • the definition of "C2-C6 alkenylene” includes “C2-C4 alkenylene”.
  • C2-C6 alkynyl refers to straight-chain and branched-chain groups having 1-3 triple bonds and 2 to 6 carbon atoms, such as ethynyl, propynyl, 1-butynyl, 2-butyne A group, a 1-pentynyl group, a 2-pentynyl group, a 3-methyl-1-butynyl group, a 1-hexyne group, a 1,3-hexadiynyl group, and a 3-hexynyl group, or the like.
  • the definition of "C2-C6 alkynyl” includes “C2-C4 alkynyl”.
  • C2-C6 alkynylene refers to a group formed after the C2-C6 alkynyl group has lost a hydrogen atom, such as -C ⁇ C- and -CH 2 C ⁇ C-, or the like.
  • the definition of "C2-C6 alkynylene” includes “C2-C4 alkynylene”.
  • C6-C12 aryl refers to a monocyclic or fused bicyclic ring having 6 to 12 carbon atoms, a substituent having a conjugated ⁇ -electron system, such as a phenyl group and a naphthyl group, or the like.
  • the definition of "C6-C12 aryl” includes “C6-C10 aryl”.
  • C6-C12 arylene refers to a group formed after the C6-C12 aryl group has lost a hydrogen atom, and includes a monocyclic or bicyclic arylene group such as a phenylene group, a naphthylene group, or the like.
  • the definition of "C6-C12 arylene” is included “C6-C10 arylene”.
  • 5-12 membered heteroaryl refers to a monocyclic or fused polycyclic ring having 5-12 members and having one or more heteroatoms selected from O, S, N or P heteroatoms on the ring system.
  • the substituent is preferably a 5- to 10-membered monocyclic or fused bicyclic ring and has 1 to 5 hetero atoms selected from O, S, N or P on the ring system, further preferably from a 5-8 membered monocyclic heteroaryl group.
  • an 8-10 membered bicyclic heteroaryl group preferably selected from the group consisting of a 5-6 membered monocyclic heteroaryl group, a benzo 5-6 membered monocyclic heteroaryl group, a 5-6 membered monocyclic heteroaryl group, and a 5-6 membered list.
  • Cycloheteroaryl such as pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuranyl, fluorenyl, oxazolyl, isodecyl, benzimidazolyl, benzothiophene
  • C3-C8 cycloalkyl refers to a saturated carbocyclic group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or the like.
  • the definition of “C3-C8 cycloalkyl” includes “C3-C6 cycloalkyl”.
  • C3-C8 cycloalkylene refers to a group formed after a C3-C8 cycloalkyl group loses a hydrogen atom, such as a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, and a cyclohexylene group, or the like. group.
  • the definition of "C3-C8 cycloalkylene” includes “C3-C6 cycloalkylene".
  • C3-C8 cycloalkenyl refers to a carbocyclic group having from 3 to 8 carbon atoms and having from 1 to 3 double bonds but not having a fully conjugated ⁇ -electron system, such as a cyclopropenyl group or a cyclobutenyl group. , cyclohexadienyl and cycloheptatrienyl, or the like.
  • the definition of "C3-C8 cycloalkenyl” includes “C3-C6 cycloalkenyl”.
  • 3-12 membered heterocyclic group refers to a monocyclic or fused bicyclic ring having 3 to 12 members and having one or more (preferably 1 to 5) heterocyclic groups selected from O, S, N or P on the ring system.
  • a saturated ring system substituent of an atom such as piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, or the like.
  • the definition of "3-12 membered heterocyclic group” includes "4-7 membered heterocyclic group”.
  • halogen means fluoro, chloro, bromo or iodo; preferably fluoro, chloro or bromo.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy and tert-butoxy, or the like.
  • the definition of "C1-C6 alkoxy” includes “C1-C4 alkoxy”.
  • C1-C6 alkyleneoxy refers to a group formed after the C1-C6 alkoxy group loses a hydrogen atom, such as -OCH 2 -, -OCH 2 -CH 2 -, -OCH(CH 3 )-, - OCH 2 -CH 2 -CH 2 -, -OCH 2 -CH(CH 3 )-, and -OCH 2 -CH(CH 3 )-CH 2 -, or the like.
  • the definition of "C1-C6 alkyleneoxy” includes "C1-C4 alkyleneoxy".
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the present invention provides a compound of formula I:
  • the compound of the formula (I) according to the invention and its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof are particularly preferably selected from one of the following compounds:
  • the present invention also provides a process for the preparation of the compound of the formula (I).
  • the materials and reagents used in the present invention are commercially available unless otherwise specified.
  • a method for preparing a racemate, a mixture thereof, a pharmaceutically acceptable salt thereof, a water of crystallization or a solvate, and the reaction route is as follows:
  • X 1 , X 2 , X 3 , X 4 , X 5 , Q and G have the same definitions as described above;
  • Rx is selected from C1-C6 alkyl, preferably from methyl or ethyl;
  • the compound of formula (I)-1 is cyclized with hydrazine hydrate to give a compound of formula (I); preferably, the compound of formula (I)-1 and hydrazine hydrate can be carried out in a suitable solvent selected from the group consisting of a solvent, preferably from one or more of methanol, ethanol, isopropanol, acetonitrile and dioxane; the temperature of the reaction is selected from room temperature to 100 ° C, and the reaction time is selected from 10 minutes to 24 hours;
  • the compound of the formula (I) thus obtained can be further converted by a substitution reaction, a reduction reaction, a condensation reaction or the like as needed.
  • a substitution reaction a reduction reaction, a condensation reaction or the like as needed.
  • G is a -L3-halogen-substituted C6-C12 aryl group
  • a compound such as an amine, an alcohol or a 3-12 membered heterocyclic group containing a nitrogen atom may be substituted to form a novel compound of the formula (I)
  • G is a -L3-nitro-substituted C6-C12 aryl group
  • an amino group can be obtained by a reduction reaction, and if necessary, it can be further condensed with a carboxylic acid to form a novel compound of the formula (I), or an amino group and
  • the acid halide is subjected to a substitution reaction to form a novel compound of the formula (I);
  • G is a -L3-substituted or
  • the compound I b is dissolved in a solvent, a base is added, and after stirring for 5 to 10 minutes, the compound I h is added, and after argon gas protection, the reaction is stirred at room temperature to obtain a compound (I)-1, which is anhydrous ethanol or Methylene chloride, the base is sodium ethoxide or triethylamine;
  • Compound I b can be prepared by the following method:
  • Step h adding the compound G-Cl to dichloromethane, adding a hydrazine hydrate solution at room temperature, stirring the reaction to obtain a compound I f ;
  • Step i Dissolving I f in a solvent, adding sodium carbonate, stirring for 5 min, adding a toluene solution of glyoxylate, and stirring the reaction at 50 ° C to obtain a compound I g , the solvent is 1,4-dioxane And water;
  • Step j dissolving the compound I g in ethyl acetate, adding N-chlorosuccinimide, and stirring the reaction at room temperature to obtain the product I h ;
  • Compound I h can also be prepared by the following method:
  • the compound G-NH 2 was suspended in a solvent, and an aqueous solution of sodium nitrite was added thereto in an ice bath. After an ice bath reaction for half an hour, the solution of sodium acetate and 2-chloroacetoacetate in ethanol was further added, and the reaction was stirred to obtain a compound I. h , the solvent is water and concentrated hydrochloric acid;
  • Step p dissolving the compound I m and isocyanurate in 1,4-dioxane, adding a catalytic amount of 1,3-bis(diphenylphosphino)propane under argon, stirring at 110 ° C Reaction to give compound I n ;
  • Step q The compound I n and G-OH are dissolved in tetrahydrofuran, triphenylphosphine is added, and a toluene solution of diethyl azodicarboxylate is added dropwise under a nitrogen atmosphere, and the reaction is stirred at room temperature to obtain a compound (I)-1. ;
  • Compound I m can be prepared by the following method:
  • Step m dissolving Q-COOH in dry dichloromethane, adding oxalyl chloride and a catalytic amount of DMF at room temperature, and stirring at room temperature to obtain compound Ik ;
  • Step n adding cyanomethyltriphenylphosphonium chloride and triethylamine to dichloromethane, adding a solution of compound Ik in dichloromethane at room temperature, stirring the reaction to obtain compound I l ;
  • Step o The compound I l is placed in a microwave tube, and the reaction is stirred at 110 ° C to obtain a compound I m ;
  • the compounds of the invention inhibit the activity of one or more FGFR enzymes.
  • a compound of the invention can be used to inhibit the activity of the enzyme in an individual or patient in a cell in need of inhibition of the FGFR enzyme by administering an inhibitory amount of a compound of the invention to the cell, subject or patient.
  • the compounds of the invention are inhibitors of one or more of FGFR1, FGFR2, FGFR3, and FGFR4, for example, all of the above enzyme activities are inhibited or one or more FGFR enzymes are selectively inhibited.
  • the above selectivity may be such that the inhibition IC50 value is 2, 3, 5, 10, 50 or 100 times and above.
  • the compounds of the invention are useful in the treatment of various diseases associated with FGFR enzyme activity, abnormal expression or activity of FGFR ligands.
  • the abnormal proliferation disease associated with FGFR activity or expression amount includes, but is not limited to, the following cancer or tumor diseases: mammalian cancer or tumor (such as a duct or lobular tumor), respiratory tumor (small cell lung cancer, non-small cell lung cancer, small) Cell/non-small cell cancer, bronchial carcinoma, bronchial adenoma, pleural pulmonary blastoma), brain tumors (eg brain stem and hypothalamic tumor, astrocytoma, malignant glioma, medulloblastoma, chamber tube)
  • Membrane cell Tumor pigmented neuroectodermal tumor, pineal tumor, digestive organ tumor (esophageal cancer, gastric cancer, gallbladder cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer), liver tumor (especially hepatocellular carcinoma,
  • exemplary cancers include proliferative blood diseases such as lymphoma and leukemia in solid form and blood cells, myeloproliferative diseases such as acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, hair Cellular leukemia and AIDS-associated lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, and central nervous system lymphoma.
  • proliferative blood diseases such as lymphoma and leukemia in solid form and blood cells
  • myeloproliferative diseases such as acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, hair Cellular leukemia and AIDS-associated lymphoma
  • Hodgkin's lymphoma non-Hodgkin's lymphoma
  • cancers that can be treated with the compounds of the invention include ocular tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphoma, and osteosarcoma.
  • the compounds of the invention are useful in the treatment of skeletal and chondrocyte disorders including, but not limited to, achondroplasia, rib dysplasia, dwarfism, lethal bone dysplasia (TD), Bill-History Tevenson skin gyrus syndrome, Feifu syndrome and craniosynostosis syndrome.
  • the compounds of the invention are also useful in the treatment of hypophosphatemia including, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemia, autosomal dominant hypophosphatemia, and tumor-induced osteomalacia.
  • the compounds of the invention may additionally be useful in the treatment of fibrotic diseases, such as diseases characterized by fibrosis of disease symptoms or conditions.
  • fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.
  • the compounds of the invention are also useful in the treatment of psoriasis, plaque, bullous skin disease, atherosclerosis, restenosis, mesangial cell proliferative disorders, glomerular lesions, diabetic nephropathy, nephropathy and benign Benign prostatic hyperplasia.
  • the compounds of the invention are also useful in the treatment of a variety of ocular diseases including, for example, age-related macular degeneration, dry macular degeneration, ischemic retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and retinopathy of prematurity.
  • the compounds of the invention are also useful for preventing or inhibiting the metastasis of a typical tumor.
  • the compounds of the invention may also be used in combination therapy, i.e. with one or more other agents or methods of treatment, such as antiviral agents, chemotherapeutic or other anticancer agents, immunopotentiators, immunosuppressive agents, radioactive, anti-tumor In combination with an antiviral vaccine, a cellular interferon therapy, and/or a tyrosine kinase inhibitor, for the treatment of a FGFR related disease, disorder, or condition.
  • agents or methods of treatment such as antiviral agents, chemotherapeutic or other anticancer agents, immunopotentiators, immunosuppressive agents, radioactive, anti-tumor In combination with an antiviral vaccine, a cellular interferon therapy, and/or a tyrosine kinase inhibitor, for the treatment of a FGFR related disease, disorder, or condition.
  • the agent may be combined with a compound of the invention in a single dosage form, or the agent may act as a nucleoside and nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, and other antiviral drugs.
  • the present inventors have found that a five-membered heterocyclic [3,4-d]pyridazinone compound has FGFR kinase inhibitory activity.
  • the five-membered heterocyclic [3,4-d]pyridazinone compounds reported in the present invention provide more options for the treatment of various diseases associated with FGFR activity, abnormal expression or activity of FGFR ligands, particularly cancer. And other diseases with abnormal proliferation.
  • the compounds of the present invention exhibit comparable or even better therapeutic effects to existing FGFR inhibitors in zoological experiments.
  • A1a (1 g, 4.54 mmol) was dissolved in 15 mL of dry THF. EtOAc (EtOAc, EtOAc, EtOAc. The solvent was evaporated under reduced pressure, and 15 mL of ice water was added, and the mixture was acidified to pH 4-5 with 1N HCl solution, and a pale yellow solid was precipitated, and filtered to give 800 mg of solid and dried under reduced pressure. reaction. MS (ESI, m/z): 216 (M+H) + .
  • Step 4 Preparation of ethyl 4-cyano-5-(3-methyl-1-benzothiophen-2-yl)-1-phenyl-1H-pyrazole-3-carboxylate (A1d)
  • A1b (700 mg, 3.25 mmol) was added to 10 mL of dry DCM, EtOAc (l. After TLC was used to detect the reaction of the starting material, 20 mL of water and ethyl acetate (3 ⁇ 30 mL) were added to extract, and the organic layer was combined, then washed with water (3 ⁇ 20 mL), 50 mL of saturated NaCl solution, dried Na 2 SO 4 and filtered. The solvent was evaporated under reduced pressure and purified by flash chromatography (EtOAc/EtOAc/EtOAc/EtOAc) MS (ESI, m/z): 384 (M+H) + .
  • Compound A2 was prepared in the same manner as in Example 1 except that ethyl 3-methyl-1-benzothiophene-2-carboxylate was replaced by ethyl 2-naphthoate. The yield of the next step was 49.5%.
  • Example 2 The same as in Example 1 except that ethyl 3-methyl-1-benzothiophene-2-carboxylate was replaced with ethyl 1,3-dimethyl-1H-indole-2-carboxylate.
  • the compound A3 was prepared in the same manner, and the yield of the final step was 32%.
  • MS (ESI, m / z) 371 (M + H) +.
  • Example 1 In addition to ethyl 3,5-dimethyl-1-benzofuran-2-carboxylate in place of ethyl 3-methyl-1-benzothiophene-2-carboxylate, with Example 1 Compound A4 was prepared in the same manner, and the final reaction yield was 40%.
  • 1 H NMR (500MHz, DMSO- d 6) ⁇ 11.49 (s, 1H), 7.49-7.41 (m, 7H), 7.27-7.15 (m, 1H), 5.19 (s, 2H), 2.40 (s, 3H ), 1.87 (s, 3H).
  • Compound A5 was prepared in the same manner as in Example 1 except that ethyl 3-methyl-1-benzothiophene-2-carboxylate was replaced by ethyl 3-quinolinecarboxylate. %. MS (ESI, m/z): 355 (M+H) + .
  • Example 7 Compound 4-Amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-2-phenyl-2,6-dihydro-7H-pyrazolo[3 ,4-d]Preparation of pyridazine-7-one (A7)
  • Example 8 Compound 4-Amino-3-(6-fluoro-3-methyl-1-benzofuran-2-yl)-2-phenyl-2,6-dihydro-7H-pyrazolo[3 ,4-d]Preparation of pyridazine-7-one (A8)
  • Step 1 Preparation of 4-amino-2-(4-bromophenyl)-3-(3,5-dimethyl-1-benzofuran-2-yl)-2,6-dihydro-7H-pyridyl Oxazo[3,4-d]pyridazin-7-one
  • Example 11 Compound 4-Amino-2-(4- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ phenyl)-3-(3,5-dimethyl-1-benzophenanyl) Preparation of furan-2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A11)
  • Compound A11 was prepared in the same manner as in Example 9 except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethyldiamine hydrochloride. %. MS (ESI, m / z) : 472 (M + H) +.
  • Example 12 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[4-(morpholin-4-yl)phenyl]-2,6 -Preparation of dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A12)
  • Example 15 Compound 4-Amino-2- ⁇ 4-[2-(dimethylamino)ethoxy]phenyl ⁇ -3-(3,5-dimethyl-1-benzofuran-2-yl) -2,6-Dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A15)
  • Compound A15 was prepared in the same manner as in Example 9 except that N,N-dimethylethanolamine was replaced by N,N-dimethylethanolamine. MS (ESI, m / z) : 459 (M + H) +.
  • Example 16 Compound 4-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)phenyl]-3-(3,5-dimethyl-1-benzofuran-2-yl Preparation of-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A16)
  • Compound A16 was prepared in the same manner as in Example 9 except that N,N-dimethylmethyldiamine hydrochloride was replaced with 1-cyclopropylpiperazine. MS (ESI, m / z) : 496 (M + H) +.
  • Example 17 Compound 4-Amino-2- ⁇ 4-[3-(dimethylamino)azetidin-1-yl]phenyl ⁇ -3-(3,5-dimethyl-1-benzofuran- Preparation of 2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A17)
  • Example 18 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[4-(4-ethylpiperazin-1-yl)phenyl] -2,6-Dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A18)
  • Example 20 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-(4- ⁇ [(1-methylpiperidin-4-yl)- Of amino]amino ⁇ phenyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A20)
  • Compound A20 was prepared in the same manner as in Example 9 except that (N-methyl-4-piperidine-)methylamine was replaced by N,N-dimethyldiamine hydrochloride. 35%. MS (ESI, m / z) : 498 (M + H) +.
  • Example 21 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 4-[4-(methoxymethyl)piperidine Of -1-yl]phenyl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A21)
  • Example 22 Compound 4-Amino-2- ⁇ 4-[3-(diethylamino)pyrrolidin-1-yl]phenyl ⁇ -3-(3,5-dimethyl-1-benzofuran- Preparation of 2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A22)
  • Step 3 Preparation of ethyl (2Z)-chloro[2-(1-ethylpiperidin-4-yl)indenyl]acetate (A23c)
  • Step 4 Preparation of 4-amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-2-(1-ethylpiperidin-4-yl)-2,6- Dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A23)
  • step 1
  • Compound A26 was prepared in the same manner as in Example 25 except that acryloyl chloride was replaced by (E)-4-(dimethylamino)but-2-enoyl chloride. MS (ESI, m/z): 518 (M+H) + .
  • Example 30 Compound 4-Amino-2- ⁇ 1-[(2E)-4-(dimethylamino)but-2-enoyl]piperidin-4-yl ⁇ -3-(3,5-dimethyl Preparation of 1-benzofuran-2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A30)
  • Compound A30 was prepared in the same manner as in Example 29 except that acryloyl chloride was replaced by (E)-4-(dimethylamino)but-2-enoyl chloride. MS (ESI, m/z): 490 (M+H) + .
  • Example 31 Compound 4-Amino-2- ⁇ 1-[(2E)-4-(azetidin-1-yl)but-2-enoyl]piperidin-4-yl ⁇ -3-(3,5 Of 2-dimethyl-1-benzofuran-2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A31)
  • Compound A31 was prepared in the same manner as in Example 29 except that acryloyl chloride was replaced by (E)-4-(azetidin-1-yl)but-2-enoyl chloride. MS (ESI, m/z): 520 (M+H) + .
  • Example 32 Compound N-(4-[4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-carbonyl-6,7-dihydro-2H-pyridyl Preparation of oxazo[3,4-d]pyridazin-2-yl]-2- ⁇ [(dimethylamino)ethyl](methyl)amino ⁇ phenyl)prop-2-enamide (A32)
  • A33 was prepared in the same manner as in Example 32 except that 2-(N,N',N'-trimethylethylenediamine)-4-aminonitrobenzene was replaced with 4-nitrocyclohexylamine.
  • MS (ESI, m / z) 447 (M + H) +.
  • Example 34 Compound 4-Amino-2-(1- ⁇ (2E)-4-[cyclopropyl(methyl)amino]but-2-enoyl ⁇ piperidin-4-yl)-3-(3, Preparation of 5-dimethyl-1-benzofuran-2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A34)
  • Compound A34 was prepared in the same manner as in Example 29 except that acryloyl chloride was replaced by 4-(N-methyl-N-cyclopropyl)aminobut-2-enoyl chloride. MS (ESI, m / z) : 516 (M + H) +.
  • Compound A35 was prepared in the same manner as in Example 33 except that acryloyl chloride was replaced with dimethylaminoacetyl chloride. MS (ESI, m/z): 478 (M+H) + .
  • Example 36 Compound 4-Amino-2- ⁇ 1-[2-(2-dimethylamino)ethyl]piperidin-4-yl ⁇ -3-(3,5-dimethylbenzofuran-2-yl) Preparation of -2H-pyrazolo[3,4-d]pyridazin-7(6H)-one (A36)
  • A36a was prepared in the same manner as in Example A4.
  • Step 2 Preparation of 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (A36b)
  • Step 3 Preparation of (E)-tert-butyl 4-(2-(2-ethoxy-2-carbonylethylidene)indenyl)piperidine-1-carboxylate (A36c)
  • A36b (2g, 9.29mmol) was dissolved in a 1:1 solution of 1,4-dioxane and water, sodium carbonate (1g, 10.22mmol) was added, stirred for 5min, then added toluene solution of ethyl glyoxylate (2.21) The reaction was stirred at 50 ° C, and the reaction was completed by TLC, and then the column was rapidly separated to give the compound 2 g in a yield of 65%. MS (ESI, m / z) : 299 (M + H) +.
  • Step 4 Preparation of (Z)-tert-butyl 4-(2-(1-chloro-2-ethoxy-2-carbonylethylidene)indenyl)piperidine-1-carboxylate (A36d)
  • Step 5 Preparation of tert-butyl 4-(4-cyano-5-(3,5-dimethylbenzofuran-2-yl)-3-(ethyl ester ⁇ ethoxycarbonyl>)-1H- Pyrazol-1-yl)piperidine-1-carboxylate (A36e)
  • A36a (700 mg, 3.25 mmol) was added to 10 mL of anhydrous EtOH. NaOEt (0.42 g, 6.6 mmol) was added and stirred for 10 min, then A36d (1.1 g, 3.28 mmol) was added and allowed to react at room temperature. After TLC was used to detect the reaction of the starting material, 20 mL of water and ethyl acetate (3 ⁇ 30 mL) were added to extract, and the organic layer was combined, then washed with water (3 ⁇ 20 mL), 50 mL of saturated NaCl solution, dried Na 2 SO 4 and filtered.
  • Step 6 Preparation of tert-butyl 4-(4-amino-3-(3,5-dimethylbenzofuran-2-yl)-7-carbonyl-6,7-dihydro-2H-pyrazole [ 3,4-d]pyridazin-2-yl)piperidine-1-carboxylate (A36f)
  • Step 7 Preparation of 4-amino-3-(3,5-dimethylbenzofuran-2-yl)-2-(piperidin-4-yl)-2H-pyrazolo[3,4-d] Pyridazine-7(6H)-one hydrochloride (A36g)
  • Step 8 Preparation of 4-amino-2-(1-(2-(2-dimethylamino)ethyl)piperidin-4-yl)-3-(3,5-dimethylbenzofuran-2-yl) -2H-pyrazolo[3,4-d]pyridazin-7(6H)-one (A36)
  • Example 37 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[(1-ethylpiperidin-4-yl)methyl]-2 Of 6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A37)
  • Compound 37 was prepared in the same manner as in Example 36 except that 1-(chloromethyl)-1-ethylpiperidine was substituted for 1-BOC-4-chloropiperidine. The yield of the next step was 60.7%. MS (ESI, m / z) : 421 (M + H) +.
  • Example 38 Compound 2-[(1-Acrylpiperidin-4-yl)methyl]-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2 Of 6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A38)
  • Example 39 Compound 2-[(1-Acyrylpyrrolidin-2-yl)methyl]-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2 Of 6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A39)
  • Example 36 The same procedure as in Example 36 except that 1-BOC-3-chloropiperidine was replaced with 1-BOC-3-chloropiperidine and 2-chloro-N,N-dimethylethylamine was replaced with acryloyl chloride. A compound was prepared. MS (ESI, m/z): 437 (M+H) + .
  • Example 41 Compound 4-Amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-2-(1-propionylpiperidin-4-yl)-2,6- Preparation of dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A41)
  • Example 42 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,6- Preparation of dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A42)
  • Example 43 Compound 2-[(1-Acyrylpyrrolidin-3-yl)methyl]-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2 Of 6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A43)
  • Example 44 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 4-[(5-carbonylpyrrolidin-3-yl)amino]benzene Preparation of yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A44)
  • Example 46 Compound 4-Amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-2- ⁇ 3-[2-(dimethylamino)ethyl]azetidine Preparation of -1-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A46)
  • Example 47 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 1-[(4-methylpiperazin-1-yl)carbonyl] Preparation of pyrrolidin-3-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A47)
  • Example 36 The same procedure as in Example 36 except that 1-BOC-3-chloropyrrolidine was substituted for 0 and 4-methyl-piperazine-1-carbonyl chloride was substituted for 2-chloro-N,N-dimethylethylamine.
  • the compound was prepared in a manner. MS (ESI, m/z): 495 (M+H) + .
  • Example 48 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 1-[(1,1-dioxythiomorpholin-4-yl) Preparation of carbonyl]pyrrolidin-3-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A48)
  • Example 49 Compound 4-Amino-2- ⁇ 1-[(dimethylamino)acetyl]pyrrolidin-3-yl ⁇ -3-(3,5-dimethyl-1-benzofuran-2-yl Preparation of-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A49)
  • Example 50 Compound 4-Amino-2- ⁇ [N-cyclohexyl-(2E)-4-methoxybut-2-enamide]-4-yl ⁇ -3-(3,5-dimethyl- Preparation of 1-benzofuran-2-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A50)
  • Example 51 The compound 2-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2,6-di Preparation of hydrogen-7H-pyrazolo[3,4-d]pyridazin-7-one (A51)
  • Example 52 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[1-(2-fluoroacryloyl)pyrrolidin-3-yl]- Preparation of 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A52)
  • Example 53 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 1-[2-(pyrrolidin-1-ylmethyl)acryloyl Of pyrrolidin-3-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A53)
  • Example 54 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[1-(2-fluoroacryloyl)piperidin-4-yl]- Preparation of 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A54)
  • Example 55 Compound 2-( ⁇ 4-[4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-carbonyl-6,7-dihydro-2H- Preparation of pyrazolo[3,4-d]pyridazin-2-yl]piperidin-1-yl ⁇ carbonyl)prop-2-enenitrile (A55)
  • Example 56 Compound 4-Amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-2- ⁇ 1-[(2E)-4-(cyclopropylamino)butyl Preparation of 2-enoyl]piperidin-4-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A56)
  • Example 58 Compound N- ⁇ 4-[4-Amino-3-(5-chloro-3-methyl-1-benzofuran-2-yl)-7-carbonyl-6,7-dihydro-2H- Preparation of pyrazolo[3,4-d]pyridazin-2-yl]cyclohexyl ⁇ -2-fluoroprop-2-enamide (A58)
  • Example 60 Compound (2E)-N- ⁇ 4-[4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-carbonyl-6,7-dihydro Preparation of -2H-pyrazolo[3,4-d]pyridazin-2-yl]cyclohexyl ⁇ -4-(4-methylpiperazin-1-yl)but-2-enamide (A60)
  • Example 63 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-[1-(4-hydroxybut-2-ynyl)pyrrolidine-3 Of -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A63)
  • Example 65 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2-(1- ⁇ (2E)-4-[(3R)-3-fluoro Pyrrolidin-1-yl]but-2-enoyl ⁇ piperidin-4-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A65) Preparation
  • Example 66 Compound 4-Amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-2- ⁇ 1-[(2E)-4-(4-hydroxypiperidine-1 Of -butyryl-2-enoyl]piperidin-4-yl ⁇ -2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A66)
  • Example 68 Compound 1-[(1-Acrylpiperidin-4-yl)methyl]-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-1 Of 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (A68)
  • Example 69 Compound 1-[(3S)-1-Acyrylpyrrolidin-3-yl]-4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-1 Of 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (A69)
  • Example 70 Compound (2E)-N- ⁇ 4-[4-Amino-3-(1-methyl-1H-benzimidazol-2-yl)-7-carbonyl-6,7-dihydro-2H- Preparation of pyrazolo[3,4-d]pyridazin-2-yl]phenyl ⁇ -4-(dimethylamino)but-2-enamide (A70) except ethyl 1-methyl-1H- Benzo[d]imidazole-2-carboxylate replaces ethyl 3,5-dimethylbenzofuran-2-carboxylate with (2E)-4-(dimethylamino)but-2-enoyl chloride The compound was prepared in the same manner as in Example 25 except for the replacement of acryloyl chloride, and the yield of the next step was 56.5%. MS (ESI, m/z): 484 (M+H) + .
  • Example 72 Compound (2E)-N- ⁇ 4-[4-Amino-3-(1,3-benzothiazol-2-yl)-7-carbonyl-6,7-dihydro-2H-pyridyl Preparation of oxazo[3,4-d]pyridazin-2-yl]phenyl ⁇ -4-(dimethylamino)but-2-enamide (A72)
  • Example 75 Compound 4-Amino-2-[1-(cyclopropylcarbonyl)piperidin-4-yl]-3-(3,5-dimethyl-1-benzofuran-2-yl)-2 Of 6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (A75)
  • Example 80 Compound 2-(1-Propylpiperidin-4-yl)-4-amino-3-(5-fluoro-3-methylbenzofuran-2-yl)-2,6-dihydro- Preparation of 7H-pyrazolo[3,4-d]pyridazin-7-one (A80)
  • Example 36 The same procedure as in Example 36 except that 1-BOC-4-chloropiperidine was replaced with N-BOC-4-chlorocyclohexylamine and 2-chloro-N,N-dimethylethylamine was replaced with acryloyl chloride.
  • the compound was prepared in a manner. MS (ESI, m / z) : 447 (M + H) +.
  • the present invention is also directed to the inhibitory effect of a five-membered heterocyclic [3,4-d]pyrazinone compound on FGFR kinase, FGFR-dependent tumor cell proliferation inhibition, and the growth inhibition of subcutaneous transplantation of FGFR-dependent tumor in nude mice.
  • Pharmacological experiments The experimental materials required for pharmacological experiments are commercially available unless otherwise stated.
  • Enzyme reaction substrate poly-glutamic acid-tyrosine peptide Poly(Glu, Tyr) 4:1 Sigma, Cat. No. P7244
  • anti-phosphotyrosine monoclonal antibody PY99 Santa Cruz, Cat. No. SC -7020
  • kinase recombinant protein FGFR1 Millipore, Cat. No. 14-482
  • horseradish peroxidase-labeled goat anti-Mouse IgG Antibody H&L Chain Specific Peroxidase Conjugate (Calbiochem, Cat. No. 401215 ).
  • Precision electronic balance (Sartotius, Cat. No. BP210D), adjustable wavelength microplate reader (Molecular Device, Cat. No. SpectraMax 190).
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated ELISA plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 ⁇ L/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • the compound is diluted with DMSO to a suitable concentration, 1 ⁇ L/well or containing the corresponding concentration of DMSO (negative control well), and then the FGFR kinase domain recombinant protein diluted with 49 ⁇ L of reaction buffer is added to initiate the reaction, and each experiment requires an enzyme-free control. Two holes in the hole.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm).
  • the plate was washed three times with T-PBS.
  • One anti-PY99 dilution was added to 100 ⁇ L/well, and the reaction was shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • a second anti-horseradish peroxidase-labeled goat anti-mouse IgG dilution was added at 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • the inhibition rate of the sample is obtained by the following formula:
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • Human acute myeloid leukemia cell line KG1 cells (FGFR1 fusion protein expressed in the cytoplasm, FGFR1-dependent tumor cell line) (ATCC, Cat. No. CCL-246), cell culture medium RPMI-1640 (Corning Cellgro, No. 10-040-CVR), fetal bovine serum (Life Technologies, Cat. No. 10099-141) was purchased from the company; CCK-8 cell counting kit (DOJINDO, Cat. No. FK808). Adjustable wavelength microplate reader (Molecular Device, Cat. No. SpectraMax 190).
  • the inhibitory effect of the compound on KG1 proliferation was detected by CCK-8 cell counting kit (Dojindo): cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and cultured overnight, at different concentrations. The compound was allowed to act for 72 hr and the solvent control group (negative control) was set. After the cells were treated for 72 hours, 10 ⁇ L of CCK-8 reagent was added to each well, placed in a 37 ° C incubator for 2-4 hours, and then read with a full-wavelength microplate microplate SpectraMax 190, and the wavelength was determined to be 450 nm.
  • the inhibition rate of a compound against cell proliferation is calculated by the following formula:
  • Inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the tested compound has a good inhibitory activity against FGFR kinase and also has a good proliferation inhibitory activity against its dependent tumor cell line.
  • Example A26 was a white powder, and stored at -20 ° C in the dark. Before use, use 5% Tween80 in physiological saline to the desired concentration (light yellow suspension) and use once a week.
  • the positive control drug AZD4547 (batch number: Lot: S0902A) was a white powder, and stored at -20 ° C in the dark. Before use, use a physiological saline solution containing 1% Tween 80 to the desired concentration (white suspension) and use it once a week.
  • the dose setting A26 dose was set to 50 mg/kg and 10 mg/kg; the positive control drug AZD4547 dose was set to 12.5 mg/kg.
  • Human lung cancer NCI-H1581 cell line (ATCC, Cat. No. CRL-5878).
  • the cell strain was inoculated subcutaneously into the right axilla of the nude mice, and the amount of cells inoculated was 5 ⁇ 10 6 /piece, and the transplanted tumor was formed and used in the body for one generation.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the nude mice were subcutaneously transplanted with a vernier caliper to measure the diameter of the transplanted tumor. After the tumor was grown to an average volume of about 220 mm3, the animals were randomly divided into groups. A26 50mg/kg and 10mg/kg group, once a day intraperitoneal injection, continuous administration for 13 days; positive control drug AZD4547 12.5mg / kg group, oral administration once a day, continuous administration for 13 days.
  • the solvent control group was given the same amount of physiological saline.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V0 is the tumor volume measured when the cage is administered (ie, d 0 )
  • Vt is the tumor volume at each measurement.
  • T/C (%) (TRTV / CRTV) ⁇ 100%, TRTV: treatment group RTV; CRTV: negative control group RTV.
  • the experimental results are shown in Table 2, Figures 1, 2 and Figure 3.
  • the positive control drug AZD4547 12.5mg/kg group was orally administered once a day for 13 days, which partially inhibited the growth of human lung cancer NCI-H1581 nude mice.
  • the percentage of T/C obtained on the 13th day was It is 16.39%.
  • A26 50mg/kg and 10mg/kg group, once daily intraperitoneal administration, continuous administration for 13 days significantly inhibited the growth of human lung cancer NCI-H1581 nude mice subcutaneous xenografts, T/C obtained on the 13th day
  • the percentages are 2.20% and 19.88%, respectively.
  • the mice in each group were in good condition, their body weight increased, and no mice died.
  • the tested compound has a good inhibitory effect on the growth of human lung cancer NCI-H1581 nude mice subcutaneously transplanted tumor, the pharmacodynamic activity is better than the positive drug, and the compound has good tolerance at the tested dose. Sex.
  • the five-membered heterocyclic [3,4-d]pyrazinone compound of the present invention has low toxicity and good solubility.
  • the preparation method of the five-membered heterocyclic [3,4-d]pyrazinone compound and the derivative thereof of the invention has the advantages of mild reaction conditions, abundant raw materials, easy operation, simple post-treatment, and good selectivity.
  • the five-membered heterocyclic [3,4-d]pyridazinone compounds and derivatives thereof of the present invention have a good inhibitory activity and excellent selectivity for proliferation of FGFR kinase and FGFR-dependent tumor cell lines.
  • the compounds of the present invention are useful for use in the treatment of various diseases associated with FGFR enzyme activity, abnormal expression or activity of FGFR ligands, such as cancer, tumors and the like.

Abstract

本发明提供了一种作为FGFR激酶抑制剂的五元杂环并哒嗪酮类化合物及其制备和应用，具体地，本发明提供了一种如下式（I）所示的化合物；其中，各基团的定义如说明书中所述。本发明的化合物具有很好的FGFR激酶抑制活性，可以用于制备一系列治疗FGFR激酶活性相关的疾病的药物。

Description

五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用 技术领域
本发明提供了一类五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合及其应用，该类化合物具有具有FGFR激酶抑制活性，可用于治疗与FGFR酶活，FGFR配体异常表达或活性相关的各种疾病，如癌症、肿瘤等疾病的药物中的用途。
背景技术
据世界卫生组织(WHO)统计，全球每年因癌症死亡的人口大约有820万，占总的人口死亡数量中13％。该数据还在持续增长，WHO预计在接下来的20年，全球因癌症死亡的人口会增长70％(来自WHO，fact sheet by Cancer,Globocan 2012)。
肿瘤的发生、演化、扩散及肿瘤血管的发生依赖于各种信号转导通路。靶向治疗则是一种干扰这些信号通路来达到阻止癌细胞增长的药物疗法，相比于传统的化疗方法，靶向治疗能更特异性地作用于致癌位点，抑制肿瘤细胞增长，而减少对正常组织细胞的伤害。到目前为止FDA共批准了26个小分子靶向药物上市，例如，基于ABL酪氨酸激酶开发的抗癌药物伊马替尼(imatinib)、基于EGFR、HER2/4酪氨酸激酶开发的阿法替尼(Afatinib)、基于MEK酪氨酸激酶开发的曲美替尼(Trametinib)等，靶向治疗无疑对癌症治疗产生了重大影响(Nature Reviews Clinical Oncology(2015)doi:10.1038/nrclinonc.2015.213)。
成纤维细胞生长因子受体(fibroblast growth factor receptors,FGFR)家族属于受体酪氨酸蛋白激酶(RTKs)，包括四种受体亚型(FGFR1、FGFR2、FGFR3和FGFR4)。在FGF信号转导通路中，成纤维细胞生长因子与FGFR受体结合后，诱导FGFR二聚化并磷酸化FGFR胞质内结构端的酪氨酸，激活下游FRS2-Ras-MAPK、PLCγ以及PI3K-AKT/PKB信号通路。生理状态下，FGFR信号通路参与调节胚胎发育、细胞增殖和迁移、新生血管生成等多个过程(Cytokine&Growth Factor Reviews 16(2005)233–247)。研究发现FGFR突变激活或高表达与人类肿瘤的发生发展密切相关。细胞中的FGFR激活突变或过表达可导致FGFR信号通路的持续性和过度激活，使细胞获得过度增殖、凋亡逃避等致癌性的功能。同时，研究发现在人体多种癌细胞中出现FGFR异常表达，如乳腺癌、肺癌、卵巢癌、胃癌、子宫瘤、恶性胶质瘤、膀胱癌、肝癌，实体瘤等(Cancer Discovery.2013；3(3):264-279；Annals of Oncology.2014；25:552-563)。因此FGFR被公认为是抗肿瘤药物研发的重要靶点，是目前药物研发最热门靶点之一。
研究表明牵涉到FGF/FGFR的癌症类型包括(但不限于)：癌瘤(例如膀胱癌、乳腺癌、子***、结肠直肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌)；造血恶性疾病(例如多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、急性骨髓性白血病、非霍奇金氏淋巴瘤、骨髓增生型赘生物和瓦尔登特伦氏巨球蛋白血症)；和其他赘生物(例如神经胶母细胞瘤、黑素瘤和横纹肌肉瘤)。除在致癌性赘生物中的作用外，FGFR活化也牵涉于骨骼和软骨细胞病症中，包括(但不限于)软骨发育不全和颅缝早闭综合征。
持续需要开发用于治疗癌症和其他疾病的新药物，本发明所述的FGFR抑制剂帮助解决此需要。
发明内容
本发明提供了一类结构新颖的、有效的五元杂环并[3,4-d]哒嗪酮类FGFR小分子抑制 剂。
本发明的第一方面，提供了一种如下式(I)所示的化合物，或其药学上可接受的盐：
Figure PCTCN2017085765-appb-000001
其中，
X1选自CH、C、N；优选为CH或C；
X2和X3各自独立地选自CH、C、NH、N、O或者S；优选为NH、N、CH或者C；
X4和X5为C；
且X1，X2，X3，X4和X5共同形成芳香性五元环；
Q选自：取代或未取代的萘基、取代或未取代的8-10元双环杂芳基；
或者Q选自-L-A，其中L为取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4的亚烯基、C2-C4的亚炔基、C1-C4的亚烷氧基、-(C1-C4烷基)-NH-、-CO-NH-、-NH-CO-；A选自取代或未取代的C6-C12芳基、取代或未取代的5-8元单环杂芳基、取代或未取代的8-10元双环杂芳基；
G为各自独立地位于X2和/或X3上的选自下组的1-2个取代基：卤素、羟基、氰基、-L3-取代或未取代的C6-C12芳基、-L3-取代或未取代的5-12元杂芳基、-L3-取代或未取代的3-12元杂环基、-L3-取代或未取代的C3-C8环烷基、-(CH2)m-L1-R1、-(CH2)m-N(R2)(R3)、-(CH2)m-C(＝O)-N(R2)(R4)；
其中，所述的基团G上还可以任选地具有1-3个各自独立的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基；其中，Lx1、Lx2、Lx3、Lx4和Lx5各自独立地选自下组：无、羰基(C＝O)、氧基(-O-)、-C＝S-、-S(O)2-、-CH2-、-CH＝CH-、C3-C8亚环烯基、-C≡C-、-NH-、-N(R5)-；M选自下组：H、-OH、卤素、氰基、-N(R2)(R3)、-CH3、-C(＝O)CH3、C1-C6烷氧基、3-12元杂环基、C3-C8环烷基、5-12元杂芳基、C3-C8环烯基；
所述的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基可以进一步地被一个或多个卤素、C1-C6烷基、C1-C6烷氧基、氰基、羟基、＝O、＝CH2(即亚甲基通过双键取代基团上的两个氢原子)、乙烯基(-CH＝CH2)、-(CH2)k-N(R2)(R3)、-(C1-C6烷基)-OR2、3-12元杂环基或C3-C8环烷基所取代；
k选自0、1、2或3；`
m选自0、1、2、3或4；
L1为无、O、或-C(＝O)O-；
L3为无，或取代或未取代的C1-C4亚烷基；
R1、R3和R4各自独立地选自：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的3-12元杂环基，-(C1-C6烷基)-N(C1-C6烷基)(C1-C6烷基)、-(C1-C6烷基)-O-(C1-C6烷基)、或取代或未取代的苯基；
R2选自氢、或C1-C4烷基；
或者R2和R3、R2和R4与相连的氮原子共同构成取代或未取代的4-7元杂环，所述的杂环含有1～3个选自N、O、S中的杂原子，并且至少一个杂原子为N；
R5选自氢、C1-C4烷基、C3-C6环烷基、甲酰基、C1-C4烷基羰基、或C1-C4烷氧羰基；
所述取代是指基团上的一个或多个氢原子被选自下组(优选1-5个)的基团取代：羟基、卤素、氰基、硝基、氨基、羧基、-CH2OH、-CONH2、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷胺基、C1-C4烷酰基、C1-C4烷磺酰基、C1-C4烷氧羰基、C1-C4烷磺酰胺基、氧代(＝O)、:CH2、C3-C6环烷基、4-7元杂环基、-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基)、吡咯烷酮基、哌啶基、C3-C6环烷基羰基、苯基、C2-C4炔基、取代或未取代的5-10元杂芳基；所述C1-C6烷氧基、C1-C6烷基和C1-C6烷胺基的取代基独立地选自1～3个如下基团：氧代、卤素、氰基、环丙基、羟基、氨基、-N(C1-C4烷基)(C1-C4烷基)；所述5-10元杂芳基上取代基选自1-3个如下基团：C1-C6烷基、-C1-C4亚烷基-N(C1-C4烷基)(C1-C4烷基)；
所述C1-C6烷氧基、C1-C6烷基和C1-C6烷胺基包括直链或支链；
且所述的化合物不为如下任一结构：
Figure PCTCN2017085765-appb-000002
在另一优选例中，所述C1-C6烷基选择性地被氰基、羟基、-(C1-C4烷基)-O-(C1-C4烷基)-O-(C1-C4烷基)、-O-CO-(C1-C4烷基)、羰基(＝O)、C1-C4烷氧羰基、氨基、-CONH2-、-NH-CO-(C1-C4烷基)、吡咯烷酮、哌啶、吗啉、-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基)、C3-C6环烷基、或者1-3个卤素所取代。
在另一优选例中，所述C3-C6环烷基选择性地被1～2个各自独立选自C1-C4烷基、羟基、卤素、或氨基取代。
在另一优选例中，所述4-7元杂环基选择性地被1～2个各自独立地选择自C1-C4烷基、C1-C4烷氧基、羟基、氨基、氧代、-CONH2中的基团所取代；所述苯基选择性被1～2个各自独立地选自氟、氯、溴、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C1-C4烷氧基取代。
在另一优选例中，所述的取代是指选自下组的羟基、卤素、氰基、硝基、氨基、羧基、-CH2OH、-CONH2、取代或未取代的C1-C6烷基、卤素取代或未取代的C1-C4烷氧基或C1-C4烷胺基、C1-C4烷酰基、C1-C4磺酰基、C1-C4磺酰胺基、C2-C6炔基、取代或未取代的5-10元杂芳基；所述C1-C6烷基取代基独立地1～3个选自氧代、卤素、氰基、环丙基、羟基、氨基、-N(C1-C6烷基)(C1-C6烷基)；所述5-10元杂芳基上取代基选自C1-C6烷基、-(C1-C6烷基)-N(C1-C6烷基)(C1-C6烷基)；
在另一优选例中，所述G不为未取代的苯基。
在另一优选例中，当X2为N时，所述G不为未取代的苯基。
在另一优选例中，当G位于X2且Q为
Figure PCTCN2017085765-appb-000003
时，所述G不为未取代的苯基。
在另一优选例中，Lx1、Lx2、Lx3、Lx4和Lx5中至少一个为-NH-。
在另一优选例中，Lx1、Lx2、Lx3、Lx4和Lx5中至少一个为-CH＝CH-。
在另一优选例中，Lx1、Lx2、Lx3、Lx4和Lx5中至少一个为-C≡C-。
在另一优选例中，Q选自下组取代或未取代的基团：萘基、苯并5-6元单环杂芳基、5-6元单环杂芳基并5-6元单环杂芳基；
或者Q选自-L-A，其中L为未取代或卤素取代的C1-C4亚烷基、未取代或卤素取代的C2-C4的亚烯基、C2-C4的亚炔基、C1-C4的亚烷氧基、-(C1-C4烷基)-NH-、-CO-NH-、-NH-CO-；A选自取代或未取代的C6-C12芳基、取代或未取代的5-6元的单环杂芳基。
在另一优选例中，所述Q选自下组取代或未取代的基团：萘、吲哚、吲唑、异吲哚、苯并咪唑、苯并呋喃、苯并噻吩、苯并噻唑、喹啉、异喹啉、苯并嘧啶或者苯并吡喃；
在另一优选例中，所述的L选自下组：未取代或卤素取代的C1-C3直链或支链的亚烷基、未取代或卤素取代的C2-C4直链或支链的烯基、未取代或卤素取代的C2-C4直链或支链的炔基、-CO-NH-、-NH-CO-。
在另一优选例中，所述的A选自下组取代或未取代的基团：吡咯基、呋喃基、吡唑基、噁唑基、异噁唑基、咪唑基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基；
在另一优选例中，所述的G独立地选自下组的1-2个取代基：卤素、羟基、氰基、-L3-取代或未取代的C6-C10芳基、-L3-取代或未取代的5-10元杂芳基、-L3-取代或未取代的4-7元杂环基、-L3-取代或未取代的C3-C6环烷基、-(CH2)m-L1-R1、-(CH2)m-N(R2)(R3)、-(CH2)m-C(＝O)-N(R2)(R4)；
其中，L3为无、取代或未取代的亚甲基、取代或未取代的亚乙基；且所述的基团G上还可以任选地具有1-3个各自独立的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基，其中Lx1、Lx2、Lx3、Lx4和Lx5各自独立地选自下组：无、羰基(C＝O)、氧基(-O-)、-C＝S-、-S(O)2-、-CH2-、-CH＝CH-、C3-C6亚环烯基、亚乙炔基(-C≡C-)、-NH-、-N(R5)-；
M选自下组：H、-OH、卤素、氰基、-N(R2)(R3)、-CH3、-C(＝O)CH3、C1-C4烷氧基、4-7元杂环基、C3-C6环烷基、5-10元杂芳基、C3-C6环烯基；所述的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基可以进一步地被一个或多个卤素、C1-C6烷基、氰基、羟基、氧原子(＝O)、＝CH2、-(CH2)k-N(R2)(R3)、-(C1-C6烷基)-OR2、3-12元杂环基或C3-C6环烷基所取代；
R1、R3、R4各自独立地选自：氢、卤素、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的4-7元杂环基、取代或未取代的苯基；
或者R2和R3、R2和R4与相连的氮原子共同构成取代或未取代的4-7元饱和杂环，所述的杂环含有1～3个选自N、O、S中的杂原子，并且至少一个杂原子为N；
R5选自氢、C1-C4烷基、C3-C6环烷基、甲酰基、C1-C4烷基羰基、C1-C4烷氧羰基。
在另一优选例中，X1为C，而X2和X3皆为N；或X1为C，X2为CH而X3为N；或X1为C，X2为C而X3为N。
在另一优选例中，X1、X2、X3、X4、X5、Q、G、-Lx1-Lx2-Lx3-Lx4-Lx5-M、A、m、L1、L3、R1、R2、R3、R4各自独立地为实施例中各个化合物所对应的基团。
在另一优选例中，所述的化合物选自表格中化合物A1-A92。
本发明的第二方面，提供了一种如本发明第一方面所述的式(I)化合物的制备方法，所述方法包括步骤：
Figure PCTCN2017085765-appb-000004
其中，X1，X2，X3，X4，X5，Q和G的定义与上文对应的描述相同；Rx选自C1-C6烷基；
式(I)-1化合物与水合肼经环合反应得到式(I)化合物。
在另一优选例中，Rx为甲基或乙基。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物，或其药学上可接受的盐的用途，用于：
(a)制备治疗与FGFR激酶活性或表达量相关的疾病的药物；
(b)制备FGFR激酶靶向抑制剂；
(c)体外非治疗性地抑制FGFR激酶的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与FGFR激酶活性或表达量相关的疾病。
在另一优选例中，所述与FGFR活性或表达量相关的疾病选自癌瘤、造血恶性疾病、其他赘生物、骨骼和软骨细胞病症、低磷酸盐血症、纤维性疾病、银屑病、斑痕瘤、大疱性皮肤病、动脉粥样硬化、再狭窄、肾小球膜细胞增殖病症、肾小球病变、糖尿病性肾病变、肾病和良性***增生、眼病、以及颅缝早闭综合征；较佳地为选自下组的癌瘤：膀胱癌、乳腺癌、子***、结肠直肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食道癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓性白血病、霍奇金氏淋巴瘤或非霍奇金氏淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、毛细胞淋巴瘤、博吉特氏淋巴瘤、神经胶母细胞瘤、黑素瘤和横纹肌肉瘤。
在另一优选例中，所述FGFR激酶选自下组：FGFR1、FGFR2、FGFR3、FGFR4，或其组合；和/或
在另一优选例中，所述的肿瘤细胞为胃癌细胞株、肺癌细胞株、白血病细胞株、膀胱癌细胞株、肝癌细胞株。
在另一优选例中，所述与FGFR激酶活性或表达量相关的疾病选自下组：膀胱癌、乳腺癌、子***、结肠直肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、急性骨髓性白血病、非霍奇金氏淋巴瘤、骨髓增生型赘生物和瓦尔登特伦氏巨球蛋白血症。
在另一优选例中，所述专利化合物可用于预防或抑制一般肿瘤的转移。
本发明的第四方面，提供了一种药物组合物，所述的药物组合物包括：(i)有效量的式I化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。
在另一优选例中，所述的有效量是指治疗有效量或抑制有效量，较佳地为0.01～99.9％。
在另一优选例中，所述的药物组合物用于抑制FGFR激酶活性。
在另一优选例中，所述药物组合用于治疗与FGFR激酶活性或表达量相关的疾病。
本发明的第五方面，提供了一种抑制FGFR激酶活性的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如本发明第四方面所述的药物组合物。
在另一优选例中，所述的抑制是体内抑制或体外抑制。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1、A26对人肺癌NCI-H1581裸小鼠移植瘤的生长抑制作用；
图2、A26对人肺癌NCI-H荷瘤鼠体重的影响；
图3、Somcl-15-290对人肺癌NCI-H1581裸小鼠移植瘤生长图。
具体实施方式
本发明人基于长期而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有FGFR激酶抑制活性。且所述的化合物在极低浓度(可低至≤100nmol/L)下，即对一系列FGFR激酶产生抑制作用，抑制活性相当优异，因而可以用于治疗与FGFR激酶活性或表达量相关的疾病如肿瘤。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“C1-C6烷基”指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基和异己基，或类似基团。所述的“C1-C6烷基”定义中包括“C1-C4烷基”。
术语“C1-C6亚烷基”指C1-C6烷基失去一个氢原子之后形成的基团，例如-CH2-、-CH2-CH2-、-CH2-CH2-CH2-和-CH2-CH(CH3)-CH2-，或类似基团。所述的“C1-C6亚烷基”定义中包括“C1-C4亚烷基”。术语“C2-C6烯基”指具有1-3个双键和2-6个碳原子的直链或支链基团，例如乙烯基、丙烯基、异丙烯基、1-丁烯基、2-丁烯基、2-甲基-1-丙烯基、1,3-丁二烯基和1,3,5-己三烯基，或类似基团。所述的“C2-C6烯基”定义中包括“C2-C4烯基”。
术语“C2-C6亚烯基”指C2-C6烯基失去一个氢原子之后形成的基团，例如-CH＝CH-和-CH2CH＝CH-，或类似基团。所述的“C2-C6亚烯基”定义中包括“C2-C4亚烯基”。
术语“C2-C6炔基”指具有1-3个叁键和2-6个碳原子的直链和支链基团，例如乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、1-己炔、1,3-己二炔基和3-己炔基，或类似基团。所述的“C2-C6炔基”定义中包括“C2-C4炔基”。
术语“C2-C6亚炔基”指C2～C6炔基失去一个氢原子之后形成的基团，例如-C≡C-和-CH2C≡C-，或类似基团。所述的“C2-C6亚炔基”定义中包括“C2-C4亚炔基”。
术语“C6-C12芳基”指具有6-12个碳原子的单环或稠合双环，具有共轭的π电子体系的取代基，例如苯基和萘基，或类似基团。所述的“C6-C12芳基”定义中包括“C6-C10芳基”。
术语“C6-C12亚芳基”指C6-C12芳基失去一个氢原子之后形成的基团，包括单环或双环亚芳基，例如亚苯基、亚萘基，或类似基团。所述的“C6-C12亚芳基”定义中包括 “C6-C10亚芳基”。
术语“5-12元杂芳基”指具有5-12元的单环或稠合多环且环系上具有一个或多个选自O、S、N或P的杂原子的非饱和环系取代基，优选自5-10元的单环或稠和双环且环系上具有1-5个选自O、S、N或P的杂原子，进一步优选自5-8元单环杂芳基或8-10元双环杂芳基，最优选自5-6元单环杂芳基、苯并5-6元单环杂芳基、5-6元单环杂芳基并5-6元单环杂芳基，例如吡啶基、噻吩基、呋喃基、吡咯基、噻唑基、咪唑基、苯并呋喃基、吲哚基、吲唑基、异吲哚基、苯并咪唑基、苯并噻吩基、苯并噻唑基、喹啉基、异喹啉基、苯并嘧啶基和苯并吡喃基，或类似基团。
术语“C3-C8环烷基”指具有3-8个碳原子的饱和碳环基，例如环丙基、环丁基、环戊基和环己基，或类似基团。所说的“C3-C8环烷基”定义中包括“C3-C6环烷基”。
术语“C3-C8亚环烷基”指C3-C8环烷基失去一个氢原子之后形成的基团，例如亚环丙基、亚环丁基、亚环戊基和亚环己基，或类似基团。所述的“C3-C8亚环烷基”定义中包括“C3-C6亚环烷基”。
术语“C3-C8环烯基”指具有3-8个碳原子并含有1-3个双键，但不具有完全共轭的π电子***的碳环基，例如环丙烯基、环丁烯基、环己二烯基和环庚三烯基，或类似基团。所述的“C3-C8环烯基”定义中包括“C3-C6环烯基”。
术语“3-12元杂环基”指具有3-12元的单环或稠合双环且环系上具有一个或多个(优选1-5个)选自O、S、N或P的杂原子的饱和环系取代基，例如哌啶基、吡咯烷基、哌嗪基、四氢呋喃基、吗啉基，或类似基团。所述的“3-12元杂环基”定义中包括“4-7元杂环基”。
术语“卤素”指氟、氯、溴或碘；优选地为氟、氯或溴。
术语“C1-C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基、或类似基团。所述的“C1-C6烷氧基”定义中包括“C1-C4烷氧基”。
术语“C1-C6亚烷氧基”指C1-C6烷氧基失去一个氢原子之后形成的基团，例如-OCH2-、-OCH2-CH2-、-OCH(CH3)-、-OCH2-CH2-CH2-、-OCH2-CH(CH3)-、和-OCH2-CH(CH3)-CH2-，或类似基团。所述的“C1-C6亚烷氧基”定义中包括“C1-C4亚烷氧基”。
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化 合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
式I化合物
本发明提供了一种如下式I所示的化合物：
Figure PCTCN2017085765-appb-000005
以及通式(I)化合物中的手性碳原子的构型为R型或S型。
本发明所述的通式(I)类化合物及其对映异构体、非对映异构体、外消旋体及其混合物或其药学上可接受的盐具体优选自下列化合物之一：
Figure PCTCN2017085765-appb-000006
Figure PCTCN2017085765-appb-000007
Figure PCTCN2017085765-appb-000008
Figure PCTCN2017085765-appb-000009
Figure PCTCN2017085765-appb-000010
Figure PCTCN2017085765-appb-000011
Figure PCTCN2017085765-appb-000012
Figure PCTCN2017085765-appb-000013
Figure PCTCN2017085765-appb-000014
Figure PCTCN2017085765-appb-000015
Figure PCTCN2017085765-appb-000016
Figure PCTCN2017085765-appb-000017
本发明还提供了通式(I)化合物的制备方法，本发明所用原料及试剂如无特殊说明，均为商业购买。
本发明的第二方面，提供一种通式(I)所示的五元杂环并[3,4-d]哒嗪酮类化合物、其对映异构体、非对映异构体、外消旋体、其混合物、其药学上可接受的盐、结晶水或溶剂合物的制备方法，其反应路线如下：
Figure PCTCN2017085765-appb-000018
其中，X1，X2，X3，X4，X5，Q和G的定义与前述相同；
Rx选自C1-C6烷基，优选自甲基或乙基；
式(I)-1化合物与水合肼经环合反应得到式(I)化合物；优选地，式(I)-1化合物与水合肼可在合适的溶剂中进行，所述合适的溶剂选自极性溶剂，优选自甲醇、乙醇、异丙醇、乙腈和二氧六环中的一种或多种；所述反应的温度选自室温～100℃，反应时间选自10分钟～24小时；
根据需要，所制得的式(I)化合物还可以经过取代反应、还原反应、缩合反应等进一步发生转化。比如：当G为-L3-卤素取代的C6-C12芳基时，可与胺、醇或含有氮原子的3-12元杂环基等化合物经取代反应生成新的式(I)化合物；当G为-L3-硝基取代的C6-C12芳基时，可经还原反应得到氨基物，根据需要，可进一步与羧酸经缩合反应生成新的式(I)化合物，又或者，氨基物与酰卤经取代反应生成新的式(I)化合物；当G为-L3-取代或未取代的含有氮原子的3-12元杂环基或-L3-氨基取代的C3-C8环烷基时，可与酰卤或卤代物经取代反应生成新的式(I)化合物；
式(I)-1化合物可通过如下反应路线制备：
(1)当X1、X4和X5皆为C，X2和X3皆为N时，
Figure PCTCN2017085765-appb-000019
将化合物Ib溶解于溶剂中，加入碱，搅拌5～10min后加入化合物Ih，用氩气保护后，于室温搅拌反应，得到化合物(I)-1，所述的溶剂为无水乙醇或二氯甲烷，所述的碱为乙醇钠或三乙胺；
化合物Ib可由如下方法制备：
Figure PCTCN2017085765-appb-000020
将化合物Ia溶解于干燥的四氢呋喃中，于室温下加入钠氢和乙腈，50℃搅拌反应得化合物Ib；
化合物Ih可由如下方法制备：
Figure PCTCN2017085765-appb-000021
步骤h：将化合物G-Cl加入二氯甲烷中，于室温下加入水合肼溶液，搅拌反应得到化合物If；
步骤i：将If溶解于溶剂中，加入碳酸钠，搅拌5min后加入乙醛酸酯的甲苯溶液，于50℃搅拌反应，得到化合物Ig，所述溶剂为1,4-二氧六环和水；
步骤j：将化合物Ig溶于乙酸乙酯中，加入N-氯代琥珀酰亚胺，于室温搅拌反应，得到产物Ih；
化合物Ih也可由如下方法制备：
Figure PCTCN2017085765-appb-000022
将化合物G-NH2混悬于溶剂中，于冰浴下加入亚硝酸钠的水溶液，冰浴反应半小时后继续加醋酸钠和2-氯乙酰乙酸酯的乙醇溶液，搅拌反应得到化合物Ih，所述溶剂为水和浓盐酸；
(2)当X1、X4和X5皆为C，X2为CH、X3为N时，
Figure PCTCN2017085765-appb-000023
步骤p：将化合物Im和异氰乙酸酯溶于1,4-二氧六环中，氩气保护下加入催化量1,3-双(二苯膦基)丙烷，于110℃下搅拌反应，得到化合物In；
步骤q：将化合物In和G-OH溶于四氢呋喃中，加入三苯基膦，氮气保护下滴加偶氮二甲酸二乙酯的甲苯溶液，于室温搅拌反应，得到化合物(I)-1；
化合物Im可由如下方法制备:
Figure PCTCN2017085765-appb-000024
步骤m：将Q-COOH溶解于干燥的二氯甲烷中，于室温下加入草酰氯和催化量的DMF，室温搅拌反应得化合物Ik；
步骤n：将氰甲基三苯基氯化磷和三乙胺加入二氯甲烷中，于室温下加入化合物Ik的二氯甲烷溶液，搅拌反应得到化合物Il；
步骤o：将化合物Il置于微波管中，于110℃搅拌反应，得到化合物Im；
FGFR活性抑制剂及其应用
本发明化合物可抑制一种或多种FGFR酶的活性。举例而言，本发明化合物可用于抑制需要抑制FGFR酶的细胞中个体或患者中该酶的活性，其通过将抑制量的本发明化合物施用该细胞、个体或患者而达成。
在一些实施例方案中，本发明化合物为FGFR1、FGFR2、FGFR3和FGFR4中的一或多者的抑制剂，例如对于上述酶活性全部有抑制作用或者选择性地抑制一种或多种FGFR酶。上述的选择性可以是抑制IC50值为2倍、3倍、5倍、10倍、50倍或100倍及以上。
作为FGFR抑制剂，本发明化合物适用于治疗与FGFR酶活，FGFR配体异常表达或活性相关的各种疾病。所述与FGFR活性或表达量相关的增殖异常疾病包含但不限与以下癌症或肿瘤疾病：哺乳动物癌症或肿瘤(如管道或者小叶肿瘤),呼吸道肿瘤(小细胞肺癌，非小细胞肺癌，小细胞/非小细胞癌症，支气管癌，支气管腺瘤，胸膜肺母细胞瘤)，脑肿瘤(如脑干和下丘脑肿瘤、星形细胞瘤、恶性胶质瘤、成神经管细胞瘤、室管膜细胞 瘤、色素性神经外胚瘤、松果体肿瘤)，消化器官肿瘤(食管癌，胃癌，胆囊癌，小肠癌，大肠癌，直肠癌，***癌)，肝脏肿瘤(特别指肝细胞癌、胆管细胞癌、混合型肝癌)，头颈部肿瘤(喉癌、咽喉癌、鼻咽癌、口咽癌、眼癌、口腔癌)，皮肤癌(鳞状上皮细胞癌、卡波西肉瘤、恶性黑色素瘤、梅克尔细胞癌、非黑色素瘤皮肤癌)，软组织肿瘤(特别指软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤、横纹肌肉瘤)，眼部肿瘤(特别指眼内黑色素瘤、葡萄膜黑素瘤、成视网膜细胞瘤)，内分泌和外分泌腺肿瘤(如甲状腺和甲状旁腺肿瘤、胰腺和唾腺肿瘤)，泌尿道肿瘤(膀胱癌、***肿瘤、肾癌、肾盂和输尿管肿瘤)，生殖器官肿瘤(女性的子宫内膜癌、子***、卵巢癌、***癌、外阴癌、子宫癌，以及男性的***癌和睾丸癌)，以及这些肿瘤转移肿瘤。
其它示例性癌症还包括在固体形态和血液细胞的增生性血液疾病如淋巴瘤和白血病，骨髓增生性疾病如急性髓系白血病、急性淋巴细胞白血病、慢性骨髓细胞性白血病、慢性粒细胞白血病、毛细胞白血病和AIDS相关的淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、以及中枢神经***淋巴瘤。
可用本发明化合物治疗的其他癌症包括眼肿瘤、神经胶母细胞瘤、黑素瘤、横纹肌肉瘤、淋巴瘤和骨肉瘤。
除致癌性赘生物以外，本发明化合物可适用于治疗骨骼和软骨细胞病症，包括(但不限于)软骨发育不全、季肋发育不全、侏儒症、致死性骨发育不全(TD)、比尔-史蒂文森皮肤回旋综合征、斐弗综合征和颅缝早闭综合征。
本发明化合物也可适用于治疗低磷酸盐血症，包括例如X-连锁低磷酸血性佝偻病、常染色体隐性低磷酸血性佝偻病、常染色体显性低磷酸血性佝偻病和肿瘤诱发的骨软化症。
本发明化合物可另外适用于治疗纤维性疾病，诸如疾病症状或病症的特征为纤维化的疾病。示例纤维变性疾病包括肝硬化、肾小球性肾炎、肺纤维化、全身性纤维化、类风湿性关节炎和创伤愈合。
本发明化合物也可适用于治疗银屑病、斑痕瘤、大疱性皮肤病、动脉粥样硬化、再狭窄、肾小球膜细胞增殖病症、肾小球病变、糖尿病性肾病变、肾病和良性***增生。
本发明化合物也可适用于治疗各种眼病，包括例如年龄相关的黄斑变性、干性黄斑变性、缺血型视网膜静脉阻塞、糖尿病性黄斑水肿、糖尿病性视网膜病变和早产儿视网膜病变。
本发明化合物也可适用于预防或抑制一般肿瘤的转移。
本发明的化合物还可以用于组合疗法，即与一种或多种其它药剂或治疗方法，诸如抗病毒剂、化学治疗剂或其他抗癌剂、免疫增强剂、免疫抑制剂、放射性、抗肿瘤和抗病毒疫苗、细胞介素疗法和/或酪氨酸激酶抑制剂组合用于治疗FGFR相关疾病、病症或病状。所述药剂可与本发明化合物以单一剂型组合，或所述药剂可作为包含核苷和核苷酸逆转录酶抑制剂、非核苷逆转录酶抑制剂、蛋白酶抑制剂和其他抗病毒药物。
与现有技术相比，本发明的主要优点包括：
1.本发明人发现五元杂环并[3,4-d]哒嗪酮类化合物具有FGFR激酶抑制活性。本发明报道的五元杂环并[3,4-d]哒嗪酮类化合物为与FGFR酶活，FGFR配体异常表达或活性相关的各种疾病的治疗提供了更多选择，特别是癌症及其它增殖异常的疾病。
2.本发明化合物在动物学实验中，体现出与现有FGFR抑制剂相当乃至更佳的治疗效果。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中，化学实验的收率百分比按摩尔比计算，药理学实验的试剂溶液百分比按体积计算。
本发明中用到的起始原料未经特别说明，均为商业购买。
如下定义反应式和实施例中所用的某些缩写：
DMF 二甲基甲酰胺
THF 四氢呋喃
NCS 氯代琥珀酰亚胺
TEA 三乙胺
TLC 薄层层析色谱
Pd2(dba)3 三(二亚苄基丙酮)二钯
BINAP (±)-2,2’-双-(二苯膦基)-1,1’-联萘
BOC 叔丁氧羰基
DCM 二氯甲烷
DMSO 二甲基亚砜
MW 微波
实施例1 化合物4-氨基-3-(3-甲基-1-苯并噻吩-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A1)的制备
反应式1.1
Figure PCTCN2017085765-appb-000025
步骤1:制备乙基3-甲基-1-苯并噻吩-2-羧酸酯(A1a)
将2-溴苯乙酮(2g,10.05mmol)溶于20mL DMF中，加入碳酸钾(2.08g,15.07mmol),然后在室温下加入硫代乙醇酸乙酯(1.2mL,11.05mmol),氮气保护，在100℃下搅拌过夜。TLC检测原料反应完全后，将反应液冷至室温，加入水50mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×50mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝15/1,v/v)分离纯化得产物1.2g，产率54.50％。MS(ESI,m/z):221(M+H)+。
步骤2:制备3-(3-甲基-1-苯并噻吩-2-基)-3-羰基丙腈(A1b)
将A1a(1g,4.54mmol)溶于15mL干燥的四氢呋喃中，加入钠氢(236mg,5.9mmol)，然后加入乙腈(472μl,9.08mmol)，氮气保护下于60℃下搅拌过夜。反应液直接减压蒸除溶剂，加入15mL冰水，再用1N HCl溶液酸化pH至4-5，有淡黄色固体析出，抽滤得到800mg固体再减压干燥，未经纯化直接用于下步反应。MS(ESI,m/z):216(M+H)+。
反应式1.2
Figure PCTCN2017085765-appb-000026
步骤3:制备乙基(2Z)-氯(2-苯基肼亚基)乙酸酯(A1c)
将苯胺(8g,83.33mmol)加入到30mL水/HCl＝5/1的混合溶剂中,冰浴条件下滴加亚硝酸钠(6.32g,91.66mmol)的水溶液，搅拌半小时后，再加乙酸钠(7.52g,91.66mmol)，以及25mL 2-氯乙酰乙酸乙酯(15.1g,91.66mmol)的乙醇溶液。TLC检测原料反应完全后，加入水40mL，乙酸乙酯(3×80mL)萃取，合并有机层，再依次用水(3×50mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝20/1,v/v)分离纯化得产物12.5g，产率66.2％。MS(ESI,m/z):227(M+H)+。
反应式1.3
Figure PCTCN2017085765-appb-000027
步骤4：制备乙基4-氰基-5-(3-甲基-1-苯并噻吩-2-基)-1-苯基-1H-吡唑-3-羧酸酯(A1d)
将A1b(700mg,3.25mmol)加入到10mL干燥的DCM中，加入TEA(1.32g,13.01mmol)，搅拌10min后，再加入A1c(884mg,3.9mmol)，室温反应。TLC检测原料反应完全后，加入水20mL，乙酸乙酯(3×30mL)萃取，合并有机层，再依次用水(3×20mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝4/1,v/v)分离纯化得到互变异构体的混合产物680mg,产率51.9％。MS(ESI,m/z):388(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.84–7.78(m,1H),7.76–7.73(m,1H),7.48–7.43(m,2H),7.40–7.34(m,5H),4.54(q,J＝7.1Hz,2H,major),4.12(q,J＝7.1Hz,2H,minor),2.26(s,3H,major),2.05(s,2H,minor),1.48(t,J＝7.1Hz,3H,major),1.26(t,J＝7.1Hz,3H,minor)。
步骤5：制备A1
将上述A1d(600mg,1.55mmol)混合物溶于5mL无水乙醇中，然后加入水合肼(543μl,10.84mmol)，90℃回流过夜。TLC检测原料反应完全后，减压蒸除溶剂，经快速分离柱层析(二氯甲烷/甲醇＝15/1,v/v)分离纯化得产物400mg,产率69.2％。MS(ESI,m/z):374(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.00(m,1H),7.85–7.79(m,1H),7.44–7.35(m,7H),5.00(s,2H),2.12(s,3H)。
实施例2 化合物4-氨基-3-(萘-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A2)的制备
除了以2-萘甲酸乙酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A2,最后一步反应产率49.5％。
MS(ESI,m/z):354(M+H)+。
实施例3 化合物4-氨基-3-(1,3-二甲基-1H-吲哚-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A3)的制备
反应式3.1
Figure PCTCN2017085765-appb-000028
步骤1：制备乙基3-甲基-1H-吲哚-2-羧酸酯
将2-溴苯乙酮(3g,15.07mmol)，CuI(287mg,1.51mmol)和碳酸铯(9.82g,30.14mmol)加入到40mL的DMSO中，氮气保护，于50℃下缓慢滴加氰乙酸乙酯，待反应完全后，加入水40mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝4/1,v/v)分离纯化得到产物1.5g，产率49％。MS(ESI,m/z):204(M+H)+。
步骤2：制备乙基1,3-二甲基-1H-吲哚-2-羧酸酯
将上步产物(1.3g,6.4mmol)溶于10mL的干燥的DMF中，加入钠氢(184mg,7.68mmol)，搅拌2h后加入碘甲烷(448μl,7.68mmol)，继续反应至完全，加入水40mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝6/1,v/v)分离纯化得到产物1.25g，产率89.9％。MS(ESI,m/z):218(M+H)+。
步骤3：制备A3
除了以乙基1,3-二甲基-1H-吲哚-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A3，最后一步反应产率32％。MS(ESI,m/z):371(M+H)+。
实施例4 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A4)的制备
反应式4.1
Figure PCTCN2017085765-appb-000029
步骤1：制备乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯(A4a)
将2-羟基-5-甲基苯乙酮(10g,65.26mmol)溶于70mL的干燥DMF中，加入无水碳酸钾(13.53g,97.88mmol)，再加入溴乙酸乙酯(8.72mL,78.31mmol)，100℃加热搅拌过夜，TLC检测原料反应完全后，加入水80mL，乙酸乙酯(3×100mL)萃取，合并有机层，再依次用水(3×80mL)，饱和NaCl溶液80mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝10/1,v/v)分离纯化得产物7.5g，产率52.7％。MS(ESI,m/z):219(M+H)+。
步骤2:制备A4
除了以乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A4，最后一步反应产率40％。1H NMR(500MHz,DMSO-d6)δ11.49(s,1H),7.49–7.41(m,7H),7.27–7.15(m,1H),5.19(s,2H),2.40(s,3H),1.87(s,3H).
实施例5 化合物4-氨基-2-苯基-3-(喹啉-3-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A5)的制备
除了以3-喹啉羧酸乙酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A5，最后一步反应产率53％。MS(ESI,m/z):355(M+H)+。
实施例6 化合物4-氨基-3-(6-氯-3-甲基-1-苯并呋喃-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A6)的制备
除了以乙基6-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A6，最后一步反应产率32％。1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.78(d,J＝1.4Hz,1H),7.67(d,J＝8.4Hz,1H),7.48–7.40(m,5H),7.37(dd,J＝8.4,1.4Hz,1H),5.25(s,2H),1.92(s,3H).
实施例7 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A7)的制备
除了以乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A7，最后一步反应产率37％。1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.78(d,J＝2.1Hz,1H),7.61(d,J＝8.8Hz,1H),7.49–7.38(m,6H),5.24(s,2H),1.92(s,3H).
实施例8 化合物4-氨基-3-(6-氟-3-甲基-1-苯并呋喃-2-基)-2-苯基-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A8)的制备
除了以乙基6-氟-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备化合物A8，最后一步反应产率39％。1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),7.75–7.65(m,1H),7.56(dd,J＝9.2,2.2Hz,1H),7.49–7.41(m,5H),7.25–7.17(m,1H),5.23(s,2H),1.92(s,3H).
实施例9 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(4-{[(二甲氨基)甲基]氨基}苯基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A9)的制备
步骤1：制备4-氨基-2-(4-溴苯基)-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮
除了以乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯替换乙基3-甲基-1-苯并噻吩-2-羧酸酯之外，以与实施例1相同的方式制备该化合物，反应产率41％。MS(ESI,m/z):451(M+H)+
反应式9.1
Figure PCTCN2017085765-appb-000030
步骤2：制备A9
将上一步的产物(200mg,0.44mmol)溶于5mL甲苯中，加入N,N-二甲基甲二胺盐酸盐(147mg,1.33mmol)，Pd2(dba)3(81mg,0.09mmol)，BINAP(55mg,0.09mmol)和叔丁醇钠(128mg,1.33mmol)，氩气保护下，于100℃加热搅拌过夜，TLC检测原料反应完全后，加入水20mL，乙酸乙酯(3×30mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液40mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(二氯甲烷/甲醇＝15/1,v/v)分离纯化得产物86mg，产率43.6％。MS(ESI,m/z):509(M+H)+。
实施例10 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(1-丙酰哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A10)的制备
除了以丙酰氯替换丙烯酰氯之外，以与实施例29相同的方式制备化合物,最后一步反应产率42％。MS(ESI,m/z):435(M+H)+。
实施例11 化合物4-氨基-2-(4-{[2-(二甲氨基)乙基](甲基)氨基}苯基)-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A11)的制备
除了以N,N,N’-三甲基乙二胺替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A11，最后一步反应产率42％。MS(ESI,m/z):472(M+H)+。
实施例12 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[4-(吗啉-4-基)苯基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A12)的制备
除了以吗啉替换N,N,N’-三甲基乙二胺之外，以与实施例9相同的方式制备化合物A12，最后一步反应产率34％。MS(ESI,m/z):457(M+H)+。
实施例13 化合物4-氨基-2-(4-氯苯基)-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A13)的制备
除了以对氯苯胺替换苯胺之外，以与实施例1相同的方式制备化合物A13，最后一步反应产率40％。1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),7.59–7.48(m,3H),7.42(s,1H),7.30(d,J＝7.5Hz,2H),7.07(d,J＝8.0Hz,1H),5.16(s,2H),2.46(s,3H),1.89(s,3H)。
实施例14 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{4-[2-(吡咯烷-1-基)乙氧基]苯基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A14)的制备
除了以N-(2-羟乙基)-吡咯烷替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A14，最后一步反应产率14％。MS(ESI,m/z):485(M+H)+。
实施例15 化合物4-氨基-2-{4-[2-(二甲氨基)乙氧基]苯基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A15)的制备
除了以N,N-二甲基乙醇胺替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A15，最后一步反应产率16％。MS(ESI,m/z):459(M+H)+。
实施例16 化合物4-氨基-2-[4-(4-环丙基哌嗪-1-基)苯基]-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A16)的制备
除了以1-环丙基哌嗪替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A16。MS(ESI,m/z):496(M+H)+。
实施例17 化合物4-氨基-2-{4-[3-(二甲氨基)吖丁啶-1-基]苯基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A17)的制备
除了以3-(二甲氨基)氮杂环丁烷二盐酸盐替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A16,最后一步反应产率27％。MS(ESI,m/z):470(M+H)+。
实施例18 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[4-(4-乙基哌嗪-1-基)苯基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A18)的制备
除了以N-乙基哌嗪替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A18。MS(ESI,m/z):484(M+H)+。
实施例19 化合物4-氨基-2-(4-{[3-(二甲氨基)丙基](甲基)氨基}苯基)-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A19)的制备
除了以N,N,N’-三甲基-1,3-丙二胺替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A19,最后一步反应产率33％。MS(ESI,m/z):486(M+H)+。
实施例20 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(4-{[(1-甲基哌啶-4-基)甲基]氨基}苯基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A20)的制备
除了以(1-甲基-4-哌啶-)甲胺替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A20,最后一步反应产率35％。MS(ESI,m/z):498(M+H)+。
实施例21 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{4-[4-(甲氧基甲基)哌啶 -1-基]苯基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A21)的制备
除了以4-(甲氧基甲基)哌啶替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A21,最后一步反应产率26％。MS(ESI,m/z):499(M+H)+。
实施例22 化合物4-氨基-2-{4-[3-(二乙胺基)吡咯烷-1-基]苯基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A22)的制备
除了以3-(二乙氨基)吡咯烷替换N,N-二甲基甲二胺盐酸盐之外，以与实施例9相同的方式制备化合物A22,最后一步反应产率34％。MS(ESI,m/z):512(M+H)+。
实施例23 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-(1-乙基哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A23)的制备
反应式23.1
Figure PCTCN2017085765-appb-000031
步骤1：制备1-乙基哌啶-4-基甲磺酸酯(A23a)
将N-乙基-4-羟基哌啶(3g,23.22mmol)溶于20mL干燥的四氢呋喃中，加入TEA，在冰浴条件下缓慢滴加甲磺酰氯(1.98mL,25.54mmol)，室温搅拌至反应完全。加入水40mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝4/1,v/v)分离纯化得产物4.0g，产率81.2％。MS(ESI,m/z):208(M+H)+。
步骤2：制备乙基(2E)-[2-(1-乙基哌啶-4-基)肼亚基]乙酸酯(A23b)
将A23a(3g,14.47mmol)溶于15mL的无水乙醇中，加入水合肼(1.45mL,28.95mmol),50℃加热搅拌反应。反应完全后，减压浓缩溶剂，未经纯化，直接用于下一步反应。将浓缩后的剩余物溶于20mL的混合溶剂(1,4-二氧六环/水＝5/1)中，加入乙醛酸乙酯的甲苯溶液(8.6mL,41.89mmol)和碳酸钠(4.44g,41.89mmol)，50℃加热搅拌反应。加入水40mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝6/1,v/v)分离纯化得产物3.7g。MS(ESI,m/z):228(M+H)+。
步骤3：制备乙基(2Z)-氯[2-(1-乙基哌啶-4-基)肼亚基]乙酸酯(A23c)
将A23b(3g,13.2mmol)溶于15mL的乙酸乙酯中，加入NCS(2.47g,18.48mmol)，50℃加热搅拌至反应完全。加入水40mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝6/1,v/v)分离纯化得产物2.9g，产率84.0％。MS(ESI,m/z):262(M+H)+。
步骤4：制备4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-(1-乙基哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A23)
除了以乙基(2Z)-氯[2-(1-乙基哌啶-4-基)肼亚基]乙酸酯替换乙基(2Z)-氯(2-苯基肼亚基)乙酸酯之外，以与实施例7相同的方式制备化合物A23,最后一步反应产率31％。MS(ESI,m/z):427(M+H)+。
实施例24 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(1-乙基哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A24)的制备
除了以乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯替换乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例23相同的方式制备化合物A24，最后一步反应产率37％。1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),7.60(d,J＝1.5Hz,1H),7.55(d,J＝7.5Hz,1H),7.42–7.35(m,1H),5.21(s,2H),3.87–3.79(m,1H),3.24(t,J＝7.1Hz,2H),2.56–2.51(m,4H),1.90(s,3H),1.83–1.76(m,4H),1.18(q,J＝7.1Hz,3H).
实施例25 化合物N-{4-[4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}丙-2-烯酰胺(A25)的制备
反应式25.1
Figure PCTCN2017085765-appb-000032
步骤1:
除了以对硝基苯胺替换苯胺之外，以与实施例7相同的方式制备化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-(4-硝基苯基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮，反应产率33％。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.35–8.28(m,2H),7.76–7.69(m,2H),7.52–7.44(m,2H),7.25(dd,J＝8.5,1.3Hz,1H),5.27(s,2H),1.97(s,3H).
步骤2：
将上步产物(1g,2.29mmol)溶于10mL甲醇中，加入氯化铵(367mg,6.87mmol)和铁粉(384mg,6.87mmol)，于70℃加热搅拌至反应完全。溶剂直接减压旋干，得到淡黄色固体，未经纯化直接用于下一步反应。
将上述得到的产物1g溶于10mL的乙腈中，加入碳酸钾(679mg,4.92mmol)，搅拌下再加入丙烯酰氯(404μL,4.92mmol)，室温搅拌至反应完全。加入水30mL，乙酸乙酯(3×40mL)萃取，合并有机层，再依次用水(3×30mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(二氯甲烷/甲醇＝10/1,v/v)分离纯化得产物200mg(化合物A25)。1H NMR(400MHz,DMSO--d6)δ11.50(s,1H),10.43(s,1H),7.82–7.69(m,3H),7.64(d,J＝8.8Hz,1H),7.47–7.35(m,3H),6.43(dd,J＝17.0,10.1Hz,1H),6.26(d,J＝17.0Hz,1H),5.78(d,J＝10.1Hz,1H),5.23(s,2H),1.95(s,3H).
实施例26 化合物(2E)-N-{4-[4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}-4-(二甲氨基)丁-2-烯酰胺(A26)的制备
除了以(E)-4-(二甲氨基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例25相同的方式制备化合物A26。MS(ESI,m/z):518(M+H)+。
实施例27 化合物(2E)-N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}-4-(吖丁啶-1-基)丁-2-烯酰胺(A27)的制备
除了以乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯替换乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯，以(E)-4-(吖丁啶-1-基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例25相同的方式制备化合物A27。MS(ESI,m/z):510(M+H)+。
实施例28 化合物(2E)-N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}-4-(吗啉-4-基)丁-2-烯酰胺(A28)的制备
除了以(E)-4-(吗啉-4-基)丁-2-烯酰氯替换(E)-4-(吖丁啶-1-基)丁-2-烯酰氯之外，以与 实施例27相同的方式制备化合物A28。MS(ESI,m/z):540(M+H)+。
实施例29 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A29)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物A29。MS(ESI,m/z):433(M+H)+。
实施例30 化合物4-氨基-2-{1-[(2E)-4-(二甲氨基)丁-2-烯酰]哌啶-4-基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A30)的制备
除了以(E)-4-(二甲氨基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例29相同的方式制备化合物A30。MS(ESI,m/z):490(M+H)+。
实施例31 化合物4-氨基-2-{1-[(2E)-4-(吖丁啶-1-基)丁-2-烯酰]哌啶-4-基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A31)的制备
除了以(E)-4-(吖丁啶-1-基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例29相同的方式制备化合物A31。MS(ESI,m/z):502(M+H)+。
实施例32 化合物N-(4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]-2-{[(二甲氨基)乙基](甲基)氨基}苯基)丙-2-烯酰胺(A32)的制备
除了以乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯替换乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯，以2-(N,N’,N’-三甲基乙二胺)-4-氨基硝基苯替换对氨基硝基苯之外，以与实施例25相同的方式制备A32。MS(ESI,m/z):541(M+H)+
实施例33 化合物N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}丙-2-烯酰胺(A33)的制备
除了以4-硝基环己基胺替换2-(N,N’,N’-三甲基乙二胺)-4-氨基硝基苯之外，以与实施例32相同的方式制备A33。MS(ESI,m/z):447(M+H)+。
实施例34 化合物4-氨基-2-(1-{(2E)-4-[环丙基(甲基)氨基]丁-2-烯酰}哌啶-4-基)-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A34)的制备
除了以4-(N-甲基-N-环丙基)氨基丁-2-烯酰氯替换丙烯酰氯之外，以与实施例29相同的方式制备化合物A34。MS(ESI,m/z):516(M+H)+。
实施例35 化合物N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-N,N-二甲基甘氨酰胺(A35)的制备
除了以二甲氨基乙酰氯替换丙烯酰氯之外，以与实施例33相同的方式制备化合物A35。MS(ESI,m/z):478(M+H)+。
实施例36 化合物4-氨基-2-{1-[2-(二甲氨基)乙基]哌啶-4-基}-3-(3,5-二甲基苯并呋喃-2-基)-2H-吡唑并[3,4-d]哒嗪-7(6H)-酮(A36)的制备
步骤1：制备3-(3,5-二甲基苯并呋喃-2-基)-3-羰基丙腈(A36a)
以与实施例A4相同方式制备A36a。
反应式36.1
Figure PCTCN2017085765-appb-000033
步骤2：制备4-肼基哌啶-1-羧酸叔丁酯(A36b)
将化合物1-BOC-4-氯哌啶(2g，9.10mmol)加入DCM中，于室温下加入水合肼(0.7mL，14mmol)溶液，TLC检测原料反应完全后，直接蒸干得到化合物1.8g，产率93％， 无需纯化直接用于下一步。MS(ESI,m/z):215(M+H)+
步骤3：制备(E)-叔-丁基4-(2-(2-乙氧基-2-羰基亚乙基)肼基)哌啶-1-羧酸酯(A36c)
将A36b(2g，9.29mmol)溶解于1,4-二氧六环和水1:1溶液中，加入碳酸钠(1g，10.22mmol)，搅拌5min后加入乙醛酸乙酯的甲苯溶液(2.21mL，10.22mmol)，于50℃搅拌反应，TLC检测原料反应完全后，快速分离柱得到化合物2g，产率为65％。MS(ESI,m/z):299(M+H)+。
步骤4：制备(Z)-叔-丁基4-(2-(1-氯-2-乙氧基-2-羰基亚乙基)肼基)哌啶-1-羧酸酯(A36d)
将化合物A36c(2g，6.68mmol)溶于乙酸乙酯中，加入NCS(1.78，13.36mmol)，于室温搅拌反应，TLC检测原料反应完全后，加入水50mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×50mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂直接得到产物2g，产率76％。
MS(ESI,m/z):333(M+H)+。
反应式36.2
Figure PCTCN2017085765-appb-000034
步骤5：制备叔-丁基4-(4-氰基-5-(3,5-二甲基苯并呋喃-2-基)-3-(乙酯基<乙氧羰基>)-1H-吡唑-1-基)哌啶-1-羧酸酯(A36e)
用氩气保护下，将A36a(700mg,3.25mmol)加入到10mL无水EtOH中，加入NaOEt(0.42g,6.6mmol)，搅拌10min后，再加入A36d(1.1g,3.28mmol)，室温反应。TLC检测原料反应完全后，加入水20mL，乙酸乙酯(3×30mL)萃取，合并有机层，再依次用水(3×20mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝4/1,v/v)分离纯化得到互变异构体的混合产物680mg,产率50.9％。MS(ESI,m/z):492(M+H)+。
步骤6：制备叔丁基4-(4-氨基-3-(3,5-二甲基苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基)哌啶-1-羧酸酯(A36f)
将上述A36e(600mg,1.55mmol)混合物溶于5mL无水乙醇中，然后加入水合肼(543μl,10.84mmol)，90℃回流过夜。TLC检测原料反应完全后，减压蒸除溶剂，经快速分离柱层析(二氯甲烷/甲醇＝15/1,v/v)分离纯化得产物400mg,产率69.2％。MS(ESI,m/z):478(M+H)+。
反应式36.3
Figure PCTCN2017085765-appb-000035
步骤7：制备4-氨基-3-(3,5-二甲基苯并呋喃-2-基)-2-(哌啶-4-基)-2H-吡唑并[3,4-d]哒嗪-7(6H)-酮盐酸盐(A36g)
将上述A36f(500mg，1.0mmol)加入到20mL的4N的盐酸1,4-二氧六环溶液中，室温搅拌3小时，TCL检测反应完全，直接减压浓缩至干得到产物0.4g，产率98％。MS(ESI,m/z):378(M+H)+。
步骤8：制备4-氨基-2-(1-(2-(二甲氨基)乙基)哌啶-4-基)-3-(3,5-二甲基苯并呋喃-2-基)-2H-吡唑并[3,4-d]哒嗪-7(6H)-酮(A36)
将上述A36g(0.5g，1.32mmol)加入到20mL的DCM中，加入0.36mmL的TEA，室温搅拌10min，向反应液中加入2-氯-N,N-二甲基乙胺(142mg，1.32mmol)，室温搅拌2小时。TLC检测原料反应完全后，加入水20mL，DCM(3×30mL)萃取，合并有机层，再依次用水(3×20mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(二氯甲烷/乙酸乙酯＝4/1,v/v)分离纯化得到产物300mg，产率52.2％。MS(ESI,m/z):449(M+H)+。
实施例37 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[(1-乙基哌啶-4-基)甲基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A37)的制备
除了以4-(氯甲基)-1-乙基哌啶替换1-BOC-4-氯哌啶之外，以与实施例36相同的方式制备化合物37，最后一步反应产率60.7％。MS(ESI,m/z):421(M+H)+。
实施例38 化合物2-[(1-丙烯酰哌啶-4-基)甲基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A38)的制备
除了以1-BOC-4-(氯甲基)哌啶替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物38，最后一步反应产率40.7％。MS(ESI,m/z):447(M+H)+。
实施例39化合物2-[(1-丙烯酰吡咯烷-2-基)甲基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A39)的制备
除了以1-BOC-2-(氯甲基)吡咯烷替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物39。MS(ESI,m/z):433(M+H)+
实施例40 化合物2-(1-丙烯酰哌啶-3-基)-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A40)的制备
除了以1-BOC-3-氯哌啶替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):433(M+H)+。
实施例41 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-(1-丙酰哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A41)的制备
除了以丙酰氯替换2-氯-N,N-二甲基乙胺和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物41。MS(ESI,m/z):455(M+H)+。
实施例42 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(四氢-2H-吡喃-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A42)的制备
除了以4-氨基四氢-2H-吡喃替换苯胺之外，以与实施例4相同的方式制备化合物。MS(ESI,m/z):380(M+H)+。
实施例43 化合物2-[(1-丙烯酰吡咯烷-3-基)甲基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A43)的制备
除了以1-BOC-3-(氯甲基)吡咯烷替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):433(M+H)+。
实施例44 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{4-[(5-羰基吡咯烷-3-基)氨基]苯基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A44)的制备
除了以4-((4-氨基苯基)氨基)吡咯烷-2-酮替换苯胺和以3-(3,5-二甲基苯并呋喃-2-基)-3-羰基丙腈替换3-(3-甲基-1-苯并噻吩-2-基)-3-羰基丙腈之外，以与实施例1相同的 方式制备化合物。MS(ESI,m/z):470(M+H)+。
实施例45 化合物2-[(1-丙烯酰吖丁啶-3-基)甲基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A45)的制备
除了以1-BOC-3-(氯甲基)吖丁啶替换1-BOC-4-氯哌啶之外，以与实施例29相同的方式制备化合物。MS(ESI,m/z):419(M+H)+。
实施例46 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-{3-[2-(二甲氨基)乙基]吖丁啶-1-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A46)的制备
除了以乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯和以1-BOC-3-氯吖丁啶替换1-BOC-4-氯哌啶之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):441(M+H)+。
实施例47 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{1-[(4-甲基哌嗪-1-基)羰基]吡咯烷-3-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A47)的制备
除了以1-BOC-3-氯吡咯烷替换0，以4-甲基哌嗪-1-甲酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):491(M+H)+。
实施例48 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{1-[(1,1-二氧化硫代吗啉-4-基)羰基]吡咯烷-3-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A48)的制备
除了以1,1-二氧化硫代吗啉-4-甲酰氯替换4-甲基哌嗪-1-甲酰氯之外，以与实施例47相同的方式制备化合物,最后一步反应产率61.5％。MS(ESI,m/z):526(M+H)+。
实施例49 化合物4-氨基-2-{1-[(二甲氨基)乙酰基]吡咯烷-3-基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A49)的制备
除了以以二甲氨基乙酰氯替换4-甲基哌嗪-1-甲酰氯，以与实施例47相同的方式制备化合物。MS(ESI,m/z):450(M+H)+。
实施例50 化合物4-氨基-2-{[N-环己基-(2E)-4-甲氧基丁-2-烯酰胺]-4-基}-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A50)的制备
除了以(2E)-4-甲氧基丁-2-烯酰氯替换丙烯酰氯之外，以与实施例33相同的方式制备化合物，最后一步反应产率65.5％。MS(ESI,m/z):491(M+H)+。
实施例51 化合物2-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A51)的制备
除了以丙烯酰氯替换4-甲基哌嗪-1-甲酰氯之外，以与实施例47相同的方式制备化合物，最后一步反应产率42.5％。MS(ESI,m/z):419(M+H)+。
实施例52 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[1-(2-氟丙烯酰)吡咯烷-3-基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A52)的制备
除了以2-氟丙烯酰氯替换4-甲基哌嗪-1-甲酰氯之外，以与实施例47相同的方式制备化合物，最后一步反应产率41.5％。MS(ESI,m/z):437(M+H)+。
实施例53 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{1-[2-(吡咯烷-1-基甲基)丙烯酰]吡咯烷-3-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A53)的制备
除了以2-(吡咯烷-1-基甲基)丙烯酰氯替换4-甲基哌嗪-1-甲酰氯之外，以与实施例47相同的方式制备化合物，最后一步反应产率34.5％。MS(ESI,m/z):502(M+H)+。
实施例54 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[1-(2-氟丙烯酰)哌啶-4-基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A54)的制备
除了以2-氟丙-2-烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物，最后一步反应产率68.5％。MS(ESI,m/z):451(M+H)+。
实施例55 化合物2-({4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]哌啶-1-基}羰基)丙-2-烯腈(A55)的制备
除了以2-氰基丙-2-烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物，最后一步反应产率23.5％。MS(ESI,m/z):458(M+H)+。
实施例56 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-{1-[(2E)-4-(环丙基氨基)丁-2-烯酰]哌啶-4-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A56)的制备
除了以(E)-4-(环丙基氨基)丁-2-烯酰氯替换2-氯-N,N-二甲基乙胺和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物，最后一步反应产率43.5％。MS(ESI,m/z):522(M+H)+。
实施例57 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-{1-[(2E)-4-(吡咯烷-1-基)丁-2-烯酰]哌啶-4-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A57)的制备
除了以(E)-4-(吡咯烷-1-基)丁-2-烯酰氯替换2-氯-N,N-二甲基乙胺和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物，最后一步反应产率56.5％。MS(ESI,m/z):536(M+H)+。
实施例58 化合物N-{4-[4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-2-氟丙-2-烯酰胺(A58)的制备
除了以2-氟丙-2-烯酰氯替换丙烯酰氯和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例33相同的方式制备化合物，最后一步反应产率34.7％。MS(ESI,m/z):485(M+H)+。
实施例59 化合物N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-2-氰基丙-2-烯酰胺(A59)的制备
除了以2-氰基丙-2-烯酰氯替换丙烯酰氯之外，以与实施例33相同的方式制备化合物，最后一步反应产率61.5％。MS(ESI,m/z):472(M+H)+。
实施例60 化合物(2E)-N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-4-(4-甲基哌嗪-1-基)丁-2-烯酰胺(A60)的制备
除了以(2E)-4-(4-甲基哌嗪-1-基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例33相同的方式制备化合物，最后一步反应产率61.5％。MS(ESI,m/z):559(M+H)+。
实施例61 化合物(2Z)-N-{4-[4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-4-(二甲氨基)-2-氟丁-2-烯酰胺(A61)的制备
除了以(Z)-4-(二甲氨基)-2-氟丁-2-烯酰氯替换丙烯酰氯和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，之外，以与实施例33相同的方式制备化合物，最后一步反应产率67.5％。MS(ESI,m/z):542(M+H)+。
实施例62 化合物4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-2-[1-(丙-2-炔酰)哌啶-4-基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A62)的制备
除了以丙炔酰氯替换2-氯-N,N-二甲基乙胺和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物，最后一步反应产率74.5％。MS(ESI,m/z):451(M+H)+。
实施例63 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-[1-(4-羟基丁-2-炔酰)吡咯烷-3-基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A63)的制备
除了以4-羟基丁-2-炔酰氯替换4-甲基哌嗪-1-甲酰氯之外与实施例47相同的方式制备化合物，最后一步反应产率67.5％。MS(ESI,m/z):447(M+H)+。
实施例64 化合物N-{4-[4-氨基-3-(5-氯-3-甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢 -2H-吡唑并[3,4-d]哒嗪-2-基]环己基}丁-2-炔酰胺(A64)的制备
除了以丁-2-炔酰氯替换丙烯酰氯和用乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例33相同的方式制备化合物，最后一步反应产率65.5％。MS(ESI,m/z):479(M+H)+。
实施例65 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-(1-{(2E)-4-[(3R)-3-氟吡咯烷-1-基]丁-2-烯酰}哌啶-4-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A65)的制备
除了以(R,E)-4-(3-氟吡咯烷-1-基)丁-2-烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物，最后一步反应产率61.5％。MS(ESI,m/z):534(M+H)+。
实施例66 化合物4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-2-{1-[(2E)-4-(4-羟基哌啶-1-基)丁-2-烯酰]哌啶-4-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A66)的制备
除了以(2E)-4-(4-羟基哌啶-1-基)丁-2-烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物，最后一步反应产率54.5％。MS(ESI,m/z):546(M+H)+。
实施例67 化合物1-(1-丙烯酰哌啶-4-基)-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-1,3a,6,7a-四氢-7H-吡咯并[2,3-d]哒嗪-7-酮(A67)的制备
反应式67.1
Figure PCTCN2017085765-appb-000036
步骤1
将3,5-二甲基苯并呋喃-2-羧酸(6g，31.55mmol)溶解于干燥的二氯甲烷中，于室温下加入草酰氯(4g，31.55mmol)和催化量的DMF，室温搅拌反应。TLC检测原料反应完全后，直接旋干得产物3,5-二甲基苯并呋喃-2-酰氯6.5g，产率98％。MS(ESI,m/z):208(M+H)+
步骤2
将氰甲基三苯基氯化磷(5.8g，19.17mmol)和三乙胺(1.94g，38.34mmol)加入二氯甲烷中，于室温下加入上步产物(4g，19.17mmol)的二氯甲烷溶液，室温搅拌反应，TLC检测原料反应完全后。快速制备分离得到产物2-(3,5-二甲基苯并呋喃-2-基)-2-(三苯基正膦亚基)乙酰腈3.5g，产率50％。MS(ESI,m/z):368(M+H)+
步骤3
将上步产物(2g，4.49mmol)置于微波管中，于110℃搅拌反应，得到产物3-(3,5-二甲基苯并呋喃-2-基)丙炔腈0.8g，产率95％。MS(ESI,m/z):195(M+H)+
反应式67.2
Figure PCTCN2017085765-appb-000037
步骤4
将上步产物(2g，10.25mmol)和异氰乙酸乙酯(1.16g，10.25mmol)溶于1,4-二氧六环中，氩气保护下加入催化量1,3-双(二苯膦基)丙烷(0.39g，1.02mmol)，于110℃下搅拌反应，得到产物，产率TLC检测原料反应完全后，将反应液冷至室温，加入水50mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×50mL)，饱和NaCl溶液50mL洗涤， 无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝15/1,v/v)分离纯化得产物乙基3-氰基-4-(3,5-二甲基苯并呋喃-2-基)-1H-吡咯-2-羧酸酯1.2g，产率45.50％。MS(ESI,m/z):308(M+H)+
步骤5
将上步产物(2g，6.49mmol)和1-(4-羟基哌啶)丙-2-烯-1-酮(1.01g，6.49mmol)溶于THF中，加入三苯基膦(0.17g，0.64mmol)，氮气保护下滴加偶氮二甲酸二乙酯的甲苯溶液(2.1mL,6.49mmol)，于室温搅拌反应，产率TLC检测原料反应完全后，加入水50mL，乙酸乙酯(3×50mL)萃取，合并有机层，再依次用水(3×50mL)，饱和NaCl溶液50mL洗涤，无水Na2SO4干燥，过滤，减压蒸除溶剂，经快速分离柱层析(石油醚/乙酸乙酯＝15/1,v/v)分离纯化得产物乙基1-(1-丙烯酰哌啶-4-基)-3-氰基-4-(3,5-二甲基苯并呋喃-2-基)-1H-吡咯-2-羧酸酯1.2g，产率65.50％。MS(ESI,m/z):445(M+H)+
反应式67.3
Figure PCTCN2017085765-appb-000038
步骤6
将上步产物(1g，2.24mmol)溶于乙醇中，加入水合肼溶液(0.47mL，8.98mmol)，60度油浴加热。产率TLC检测原料反应完全后，将反应液冷至室温。旋干直接快速制备柱得化合物A67 0.5g，产率50％。MS(ESI,m/z):432(M+H)+。
实施例68 化合物1-[(1-丙烯酰哌啶-4-基)甲基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(A68)的制备
除了以1-[4-(羟甲基)哌啶-1-基]丙-2-烯-1-酮替换1-(4-羟基哌啶)丙-2-烯-1-酮之外，以与实施例67相同的方式制备化合物，最后一步反应产率34.5％。MS(ESI,m/z):446(M+H)+。
实施例69 化合物1-[(3S)-1-丙烯酰吡咯烷-3-基]-4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(A69)的制备
除了以1-[(3S)-3-羟基吡咯烷-1-基]丙-2-烯-1-酮替换1-(4-羟基哌啶)丙-2-烯-1-酮之外，以与实施例67相同的方式制备化合物，最后一步反应产率56.5％。MS(ESI,m/z):418(M+H)+。
实施例70 化合物(2E)-N-{4-[4-氨基-3-(1-甲基-1H-苯并咪唑-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}-4-(二甲氨基)丁-2-烯酰胺(A70)的制备除了以乙基1-甲基-1H-苯并[d]咪唑-2-羧酸酯替换乙基3,5-二甲基苯并呋喃-2-羧酸酯和以(2E)-4-(二甲氨基)丁-2-烯酰氯替换丙烯酰氯之外，以与实施例25相同的方式制备化合物，最后一步反应产率56.5％。MS(ESI,m/z):484(M+H)+。
实施例71 化合物(2E)-N-{4-[4-氨基-3-(1,3-二甲基-1H-吲哚-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}-4-(二甲氨基)丁-2-烯酰胺(A71)的制备
除了以乙基1,3-二甲基-1H-吲哚-2-羧酸酯替换乙基1-甲基-1H-苯并[d]咪唑-2-羧酸酯之外，以与实施例71相同的方式制备化合物，最后一步反应产率23.5％。MS(ESI,m/z):497(M+H)+。
实施例72 化合物(2E)-N-{4-[4-氨基-3-(1,3-苯并噻唑-2-基)-7-羰基-6,7-二氢-2H-吡 唑并[3,4-d]哒嗪-2-基]苯基}-4-(二甲氨基)丁-2-烯酰胺(A72)的制备
除了以乙基苯并[d]噻唑-2-羧酸酯替换乙基1-甲基-1H-苯并[d]咪唑-2-羧酸酯之外，以与实施例71相同的方式制备化合物，最后一步反应产率42.5％。MS(ESI,m/z):487(M+H)+。
实施例73 化合物(2E)-N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-1H-吡咯并[2,3-d]哒嗪-1-基]环己基}-4-(吖丁啶-1-基)丁-2-烯酰胺(A73)的制备
除了以(E)-4-(吖丁啶-1-基)-N-(4-羟基环己基)丁-2-烯酰胺替换1-(4-羟基哌啶)丙-2-烯-1-酮之外，以与实施例67相同的方式制备化合物，最后一步反应产率51.5％。MS(ESI,m/z):515(M+H)+。
实施例74 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-[(3,5-二甲氧苯基)乙炔基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A74)的制备
除了以乙基3-(3,5-二甲氧苯基)丙-2-炔酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例29相同的方式制备化合物，最后一步反应产率57.5％。MS(ESI,m/z):449(M+H)+。
实施例75 化合物4-氨基-2-[1-(环丙基羰基)哌啶-4-基]-3-(3,5-二甲基-1-苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A75)的制备
除了以环丙酰氯替换丙烯酰氯之外，以与实施例29相同的方式制备化合物，最后一步反应产率56.5％。MS(ESI,m/z):447(M+H)+。
实施例76 化合物N-{4-[4-氨基-3-(3,5-二甲基-1-苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]环己基}-2-氰基乙酰胺(A76)的制备
除了以氰基乙酰氯替换丙烯酰氯之外，以与实施例33相同的方式制备化合物，最后一步反应产率45.5％。MS(ESI,m/z):460(M+H)+。
实施例77 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-[(3,5-二乙氧苯基)乙炔基]-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A77)的制备
除了以乙基3-(3,5-二乙氧苯基)丙-2-炔酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例29相同的方式制备化合物，最后一步反应产率81.5％。MS(ESI,m/z):473(M+H)+。
实施例78 化合物N-{4-[4-氨基-3-[(3,5-二甲氧苯基)乙炔基]-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基]苯基}丙-2-烯酰胺(A78)的制备
除了以乙基3-(3,5-二甲氧苯基)丙-2-炔酸酯替换乙基5-氯-3-甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例25相同的方式制备化合物，最后一步反应产率45％。MS(ESI,m/z):457(M+H)+。
实施例79 化合物2-(1-丙烯酰哌啶-3-基)-4-氨基-3-(5-甲氧基-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A79)的制备
除了以1-BOC-3-氯哌啶替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺，以及乙基3-甲基-5-甲氧基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):449(M+H)+。
实施例80 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(5-氟-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A80)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-5-氟-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):437(M+H)+。
实施例81 2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(3-甲基-5-(三氟甲基)苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(81)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-5-三氟甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):487(M+H)+。
实施例82 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(3,6-二甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A82)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-6-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):433(M+H)+。
实施例83 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(6-氟-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A83)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-6-氟-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):437(M+H)+。
实施例84 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(6-氯-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A84)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-6-氯-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):453(M+H)+。
实施例85 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(3-乙基-5-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A85)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-乙基-5-甲基-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):447(M+H)+。
实施例86 化合物2-(1-丙烯酰哌啶-4-基)-4-氨基-3-(5-氯-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A86)的制备
除了以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-5-氯-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):453(M+H)+。
实施例87 化合物2-(1-丙烯酰哌啶-3-基)-4-氨基-3-(5-氯-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A87)的制备
除了以1-BOC-3-氯哌啶替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺以及乙基3-甲基-5-氯-1-苯并呋喃-2-羧酸酯替换乙基3,5-二甲基-1-苯并呋喃-2-羧酸酯之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):453(M+H)+。
实施例88 化合物N-(4-(4-氨基-3-(3,5-二甲基苯并呋喃-2-基)-7-羰基-6,7-二氢-2H-吡唑并[3,4-d]哒嗪-2-基)环己基)丙烯酰基酰胺(A88)的制备
除了以N-BOC-4-氯环己基胺替换1-BOC-4-氯哌啶和以丙烯酰氯替换2-氯-N,N-二甲基乙胺之外，以与实施例36相同的方式制备化合物。MS(ESI,m/z):447(M+H)+。
实施例89 化合物(E)-2-(1-丁-2-烯酰哌啶-3-基)-4-氨基-3-(5-甲基-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A89)的制备
除了以丁-2-烯酰氯替换丙烯酰氯替换之外，以与实施例40相同的方式制备化合物。 MS(ESI,m/z):447.0(M+H)+。
实施例90 (E)-2-(1-戊-2-烯酰哌啶-3-基)-4-氨基-3-(5-甲基-3-甲基苯并呋喃-2-基)-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A90)的制备
除了以戊-2-烯酰氯替换丙烯酰氯替换之外，以与实施例40相同的方式制备化合物。MS(ESI,m/z):461.1(M+H)+。
实施例91 4-氨基-3-(5-甲基-3-甲基-1-苯并呋喃-2-基)-2-{1-[(2E)-4-(N,N-二甲基)丁-2-烯酰]哌啶-3-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A91)的制备
除了以(E)-4-(二甲氨基)丁-2-烯酰氯替换丙烯酰氯替换之外，以与实施例40相同的方式制备化合物。MS(ESI,m/z):490.0(M+H)+。
实施例92 4-氨基-3-(5-甲基-3-甲基-1-苯并呋喃-2-基)-2-{1-[(2E)-4-(吡咯烷-1-基)丁-2-烯酰]哌啶-3-基}-2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮(A92)的制备
除了以(E)-4-(吡咯烷-1-基)丁-2-烯酰替换丙烯酰氯替换之外，以与实施例40相同的方式制备化合物。MS(ESI,m/z):516.0(M+H)+。
药理学实验
本发明还针对五元杂环并[3,4-d]哒嗪酮类化合物对FGFR激酶、FGFR依赖性的肿瘤细胞增殖抑制活性，及裸小鼠皮下移植FGFR依赖肿瘤的生长抑制作用进行了药理学实验。药理学实验所需要的实验材料除特殊说明外，均为商业购买。
一、FGFR激酶抑制剂活性实验
1、试验材料
酶反应底物多聚谷氨酸-酪氨酸肽段Poly(Glu,Tyr)4:1(Sigma，货号No.P7244)、抗磷酸化酪氨酸单抗PY99(Santa Cruz，货号No.SC-7020)、激酶重组蛋白FGFR1(Millipore，货号No.14-482)、辣根过氧化物酶标记羊抗鼠二抗Goat Anti-Mouse IgG Antibody,H&L Chain Specific Peroxidase Conjugate(Calbiochem，货号No.401215)。精密电子天平(Sartotius，货号No.BP210D)、可调波长式微孔板酶标仪(Molecular Device，货号No.SpectraMax 190)。
2、试验方法
将酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl,pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体后洗板，用200μL/孔的T-PBS(含0.1％Tween-20的PBS)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液50μL，终浓度5μM。化合物用DMSO稀释成合适的浓度，1μL/孔或者或含相应浓度的DMSO(阴性对照孔)，再加入用49μL反应缓冲液稀释的FGFR激酶域重组蛋白启动反应，每次实验需设无酶对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的OPD显色液100μL/孔(用含有0.03％H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH＝5.4)稀释)，25℃避光反应1-10分钟。加入2M H2SO4 50μL/孔中止反应，用可调波长式微孔板酶标仪SPECTRA MAX 190读数，波长为490nm。
样品的抑制率通过下列公式求得：
Figure PCTCN2017085765-appb-000039
IC50值采用酶标仪随机附带软件以四参数法回归求得。
二、FGFR依赖性肿瘤细胞增殖抑制活性测试
1、试验材料
人急性髓源白血病细胞株KG1细胞(细胞中FGFR1融合蛋白表达在胞浆中，为FGFR1依赖性肿瘤细胞株)(ATCC,货号No.CCL-246)、细胞培养液RPMI-1640(Corning Cellgro，货号No.10-040-CVR)、胎牛血清(Life Technologies，货号No.10099-141)购自公司；CCK-8细胞计数试剂盒(DOJINDO，货号No.FK808)。可调波长式微孔板酶标仪(Molecular Device，货号No.SpectraMax 190)。
2、试验方法
化合物对KG1的增殖抑制作用采用CCK-8细胞计数试剂盒(Dojindo)检测：处于对数生长期的细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。
化合物对细胞增殖的抑制率由以下公式计算：
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％
IC50值采用酶标仪随机附带软件以四参数法回归求得。
表1：部分化合物对FGFR激酶及FGFR依赖性肿瘤细胞株增殖抑制活性测定结果(A≤100nM；100nM<B≤1000nM)
实施例编号 FGFR1IC50 KG1IC50
A4 A B
A7 A B
A8 A B
A9 A B
A10 A B
A11 A B
A13 A B
A23 A A
A24 A A
A25 A A
A26 A A
A27 A A
A28 A A
A29 A A
A30 A A
A31 A N/A
A32 A N/A
A33 A A
A34 A N/A
A35 A B
A36 A N/A
A38 A N/A
A39 A N/A
A40 A A
A41 A B
A42 A N/A
A43 A N/A
A45 A N/A
A51 A A
A52 A A
A54 A N/A
A55 A A
A56 A N/A
A62 A A
A79 A A
A80 B B
A81 B N/A
A82 A A
A83 A A
A84 A A
A85 A A
A86 A A
A87 A A
A88 A A
由以上可见，所测试的化合物对FGFR激酶有很好的抑制剂活性，对其依赖性肿瘤细胞株也有很好的增殖抑制活性。
三、荷瘤小鼠肿瘤生长抑制实验
实验测试了五元杂环并[3,4-d]哒嗪酮类化合物对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长抑制作用及作用强度。
1、试验材料
受试物：实施例A26为白色粉末，-20℃避光保存。临用前用含5％Tween80的生理盐水配置到所需浓度(浅黄色混悬液)后使用，每周配制一次。
阳性对照药物：AZD4547(批号：Lot:S0902A)为白色粉末，-20℃避光保存。临用前用含1％Tween 80的生理盐水配置到所需浓度(白色混悬液)后使用，每周配制一次。
剂量设：A26剂量设置为50mg/kg和10mg/kg；阳性对照药物AZD4547剂量设置为12.5mg/kg。
动物：BALB/cA裸小鼠，雄性，3-4周龄，中科院上海药物研究所生产，质量合格证编号No.311613700000120，生产许可证号：SCXK(沪)2013-0017。上海药物所使用许可证编号：SYXK(沪)2013-0049，每组动物数：溶剂对照组12只，给药组6只。
细胞株
人肺癌NCI-H1581细胞株(ATCC,货号No.CRL-5878)。用该细胞株接种裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，形成移植瘤后在体内传1代后使用。
2、试验方法
取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至平均体积约为220mm3后将动物随机分组。A26 50mg/kg和10mg/kg组，每天腹腔注射给药一次，连续给药13天；阳性对照药物AZD4547 12.5mg/kg组，每天口服给药一次，连续给药13天。溶剂对照组则给以等量生理盐水。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b2，其中a、 b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV。
3、试验结果
实验结果如表2、图1、2以及图3照片所示。阳性对照药物AZD4547 12.5mg/kg组每天口服给药一次，连续给药13天，对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长有部分的抑制作用，第13天所得T/C百分数为为16.39％。A26 50mg/kg和10mg/kg组，每天腹腔注射给药一次，连续给药13天，对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长有显著的抑制作用，第13天所得T/C百分数分别为2.20％和19.88％。实验期间，各组小鼠状态良好，体重均有增长，无小鼠死亡。
表2. A26对人肺癌NCI-H1581裸小鼠移植瘤的实验治疗作用
Figure PCTCN2017085765-appb-000040
t student’s test vs溶剂对照组，*p<0.05
由以上可见，所测试的化合物对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长有很好的抑制作用，药效活性优于阳性药，且化合物在所测试的剂量下具有良好的耐受性。
工业实用性
本发明的五元杂环并[3,4-d]哒嗪酮类化合物毒性低，溶解性好。
本发明的五元杂环并[3,4-d]哒嗪酮类化合物及其衍生物的制备方法具有反应条件温和、原料丰富易得、操作及后处理简单、对应选择性好等优点。
本发明的五元杂环并[3,4-d]哒嗪酮类化合物及其衍生物对FGFR激酶及FGFR依赖性的肿瘤细胞株增殖有很好的抑制活性和优良的选择性。
因此，本发明的化合物可用于可用于治疗与FGFR酶活，FGFR配体异常表达或活性相关的各种疾病，如癌症、肿瘤等疾病的药物中的用途。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如下式(I)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2017085765-appb-100001
    其中，
    X1选自CH、C、N；优选为CH或C；
    X2和X3各自独立地选自CH、C、NH、N、O或者S；优选为NH、N、CH或者C；
    X4和X5为C；
    且X1，X2，X3，X4和X5共同形成芳香性五元环；
    Q选自：取代或未取代的萘基、取代或未取代的8-10元双环杂芳基；
    或者Q选自-L-A，其中L为取代或未取代的C1-C4亚烷基、取代或未取代的C2-C4的亚烯基、C2-C4的亚炔基、C1-C4的亚烷氧基、-(C1-C4烷基)-NH-、-CO-NH-、-NH-CO-；A选自取代或未取代的C6-C12芳基、取代或未取代的5-8元单环杂芳基、取代或未取代的8-10元双环杂芳基；
    G为各自独立地位于X2和/或X3上的选自下组的1-2个取代基：卤素、羟基、氰基、-L3-取代或未取代的C6-C12芳基、-L3-取代或未取代的5-12元杂芳基、-L3-取代或未取代的3-12元杂环基、-L3-取代或未取代的C3-C8环烷基、-(CH2)m-L1-R1、-(CH2)m-N(R2)(R3)、-(CH2)m-C(＝O)-N(R2)(R4)；
    其中，所述的基团G上还可以任选地具有1-3个各自独立的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基；其中，Lx1、Lx2、Lx3、Lx4和Lx5各自独立地选自下组：无、羰基(C＝O)、氧基(-O-)、-C＝S-、-S(O)2-、-CH2-、-CH＝CH-、C3-C8亚环烯基、-C≡C-、-NH-、-N(R5)-；M选自下组：H、-OH、卤素、氰基、-N(R2)(R3)、-CH3、-C(＝O)CH3、C1-C6烷氧基、3-12元杂环基、C3-C8环烷基、5-12元杂芳基、C3-C8环烯基；
    所述的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基可以进一步地被一个或多个卤素、C1-C6烷基、C1-C6烷氧基、氰基、羟基、＝O、＝CH2、乙烯基(-CH＝CH2)、-(CH2)k-N(R2)(R3)、-(C1-C6烷基)-OR2、3-12元杂环基或C3-C8环烷基所取代；
    k选自0、1、2或3；
    m选自0、1、2、3或4；
    L1为无、O、或-C(＝O)O-；
    L3为无，或取代或未取代的C1-C4亚烷基；
    R1、R3和R4各自独立地选自：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的3-12元杂环基，-(C1-C6烷基)-N(C1-C6烷基)(C1-C6烷基)、-(C1-C6烷基)-O-(C1-C6烷基)、或取代或未取代的苯基；
    R2选自氢、或C1-C4烷基；
    或者R2和R3、R2和R4与相连的氮原子共同构成取代或未取代的4-7元杂环，所述的杂环含有1～3个选自N、O、S中的杂原子，并且至少一个杂原子为N；
    R5选自氢、C1-C4烷基、C3-C6环烷基、甲酰基、C1-C4烷基羰基、或C1-C4烷氧 羰基；
    所述取代是指基团上的一个或多个氢原子被选自下组(优选1-5个)的基团取代：羟基、卤素、氰基、硝基、氨基、羧基、-CH2OH、-CONH2、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷胺基、C1-C4烷酰基、C1-C4烷磺酰基、C1-C4烷氧羰基、C1-C4烷磺酰胺基、氧代(＝O)、:CH2、C3-C6环烷基、4-7元杂环基、-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基)、吡咯烷酮基、哌啶基、C3-C6环烷基羰基、苯基、C2-C4炔基、取代或未取代的5-10元杂芳基；所述C1-C6烷氧基、C1-C6烷基和C1-C6烷胺基的取代基独立地选自1～3个如下基团：氧代、卤素、氰基、环丙基、羟基、氨基、-N(C1-C4烷基)(C1-C4烷基)；所述5-10元杂芳基上取代基选自1-3个如下基团：C1-C6烷基、-C1-C4亚烷基-N(C1-C4烷基)(C1-C4烷基)；
    所述C1-C6烷氧基、C1-C6烷基和C1-C6烷胺基包括直链或支链；
    且所述的化合物不为如下任一结构：
    Figure PCTCN2017085765-appb-100002
  2. 如权利要求1所述的式(I)化合物，其特征在于，Q选自下组取代或未取代的基团：萘基、苯并5-6元单环杂芳基、5-6元单环杂芳基并5-6元单环杂芳基；
    或者Q选自-L-A，其中L为未取代或卤素取代的C1-C4亚烷基、未取代或卤素取代的C2-C4的亚烯基、C2-C4的亚炔基、C1-C4的亚烷氧基、-(C1-C4烷基)-NH-、-CO-NH-、-NH-CO-；A选自取代或未取代的C6-C12芳基、取代或未取代的5-6元的单环杂芳基。
  3. 如权利要求1所述的式(I)化合物，其特征在于，G独立地选自下组的1-2个取代基：卤素、羟基、氰基、-L3-取代或未取代的C6-C10芳基、-L3-取代或未取代的5-10元杂芳基、-L3-取代或未取代的4-7元杂环基、-L3-取代或未取代的C3-C6环烷基、-(CH2)m-L1-R1、-(CH2)m-N(R2)(R3)、-(CH2)m-C(＝O)-N(R2)(R4)；
    其中，L3为无、取代或未取代的亚甲基、取代或未取代的亚乙基；
    且所述的基团G上还可以任选地具有1-3个各自独立的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基，其中Lx1、Lx2、Lx3、Lx4和Lx5各自独立地选自下组：无、羰基(C＝O)、氧基(-O-)、-C＝S-、-S(O)2-、-CH2-、-CH＝CH-、C3-C6亚环烯基、亚乙炔基(-C≡C-)、-NH-、-N(R5)-；
    M选自下组：H、-OH、卤素、氰基、-N(R2)(R3)、-CH3、-C(＝O)CH3、C1-C4烷氧基、4-7元杂环基、C3-C6环烷基、5-10元杂芳基、C3-C6环烯基；
    所述的-Lx1-Lx2-Lx3-Lx4-Lx5-M取代基可以进一步地被一个或多个卤素、C1-C6烷基、氰基、羟基、氧原子(＝O)、＝CH2、-(CH2)k-N(R2)(R3)、-(C1-C6烷基)-OR2、3-12元杂环基或C3-C6环烷基所取代；
    R1、R3、R4各自独立地选自：氢、卤素、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的4-7元杂环基、取代或未取代的苯基；
    或者R2和R3、R2和R4与相连的氮原子共同构成取代或未取代的4-7元饱和杂环，所述的杂环含有1～3个选自N、O、S中的杂原子，并且至少一个杂原子为N；
    R5选自氢、C1-C4烷基、C3-C6环烷基、甲酰基、C1-C4烷基羰基、C1-C4烷氧羰基。
  4. 如权利要求1所述的式(I)化合物，其特征在于，X1为C，而X2和X3皆为N； 或X1为C，X2为CH，而X3为N；或X1为C，X2为C，而X3为N。
  5. 如权利要求1所述的式(I)化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2017085765-appb-100003
    Figure PCTCN2017085765-appb-100004
    Figure PCTCN2017085765-appb-100005
    Figure PCTCN2017085765-appb-100006
    Figure PCTCN2017085765-appb-100007
    Figure PCTCN2017085765-appb-100008
    Figure PCTCN2017085765-appb-100009
    Figure PCTCN2017085765-appb-100010
    Figure PCTCN2017085765-appb-100011
    Figure PCTCN2017085765-appb-100012
    Figure PCTCN2017085765-appb-100013
    Figure PCTCN2017085765-appb-100014
  6. 如权利要求1所述的式(I)化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2017085765-appb-100015
    其中，X1，X2，X3，X4，X5，Q和G的定义与相对应的权利要求相同；Rx选自C1-C6烷基；
    式(I)-1化合物与水合肼经环合反应得到式(I)化合物。
  7. 如权利要求1所述的化合物，或其药学上可接受的盐的用途，其特征在于，用于：
    (a)制备治疗与FGFR激酶活性或表达量相关的疾病的药物；
    (b)制备FGFR激酶靶向抑制剂；
    (c)体外非治疗性地抑制FGFR激酶的活性；
    (d)体外非治疗性地抑制肿瘤细胞增殖；和/或
    (e)治疗与FGFR激酶活性或表达量相关的疾病。
  8. 如权利要求7所述的用途，其特征在于，，所述与FGFR活性或表达量相关的疾病选自癌瘤、造血恶性疾病、其他赘生物、骨骼和软骨细胞病症、低磷酸盐血症、纤维性疾病、银屑病、斑痕瘤、大疱性皮肤病、动脉粥样硬化、再狭窄、肾小球膜细胞增殖病症、肾小球病变、糖尿病性肾病变、肾病和良性***增生、眼病、以及颅缝早闭综合征；较佳地为选自下组的癌瘤：膀胱癌、乳腺癌、子***、结肠直肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食道癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓性白血病、霍奇金氏淋巴瘤或非霍奇金氏淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、毛细胞淋巴瘤、博吉特氏淋巴瘤、神经胶母细胞瘤、黑素瘤和横纹肌肉瘤。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括：(i)有效量的式I化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。
  10. 一种抑制FGFR激酶活性的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如权利要求9所述的药物组合物。
PCT/CN2017/085765 2016-05-24 2017-05-24 五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用 WO2017202343A1 (zh)

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