WO2016026445A1 - 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 - Google Patents

作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 Download PDF

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WO2016026445A1
WO2016026445A1 PCT/CN2015/087556 CN2015087556W WO2016026445A1 WO 2016026445 A1 WO2016026445 A1 WO 2016026445A1 CN 2015087556 W CN2015087556 W CN 2015087556W WO 2016026445 A1 WO2016026445 A1 WO 2016026445A1
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group
unsubstituted
compound
substituted
halogenated
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PCT/CN2015/087556
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English (en)
French (fr)
Inventor
耿美玉
刘磊
江磊
黄敏
查传涛
艾菁
王磊
曹建华
丁健
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上海海和药物研究开发有限公司
中国科学院上海药物研究所
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Priority to RU2017105781A priority Critical patent/RU2719428C2/ru
Priority to AU2015306561A priority patent/AU2015306561B2/en
Priority to BR112017003312-7A priority patent/BR112017003312B1/pt
Priority to EP15833329.4A priority patent/EP3184521B1/en
Priority to ES15833329T priority patent/ES2904544T3/es
Priority to MX2017002206A priority patent/MX2017002206A/es
Priority to MYPI2017000250A priority patent/MY188447A/en
Priority to KR1020197026420A priority patent/KR102166002B1/ko
Priority to CA2958503A priority patent/CA2958503C/en
Priority to US15/504,854 priority patent/US10562900B2/en
Priority to KR1020177007663A priority patent/KR102022866B1/ko
Priority to JP2017509744A priority patent/JP6445684B2/ja
Publication of WO2016026445A1 publication Critical patent/WO2016026445A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicine, and in particular, the present invention relates to a carbazole compound as an FGFR kinase inhibitor, and to the preparation and use thereof.
  • Receptor tyrosine kinase plays a key role in tumor development, invasion and metastasis, drug resistance and other aspects due to its abnormal expression activation or gene mutation. Has become an important target for the development of anti-tumor drugs.
  • fibroblast growth factor receptors FGFRs
  • FGFs Fibroblast Growth Factors Due to gene amplification, mutation, fusion or ligand induction, FGFR members continue to activate, induce tumor cell proliferation, invasion, migration, promote angiogenesis, and promote tumor development.
  • FGFRs are highly expressed and abnormally activated in a variety of tumors, and are closely related to the poor prognosis of cancer patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer. , keratinoma, myeloma, rhabdomyosarcoma, etc.
  • cancer patients such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer.
  • keratinoma myeloma
  • rhabdomyosarcoma etc.
  • Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer squamous cell carcinoma, and studies on proliferation and signaling pathways of FGFR1-expanded lung cancer cell lines show that FGFR selective inhibitors can effectively inhibit the activation of FGFR1 signaling pathway.
  • the expansion of the chromosome (8p11–12) region in which FGFR1 is located accounts for approximately 10% of ER-positive patients, and its high expression of FGFR1 mRNA and poor prognosis of patients are associated with FGFR2 gene amplification or mutation leading to FGFR2 signaling.
  • Abnormal activation of the pathway is mainly associated with gastric cancer, triple-negative breast cancer, and endometrial cancer.
  • the expansion rate of FGFR2 in gastric cancer tissues is 5%-10%.
  • FGFR2 amplification accounts for 4% of refractory triple negative breast cancer.
  • Endometrial cancer is a common gynaecological genital tumor, and FGFR2 mutations account for about 12% of endometrial cancer.
  • FGFR3 mutations accounted for 50%-60% in non-invasive bladder cancer, and FGFR3 mutations accounted for 10%-15% in invasive bladder cancer.
  • FGFR3t(4;14)(p16.3;q32) gene rearrangement accounts for 15–20% in multiple myeloma.
  • FGFR and its ligand FGFs of various subtypes in liver cancer have abnormal expression and activation, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGF8, FGF9 and the like.
  • a number of preclinical and clinical studies have demonstrated the importance of abnormal activation of the FGF/FGFR axis in liver cancer. It should not be overlooked that abnormal activation of the FGF/FGFR axis is closely related to resistance to EGFR inhibitors, neovascular inhibitors, and endocrine therapy. Therefore, the development of targeted FGFR inhibitors has become a hot topic in the research of anti-tumor drugs.
  • L is selected from the group consisting of H, tetrahydropyranyl (THP);
  • Each X is independently selected from the group consisting of Cl, F, H, CN;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a 5- to 8-membered arylene group which is unsubstituted, substituted or unsubstituted, or a substituted or unsubstituted 5 to 8 membered heteroarylene group, wherein the heteroaryl group contains at least one member selected from the group consisting of a hetero atom: nitrogen, oxygen, or sulfur; a substituted or unsubstituted 3 to 12 membered saturated heterocyclic ring or carbocyclic ring, wherein the heterocyclic ring contains at least one hetero atom selected from the group consisting of nitrogen, oxygen, or sulfur;
  • R is H, or a substituted or unsubstituted group selected from the group consisting of:
  • M is selected from the group consisting of substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C6-C10 arylene, substituted or unsubstituted C1-C10 heteroarylene, or M No
  • substitutions means that one or more hydrogen atoms on the above group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1. -C6 alkoxy, unsubstituted or halogenated C1-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl, unsubstituted or Halogenated C1-C6 alkylene-hydroxy, unsubstituted or C1-C6 alkyl substituted amine.
  • the ring A is a heteroaryl group or a saturated heterocyclic ring selected from the group consisting of the following, or the ring A is absent:
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from: N or CH;
  • B 1 , B 2 , B 3 , B 4 are each independently selected from: N or CH.
  • the ring A is a heteroaryl group or a saturated heterocyclic ring selected from the group consisting of the following, or the ring A is absent:
  • R is a substituted or unsubstituted group selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, halogen, C1-C6 straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
  • R 5 is selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkylene-hydroxy, C1- C6 alkoxyalkyl, unsubstituted or alkyl substituted amine, C1-C8 cycloalkyl.
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched Alkylcarbonyl, C1-C6 straight or branched alcohol group (alkylene-hydroxy);
  • G 1 , G 2 , G 3 , G 4 are each independently selected from the group consisting of H, halogen, C1-C6 straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
  • G 5 is selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkyl-hydroxy, C1-C6 Alkoxyalkyl, unsubstituted or alkyl substituted amine, C1-C8 cycloalkyl;
  • E 1 and E 2 are each independently selected from the group consisting of H, halogen, straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
  • E 3 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkylene-hydroxy, a C1-C6 alkoxyalkyl group, an unsubstituted or alkyl-substituted amine group, a C1-C8 cycloalkyl group;
  • R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight chain Or a branched alcohol group (alkylene-hydroxyl group), or R13 and R14, R15 and R16 are bonded to a carbon atom to form a 5- to 7-membered ring;
  • C0-C3 alkyl is an alkylene group having no or 1-3 carbon atoms
  • the C1-C6 alkyl group is an alkylene group having 1 to 6 carbon atoms.
  • L is selected from the group consisting of H, tetrahydropyranyl (THP);
  • Each X is independently selected from the group consisting of H, Cl, F, CN;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a substituted or unsubstituted 6-membered aryl group, or a substituted or unsubstituted 5 to 6-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of nitrogen and oxygen. Or sulfur;
  • M is selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, or M is absent; said substitution 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-C4 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3- C8 cycloalkyl, unsubstituted or halogenated C2-C4 alkylcarbonyl, unsubstituted or halogenated C1-C4 alkyl-hydroxy, unsubstituted or C1-C6 alkyl substituted amine.
  • a substituent selected from the group consisting of: Halogen, unsubstituted or halogenated C1-C4 alkyl,
  • Each X is independently selected from the group consisting of H, Cl, and F;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a group selected from the group consisting of: phenyl, pyrazolyl, pyridyl, thiazolyl, pyrimidine, pyrazine or piperidinyl;
  • M is selected from the group consisting of a substituted or unsubstituted C1-C3 alkylene group, or M is absent;
  • any one or more of the hydrogen atoms on the substituent is substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C6.
  • a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C6.
  • the compound of formula I is a compound shown in Table A below:
  • L, X, W, Y, Z, Ring A or R are the corresponding groups in the specific compounds described in the examples.
  • each group is as defined in claim 1.
  • the reaction in the step (a), is carried out in the presence of a copper salt; preferably, the copper salt is selected from the group consisting of CuI, Cu, CuCl, Cu 2 O , CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • a copper salt is selected from the group consisting of CuI, Cu, CuCl, Cu 2 O , CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • the reaction in the step (a), is carried out in the presence of a ligand; preferably, the ligand is a bidentate amine ligand; more preferably, the The ligand is selected from the group consisting of N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine, or a combination thereof .
  • the reaction in the step (a), is carried out in the presence of a base; preferably, the base is an inorganic base, more preferably selected from the group consisting of K 2 CO 3 K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
  • the base is an inorganic base, more preferably selected from the group consisting of K 2 CO 3 K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
  • the inert solvent is selected from the group consisting of toluene, dioxane, THF, DMF, or a combination thereof.
  • the method further includes the steps of:
  • L is selected from the group consisting of tetrahydropyranyl (THP);
  • the reaction in the step (b), is carried out in the presence of an acid; preferably, the acid is selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, TFA, or combination.
  • an acid preferably, the acid is selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, TFA, or combination.
  • the inert solvent is selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, Or a combination thereof.
  • the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
  • the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, or a combination thereof.
  • the tumor cell is a leukemia cell line; preferably a myeloid leukemia cell line; more preferably an acute myeloid leukemia cell line KG1 cell.
  • 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 99.99%.
  • the pharmaceutical composition is for inhibiting the activity of FGFR kinase.
  • the pharmaceutical composition 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, or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, Or administering to the subject, an inhibitory effective amount of the pharmaceutical composition of the fourth aspect of the invention.
  • the inhibition is non-therapeutic inhibition in vitro.
  • an inhibitory effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof when administered to a subject, the inhibitory effective amount is from 0.001 to 500 nmol/L, The preferred ground is 0.01-200 nmol/L.
  • a sixth aspect of the invention provides a method of treating a disease associated with FGFR kinase activity or expression, characterized in that the method comprises: administering to a subject a therapeutically effective amount of the first aspect of the invention A compound of formula I, or a pharmaceutical composition according to the fourth invention of the invention.
  • the disease associated with FGFR activity or expression is a tumor, preferably selected from the group consisting of Group of tumors: endometrial cancer, breast cancer, stomach cancer, bladder cancer, myeloma, liver cancer.
  • a seventh aspect of the invention provides a method of inhibiting tumor cells in vitro, the method comprising: administering an inhibitory effective amount of a compound of formula I according to the first aspect of the invention to a subject, or a fourth aspect of the invention
  • the pharmaceutical composition of aspect is provided.
  • the inventors have conducted long-term and intensive studies to prepare a class of compounds having the structure shown in Formula I, and have 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, A sec-butyl group, a tert-butyl group, or the like.
  • C1-C6 alkylene refers to the above C1 ⁇ C6 alkyl group formed after the loss of a hydrogen atom, for example -CH 2 -, - CH 2 -CH 2 -, or the like.
  • C6-C10 arylene refers to a group formed by an aryl group having 6 to 10 carbon atoms which loses a hydrogen atom, and includes a monocyclic or bicyclic arylene group such as a phenylene group, a naphthylene group, or the like. Group.
  • 6-membered aryl refers to phenyl
  • 5-8 membered aryl refers to a carbon-unsaturated substituent of a 5-8 membered ring, such as a phenyl group, or the like.
  • 5- to 8-membered heteroaryl refers to a non-saturated ring-based substituent having a heterocyclic ring selected from O, S, N or P on a ring system having 5-8 members, such as pyridyl, Thienyl, or a similar group.
  • saturated 3- to 12-membered carbocyclic ring means a saturated carbocyclic ring having 3 to 12 carbon atoms, such as a cyclohexyl group, or the like.
  • 3- to 12-membered heterocyclic ring refers to a saturated ring system substituent having a hetero atom of one or more selected from O, S, N or P in a ring system having 3 to 12 members, such as piperidinyl, pyrrolyl. , or a similar group.
  • halogen refers to F, Cl, Br and I.
  • 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 selected from Substituents of the group are substituted: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each of the chiral carbon atoms may be optionally 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,
  • L is selected from the group consisting of H, tetrahydropyranyl (THP);
  • Each X is independently selected from the group consisting of Cl, F, H, CN;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a non-, substituted or unsubstituted 5-8-membered aryl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of a nitrogen, oxygen, or sulfur; a substituted or unsubstituted 3 to 12 membered saturated heterocyclic ring or carbocyclic ring, wherein said heterocyclic ring comprises at least one hetero atom selected from the group consisting of nitrogen, oxygen, or sulfur; Or
  • R is H or a substituted or unsubstituted group selected from the group consisting of:
  • M is selected from the group consisting of: a substituted, unsubstituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C6-C10 arylene group, a substituted or unsubstituted C1-C10 heteroarylene group;
  • substitution 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 or halogenated C2-C6 acyl, Unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • the ring A is a heteroaryl group selected from the group consisting of:
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from: N or CH;
  • B 1 , B 2 , B 3 , and B 4 are each independently selected from: N or CH.
  • the ring A is a heteroaryl group selected from the group consisting of:
  • R is a substituted or unsubstituted group selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, halogen, C1-C6 linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkane base;
  • R 5 is selected from the group consisting of H, a C1-C6 linear alkyl or branched alkyl group, a C1-C6 linear or branched acyl group, and a C1-C6 linear or branched alkylene-hydroxy group.
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched Chain acyl group, C1-C6 linear or branched alcohol group (alkylene-hydroxyl group);
  • G 1 , G 2 , G 3 , G 4 are each independently selected from the group consisting of H, halogen, C1-C6 linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkane Base or
  • G 5 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight or branched alkyl-hydroxy;
  • E 1 and E 2 are each independently selected from the group consisting of H, halogen, linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkyl;
  • E 3 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight or branched alkylene-hydroxy;
  • R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight chain Or branched alcohol groups (alkylene-hydroxy);
  • C0-C3 alkyl is an alkylene group having no or 1-3 carbon atoms
  • the C1-C6 alkyl group is an alkylene group having 1 to 6 carbon atoms.
  • L is selected from the group consisting of H, tetrahydropyranyl (THP);
  • Each X is independently selected from the group consisting of H, Cl, F, CN;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a substituted or unsubstituted 6-membered aryl group, or a substituted or unsubstituted 5 to 6-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of nitrogen and oxygen. Or sulfur;
  • M is selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, or M is absent;
  • substitution 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-C4 alkyl, unsubstituted or halogenated C2-C4 acyl, Unsubstituted or halogenated C1-C4 alkyl-hydroxy.
  • L is H
  • Each X is independently selected from the group consisting of H, Cl, and F;
  • W, Y, Z are each independently selected from: N or CH;
  • Ring A is a group selected from the group consisting of: phenyl, pyrazolyl, pyridyl, thiazolyl, piperidinyl;
  • M is selected from the group consisting of a substituted or unsubstituted C1-C3 alkylene group, or M is absent;
  • substitution 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-C4 alkyl, unsubstituted or halogenated C2-C4 acyl, Unsubstituted or halogenated C1-C4 alkyl-hydroxy.
  • the compound of formula I is a compound selected from the group consisting of:
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature.
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 48 hours.
  • a preferred method of preparing a compound of formula I comprises the steps of:
  • the reaction is carried out in the presence of a copper salt; preferably, the copper salt is selected from, but not limited to, the following groups: CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • the copper salt is selected from, but not limited to, the following groups: CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • the reaction is carried out in the presence of a ligand; preferably, the ligand is a bidentate amine ligand; more preferably, the ligand is selected from (but not limited to) The lower group: N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine, or a combination thereof.
  • the reaction is carried out in the presence of a base; preferably, the base is an inorganic base, more preferably selected from, but not limited to, the following group: K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
  • the base is an inorganic base, more preferably selected from, but not limited to, the following group: K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
  • the inert solvent is selected from, but not limited to, the lower group: toluene, dioxane, THF, DMF, or a combination thereof.
  • the method further includes the steps of:
  • the reaction is carried out in the presence of an acid; preferably, the acid is selected from, but not limited to, the lower group: hydrochloric acid, p-toluenesulfonic acid, TFA, or a combination thereof.
  • an acid preferably, the acid is selected from, but not limited to, the lower group: hydrochloric acid, p-toluenesulfonic acid, TFA, or a combination thereof.
  • the inert solvent is selected from, but not limited to, the following group: dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, or a combination thereof .
  • a more preferred preparation method comprises the following steps:
  • Compound A2 can be reacted with Compound A1 and DHP in an inert solvent (DCM, THF, etc.) under the catalysis of an acid such as, but not limited to, p-toluenesulfonic acid, trifluoroacetic acid.
  • an inert solvent DCM, THF, etc.
  • Compound A4 may be subjected to Suzuki coupling by a corresponding boronic acid or ester in an inert solvent (such as dioxane and water, toluene and water, DMSO, THF, DMF, etc.) in a catalyst (such as four ( Triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), bis(dibenzylideneacetone)palladium, dichlorobis(triphenylphosphine)palladium, triphenyl Palladium phosphinate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, etc.) and bases (such as potassium carbonate, potassium fluoride, fluorine) Antimony, sodium fluoride, potassium phosphate, potassium hydrate hydrate, sodium carbonate, sodium hydrogencarbonate
  • Compound A5 can be obtained by slowly dropping SO 2 Cl 2 from compound A4 in an inert solvent (dichloromethane, THF, acetonitrile) and stirring at room temperature.
  • an inert solvent dichloromethane, THF, acetonitrile
  • Compound A6 can be obtained by deprotecting compound A5, and adding an acid (such as hydrochloric acid, in an inert solvent (such as dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.) Toluenesulfonic acid, TFA) gave compound A6.
  • an acid such as hydrochloric acid
  • an inert solvent such as dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.
  • Compound A7 may be added with compound A6, iodine and NaOH in an inert solvent (1,4-dioxane, DMF, etc.). Stir at room temperature.
  • Compound A8 can be reacted with Compound A7 and DHP in an inert solvent (DCM, THF, etc.) under the catalysis of an acid such as, but not limited to, p-toluenesulfonic acid, trifluoroacetic acid.
  • an inert solvent DCM, THF, etc.
  • Compound A10 may be amidated by aromatization of compound A8 and compound A9.
  • the reaction is carried out in the presence of one or more of the following: a copper salt, which may be, but not limited to, CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • a copper salt which may be, but not limited to, CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
  • a ligand which may be a bidentate amine ligand, including but not limited to N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N, N'-dimethyl- 1,2-cyclohexanediamine, a base
  • the base may be, but not limited to, an inorganic base such as K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3
  • the solvent of the reaction may be, but not limited to, toluene, Oxycyclohexane, THF, DMF.
  • Compound A11 can be obtained by deprotecting compound A10 using an appropriate acid such as, but not limited to, hydrochloric acid, p-toluenesulfonic acid, TFA in an inert solvent (such as dichloromethane, methanol, ethanol, isopropanol, n-butyl)
  • an inert solvent such as dichloromethane, methanol, ethanol, isopropanol, n-butyl
  • Compound 11 is obtained by alcohol, tert-butanol, isobutanol or the like.
  • the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
  • the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, or a combination thereof.
  • the tumor cell is a leukemia cell line; preferably a myeloid leukemia cell line; more preferably an acute myeloid leukemia cell line KG1 cell.
  • the compounds of formula I of the present invention are useful in the preparation of 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 refers to a therapeutically effective amount or an inhibitory effective amount.
  • the pharmaceutical composition is for inhibiting the activity of FGFR kinase.
  • the pharmaceutical composition is for treating a disease associated with FGFR kinase activity or expression.
  • the compounds of the formula I according to the invention may also be used in a method for inhibiting the activity of FGFR kinase, characterized by comprising the step of administering an inhibitory effective amount of a compound of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject. Or administering an inhibitory effective amount of the pharmaceutical composition of claim 7 to the subject.
  • the inhibition is non-therapeutic inhibition in vitro.
  • an inhibitory effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof when administered to a subject, the inhibitory effective amount is from 0.001 to 500 nmol/L, The preferred ground is 0.01-200 nmol/L.
  • the invention also provides a method of treating a disease associated with FGFR kinase activity or expression, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula I, or said compound comprising formula I as effective A pharmaceutical composition of the ingredients.
  • the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
  • the compound of the present invention has excellent inhibitory activity against FGFR kinase (Kinase) such as FGFR1, FGFR2, FGFR3, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates
  • a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with FGFR activity or expression.
  • the compounds of the invention are useful in the treatment The following diseases: endometrial cancer, breast cancer, stomach cancer, bladder cancer, myeloma, liver cancer and so on.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • FGFR inhibitor having a novel structure and inhibiting the activity of various FGFR kinases at very low concentrations.
  • a class of pharmaceutical compositions for treating diseases associated with FGFR kinase activity is provided.
  • 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, and 125 ⁇ L/well coated with the 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 added with each kinase kinase domain recombinant protein diluted with 49 ⁇ L of reaction buffer to initiate the reaction, each experiment requires ATP-free Two wells of the control well.
  • 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.
  • Some IC 50 information is provided in the table below.
  • the symbol + represents an IC 50 of less than 100 nm
  • the symbol ++ represents an IC 50 of 100 nm to 500 nm
  • N/A represents no data.
  • CCK-8 cell counting kit for growth inhibition of acute myeloid leukemia cell line KG1 cells (FGFR1 fusion protein expressed in the cytoplasm, FGFR1-dependent tumor cell line, purchased from ATCC cell bank) Detection.
  • the specific steps are as follows: KG1 cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and after incubation overnight, different concentrations of compounds were added for 72 hr, and a solvent control group (negative control) was set. After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo).
  • inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well ⁇ 100%.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the IC 50 values for some of the compounds are provided in the table below.
  • the symbol + represents an IC 50 of less than 200 nm
  • the symbol ++ represents an IC 50 of 200 nm to 1000 nm.

Abstract

本发明提供了一种作为FGFR激酶抑制剂的吲唑类化合物及其制备和应用，具体地，本发明提供了一种如式（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

作为FGFR激酶抑制剂的吲唑类化合物及其制备和应用 技术领域
本发明属于药物领域，具体地，本发明涉及一种作为FGFR激酶抑制剂的吲唑类化合物，及其制备和应用。
背景技术
受体酪氨酸激酶由于其异常表达激活或基因突变，在肿瘤发生发展、侵袭转移、药物抗性等各个环节均发挥关键作用。已成为抗肿瘤药物研发的重要靶点。其中，成纤维生长因子受体(fibroblast growth factor receptors,FGFRs)是受体酪氨酸激酶家族的重要成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。其配体是成纤维细胞生长因子(Fibroblast Growth Factors,FGFs)。由于基因扩增、突变、融合或配体诱导等原因，FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭、迁移，促进血管生成，促进肿瘤的发生发展。FGFRs在多种肿瘤中高表达并异常激活，与肿瘤病人的不良预后密切相关，如非小细胞肺癌、乳腺癌、胃癌、膀胱癌、子宫内膜癌、***癌、***、结肠癌、食管癌、角质母细胞瘤、骨髓瘤、横纹肌肉瘤等。研究显示，FGFR1扩增占非小细胞肺癌鳞癌的20％，并通过对FGFR1扩增的肺癌细胞株体外增殖、信号通路等研究显示FGFR选择性抑制剂可以非常有效抑制FGFR1信号通路的活化和细胞的增殖。在乳腺癌当中，FGFR1所在的染色体(8p11–12)区域的扩增约占到ER阳性患者的10％，并且其与FGFR1mRNA的高表达以及病人的预后不良相关FGFR2基因扩增或者突变导致FGFR2信号通路的异常激活主要与胃癌、三阴性乳腺癌、子宫内膜癌等相关。胃癌组织中FGFR2的扩增率为5％-10％。对313例胃癌组织分析显示，FGFR2的扩增与肿瘤大小、局部浸润程度、***转移情况以及远端转移的发生显著相关，而且具有FGFR2扩增的胃癌一般为进展性肿瘤，具有较差的预后，病人总体存活率相对较低。FGFR2扩增在难治性的三阴性乳腺癌中占到4％。子宫内膜癌是常见的妇科生殖道肿瘤，FGFR2的突变大约占到子宫内膜癌的12％。在非侵袭性膀胱癌中FGFR3突变占到50％-60％，侵袭性膀胱癌中FGFR3突变占到10％-15％。在多发性骨髓瘤中FGFR3t(4；14)(p16.3；q32)基因重排占到15–20％。此外，在肝癌中多种亚型的FGFR及其配体FGFs具有异常的表达及活化，如FGFR2、FGFR3、FGFR4、FGF19、FGF2、FGF5、FGF8、FGF9等。多项临床前及临床研究均表明FGF/FGFR轴线异常激活在肝癌中的重要性。不容忽视的是，FGF/FGFR轴线的异常活化与EGFR抑制剂、新生血管抑制剂以及内分泌治疗等的耐药密切相关。因此，靶向FGFR抑制剂的研发已成为抗肿瘤药物研究的前沿热点。
发明内容
本发明的目的是提供一种新型靶向FGFR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 PCTCN2015087556-appb-000001
其中，
L选自下组：H、四氢吡喃基(THP)；
各个X各自独立地选自下组：Cl、F、H、CN；
W、Y、Z各自独立地选自：N或CH；
环A为无、取代或未取代的5～8元亚芳基，或取代或未取代的5元～8元亚杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫；取代或未取代的3元～12元饱和杂环或碳环，其中，所述的杂环包含至少一个选自下组的杂原子：氮、氧，或硫；
R为H，或取代或未取代的选自下组的基团：
Figure PCTCN2015087556-appb-000002
其中，M选自下组：取代或未取代的C1-C6的亚烷基、取代或未取代的C6-C10的亚芳基、取代或未取代的C1-C10的亚杂芳基、或M为无；
所述的任一取代是指上述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C1-C6烷氧基、未取代或卤代的C1-C6烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C6亚烷基-羟基、未取代或C1-C6烷基取代的胺基。
在另一优选例中，所述的环A是选自下组的杂芳基或饱和杂环、或环A不存在：
Figure PCTCN2015087556-appb-000003
其中，Q1、Q2、Q3、Q4各自独立地选自：N或CH；
B1、B2、B3、B4各自独立地选自：N或CH。
在另一优选例中，所述的环A是选自下组的杂芳基或饱和杂环，或环A不存在：
Figure PCTCN2015087556-appb-000004
在另一优选例中，R为取代或未取代的选自下组的基团：
Figure PCTCN2015087556-appb-000005
其中，
R1、R2、R3、R4各自独立地选自下组：H、卤素、C1-C6直链或支链烷基、卤代的C1-C6直链或支链烷基；
R5选自下组：H、C1-C6直链或支链烷基，C1-C6直链或支链的烷基羰基，C1-C6直链或支链的亚烷基-羟基、C1-C6烷氧基烷基、未取代或烷基取代胺基、C1-C8环烷基。
R6、R7、R8、R9、R10、R11、R12各自独立地选自下组：H、C1-C6直链或支链烷基，C1-C6直链或支链的烷基羰基，C1-C6直链或支链的醇基(亚烷基-羟基)；
G1、G2、G3、G4各自独立地选自下组：H、卤素、C1-C6直链或支链烷基、卤代的C1-C6直链或支链烷基；
G5选自下组：H、C1-C6直链或支链烷基、C1-C6直链或支链的烷基羰基、C1-C6直链或支链的烷基-羟基、C1-C6烷氧基烷基、未取代或烷基取代胺基、C1-C8环烷基；
E1、E2各自独立地选自下组：H、卤素、直链或支链烷基、卤代的C1-C6直链或支链烷基；
E3选自下组：H、C1-C6直链烷基或支链烷基、C1-C6直链或支链的烷基羰基、C1-C6 直链或支链的亚烷基-羟基、C1-C6烷氧基烷基、未取代或烷基取代胺基、C1-C8环烷基；
R13、R14、R15、R16各自独立地选自下组：H、C1-C6直链或支链烷基，C1-C6直链或支链的烷基羰基，C1-C6直链或支链的醇基(亚烷基-羟基)、或R13和R14、R15和R16与碳原子相连形成5元-7元环；
C0-C3 alkyl为无、或具有1-3个碳原子的亚烷基；
C1-C6 alkyl为具有1-6个碳原子的亚烷基。
在另一优选例中，
L选自下组：H、四氢吡喃基(THP)；
各个X各自独立地选自下组：H、Cl、F、CN；
W、Y、Z各自独立地选自：N或CH；
环A为取代或未取代的6元芳基，或取代或未取代的5元～6元杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫；
M选自下组：取代或未取代的C1-C4的亚烷基、或M不存在；所述的取代是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-C4烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C2-C6烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C4烷基羰基、未取代或卤代的C1-C4烷基-羟基、未取代或C1-C6烷基取代的胺基。在另一优选例中，
L为H；
各个X各自独立地选自下组：H、Cl、F；
W、Y、Z各自独立地选自：N或CH；
环A为选自下组的基团：无、苯基、吡唑基、吡啶基、噻唑基、嘧啶、吡嗪或哌啶基；
M选自下组：取代或未取代的C1-C3的亚烷基、或M不存在；
所述的任一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-C4烷基、未取代或卤代的C2-C6烷氧基、未取代或卤代的C2-C6烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C4烷基-羟基、未取代或C1-C4烷基取代的胺基。
在另一优选例中，所述的式I化合物是下表A中所示的化合物：
表A
Figure PCTCN2015087556-appb-000006
Figure PCTCN2015087556-appb-000007
Figure PCTCN2015087556-appb-000008
Figure PCTCN2015087556-appb-000009
在另一优选例中，L、X、W、Y、Z、环A或R为实施例中所述具体化合物中所对应的基团。
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，包括步骤：
Figure PCTCN2015087556-appb-000010
(a)在惰性溶剂中，用式I-8化合物和式I-9化合物反应，得到式I化合物；
上述各式中，各基团的定义如权利要求1中所述。
在另一优选例中，所述的(a)步骤中，所述的反应在铜盐存在下进行；较佳地，所述的铜盐选自下组：CuI、Cu、CuCl、Cu2O、CuO、Cu(OAc)2、CuSO4·5H2O、Cu(acac)2、CuCl2、CuSCN，或其组合。
在另一优选例中，所述的(a)步骤中，所述的反应在配体存在下进行；较佳地，所述的配体为二齿胺配体；更佳地，所述的配体选自下组：N1,N2-二甲基-乙二胺、(1R,2R)-(-)-N,N’-二甲基-1,2-环己二胺，或其组合。
在另一优选例中，所述的(a)步骤中，所述的反应在碱存在下进行；较佳地，所述的碱为无机碱，更佳地选自下组：K2CO3、K3PO4、Cs2CO3，或其组合。
在另一优选例中，所述的惰性溶剂选自下组：甲苯、二氧六环、THF、DMF，或其组合。
在另一优选例中，所述方法还包括步骤：
Figure PCTCN2015087556-appb-000011
(b)在惰性溶剂中，用式I化合物进行脱保护，得到式I’化合物；
其中，L选自下组：四氢吡喃基(THP)；
其余各基团的定义如上文中所述。
在另一优选例中，所述的(b)步骤中，所述的反应在酸存在下进行；较佳地，所述的酸选自下组：盐酸，对甲苯磺酸，TFA，或其组合。
在另一优选例中，所述的(b)步骤中，所述的惰性溶剂选自下组：二氯甲烷，甲醇、乙醇、异丙醇、正丁醇、叔丁醇、异丁醇，或其组合。
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为肿瘤，较佳地为选自下组的肿瘤：子宫内膜癌、乳腺癌、胃癌、膀胱癌、骨髓瘤、肝癌。
在另一优选例中，所述FGFR激酶选自下组：FGFR1、FGFR2、FGFR3，或其组合。
在另一优选例中，所述的肿瘤细胞为白血病细胞株；较佳地为髓源白血病细胞株；更佳地为急性髓源白血病细胞株KG1细胞。
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0.01～99.99％。
在另一优选例中，所述的药物组合物用于抑制FGFR激酶的活性。
在另一优选例中，所述的药物组合物用于治疗与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，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，所述的抑制是体外非治疗性的抑制。
在另一优选例中，当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时，所述的抑制有效量为0.001-500nmol/L，较佳地为0.01-200nmol/L。
本发明的第六方面，提供了一种治疗与FGFR激酶活性或表达量相关的疾病的方法，其特征在于，所述方法包括：对治疗对象施用治疗有效量的如本发明第一方面所述的式I化合物，或如本发明第四发明所述的药物组合物。
在另一优选例中，所述与FGFR活性或表达量相关的疾病为肿瘤，较佳地为选自下 组的肿瘤：子宫内膜癌、乳腺癌、胃癌、膀胱癌、骨髓瘤、肝癌。
本发明的第七方面，提供了一种体外抑制肿瘤细胞的方法，所述方法包括：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，或如本发明第四方面所述的药物组合物。
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。
具体实施方式
本发明人经过长期而深入的研究，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，或类似基团。
术语“C1-C6亚烷基”指如上文所述的C1～C6烷基失去一个氢原子之后形成的基团，例如-CH2-、-CH2-CH2-，或类似基团。
术语“C6-C10亚芳基”指具有6-10个碳原子的芳基失去一个氢原子形成的基团，包括单环或二环亚芳基，例如亚苯基、亚萘基，或类似基团。
术语“6元芳基”指苯基。
术语“5～8元芳基”指5-8元环的碳非饱和系的取代基，如苯基，或类似基团。
术语“5元～8元杂芳基”指具有5-8元的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，如吡啶基、噻吩基，或类似基团。
术语“饱和3～12元碳环”指具有3-12个碳原子的饱和碳环，例如环己基，或类似基团。
术语“3～12元杂环”指具有3-12元的环系上具有一个或多个选自O、S、N或P的杂原子的饱和环系取代基，如哌啶基，吡咯基，或类似基团。
术语“卤素”指F、Cl、Br和I。
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
Figure PCTCN2015087556-appb-000012
其中，
L选自下组：H、四氢吡喃基(THP)；
各个X各自独立地选自下组：Cl、F、H、CN；
W、Y、Z各自独立地选自：N或CH；
环A为无、取代或未取代的5～8元芳基，或取代或未取代的5元～8元杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫；取代或未取代的3元～12元饱和杂环或碳环，其中，所述的杂环包含至少一个选自下组的杂原子：氮、氧，或硫；或为
Figure PCTCN2015087556-appb-000013
R为H或取代或未取代的选自下组的基团：
Figure PCTCN2015087556-appb-000014
其中，M选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C6-C10的亚芳基、取代或未取代的C1-C10的亚杂芳基；
所述的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。
在另一优选例中，所述的环A是选自下组的杂芳基：
Figure PCTCN2015087556-appb-000015
其中，Q1、Q2、Q3、Q4为各自独立地选自：N或CH；
B1、B2、B3、B4为各自独立地选自：N或CH。
在另一优选例中，所述的环A是选自下组的杂芳基：
Figure PCTCN2015087556-appb-000016
在另一优选例中，R为取代或未取代的选自下组的基团：
Figure PCTCN2015087556-appb-000017
其中，
R1、R2、R3、R4各自独立地选自下组：H、卤素、C1-C6直链烷基或支链烷基、卤代的C1-C6直链烷基或支链烷基；
R5选自下组：H、C1-C6直链烷基或支链烷基，C1-C6直链或支链的酰基，C1-C6直链或支链的亚烷基-羟基。
R6、R7、R8、R9、R10、R11、R12各自独立地选自下组：H、C1-C6直链烷基或支链烷基，C1-C6直链或支链的酰基，C1-C6直链或支链的醇基(亚烷基-羟基)；
G1、G2、G3、G4各自独立地选自下组：H、卤素、C1-C6直链烷基或支链烷基、卤代的C1-C6直链烷基或支链烷基或
G5选自下组：H、C1-C6直链烷基或支链烷基、C1-C6直链或支链的酰基、C1-C6直链或支链的烷基-羟基；
E1、E2各自独立地选自下组：H、卤素、直链烷基或支链烷基、卤代的C1-C6直链烷基或支链烷基；
E3选自下组：H、C1-C6直链烷基或支链烷基、C1-C6直链或支链的酰基、C1-C6直链或支链的亚烷基-羟基；
R13、R14、R15、R16各自独立地选自下组：H、C1-C6直链烷基或支链烷基，C1-C6直链或支链的酰基，C1-C6直链或支链的醇基(亚烷基-羟基)；
C0-C3 alkyl为无、或具有1-3个碳原子的亚烷基；
C1-C6 alkyl为具有1-6个碳原子的亚烷基。
在另一优选例中，L选自下组：H、四氢吡喃基(THP)；
各个X各自独立地选自下组：H、Cl、F、CN；
W、Y、Z各自独立地选自：N或CH；
环A为取代或未取代的6元芳基，或取代或未取代的5元～6元杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫；
M选自下组：取代或未取代的C1-C4的亚烷基、或M不存在；
所述的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-C4烷基、未取代或卤代的C2-C4酰基、未取代或卤代的C1-C4烷基-羟基。
在另一优选例中，L为H；
各个X各自独立地选自下组：H、Cl、F；
W、Y、Z各自独立地选自：N或CH；
环A为选自下组的基团：无、苯基、吡唑基、吡啶基、噻唑基、哌啶基；
M选自下组：取代或未取代的C1-C3的亚烷基、或M不存在；
所述的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-C4烷基、未取代或卤代的C2-C4酰基、未取代或卤代的C1-C4烷基-羟基。
在另一优选例中，所述的式I化合物是选自下组的化合物：
Figure PCTCN2015087556-appb-000018
Figure PCTCN2015087556-appb-000019
Figure PCTCN2015087556-appb-000020
Figure PCTCN2015087556-appb-000021
式I化合物的制备
制备方法
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
本发明使用的式I-8化合物和式I-9化合物的制备方法是已知的。通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
一种优选的式I化合物的制备方法包括步骤：
Figure PCTCN2015087556-appb-000022
(a)在惰性溶剂中，用式I-8化合物和式I-9化合物反应，得到式I化合物；
上述各式中，各基团的定义如上文中所述。
在另一优选例中，所述的反应在铜盐存在下进行；较佳地，所述的铜盐选自(但并不限于)下组：CuI、Cu、CuCl、Cu2O、CuO、Cu(OAc)2、CuSO4·5H2O、Cu(acac)2、CuCl2、CuSCN，或其组合。
在另一优选例中，所述的反应在配体存在下进行；较佳地，所述的配体为二齿胺配体；更佳地，所述的配体选自(但并不限于)下组：N1,N2-二甲基-乙二胺、(1R,2R)-(-)-N,N’-二甲基-1,2-环己二胺，或其组合。
在另一优选例中，所述的反应在碱存在下进行；较佳地，所述的碱为无机碱，更佳地选自(但并不限于)下组：K2CO3、K3PO4、Cs2CO3，或其组合。
在另一优选例中，所述的惰性溶剂选自(但并不限于)下组：甲苯、二氧六环、THF、DMF，或其组合。
在另一优选例中，所述方法还包括步骤：
Figure PCTCN2015087556-appb-000023
(b)在惰性溶剂中，用式I化合物进行脱保护，得到式I’化合物；其余各基团的定义如上文中所述。
在另一优选例中，所述的反应在酸存在下进行；较佳地，所述的酸选自(但并不限于)下组：盐酸，对甲苯磺酸，TFA，或其组合。
在另一优选例中，所述的惰性溶剂选自(但并不限于)下组：二氯甲烷，甲醇、乙醇、异丙醇、正丁醇、叔丁醇、异丁醇，或其组合。
一种较为优选的制备方法包括以下步骤：
Figure PCTCN2015087556-appb-000024
(1)化合物A2可由化合物A1和DHP在酸(例如但不限于对甲基苯磺酸，三氟乙酸)的催化下于惰性溶剂(DCM，THF等)中反应。
(2)化合物A4可由相应的硼酸或者酯进行铃木耦合(Suzuki coupling)，在惰性溶剂(如二氧六环和水、甲苯和水、DMSO、THF、DMF等)中，在催化剂(如四(三苯基膦)钯、三(二亚苄基丙酮)二钯(Pd2(dba)3)、双(二亚苄基丙酮)钯、二氯二(三苯基膦)钯、三苯基膦醋酸钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯等)和碱(如碳酸钾、氟化钾、氟化铯、氟化钠、磷酸钾、水合磷酸钾、碳酸钠、碳酸氢钠、1,8-二氮杂二环[5.4.0]十一碳-7-烯、三乙胺、二异丙基乙胺、吡啶或其组合等)的存在下，进行Suzuki偶联反应一段时间(如1-4小时)，得到化合物A4；
(3)化合物A5可由化合物A4在惰性溶剂(二氯甲烷，THF，乙腈)，缓慢滴加SO2Cl2，室温下搅拌得到。
(4)化合物A6可由化合物A5脱保护得到，在惰性溶剂中(如二氯甲烷，甲醇、乙醇、异丙醇、正丁醇、叔丁醇、异丁醇等)加入酸(如盐酸，对甲苯磺酸，TFA)得到化合物A6。
(5)化合物A7可由加入化合物A6，碘和NaOH在惰性溶剂(1,4-二氧六环，DMF等)。室温下搅拌得到。
(6)化合物A8可由化合物A7和DHP在酸(例如但不限于对甲基苯磺酸，三氟乙酸)的催化下于惰性溶剂(DCM，THF等)中反应。
(7)化合物A10可由化合物A8和化合物A9芳酰胺化反应，较佳地，所述的反应在以下一种或多种试剂存在下进行：铜盐，所述铜盐可以是但不限于CuI、Cu、CuCl、Cu2O、CuO、Cu(OAc)2、CuSO4·5H2O、Cu(acac)2、CuCl2、CuSCN，或其组合。配体，所述配体可以是二齿胺配体，包括但不限于N1,N2-二甲基-乙二胺、(1R,2R)-(-)-N,N’-二甲基 -1,2-环己二胺，碱，所述的碱可以是但不限于K2CO3、K3PO4、Cs2CO3等无机碱，反应的溶剂可以是但不限于：甲苯、二氧六环、THF，DMF。
(8)化合物A11可由化合物A10脱保护得到，使用适当的酸(诸如但不限于盐酸、对甲苯磺酸、TFA)在惰性溶剂中(如二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、叔丁醇、异丁醇等)得到化合物11。
式I化合物的应用
所述的式I化合物可用于以下的一种或多种用途：
(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；
(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为肿瘤，较佳地为选自下组的肿瘤：子宫内膜癌、乳腺癌、胃癌、膀胱癌、骨髓瘤、肝癌。
在另一优选例中，所述FGFR激酶选自下组：FGFR1、FGFR2、FGFR3，或其组合。
在另一优选例中，所述的肿瘤细胞为白血病细胞株；较佳地为髓源白血病细胞株；更佳地为急性髓源白血病细胞株KG1细胞。
本发明的式I化合物可用于制备一种药物组合物，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。
在另一优选例中，所述的药物组合物用于抑制FGFR激酶的活性。
在另一优选例中，所述的药物组合物用于治疗与FGFR激酶活性或表达量相关的疾病。
本发明的式I化合物还可以用于抑制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7所述的药物组合物。
在另一优选例中，所述的抑制是体外非治疗性的抑制。
在另一优选例中，当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时，所述的抑制有效量为0.001-500nmol/L，较佳地为0.01-200nmol/L。
特别地，本发明还提供了一种治疗与FGFR激酶活性或表达量相关的疾病的方法，所述方法包括：对治疗对象施用治疗有效量的式I化合物，或所述含有式I化合物作为有效成分的药物组合物。
在另一优选例中，所述与FGFR活性或表达量相关的疾病为肿瘤，较佳地为选自下组的肿瘤：子宫内膜癌、乳腺癌、胃癌、膀胱癌、骨髓瘤、肝癌。
药物组合物和施用方法
由于本发明化合物具有优异的对FGFR激酶(Kinase)例如FGFR1、FGFR2、FGFR3的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与FGFR活性或表达量相关的疾病。根据现有技术，本发明化合物可用于治疗 以下疾病：子宫内膜癌、乳腺癌、胃癌、膀胱癌、骨髓瘤、肝癌等等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2015087556-appb-000025
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的FGFR抑制剂及其制备和应用，所述的抑制剂在极低浓度下即可抑制各类FGFR激酶的活性。
3.提供了一类治疗与FGFR激酶活性相关疾病的药物组合物。
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。除非另外说明，否则百分比和份数按重量计算。
各实施例中：
LCMS仪器：Pump Agilent 1100 UV检测器：Agilent 1100 DAD
Mass Spectrometer API 3000
层析柱：Waters sunfire C18,4.6×50mm,5um
流动相：A—乙腈  B-H2O(0.1％FA)
实施例1
合成路线1
Figure PCTCN2015087556-appb-000026
在干燥的250mL圆底烧瓶中加入1(10.00g，51.0mmol),p-TSA(1.75g，10.2mmol)和二氯甲烷(100.0mL)，缓慢滴加DHP(8.56g，102.0mmol)，室温下搅拌4.0h。反应完毕后，反应液用100.0mL水稀释，200mL二氯甲烷萃取2次，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物2(8.90g，62％)。LCMS:281(M+H)+,RT＝1.626mim。
Figure PCTCN2015087556-appb-000027
在干燥的250mL圆底烧瓶中室温下依次加入化合物2(8.90g，31.7mmol)，3(5.77g，31.7mmol)，Pd(PPh3)4(3.66g，3.17mmol)，K2CO3(8.75g，63.4mmol)，1,4-二氧六环(60.0mL)和水(15.0mL)，搅拌至均匀分散于体系中。在氮气保护下，加热回流4.0h。 反应液冷却至室温，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:10)得化合物4(8.10g，76％)。LC MS:339(M+H)+,RT＝1.626mim.
Figure PCTCN2015087556-appb-000028
在干燥的250mL圆底烧瓶中加入化合物4(7.90g，23.4mmol)和二氯甲烷(50.0mL)，缓慢滴加SO2Cl2(7.15g，46.7mmol)，室温下搅拌4.0h。反应液加入50.0mL水稀释，200mL二氯甲烷萃取2次，饱和NaHCO3溶液洗剂，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物5(8.50g，89％)。LC MS:407(M+H)+,RT＝1.798mim.
Figure PCTCN2015087556-appb-000029
在干燥的250mL圆底烧瓶中加入化合物5(8.50g，20.9mmol)和盐酸甲醇溶液(1M)(80.0mL)，加热回流16.0h。反应液旋干溶剂得7.50g的化合物6，无需纯化直接用于下一步。LCMS:323(M+H)+,RT＝1.592mim。
Figure PCTCN2015087556-appb-000030
在干燥的250mL圆底烧瓶中加入化合物6(7.40g，23.0mmol)，碘(11.68g，46.0mmol)，NaOH(1.84g，46.0mmol)和1,4-二氧六环(60.0mL)。室温下搅拌2.0h。反应完毕后，加入200mL水，混合物用200mL二氯甲烷萃取2次，有机相用饱和硫代硫酸钠溶液洗涤，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物7(9.50g，92％)。LC MS:449(M+H)+,RT＝1.644mim.
Figure PCTCN2015087556-appb-000031
在干燥的250mL圆底烧瓶中加入7(9.30g，20.76mmol),p-TSA(0.71g，4.152mmol)和二氯甲烷(50.0mL),缓慢滴加DHP(3.48g，41.52mmol)，室温下搅拌4.0h。反应液用50.0mL水稀释，200mL二氯甲烷萃取2次，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物8(7.70g，70％)。LC MS:281(M+H)+，RT＝2.165mim.
1H NMR(CDCl3,400MHz)δ(ppm)7.56(d,1H,J＝8.0Hz),7.45(s,1H),7.09(d,1H,J＝8.0Hz),6.65(s,1H),5.70(t,1H,J＝4.0Hz),4.03(s,1H),3.98(s,6H),3.69(t,1H,J＝8.0Hz),2.53(t,1H,J＝10Hz),2.12(m,2H),1.68-1.74(m,2H),1.56-1.63(m,1H).
Figure PCTCN2015087556-appb-000032
将化合物9(10g,82.6mmol)置于500mL单口瓶中，加入200mL DMSO。室温下加入(2R,6S)-2,6-dimethylpiperazine(14g,124mmol)和K2CO3(28.5g,206.5mmol)，搅拌均匀。然后加热到130℃，反应8h。反应完毕后，倒入1L水中。用乙酸乙酯(150mL*3)萃取三次。有机相用100mL饱和食盐水洗涤，无水硫酸钠干燥，旋干溶剂，得微黄色固体15g,产率85％。
1H NMR(400MHz,CDCl3)δ(ppm)7.48(2H,d,J＝8.8Hz),6.85(2H,d,J＝8.0Hz),3.65(2H,dd,J1＝12.0Hz,J2＝2.0Hz),2.95-3.01(2H,m),2.42(2H,t,J＝11.4Hz),1.15(6H,d,J＝6.4Hz).
Figure PCTCN2015087556-appb-000033
把化合物11(9.03g,42mmol)溶解于175mL乙醇中，然后室温下向溶液中依次加入NaOH(6.0N,105ml)和H2O2(16.1ml)。升温至50摄氏度，搅拌5个小时。反应完毕后，冷却至0摄氏度，用3N的硫酸调至PH值为7.旋蒸掉有机相，0度下搅拌30分钟。过滤得到白色固体6.5g，产率为66％。
1H NMR(400MHz,DMSO-d6):δ(ppm)7.76(2H,d,J＝8.8Hz),7.73(1H,br),7.04(1H,br),6.97(2H,d,J＝8.8Hz),3.85(2H,d,J＝11.2Hz),3.08(2H,br),2.45(2H,t,J＝11.6Hz),1.15(6H,d,J＝6.4Hz).
Figure PCTCN2015087556-appb-000034
把化合物8(2.0g,3.75mmol)溶解于20mL无水DMF中，然后室温下向溶液中依次加入反式-N,N’-二甲基-1,2-环己二胺(107mg,0.75mmol)、CuI(36mg,0.19mmol)、K3PO4(1.6g,7.5mmol)和12(1.05g,4.5mmol)。氮气置换3次，升温至110摄氏度，搅拌16个小时。反应完毕后，旋蒸掉溶剂得粗产品，柱层析(二氯甲烷:甲醇＝40:1)得白色固体0.98g，产率为41％。
1H NMR(CDCl3,400MHz)δ(ppm)8.46(s,1H),8.22(d,1H,J＝8.0Hz),7.86(d,2H,J＝8.0Hz),7.35(s,1H),7.01(d,1H,J＝8.0Hz),6.94(d,2H,J＝8.0Hz),6.62(s,1H),,5.61(m,1H),3.96(s,6H),3.71(m,3H),3.06(m,2H),2.48(m,3H),2.06(m,3H),1.70(m,3H),1.20(s,3H),1.18(s,3H).
Figure PCTCN2015087556-appb-000035
把化合物13(0.86g,1.35mmol)溶解于10mL二氯甲烷中，然后室温下向溶液中加入三氟乙酸(5ml)。室温下搅拌4个小时。反应完毕后，旋蒸掉溶剂得粗产品，柱层析(二氯甲烷:甲醇＝20:1)得白色固体0.61g，产率为82％。
1H NMR(CDCl3,400MHz)δ(ppm)8.79(s,1H),8.15(d,1H,J＝8.0Hz),7.86(d,2H,J＝8.0Hz),7.26(s,1H),6.99(d,1H,J＝8.0Hz),6.89(d,2H,J＝8.0Hz),6.62(s,1H),3.96(s,6H),3.65(m,2H),3.06(m,2H),1.17(s,3H),1.15(s,3H).
使用类似方法可得到如下化合物：
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000036
1H NMR(CDCl3,400MHz)δ(ppm)8.83(s,1H),8.21(d,1H,J＝8.0Hz),7.89(d,2H,J＝8.0Hz),7.23(s,1H),6.99(d,1H,J＝8.0Hz),6.91(d,2H,J＝8.0Hz),6.61(s,1H),3.95(s,6H),3.33(m,4H),2.56(m,4H),2.35(s,3H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
Figure PCTCN2015087556-appb-000037
1H NMR(MeOD,400MHz)δ(ppm)8.03(d,2H,J＝8.0Hz),7.84(d,1H,J＝8.0Hz),7.53(d,2H,J＝8.0Hz),7.29(s，1H),6.93(d,1H,J＝8.0Hz),6.87(s,1H),3.97(s,6H),3.68(s,2H),2.98(br,4H),2.56(br,4H),2.54(s,3H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-***啉苯酰胺
Figure PCTCN2015087556-appb-000038
1H NMR(MeOD,400MHz)δ(ppm)8.02(d,2H,J＝8.0Hz),7.97(d,1H,J＝8.0Hz),7.32(s,1H),7.07(d,2H,J＝8.0Hz),7.99(d,1H,J＝8.0Hz),6.88(s,1H),3.98(s,6H),3.84(t,4H,J＝5.2Hz),3.33(t,4H,J＝5.2Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000039
1H NMR(MeOD,400MHz)δ(ppm)8.09(m,3H),7.36(s,1H),7.20(m,2H),7.99(m,1H),6.89(s,1H),3.97(s,6H),3.27(m,2H),1.4(t,3H,J＝6.4Hz).
4-((4-乙酰基-1-基)甲基)-N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)苯甲酰胺
Figure PCTCN2015087556-appb-000040
1H NMR(DMSO-d6,400MHz)δ(ppm)12.88(s,1H),10.81(s,1H),8.06(d,2H,J＝8.0Hz),7.77(d,1H,J＝8.0Hz),7.78(d,2H,J＝8.0Hz),7.29(s,1H),7.00(s,1H),6.85(d,1H,J＝8.0Hz),3.97(s,6H),3.59(s,2H),2.40(t,2H,J＝4.8Hz),2.33(t,2H,J＝4.8Hz),1.98(s,3H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((2-(二甲基氨基)乙基)氨基)苯甲酰胺
Figure PCTCN2015087556-appb-000041
1H NMR(400MHz,DMSO-d6/D2O)δ(ppm)7.87(2H,s),7.71(1H,s),7.29(1H,s),7.10-6.60(4H,m),3.91(6H,s),3.70(2H,s),3.48(2H,s),2.80(6H,s).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-5-((3R，5S)-3,5-二甲基-1-基)吡啶酰胺
Figure PCTCN2015087556-appb-000042
1H NMR(DMSO-d6,400MHz)δ(ppm)12.89(1H,br),10.48(1H,s),9.06(1H,br),8.51(2H,br),8.05(1H,d,J＝8.8Hz),7.94(1H,d,J＝8.4Hz),7.60-7.63(1H,m),7.29(1H,s),7.01(1H,s),4.22(2H,d,J＝14.4Hz),3.97(6H,s),2.84(2H,t,J＝12.6Hz),2.54-2.58(2H,m),1.30(6H,d,J＝6.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(3,3-二甲基-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000043
1H NMR(400MHz,DMSO-d6)δ(ppm)12.85(s,1H),10.57(s,1H),8.01(2H,d,J＝8.8Hz),7.76(1H,d,J＝8.4Hz),7.29(s,1H),7.07(2H,d,J＝8.8Hz),7.01(1H,s),6.85(d,1H,J＝8.4Hz),3.98(s,6H),3.18-3.50(m,6H),1.31(s,6H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-3-(4-甲基-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000044
1H NMR(400MHz,DMSO-d6)δ(ppm)12.92(1H,s),10.83(1H,s),9.60-9.20(1H,m),7.78(1H,d,J＝8.4Hz),7.68(1H,s),7.58(1H,d,J＝7.6Hz),7.44(1H,t,J＝8.0Hz),7.30(1H,s),7.26(1H,dd,J1＝1.6Hz,J2＝8.0Hz),7.00(1H,s),6.87(1H,d,J＝8.4Hz),3.97(6H,s),3.30-3.10(4H,m),3.10-2.80(4H,m),2.88(3H,s).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-异丙-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000045
1H NMR(MeOD,400MHz)δ(ppm)8.08(br,2H),7.99(br,1H),7.33(br,1H),7.18(br,2H),7.02(br,1H),6.89(s,1H),4.11-4.17(m,2H),3.57-3.64(m,3H),3.19-3.37(m,4H),1.42(6H,d,J＝6.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000046
1H NMR(MeOD,400MHz)δ(ppm)8.00(2H,d,J＝9.2Hz),7.83(1H,d,J＝8.4Hz),7.28(s,1H),7.10(2H,d,J＝9.2Hz),6.90(1H,d,J＝8.4Hz),6.88(s,1H),3.97(s,6H),3.48-3.51(m,4H),3.18-3.25(m,4H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((3(二甲基氨基)丙基)氨基)苯甲酰胺
Figure PCTCN2015087556-appb-000047
1H NMR(400MHz,DMSO-d6)δ(ppm)12.87(1H,br),10.39(s,1H),9.57(1H,br),7.80(2H,d,J＝8.8Hz),7.75(1H,d,J＝8.4Hz),7.27(s,1H),6.84(1H,d,J＝8.4Hz),6.66(2H,d,J-8.8Hz),3.98(6H,s),3.20(4H,t,J＝6.8Hz),2.80(s,6H),1.89-1.96(m,2H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-(2-羟乙基)哌嗪基)苯甲酰胺
Figure PCTCN2015087556-appb-000048
1H NMR(400MHz,DMSO-d6)δ(ppm)12.85(1H,br),10.62(1H,s),9.73(1H,br),8.05(2H,d,J＝8.8Hz),7.76(1H,d,J＝8.4Hz),7.29(1H,s),7.13(2H,d,J＝8.8Hz),6.87(1H,s),6.86(1H,d,J＝8.4Hz),4.06-4.08(m,2H),3.98(6H,s),3.80(2H,t,J＝4.8Hz),3.56-3.60(m,2H),3.14-3.28(m,6H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(2-(二甲基氨基)乙酰氨基)苯甲酰胺
Figure PCTCN2015087556-appb-000049
1H NMR(400MHz,DMSO-d6)δ(ppm)12.92(1H,s),10.78(1H,s),10.08(1H,s),8.12(2H,d,J＝8.8Hz),7.89(2H,d,J＝8.8Hz),7.83(1H,d,J＝8.4Hz),7.34(1H,s),7.06(1H,s),6.91(1H,d,J＝8.4Hz),4.03(6H,s),3.18(s,2H),2.35(s,6H).
N-(6-(3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((3R，5S)-3,5-二甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000050
1H NMR(d6-DMSO,400MHz)δppm 12.78(s,1H),10.50(s,1H),7.97(d,2H,J＝9.2Hz),7.76(d,1H,J＝8.4Hz),7.66(s,1H),7.36(d,1H,J＝8.4Hz),7.01(d,2H,J＝8.8Hz),6.84(d,2H,J＝2.0Hz),6.53(s,1H),3.83(s,6H),3.76(d,2H,J＝6.8Hz),2.83(s,2H),2.24(t,3H,J＝6.8Hz),1.23(s,4H),1.04(d,6H,J＝6.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-特戊酰基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000051
1H NMR(d6-DMSO，400MHz)δppm 12.81(s,1H),10.6(s,1H),8.01(d,2H,J＝8.8Hz),7.75(d,1H,J＝4.4Hz),7.27(s,1H),7.03(d,2H,J＝8.8Hz),7.00(s,1H),6.84(d,1H,j＝8.8Hz),4.00(s,6H),3.70-3.72(m,4H),3.30-3.32(m,4H),1.23(s,9H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-1-(2-羟基乙基)-1H-吡唑-4-甲酰胺
Figure PCTCN2015087556-appb-000052
1H NMR(d6-DMSO,400MHz)δppm 12.84(brs,1H),10.53(s,1H),8.41(s,1H),8.11(s,1H),7.80(d,1H,J＝8.4Hz),7.26(s,1H),7.01(d,1H,J＝3.2Hz),6.84(d,1H,J＝8.4Hz),4.21(t,2H,J＝5.2Hz),3.94(s,6H),3.77(t,2H,J＝5.2Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-2,3-二氢咪唑并[5,1-B]噁唑-7-甲酰胺
Figure PCTCN2015087556-appb-000053
1H NMR(d6-DMSO,400MHz)δppm 12.80(brs,1H),10.18(s,1H),8.07(s,1H),7.77(d,1H,J＝8.0Hz),7.25(s,1H),7.00(s,1H),6.83(dd,1H,J1＝0.8Hz,J2＝8.4Hz),5.23(t,2H,J＝7.6Hz),4.33(t,2H,J＝8.0Hz),3.97(s,6H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(3-(二甲基氨基)-3-氧代丙基)苯甲酰胺
Figure PCTCN2015087556-appb-000054
1H NMR(d6-DMSO,400MHz)δppm 12.90(s,1H),10.78(s,1H),8.00(d,2H,J＝8.4Hz),7.77(d,1H,J＝8.4Hz),7.42(d,2H,J＝8.0Hz),7.03(s,1H),7.01(d,1H),6.86(d,1H,J＝8.4Hz),3.98(s,6H),2.91(t,2H,J＝14.4Hz),2.84(s,3H),2.67(t,2H,J＝14.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((二甲基氨基)甲基)苯甲酰胺
Figure PCTCN2015087556-appb-000055
1H NMR(d6-DMSO,400MHz)δppm 12.95(s,1H),10.97(s,1H),9.85(d,1H,J＝2.8Hz),8.17(d,2H,J＝8.0Hz),7.78(d,1H,J＝8.0Hz),7.66(d,2H,J＝8.4Hz),7.31(s,1H),7.00(s,1H),6.87(d,1H,J＝8.4Hz),4.39(d,2H,J＝4.4Hz),3.97(s,6H),2.79(t,6H,J＝3.6Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(二甲基氨基)苯甲酰胺
Figure PCTCN2015087556-appb-000056
1H NMR(d6-DMSO,400MHz)δppm 12.82(s,1H),10.47(s,1H),7.98(d,2H,J＝6.4Hz),7.76(d,1H,J＝8.0Hz),7.28(s,1H),7.03(s,1H),7.01(s,1H),6.84(d,1H,J＝8.4Hz),6.78(d,2H,J＝6.8Hz),3.98(s,6H),3.18(s,6H).
4-(4-乙酰基哌嗪-1-基)-N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑-3-基)苯甲酰胺
Figure PCTCN2015087556-appb-000057
1H NMR(d6-DMSO，400MHz)δppm 12.89(s,1H),10.62(s,1H),8.06(d,2H,J＝8.8Hz),7.82(d,1H,J＝8.4Hz),7.34(s,1H),7.10(d,2H,J＝8.8Hz),7.06(s,1H),6.84(d,1H,j＝8.4Hz),4.03(s,6H),3.65-3.66(m,4H),3.38-3.43(m,4H),2.10(s,3H).
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吲唑-3-基)-4-(4-(二甲基氨基)哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000058
1H NMR(CDCl3,400MHz)δppm 8.48(s,1H),8.23(d,1H,J＝8Hz)，7.88(d,2H,J＝8.8Hz)，7.02(d,1H,J＝8.8Hz)，6.79(d,2H,J＝8.4Hz),6.63(s,1H),3.97(s,6H)，3.93(d,2H,J＝14Hz),2.84-2.87(m,2H),2.33(m,7H),1.95(d,4H,J＝12Hz)。LCMS:568(M+H)+，RT＝1.25min
合成路线2
Figure PCTCN2015087556-appb-000059
在干燥的50mL圆底烧瓶中加入化合物38(1.20g，3.55mmol)和乙腈(20.0mL)。N2保护0℃下分批加入Select Flour(2.51g，7.1mmol),室温搅拌18.0h。反应液用水稀释，乙酸乙酯萃取，有机相依次用水，饱和NaHCO3，饱和食盐水洗涤。无水硫酸钠干燥，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:8)得粗产物化合物39(629mg,47％)。LCMS:374.9(M+H)+，RT＝1.243min.
Figure PCTCN2015087556-appb-000060
在干燥的50mL圆底烧瓶中加入化合物39(629mg,1.68mmol)和二氯甲烷(10.0mL)，冰浴下缓慢滴加TFA(2mL)，室温下搅拌3.0h。旋干溶剂，剩余物用冰水稀释，饱和NaHCO3溶液调节pH＝8，乙酸乙酯萃取，有机相用水洗。无水硫酸钠干燥，旋干溶剂得粗产物化合物40(460mg,94％)。LCMS:291.0(M+H)+，RT＝1.233min.
Figure PCTCN2015087556-appb-000061
在干燥的50mL圆底烧瓶中加入化合物40(460mg，1.59mmol)，水溶液NaOH(5.3mL，3N)和1,4-二氧六环(6.0mL)。零度下滴加碘(484.0mg，1.90mmol)的1,4-二氧六环溶液。室温搅拌18.0h。饱和硫代硫酸钠溶液洗剂，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，旋干得粗产物41(633.0mg,95.6％)无需纯化直接用于下一步。LCMS:416.9(M+H)+，RT＝1.540min。
Figure PCTCN2015087556-appb-000062
在干燥的50mL圆底烧瓶中加入41(633.0mg，1.52mmol),p-TSA(58.0mg，0.30mmol)和二氯甲烷(6.0mL)，缓慢滴加DHP(256.0mg，3.04mmol)，室温下搅拌18.0h。反应液用20.0mL水稀释，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:12)得化合物42(260.0mg,34％)。
Figure PCTCN2015087556-appb-000063
在干燥的25mL三口烧瓶中加入42(260mg，0.52mmol)，5a(145mg，0.62mmol)，5b(148.0mg，1.04mmol)，K3PO4(331.0mg，1.56mmol)，CuI(99mg，0.52mmol)，和干燥的DMF(3.0mL)，120℃下搅拌6.0h。反应液用20.0mL水稀释，乙酸乙酯萃取，合并有机相，依次用水和饱和食盐水洗，无水硫酸钠干燥，旋干溶剂得粗产物化合物43(290mg,92％)无需纯化直接用于下一步。LCMS:606.1(M+H)+，RT＝1.063min.
Figure PCTCN2015087556-appb-000064
在干燥的25mL圆底烧瓶中加入43(290.0mg，0.48mmol)和二氯甲烷(10.0mL)，冰水浴缓慢滴加TFA(2.0mL)，室温下搅拌4.0h。旋干溶剂得粗产物，酸性prep-HPLC制备得化合物44(50.2mg,21％,TFA盐)。LCMS:522.1(M+H)+，RT＝1.227min.
1H NMR(d6-DMSO,400MHz)δppm 12.91(brs,1H),10.64(d,1H,J＝3.2Hz),9.01(m,1H),8.45(m,1H),8.04(d,2H,J＝8.8Hz),7.78(d,1H,J＝8.4Hz),7.52(s,1H),7.09(m,4H),4.12(d,2H,J＝13.8Hz),3.92(s,6H),2.77(m,3H),1.29(d,6H,J＝6.4Hz).
使用类似方法可得到如下化合物：
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000065
1H NMR(d6-DMSO,400MHz)δppm 12.95(s,1H),10.62(s,1H),9.78(s,1H),8.04(d,2H,J＝8.8Hz),7.79(d,1H,J＝8.4Hz),7.52(s,1H),7.02-7.18(m,4H),4.08(d,2H,J＝12.0Hz),3.92(s,6H),3.47-3.63(m,2H),3.01-3.27(m,4H),2.88(s,3H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(3,3-二甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000066
1H NMR(d6-DMSO,400MHz)δppm 12.91(s,1H),10.63(s,1H),8.91(s,2H),8.03(d,2H,J＝9.2Hz),7.78(d,1H,J＝8.0Hz),7.52(s,1H),7.02-7.16(m,4H),3.86(s,6H),3.51(m,2H),3.43(m,2H),3.30(s,2H),1.26(t,3H,J＝7.2Hz).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000067
1H NMR(d6-DMSO,400MHz)δppm 12.95(s,1H),10.62(s,1H),9.78(s,1H),8.04(d,2H,J＝8.8Hz),7.79(d,1H,J＝8.4Hz),7.52(s,1H),7.02-7.18(m,4H),4.08(d,2H,J＝12.0Hz),3.92(s,6H),3.47-3.63(m,2H),3.21-3.22(m,2H),3.01-3.27(m,4H),1.27(t,3H,J＝7.2Hz).
N-(6-(2,6-二氟-3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000068
1H NMR(d-MeOD,400MHz)δppm 8.50(d,1H,J＝8.4Hz)),7.99(d,2H,J＝8.8Hz),7.30(d,1H,J＝8.4Hz),7.08(d,2H,J＝8.8Hz),7.01(s,1H)，3.93(s,6H),3.45(s,4H),2.80(s,4H),2.49(s,3H).LC MS:509(M+H)+，RT＝1.18min
合成路线3
Figure PCTCN2015087556-appb-000069
在干燥的50mL圆底烧瓶中加入化合物49(1.20g，3.55mmol)和乙腈(20.0mL)。N2保护0℃下分批加入Select Flour(2.51g，7.1mmol),室温搅拌18.0h。反应液用水稀释，乙酸乙酯萃取，有机相依次用水，饱和NaHCO3，饱和食盐水洗涤。无水硫酸钠干燥，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:8)得粗产物化合物50(629mg,47％)。LCMS:374.9(M+H)+，RT＝1.243min
Figure PCTCN2015087556-appb-000070
在干燥的50mL圆底烧瓶中加入化合物50(629mg，1.68mmol)和二氯甲烷(10.0mL)，冰浴下缓慢滴加TFA(2mL)，室温下搅拌3.0h。旋干溶剂，剩余物用冰水稀释，饱和NaHCO3溶液调节pH＝8，乙酸乙酯萃取，有机相用水洗。无水硫酸钠干燥，旋干溶剂得粗产物化合物51(460mg,95％)。LCMS:291.0(M+H)+，RT＝1.233min.
Figure PCTCN2015087556-appb-000071
在干燥的50mL圆底烧瓶中加入化合物51(460mg，1.59mmol)，水溶液NaOH(5.3mL，3N)和1,4-二氧六环(6.0mL)。零度下滴加碘(484.0mg，1.90mmol)的1,4-二氧六环溶液。室温搅拌18.0h。饱和硫代硫酸钠溶液洗剂，乙酸乙酯萃取，有机相依次用水和饱和食 盐水洗涤，无水硫酸钠干燥，旋干得粗产物52(633.0mg,96％)无需纯化直接用于下一步。LCMS:416.9(M+H)+，RT＝1.540min。
Figure PCTCN2015087556-appb-000072
在干燥的50mL圆底烧瓶中加入52(633.0mg，1.52mmol),p-TSA(58.0mg，0.30mmol)和二氯甲烷(6.0mL)，缓慢滴加DHP(256.0mg，3.04mmol)，室温下搅拌18.0h。反应液用20.0mL水稀释，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:12)得化合物53(265.0mg,26％)。
Figure PCTCN2015087556-appb-000073
在干燥的25mL三口烧瓶中加入53(193mg，0.40mmol)，5a(112mg，0.48mmol)，5b(114.0mg，0.81mmol)，K3PO4(256.0mg，1.21mmol)，CuI(76mg，0.40mmol)，和干燥的DMF(3.0mL)，120℃下搅拌6.0h。反应液用30.0mL水稀释，乙酸乙酯萃取，合并有机相，依次用水和饱和食盐水洗，无水硫酸钠干燥，旋干溶剂得粗产物化合物54(240mg，99％)，无需纯化直接用于下一步。LCMS:588.1(M+H)+，RT＝1.320min.
Figure PCTCN2015087556-appb-000074
在干燥的25mL圆底烧瓶中加入54(240.0mg，0.41mmol)和二氯甲烷(7.5mL)，冰水浴缓慢滴加TFA(1.5mL)，室温下搅拌4.0h。旋干溶剂得粗产物，酸性prep-HPLC制备得化合物55(70.8mg，34％，TFA salt)。LCMS:522.1(M+H)+，RT＝1.227min.
1H NMR(d6-DMSO，400MHz)δppm 12.95(brs,1H),10.61(s,1H),9.17(m,1H),8.57(m,1H),8.03(d,2H,J＝9.2Hz),7.76(m,1H),7.59(s,1H),7.22(d,1H,J＝8.8Hz),7.13(d,2H,J＝9.2Hz),6.76(dd,1H,J1＝2.8Hz,J2＝6.8Hz),6.61(m,1H),4.01(d,2H,J＝12.4Hz),3.88(s,1H),3.84(s,3H),3.81(s,3H),3.30-3.50(m,2H),2.75(t,2H,J＝6.4Hz),1.29(d,6H,J＝6.4Hz).
合成路线4
Figure PCTCN2015087556-appb-000075
在干燥的250mL圆底烧瓶中加入56(10.00g，51.0mmol),p-TSA(1.75g，10.2mmol)和二氯甲烷(100.0mL)，缓慢滴加DHP(8.56g，102.0mmol)，室温下搅拌4.0h。反应完毕后，反应液用100.0mL水稀释，200mL二氯甲烷萃取2次，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物57(8.90g，62％)。LCMS:281(M+H)+,RT＝1.626min。
Figure PCTCN2015087556-appb-000076
在干燥的250mL圆底烧瓶中室温下依次加入化合物57(8.90g，31.7mmol)，3(5.77g，31.7mmol)，Pd(PPh3)4(3.66g，3.17mmol)，K2CO3(8.75g，63.4mmol)，1,4-二氧六环(60.0mL)和水(15.0mL)，搅拌至均匀分散于体系中。在氮气保护下，加热回流4.0h。反应液冷却至室温，旋干溶剂得粗产品，柱层析(乙酸乙酯:石油醚＝1:10)得化合物58(8.10g，76％)。LCMS:339(M+H)+,RT＝1.626min.
Figure PCTCN2015087556-appb-000077
在干燥的250mL圆底烧瓶中加入化合物58(7.90g，23.4mmol)和二氯甲烷(50.0mL)，缓慢滴加SO2Cl2(7.15g，46.7mmol)，室温下搅拌4.0h。反应液加入50.0mL水稀释，200mL二氯甲烷萃取2次，饱和NaHCO3溶液洗剂，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物59(8.50g，89％)。LCMS:407(M+H)+,RT＝1.798min.
Figure PCTCN2015087556-appb-000078
在干燥的250mL圆底烧瓶中加入化合物59(0.972g，3mmol)，NIS(1.6g，7mmol)，和DCM(10.0mL)。室温下搅拌2.0h。反应完毕后，加入200mL水，混合物用200mL二氯甲烷萃取2次，有机相用饱和硫代硫酸钠溶液洗涤，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物60(1.1g，82％)。LCMS:450(M+H)+,RT＝1.644min.
Figure PCTCN2015087556-appb-000079
在干燥的250mL圆底烧瓶中加入60(9.30g，20.76mmol),p-TSA(0.71g，4.152mmol)和二氯甲烷(50.0mL),缓慢滴加DHP(3.48g，41.52mmol)，室温下搅拌4.0h。反应液用50.0mL水稀释，200mL二氯甲烷萃取2次，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物61(7.70g，70％)。LCMS:281(M+H)+，RT＝2.165min.
Figure PCTCN2015087556-appb-000080
把化合物61(2.0g,3.75mmol)溶解于20mL无水DMF中，然后室温下向溶液中依次加入反式-N,N’-二甲基-1,2-环己二胺(107mg,0.75mmol)、CuI(36mg,0.19mmol)、K3PO4(1.6g,7.5mmol)和A12(1.05g,4.5mmol)。氮气置换3次，升温至110摄氏度，搅拌16个小时。反应完毕后，旋蒸掉溶剂得粗产品，柱层析(二氯甲烷:甲醇＝40:1)得62白色固体0.98g，产率为41％。
Figure PCTCN2015087556-appb-000081
把化合物62(0.86g,1.35mmol)溶解于10mL二氯甲烷中，然后室温下向溶液中加入三氟乙酸(5ml)。室温下搅拌4个小时。反应完毕后，旋蒸掉溶剂得粗产品，柱层析(二氯甲烷:甲醇＝20:1)得白色固体63(0.61g，产率为82％)。
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
1H NMR(d6-DMSO,400MHz)δppm 13.37(s,1H),10.81(s,1H),8.39(d,1H,J＝8.4Hz),8.01(d,2H,J＝8.8Hz),7.08-7.02(m,4H),3.98(s,6H),3.32(m,4H),2.45(m,4H),2.23(s,3H).
使用类似方法可得到如下化合物：
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑[3,4-b]吡啶-3-基)-4-((3S,5R)-3,5-二甲基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000082
1H NMR(CDCl3,400MHz)δppm 10.76(br s,1H),8.97(s,1H),8.87(d,1H,J＝8.4Hz),7.90(d,2H,J＝8.8Hz),7.16(d,1H,J＝8.4Hz),6.95(d,2H,J＝8.8Hz),6.66(s,1H),3.97(s,6H),3.70(d,2H,J＝12.0Hz),3.02(m,2H),2.46(t,2H,J＝11.2Hz),1.16(d,6H,J＝6.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吲唑[3,4-b]吡啶-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000083
1H NMR(CDCl3,400MHz)δppm 10.13(s,1H),8.86(d,1H,J＝8.4Hz),8.66(s,1H),7.90(d,2H,J＝8.8Hz),7.16(d,1H,J＝8.4Hz),6.95(d,2H,J＝8.8Hz),6.67(s,1H),3.97(s,6H),3.41-3.79(m,4H),2.64-2.60(m,4H),2.49(q,2H,J＝7.2Hz),1.15(t,3H,J＝7.2Hz).
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-((3R,5S)-3,5-二甲哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000084
1H NMR(d6-DMSO,400MHz)δppm 13.36(s,1H),10.77(s,1H),8.34(d,1H,J＝8.4Hz),7.98(d,2H,J＝8Hz),7.30(d,1H,J＝8Hz),7.00(d,2H,J＝8.8Hz)，6.82(d,1H,J＝2.8Hz),6.73(d,1H,J＝2.8Hz),3.91(s,3H)，3.84(s,3H),3.75(d，2H,J＝10.4Hz),2.81(s,2H),2.26(s,1H),2.22(d,2H,J＝11.2Hz),1.04(s，3H),1.03(s，3H)。LCMS:521(M+H)+，RT＝1.233min
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-(4-(二甲基氨基)哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000085
1H NMR(d6-DMSO,400MHz)δppm 10.81(s,1H),8.381(d,1H,J＝8.4Hz),8.00(d,2H,J＝8.8Hz),7.01-7.07(m，4H),3.99(s，6H),3.49-3.51(m，3H),3.26(s，4H),3.17(s，3H),2.55-258(m，5H)。LCMS:585(M+H)+，RT＝1.225min.
N-(6-(3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-(((3R,5S)-3,5-二甲哌嗪-1-基))苯甲酰胺
Figure PCTCN2015087556-appb-000086
1H NMR(d6-DMSO,400MHz)δppm 13.34(s,1H),10.77(s,1H)8.36(d,1H,J＝8.8Hz),7.98(d,2H,J＝8.8Hz),7.74(s，1H),7.31(d，2H,J＝1.6Hz),7.00(d，2H,J＝8.8Hz),6.62(s，1H),3.84(s，6H),3.75(d，2H,J＝11.2Hz),2.81(s,2H),2.26(s.1H),2.22(d,2H,J＝10.8Hz),1.04(d,6H,J＝6Hz).LCMS:487(M+H)+，RT＝1.113min.
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑[3,4-b]吡啶-3-基)吡啶甲酰胺
Figure PCTCN2015087556-appb-000087
1H NMR(d6-DMSO,400MHz)δppm 8.74(s,2H),8.41(d,1H,J＝8.0Hz),8.02(d,2H,J＝5.6Hz),7.04(s,2H),3.98(s,6H).LCMS:445(M+H)+，RT＝1.409min.
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-吗啉苯甲酰胺
Figure PCTCN2015087556-appb-000088
1H NMR(d6-DMSO,400MHz)δppm 13.42(s,1H),10.86(s,1H),8.41(d,1H,J＝7.2Hz),8.05(s，3H),7.07(s,4H),4.00(s,6H),3.77(s,4H),3.30(s,4H).LCMS:528(M+H)+,RT＝1.643min.
Figure PCTCN2015087556-appb-000089
1H NMR(d6-DMSO,400MHz)δppm 13.47(brs,1H),11.03(s,1H),9.28(s,1H),8.89(s,1H),8.71(s,1H),8.41(d,J＝8.0Hz,1H),8.28-8.30(m,1H),7.05-7.12(m,3H),4.66(d,J＝9.2Hz,2H),3.98(s,6H),3.46(brs,2H),2.83-2.92(m,2H),1.30(d,J＝6.4Hz,6H).
Figure PCTCN2015087556-appb-000090
1H NMR(d-MeOD,400MHz)δppm 8.52(d,J＝8.0Hz,1H),8.03(d,J＝8.0Hz,2H),7.15-7.13(m,3H),6.94(s,1H),3.99(s,6H),3.58-3.57(m,2H),3.44-3.40(m,4H),1.50(s,6H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(2,6-二氮杂螺[3.3]庚烷-2-基)苯甲酰胺
Figure PCTCN2015087556-appb-000091
1H NMR(d-MeOD,400MHz)δppm 8.49(d，1H，J＝8.4Hz)，7.94(d，2H，J＝8.8Hz)，7.12(d，1H，J＝8.4Hz)，6.94(S，1H)，6.55(d，2H，J＝8.4Hz)，4.08(S，4H)，3.98(S， 6H)，3.83(S，4H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(4-甲基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000092
1H NMR(DMSO-d6,400MHz)δppm 8.84(s,1H),8.37(d,1H,J＝8.4Hz),8.20(d,1H,J＝7.6Hz),7.03(s,2H),6.92(d,1H,J＝8.8Hz),3.98(s,6H),3.63(s,4H),2.41(t,4H,J＝4.0Hz),2.22(s,3H).LCMS:542.2[M+H]+，RT＝1.18min。
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(4-乙基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000093
1H NMR(DMSO-d6,400MHz)δppm 13.40(s,1H),10.91(s,1H),8.84(d,1H,J＝2.4Hz),8.41(d,1H,J＝8.4Hz),8.19(dd,1H,J1＝J2＝2.4Hz),7.09(t,2H,J＝12.4Hz),6.93(d,1H,J＝9.2Hz),3.98(s,6H),3.65(t,4H,J＝3.6Hz),2.45(t,4H,J＝4.8Hz),2.39(q,2H,J＝7.2Hz),1.05(t,3H,J＝6.8Hz).LCMS:556.2[M+H]+，RT＝1.19min。
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(3,3-二甲基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000094
1H NMR(DMSO-d6,400MHz)δppm 13.39(s,1H),10.86(s,1H),8.81(d,1H,J＝2.0Hz),8.40(d,1H,J＝8.0Hz),8.16(dd,1H,J1＝2.4Hz,J2＝2.4Hz),7.08(t,2H,J＝8.4Hz),6.90(d,1H,J＝9.2Hz),3.99(s,6H),3.60(t,2H,J＝4.0Hz),3.43(s,2H),2.82(t,2H,J＝4.4Hz),1.04(s,6H).LCMS:556.2[M+H]+，RT＝1.21min。
6-(4-环丙基哌嗪-1-基)-N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)烟酰胺
Figure PCTCN2015087556-appb-000095
1H NMR(DMSO-d6,400MHz)δppm 13.40(s,1H),10.92(s,1H),8.85(d,1H,J＝1.6Hz),8.41(d,1H,J＝8.4Hz),8.20(dd,1H,J1＝2.0Hz,J2＝1.6Hz),7.08(t,2H,J＝8.0Hz), 6.94(d,1H,J＝9.2Hz),3.98(s,6H),3.62(s,4H),2.62(s,4H),1.66(d,1H,J＝3.6Hz),0.46(d,2H,J＝4.4Hz),0.38(d,2H,J＝2.4Hz).LCMS:568.2[M+H]+，RT＝1.21min。
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-(4-环丙基哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000096
1H NMR(d6-DMSO,400MHz)δppm 8.34(d,1H,J＝8Hz),8.00(d,2H,J＝8.8Hz),7.02(t,4H,J＝7.8Hz),3.98(s,6H)，3.26(s,4H)，2.67(s,4H)，1.66(s,1H),0.45(d,2H,J＝4.8Hz),0.363(s,2H)。LCMS:567(M+H)+，RT＝1.22min.
合成路线5
Figure PCTCN2015087556-appb-000097
氮气保护下在干燥的250mL三口瓶中加入74(10.00g，43.9mmol)和四氢呋喃(100.0mL)，-78℃缓慢滴加异丙基氯化镁氯化锂络合物溶液(2M)(24.2mL，48.3mmol)，-78℃—-35℃下搅拌半小时，然后在-78℃下缓慢滴加DMF(9.6g，131.6mmol)，在-35℃下搅拌4个小时。反应用饱和氯化铵溶液在-78℃下淬灭，反应液用100.0mL水稀释，200mL乙酸乙酯萃取2次，合并有机相，无水硫酸钠干燥，旋干溶剂得化合物75(2.1g，31％)为白色固体。
1H NMR(DMSO-d6,400MHz)δppm 10.19(s,1H),9.12(s,1H).
Figure PCTCN2015087556-appb-000098
化合物75(2.0g，11.3mmol)溶入THF(10mL)中，在0℃加入水合肼(1.33g，22.6mmol)的THF(20mL)溶液，反应液在室温下搅拌半小时过硅胶柱纯化得到化合物76为黄色固体(1.0g，57％)。LCMS:155(M+H)+,RT＝0.929min.
Figure PCTCN2015087556-appb-000099
把化合物76(1.0g，6.5mmol)，DHP(1.1g，13mmol)和PTSA(224mg，1.3mmol)溶入30ml二氯甲烷中室温过夜，混合物拌硅胶过柱纯化得到黄色固体化合物77(1.0g，65％)。LCMS:239(M+H)+,RT＝1.32min。
Figure PCTCN2015087556-appb-000100
化合物77(900mg，3.8mmol)，3,5-二甲氧基苯硼酸(826mg，4.5mmol)， Pd(dppf)Cl2(415mg，0.57mmol)和磷酸钾(960mg，4.5mmol)溶入1,4-二氧六环(12mL)中110℃微波反应90分钟，过硅胶柱纯化得到黄色固体化合物78(950mg，74％)。LCMS:341(M+H)+,RT＝1.803min。
Figure PCTCN2015087556-appb-000101
化合物78(500mg，1.5mmol)溶入10mL二氯甲烷中，0℃下加入磺酰氯(446mg，3.3mmol)，室温搅拌4小时，LCMS检测无原料剩余，反应液加少量水淬灭过硅胶柱纯化得到白色固体化合物79(460mg，84％)。LC MS:325(M+H)+,RT＝1.24min.
Figure PCTCN2015087556-appb-000102
化合物79(400mg，1.23mmol)和NIS(554mg，2.46mmol)溶入5mL DMF中80℃过夜。反应液油泵旋干过硅胶柱纯化得化合物80(370mg，67％)。LCMS:450(M+H)+，RT＝1.577min.
Figure PCTCN2015087556-appb-000103
将化合物80(370mg,0.82mmol)，DHP(138mg，1.64mmol)和PTSA(28mg，0.16mmol)溶入10mL二氯甲烷中室温搅拌4小时，混合物过柱纯化得黄色固体化合物81(450mg，100％)。LCMS:534(M+H)+，RT＝1.964min。
Figure PCTCN2015087556-appb-000104
把化合物81(100mg,0.19mmol)，4-(4-甲基哌嗪-1-基)苯甲酰胺(82mg，0.37mmol)，CuI(7mg，0.037mmol)，K3PO4(119mg，0.56mmol)和N,N’-二甲基-1,2-环己二胺(5mg，0.037mmol)溶解于3mL DMF中，110℃搅拌过夜，旋干过柱纯化，得到褐色油状化合物82为55mg，产率为47％。LCMS:626(M+H)+，RT＝1.37min。
Figure PCTCN2015087556-appb-000105
把化合物82(55mg,0.088mmol)和2mL三氟乙酸溶于2mL二氯甲烷中，室温过夜，反应完毕后，旋蒸掉溶剂得粗产品，pre-TLC纯化后pre-HPLC纯化得4mg黄色固体产物83，产率为8％。LCMS:542(M+H)+，RT＝1.27min。
1H NMR(d-MeOD,400MHz)δppm 9.76(s，1H)，8.06(d，2H，J＝8.8Hz),7.16(d，2H，J＝8.8Hz)，6.96(s，1H)，4.13(d，2H，J＝10Hz)，3.99(s，6H)，3.63(d，2H，J＝2.8Hz)，3.21-3.17(m，4H)，2.99(s，3H)。
使用类似方法可得到如下化合物：
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吡唑[3,4-d]并嘧啶-3-基)-4-((3R,5S)-3,5-二甲哌嗪-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000106
1H NMR(d-MeOD,400MHz)δppm 9.76(s,1H),8.05(d，2H，J＝8.8Hz)，7.17(d，2H，J＝8.8Hz)，6.96(s，1H)，3.99(s，6H)，3.53-3.49(m,2H),3.42-3.38(m，2 H),2.86-2.80(m，2H),1.48(d，6H，J＝5.2Hz)。LCMS:556(M+H)+，RT＝1.33min。
使用合成化合物63的方法可得到以下化合物：
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(4-甲基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000107
1H NMR(DMSO-d6,400MHz)δppm 8.84(s,1H),8.37(d,1H,J＝8.4Hz),8.20(d,1H,J＝7.6Hz),7.03(s,2H),6.92(d,1H,J＝8.8Hz),3.98(s,6H),3.63(s,4H),2.41(t,4H,J＝4.0Hz),2.22(s,3H).LCMS:542.2[M+H]+，RT＝1.18min。
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(4-乙基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000108
1H NMR(DMSO-d6,400MHz)δppm 13.40(s,1H),10.91(s,1H),8.84(d,1H,J＝2.4Hz),8.41(d,1H,J＝8.4Hz),8.19(dd,1H,J1＝J2＝2.4Hz),7.09(t,2H,J＝12.4Hz),6.93(d,1H,J＝9.2Hz),3.98(s,6H),3.65(t,4H,J＝3.6Hz),2.45(t,4H,J＝4.8Hz),2.39(q,2H,J＝7.2Hz),1.05(t,3H,J＝6.8Hz).LCMS:556.2[M+H]+，RT＝1.19min。
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-6-(3,3-二甲基哌嗪-1-基)烟酰胺
Figure PCTCN2015087556-appb-000109
1H NMR(DMSO-d6,400MHz)δppm 13.39(s,1H),10.86(s,1H),8.81(d,1H,J＝2.0Hz),8.40(d,1H,J＝8.0Hz),8.16(dd,1H,J1＝2.4Hz,J2＝2.4Hz),7.08(t,2H,J＝8.4Hz),6.90(d,1H,J＝9.2Hz),3.99(s,6H),3.60(t,2H,J＝4.0Hz),3.43(s,2H),2.82(t,2H,J＝4.4Hz),1.04(s,6H).LCMS:556.2[M+H]+，RT＝1.21min。
6-(4-环丙基哌嗪-1-基)-N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)烟酰胺
Figure PCTCN2015087556-appb-000110
1H NMR(DMSO-d6,400MHz)δppm 13.40(s,1H),10.92(s,1H),8.85(d,1H,J＝1.6Hz),8.41(d,1H,J＝8.4Hz),8.20(dd,1H,J1＝2.0Hz,J2＝1.6Hz),7.08(t,2H,J＝8.0Hz),6.94(d,1H,J＝9.2Hz),3.98(s,6H),3.62(s,4H),2.62(s,4H),1.66(d,1H,J＝3.6Hz),0.46(d,2H,J＝4.4Hz),0.38(d,2H,J＝2.4Hz).LCMS:568.2[M+H]+，RT＝1.21min。
N-(6-(2,6-二氯-3,5-二甲氧苯基)-1H-吡唑[3,4-b]并吡啶-3-基)-4-(4-环丙基哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000111
1H NMR(d6-DMSO,400MHz)δppm 8.34(d,1H,J＝8Hz),8.00(d,2H,J＝8.8Hz),7.02(t,4H,J＝7.8Hz),3.98(s,6H)，3.26(s,4H)，2.67(s,4H)，1.66(s,1H),0.45(d,2H,J＝4.8Hz),0.363(s,2H)。LCMS:567(M+H)+，RT＝1.22min.
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4--((3S，5R)-3,4,5-三甲基哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000112
1H NMR(400MHz,DMSO-d6):13.41(s,1H),10.90(s,1H),9.38(s,1H),8.39(d,1H,J＝8.0Hz),8.06(d,2H,J＝8.8Hz),7.16(d,2H,J＝9.2Hz),7.09(d,1H,J＝12.4Hz),7.05(s,1H),4.19(d,2H,J＝13.6Hz),3.99(s,6H),3.35-3.44(m,2H),2.90-2.95(m,2H),2.88(d, 3H,J＝4.4Hz),1.39(d,6H,J＝6.4Hz).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(3,3-二甲基哌嗪-1-基)-3-氟苯甲酰胺
Figure PCTCN2015087556-appb-000113
1H NMR(400MHz,DMSO-d6):13.48(s,1H),11.10(s,1H),8.86(brs,1H),8.39(d,1H,J＝8.0Hz),7.96～7.92(m,2H),7.25(t,1H,J＝8.8Hz),7.10(d,1H,J＝2.8Hz),7.05(s,1H),3.99(s,6H),3.35(s,4H),3.18(s,2H),1.41(s,6H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-甲酰胺
Figure PCTCN2015087556-appb-000114
1H NMR(400MHz,DMSO-d6):13.46(s,1H),11.08(s,1H),9.00(s,2H),8.42(d,1H,J＝8.4Hz),8.33(s,1H),7.09(d,1H,J＝8.4Hz),7.05(s,1H),3.99(s,6H),3.85-3.88(m,4H),2.38-2.40(m,4H),2.23(s,3H).
使用类似合成44的方法可得到如下化合物：
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000115
1H NMR(400MHz,DMSO-d6):12.85(s,1H),10.38(s,1H),7.87(d,2H,J＝8.8Hz),7.77(d,1H,J＝8.4Hz),7.50(s,1H),7.08(t,2H,J＝8.4Hz),6.62(d,2H,J＝8.8Hz),6.34(d,1H,J＝6.4Hz),3.92(s,6H),3.77-3.82(m,1H),1.91-2.00(m,2H),1.65-1.73(m,2H),1.55-1.62(m,2H),1.45-1.51(m,2H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
Figure PCTCN2015087556-appb-000116
1H NMR(400MHz,DMSO-d6):13.01(s,1H),10.91(s,1H),8.10(s,2H),7.79(s,1H), 7.54(s,3H),7.08(s,2H),3.91(s,6H),3.83(s,2H),3.36-3.48(m,2H),2.95-3.14(m,4H),2.79(s,3H),2.50-2.58(m,2H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000117
1H NMR(400MHz,DMSO-d6):13.91(s,1H),10.56(s,1H),9.81(s,1H),8.02(d,2H,J＝8.4Hz),7.78(d,1H,J＝8.4Hz),7.52(s,1H),7.06-7.09(m,2H),6.89(d,2H,J＝8.8Hz),3.92(s,6H),3.85-3.96(m,2H),3.67-3.74(m,1H),3.45-3.58(m,3H),3.12-3.26(m,1H),2.86(d,3H,J＝3.6Hz),2.15-2.25(m,2H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-甲酰胺
Figure PCTCN2015087556-appb-000118
1H NMR(400MHz,DMSO-d6):12.99(s,1H),10.95(s,1H),9.08(s,2H),7.84(d,1H,J＝8.4Hz),7.54(s,1H),7.06-7.11(m,2H),4.75-4.95(m,2H),3.92(s,6H),3.35-3.55(m,2H),3.05-3.35(m,4H),2.84(s,3H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(3,3-二甲基哌嗪-1-基)-3-甲氧基苯甲酰胺
Figure PCTCN2015087556-appb-000119
1H NMR(400MHz,MeOD):7.86(d,1H,J＝8.4Hz),7.69-7.72(m,2H),7.54(s,1H),7.18(d,1H,J＝8.4Hz),7.09(d,1H,J＝8.0Hz),6.94(t,1H,J＝8.0Hz),3.98(s,3H),3.93(s,6H),3.42-3.45(m,2H),3.35-3.39(m,2H),3.19(s,2H),1.54(s,6H).
N-(6-(2,6-二氟-3,5-二甲氧基苯基)-1H-吲唑-3-基)-4-(3-(二甲氨基)吡咯烷-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000120
1H NMR(400MHz,DMSO-d6):12.88(s,1H),10.51(s,1H),8.00-8.01(m,2H),7.78-7.80(m,1H),7.51(s,1H),7.08(s,2H),6.65-6.67(m,2H),3.92(s,6H),3.62-3.71(m, 1H),3.51-3.60(m,1H),2.50(s,6H),2.26-2.35(m,2H),1.97-2.15(m,1H).
使用合成化合物63的方法可得到以下化合物：
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(3,3,5,5-四甲基哌啶-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000121
1H NMR(400MHz,MeOD):8.51(d,1H,J＝8.4Hz),8.03(d,1H,J＝7.6Hz),7.12-7.22(m,3H),6.95(s,1H),3.99(s,6H),3.47(s,4H),1.52(s,12H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)基)-4-(3-(二甲氨基)吡咯烷-1-基)苯甲酰胺
Figure PCTCN2015087556-appb-000122
1H NMR(400MHz,MeOD):8.27(d,1H,J＝8.4Hz),8.01(d,2H,J＝8.4Hz),7.12(d,1H,J＝8.4Hz),6.94(s,1H),6.79(d,2H,J＝8.4Hz),4.06-4.13(m,1H),3.99(s,6H),3.85-3.93(m,1H),3.70-3.75(m,1H),3.61-3.65(m,1H),3.46-3.52(m,1H),3.01(s,6H),2.60-2.67(m,1H),2.26-2.36(m,1H).
N-(6-(2,6-二氯-3,5-二甲氧基苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(3,3-二甲基哌嗪-1-基)-3-甲氧基苯甲酰胺
Figure PCTCN2015087556-appb-000123
1H NMR(400MHz,DMSO-d6):13.46(s,1H),11.07(s,1H),8.41(d,1H,J＝8.4Hz),7.23-7.50(m,2H),7.06-7.11(m,3H),3.99(s,6H),3.92(s,3H),3.29(s,2H),3.25(s,2H),3.07(s,2H),2.58(s,1H),1.41(s,6H).
实施例2 化合物在分子水平对FGFR1、FGFR2、FGFR3、KDR激酶酶活的影响
1.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，150mMNaCl,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 MnCl2,0.2 mM 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反应缓冲液稀释的各激酶激酶域重组蛋白启动反应，每次实验需设无ATP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0.1 M柠檬酸-柠檬酸钠缓冲液(pH＝5.4)稀释)，25℃避光反应1-10分钟。(OPD溶解时需用超声，显色液需现配现用)。加入2 M H2SO450μL/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 PCTCN2015087556-appb-000124
IC50值采用酶标仪随机附带软件以四参数法回归求得。
2.结果
下表中提供部分IC50资料。符号+代表IC50小于100nm，符号++代表IC50为100nm至500nm，N/A代表暂无数据。
Figure PCTCN2015087556-appb-000125
Figure PCTCN2015087556-appb-000126
结果显示，本发明化合物在极低浓度(≤100nm)下，即可有效抑制各类FGFR激酶的活性。
实施例3 化合物对FGFR1介导的肿瘤细胞增殖能力的影响试验
1、试验方法
化合物对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，购自ATCC细胞库)的生长抑制检测CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的KG1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，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，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。采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC50值采用酶标仪随机附带软件以四参数法回归求得。
2.结果
下表中提供部分化合物的IC50值。符号+代表IC50小于200nm，且符号++代表IC50为200nm至1000nm。
Figure PCTCN2015087556-appb-000127
结果显示，本发明化合物在极低浓度(≤1000nm，较佳地≤200nm)下，即可有效抑制肿瘤细胞增殖。
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 PCTCN2015087556-appb-100001
    其中，
    L选自下组：H、四氢吡喃基(THP)；
    各个X各自独立地选自下组：Cl、F、H、CN；
    W、Y、Z各自独立地选自：N或CH；
    环A为无、取代或未取代的5～8元亚芳基，或取代或未取代的5元～8元亚杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫；取代或未取代的3元～12元饱和杂环或碳环，其中，所述的杂环包含至少一个选自下组的杂原子：氮、氧，或硫；或为
    Figure PCTCN2015087556-appb-100002
    R为H，或取代或未取代的选自下组的基团：
    Figure PCTCN2015087556-appb-100003
    其中，M选自下组：取代或未取代的C1-C6的亚烷基、取代或未取代的C6-C10的亚芳基、取代或未取代的C1-C10的亚杂芳基、或M为无；
    所述的任一取代是指上述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C1-C6烷氧基、未取代或卤代的C2-C6烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C6亚烷基-羟基、未取代或C1-C6烷基取代的胺基。
  2. 如权利要求1所述的化合物，其特征在于，
    L选自下组：H、四氢吡喃基(THP)；
    各个X各自独立地选自下组：H、Cl、F、CN；
    W、Y、Z各自独立地选自：N或CH；
    环A为取代或未取代的6元芳基，或取代或未取代的5元～6元杂芳基，其中，所述的杂芳基包含至少一个选自下组的杂原子：氮、氧，或硫，或取代或未取代的5元～6元饱和杂环或碳环，其中所述的杂环包含至少一个选自下组的杂原子：氮、氧，或硫；
    M选自下组：取代或未取代的C1-C4的亚烷基、或M不存在；
    所述的取代是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-C4烷基、未取代或卤代的C1-C4烷氧基、未取代或卤代的C1-C4烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C4烷基-羟基、未取代或C1-C6烷基取代的胺基。
  3. 如权利要求1所述的化合物，其特征在于，
    L为H；
    各个X各自独立地选自下组：H、Cl、F；
    W、Y、Z各自独立地选自：N或CH；
    环A为选自下组的基团：无、苯基、吡唑基、吡啶基、噻唑基、嘧啶、吡嗪或哌啶基；
    M选自下组：取代或未取代的C1-C3的亚烷基、或M不存在；
    所述的任一取代是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-C4烷基、未取代或卤代的C1-C4烷氧基、未取代或卤代的C2-C4烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C4烷基-羟基、未取代或C1-C6烷基取代的胺基。
  4. 如权利要求1所述的式I化合物，其特征在于，所述的式I化合物为选自下组的化合物：14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、44、45、46、47、48、54、55、62、63、64、65、66、67、68、69、70、71、72、73、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101，或表A所示的化合物。
  5. 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 PCTCN2015087556-appb-100004
    在惰性溶剂中，用式I-8化合物和式I-9化合物反应，得到式I化合物；
    上述各式中，各基团的定义如权利要求1中所述。
  6. 如权利要求5所述的方法，其特征在于，所述方法还包括步骤：
    Figure PCTCN2015087556-appb-100005
    在惰性溶剂中，用式I化合物进行脱保护，得到式I’化合物；
    其中，L选自下组：四氢吡喃基(THP)；
    其余各基团的定义如权利要求1中所述。
  7. 如权利要求1所述的化合物的用途，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FGFR激酶选自下组：FGFR1、FGFR2、FGFR3，或其组合；和/或
    所述的肿瘤细胞为白血病细胞株；较佳地为髓源白血病细胞株；更佳地为急性髓源白血病细胞株KG1细胞。
  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。
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