WO2017140269A1 - 一类取代的氨基六元氮杂环类化合物及其制备和用途 - Google Patents

一类取代的氨基六元氮杂环类化合物及其制备和用途 Download PDF

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WO2017140269A1
WO2017140269A1 PCT/CN2017/073966 CN2017073966W WO2017140269A1 WO 2017140269 A1 WO2017140269 A1 WO 2017140269A1 CN 2017073966 W CN2017073966 W CN 2017073966W WO 2017140269 A1 WO2017140269 A1 WO 2017140269A1
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compound
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substituted
ring
unsubstituted
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PCT/CN2017/073966
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English (en)
French (fr)
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张翱
耿美玉
邢莉
艾菁
宋子兰
彭霞
顾王婷
丁健
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中国科学院上海药物研究所
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Priority to ES17752701T priority Critical patent/ES2850023T3/es
Priority to KR1020187026987A priority patent/KR20180110151A/ko
Priority to US15/998,927 priority patent/US11834432B2/en
Priority to BR112018016264-7A priority patent/BR112018016264A2/zh
Priority to JP2018544113A priority patent/JP6666458B2/ja
Priority to EA201800445A priority patent/EA037876B1/ru
Priority to EP17752701.7A priority patent/EP3418277B1/en
Priority to SG11201806974PA priority patent/SG11201806974PA/en
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Priority to CA3014853A priority patent/CA3014853C/en
Priority to NZ745474A priority patent/NZ745474A/en
Priority to CN201780012327.2A priority patent/CN108699030B/zh
Priority to AU2017220984A priority patent/AU2017220984B2/en
Publication of WO2017140269A1 publication Critical patent/WO2017140269A1/zh
Priority to IL261215A priority patent/IL261215B2/en

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    • 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
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • 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
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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a substituted aminopyridine compound having tyrosine kinase selective inhibitory activity, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvent compound, a process for the preparation thereof, and a preparation thereof for prevention or treatment and biological treatment
  • Fibroblast growth factor receptors are receptor tyrosine kinases, family members of which have FGFR1, FGFR2, FGFR3, and FGFR4. Their basic structures include the extracellular domain, the transmembrane region, and the tyrosine kinase domain.
  • the outer region consists of three immunoglobulin-like domains, including an acidic structural framework, a membrane domain, and a mitotic phase intracellular tyrosine kinase domain.
  • tyrosine kinases when the ligand binds to FGFR, the receptor dimerizes, and the formation of a ternary (FGF-FGFR-HPSG) complex dimerizes the structure of the FGFR, causing intracellular tyramine.
  • Intramolecular phosphorylation of the acid region and the terminal carboxylic acid moiety followed by attachment of the FGFR receptor substrate (FRS2 ⁇ ) and phospholipase C (PLC ⁇ ) to activate a series of downstream signaling pathways, such as Ras/mitogen-activated protein kinase (MAPK) Pathway and phosphoinositide kinase 3 (PI3K)/Akt pathway, which in turn stimulates some physiological processes in the cell, such as cell proliferation, survival, migration and angiogenesis.
  • FSS2 ⁇ FGFR receptor substrate
  • PLC ⁇ phospholipase C
  • FGFR activation is closely related to the occurrence and development of various tumors and drug resistance.
  • FGFRs participate in tumorigenesis mainly through three mechanisms: chromosomal translocation, gene mutation, gene amplification or overexpression.
  • the chromosomal translocation of the FGFR1 gene or its fusion gene is mainly present in multiple myeloma; both FGFR2 and FGFR3 mutations are expressed in lung squamous cell carcinoma, and the FGFR4Y367C mutation in the transmembrane region enables continuous activation of breast cancer cells;
  • FGFR amplification occurs in a variety of different cancers,
  • FGFR1 amplification occurs in patients with rectal cancer, lung cancer and kidney cancer, in addition, in about 10% of breast cancer, especially estrogen receptor-positive patients,
  • FGFR1 8p11-12 Amplification occurs at the point, and patients with gastric cancer and rectal cancer also show amplification of FGFR2, and FGFR3 amplification is most common in patients
  • TKI small molecule tyrosine kinase inhibitors
  • Some FGFR inhibitors have entered the clinical research stage and can be classified into selective FGFR inhibitors and non-selective FGFR inhibitors depending on their range of action.
  • Such inhibitors mainly inhibit FGFR activation by targeting the ATP binding site of the FGFR intracellular kinase domain, and can be applied to tumor types in which FGFRs are overexpressed, FGFRs are mutated or FGFR-fusion proteins are expressed.
  • AZD4547, BGJ398, LY2874455 and AL-3810 are all selective FGFR inhibitors that have entered the clinic and have strong anti-tumor activity. According to reports in the literature, AZD-4547, BGJ-398, AL-3810 are potent inhibitors of FGFR1-3, while LY2874455 is a pan-FGFR inhibitor (acting on FGFR1-4).
  • FGFR inhibitors Due to the highly similar structure of PDGFRs, VEGFRs and FGFRs kinase domains, most FGFR TKIs have the activity of inhibiting PDGFR and VEGFR. Therefore, FGFR inhibitors have large toxic side effects, and the development of FGFR inhibitors still faces great challenges. In terms of structure, the structure of FGFR inhibitors is very limited.
  • X is selected from the group consisting of CH or N;
  • Ring A may be selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, wherein said substituent means that one or more hydrogen atoms on the group are selected from Substituents substituted for the following group: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogen, halogenated C1-C8 alkyl;
  • R 1 is selected from -CONHR 3 , -COOR 3 ;
  • R 2 is selected from the group consisting of a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted 4-10 membered heterocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C8 alkylamino group, -NHCOR 3 ; wherein the substituent group is further substituted by one or more substituents selected from the group consisting of C1-C8 alkyl, hydroxy, hydroxy C1- C8 alkyl, -COOR 3 , amino substituted C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl unsubstituted or substituted by one or more halogen atoms, hydroxy or C1-C8 alkyl;
  • R 3 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C2-C10 alkenyl.
  • ring A is selected from substituted or unsubstituted 6-10 membered aryl groups, Substituted or unsubstituted 5-10 membered heteroaryl.
  • Ring A is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl.
  • ring A is selected from the group consisting of substituted or unsubstituted benzene rings, naphthalene rings, pyridine rings, pyrazine rings, thiophene rings, furan rings, imidazole rings. , pyrrole ring, oxazole ring, thiazole ring, pyrazole ring, anthracene ring, pyrimidine ring, benzofuran ring, benzothiazole ring, benzimidazole ring, quinoline ring, isoquinoline ring;
  • Ring A is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted thiazole ring, a substituted or unsubstituted oxazole ring, a substituted or unsubstituted Substituted pyrimidine ring.
  • R 2 is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted a 5-6 membered heterocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C4 alkylamino group, -NHCOR 3 ; wherein said substituent refers to a group further selected from one or more selected from the group consisting of Substituent substitution: C1-C8 alkyl, hydroxy, hydroxy C1-C8 alkyl, -COOR 3 , amino-substituted C3-C10 cycloalkyl, unsubstituted or substituted by one or more halogen atoms, hydroxy or C1-C8 alkane A substituted 4-10 membered heterocycloalkyl group.
  • R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl.
  • R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl.
  • R 3 is selected from the group consisting of hydrogen, methyl, and vinyl.
  • the compound is selected from the group consisting of compounds S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17. , S18, S19, S20, S21, S22, S23 or S24.
  • Q is a leaving group, preferably a halogen; and the ring A, X, R1, R2 are as defined in the first aspect of the invention.
  • the reaction is in Pd 2 (dba) 3 [tris(dibenzylideneacetone) dipalladium], Xantphos [4,5-bisdiphenylphosphino-9,9-dimethyl Oxanthene], in the presence of cesium carbonate.
  • the reaction comprises: Compound A, Compound B (1.0-1.5 eq), Pd 2 (dba) 3 [tris(dibenzylideneacetone) dipalladium] (0.05-0.2 eq) Xantphos [4,5-bisdiphenylphosphino-9,9-dimethyloxaindole] (0.1-0.5 eq) and cesium carbonate (1-3 eq) were dissolved in an inert solvent and reacted under nitrogen.
  • the inert solvent is 1,4-dioxane.
  • reaction is carried out at 100 °C.
  • reaction time is from 1 to 10 h.
  • reaction after the reaction is completed, it is extracted with dichloromethane and water, and the organic phase is washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was sampled to obtain a compound.
  • a pharmaceutical composition comprising: a therapeutically effective amount of a compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof And optionally a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is a pharmaceutical composition for treating a tumor, or a pharmaceutical composition for treating a disease associated with a tyrosine kinase (preferably FGFR, more preferably FGFR1) activity.
  • a tyrosine kinase preferably FGFR, more preferably FGFR1
  • the pharmaceutical composition is for use in the treatment of a disease associated with abnormal expression of the FGF/FGFR signaling pathway.
  • a compound according to the first aspect of the invention or an optical isomer, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof, for the preparation of a prophylaxis And/or drugs for the treatment of diseases associated with FGFR.
  • the tumor-related disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, myeloma, liver cancer, melanoma, head and neck cancer, and thyroid cancer.
  • renal cell carcinoma, glioblastoma, and testicular cancer preferably breast cancer, non-small cell lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer , thyroid cancer, renal cell carcinoma, glioblastoma, and testicular cancer; more preferably non-small cell lung cancer, gastric cancer, multiple myeloma.
  • a protein tyrosine kinase activity inhibitor comprising an inhibitory effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, is provided A drug, a hydrate or a solvate thereof.
  • a pharmaceutical composition for treating a disease associated with cancer or protein tyrosine kinase activity comprising a therapeutically effective amount of a compound according to the first aspect of the invention, Or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.
  • a method for treating or preventing a disease associated with cancer or protein tyrosine kinase activity comprising: administering a therapeutic or prophylactically effective amount to a subject to be treated or prevented as in the first aspect of the present invention
  • a compound according to the invention, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, or a pharmaceutical composition according to the invention comprising: administering a therapeutic or prophylactically effective amount to a subject to be treated or prevented as in the first aspect of the present invention
  • Figure 1 is a graph showing the results of S10 inhibition of FGFR2 and downstream signaling molecules in SNU16 gastric cancer cell lines.
  • heterocyclyl as used herein is a cyclic group having 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of the following: Group: O, N or S.
  • the alkyl group is preferably an aliphatic alkyl group, and may be a linear alkyl group, a branched alkyl group, a spirocycloalkyl group, a bridged alkyl group, an olefin alkyl group, an alkyne group, a cycloalkyl group, Cycloalkenyl, cycloalkynyl, alkoxyalkyl, alkoxyalkyl, cycloalkylalkyl, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, allyl, propargyl, cyclobutenyl, cyclohexenyl; in the form of "C1-C8
  • the alkenyl group is preferably a vinyl group, a propenyl group, a butenyl group, a styryl group, a phenylpropenyl group, or the like.
  • the cycloalkyl group may be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent including 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl group. Contains 3 to 10 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl.
  • the heterocyclic group refers to a saturated or partially saturated monocyclic or polycyclic cyclic substituent including a 4- to 10-membered heterocyclic group, and the heterocyclic group has one or more hetero atoms therein (nitrogen, A saturated or unsaturated monocyclic ring, a fused ring, a fused ring, a bridged ring, or the like, of oxygen or sulfur.
  • the heterocyclic group described herein includes, but is not limited to, a group selected from the group consisting of a morpholine ring, a piperidine ring, a piperazine ring, an N-alkyl or acyl substituted piperazine ring, and a high piperazine ring. , N-alkyl or acyl substituted homopiperazine ring, pyrrole, tetrahydropyrrole, 7H-indole, and the like.
  • the aryl group refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms), and the group has a conjugated ⁇ -electron system such as a phenyl group and Naphthyl.
  • the aryl ring may be fused to a heterocyclic, heteroaryl or cycloalkyl ring, non-limiting examples containing benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyridin Oxazole, quinoline, benzopyrene, benzodihydrofuran.
  • the heteroaryl group refers to a heteroaromatic system comprising from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl group can be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • the valence tautomers include interconversion through some bonding electron recombination.
  • the pharmaceutically acceptable salt is not particularly limited, and preferably includes: a mineral acid salt, an organic acid salt, an alkyl sulfonate, and an aryl sulfonate;
  • the inorganic acid salt includes a hydrochloride Hydrobromide, nitrate, sulfuric acid Salt, phosphate, etc.;
  • the organic acid salt includes formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.
  • the alkyl sulfonate includes a methylsulfonate, an ethylsulfonate, etc.; the arylsulfonate includes a besylate, a p-toluenesulfonate, and the like.
  • the pharmaceutically acceptable solvate of the compound represented by the general formula (I) is not particularly limited, and preferably includes a compound represented by the general formula (I) and water, ethanol, isopropanol, diethyl ether, a solvate such as acetone.
  • the present inventors designed and synthesized a series of novel compounds by studying the structure-activity relationship between the crystal structure of FGFR and other tyrosine kinase inhibitors, and screening these compounds by molecular, cellular and animal models.
  • FGFR activity can be significantly inhibited, and cell levels can also significantly inhibit FGFR-induced proliferation of various cancer cells, and can also significantly inhibit tumor growth in animals.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, of the formula:
  • any one of X, ring A, R 1 , R 2 and R 3 is a group corresponding to the specific compound described in the examples.
  • aminopyridine compound of the formula (I) of the present invention is selected from the compounds of the following Table 1:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount selected from the group consisting of aminopyridine compounds of the formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates and solvates thereof
  • a pharmaceutically acceptable carrier that can be used to treat a disease associated with cancer or the like.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • a pharmaceutical composition of one or more of the aminopyridine compounds (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and hydrates and solvates thereof, can be used as a protein tyrosine kinase inhibitor, especially as FGFR inhibitor for the treatment of cancer.
  • the FGFR preferably comprises FGFR1.
  • the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction of the free base of the compound with an inorganic or organic acid.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • the compound of the present invention has excellent inhibitory activity against FGFR kinase (Kinase) such as FGFR1 and FGFR2, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and
  • the 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, such as prevention and/or treatment of diseases associated with abnormal expression of the FGF/FGFR signaling pathway.
  • the compounds of the present invention are useful for the treatment of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck.
  • these cancers are selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, and renal cells.
  • Cancer, glioblastoma and testicular cancer Most particularly, the cancer is non-small cell lung cancer, gastric cancer or multiple myeloma.
  • 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 agent (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • 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) absorption 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 perfumes.
  • 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.
  • the synthesis method of the compound 1-1 is referred to the literature method WO2011140009.
  • the synthesis method of the compound 2-1 is the same as the compound 1-5.
  • the synthesis method of the compound 3-1 is the same as the compound 1-5.
  • the synthesis method of the compound 9-1 is the same as that of 5-5.
  • the synthesis method of the compound 9-2 is the same as that of S1.
  • the synthesis method of the compound 10-1 is the same as that of 5-5.
  • the synthesis method of the compound 10-2 is the same as that of S1.
  • the synthesis method of the compound 11-1 is the same as that of 5-5.
  • the synthesis method of the compound 12-2 is the same as that of 5-5.
  • the synthesis method of the compound 13-1 is the same as that of 5-5.
  • the synthesis method of the compound 13-2 is the same as that of S1.
  • the synthesis method of the compound 14-1 is the same as that of 5-5.
  • the synthesis method of the compound 14-2 is the same as that of S1.
  • the synthesis method of the compound 15-1 is the same as that of 5-5.
  • the synthesis method of the compound 15-2 is the same as that of S1.
  • the synthesis method of the compound 16-1 is the same as that of 5-5.
  • the synthesis method of the compound 20-1 was the same as that of 1-7.
  • the synthesis method of the compound 20-2 is the same as that of S1.
  • the synthesis method of the compound 21-2 is the same as that of S1.
  • the synthesis method of the compound 22-1 is the same as that of 21-3.
  • the synthesis method of the compound 24-2 is the same as that of S1.
  • Enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated ELISA plate. The reaction was carried out at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed, and the plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200 ⁇ L/well) 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
  • 50 ⁇ L of the FGFR1 kinase domain recombinant protein diluted in reaction buffer was added to initiate the reaction, and two wells without ATP control wells were required for each experiment.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • Horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution (antibody diluted with BSA 5 mg/ml T-PBS 1:2000) was added, 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the molecular level test results show that the compounds have strong inhibitory activity against FGFR, and half of the compounds have an IC 50 of less than 10 nM.
  • the inhibitory effect of the compound on proliferation of SNU16 cells was detected by CCK-8 Cell Counting Kit (Dojindo).
  • the specific steps are as follows: SNU16 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). Add 10 ⁇ L of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
  • the inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
  • Inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the results of SNU16 cell proliferation inhibition assay showed that the compounds have strong inhibitory activity, and some compounds have an IC 50 of less than 10 nM.
  • Tyrosine kinase zymogram
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h;
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the peak concentration C max and T max is time to peak found
  • AUC 0-t value calculated by the trapezoidal method
  • AUC 0- ⁇ AUC 0-t + C t / k e
  • C t is the blood concentration of the last measurable time point
  • Absolute bioavailability F (AUC gavage ⁇ D vein ) / (AUC vein ⁇ D gavage ) ⁇ 100%.
  • Human lung cancer NCI-H1581 cell line was preserved in our laboratory.
  • the cell strain was used to inoculate the right axilla of the nude mice, and the inoculation amount was 5 ⁇ 10 6 /piece, and the transplanted tumor was directly inoculated.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the transplanted tumor diameter was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to an average volume of about 150-160 mm 3 .
  • S10 The 10 mg/kg, 5 mg/kg, and 2.5 mg/kg groups were orally administered once a day for two weeks.
  • the solvent control group was given an equal amount of water for injection.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • the tumor inhibition rate T/C percentages were 10.03%, 17.18%, and 40.19%, respectively.
  • the animals in each group were in good condition and no mice died.
  • Human gastric cancer SNU-16 cell line was preserved in our laboratory. The cell strain was used to inoculate the right axilla of the nude mice, and the inoculation amount was 5 ⁇ 10 6 /piece, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the nude mice were transplanted subcutaneously with a vernier caliper to measure the diameter of the transplanted tumor.
  • the animals were randomly divided into tumors with an average tumor volume of about 100 mm 3 .
  • S10 30 mg/kg and 10 mg/kg group were orally administered once a day for 21 days; AZD4547 10 mg/kg group was orally administered once a day for 21 days; the solvent control group was given an equal amount of water for injection.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • the experimental results are shown in the table below.
  • the positive control drug AZD4547 10 mg/kg group was orally administered once a day for 21 days, which partially inhibited the growth of subcutaneous xenografts of human gastric cancer SNU-16 nude mice.
  • the percentage of C is 59.80%.
  • T/C is the relative tumor proliferation rate, and the smaller the value, the higher the antitumor activity.
  • the compound S10 was administered at a dose of 2.5 mg/kg, the T/C value was 40%, and the compound E7090 was administered at a dose of 6.25 mg/kg, and the T/C value was 46%, indicating that the same antitumor effect was achieved.
  • Compound E7090 was administered in a dose of 2 to 3 times that of S10. Comparing the other results also showed that the inhibitory effect of compound S10 on the growth of human lung cancer NCI-H1581 nude mice was significantly higher than that of E7090 compound.
  • the newly designed compound has excellent enzyme inhibitory activity against FGFR, and also has significant inhibitory activity on dependent cell proliferation, can target FGFR at the cellular level and inhibit signal transduction of the corresponding downstream signaling pathway, and
  • the representative compound S10 also has good pharmacokinetic properties, is highly sensitive to FGFR-dependent gastric cancer and lung cancer, inhibits the growth of human lung cancer NCI-H1581 nude mice, and inhibits the growth of human gastric cancer SNU-16 nude mice. The effect is significantly higher than the E7090 compound. Therefore, these compounds have good prospects for research and development as novel FGFR inhibitors.

Abstract

本发明提供了一类取代的六元氮杂环类化合物及其制备和用途，具体地，本发明提供了一种如下式(I)所示的化合物，其中，各基团的定义如说明书中所述。本发明化合物具有优异的酪氨酸激酶抑制活性，故能够用于制备一系列治疗与酪氨酸激酶活性相关的疾病的药物。

Description

一类取代的氨基六元氮杂环类化合物及其制备和用途 技术领域
本发明涉及具有酪氨酸激酶选择性抑制活性的一类取代的氨基吡啶类化合物及其药学上可接受的盐或药学上可接受的溶剂化合物、其制备方法及其在制备预防或治疗与生物体内和成纤维生长因子受体相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病，以及与血管新生或癌转移相关的疾病的药物，尤其是用于治疗或预防肿瘤生长与转移的药物中的用途。
背景技术
成纤维生长因子受体(FGFRs)是一种受体酪氨酸激酶，家族成员有FGFR1，FGFR2，FGFR3，FGFR4，其基本结构包括胞外区、跨膜区、酪氨酸激酶区，其中胞外区由3个免疫球蛋白样结构域组成，包括一个酸性结构框架，一个膜域和一个***期细胞内酪氨酸激酶域。与其他酪氨酸激酶一样，当配体和FGFR结合时，受体发生二聚，形成的三元(FGF-FGFR-HPSG)复合物二聚化使得FGFR的结构发生改变，引起细胞内酪氨酸区域以及末端羧酸部位发生分子内的磷酸化转移，随后连接FGFR受体底物(FRS2α)和磷脂酶C(PLCγ)激活一系列下游信号通路，如Ras/丝裂原激活蛋白激酶(MAPK)通路及磷酸肌醇激酶3(PI3K)/Akt通路，进而激发细胞内一些生理过程，如细胞增殖、生存、迁移和血管生成等。
FGFR活化与多种肿瘤的发生发展以及耐药密切相关。FGFRs主要通过染色体易位、基因突变、基因扩增或过度表达这三种机制参与肿瘤的发生。FGFR1基因或其融合基因的染色体易位主要存在于多发性骨髓瘤中；FGFR2和FGFR3突变均在肺鳞状细胞癌中有表达，跨膜区FGFR4Y367C突变使得乳腺癌细胞持续活化；据文献报道，FGFR扩增出现在各种不同癌症中，FGFR1扩增出现在直肠癌、肺癌及肾癌病人中，此外，在约10％的乳腺癌尤其是***受体阳性病人中，FGFR1 8p11-12位点出现扩增，胃癌和直肠癌患者也表现出FGFR2的扩增，FGFR3扩增在膀胱癌患者中最为常见。因此，靶向FGFR激酶抑制剂的研究在恶性肿瘤治疗上具有非常重要的意义。
近年来以FGFRs为治疗靶点的小分子酪氨酸激酶抑制剂(TKI)研发已成为抗肿瘤药物研究的热点。一些FGFR抑制剂已进入临床研究阶段，根据其作用范围不同可分为选择性FGFR抑制剂和非选择性FGFR抑制剂。这类抑制剂主要以FGFR胞内激酶域ATP结合位点为靶点抑制FGFR激活，可应用于FGFRs过表达、FGFRs突变或表达FGFR-融合蛋白的肿瘤类型。AZD4547、BGJ398、LY2874455及AL-3810都是目前已进入临床，抗肿瘤活性强的选择性FGFR抑制剂。据文献报道，AZD-4547、BGJ-398、AL-3810是FGFR1-3的强效抑制剂，而LY2874455是一个pan-FGFR抑制剂(作用于FGFR1-4)。
Figure PCTCN2017073966-appb-000001
由于PDGFRs、VEGFRs和FGFRs激酶域结构高度相似，大多数FGFR TKI同时具有抑制PDGFR、VEGFR的活性，因而FGFR抑制剂具有较大毒副作用，FGFR的抑制剂研发仍面临很大的挑战。在结构方面，FGFR抑制剂的结构种类非常有限。
综上所述，本领域还需要开发具有新型结构的FGFR抑制剂。
发明内容
本发明的目的是提供一类结构新颖，且具有优异活性的FGFR激酶抑制剂。
本发明的第一方面，提供了一种如下式所示的式I化合物，或其药学上可接受的盐：
Figure PCTCN2017073966-appb-000002
其中：
X选自下组：CH或N；
环A可选自取代或未取代的6-10元芳基、取代或未取代的5-12元杂芳基，其中，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：C1-C8烷基、C1-C8烷氧基、C1-C8烷氨基、卤素、卤代C1-C8烷基；
R1选自-CONHR3、-COOR3；
R2选自下组：取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的4-10元杂环基，取代或未取代的氨基，取代或未取代的C1-C8烷氨基，-NHCOR3；其中，所述的取代指基团进一步被一个或多个选自下组的取代基取代：C1-C8烷基，羟基，羟基C1-C8烷基，-COOR3，氨基取代的C3-C10环烷基，未取代或被一个或多个卤素原子、羟基或C1-C8烷基取代的4-10元杂环烷基；
R3选自氢、C1-C8烷基，C2-C10烯基。
在另一优选例中，在所述的式I化合物中，环A选自取代或未取代的6-10元芳基、 取代或未取代的5-10元杂芳基。
在另一优选例中，在所述的式I化合物中，环A选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基。
在另一优选例中，在所述的式I化合物中，环A选自取代或未取代的以下基团：苯环、萘环、吡啶环、吡嗪环、噻吩环、呋喃环、咪唑环、吡咯环、噁唑环、噻唑环、吡唑环、吲哚环、嘧啶环、苯并呋喃环、苯并噻唑环、苯并咪唑环、喹啉环、异喹啉环；
在另一优选例中，在所述的式I化合物中，环A选自下组：取代或未取代的苯环、取代或未取代噻唑环、取代或未取代的噁唑环、取代或未取代的嘧啶环。
在另一优选例中，所述的式I化合物中，R2选自下组：取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的5-6元杂环基，取代或未取代的氨基，取代或未取代的C1-C4烷氨基，-NHCOR3；其中，所述的取代指基团进一步被一个或多个选自下组的取代基取代：C1-C8烷基，羟基，羟基C1-C8烷基，-COOR3，氨基取代的C3-C10环烷基，未取代或被一个或多个卤素原子、羟基或C1-C8烷基取代的4-10元杂环烷基。
在另一优选例中，在所述的式I化合物中，R3选自氢、C1-C6烷基，C2-C6烯基。
在另一优选例中，在所述的式I化合物中，R3选自氢、C1-C4烷基，C2-C4烯基。
在另一优选例中，在所述的式I化合物中，R3选自氢、甲基、乙烯基。
在另一优选例中，所述的化合物选自下组：化合物S1、S2、S3、S4、S5、S6、S7、S8、S9、S10、S11、S12、S13、S14、S15、S16、S17、S18、S19、S20、S21、S22、S23或S24。
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，包括步骤：
Figure PCTCN2017073966-appb-000003
在惰性溶剂中，用式A化合物与式B化合物反应，得到式I化合物；
其中，Q为离去基团，优选地为卤素；环A、X、R1、R2的定义如本发明第一方面中所述。
在另一优选例中，所述的反应在Pd2(dba)3[三(二亚苄基丙酮)二钯]、Xantphos[4,5-双二苯基膦-9,9-二甲基氧杂蒽]、碳酸铯存在下进行。
在另一优选例中，所述的反应包括：将化合物A、化合物B(1.0-1.5eq)、Pd2(dba)3[三(二亚苄基丙酮)二钯](0.05-0.2eq)、Xantphos[4,5-双二苯基膦-9,9-二甲基氧杂蒽](0.1-0.5eq)、碳酸铯(1-3eq)溶解于惰性溶剂中，氮气保护下反应。
在另一优选例中，所述的惰性溶剂为1,4-二氧六环。
在另一优选例中，所述的反应在100℃下进行。
在另一优选例中，所述的反应时间为1-10h。
在另一优选例中，所述的反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗， 无水硫酸钠干燥后拌样过柱得化合物。
本发明的第三方面，提供了一种药物组合物，包括：治疗有效量的如本发明第一方面中所述的化合物，或其药用盐、其前药、其水合物或溶剂合物，和任选的药学上可接受的载体或赋形剂。
在另一优选例中，所述的药物组合物是用于***的药物组合物，或用于治疗酪氨酸激酶(优选为FGFR，更优选为FGFR1)活性相关疾病的药物组合物。
在另一优选例中，所述的药物组合物用于治疗FGF/FGFR信号通路异常表达相关疾病。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体、药学上可接受的盐、酯、前药或水合物的用途，用于制备预防和/或治疗与FGFR相关疾病的药物。
在另一优选例中，所述的肿瘤相关疾病选自下组：乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌；优选为乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌；更优选为非小细胞肺癌、胃癌、多发性骨髓瘤。
本发明的第五方面，提供了一种蛋白酪氨酸激酶酶活抑制剂，所述的抑制剂含有抑制有效量的如本发明第一方面所述的化合物，或其药用盐、其前药、其水合物或溶剂合物。
本发明的第六方面，提供了一种用于治疗癌症或蛋白酪氨酸激酶活性相关疾病的药物组合物，所述药物组合物包括治疗有效量的如本发明第一方面所述的化合物，或其药用盐、其前药、其水合物或溶剂合物作为活性组分。
本发明的第七方面，提供了一种治疗或预防癌症或蛋白酪氨酸激酶活性相关疾病的方法，其特征在于，包括：对治疗或预防对象施用治疗或预防有效量的如本发明第一方面所述的化合物，或其药用盐、其前药、其水合物或溶剂合物，或如本发明所述的药物组合物。
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。
附图说明
图1为S10抑制SNU16胃癌细胞株中FGFR2及下游信号分子磷酸化结果图。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，将文献报道的FGFR抑制剂AL-3810骨架中的喹啉换为氨基吡啶,可以得到一类结构新颖的以氨基吡啶为母核的化合物。在此基础上，通过引入不同水溶性基团取代的芳香环，可以获得一类新的具有较好FGFR抑制活性及代谢性质的氨基吡啶衍生物。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“杂环基”是具有1、2、3、4或5个选自下组的杂原子的环状基 团：O、N或S。
在本文中，所述的烷基优选为脂肪族烷基，可以是直链烷基、支链烷基、螺环烷基、桥环烷基、烯烷基、炔烷基、环烷基、环烯基、环炔基、烷氧烷基、烷氧酰基烷基、环烷基烷基，非限制性地包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、烯丙基、炔丙基、环丁烯基、环己烯基；形如“C1-C8”的表述意在包括具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的相应基团，例如，“C1-C8烷基”指具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的烷基，“C2-C10烯基”指具有2个、3个、4个、5个、6个、7个、8个、9个或10个碳原子的烯基。
在本文中，所述烯基优选为乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基，或类似基团。
在本文中，所述环烷基可以为饱和或者部分不饱和单环或多环环状烃取代基，其中包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基包含3至10个碳原子。单环环烷基非限制实施例包含环丙基、环丁基、环戊烯基、环己基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述杂环基指饱和或部分饱和单环或者多环的环状取代基，其中包括4至10元杂环基，且所述的杂环基为其中含有一个或多个杂原子(氮、氧、硫)的饱和或者非饱和的单环、并环、螺环、稠环、桥环等。本文中所述的杂环基包括，但不局限于选自下组的基团：吗啉环，哌啶环，哌嗪环，N-烷基或酰基取代的哌嗪环，高哌嗪环，N-烷基或酰基取代的高哌嗪环，吡咯，四氢吡咯，7H-嘌呤等。
所述芳基指6至10元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，且所述的基团具有共轭的π电子体系，例如苯基和萘基。所述芳基环可以与杂环基、杂芳基或环烷基环稠合，非限制性实施例含苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃。
所述杂芳基指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述的杂芳基可以稠合于芳基、杂环基或者环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
除非特别说明，本发明所描述的结构式意在包括所有的互变异构、光学异构和立体异构形式(如对映异构体、非对映异构体，几何异构体或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体、互变异构体或其对映异构体、非对映异构体或几何异构体或构象异构体或互变异构体的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中，所述的药学上可接受的盐没有特别的限制，优选包括：无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐；所述无机酸盐包括盐酸盐、氢溴酸盐、硝酸盐、硫酸 盐、磷酸盐等；所述有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等；所述烷基磺酸盐包括甲基磺酸盐、乙基磺酸盐等；所述芳基磺酸盐包括苯磺酸盐、对甲苯磺酸盐等。
在本文中，所述通式(I)表示的化合物的药学上可接受的溶剂合物没有特别的限制，优选包括：通式(I)表示的化合物与水、乙醇、异丙醇、***、丙酮等的溶剂合物。
式(I)化合物
本发明人通过对FGFR的晶体结构和其它的酪氨酸激酶抑制剂构效关系的研究，设计合成了一系列结构新颖的化合物，通过分子、细胞以及动物模型对这些化合物进行筛选，发现这些化合物在分子水平能够明显抑制FGFR酶活性，细胞水平对FGFR诱导的各种癌细胞增殖也有明显抑制作用，而且在动物体内也可以显著抑制肿瘤生长。
具体地，本发明提供了一种如下式所示的式I化合物，或其药学上可接受的盐：
Figure PCTCN2017073966-appb-000004
在另一优选例中，所述的化合物中，X、环A、R1、R2、R3中任一个分别为实施例中所述具体化合物中所对应的基团。
优选的，本发明通式(I)所示的氨基吡啶类化合物选自下表1中的化合物：
表1
Figure PCTCN2017073966-appb-000005
Figure PCTCN2017073966-appb-000006
Figure PCTCN2017073966-appb-000007
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物，所述药物组合物包含治疗有效量的选自式(I)所示氨基吡啶类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地，药学上可接受的载体，其可用于治疗癌症等相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明所述的式(I)所示氨基吡啶类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种，或者上述包含治疗有效量的选自式(I)所示氨基吡啶类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物可以作为蛋白酪氨酸激酶抑制剂，尤其是作为FGFR抑制剂，用于治疗癌症。所述的FGFR优选地包括FGFR1。
本发明化合物的药用盐的制备，可以采用化合物的游离碱与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
由于本发明化合物具有优异的对FGFR激酶(Kinase)例如FGFR1和FGFR2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，例如预防和/或治疗与FGF/FGFR信号通路异常表达相关疾病的。根据现有技术，本发明化合物可用于治疗以下疾病：所述的癌症包括乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。更特别的是，这些癌症选自：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。最特别的是，该癌症是非小细胞肺癌、胃癌或多发性骨髓瘤。
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 PCTCN2017073966-appb-000008
、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、矫味剂和香料。
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。
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。
一、制备实施例
1H-NMR用Varian MercuryAMX300型仪测定；MS用VG ZAB-HS或VG-7070型仪测定，除注明外均为EI源(70ev)；所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得；除说明外，所有反应均是在氮气保护下进行并TLC跟踪，后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程；产品的纯化除说明外均使用硅胶(200～300目)柱色谱法；其中硅胶(200～300目)由青岛海洋化工厂生产，GF254薄层硅胶板由烟台江友硅胶开发有限公司生产。
制备实施例1化合物S1的制备
Figure PCTCN2017073966-appb-000009
化合物1-1的合成方法参照文献方法WO2011140009。
化合物1-3的合成：
称量化合物1-1、化合物1-2(1.5eq)于单口瓶中，加入乙腈溶解，然后加入DIPEA，70℃下反应过夜。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，PE：EA＝5:1得化合物1-3。
化合物1-4的合成
将化合物1-3溶解于甲醇中，加入2eq的氢氧化钠水溶液，60℃下加热反应4h。反应完全后，将反应液冷却至室温，用2N HCl调PH至5～6，有大量固体析出，抽滤，得到化合物1-4。
化合物1-5的合成
将化合物1-5溶解于二氯甲烷中，冰浴下加入DMF[N,N-二甲基甲酰胺](10eq)，氯化亚砜(4eq)，加毕升至室温反应2h，反应完全后将反应液旋干，然后再用DCM溶解，将其加到冷却至0℃的氨水二氯甲烷溶液中，室温反应5h。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，CH2Cl2:MeOH＝50:1得化合物1-5。
化合物1-6的合成参考文献J.Med.Chem.2008,51,1649-1667。
化合物1-7的合成
称量化合物1-6、甲胺盐酸盐(2.5eq)、EDCI[1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐](1.5eq)、HOBt[1-羟基苯并***](1eq)于单口瓶中，用二氯甲烷溶解，然后加入DIPEA[二异丙基乙胺](2.5eq)，室温反应过夜。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，PE:EA(体积比)＝1:1得化合物1-7。
化合物S1的合成：
将化合物1-5、化合物1-7(1.2eq)、Pd2(dba)3[三(二亚苄基丙酮)二钯](0.1eq)、Xantphos[4,5-双二苯基膦-9,9-二甲基氧杂蒽](0.2eq)、碳酸铯(2eq)溶解于1,4-二氧六环中，氮气保护，100℃下反应5h。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，CH2Cl2:MeOH＝50:1得化合物S1。S1的分析数据：1H NMR(300MHz,CDCl3)δ8.66(s,1H),8.39(d,J＝9.1Hz,1H),8.12(d,J＝5.6Hz,1H),8.01(s,1H),7.82(t,J＝8.8Hz,3H),7.56(s,2H),7.45(t,J＝7.6Hz,1H),7.33(d,J＝9.9Hz,1H),6.92(d,J＝8.6Hz,2H),6.66(d,J＝4.2Hz,1H),6.22(d,J＝5.0Hz,1H),5.28–5.18(m,0.5H),5.09–4.97(m,0.5H),4.03(t,J＝5.1Hz,2H),3.85–3.72(m,2H),3.36–3.21(m,2H),3.07(d,J＝4.8Hz,3H),2.92(t,J＝5.0Hz,2H).
制备实施例2化合物S2的制备
Figure PCTCN2017073966-appb-000010
化合物2-1的合成方法与化合物1-5相同。
化合物S2的合成方法与S1相同。S2的分析数据：1H NMR(300MHz,CDCl3)δ8.53(s,1H),8.36(d,J＝9.0Hz,1H),8.10(d,J＝5.6Hz,1H),7.98(s,1H),7.79(t,J＝7.7Hz,3H),7.53(d,J＝7.1Hz,2H),7.42(t,J＝7.6Hz,1H),7.34–7.26(m,1H),6.88(d,J＝8.7Hz,2H),6.62(d,J＝4.7Hz,1H),6.01(s,1H),4.03(t,J＝5.0Hz,2H),3.68(t,J＝12.0Hz,4H),3.05(d,J＝4.9Hz,3H),2.94(t,J＝4.9Hz,2H)。
制备实施例3化合物S3的制备
Figure PCTCN2017073966-appb-000011
化合物3-1的合成方法与化合物1-5相同。
化合物3-2的合成方法与S1相同。
化合物S3的合成：
将化合物3-2溶于甲醇中，加入2N的盐酸甲醇(30eq)溶液，室温反应过夜。反应完全后，旋干反应液，用饱和碳酸氢钠溶液和DCM萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，CH2Cl2:MeOH＝30:1得化合物S3。S3的分析数据：1H NMR(300MHz,CDCl3)δ8.58(s,1H),8.41(d,J＝9.1Hz,1H),8.15(d,J＝5.1Hz,1H),8.02(s,1H),7.84(t,J＝7.7Hz,3H),7.57(s,2H),7.51–7.42(m,1H),7.35(d,J＝9.7Hz,1H),6.95(d,J＝8.2Hz,2H),6.67(d,J＝5.7Hz,1H),6.12(s,1H),3.88(s,2H),3.09(d,J＝4.0Hz,3H),0.77(s,2H),0.65(s,2H).
制备实施例4化合物S4的制备
Figure PCTCN2017073966-appb-000012
化合物4-1的合成方法与1-5相同。
化合物S4的合成方法与S1相同。S4的分析数据：1H NMR(300MHz,CDCl3)δ8.87(s,1H),8.34(d,J＝9.2Hz,1H),8.06(d,J＝5.6Hz,1H),7.99(s,1H),7.79(t,J＝7.0Hz,3H),7.55–7.46(m,2H),7.40(t,J＝7.6Hz,1H),7.33–7.26(m,1H),6.91(d,J＝8.4Hz,2H),6.62(d,J＝4.9Hz,1H),6.51–6.42(m,1H),4.11(t,J＝5.8Hz,2H),3.00(d,J＝4.7Hz,3H),2.88(t,J＝5.7Hz,2H),2.59(s,4H),2.35(s,1H),1.78(s,4H)。
制备实施例5化合物S5的制备
Figure PCTCN2017073966-appb-000013
化合物5-3的合成
称量原料5-1(1eq)和原料5-2(2eq)于单口瓶中，用DMSO[二甲基亚砜]溶解，加入碳酸钾(3eq)，110℃反应过夜。反应完全后将反应液冷却，倒入水中，用乙酸乙酯萃取三次，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，DCM[二氯甲烷]:MeOH[甲醇](体积比)＝30:1得化合物5-3。
化合物5-4的合成
将化合物5-3溶解于甲醇中，加入2eq的氢氧化钠水溶液，60℃下加热反应4h。反应完全后，将反应液冷却至室温，用2N HCl调PH至5～6，有大量固体析出，抽滤，得到化合物5-4。
化合物5-5的合成
将化合物5-4溶解于二氯甲烷中，冰浴下加入DMF[N,N-二甲基甲酰胺](10eq)，氯化亚砜(4eq)，加毕升至室温反应2h，反应完全后将反应液旋干，然后再用DCM溶解，将其加到冷却至0℃的氨水二氯甲烷溶液中，室温反应4h。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，CH2Cl2:MeOH＝15:1得化合物5-5。
化合物S5的合成方法与S1相同。S5的分析数据：1H NMR(300MHz,CDCl3)δ8.64(s,1H),8.36(d,J＝9.2Hz,1H),8.12(d,J＝5.7Hz,1H),8.01(d,J＝1.8Hz,1H),7.82(d,J＝8.2Hz,1H),7.74(d,J＝8.8Hz,2H),7.53(d,J＝7.2Hz,2H),7.48–7.38(m,1H),7.32(dd,J＝9.2,2.3Hz,1H),6.86(d,J＝8.9Hz,2H),6.64(dd,J＝5.7,2.2Hz,1H),6.34(s,1H),3.33(d,J＝4.5Hz,4H),3.04(d,J＝4.8Hz,3H),2.61–2.48(m,4H),2.33(s,3H).
制备实施例6化合物S6的制备
Figure PCTCN2017073966-appb-000014
化合物6-1的合成参考文献方法WO2001060846.
化合物6-2的合成方法同S1.
S6的合成方法与S3相同。S6的分析数据：1H NMR(300MHz,CDCl3)δ8.83(s,1H),8.31(d,J＝9.2Hz,1H),8.10–7.93(m,2H),7.73(dd,J＝13.3,8.3Hz,3H),7.46(d,J＝7.7Hz,2H),7.40–7.33(m,1H),7.24(d,J＝9.9Hz,2H),6.57(d,J＝5.1Hz,1H),6.36(s,1H),3.20(d,J＝11.8Hz,2H),2.97(d,J＝4.4Hz,3H),2.69(dd,J＝25.0,13.5Hz,2H),1.73(dd,J＝31.8,11.6Hz,4H).
制备实施例7化合物S7的制备
Figure PCTCN2017073966-appb-000015
化合物7-1的合成方法与5-5相同。
化合物S7的合成方法与S1相同。S7的分析数据：1H NMR(300MHz,CDCl3)δ8.55(s,1H),8.40(d,J＝9.2Hz,1H),8.15(d,J＝5.8Hz,1H),8.03(d,J＝1.7Hz,1H),7.82(dd,J＝17.4,8.4Hz,3H),7.57(d,J＝5.6Hz,2H),7.51–7.43(m,1H),7.35(dd,J＝9.1,2.3Hz,1H),6.89(d,J＝8.8Hz,2H),6.66(dd,J＝5.7,2.1Hz,1H),6.13(s,1H),3.92–3.81(m,4H),3.36–3.23(m,4H),3.09(d,J＝4.9Hz,3H).
制备实施例8化合物S8的制备
Figure PCTCN2017073966-appb-000016
化合物8-1的合成方法与5-5相同。
化合物S8的合成方法与S1相同。S8的分析数据：1H NMR(300MHz,CDCl3)δ8.55(s,1H),8.40(d,J＝9.2Hz,1H),8.15(d,J＝5.7Hz,1H),8.03(s,1H),7.81(dd,J＝21.6,8.4Hz,1H),7.56(s,1H),7.47(t,J＝7.6Hz,1H),7.35(d,J＝8.8Hz,1H),7.26(s,1H),6.88(d,J＝8.6Hz,1H),6.66(d,J＝4.8Hz,1H),6.14(d,J＝4.4Hz,1H),3.87–3.71(m,1H),3.59(d,J＝12.0Hz,1H),3.09(d,J＝4.7Hz,1H),2.51(t,J＝11.3Hz,1H),1.27(d,J＝6.2Hz,1H).
制备实施例9化合物S9的制备
Figure PCTCN2017073966-appb-000017
化合物9-1的合成方法与5-5相同。
化合物9-2的合成方法与S1相同。
化合物S9的合成方法与S3相同。S9的分析数据：1H NMR(300MHz,CDCl3)δ8.54(s,1H),8.39(d,J＝8.9Hz,1H),8.15(d,J＝5.7Hz,1H),8.03(s,1H),7.84(d,J＝8.5Hz,1H),7.76(d,J＝8.5Hz,2H),7.56(s,2H),7.46(t,J＝7.6Hz,1H),7.34(d,J＝9.0Hz,1H),6.88(d,J＝8.7Hz,2H),6.66(d,J＝5.9Hz,1H),6.17(s,1H),3.67(d,J＝11.9Hz,2H),3.18–3.01(m,5H),2.96(d,J＝13.2Hz,2H),2.82(t,J＝11.4Hz,1H),2.46(t,J＝11.3Hz,1H),1.14(d,J＝6.2Hz,3H)。
制备实施例10化合物S10的制备
Figure PCTCN2017073966-appb-000018
化合物10-1的合成方法与5-5相同。
化合物10-2的合成方法与S1相同。
化合物S10的合成方法与S3相同。S10的分析数据：1H NMR(300MHz,CDCl3)δ8.51(s,1H),8.40(d,J＝9.2Hz,1H),8.15(d,J＝5.7Hz,1H),8.03(s,1H),7.85(d,J＝8.1Hz,1H),7.76(d,J＝8.6Hz,2H),7.57(d,J＝5.9Hz,2H),7.46(t,J＝7.6Hz,1H),7.38–7.31(m,1H),6.89(d,J＝8.7Hz,2H),6.70–6.62(m,1H),6.13(d,J＝3.6Hz,1H),3.67(d,J＝11.1Hz,2H),3.09(d,J＝4.7Hz,3H),2.99(td,J＝9.1,4.4Hz,2H),2.41(t,J＝11.2Hz,2H),1.15(d,J＝6.2Hz,6H)。
制备实施例11化合物S11的制备
Figure PCTCN2017073966-appb-000019
化合物11-1的合成方法与5-5相同。
化合物S11的合成方法与S1相同。S11的分析数据：1H NMR(300MHz,CDCl3)δ8.27(d,J＝9.2Hz,1H),8.06(d,J＝5.7Hz,1H),7.89(s,1H),7.79(d,J＝8.0Hz,1H),7.72(d,J＝8.6 Hz,2H),7.52(d,J＝6.8Hz,2H),7.42(t,J＝7.5Hz,1H),7.27(d,J＝5.5Hz,2H),6.84(d,J＝8.8Hz,2H),6.64(d,J＝5.7Hz,1H),3.62(t,J＝5.3Hz,2H),3.28(s,6H),2.61(s,5H),2.54(t,J＝5.4Hz,2H)。
制备实施例12化合物S12的制备
Figure PCTCN2017073966-appb-000020
化合物12-1的合成参考文献方法WO2013170774。
化合物12-2的合成方法与5-5相同。
化合物S12的合成方法与S1相同。S12的分析数据：1H NMR(300MHz,CDCl3)δ8.71(s,1H),8.43(d,J＝9.2Hz,1H),8.15(d,J＝5.8Hz,2H),8.03(d,J＝6.7Hz,1H),8.00–7.92(m,2H),7.86(d,J＝8.1Hz,1H),7.59(d,J＝6.7Hz,2H),7.49(t,J＝7.6Hz,1H),7.35(d,J＝9.1Hz,1H),6.69(d,J＝5.3Hz,1H),3.71(s,2H),3.11(d,J＝4.8Hz,3H),2.54(s,8H),2.32(s,4H).
制备实施例13化合物S13的制备
Figure PCTCN2017073966-appb-000021
化合物13-1的合成方法与5-5相同。
化合物13-2的合成方法与S1相同。
化合物S13的合成方法与S3相同。S13的分析数据：1H NMR(300MHz,CDCl3)δ12.38(s,1H),8.40(d,J＝9.2Hz,1H),8.21–8.10(m,2H),8.05(s,1H),7.84(d,J＝8.2Hz,1H),7.55(d,J＝6.4Hz,2H),7.45(t,J＝7.6Hz,1H),7.34(d,J＝11.1Hz,1H),6.93(dd,J＝17.1,8.9Hz,2H),6.64(d,J＝5.5Hz,1H),6.23(s,1H),3.48(s,2H),3.12–3.03(m,5H),2.84(s,3H),2.53(t,J＝10.8Hz,2H),1.14(d,J＝6.3Hz,6H).
制备实施例14化合物S14的制备
Figure PCTCN2017073966-appb-000022
化合物14-1的合成方法与5-5相同。
化合物14-2的合成方法与S1相同。
化合物S14的合成方法与S3相同。S14的分析数据：1H NMR(300MHz,CDCl3)δ10.28(s,1H),8.37(d,J＝9.2Hz,1H),8.17(d,J＝5.7Hz,1H),8.09(s,1H),7.98(d,J＝8.9Hz,1H),7.82(d,J＝8.1Hz,1H),7.53(d,J＝6.9Hz,2H),7.45(d,J＝7.8Hz,1H),7.34(d,J＝9.3Hz,1H),6.63(d,J＝6.3Hz,1H),6.53(d,J＝8.8Hz,1H),6.36(s,1H),6.27(d,J＝4.6Hz,1H),4.05(s,3H),3.64(d,J＝11.9Hz,2H),3.05(d,J＝4.8Hz,3H),2.98(d,J＝6.6Hz,2H),2.42(t,J＝11.2Hz,2H),1.15(d,J＝6.2Hz,6H).
制备实施例15化合物S15的制备
Figure PCTCN2017073966-appb-000023
化合物15-1的合成方法与5-5相同。
化合物15-2的合成方法与S1相同。
化合物S15的合成方法与S3相同。S15的分析数据：1H NMR(300MHz,CDCl3)δ8.40(d,J＝9.2Hz,1H),8.12(d,J＝5.6Hz,1H),7.91(d,J＝8.9Hz,1H),7.79(d,J＝8.2Hz,1H),7.50(d,J＝7.0Hz,1H),7.491–7.43(m,2H),7.24(d,J＝2.3Hz,1H),6.75(d,J＝7.7Hz,2H),6.41(d,J＝8.8Hz,1H),6.27(s,1H),6.13(s,1H),3.67(d,J＝10.9Hz,2H),3.12– 3.03(m,5H),2.45(t,J＝11.2Hz,2H),2.25(s,3H),1.17(d,J＝6.8Hz,6H)。
制备实施例16化合物S16的制备
Figure PCTCN2017073966-appb-000024
化合物16-1的合成方法与5-5相同。
化合物16-2的合成方法与S1相同。
化合物S16的合成方法与S3相同。S16的分析数据：1H NMR(300MHz,CDCl3)δ8.77(s,2H),8.49–8.36(m,2H),8.15(d,J＝5.7Hz,1H),7.97(s,1H),7.85(d,J＝8.3Hz,1H),7.57(d,J＝6.8Hz,2H),7.51–7.44(m,1H),7.34(d,J＝9.2Hz,1H),6.67(d,J＝3.5Hz,1H),6.11(d,J＝5.7Hz,1H),4.77(d,J＝12.7Hz,2H),3.10(d,J＝4.7Hz,3H),2.94–2.81(m,2H),2.54(t,J＝11.7Hz,2H),1.25(s,1H),1.16(d,J＝6.2Hz,6H).
制备实施例17化合物S17的制备
Figure PCTCN2017073966-appb-000025
化合物17-1的合成方法与5-5相同。
化合物S17的合成方法与S1相同。S17的分析数据：1H NMR(300MHz,CDCl3)δ9.61(s,1H),8.40(d,J＝9.0Hz,1H),8.19(d,J＝5.6Hz,1H),8.02(d,J＝1.8Hz,1H),7.85(d,J＝8.3Hz,1H),7.57(d,J＝6.7Hz,2H),7.47(t,J＝7.5Hz,1H),7.42(s,1H),7.36(d,J＝9.2Hz,1H),6.71–6.64(m,1H),6.08(d,J＝4.5Hz,1H),3.58–3.52(m,4H),3.10(d,J＝4.9Hz,3H),2.56–2.49(m,4H),2.36(s,3H).
制备实施例18化合物S18的制备
Figure PCTCN2017073966-appb-000026
化合物18-1的合成方法与5-5相同。
化合物S18的合成方法与S1相同。S18的分析数据：1H NMR(300MHz,CDCl3)δ9.26(s,1H),8.40(d,J＝9.2Hz,1H),8.18(d,J＝5.6Hz,1H),7.98(s,1H),7.85(d,J＝8.2Hz,1H),7.76(s,1H),7.58(d,J＝7.1Hz,2H),7.47(t,J＝7.8Hz,1H),7.35(d,J＝9.3Hz,1H),6.67(d,J＝3.8Hz,1H),6.05(d,J＝14.5Hz,1H),3.56(s,4H),3.10(d,J＝4.8Hz,3H),2.49(s,4H),2.34(s,3H).
制备实施例19化合物S19的制备
Figure PCTCN2017073966-appb-000027
化合物19-1的合成方法参照文献方法WO2012040137。
化合物19-2的合成：
将1eq的CDI[羰基二咪唑]溶于干燥的THF[四氢呋喃]中，向里加化合物19-1，40℃下反应30分钟，然后向里加氨水(20eq)的四氢呋喃溶液，30℃反应过夜。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后直接投下一步反应。
化合物S19的合成方法与S1相同。S19的分析数据：1H NMR(300MHz,DMSO-d6)δ10.62(s,1H),8.63–8.51(m,1H),8.43(s,1H),8.33(d,J＝9.3Hz,1H),8.27(d,J＝5.7Hz,1H),8.10(s,1H),8.02(dd,J＝6.9,2.0Hz,1H),7.82(dd,J＝6.8,1.9Hz,2H),7.59(d,J＝7.0Hz,2H),7.45(dd,J＝9.2,2.5Hz,1H),6.80(dd,J＝5.8,2.0Hz,1H),4.94(t,J＝5.3Hz,1H),4.14(t,J＝5.2Hz,2H),3.72(q,J＝5.4Hz,2H),2.86(d,J＝4.4Hz,3H).
制备实施例20化合物S20的制备
Figure PCTCN2017073966-appb-000028
化合物20-1的合成方法与1-7相同。
化合物20-2的合成方法与S1相同。
化合物S20的合成方法与S3相同。S20的分析数据：1H NMR(300MHz,CDCl3)δ9.19(s,1H),8.34(d,J＝5.3Hz,1H),8.17(d,J＝9.2Hz,1H),7.68(d,J＝8.1Hz,1H),7.60(d,J＝8.3Hz,2H),7.51(s,1H),7.41(dd,J＝11.5,5.6Hz,2H),7.30(d,J＝7.8Hz,1H),7.15(d,J＝9.0Hz,1H),6.63(d,J＝8.5Hz,2H),6.41(d,J＝5.6Hz,1H),3.45(d,J＝12.3Hz,2H),2.91–2.79(m,5H),2.48–2.32(m,2H),1.09(d,J＝6.2Hz,6H)。
制备实施例21化合物S21的制备
Figure PCTCN2017073966-appb-000029
化合物21-2的合成方法与S1相同。
化合物21-3的合成：
将化合物21-2溶于乙醇中，加入氯化铵(10eq)的水溶液，然后加入铁粉(5eq)，80℃下反应5h。反应完全后，抽滤，滤液旋干，然后用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，DCM：MeOH＝30:1得化合物21-3。
化合物S21的合成：
将化合物21-3溶于干燥的二氯甲烷中，氮气保护，冰浴下加入丙烯酰氯(1.3eq)，然后加入DIPEA(2eq)，加毕升至室温反应过夜。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，DCM：MeOH＝30:1得化合物S21。化合物S21的分析数据：1H NMR(300MHz,CDCl3)δ8.26(d,J＝8.9Hz,1H),8.05(d,J＝5.7Hz,2H), 7.85(s,1H),7.76(d,J＝8.4Hz,1H),7.65(s,1H),7.49(d,J＝7.4Hz,3H),7.36(dt,J＝16.1,8.1Hz,2H),7.25(d,J＝2.3Hz,1H),6.64(d,J＝6.0Hz,1H),6.37–6.15(m,2H),5.65(d,J＝9.9Hz,1H),2.95(s,3H)。
制备实施例22化合物S22的制备
Figure PCTCN2017073966-appb-000030
化合物22-1的合成方法与21-3相同。
化合物S22的合成方法与S21相同，化合物S22的分析数据：1H NMR(300MHz,DMSO)δ10.76(s,1H),10.41(s,1H),8.53(d,J＝6.5Hz,1H),8.39–8.28(m,2H),8.09–8.00(m,1H),7.97(d,J＝8.6Hz,2H),7.88–7.80(m,2H),7.75(d,J＝8.8Hz,2H),7.59(d,J＝7.0Hz,2H),6.84(d,J＝5.5Hz,1H),6.46(dd,J＝17.4,10.3Hz,1H),6.29(d,J＝17.3Hz,1H),5.80(d,J＝12.6Hz,1H),2.86(d,J＝4.5Hz,3H)。
制备实施例23化合物S23的制备
Figure PCTCN2017073966-appb-000031
化合物23-1的合成方法参照文献方法WO2013024130。
化合物S23的合成：
将化合物21-3溶于乙醇中，加入化合物23-1(2eq)，然后再加入DIPEA(2eq),75℃下反应两天。反应完全后，旋干反应液，然后用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，DCM：MeOH＝20:1得化合物S23。化合物S23的分析数据：1H NMR(300MHz,CDCl3)δ8.67(s,1H),8.34(d,J＝9.2Hz,1H),8.11(d,J＝5.8Hz,1H),7.97(d,J＝2.3Hz,1H),7.82(d,J＝8.1Hz,1H),7.62(d,J＝8.4Hz,2H),7.56–7.49(m,2H),7.43(t,J＝7.6Hz,1H),7.31(dd,J＝9.1,2.4Hz,1H),6.65(dd,J＝5.8,2.3Hz,1H),6.49(d,J＝8.4Hz,2H),6.43(d,J＝5.3Hz,1H),4.54(t,J＝5.9Hz,1H),3.76–3.64(m,4H),3.06(dd,J＝10.8,5.2Hz,5H),1.82(s,1H),1.73–1.54(m,4H)。
制备实施例24化合物S24的制备
Figure PCTCN2017073966-appb-000032
化合物24-1的合成
将化合物1-6溶于甲醇中，冰浴下加入氯化亚砜(1.5eq)，加完升至60℃下反应5h。反应完全后，旋干反应液，用DCM和饱和碳酸氢钠溶液萃取，饱和食盐水洗，无水硫酸钠干燥后直接投下一步反应。
化合物24-2的合成方法与S1相同。
化合物S24的合成方法与S3相同。S24的分析数据：1H NMR(300MHz,CDCl3)δ8.71(s,1H),8.45(d,J＝9.2Hz,1H),8.21(d,J＝5.7Hz,1H),8.09(s,1H),7.92(d,J＝8.1Hz,1H),7.81(d,J＝8.6Hz,2H),7.63(d,J＝5.9Hz,2H),7.51(t,J＝7.6Hz,1H),7.47–7.40(m,1H),6.95(d,J＝8.7Hz,2H),6.85–6.78(m,1H),6.13(d,J＝3.6Hz,1H),3.91(s,3H),3.65(d,J＝11.1Hz,2H),2.94(td,J＝9.1,4.4Hz,2H),2.39(t,J＝11.2Hz,2H),1.14(d,J＝6.2Hz,6H)。
二、试验实施例
1、化合物对受体酪氨酸激酶FGFR1酶活抑制初步评价实验
试验方法：
1、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。洗板，用T-PBS(含0.1％Tween-20的无钾离子的PBS，200μL/孔)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
2、每孔加入以反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液49μL，每孔中加入1μL待测试化合物，再加入50μL以反应缓冲液稀释的FGFR1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。弃去孔中液体，T-PBS洗板三次。
3、加入抗体PY99稀释液(抗体用含BSA 5mg/mL的T-PBS 1:500稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
4、加入辣根过氧化物酶标记的羊抗鼠二抗稀释液(抗体用含BSA 5mg/ml的T-PBS1:2000稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
5、加入2mg/ml的OPD显色液100μL/孔【用含有0.03％H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH＝5.4)稀释】，25℃避光反应1-10分钟。
6、加入2M H2SO4 50μL/孔中止反应，用可调波长式微孔板酶标仪VERSAmax读数，波长为490nm。
7、结果分析
Figure PCTCN2017073966-appb-000033
IC50值采用酶标仪随机附带软件以四参数法回归求得。
化合物对受体酪氨酸激酶FGFR酶活抑制水平见下表：
Figure PCTCN2017073966-appb-000034
分子水平测试结果显示，该类化合物对FGFR具有很强的抑制活性，半数化合物的IC50小于10nM。
2、化合物对受体酪氨酸激酶FGFR细胞水平活性评价
试验方法：
化合物对SNU16细胞的增殖抑制作用以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SNU16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对照孔-OD给药孔)/OD对照孔×100％
IC50值采用酶标仪随机附带软件以四参数法回归求得。
化合物对SNU16细胞的增殖抑制率见下表：
Figure PCTCN2017073966-appb-000035
NTa＝未测试
SNU16细胞增殖抑制实验结果显示，该类化合物具有很强的抑制活性，部分化合物IC50小于10nM。
3、化合物对FGFR2及下游信号分子磷酸化抑制实验
结果如图1中所示。结果显示，该化合物能在细胞水平上靶向FGFR并抑制相应下游信号通路的信号转导。
4、酪氨酸激酶活性抑制体外筛选试验
筛选方法：酶联免疫吸附测定(ELISA)
酪氨酸激酶：酶谱
作用时间：1h
表1.化合物对酪氨酸激酶活性的抑制率(％)
Figure PCTCN2017073966-appb-000036
表2.化合物对酪氨酸激酶活性的抑制率(％)
Figure PCTCN2017073966-appb-000037
5、部分化合物大鼠药动学研究试验
1)给药方案
SD大鼠7只，雄性，体重200-220g，随机分成2组，每组4或3只，灌胃或静脉给予化合物S10具体安排见下表：
Figure PCTCN2017073966-appb-000038
试验前禁食12h，自由饮水。给药后2h统一进食。
采血时间点及样品处理：
灌胃给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
静脉给药：给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，11000rpm离心5min，分离血浆，于-20℃冰箱中冷冻。
2)样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中S10。
采用WinNonlin 6.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
达峰浓度Cmax和达峰时间Tmax为实测值；
药时曲线下面积AUC0-t值：采用梯形法计算；AUC0-∞＝AUC0-t+Ct/ke，Ct为最后一个可测得时间点的血药浓度；
ke为消除速率常数；
消除半衰期t1/2＝0.693/ke；
清除率CL＝D/AUC0-∞；
稳态分布容积Vss＝CL×MRT；
绝对生物利用度F＝(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100％。
3)试验结果
Figure PCTCN2017073966-appb-000039
6、化合物对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长抑制作用
1)细胞株
人肺癌NCI-H1581细胞株我室保存。用该细胞株接种裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，形成移植瘤后直接接种使用。
2)实验方法
取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至平均体积约为150-160mm3后将动物随机分组。S10 10mg/kg、5mg/kg、2.5mg/kg组每天口服给药一次，连续给药两周。溶剂对照组则给以等量注射用水。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；
3)结果
实验结果见下表。S10 10mg/kg、5mg/kg和2.5mg/kg组每天口服给药一次，连续给药两周，对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长有显著的抑制作用，第14天所得肿瘤抑瘤率T/C百分数分别为10.03％、17.18％和40.19％。实验期间，各组动物状态良好，无小鼠死亡。
化合物S10对人肺癌NCI-H1581裸小鼠移植瘤的实验治疗作用
Figure PCTCN2017073966-appb-000040
7、化合物S10对人胃癌癌SNU-16裸小鼠皮下移植瘤的生长抑制作用
1)细胞株
人胃癌SNU-16细胞株我室保存。用该细胞株接种裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，形成移植瘤后再在裸小鼠体内传2代后使用。
2)实验方法
取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积至100mm3左右将动物 随机分组。S10 30mg/kg和10mg/kg组，每天口服给药一次，连续给药21天；AZD4547 10mg/kg组，每天口服给药一次，连续给药21天；溶剂对照组给等量注射用水。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV。
3)结果
实验结果如下表所示。S10 30mg/kg和10mg/kg组，每天口服给药一次，连续给药21天后，对人胃癌SNU-16裸小鼠皮下移植瘤的生长有显著的抑制作用，第21天所得T/C百分数分别为8.67％和25.35％。阳性对照药物AZD4547 10mg/kg组每天口服给药一次，连续给药21天，对人胃癌SNU-16裸小鼠皮下移植瘤的生长有部分的抑制作用，第21天所得肿瘤抑瘤率T/C百分数为59.80％。实验期间，仅S10 30mg/kg组小鼠平均体重有下降，但小鼠状态仍良好，无小鼠死亡。S10对人胃癌SNU-16裸小鼠移植瘤生长抑制作用明显高于化合物AZD4547。
S10对人胃癌SNU-16裸小鼠移植瘤的实验治疗作用
Figure PCTCN2017073966-appb-000041
8、化合物S10和同样具有氨基吡啶母核，但侧链为吲哚的类似物E7090(FGFR抑制剂，处于临床I期)相比，S10对人肺癌NCI-H1581裸小鼠移植瘤生长抑制作用更明显，对比结果见下表
Figure PCTCN2017073966-appb-000042
Figure PCTCN2017073966-appb-000043
T/C为相对肿瘤增殖率，数值越小，说明抗肿瘤活性越高。化合物S10给药剂量为2.5mg/Kg时，T/C值为40％，而化合物E7090给药剂量为6.25mg/Kg时，T/C值为46％，这说明达到相同的抗肿瘤抑制作用，化合物E7090的给药剂量是S10的2～3倍。对比其它结果同样说明化合物S10对人肺癌NCI-H1581裸小鼠移植瘤生长抑制作用明显高于E7090化合物。
9、化合物S10和E7090相比，S10对人胃癌SNU-16裸小鼠移植瘤生长抑制作用更明显，对比结果见下表
Figure PCTCN2017073966-appb-000044
化合物S10给药剂量为30mg/Kg时，相对肿瘤增值率T/C值为9％，而化合物E7090给药剂量为50mg/Kg时，相对肿瘤增值率T/C值为18％，对比结果说明在人胃癌SNU-16裸小鼠移植瘤模型中，体内达到相同的抗肿瘤活性，化合物S10的给药剂量明显低于E7090。
由此可见，新设计的化合物对FGFR具有优异的酶抑制活性，对依赖的细胞增殖也具有明显的抑制活性，能在细胞水平上靶向FGFR并抑制相应下游信号通路的信号转导，且其中的代表性化合物S10还具有良好的药代性质，对FGFR依赖的胃癌和肺癌高度敏感，对人肺癌NCI-H1581裸小鼠移植瘤生长抑制作用和人胃癌SNU-16裸小鼠移植瘤生长抑制作用明显高于E7090化合物。因此，这类化合物作为新型FGFR抑制剂具有良好的研发前景。
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 (15)

  1. 一种如下式所示的式I化合物，或其药学上可接受的盐：
    Figure PCTCN2017073966-appb-100001
    其中：
    X选自下组：CH或N；
    环A可选自取代或未取代的6-10元芳基、取代或未取代的5-12元杂芳基，其中，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：C1-C8烷基、C1-C8烷氧基、C1-C8烷氨基、卤素、卤代C1-C8烷基；
    R1选自-CONHR3、-COOR3；
    R2选自下组：取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的4-10元杂环基，取代或未取代的氨基，取代或未取代的C1-C8烷氨基，-NHCOR3；其中，所述的取代指基团进一步被一个或多个选自下组的取代基取代：C1-C8烷基，羟基，羟基C1-C8烷基，-COOR3，氨基取代的C3-C10环烷基，未取代或被一个或多个卤素原子、羟基或C1-C8烷基取代的4-10元杂环烷基；
    R3选自氢、C1-C8烷基，C2-C10烯基。
  2. 如权利要求1所述的化合物，其特征在于，所述的式I化合物中，R2选自下组：取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的5-6元杂环基，取代或未取代的氨基，取代或未取代的C1-C4烷氨基，-NHCOR3；其中，所述的取代指基团进一步被一个或多个选自下组的取代基取代：C1-C8烷基，羟基，羟基C1-C8烷基，-COOR3，氨基取代的C3-C10环烷基，未取代或被一个或多个卤素原子、羟基或C1-C8烷基取代的4-10元杂环烷基。
  3. 如权利要求1所述的化合物，其特征在于，在所述的式I化合物中，环A选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基。
  4. 如权利要求1所述的化合物，其特征在于，在所述的式I化合物中，环A选自取代或未取代的以下基团：苯环、萘环、吡啶环、吡嗪环、噻吩环、呋喃环、咪唑环、吡咯环、噁唑环、噻唑环、吡唑环、吲哚环、嘧啶环、苯并呋喃环、苯并噻唑环、苯并咪唑环、喹啉环、异喹啉环。
  5. 如权利要求1所述的化合物，其特征在于，R3选自氢、C1-C4烷基，C2-C4烯基。
  6. 如权利要求1所述的化合物，其特征在于，在所述的式I化合物中，环A选自下组：取代或未取代的苯环、取代或未取代噻唑环、取代或未取代的噁唑环、取代或未取代的嘧啶环。
  7. 如权利要求1所述的化合物，其特征在于，在所述的式I化合物中，R3选自氢、甲基、乙烯基。
  8. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2017073966-appb-100002
    Figure PCTCN2017073966-appb-100003
  9. 如权利要求1所述的化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2017073966-appb-100004
    在惰性溶剂中，用式A化合物与式B化合物反应，得到式I化合物；
    其中，Q为离去基团；环A、X、R1、R2的定义如权利要求1中所述。
  10. 一种药物组合物，其特征在于，包括：治疗有效量的如权利要求1-8中任一项所述的化合物，或其药用盐、其前药、其水合物或溶剂合物，和任选的药学上可接受的载体或赋形剂。
  11. 如权利要求1所述的化合物，或其光学异构体、药学上可接受的盐、酯、前药或水合物的用途，其特征在于，用于制备预防和/或治疗与FGFR相关疾病的药物。
  12. 如权利要求11所述的用途，其特征在于，所述的肿瘤相关疾病选自下组：乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。
  13. 一种蛋白酪氨酸激酶酶活抑制剂，其特征在于，含有抑制有效量的如权利要求1-4所述的化合物，或其药用盐、其前药、其水合物或溶剂合物。
  14. 一种用于治疗癌症或蛋白酪氨酸激酶活性相关疾病的药物组合物，其特征在于，所述药物组合物包括治疗有效量的如权利要求1-8中任一所述的化合物，或其药用盐、其前药、其水合物或溶剂合物作为活性组分。
  15. 一种治疗或预防癌症或蛋白酪氨酸激酶活性相关疾病的方法，其特征在于，包括：对治疗或预防对象施用治疗或预防有效量的如权利要求1-8中任一所述的化合物，或其药用盐、其前药、其水合物或溶剂合物，或如本发明所述的药物组合物。
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