WO2019119481A1 - 吲唑类衍生物激酶抑制剂 - Google Patents

吲唑类衍生物激酶抑制剂 Download PDF

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WO2019119481A1
WO2019119481A1 PCT/CN2017/118602 CN2017118602W WO2019119481A1 WO 2019119481 A1 WO2019119481 A1 WO 2019119481A1 CN 2017118602 W CN2017118602 W CN 2017118602W WO 2019119481 A1 WO2019119481 A1 WO 2019119481A1
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compound
group
cancer
synthesis
esi
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French (fr)
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刘静
刘青松
刘学松
王蓓蕾
蒋宗儒
余凯琳
陈程
邹凤鸣
刘青旺
刘晓川
王伟
汪文亮
胡晨
王文超
王俊杰
王黎
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中国科学院合肥物质科学研究院
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Definitions

  • the present invention relates to a novel kinase inhibitor compound, a pharmaceutical composition comprising the same, and the use of these compounds or compositions to reduce or inhibit cell or subject cKIT (especially mutant cKIT/T670I), BCR/ ABL (particularly mutant BCR-ABL/T315I), PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2 activity, and uses and methods for preventing or treating a kinase-related disorder in a subject.
  • cKIT especially mutant cKIT/T670I
  • BCR/ ABL particularly mutant BCR-ABL/T315I
  • PDGFR ⁇ PDGFR ⁇
  • PDGFR ⁇ and/or VEGFR2 activity
  • Tyrosine kinase is a class of kinases that catalyze the transfer of ⁇ -phosphate on ATP to protein tyrosine residues. It can catalyze the phosphorylation of various substrate tyrosine residues and is important in cell growth, proliferation and differentiation. effect. Abnormal kinase function is important in cancer, immune, neurological, metabolic, and infectious diseases. There are currently about 30 different drugs that target different kinases, most of which are used to treat cancer. Most of the protein tyrosine kinases discovered so far are oncogene products belonging to oncogenic RNA viruses, and can also be produced by vertebrate proto-oncogenes.
  • Tyrosine kinase inhibitors have been developed as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, as tyrosine analogs, blocking tyrosine kinase activity, and inhibiting cell proliferation.
  • ATP adenosine triphosphate
  • kinases encoded in the human genome, and almost every signaling process needs to be linked through a cascade of phosphotransformation cascades: suggesting that inhibition of kinase activity can truly eliminate cellular physiological responses.
  • the oncogene BCR (Breakpoint cluster region)-ABL fusion protein is a key factor leading to the development of chronic myeloid leukemia, and its tyrosine activity has obvious therapeutic significance.
  • the ATP binding site is highly conserved, small molecules with significant selectivity in pharmacological properties can be developed. Normal cells are generally tolerant to kinase inhibition and thus provide a therapeutic window for selective killing of tumor cells.
  • the present invention provides a novel kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • Y is selected from phenyl, thiophen-2-yl, isoxazol-3-yl, pyridin-3-yl, pyridin-4-yl, 2-pyrrolidone-5-yl, N-methyl-2(1H)- Pyridone-5-yl, and furan-2-yl;
  • R 1 is selected hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl, R 3 is optionally substituted pyridin-3-yl group, an optionally substituted phenyl group of R 3 a base, and a pyrazol-4-yl group optionally substituted with an R 3 group;
  • R 2 n represents optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from hydroxy, halo, C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 acylamino, C 1-6 alkylamino, 4-methyl-imidazol-1-yl,
  • R 3 is selected from the group consisting of halogen, aminoacyl, C 1-6 alkyl,
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from the group consisting of hydrogen and a C 1-6 alkylamino group.
  • the kinase inhibitor of the invention comprises a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl, R 3 is optionally substituted pyridin-3-yl, and optionally substituted with R 3 group Phenyl group;
  • R 2 n represents that the ortho, meta and para positions of the phenyl ring are optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, 4-methyl-imidazol-1-yl, R 3 is selected from the group consisting of halogen, aminoacyl, C 1-6 alkyl,
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from a C 1-6 alkylamino group.
  • the kinase inhibitor of the invention comprises a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl
  • R 3 is optionally substituted pyridin-3-yl group, optionally substituted with a group R 3 a phenyl group, and a pyrazol-4-yl group optionally substituted with an R 3 group;
  • R 2 n represents that the ortho, meta and para positions of the phenyl ring are optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 acylamino, C 1-6 alkylamino, 4-methyl-imidazole -1-base,
  • R 3 is selected from C 1-6 alkyl
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from the group consisting of hydrogen and a C 1-6 alkylamino group.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound, and a disease, disorder or condition in which the compound or pharmaceutical composition prevents or treats or is affected by tyrosine kinase activity or which is involved in tyrosine kinase activity.
  • Method and use are provided.
  • Figures 1a to 1c show the tumor suppressive effects of Compound 4 in a mouse model of TEL-cKIT/T670I-BaF3 cell tumor transplantation.
  • Figures 2a to 2c show the tumor suppressive effect of Compound 142 in a P210/T315I-BaF3 cell tumor-transplanted mouse model.
  • the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art.
  • naming and laboratory operations and techniques chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and procedures can be carried out by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group and may be a branched or straight chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.
  • alkyl as referred to herein includes all alkyl groups which may exist in all configurations and conformations, such as "propyl” as referred to herein includes n-propyl and isopropyl, and "butyl” includes n-butyl.
  • the base, isobutyl and tert-butyl groups, "pentyl” include n-pentyl, isopropyl, neopentyl, tert-amyl, and pent-3-yl and the like.
  • alkoxy refers to -O-alkyl, wherein alkyl is as defined herein.
  • Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • alkoxyalkyl refers to an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.
  • aryl means that the planar ring has a delocalized ⁇ -electron system and contains 4n+2 ⁇ electrons, where n is an integer.
  • the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can be optionally substituted.
  • aryl includes carbocyclic aryl (eg phenyl) and heterocyclic aryl (or "heteroaryl” or “heteroaryl”) groups (eg pyridine).
  • the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl as used herein means that each of the atoms constituting the ring in the aryl ring is a carbon atom.
  • the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and fluorenyl.
  • the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
  • aryloxy refers to -O-aryl, wherein aryl is as defined herein.
  • heteroaryl refers to a ring heteroatom comprising one or more selected from the group consisting of nitrogen, oxygen and sulfur in the aryl group.
  • the N-containing "heteroaryl” moiety means that at least one of the backbone atoms in the ring of the aryl group is a nitrogen atom.
  • the heteroaryl group can be a monovalent group or a divalent group (ie, a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole , isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, pyridazinyl, pyridazinyl, pyridazinyl, isoindole Sulfhydryl, pteridinyl, fluorenyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naph
  • alkyl (aryl) or “aralkyl” refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein.
  • Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
  • alkyl (heteroaryl) or “heteroarylalkyl” refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
  • heteroalkyl as used herein means that one or more of the backbone chains of the alkyl groups defined herein are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at a position where the heteroalkyl group is attached to the remainder of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein means that one or more of the atoms constituting the ring in the non-aryl ring is a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocycloalkyl ring may be composed of three, four, five, six, seven, eight, nine or more than nine atoms.
  • the heterocycloalkyl ring can be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxetane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, bar Bitoteric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • alkyl (heterocycloalkyl) or “heterocycloalkylalkyl” refers to an alkyl group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl examples include structures of alkyl, alkoxy or heteroalkyl groups in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by a halogen atom, the halogen atoms are the same or different from each other.
  • hydroxy refers to a radical of the formula -OH.
  • cyano refers to a radical of the formula -CN.
  • ester group refers to a chemical moiety having the formula -COOR wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amino refers to the group -NH 2.
  • aminoacyl refers to -CO-NH 2.
  • amido or “amido” refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted with one or two alkyl groups, in particular a group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that - NRR' is not -NH 2 .
  • Alkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least one compound of an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • acyl refers to a monovalent radical remaining after removal of a hydroxyl group by an organic or inorganic oxyacid having the formula R-M(O)-, wherein M is typically C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
  • arylcarbonyl refers to a carbonyl group, as defined herein, substituted by an aryl group, as defined herein.
  • optional means that one or more of the events described below may or may not occur, and includes both events occurring and events not occurring.
  • the term “optionally substituted” or “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl An alkyl group, a heterocycloalkylalkyl group, an aminoacyl group, an amino protecting group, and the like.
  • the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
  • tyrosine protein kinase as used herein is a class of kinases that catalyze the transfer of gamma-phosphate from ATP to a protein tyrosine residue, which catalyzes the tyrosine residues of various substrates. Phosphorylation plays an important role in cell growth, proliferation, and differentiation.
  • the term “inhibiting,” “inhibiting,” or “inhibiting,” a kinase refers to inhibition of phosphotransferase activity.
  • a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
  • the term “metabolized” refers to the sum of the processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • glucosinolate diphosphate catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • modulate refers to interacting directly or indirectly with a target to alter the activity of the target, by way of example only, including enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • target protein refers to a protein molecule or a portion of a protein that can be bound by a selective binding compound.
  • the target protein is a tyrosine kinase KIT (wild type or various mutations or a combination thereof), ABL (wild type or various mutations or a combination thereof), EGFR (wild type or various mutations or Combination), FLT3 (wild type or various mutations or combinations thereof), VEGFR2 (wild type or various mutations or combinations thereof), RET (wild type or various mutations or combinations thereof), PDGFR ⁇ (wild type or various mutations) Or a combination thereof, PDGFR ⁇ (wild type or various mutations or combinations thereof), BCR/ABL (wild type or various mutations or combinations thereof), FGFR1 (wild type or various mutations or combinations thereof), FGFR2 (wild type) Or various mutations or combinations thereof, FGFR3 (wild type or various mutations or combinations thereof), FGFR4 (wild type or various mutations or combinations thereof).
  • IC 50 refers to a 50% of the maximum effect is obtained in the analysis of the inhibition effect of such measurement, concentration or dosage.
  • EC 50 refers to a measured dose, concentration or amount of a compound, at a dose of 50% of maximal expression of the compound to induce, stimulate or enhance a particular reaction assays rely on specific reaction caused.
  • GI 50 refers to the concentration of a drug required to inhibit 50% of cell growth, that is, the concentration of a drug when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides a novel kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • Y is selected from phenyl, thiophen-2-yl, isoxazol-3-yl, pyridin-3-yl, pyridin-4-yl, 2-pyrrolidone-5-yl, N-methyl-2(1H)- Pyridone-5-yl, and furan-2-yl;
  • R 1 is selected hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl, R 3 is optionally substituted pyridin-3-yl group, an optionally substituted phenyl group of R 3 a base, and a pyrazol-4-yl group optionally substituted with an R 3 group;
  • R 2 n represents optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from hydroxy, halo, C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 acylamino, C 1-6 alkylamino, 4-methyl-imidazol-1-yl,
  • R 3 is selected from the group consisting of halogen, aminoacyl, C 1-6 alkyl,
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from the group consisting of hydrogen and a C 1-6 alkylamino group.
  • the kinase inhibitor of the invention comprises a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl, R 3 is optionally substituted pyridin-3-yl, and optionally substituted with R 3 group Phenyl group;
  • R 2 n represents that the ortho, meta and para positions of the phenyl ring are optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, 4-methyl-imidazol-1-yl,
  • R 3 is selected from the group consisting of halogen, aminoacyl, C 1-6 alkyl,
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from a C 1-6 alkylamino group.
  • the kinase inhibitor of the invention comprises a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • R 1 is selected from hydrogen, C 1-6 alkyl, 2- (pyridin-2-yl) vinyl
  • R 3 is optionally substituted pyridin-3-yl group, optionally substituted with a group R 3 a phenyl group, and a pyrazol-4-yl group optionally substituted with an R 3 group;
  • R 2 n represents that the ortho, meta and para positions of the phenyl ring are optionally substituted by n independent R 2 substituents, wherein n is an integer from 0 to 5, and R 2 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 acylamino, C 1-6 alkylamino, 4-methyl-imidazole -1-base,
  • R 3 is selected from C 1-6 alkyl
  • R 4 is selected from C 1-6 alkyl
  • R 5 is selected from the group consisting of hydrogen and a C 1-6 alkylamino group.
  • the substituent C 1-6 alkyl group is more preferably a methyl group, an ethyl group, an isopropyl group or a t-butyl group, the halogen is more preferably fluorine or chlorine, and the C 1-6 alkoxy group is more preferably a methoxy group. More preferably, the C 1-6 haloalkoxy group is a trifluoromethoxy group, the C 1-6 haloalkyl group is more preferably a trifluoromethyl group, and the C 1-6 alkylamino group is more preferably a dimethylamino group, C 2 ⁇ The 6 acylamino group is more preferably an acetyl group.
  • Described herein are novel kinase inhibitors.
  • Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
  • the compounds described herein are administered to a subject in need thereof to be metabolized in their bodies to produce metabolites which are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be made and/or used as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include, but are not limited to, (1) acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic
  • organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Corresponding counterions of pharmaceutically acceptable salts can be analyzed and characterized using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or lyophilization using an aqueous solution.
  • Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis.
  • Various spectral techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite of said compound Or a prodrug, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
  • the drug comprising a compound of the invention may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration.
  • Other therapeutic agents may be selected from the group consisting of immunosuppressive agents (eg, tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, guanidine, mycophenolate mofetil or FTY720), glucocorticoids (eg prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydroxyprednisolone, beclomethasone , fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylate, ary
  • therapeutic agents mentioned may also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole.
  • Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this CD, camptothecin, daunorubicin (Daunonibic
  • the other therapeutic agent may also be a cytokine such as G-CSF (granulocyte colony stimulating factor).
  • other therapeutic agents may be, for example but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (Asia) Deriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Aminopterin, 5-fluorouracil and prednisone).
  • the amount of a given drug when treating a patient in accordance with the present invention depends on a number of factors, such as the particular dosage regimen, the type of disease or disorder and its severity, and the subject in need of treatment. Or the uniqueness of the host (eg, body weight), however, depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be known in the art. The method is routinely decided. Generally, the dosage administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg per day, for dosages used in adult treatment.
  • the desired dose may conveniently be presented as a single dose, or concurrently (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted depending on the condition of the patient and in connection with the diagnosis of the physician.
  • compositions of the compounds can be used to inhibit tyrosine kinase KIT (wild type or various mutations or combinations thereof), ABL (wild type or various mutations or combinations thereof), EGFR (wild type or various mutations or combinations thereof) , FLT3 (wild type or various mutations or combinations thereof), VEGFR2 (wild type or various mutations or combinations thereof), RET (wild type or various mutations or combinations thereof), PDGFR ⁇ (wild type or various mutations or Combination), PDGFR ⁇ (wild type or various mutations or combinations thereof), BCR/ABL (wild type or various mutations or combinations thereof), FGFR1 (wild type or various mutations or combinations thereof), FGFR2 (wild type or each) Mutations or combinations thereof, FGFR3 (wild type or various mutations or combinations or combinations
  • the compounds and pharmaceutical compositions of the invention are capable of inhibiting tyrosine kinase KIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2 activity.
  • the compounds and pharmaceutical compositions of the invention can be used to treat or prevent KIT (especially mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2.
  • KIT especially mutant cKIT/T670I
  • BCR/ABL particularly mutant BCR-ABL/T315I
  • PDGFR ⁇ PDGFR ⁇
  • PDGFR ⁇ and/or VEGFR2.
  • a compound of the invention or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and a pharmaceutical composition, can be used to treat or prevent one or more diseases selected from the group consisting of solid tumors (including benign and malignant types), especially sarcoma, Gastrointestinal Stromal Tumors (GIST), Acute Myeloblastic Leukemia (AML), Chronic Myelogenous Leukemia (CML), Dermatoma, thyroid carcinoma, systemic mastocytosis, eosinophilia syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host Graft-versus-host disease (GVHD), neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminoma, psoriasis, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysp
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently added by the methods described herein and/or methods known in the art.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of use thereof.
  • the compounds described herein can be synthesized using the protocols synthesized below.
  • Compounds can be synthesized by methods analogous to those described below, using the appropriate starting materials.
  • reaction product can be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and map data.
  • the reaction system was subjected to an argon gas protection reaction at room temperature for 14 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness then evaporated LC/MS: M+H 421.18.
  • the reaction system was subjected to an argon gas protection reaction at room temperature for 4 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure, and the obtained material was neutralized with 1 mol/L of diluted hydrochloric acid to pH 3-5, and solids were precipitated. The aqueous phase was filtered to give a solid which was dried to give crude compound 1c.
  • LC/MS M+H407.17.
  • Example 3 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 4 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M + +) +: 416.
  • Example 5 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1) +: 510.25.
  • Example 6 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 7 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 8 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 476.
  • Example 9 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 10 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 495.21.
  • Example 11 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1)+: 450.
  • Example 12 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 441.21.
  • Example 13 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 488.
  • Example 14 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1)+: 428.16.
  • Example 15 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 592.
  • Example 17 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1)+: 692.26.
  • Example 18 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 466.21.
  • Example 19 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 484.
  • Example 20 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 484.
  • Example 21 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1) +: 500.
  • Example 22 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 484.
  • Example 23 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 437.
  • Example 24 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 25 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (495).
  • Example 26 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 437.
  • Example 27 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 437.
  • Example 28 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 488.
  • Example 29 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 484.
  • Example 30 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 437.
  • Example 31 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (M+1) +: 500.
  • Example 32 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 1. MS (ESI) m/z (MH): 437.
  • 6-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2c) The compound 6-nitro-1-(tetrahydro-2H-pyran-2) was added to methanol. -yl)-1H-carbazole (1.5 g), palladium on carbon (64 mg) was added and stirred at room temperature for 4 hours under hydrogen atmosphere. The mixture was filtered through Celite, and the filtrate was evaporated to dryness. LC/MS: M+H 218.21.
  • N1-(3-Chlorophenyl)-N3-(1H-indazol-6-yl)malonamide (33) 3-oxo-3-((1-(tetrahydro)-) was added to a round bottom flask.
  • 2H-Pyr-2-yl)-1H-indazol-6-yl)amino)propanoic acid 50 mg
  • N,N-dimethylformamide 5 ml
  • m-chloroaniline 25 mg
  • 2-(7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 94 mg
  • triethylamine 0.05 mL.
  • the reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness crystals crystals The reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The aqueous layer was extracted with EtOAc. The organic phase was filtered and evaporated to dryness then evaporated. The crude product was purified by column chromatography on silica gel to afford purified compound 33. LC/MS: 329.07.
  • Example 34 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1)+: 489.21.
  • Example 35 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1)+: 294.11.
  • Example 36 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (MH): 313.
  • Example 37 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33.
  • Example 38 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1) +: 385.
  • Example 39 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1) +: 347.06.
  • Example 40 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1)+: 338.
  • Example 41 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1)+: 329.
  • Example 42 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (MH): 343.
  • Example 43 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (MH): 327.21.
  • Example 44 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (495).
  • Example 45 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 33. MS (ESI) m/z (M+1) +: 41.07.
  • the reaction system was subjected to an argon gas protection reaction at room temperature for 14 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness then evaporated LC/MS: M+H 395.16.
  • the reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness crystals crystals The reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The aqueous layer was extracted with EtOAc. The organic phase was filtered and evaporated to dryness then evaporated. The crude product was purified by column chromatography on silica gel to afford purified compound 46. LC/MS: 372.13.
  • Example 47 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 390.39.
  • Example 48 The synthesis of the compound of Example 48 was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495).
  • Example 49 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495)
  • Example 50 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 520.
  • Example 51 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 540.39.
  • Example 52 N1-(2-Fluorophenyl)-N3-(3-(pyridin-3-yl)-1H-indazol-6-yl)malonamide.
  • Example 52 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 390.39.
  • Example 53 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495).
  • Example 54 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 470.42.
  • Example 55 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 408.
  • Example 56 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 458.11.
  • Example 57 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 458.11.
  • Example 59 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 408.21.
  • Example 60 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 408.21.
  • Example 61 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 458.11.
  • Example 62 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 474.
  • Example 63 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 458.11.
  • Example 64 Synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 406.
  • Example 65 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 458.21.
  • Example 66 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 44.06.
  • Example 67 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 495.
  • Example 68 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 423.
  • Example 69 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 407.21.
  • Example 70 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 537.
  • Example 71 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 403.
  • Example 72 N1-(3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-N3-(3-(4-(4-methyl) Pyrazin-1-yl)phenyl)-1H-indazole-6-yl)malonamide
  • Example 72 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 617.21.
  • Example 73 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 537.
  • Example 74 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 495.
  • Example 75 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495)
  • Example 76 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 495.
  • Example 77 N1-(2-Fluoro-3-(trifluoromethyl)phenyl)-N3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole Zol-6-yl) malonamide
  • Example 77 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 555.
  • Example 78 N1-(2-chloro-5-(trifluoromethyl)phenyl)-N3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole Zol-6-yl) malonamide
  • Example 78 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 572.
  • Example 79 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 555.
  • Example 80 N1-(2,6-Difluorophenyl)-N3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-6-yl) Malonamide
  • Example 80 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 505.
  • Example 81 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 555.
  • Example 82 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 521.
  • Example 83 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495).
  • Example 84 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 523.
  • Example 85 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 505.
  • Example 86 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 505.
  • Example 87 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 505.
  • Example 88 N1-(3-Fluoro-5-(trifluoromethyl)phenyl)-N3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole Zol-6-yl) malonamide
  • Example 88 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 555.
  • Example 89 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495).
  • Example 90 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 585.21.
  • Example 91 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (495).
  • Example 92 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 495.
  • Example 93 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 501.21.
  • Example 94 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 501.21.
  • Example 95 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 469.21.
  • Example 96 N1-(2-Fluoro-5-(trifluoromethyl)phenyl)-N3-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl) -1H-carbazol-6-yl) malonamide
  • Example 96 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 469.21.
  • Example 97 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 585.21.
  • Example 99 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 516.
  • Example 101 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 428.16.
  • Example 102 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 432.
  • Example 103 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 500.21.
  • Example 104 N1-(3-(3-Amino)phenyl-1H-indazol-6-yl)-N3-(3-fluoro-5-(trifluoromethyl)phenyl)malonamide
  • Example 104 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 500.21.
  • Example 106 N1-(3-(3-Amino)phenyl-1H-indazol-6-yl)-N3-(2-fluoro-5-(trifluoromethyl)phenyl)malonamide
  • Example 106 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 500.
  • Example 107 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 468.
  • Example 108 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 450.21.
  • Example 109 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 422.
  • Example 110 N1-(3-(3-Aminoacyl)phenyl-1H-indazol-6-yl)-N3-(3-(trifluoromethyl)phenyl)malonamide
  • Example 110 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 482.21.
  • Example 111 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 516.
  • Example 112 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 466.
  • Example 113 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 512.
  • Example 114 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1)+: 562.17.
  • Example 115 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 550.21.
  • Example 116 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 461.
  • Example 117 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 448.
  • Example 118 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 500.
  • Example 119 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (M+1) +: 404.
  • Example 120 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 46. MS (ESI) m/z (MH): 484.
  • the reaction system was heated to 150 ° C under argon for 2 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness then evaporated. The crude product was purified by column chromatography on silica gel to yield purified product 4c. LC/MS: M+H 381.16.
  • the reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness crystals crystals The reaction system was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure, and the obtained mixture was diluted with water. The aqueous layer was extracted with EtOAc. The organic phase was filtered and evaporated to dryness then evaporated. The crude product was purified by column chromatography on silica gel to afford purified compound 121. LC/MS: M+H 402.21.
  • Example 122 The synthesis of the compound was accomplished using a procedure similar to that described in Example 121. MS (ESI) m/z (M+1) +: 408.
  • Example 125 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 124. MS (ESI) m/z (M+1) +: 518.
  • Example 126 (E)-1-(2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)ethyl)-3-(3) -(trifluoromethyl)phenyl)urea
  • Example 126 The synthesis of the compound was accomplished using a procedure similar to that described in Example 124. MS (ESI) m/z (MH): 484.
  • Example 128 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 121. MS (ESI) m/z (MH): 495.
  • Example 129 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 121. MS (ESI) m/z (M+1)+: 401.
  • Example 130 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 121. MS (ESI) m/z (M+1)+: 422.21.
  • Example 131 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 121. MS (ESI) m/z (M+1)+: 517.
  • Example 132 (E)-4-((4-Methylpiperazin-1-yl)methyl)-N-(3-((3-(2-(pyridin-2-yl))vinyl)- 1H-carbazol-6-yl)thio)propyl)benzamide
  • Example 132 The synthesis of the compound was accomplished using a procedure similar to that described in Example 121. MS (ESI) m/z (495).
  • Example 133 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 121. MS (ESI) m/z (MH): 422.21.
  • the reaction system was heated to 150 ° C under argon for 2 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness then evaporated. The crude product was purified by column chromatography on silica gel to yield purified product 5b. LC/MS: M+H 424.16.
  • Example 135 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 419.26.
  • Example 136 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 495.
  • Example 137 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 437.
  • Example 138 (E)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indole Oxazol-6-yl)sulfanylpropionamide
  • Example 138 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 503.08.
  • Example 139 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 431.21.
  • Example 140 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 444.
  • Example 141 (E)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H) -carbazole-6-yl)sulfanylpropionamide
  • Example 141 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 499.21.
  • Example 142 (E)-N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-phenyl)-3-((3-) 2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 142 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (495).
  • Example 143 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 437.
  • Example 144 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 495.21.
  • Example 145 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 415.
  • Example 146 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 443.21.
  • Example 147 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 415.
  • Example 148 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 429.
  • Example 149 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 445.16.
  • Example 150 (E)-N-(4-(tert-butyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl) Sulfur) propionamide
  • Example 150 The synthesis of the compound of Example 150 was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 467.
  • Example 151 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 415.
  • Example 152 (E)-N-(4-Methoxy-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H) -carbazole-6-yl)sulfanylpropionamide
  • Example 152 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 499.
  • Example 153 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 437.
  • Example 154 (E)-N-(4-Methyl-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H- Oxazol-6-yl)thio)propanamide
  • Example 154 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (495)
  • Example 155 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (495)
  • Example 156 (E)-N-phenyl-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 156 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 401.
  • Example 157 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 487.11.
  • Example 158 (E)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2) -(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 158 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 595.
  • Example 159 (E)-N-((4-(((2-dimethylamino)ethyl))(methyl)amino)methyl)-3-(trifluoromethyl)phenyl)-3 -((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 159 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 583.
  • Example 160 (E)-N-(4-((3-(Dimethylamino)pyrrol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3) -(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 160 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 595.
  • Example 161 (E)-N-(3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((3-(2-() Pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)propanamide
  • Example 161 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 549.
  • Example 162 (E)-N-(4-((4-Methylpiperidin-1-yl)methyl)-3-(trifluoromethyl)-phenyl)-3-((3-) 2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide
  • Example 162 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 580.21.
  • Example 163 The synthesis of the compound was carried out by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1)+: 568.
  • Example 164 (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)-N-(4-(pyrrole-1- Methyl)-3-(trifluoromethyl)phenyl)propanamide
  • Example 164 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 552.
  • Example 165 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 380.
  • Example 166 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 492.
  • Example 167 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 400.04.
  • Example 168 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 316.
  • Example 169 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (MH): 318.
  • Example 170 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 366.
  • Example 171 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 316.
  • Example 172 The synthesis of the compound was accomplished using a procedure similar to that described in Example 134. MS (ESI) m/z (M+1) +: 303.07.
  • 6-iodo-3-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 6-amino-3- in a round bottom flask (Pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5 g), then acetic acid (20 mL) was added and the mixture was cooled to 0.
  • the reaction system was stirred at room temperature for 14 hours under argon atmosphere. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. After washing with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, EtOAc. The mixture was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated to dryness. Used separately The mixture was washed with saturated aqueous sodium sulfate and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated to dryness .
  • Example 174 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 173. MS (ESI) m/z (MH): 353.21.
  • Example 175 N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(6-methylpyridine) -3-yl)-1H-indazol-6-yl)thio)propanamide
  • Example 175 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 173. MS (ESI) m/z (495).
  • Example 176 3-((3-Methyl-1H-indazol-6-yl)sulfanyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-( Trifluoromethyl)phenyl)propanamide
  • Example 176 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 173. MS (ESI) m/z (M+1) +: 492.
  • Example 177 3-((3-(1-Methyl-1H pyrazol-4-yl)-1H-indazol-6-yl)sulfanyl)-N-(4-((4-methylpiperazine) -1-yl)methyl)-3-(trifluoromethyl)phenyl)propanamide
  • Example 177 The synthesis of the compound was accomplished by using a procedure similar to that described in Example 173. MS (ESI) m/z (495).
  • Example 178 N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(phenyl-1H-) Oxazol-6-yl)thio)propanamide
  • Example 178 The synthesis of the compound was accomplished using a procedure similar to that described in Example 173. MS (ESI) m/z (495).
  • mice P210/BaF3 stable expression of P210Bcr-Abl mutant gene
  • mouse P210/T315I-BaF3 stable expression mutant P210Bcr-Abl/T315I kinase
  • mouse Tel-cKit- mouse Tel-cKit-
  • BaF3 stable expression of C-KIT wild type kinase
  • mouse Tel-cKit/V559D-BaF3 stable expression of C-KIT V559D mutant kinase
  • mouse Tel-cKit/V559D/T670I-BaF3 stable expression of C-KIT V559D/T670I mutant kinase
  • mouse Tel-cKit/T670I-BaF3 stable expression of C-KIT T670I mutant kinase
  • mouse Tel-PDGFR ⁇ -BaF3 stable expression of PDGFR ⁇ kinase
  • mouse Tel-PDGFR ⁇ -BaF3 stable expression of PDGFR ⁇ kinase
  • mouse Tel-VEGFR2-BaF3 stable expression of VEGFR2 kinase
  • mouse Tel-RET-BaF3 stable expression of RET kinase
  • mouse Tel-FLT3-BaF3 stablely
  • PDGFR ⁇ , PDGFR ⁇ , VEGFRR2, RET, FLT3, FGFR1, FGFR2, FGFR3, and FGFR4 kinase region sequences were inserted into MSCV-Puro vectors with N-terminal TEL fragments and/or NPM fragments and/or TPR fragments, respectively (purchased from Clontech) ), by retrovirus method, stably transferred into mouse BaF3 cells, and removed IL-3 growth factor, and finally obtained P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT, C-KIT/V559D, C-KIT /V559D/T670I, C-KIT/T670I, PDGFR ⁇ , PDGFR ⁇ , VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3, FGFR4 transfected protein cell lines.
  • test compounds of different concentrations (0.000508 ⁇ M, 0.00152 ⁇ M, 0.00457 ⁇ M, 0.0137 ⁇ M, 0.0411 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.11 ⁇ M, 3.33 ⁇ M, 10 ⁇ M in DMSO) were separately added to the above cells. After incubating for 72 hours, the number of viable cells was detected by quantitative determination of reductase dehydrogenase in living cells using a CCK8 (Beibo, China) cell viability assay kit. The GI 50 value (unit) of the compound of the present invention against each test cell was determined, and the experimental results are shown in Table 2.
  • the main targets of the compounds of the present invention were found to be CKIT, CKIT/T670I, BCR-ABL/T315I, PDGFR ⁇ , PDGFR ⁇ , and VEGFR2.
  • the compound of the present invention has a significant inhibitory effect on TEL-CKIT/T670I-BaF3 and gastrointestinal stromal tumor GIST-T1, which can prove that these compounds can be used for the treatment of gastrointestinal stromal tumors, and for T670I point mutation production Drug-resistant gastrointestinal stromal tumors are particularly effective.
  • some preferred compounds of the invention further have an effect on P210/T315I-BaF3 cells.
  • P210/T315I-BaF3 is a BCR-ABL/T315I mutant cell line, and BCR-ABL/T315I is a common drug-resistant mutation in chronic myeloid leukemia. There is currently no particularly good small molecule inhibitor to treat this mutation. Chronic myelogenous leukemia.
  • the inventors of the present application further selected the preferred compound 142 of the present invention to test it against human chronic myeloid leukemia cell K562 (expressing the P210Bcr-Abl mutant gene) and human chronic myeloid leukemia cell MEG-01 (The GI 50 value (unit) of the human chronic myeloid leukemia cell Ku812 (expressing the P210Bcr-Abl mutant gene) (all of which were purchased from ATCC (USA)) was expressed in Table 3.
  • some of the preferred compounds of the present invention have potent inhibitory effects on P210/T315I-BaF3 cells, and these compounds are also directed against three chronic myelogenous leukemia cell lines K562, MEG-01 expressing the BCR-ABL fusion gene.
  • the proliferation of KU812 was significantly inhibited, and the GI 50 was less than 0.01 ⁇ M. This demonstrates that the preferred compounds of the invention have a better therapeutic effect on chronic myeloid leukemia and also have a therapeutic effect on chronic myeloid leukemia resistant to point mutation T315I.
  • TEL-cKIT/T670I-BaF3 or 5 ⁇ 10 6 P210/T315I-BaF3 cells were injected subcutaneously into the left side of all mice, respectively.
  • mice were orally administered methylcellulose (HKI) vehicle (5 mice) daily at a dose of 25 mg/kg mouse.
  • Compound 4 (5 mice); dose of 100 mg/kg murine imatinib (purchased from MedChem Express, China) (5 mice).
  • methylcellulose (HKI) vehicle 5 mice daily at a dose of 25 mg/kg of mouse compound 142 (from 5 days).
  • compound 142 5 mice) at a dose of 50 mg/kg murine
  • compound 142 at a dose of 100 mg/kg murine;
  • mice were sacrificed, the subcutaneous tumors were removed, and the tumors were weighed.
  • Compound 4 in the mouse tumor model of TEL-cKIT/T670I-BaF3 has shown a certain effect of inhibiting tumor in mice when the dose is 25 mg/kg, and compound 4 is resistant to mouse tumors as the number of days of administration increases. The inhibitory effect is more and more obvious, and the tumor inhibition rate is as high as 49.6%. Compound 4 not only effectively inhibited the growth of mouse tumors, but also had little effect on the body weight of mice, indicating that Compound 4 is suitable for administration to animals. This also demonstrates that the CKIT/T670I inhibitor Compound 4 of the present invention can be used to treat T670I mutant gastrointestinal stromal tumors.
  • Compound 142 in the P210/T315I-BaF3 mouse model, a dose of 25 mg/kg has been shown to have a certain effect on inhibiting tumors in mice, and compound 142 against mouse tumors has increased with the dose and the number of days of administration. The inhibitory effect is more and more significant, and the tumor inhibition rate is as high as 69% when the drug is administered at 100 mg/kg. Compound 142 not only effectively inhibited the growth of mouse tumors, but also had little effect on the body weight of mice, indicating that Compound 142 is suitable for administration to animals. This also demonstrates that the BCR-ABL/T315I inhibitor compound 142 of the present invention can be used to treat chronic myelogenous leukemia of the T315I mutation.
  • the present invention provides a novel kinase inhibitor compound which can be used for reducing or inhibiting cKIT (especially mutant cKIT/T670I), BCR/ABL (especially mutant BCR-ABL/T315I) of cells or subjects, PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2 kinase activity, and/or prevention or treatment of cKIT (especially mutant cKIT/T670I), BCR/ABL (especially mutant BCR-ABL/T315I), PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2 activity-related disorders.
  • cKIT especially mutant cKIT/T670I
  • BCR/ABL especially mutant BCR-ABL/T315I
  • PDGFR ⁇ , PDGFR ⁇ , and/or VEGFR2 activity-related disorders especially, it can be made into a corresponding drug suitable for industrial applications.

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Abstract

提供一种激酶抑制剂，其包括式（I）的化合物或其药学上可接受的盐、溶剂化物、酯、酸、代谢物或前药，还提供包括该激酶抑制剂的药物组合物，使用这些化合物或组合物来抑制细胞或受试者的选自cKIT、BCR/ABL、PDGFRα、PDGFRß和VEGFR2中的一种或多种酪氨酸激酶活性以及在受试者中预防或治疗激酶相关病症的用途和方法。

Description

[根据细则37.2由ISA制定的发明名称]　吲唑类衍生物激酶抑制剂 技术领域
本发明涉及一种新型的激酶抑制剂化合物，包括该化合物的药物组合物，以及使用这些化合物或组合物来降低或抑制细胞或受试者的cKIT(特别是突变型cKIT/T670I)、BCR/ABL(特别是突变型BCR-ABL/T315I)、PDGFRα、PDGFRβ、和/或VEGFR2活性，以及在受试者中预防或治疗激酶相关病症的用途和方法。
背景技术
酪氨酸激酶是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。激酶功能异常在癌症、免疫、神经、代谢和感染性疾病中具有重要意义。目前大约有近30种不同激酶作为靶点的药物，绝大多数用来治疗癌症。迄今发现的蛋白酪氨酸激酶中多数是属于致癌RNA病毒的癌基因产物，也可由脊椎动物的原癌基因产生。
酪氨酸激酶抑制剂可作为三磷酸腺苷(ATP)与酪氨酸激酶结合的竞争性抑制剂，也可作为酪氨酸的类似物，阻断酪氨酸激酶的活性，抑制细胞增殖，已经开发出数种抗肿瘤药物。
人类基因组中编码的激酶有518种，几乎每个信号传导过程均需要通过磷酸转化级联反应(cascade)进行联络：提示抑制激酶活性可以真正消除细胞的生理反应。例如，癌基因BCR(Breakpoint cluster region)-ABL融合蛋白是导致慢性髓性白血病发生的关键因素，其酪氨酸活性具有明显的治疗意义。虽然ATP结合位点具有高度的保守性，但可以开发在药理学特征上具有明显选择性的小分子。正常细胞通常可以耐受激酶的抑制，因此为选择性杀死肿瘤细胞提供了一个治疗的窗口。例如Dasatinib治疗Imatinib耐药的慢性髓性白血病CML，几乎可以抑制SRC家族的9个激酶(以及其它多个酪氨酸激酶)，但与传统的细胞化疗相比，其副作用还是容易耐受。因此，新的激酶抑制剂的开发具有重要的临床意义。
发明内容
本发明提供一种新型激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
Figure PCTCN2017118602-appb-000001
其中，X选自
Figure PCTCN2017118602-appb-000002
Figure PCTCN2017118602-appb-000003
Y选自苯基、噻吩-2-基、异噁唑-3-基、吡啶-3-基、吡啶-4-基、2-吡咯烷酮-5-基、N-甲基-2(1H)-吡啶酮-5-基、和呋喃-2-基；
R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
(R 2) n表示任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自羟基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000004
Figure PCTCN2017118602-appb-000005
R 3选自卤素、氨酰基、C 1-6烷基、
Figure PCTCN2017118602-appb-000006
R 4选自C 1-6烷基；
R 5选自氢和C 1-6烷基氨基。
在优选的实施方式中，本发明的激酶抑制剂包括式(Ia)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、和任选被R 3基团取代的苯基；
(R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000008
R 3选自卤素、氨酰基、C 1-6烷基、
Figure PCTCN2017118602-appb-000009
R 4选自C 1-6烷基；
R 5选自C 1-6烷基氨基。
在另外优选的实施方式中，本发明的激酶抑制剂包括式(Ib)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2017118602-appb-000010
其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
(R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000011
Figure PCTCN2017118602-appb-000012
R 3选自C 1-6烷基和
Figure PCTCN2017118602-appb-000013
R 4选自C 1-6烷基；
R 5选自氢和C 1-6烷基氨基。
本发明还涉及包括以上化合物的药物组合物，以及该化合物或药物组合物在预防或治疗由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症的方法和用途。
附图说明
图1a至1c示出化合物4在TEL-cKIT/T670I-BaF3细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
图2a至2c示出化合物142在P210/T315I-BaF3细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
具体实施方式
术语
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷、吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“烷基(杂环烷基)”或“杂环烷基烷基”是指本文定义的烷基被本文定义的杂环烷基取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
术语“羟基”是指式-OH基团。
术语“氰基”是指式-CN基团。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“氨基”是指基团-NH 2。
术语“氨酰基”是指-CO-NH 2。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH 2。“烷基氨基”包括其中-NH 2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团 的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH 2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。
术语“芳基羰基”是指本文定义的羰基被本文定义的芳基取代。
术语“任选”指后面描述的一个或多个事件可以或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本文使用的术语“酪氨酸蛋白激酶(tyrosine protein kinase，TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋白质分子或 部分蛋白质。在某些实施方式中，靶蛋白是酪氨酸激酶KIT(野生型或各种突变或其组合)、ABL(野生型或各种突变或其组合)、EGFR(野生型或各种突变或其组合)、FLT3(野生型或各种突变或其组合)、VEGFR2(野生型或各种突变或其组合)、RET(野生型或各种突变或其组合)、PDGFRα(野生型或各种突变或其组合)、PDGFRβ(野生型或各种突变或其组合)、BCR/ABL(野生型或各种突变或其组合)、FGFR1(野生型或各种突变或其组合)、FGFR2(野生型或各种突变或其组合)、FGFR3(野生型或各种突变或其组合)、FGFR4(野生型或各种突变或其组合)。
本文使用的IC 50是指在测量这样的效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC 50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。
本文使用的GI 50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本发明新型的激酶抑制剂
本发明提供一种新型激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2017118602-appb-000014
其中，X选自
Figure PCTCN2017118602-appb-000015
Figure PCTCN2017118602-appb-000016
Y选自苯基、噻吩-2-基、异噁唑-3-基、吡啶-3-基、吡啶-4-基、2-吡咯烷酮-5-基、N-甲基-2(1H)-吡啶酮-5-基、和呋喃-2-基；
R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
(R 2) n表示任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自羟基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000017
Figure PCTCN2017118602-appb-000018
R 3选自卤素、氨酰基、C 1-6烷基、
Figure PCTCN2017118602-appb-000019
R 4选自C 1-6烷基；
R 5选自氢和C 1-6烷基氨基。
在优选的实施方式中，本发明的激酶抑制剂包括式(Ia)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2017118602-appb-000020
其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、和任选被R 3基团取代的苯基；
(R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000021
R 3选自卤素、氨酰基、C 1-6烷基、
Figure PCTCN2017118602-appb-000022
R 4选自C 1-6烷基；
R 5选自C 1-6烷基氨基。
在另外优选的实施方式中，本发明的激酶抑制剂包括式(Ib)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2017118602-appb-000023
其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
(R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6 卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
Figure PCTCN2017118602-appb-000024
Figure PCTCN2017118602-appb-000025
R 3选自C 1-6烷基和
Figure PCTCN2017118602-appb-000026
R 4选自C 1-6烷基；
R 5选自氢和C 1-6烷基氨基。
在本发明中，取代基C 1-6烷基更优选为甲基、乙基、异丙基或叔丁基，卤素更优选为氟或氯，C 1-6烷氧基更优选为甲氧基，C 1-6卤代烷氧基更优选为三氟甲氧基，C 1-6卤代烷基更优选为三氟甲基，C 1-6烷基氨基更优选为二甲基氨基，C 2-6酰氨基更优选为乙酰基。
对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文描述的是新型的激酶抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐、通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1，2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺，等等。可接受的无机碱包括氢氧化铝、氢 氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物组合物
本申请还提供药物组合物，其包含至少一种式(I)、(Ia)、或(Ib)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前药，以及药学可接受的载体或赋形剂，以及者任选的其它治疗剂。
在治疗过程中，可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物：免疫抑制剂(例如他克莫司、环抱菌素、雷帕霉素、甲氨蝶岭、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如泼尼松、醋酸可的松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、氢羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、变态反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外，所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀 TM(曲妥珠单抗)、格列卫 TM(伊马替尼)、紫杉醇 TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔 TM(多西他赛)、诺雷德 TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择 TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者，其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者，其它治疗剂也可以是，例如但不限于，CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰 胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和泼尼松)。
在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
本发明的药物的用途
式(I)、(Ia)和(Ib)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或包括式(I)、(Ia)和(Ib)的化合物的药物组合物可用于抑制酪氨酸激酶KIT(野生型或各种突变或其组合)、ABL(野生型或各种突变或其组合)、EGFR(野生型或各种突变或其组合)、FLT3(野生型或各种突变或其组合)、VEGFR2(野生型或各种突变或其组合)、RET(野生型或各种突变或其组合)、PDGFRα(野生型或各种突变或其组合)、PDGFRβ(野生型或各种突变或其组合)、BCR/ABL(野生型或各种突变或其组合)、FGFR1(野生型或各种突变或其组合)、FGFR2(野生型或各种突变或其组合)、FGFR3(野生型或各种突变或其组合)、和/或FGFR4(野生型或各种突变或其组合)。
优选地，本发明的化合物和药物组合物能够抑制酪氨酸激酶KIT(特别是突变型cKIT/T670I)、BCR/ABL(特别是突变型BCR-ABL/T315I)、PDGFRα、PDGFRβ、和/或VEGFR2活性。因此，本发明的化合物和药物组合物能够用于治疗或预防KIT(特别是突变型cKIT/T670I)、BCR/ABL(特别是突变型BCR-ABL/T315I)、PDGFRα、PDGFRβ、和/或VEGFR2相关疾病。
具体地，本发明的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，以及药物组合物可用于治疗或者预防一种或多种选自以下的疾病：实体瘤(包括良性和恶性类型)、尤其肉瘤、胃肠道间质瘤(Gastrointestinal Stromal Tumors，GIST)、急性粒细胞白血病(Acute Myeloblastic Leukemia，AML)、慢性髓性白血病(Chronic Myelogenous Leukemia，CML)、间皮瘤、甲状腺癌(thyroid carcinoma)、系统性肥大细胞病、嗜酸性细胞增多综合征(HES)、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病(graft-versus-host disease，GVHD)、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、银屑病、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇 金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病(Still's disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto's thyroiditis)、奥德甲状腺炎(Ord's hyroiditis)、格雷夫斯病(Graves'disease)、类风湿性关节炎综合征(
Figure PCTCN2017118602-appb-000027
syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barré syndrome)、急性播散性脑脊髓炎、阿狄森病(Addison's disease)、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture's syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter's syndrome)、高安动脉炎(Takayasu's arteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener's granulomatosis)、全身脱毛、贝赫切特病(Behcet's disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛、或其组合。特别优选治疗胃肠道间质瘤、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、或其组合。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)、(Ia)和(Ib)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中，本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸 馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
使用本文描述的合成方法，以好的收率和纯度获得本文公开的化合物。按照本文公开的方法制备的化合物通过本领域已知的常规方法纯化，例如过滤、重结晶、色谱、蒸馏及其组合。
在式(I)、(Ia)和(Ib)的化合物的芳香环部分上的位点，可以易于发生各种代谢反应，因此适当的取代基被引入至芳香环结构上，例如，仅仅举例说明，卤素能还原、减小或消除这种代谢途径。
实施例
以下具体的非限制性实施例将被解释为仅仅是说明性的，并不以任何方式限制本公开。虽然无需进一步详细描述，但是可以相信本领域技术人员能基于本文的描述，完全利用本公开。
实施例1：(E)-N1-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)-N3-(3-甲苯基)丙二酰胺的合成
Figure PCTCN2017118602-appb-000028
(E)-3-氧代-3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基]-1H-吲唑-6-基)氨基)-丙酸甲酯(1b)：在圆底烧瓶中加入(E)-3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-胺(10.0克)后加入无水二氯甲烷(100毫升)、三乙胺(6.8毫升)，然后用冰水浴使体系冷却到0度。接着缓慢加入丙二酸甲酯单酰氯(3.9毫升)。反应体系在室温下、氩气保护反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用二氯甲烷萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品化合物1b。LC/MS：M+H 421.18。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.62(s,1H),8.22(s,1H),8.15(d,J＝8.5Hz,1H),7.86(dd,J＝24.7,13.4Hz,2H),7.69(d,J＝7.3Hz,1H),7.58(d,J＝16.4Hz,1H),7.31(d,J＝8.5Hz,2H),5.76(s,1H),3.92(d,J＝10.0Hz, 1H),3.69(s,4H),3.56(s,2H),2.43(d,J＝11.1Hz,1H),2.03(s,2H),1.80(s,1H),1.61(s,2H)。
(E)-3-氧代-3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(1c)：在圆底烧瓶中加入(E)-3-氧代-3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基]-1H-吲唑-6-基)氨基)-丙酸甲酯(8克)后加入四氢呋喃(40毫升)、水(40毫升)、氢氧化锂(2.5克)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用1摩尔/升的稀盐酸中和至pH为3-5，有固体析出。水相经过滤得析出固体，固体干燥后得粗品化合物1c。LC/MS：M+H407.17。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.62(s,1H),8.24(s,1H),8.14(d,J＝8.5Hz,1H),8.00–7.79(m,2H),7.71(d,J＝7.2Hz,1H),7.59(d,J＝16.3Hz,1H),7.33(d,J＝9.3Hz,2H),5.77(d,J＝8.6Hz,1H),3.92(d,J＝9.7Hz,1H),3.73(s,1H),3.63(s,2H),2.44(d,J＝10.5Hz,1H),2.03(s,2H),1.79(s,1H),1.60(s,2H)。
(E)-N1-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)-N3-(3-甲苯基)丙二酰胺(1)：在圆底烧瓶中加入(E)-3-氧代-3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(100毫克)后加入N,N-二甲基甲酰胺(5毫升)、间甲苯胺(27毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(120毫克)和三乙胺(0.05毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得实施例化合物1。LC/MS：M+H 412.16。1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),10.43(s,1H),10.16(s,1H),8.62(s,1H),8.18(d,J＝24.7Hz,2H),7.86(d,J＝33.3Hz,2H),7.68(s,1H),7.48(s,3H),7.23(s,3H),6.92(s,1H),3.54(s,2H),2.30(s,3H)。
实施例2：(E)-N1-(4-氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000029
实施例2化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:416.14。
实施例3：(E)-N1-苯基-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000030
实施例3 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:398.15。
实施例4：(E)-N1-(3-氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000031
实施例4 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:416.14。
实施例5：(E)-N1-(4-((4-甲基哌嗪基-1-基)甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000032
实施例5 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:510.25。
实施例6：(E)-N1-(4-氯苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000033
实施例6 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:432.11。
实施例7：(E)-N1-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)-N3-(噻吩-2-基甲基)丙二酰胺
Figure PCTCN2017118602-appb-000034
实施例7 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:418.12。
实施例8：(E)-N1-(3-溴苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000035
实施例8 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:476.06。
实施例9：(E)-N1-(3-氯苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000036
实施例9 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:432.11。
实施例10：(E)-N1-(3(4-甲基哌嗪-1-基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000037
实施例10 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:496.23。
实施例11：(E)-N1-(3-氯-4-氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000038
实施例11 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:450.10。
实施例12：(E)-N1-(3-(二甲基氨基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000039
实施例12 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:441.19。
实施例13：(E)-N1-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)-N3-(3,4,5-三甲氧基苯基) 丙二酰胺
Figure PCTCN2017118602-appb-000040
实施例13 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:488.18。
实施例14：(E)-N1-(3-甲氧基苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000041
实施例14 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:428.16。
实施例15：(E)-N1-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000042
实施例15 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:592.25。
实施例16：(E)-N1-(4-((4-异丙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000043
实施例16化 合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:606.27。
实施例17：(R,E)-N1-(4-((3-(二甲基氨基)吡咯烷-1-基)甲基)-3-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000044
实施例17 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI) m/z(M+1)+:692.26。
实施例18：(E)-N1-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)-N3-(3-三氟甲基苯基)丙二酰胺
Figure PCTCN2017118602-appb-000045
实施例18 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:466.14。
实施例19：(E)-N1-(2-氟-3-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000046
实施例19 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:484.13。
实施例20：(E)-N1-(2-氟-5-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000047
实施例20 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:484.13。
实施例21：(E)-N1-(2-氯-5-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000048
实施例21 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:500.10。
实施例22：(E)-N1-(3-氟-5-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000049
实施例22 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:484.13。
实施例23：(E)-N1-(2,3-二氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000050
实施例23 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:434.13。
实施例24：(E)-N1-(2-氯苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000051
实施例24 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:432.11。
实施例25：(E)-N1-(2,3,4-三氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000052
实施例25 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:452.12。
实施例26：(E)-N1-(3,5-二氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000053
实施例26 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:434.13。
实施例27：(E)-N1-(3,4-二氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000054
实施例27 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:434.13。
实施例28：(E)-N1-(2,3,4,5,6-五氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000055
实施例28 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:488.10。
实施例29：(E)-N1-(2-氟-4-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000056
实施例29 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:484.13。
实施例30：(E)-N1-(2,4-二氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000057
实施例30 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:434.13。
实施例31：(E)-N1-(2-氯-3-(三氟甲基)苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000058
实施例31 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:500.10。
实施例32：(E)-N1-(2,5-二氟苯基)-N3-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)丙二 酰胺
Figure PCTCN2017118602-appb-000059
实施例32 化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+:434.13。
实施例33：N1-(3-氯苯基)-N3-(1H-吲唑-6-基)丙二酰胺的合成
Figure PCTCN2017118602-appb-000060
6-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(2b)：在圆底烧瓶中加入6-硝基-1H-吲唑(1.5克)后加入四氢呋喃(40毫升)、3,4-二氢-2H-吡喃(80克)和甲磺酸(89微升)。反应体系在氩气保护下加热至回流反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品2b。LC/MS：M+H 248.09。
6-氨基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(2c)：在甲醇中加入化合物6-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(1.5克)，加钯/碳(64毫克)，氢气氛围下室温搅拌4小时。硅藻土过滤，滤液减压蒸干后得粗品2c。LC/MS：M+H 218.12。
3-氧代-3-((1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸甲酯(2d)：在圆底烧瓶中加入6-氨基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(1克)后加入无水二氯甲烷(30毫升)、三乙胺(1毫升)，然后用冰水浴使体系冷却到0度。接着缓慢加入丙二酸甲酯单酰氯(0.6毫升)。反应体系在室温下、氩气保护反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用二氯甲烷萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品2d。LC/MS：M+H 318.13。
3-氧代-3-((1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(2e)：将3-氧代-3-((1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸甲酯(1克)加入四氢呋喃(10毫升)和水(10毫升)，然后加入氢氧化锂(0.7克)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用1摩尔/升的稀盐 酸中和至pH 3-5有固体析出。水相经过滤得析出固体，固体干燥后得粗品2e。LC/MS：M+H 304.12。
N1-(3-氯苯基)-N3-(1H-吲唑-6-基)丙二酰胺(33)：在圆底烧瓶中加入3-氧代-3-((1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(50毫克)后加入N,N-二甲基甲酰胺(5毫升)、间氯苯胺(25毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(94毫克)和三乙胺(0.05毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物33。LC/MS：329.07。
实施例34：N1-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-N3-(1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000061
实施例34 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:489.21。
实施例35：N1-(1H-吲唑-6-基)-N3-苯基丙二酰胺
Figure PCTCN2017118602-appb-000062
实施例35 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:294.11。
实施例36：N1-(3-氟苯基)-N3-(1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000063
实施例36 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:313.10。
实施例37：N1-(1H-吲唑-6-基)-N3-(3-(4-甲基哌嗪-1-基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000064
实施例37 化合物的合成通过使用类似于实施例33中所述的步骤完成。
MS(ESI)m/z(M+1)+:393.19。
实施例38：N1-(1H-吲唑-6-基)-N3-(3,4,5-三甲氧基苯基)丙二酰胺
Figure PCTCN2017118602-appb-000065
实施例38 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:385.14。
实施例39：N1-(3-氯-4-氟苯基)-N3-(1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000066
实施例39 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:347.06。
实施例40：N1-(3-(二甲基氨基)苯基)-N3-(1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000067
实施例40 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:338.15。
实施例41：N1-(1H-吲唑-6-基)-N3-(3-甲氧基苯基)丙二酰胺
Figure PCTCN2017118602-appb-000068
实施例41 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:325.12。
实施例42：N1-(4-氯苯基)-N3-(3-甲基-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000069
实施例42 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:343.08。
实施例43：N1-(3-氟苯基)-N3-(3-甲基-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000070
实施例43 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:327.11。
实施例44：N1-(3-甲基-1H-吲唑-6-基)-N3-(3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000071
实施例44 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:377.11。
实施例45：N1-(4-氯-3-(三氟甲基)苯基)-N3-(3-甲基-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000072
实施例45 化合物的合成通过使用类似于实施例33中所述的步骤完成。MS(ESI)m/z(M+1)+:411.07。
实施例46：N1-苯基-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺的合成
Figure PCTCN2017118602-appb-000073
6-硝基-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(3b)：在圆底烧瓶中加入3-碘-6-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(5克)后加入1,4-二氧六环(100毫升)、水(20毫升)、3-吡啶硼酸(2.7克)、Pd(Ph 3P) 4(0.7克)和碳酸钾(5.5克)。反应体系在氩气保护下加热至80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品3b。LC/MS：M+H 325.12。
6-氨基-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(3c)：在甲醇中加入化合物6-硝基-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(3克)、钯/碳(97毫克)， 氢气氛围下室温搅拌4小时。硅藻土过滤，滤液减压蒸干后得粗品3c。LC/MS：M+H 295.15。
3-氧代-3-((吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸甲酯(3d)：在圆底烧瓶中加入6-氨基-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(1克)后加入无水二氯甲烷(30毫升)、三乙胺(0.7毫升)，然后用冰水浴使体系冷却到0度。接着缓慢加入丙二酸甲酯单酰氯(0.4毫升)。反应体系在室温下、氩气保护反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用二氯甲烷萃取。有机相用分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品3d。LC/MS：M+H 395.16。
3-氧代-3-((吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(3e)：将3-氧代-3-((吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸甲酯(1克)加入四氢呋喃(10毫升)和水(10毫升)，然后加入氢氧化锂(0.6克)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用1摩尔/升的稀盐酸中和至pH 3-5有固体析出。水相经过滤得析出固体，固体干燥后得粗品3e。LC/MS：M+H 381.14。
N1-苯基-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺(46)：在圆底烧瓶中加入3-氧代-3-((吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)氨基)丙酸(50毫克)后加入N,N-二甲基甲酰胺(5毫升)、苯胺(16毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(75毫克)和三乙胺(0.05毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物46。LC/MS：372.13。
实施例47：N1-(3-氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000074
实施例47 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:390.39。
实施例48：N1-(4-氯-3-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000075
实施例48化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:474.84。
实施例49：N1-(5-(叔丁基)异噁唑-3-基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000076
实施例49 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:419.45。
实施例50：N1-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000077
实施例50 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:520.48。
实施例51：N1-(3-(吡啶-3-基)-1H-吲唑-6-基)-N3-(3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000078
实施例51 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:540.39。
实施例52：N1-(2-氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺。
Figure PCTCN2017118602-appb-000079
实施例52 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:390.39。
实施例53：N1-(3-氯-4-氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000080
实施例53 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:424.83。
实施例54：N1-(4-甲氧基-3-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二 酰胺
Figure PCTCN2017118602-appb-000081
实施例54 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:470.42。
实施例55：N1-(2,6-二氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000082
实施例55 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:408.38。
实施例56：N1-(2-氟-5-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000083
实施例56 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:458.11。
实施例57：N1-(3-氟-5-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000084
实施例57 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:458.11。
实施例58：N1-(2,3,4-三氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000085
化合物58 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:426.11。
实施例59：N1-(2,3-二氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000086
实施例59 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI) m/z(M+1)+:408.12。
实施例60：N1-(3,5-二氟苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000087
实施例60 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:408.12。
实施例61：N1-(3-氟-5-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000088
实施例61 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:458.11。
实施例62：N1-(2-氯-5-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000089
实施例62 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:474.09。
实施例63：N1-(4-氟-3-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000090
实施例63 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:458.11。
实施例64：N1-(4-氯苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000091
实施例64 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:406.10。
实施例65：N1-(2-氟-3-(三氟甲基)苯基)-N3-(3-(吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000092
实施例65 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI) m/z(M+1)+:458.12。
实施例66：N1-(3-氯-4-氟苯基)-N3-(3-(3-氟苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000093
实施例66 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:441.06。
实施例67：N1-(4-氯-3-(三氟甲基)苯基)-N3-(3-(3-氟苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000094
实施例67 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:491.08。
实施例68：N1-(4-氯苯基)-N3-(3-(3-氟苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000095
实施例68 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:423.09。
实施例69：N1-(3-氟苯基)-N3-(3-(3-氟苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000096
实施例69 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:407.12。
实施例70：N1-(3-(3-氟苯基)-1H-吲唑-6-基)-N3-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000097
实施例70 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:537.15。
实施例71：N1-(3-(3-氟苯基)-1H-吲唑-6-基)-N3-(间-甲苯基)丙二酰胺
Figure PCTCN2017118602-appb-000098
实施例71 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:403.14。
实施例72：N1-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000099
实施例72 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:617.61。
实施例73：N1-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)-N3-(3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000100
实施例73 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:537.55。
实施例74：N1-(2-氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000101
实施例74 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:487.55。
实施例75：N1-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)-N3-(间-甲苯基)丙二酰胺
Figure PCTCN2017118602-appb-000102
实施例75 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:483.58。
实施例76：N1-(3-氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000103
实施例76 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:487.55。
实施例77：N1-(2-氟-3-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000104
实施例77 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:555.54。
实施例78：N1-(2-氯-5-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000105
实施例78 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:572.00。
实施例79：N1-(4-氟-3-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000106
实施例79 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:555.55。
实施例80：N1-(2,6-二氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000107
实施例80 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:505.54。
实施例81：N1-(2-氟-5-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000108
实施例81 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:555.55。
实施例82：N1-(3-氯-4-氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000109
实施例82 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:521.99。
实施例83：N1-(3-氯-5-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000110
实施例83 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:571.17。
实施例84：N1-(2,3,4-三氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000111
实施例84 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:523.20。
实施例85：N1-(2,3-二氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000112
实施例85 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:505.54。
实施例86：N1-(3,5-二氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000113
实施例86 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:505.54。
实施例87：N1-(3,4-二氟苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000114
实施例87 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:505.54。
实施例88：N1-(3-氟-5-(三氟甲基)苯基)-N3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000115
实施例88 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:555.55。
实施例89：N1-(3-氟-5-(三氟甲基)苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000116
实施例89 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:567.22。
实施例90：N1-(4-氯-3-(三氟甲基)苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000117
实施例90 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:585.19。
实施例91：N1-(2,3-二氟苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000118
实施例91 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:519.22。
实施例92：N1-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)-N3-(间-甲苯基)丙二酰胺
Figure PCTCN2017118602-appb-000119
实施例92 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:497.25。
实施例93：N1-(2-氟苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000120
实施例93 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:501.23。
实施例94：N1-(3-氟苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000121
实施例94 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:501.23。
实施例95：N1-(4-氟-3-(三氟甲基)苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000122
实施例95 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:569.22。
实施例96：N1-(2-氟-5-(三氟甲基)苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000123
实施例96 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:569.22。
实施例97：N1-(3-氯-5-(三氟甲基)苯基)-N3-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000124
实施例97 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:585.19。
实施例98：N1-(3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-6-基)-N3-苯基丙二酰胺
Figure PCTCN2017118602-appb-000125
实施例98 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:483.24。
实施例99：N1-(3-(3-氨基甲酰基)苯基-1H-吲唑-6-基)-N3-(3-氯-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000126
实施例99 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:516.09。
实施例100：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(4-氯-3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000127
实施例100 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:516.09。
实施例101：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(间-甲苯基)丙二酰胺
Figure PCTCN2017118602-appb-000128
实施例101 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:428.16。
实施例102：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2-氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000129
实施例102 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:432.13。
实施例103：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(4-氟-3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000130
实施例103 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:500.12。
实施例104：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3-氟-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000131
实施例104 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:500.12。
实施例105：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2,3-二氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000132
化合物105 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:450.13。
实施例106：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2-氟-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000133
实施例106 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:500.13。
实施例107：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2,3,4-三氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000134
实施例107 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:468.12。
实施例108：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3,5-二氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000135
实施例108 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:450.13。
实施例109：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3-氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000136
实施例109 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:432.14。
实施例110：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000137
实施例110 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:482.13。
实施例111：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2-氯-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000138
实施例111 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:516.10。
实施例112：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3-氯-4-氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000139
实施例112 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:466.10。
实施例113：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(4-甲氧基-3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000140
实施例113 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:512.14。
实施例114：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000141
实施例114 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:562.17。
实施例115：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2,6-二氟苯基)丙二酰胺
Figure PCTCN2017118602-appb-000142
实施例115 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:550.13。
实施例116：N1-(5-(叔丁基)异噁唑-3-基)-N3-(3-(3-氨酰基)苯基-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000143
实施例116 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:461.18。
实施例117：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(4-氯苯基)丙二酰胺
Figure PCTCN2017118602-appb-000144
实施例117 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:448.10。
实施例118：N1-(3-(3-氨酰基)苯基-1H-吲唑-6-基)-N3-(2-氟-3-(三氟甲基)苯基)丙二酰胺
Figure PCTCN2017118602-appb-000145
实施例118 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:500.13。
实施例119：N1-(3-氟苯基)-N3-(3-(6-甲基吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000146
实施例119 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:404.14。
实施例120：N1-(4-甲氧基-3-(三氟甲基)苯基)-N3-(3-(6-甲基吡啶-3-基)-1H-吲唑-6-基)丙二酰胺
Figure PCTCN2017118602-appb-000147
实施例120 化合物的合成通过使用类似于实施例46中所述的步骤完成。MS(ESI)m/z(M+1)+:484.15。
实施例121：(E)-N-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)烟酰胺的合成
Figure PCTCN2017118602-appb-000148
(E)-2-((3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)乙基-1-胺(4c)：在圆底烧瓶中加入(E)-6-碘-3-[2-(吡啶-2-基)乙烯基]-1-(四氢-2H-吡喃-2-基)-1H-吲唑(5克)后加入N,N-二甲基乙酰胺(20毫升)、2-氨基乙硫醇(1.1克)、Pd(OAc) 2(0.3克)和9,9-二甲基-4,5-双二苯基膦氧杂蒽(0.8克)、N,N-二异丙基乙胺(6.5毫升)。反应体系在氩气保护下加热至150℃反应2小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品4c。LC/MS：M+H 381.16。
(E)-N-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)烟酰胺(121)：在圆底烧瓶中加入(E)-2-((3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H吡喃-2-基)-1H-吲唑-6-基)硫)乙基-1-胺(50毫克)后加入N,N-二甲基甲酰胺(5毫升)、烟酸(19毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(75毫克)和三乙胺(0.04毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至 pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物121。LC/MS：M+H 402.13。
实施例122：(E)-5-氧代-N-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)吡咯烷-2-甲酰胺
Figure PCTCN2017118602-appb-000149
实施例122 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:408.14。
实施例123：(E)-1-甲基-2-氧代-N-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)-1,2-二氢吡啶-3-甲酰胺
Figure PCTCN2017118602-appb-000150
化合物123 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:432.14。
实施例124：(E)-1-(3,4-二氟苯基)-3-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)脲的合成
Figure PCTCN2017118602-appb-000151
在圆底烧瓶中加入(E)-2-((3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)乙基-1-胺(50毫克)后加入二氯甲烷(5毫升)、3,4-二氟苯基异氰酸酯(23毫克)。反应体系在氩气保护下室温搅拌14小时后加入三氟乙酸(1毫升)。反应体系继续在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物124。LC/MS：M+H 452.12。
实施例125：(E)-1-(4-氯-3-(三氟甲基)苯基)-3-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)脲
Figure PCTCN2017118602-appb-000152
实施例125 化合物的合成通过使用类似于实施例124中所述的步骤完成。MS(ESI)m/z(M+1)+:518.09。
实施例126：(E)-1-(2-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)乙基)-3-(3-(三氟甲基)苯基)脲
Figure PCTCN2017118602-appb-000153
实施例126 化合物的合成通过使用类似于实施例124中所述的步骤完成。MS(ESI)m/z(M+1)+:484.13。
实施例127：(E)-4-((4-甲基哌嗪-1-基)甲基)-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)-3-(三氟甲基)苯酰胺
Figure PCTCN2017118602-appb-000154
化合物127 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:595.23。
实施例128：(E)-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)呋喃-2-甲酰胺
Figure PCTCN2017118602-appb-000155
实施例128 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:405.48。
实施例129：(E)-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)苯酰胺
Figure PCTCN2017118602-appb-000156
实施例129 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:401.13。
实施例130：(E)-2-羟基-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)异烟酰胺
Figure PCTCN2017118602-appb-000157
实施例130 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:432.51。
实施例131：(E)-4-氯-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)-3-(三氟甲基)苯酰胺
Figure PCTCN2017118602-appb-000158
实施例131 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:517.96。
实施例132：(E)-4-((4-甲基哌嗪-1-基)甲基)-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)苯酰胺
Figure PCTCN2017118602-appb-000159
实施例132 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:527.25。
实施例133：(E)-N-(3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙基)噻吩-2-甲酰胺
Figure PCTCN2017118602-appb-000160
实施例133 化合物的合成通过使用类似于实施例121中所述的步骤完成。MS(ESI)m/z(M+1)+:421.11。
实施例134：(E)-N(4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺的合成
Figure PCTCN2017118602-appb-000161
(E)-(3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸甲酯(5b)：在圆底烧瓶中加入(E)-6-碘-3-[2-(吡啶-2-基)乙烯基]-1-(四氢-2H-吡喃-2-基)-1H-吲唑(5克)后加入N,N-二甲基乙酰胺(20毫升)、3-巯基丙酸甲酯(1.7克)、Pd(OAc) 2(0.3克)和9,9-二甲基-4,5-双二苯基膦氧杂蒽(0.8克)、N,N-二异丙基乙胺(6.5毫升)。反应体系在氩气保护下加热至150℃反应2小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品5b。LC/MS：M+H 424.16。
(E)-(3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸(5c)：将(E)-(3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸甲酯(1克)加入四氢呋喃(20毫升)和水(20毫升)，然后加入氢氧化锂(1.7克)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用1摩尔/升的稀盐酸中和至pH 3-5有固体析出。水相经过滤得固体，固体干燥后得粗品5c。LC/MS：M+H 410.14。
(E)-N(4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺(134)：在圆底烧瓶中加入(E)-(3-(3-(2-(2-吡啶基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸(50毫克)后加入N,N-二甲基甲酰胺(5毫升)、4-((4-甲基哌嗪-1-基)甲基)苯胺(28毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(70毫克)和三乙胺(0.05毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物134。LC/MS：M+H 513.23。
实施例135：(E)-N-(3-氟苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000162
实施例135 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:419.26。
实施例136：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(3,4,5-三甲氧基苯基)丙酰胺
Figure PCTCN2017118602-appb-000163
实施例136 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:491.16。
实施例137：(E)-N-(3-氯苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000164
实施例137 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:435.09。
实施例138：(E)-N-(4-氯-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000165
实施例138 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:503.08。
实施例139：(E)-N-(3-甲氧基苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000166
实施例139 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:431.01。
实施例140：(E)-N-(3-(二甲基氨基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000167
实施例140 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:444.17。
实施例141：(E)-N-(3-(4-甲基哌嗪-1-基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000168
实施例141 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:499.22。
实施例142：(E)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)-苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000169
实施例142 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:581.22。
实施例143：(E)-N-(3-氟-4-甲基苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000170
实施例143 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:433.14。
实施例144：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(4-(三氟甲氧基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000171
实施例144 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:485.11。
实施例145：(E)-N-苄基-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000172
实施例145 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:415.15。
实施例146：(E)-N-(4-乙酰苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000173
实施例146 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:443.14。
实施例147：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(间-甲苯基)丙酰胺
Figure PCTCN2017118602-appb-000174
实施例147 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:415.15。
实施例148：(E)-N-(3,4-二甲基苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000175
实施例148 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:429.16。
实施例149：(E)-N-(4-甲氧基苄基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000176
实施例149 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:445.16。
实施例150：(E)-N-(4-(叔丁基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000177
实施例150 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:457.18。
实施例151：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(对-甲苯基)丙酰胺
Figure PCTCN2017118602-appb-000178
实施例151 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:415.15。
实施例152：(E)-N-(4-甲氧基-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000179
实施例152 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:499.13。
实施例153：(E)-N-(3-氟-4-甲基苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000180
实施例153 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:433.14。
实施例154：(E)-N-(4-甲基-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000181
实施例154 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:483.14。
实施例155：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(3-(三氟甲基)苄基)丙酰胺
Figure PCTCN2017118602-appb-000182
实施例155 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:483.14。
实施例156：(E)-N-苯基-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000183
实施例156 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:401.14。
实施例157：(E)-N-(4-氟-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000184
实施例157 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:487.11。
实施例158：(E)-N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000185
实施例158 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:595.24。
实施例159：(E)-N-((4-(((2-二甲基氨基)乙基)(甲基)氨基)甲基)-3-(三氟甲基)苯 基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000186
实施例159 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:583.24。
实施例160：(E)-N-(4-((3-(二甲基氨基)吡咯-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000187
实施例160 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:595.24。
实施例161：(E)-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000188
实施例161 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:549.16。
实施例162：(E)-N-(4-((4-甲基哌啶-1-基)甲基)-3-(三氟甲基)-苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000189
实施例162 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:580.23。
实施例163：(E)-N-(4-(吗啉甲基)-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000190
实施例163 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:568.19。
实施例164：(E)-3-((3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫)-N-(4-(吡咯-1-基甲基)-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000191
实施例164 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:552.20。
实施例165：3-((1H-吲唑-6-基)硫)-N-(4-甲基-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000192
实施例165 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:380.10。
实施例166：3-((1H-吲唑-6-基)硫)-N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000193
实施例166 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:492.20。
实施例167：3-((1H-吲唑-6-基)硫)-N-(4-氯-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000194
实施例167 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:400.04。
实施例168：3-((1H-吲唑-6-基)硫)-N-(4-氟苯基)丙酰胺
Figure PCTCN2017118602-appb-000195
实施例168 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:316.08。
实施例169：3-((1H-吲唑-6-基)硫)-N-(噻吩-2-甲基)丙酰胺
Figure PCTCN2017118602-appb-000196
实施例169 化合物的合成通过使用类似于实施例134中所述的步骤完成。 MS(ESI)m/z(M+1)+:318.07。
实施例170：3-((1H-吲唑-6-基)硫)-N-(3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000197
实施例170 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:366.08。
实施例171：3-((1H-吲唑-6-基)硫)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017118602-appb-000198
实施例171 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:316.08。
实施例172：3-((1H-吲唑-6-基)硫)-N-(2,3-二氟苯基)丙酰胺
Figure PCTCN2017118602-appb-000199
实施例172 化合物的合成通过使用类似于实施例134中所述的步骤完成。MS(ESI)m/z(M+1)+:334.07。
实施例173：N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(吡啶-3-基)-1H-吲唑-6-基)硫)丙酰胺的合成
Figure PCTCN2017118602-appb-000200
6-碘-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(6a)：在圆底烧瓶中加入6-氨基-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(5克)，然后加入醋酸(20ml)后用冰水浴使体系冷却到0度。继续加入3摩尔/升的硫酸(11毫升)，加入亚硝酸钠(1.8克)，反应体系在氩气保护下0度搅拌4小时后，加入3摩尔/升的碘化钾(17毫升)。反应体系在氩气保护下0度搅拌3小时。反应结束后，过滤反应溶液所得固体用乙酸乙酯溶解，有机相分别用饱和碳酸氢钠、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品6a。LC/MS：M+H 406.03。
3-((3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸甲酯(6b)：在圆底烧瓶中加入6-碘-3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(2克)后加入 N,N-二甲基乙酰胺(10毫升)、3-巯基丙酸甲酯(0.7克)、醋酸钯(0.1克)和9,9-二甲基-4,5-双二苯基膦氧杂蒽(0.3克)、N,N-二异丙基乙胺(2.7毫升)。反应体系在氩气保护下加热至150℃反应2小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品6b。LC/MS：M+H 398.14。
3-((3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸(6c)：在圆底烧瓶中加入3-((3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸甲酯(1克)后加入四氢呋喃(20毫升)和水(20毫升)，然后加入氢氧化锂(0.6克)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用1摩尔/升的稀盐酸中和至pH 3-5有固体析出。水相经过滤得固体，固体干燥后得粗品6c。LC/MS：M+H 384.13。
N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(吡啶-3-基)-1H-吲唑-6-基)硫)丙酰胺(173)：在圆底烧瓶中加入(3-((3-(吡啶-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)硫)丙酸(50毫克)后加入N,N-二甲基甲酰胺(5毫升)、4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(42毫克)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(74毫克)和三乙胺(0.05毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品溶于无水二氯甲烷(5毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品化合物173。LC/MS：M+H 555.20。
实施例174：N-(3-氟苯基)-3-((3-(吡啶-3-基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000201
实施例174 化合物的合成通过使用类似于实施例173中所述的步骤完成。MS(ESI)m/z(M+1)+:393.11。
实施例175：N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(6-甲基吡啶-3-基)-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000202
实施例175 化合物的合成通过使用类似于实施例173中所述的步骤完成。MS(ESI)m/z(M+1)+:568.22。
实施例176：3-((3-甲基-1H-吲唑-6-基)硫)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000203
实施例176 化合物的合成通过使用类似于实施例173中所述的步骤完成。MS(ESI)m/z(M+1)+:492.20。
实施例177：3-((3-(1-甲基-1H吡唑-4-基)-1H-吲唑-6-基)硫)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)丙酰胺
Figure PCTCN2017118602-appb-000204
实施例177 化合物的合成通过使用类似于实施例173中所述的步骤完成。MS(ESI)m/z(M+1)+:558.22。
实施例178：N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(苯基-1H-吲唑-6-基)硫)丙酰胺
Figure PCTCN2017118602-appb-000205
实施例178 化合物的合成通过使用类似于实施例173中所述的步骤完成。MS(ESI)m/z(M+1)+:554.21。
实施例179：对癌细胞增殖的影响
通过测试本发明的化合物对癌细胞生长的影响(表2)，进一步评估文中化合物对癌细胞增殖的抑制作用、及其对抑制癌细胞增殖的选择性。本实施例中选用了、人胃肠道间质瘤细胞系细胞GIST-T1(表达野生型C-KIT基因)(购自Cosmo Bio Co.,Ltd.(日本))、小鼠原B细胞BaF3(购自ATCC)。此外，本实施例还选用了小鼠P210/BaF3(稳定表达P210Bcr-Abl突变型基因)、小鼠P210/T315I-BaF3(稳定表达突变型P210Bcr-Abl/T315I激酶)、小鼠Tel-cKit-BaF3(稳定表达C-KIT野生型激酶)、小鼠Tel-cKit/V559D-BaF3(稳定表达C-KIT V559D突变型激酶)、小鼠Tel-cKit/V559D/T670I-BaF3(稳定表达C-KIT V559D/T670I突变型激酶)、小 鼠Tel-cKit/T670I-BaF3(稳定表达C-KIT T670I突变型激酶)、小鼠Tel-PDGFRα-BaF3(稳定表达PDGFRα激酶)、小鼠Tel-PDGFRβ-BaF3(稳定表达PDGFRβ激酶)、小鼠Tel-VEGFR2-BaF3(稳定表达VEGFR2激酶)、小鼠Tel-RET-BaF3(稳定表达RET激酶)、小鼠Tel-FLT3-BaF3(稳定表达FLT3激酶)、小鼠Tel-FGFR1-BaF3(稳定表达FGFR1激酶)、小鼠Tel-FGFR2-BaF3(稳定表达FGFR2激酶)、小鼠Tel-FGFR3-BaF3(稳定表达FGFR3激酶)、小鼠Tel-FGFR4-BaF3(稳定表达FGFR4激酶)。上述细胞系均由本实验室构建，构建方法为：经PCR分别扩增人类P210Bcr-Abl、P210Bcr-Abl/T315I、C-KIT、C-KIT V559D、C-KIT V559D/T670I、C-KIT T670I、PDGFRα、PDGFRβ、VEGFR2、RET、FLT3、FGFR1、FGFR2、FGFR3、FGFR4激酶区序列，并分别插入到带有N端TEL片段和/或NPM片段和/或TPR片段的MSCV-Puro载体(购自Clontech)，通过逆转录病毒方法，稳定转入小鼠BaF3细胞，并且撤除IL-3生长因子，最终得到依赖P210Bcr-Abl、P210Bcr-Abl/T315I、C-KIT、C-KIT/V559D、C-KIT/V559D/T670I、C-KIT/T670I、PDGFRα、PDGFRβ、VEGFR2、RET、FLT3、FGFR1、FGFR2、FGFR3、FGFR4转入蛋白的细胞系。
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM于DMSO中)的测试化合物分别加入到上述细胞中，并孵育72小时，用CCK8(贝博，中国)细胞活力检测试剂盒，通过对活细胞中的还原脱氢酶进行定量测定来检测活细胞数目。确定本发明的化合物针对各测试细胞的GI 50值(单位)，实验结果见表2。
表2
Figure PCTCN2017118602-appb-000206
Figure PCTCN2017118602-appb-000207
Figure PCTCN2017118602-appb-000208
Figure PCTCN2017118602-appb-000209
表2(续)
Figure PCTCN2017118602-appb-000210
Figure PCTCN2017118602-appb-000211
Figure PCTCN2017118602-appb-000212
Figure PCTCN2017118602-appb-000213
Figure PCTCN2017118602-appb-000214
表2(续)
Figure PCTCN2017118602-appb-000215
Figure PCTCN2017118602-appb-000216
Figure PCTCN2017118602-appb-000217
Figure PCTCN2017118602-appb-000218
通过测试发现本发明的化合物的主要靶点是CKIT、CKIT/T670I、BCR-ABL/T315I、PDGFRα、PDGFRβ、和VEGFR2。本发明的化合物对TEL-CKIT/T670I-BaF3、胃肠道间质瘤GIST-T1有明显的抑制作用，这可以证明这些化合物能够用于治疗胃肠道间质瘤，并且对于T670I点突变产生耐药的胃肠道间质瘤特别有效。此外，本发明的一些优选化合物还进一步对P210/T315I-BaF3细胞有作用。P210/T315I-BaF3是一种BCR-ABL/T315I突变的细胞系，而BCR-ABL/T315I是慢性髓性白血病临床中常见的耐药突变，目前没有特别好的小分子抑制剂能够治疗该突变的慢性髓性白血病。
基于以上发现，本申请的发明人进一步选用本发明的优选化合物142进行测试，确定其对人慢性髓性白血病细胞K562(表达P210Bcr-Abl突变型基因)、人慢性髓性白血病细胞MEG-01(表达P210Bcr-Abl突变型基因)、人慢性髓性白血病细胞Ku812(表达P210Bcr-Abl突变型基因)(上述细胞均购自ATCC(美国)) 的GI 50值(单位)，实验结果见表3。
表3
GI 50/μM 化合物142
K562 0.0012
KU812 0.005
MEG01 0.0014
如上表所示，本发明的一些优选化合物对P210/T315I-BaF3细胞有很强的抑制作用，并且这些化合物还对三种表达BCR-ABL融合基因的慢性髓性白血病细胞系K562、MEG-01、KU812的增殖有显著的抑制，GI 50均小于0.01μM。这证明本发明的优选化合物对慢性髓性白血病有较好的治疗效果，并且对点突变T315I引起的耐药的慢性髓性白血病也有一定的治疗作用。
实施例180：动物实验
在本实施例中，分别测试化合物4和化合物142在TEL-cKIT/T670I-BaF3及P210/T315I-BaF3的小鼠模型中的实验结果。
实验步骤如下：
(1)从北京维通利华实验动物有限责任公司购买饲养4-6周龄的Bal b/c雌性小鼠，饲养于SPF级实验室中，饮水及垫料均经高压消毒无菌处理，有关小鼠的所有操作均在无菌条件下进行；
(2)第0天分别在所有小鼠左侧背部皮下分别注入约5×10 6个TEL-cKIT/T670I-BaF3或5×10 6个P210/T315I-BaF3细胞；
(3)对于TEL-cKIT/T670I-BaF3的小鼠模型从第6天开始，每天使对应小鼠口服给药甲基纤维素(HKI)溶媒(5只小鼠)；剂量为25mg/kg鼠重的化合物4(5只小鼠)；剂量为100mg/kg鼠重的伊马替尼(购自MedChem Express,中国)(5只小鼠)。对于P210/T315I-BaF3的小鼠模型从第6天开始，每天使对应小鼠口服给药甲基纤维素(HKI)溶媒(5只小鼠)；剂量为25mg/kg鼠重的化合物142(5只小鼠)；剂量为50mg/kg鼠重的化合物142(5只小鼠)；剂量为100mg/kg鼠重的化合物142(5只小鼠)；
(4)从第6天开始，每天用游标卡尺测量皮下肿瘤的长/宽，并每天记录小鼠体重，分别确定化合物4和化合物142对小鼠体重的影响；
(5)第18天处死小鼠，取出皮下肿瘤，将肿瘤称重比较；
(6)统计内皮下肿瘤生长趋势，肿瘤体积计算方法：长×宽×宽/2mm 3。
实验结果如图1a-c和2a-c所示。化合物4在TEL-cKIT/T670I-BaF3的小鼠肿瘤模型中，用药剂量为25mg/kg时已经表现出一定的抑制小鼠肿瘤的效果，且随 着用药天数的增加，化合物4对小鼠肿瘤的抑制作用愈发显著，抑瘤率高达49.6％。化合物4不仅有效地抑制小鼠肿瘤的生长，并且对小鼠的体重基本没有影响，表明化合物4可适用于动物给药。这也证明了本发明的CKIT/T670I抑制剂化合物4能够用于治疗T670I突变的胃肠道间质瘤。对于化合物142在P210/T315I-BaF3小鼠模型中，用药剂量为25mg/kg时已经表现出一定的抑制小鼠肿瘤的效果，且随着用药剂量及用药天数的增加，化合物142对小鼠肿瘤的抑制作用愈发显著，用药100mg/kg时抑瘤率高达69％。化合物142不仅有效地抑制小鼠肿瘤的生长，并且对小鼠的体重基本没有影响，表明化合物142可适用于动物给药。这也证明了本发明的BCR-ABL/T315I抑制剂化合物142能够用于治疗T315I突变的慢性髓性白血病。
工业应用性
本发明提供一种新型激酶抑制剂化合物，其可以用于降低或抑制细胞或受试者的cKIT(特别是突变型cKIT/T670I)、BCR/ABL(特别是突变型BCR-ABL/T315I)、PDGFRα、PDGFRβ、和/或VEGFR2激酶活性，并且/或者在受试者中预防或治疗cKIT(特别是突变型cKIT/T670I)、BCR/ABL(特别是突变型BCR-ABL/T315I)、PDGFRα、PDGFRβ、和/或VEGFR2活性相关病症。因而，可将其制成相应的药物，适于工业应用。
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。

Claims (17)

  1. 一种激酶抑制剂，其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
    Figure PCTCN2017118602-appb-100001
    其中，X选自
    Figure PCTCN2017118602-appb-100002
    Figure PCTCN2017118602-appb-100003
    Y选自苯基、噻吩-2-基、异噁唑-3-基、吡啶-3-基、吡啶-4-基、2-吡咯烷酮-5-基、N-甲基-2(1H)-吡啶酮-5-基、和呋喃-2-基；
    R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
    (R 2) n表示任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自羟基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
    Figure PCTCN2017118602-appb-100004
    Figure PCTCN2017118602-appb-100005
    R 3选自卤素、氨酰基、C 1-6烷基、
    Figure PCTCN2017118602-appb-100006
    R 4选自C 1-6烷基；
    R 5选自氢和C 1-6烷基氨基。
  2. 根据权利要求1所述的激酶抑制剂，其包括(Ia)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
    Figure PCTCN2017118602-appb-100007
    其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、 和任选被R 3基团取代的苯基；
    (R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
    Figure PCTCN2017118602-appb-100008
    R 3选自卤素、氨酰基、C 1-6烷基、
    Figure PCTCN2017118602-appb-100009
    R 4选自C 1-6烷基；
    R 5选自C 1-6烷基氨基。
  3. 根据权利要求1所述的激酶抑制剂，其包括(Ib)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
    Figure PCTCN2017118602-appb-100010
    其中R 1选自氢、C 1-6烷基、2-(吡啶-2-基)乙烯基、任选被R 3基团取代的吡啶-3-基、任选被R 3基团取代的苯基、和任选被R 3基团取代的吡唑-4-基；
    (R 2) n表示在苯环的邻位、间位和对位任选被n个独立的R 2取代基所取代，其中n为0-5的整数，R 2独立地选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6酰氨基、C 1-6烷基氨基、4-甲基-咪唑-1-基、
    Figure PCTCN2017118602-appb-100011
    Figure PCTCN2017118602-appb-100012
    R 3选自C 1-6烷基和
    Figure PCTCN2017118602-appb-100013
    R 4选自C 1-6烷基；
    R 5选自氢和C 1-6烷基氨基。
  4. 根据权利要求1所述的激酶抑制剂，其包括以下化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
    Figure PCTCN2017118602-appb-100014
    Figure PCTCN2017118602-appb-100015
    Figure PCTCN2017118602-appb-100016
    Figure PCTCN2017118602-appb-100017
    Figure PCTCN2017118602-appb-100018
    Figure PCTCN2017118602-appb-100019
    Figure PCTCN2017118602-appb-100020
    Figure PCTCN2017118602-appb-100021
    Figure PCTCN2017118602-appb-100022
    Figure PCTCN2017118602-appb-100023
  5. 一种药物组合物，其包括如权利要求1-4中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物，以及药学上可接受的载体或赋形剂，以及任选的其它治疗剂。
  6. 根据权利要求1-4中任一项所述的激酶抑制剂在制备用于抑制选自cKIT、BCR/ABL、PDGFRα、PDGFRβ、和VEGFR2中的一种或多种的酪氨酸激酶活性的药物中的用途。
  7. 根据权利要求6所述的用途，其中所述激酶抑制剂用于抑制选自突变型cKIT/T670I和突变型BCR-ABL/T315I中的一种或多种的酪氨酸激酶活性。
  8. 根据权利要求1-4中任一项所述的激酶抑制剂在制备用于治疗或预防由选自cKIT、BCR/ABL、PDGFRα、PDGFRβ、和VEGFR2中的一种或多种的酪氨酸激酶活性调节的或者受其影响的疾病、障碍或病症的药物中的用途。
  9. 根据权利要求8所述的用途，其中所述疾病、障碍或病症由选自突变型cKIT/T670I和突变型BCR-ABL/T315I中的一种或多种酪氨酸激酶活性调节或者受其影响。
  10. 根据权利要求8或9所述的用途，其中所述疾病、障碍或病症选自：实体瘤、尤其肉瘤、胃肠道间质瘤、急性粒细胞白血病、慢性髓性白血病、间皮瘤、甲状腺癌、系统性肥大细胞病、嗜酸性细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、银屑病、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛、或其组合。
  11. 根据权利要求8或9所述的用途，其中所述疾病、障碍或病症选自：胃肠道间质瘤、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、或其组合。
  12. 根据权利要求1-4中任一项所述的激酶抑制剂，用于抑制选自cKIT、BCR/ABL、PDGFRα、PDGFRβ、和VEGFR2中的一种或多种的酪氨酸激酶活性。
  13. 根据权利要求12所述的激酶抑制剂，用于抑制选自突变型cKIT/T670I和突变型BCR-ABL/T315I中的一种或多种的酪氨酸激酶活性。
  14. 根据权利要求1-4中任一项所述的激酶抑制剂，用于治疗或预防由选自cKIT、BCR/ABL、PDGFRα、PDGFRβ、和VEGFR2中的一种或多种的酪氨酸激 酶活性调节的或者受其影响的疾病、障碍或病症。
  15. 根据权利要求14所述的激酶抑制剂，其中所述疾病、障碍或病症由选自突变型cKIT/T670I和突变型BCR-ABL/T315I中的一种或多种酪氨酸激酶活性调节或者受其影响。
  16. 根据权利要求14或15所述的激酶抑制剂，其中所述疾病、障碍或病症选自：实体瘤、尤其肉瘤、胃肠道间质瘤、急性粒细胞白血病、慢性髓性白血病、间皮瘤、甲状腺癌、系统性肥大细胞病、嗜酸性细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、银屑病、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛、或其组合。
  17. 根据权利要求14或15所述的激酶抑制剂，其中所述疾病、障碍或病症选自：胃肠道间质瘤、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、或其组合。
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