WO2017206962A1 - Flt3激酶的新型抑制剂及其用途 - Google Patents

Flt3激酶的新型抑制剂及其用途 Download PDF

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WO2017206962A1
WO2017206962A1 PCT/CN2017/087159 CN2017087159W WO2017206962A1 WO 2017206962 A1 WO2017206962 A1 WO 2017206962A1 CN 2017087159 W CN2017087159 W CN 2017087159W WO 2017206962 A1 WO2017206962 A1 WO 2017206962A1
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flt3
group
compound
alkyl
cancer
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PCT/CN2017/087159
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English (en)
French (fr)
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刘青松
刘静
李希祥
王傲莉
齐紫平
吴宏
吴佳昕
王文超
胡晨
陈程
王黎
王蓓蕾
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合肥中科普瑞昇生物医药科技有限公司
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Priority to EP17805907.7A priority Critical patent/EP3466952B1/en
Priority to US16/306,647 priority patent/US10975082B2/en
Publication of WO2017206962A1 publication Critical patent/WO2017206962A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a novel FLT3 kinase inhibitor compound, a pharmaceutical composition comprising the same, and the use of these compounds and compositions to reduce or inhibit wild-type FLT3 kinase and/or mutant FLT3 in cells or in a subject
  • the activity of a kinase, and the use and method of preventing or treating a condition associated with FLT3 in a subject are novel FLT3 kinase inhibitor compound, a pharmaceutical composition comprising the same, and the use of these compounds and compositions to reduce or inhibit wild-type FLT3 kinase and/or mutant FLT3 in cells or in a subject.
  • Protein kinases are enzyme components of signal transduction pathways that catalyze the transfer of terminal phosphates of ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins.
  • Overexpression or inappropriate expression of normal or mutated protein kinases in mammals has been the subject of extensive research and has been shown to play an important role in the development of many diseases including diabetes, angiogenesis, psoriasis. , restenosis, eye disease, schizophrenia, rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer. Therefore, inhibitors of protein kinases have particular applications in the treatment of human and animal diseases.
  • FLT3 (Fms-like tyrosine kinase 3) is a FMS-like tyrosine kinase 3, which belongs to the class of receptor tyrosine kinase III (RTK III) family, which is the same as c-Kit, c-FMS and PDGFR.
  • the protein structure includes an extracellular region consisting of five immunoglobulin (Ig)-like domains, a transmembrane region, a proximal membrane region (JM), and two intracellular regions separated by a kinase insertion region.
  • Tyrosine kinase (TK) region (SDLyman et al, Oncogene, 1993, 8, 815-822).
  • FLT3 mutations were first discovered in acute myeloid leukemia (AML) cells, and the mutation type was internal tandem repeat (FLT3/ITD). In recent years, many studies have confirmed that activating mutations in FLT3 play an important pathological role in the development of AML and the progression of the disease.
  • AML acute myeloid leukemia
  • FLT3/ITD internal tandem repeat
  • AML patients with FLT3/ITD activating mutations usually have unique clinical features such as high peripheral blood white blood cell count, poor clinical prognosis, and recurrence, and because the detection method of FLT3 activating mutation is simple and easy, more and more researchers Committed to the development of FLT3 as a routine detection of AML to guide the treatment and prognosis of patients with AML and as a means of detection of minimal residual leukemia, and as a new target for chemotherapy drugs in leukemia patients.
  • Hematological malignancies are cancers of the body's blood formation and immune system, bone marrow and lymphoid tissues. Although in normal bone marrow, FLT3 expression is restricted to early progenitor cells, but in the blood In malignant tumors, FLT3 is expressed at high levels or FLT3 mutations cause uncontrolled FLT3 receptor and downstream molecular channel induction, possibly RAS activation.
  • Hematological malignancies include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma—for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia Or acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated cell leukemia (AUL), degenerative developmental large cell lymphoma (ALCL), adult T cell ALL, AML (AML/TMDS) with mixed lineage dysplasia, mixed lineage leukemia (MLL), spinal dysplasia Signs (MDSs), myelodysplastic disorders (MPD), multiple myeloma (MM), and myeloma (Kottaridis, PD, REG
  • FLT3 and mutant FLT3 have become a research hotspot, mainly for the development of small molecule tyrosine kinase inhibitors, which inhibits the activity by competing with the FLT3 tyrosine kinase for ATP binding sites.
  • the kinase inhibitors that have entered the clinical inhibition of FLT3 are AC220 and the like.
  • some patients who have been treated with existing drugs are found to be resistant to the drug at a later stage of treatment. Studies have shown that such resistance is caused by high expression of the ligand FL (FLT3Ligand) co-expressed with FLT3.
  • the present invention provides a novel FLT3 kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite, or precursor thereof medicine:
  • X and Y is C and the other is selected from C and N;
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 alkylamino, C 1-8 haloalkoxy, C 1-8 Aminoalkyl, C 1-8 aminoalkoxy, C 1-8 alkylamino C 1-8 alkoxy, quaternary ammonium C 1-8 alkoxy, C 1-8 alkanoyl C 1-8 alkyl, Arylcarbonyl C 1-8 alkyl, C 1-8 alkanoyl C 1-8 alkoxy, arylcarbonyl C 1-8 alkoxy, aminosulfonyl, C 1-8 alkylaminosulfonyl, C 3-6 heterocycloalkyl, aminoacyl, C 1-8 alkylaminocarbonyl, C 3-6 heterocycloalkylcarbonyl, C 3-6 cycloalkyl, C 1-8 alkyl (C 3-6 hetero Cycloalkyl), C 1-8 alk
  • R 2 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkylamino C 1-8 alkyl, aryl and heteroaryl, wherein aryl and heteroaryl are optionally 1-3 R 4 groups are substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, and C 1-8 haloalkyl;
  • R 4 is independently selected from halogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 aminoalkyl, C 1-8 Alkanoyl, C 1-8 alkylsulfonyl, and aminoacyl.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) provided herein, or a pharmaceutically acceptable salt, solvate, isomer, ester, acid thereof, or a pharmaceutically acceptable salt thereof , a metabolite or prodrug, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
  • the invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, of the invention.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • a solvate, isomer, ester, acid, metabolite or prodrug to reduce or inhibit wild-type FLT3 kinase and/or mutant FLT3 kinase activity in vivo or in vitro.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, or a pharmaceutical combination comprising a compound of formula (I) Use in the preparation of a medicament for the treatment of a condition associated with FLT3.
  • condition is responsive to wild-type FLT3 or mutant FLT3 kinase inhibition.
  • FLT3 mutations include ITD mutations and point mutations, especially FLT3/ITD mutations.
  • Figure 1 shows the effect of Compound 1 on the upstream and downstream signaling pathways of FLT3 in three cells, wherein Figures 1a, 1b and 1c show the results in MOLM-14, MOLM-13 and MV-4-11 cells, respectively;
  • Figure 2 shows the effect of Compound 1 on proteases closely related to apoptosis in three cells, wherein Figures 1a, 1b and 1c show MOLM-13, MV-4-11 and MOLM-14 cells, respectively. result;
  • Figures 3a, 3b and 3c show the effect of Compound 1 on the cell cycle of MOLM-13, MOLM-14 and MV-4-11 cell lines, respectively;
  • Figure 4 is a graph showing the inhibitory effect of Compound 1 on tumors in a subcutaneous tumor-bearing model in nude mice, wherein Figure 4a shows a graph of the body weight of mice as a function of the number of days of administration of the compound; Figure 4b shows that the relative size of the tumor varies with the number of days of administration of the compound. Graph; Figure 4c shows the tumor inhibition rate in the different dose groups.
  • 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.
  • Conventional methods are well known and described in various general and more specific documents, which are cited and discussed in this specification.
  • Alkyl means an aliphatic hydrocarbon group which 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.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. It will be understood that "alkyl” as referred to herein includes all alkyl groups which may be present in all configurations and conformations, such as “butyl” as referred to herein, including n-butyl, isobutyl and t-butyl.
  • Alkoxy means an -O-alkyl group 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 means an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.
  • cyano refers to a radical of the formula -CN.
  • amino refers to the group -NH 2.
  • aminoacyl refers to -CO-NH 2.
  • aminomido or “amido” refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.
  • quaternary ammonium group refers to -N + RR'R", wherein R, R' and R" are each independently selected from C 1-8 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 .
  • aralkylamino refers to a group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
  • hydroxyalkyl or “hydroxyalkyl” refers to an alkyl substituent further substituted with one or more hydroxy groups.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • alkylcarbonyl or “alkanoyl” refers to a carbonyl group further substituted with an alkyl group.
  • alkylcarbonylalkyl or “alkanoylalkylalkyl” refers to an alkyl group further substituted with an alkylcarbonyl group.
  • alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted with an alkylcarbonyl group.
  • alkoxycarbonyl refers to a carbonyl group which is further substituted with an alkoxy group.
  • Alkylaminoalkyl means an alkyl group, as defined herein, substituted by an alkylamino group, as defined herein.
  • Alkylaminosulfonyl means that a sulfone group, as defined herein, is substituted with an alkylamino group, as defined herein.
  • Alkylaminocarbonyl means a carbonyl group, as defined herein, substituted by an alkylamino group, as defined herein.
  • Alkylsulfoneamino or "cycloalkylsulfonylamino” means an amino group, as defined herein, substituted by an alkylsulfone or cycloalkylsulfone 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).
  • Alkyl(aryl) or “aralkyl” means 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.
  • arylcarbonyl refers to a carbonyl group, as defined herein, substituted by an aryl group, as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen.
  • the cycloalkyl group includes a group having 3 to 8 ring atoms.
  • the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group” having 3 to 6 carbon atoms.
  • Alkyl(cycloalkyl) or “cycloalkylalkyl” refers to an alkyl group, as defined herein, substituted by a cycloalkyl group, as defined herein.
  • Non-limiting alkyl (cycloalkyl) groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • 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. Miscellaneous The atom(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.
  • 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 Mercapto, pteridinyl, fluorenyl, oxadiazolyl, thiadiazolyl, furyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthalene Pyridyl and
  • 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 gums, 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 (heteroaryl) or “heteroarylalkyl” refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
  • alkyl (heterocycloalkyl) or “heterocycloalkylalkyl” refers to an alkyl group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • heterocycloalkylcarbonyl refers to a carbonyl group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • heterocycloalkylamino refers to a heterocycloalkane as defined herein, wherein the amino group is as defined herein. Substituted.
  • 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.
  • 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.
  • substituted means that the group mentioned may be substituted by one or more additional groups, each of which is independently and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl , hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, alkylcarbonyl, alkoxycarbonyl, alkyl (heteroaryl), alkyl (heterocycloalkyl), alkane Sulfone group, aminoacyl group, and the like.
  • 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. This includes 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.
  • prodrug includes compounds having moieties that can be metabolized in the body. Typically, the prodrug is metabolized in vivo to the active drug by esterase or by other mechanisms. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form or hydroxyl group with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g.
  • acylamino lower alkyl ester eg acetoxymethyl ester
  • acyloxy lower alkyl ester eg pivaloyloxymethyl ester
  • aryl ester phenyl Ester
  • aryl lower alkyl esters eg benzyl esters
  • substituted eg substituted by methyl, halogen or methoxy substituents
  • aryl and aryl lower alkyl esters amides, lower alkyl amides , a lower alkyl amide and a hydroxy amide.
  • Preferred prodrug moieties are propionates and acyl esters.
  • Prodrugs which are converted to the active form by other mechanisms in vivo are also included.
  • the compounds of the invention are prodrugs of any of the formulae herein.
  • the enantiomerically enriched compounds, racemates, or mixtures of diastereomers can be used to carry out the process of the invention.
  • 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 FLT3.
  • Drug resistance refers to the tolerance of microorganisms, parasites, and tumor cells to the action of chemotherapeutic drugs. Once drug resistance occurs, the chemotherapy effect of drugs is significantly reduced. Drug resistance can be divided into resistance and natural resistance according to its causes. For anti-tumor drugs, the insensitivity of tumor cells to malignant tumor drugs, that is, drug resistance, is an important cause of tumor chemotherapy failure, and it is also an urgent problem to be solved for tumor chemotherapy.
  • the drug resistance involved in the present invention generally refers to a patient suffering from a disease associated with FLT3 undergoing the present invention. Drug resistance produced after treatment with drugs other than the compound.
  • 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.
  • EGFR epidermal growth factor receptor
  • BMX bone tyrosine kinase
  • ABL as used in this specification refers to a protein expressed by an Abelson murine leukemia virus oncogene.
  • MET refers to the hepatocyte growth factor receptor, also known as HGFR.
  • a protein carrying a specific mutation is expressed by the following method: "/", "-” or “[]” is used to link the specific mutation after the name of the mutated protein.
  • a FLT3 mutant kinase with an internal tandem repeat is abbreviated as FLT3/ITD, FLT3-ITD or FLT3 [ITD]
  • a FLT3 mutant kinase with D835Y is abbreviated as FLT3/D835Y, FLT3/D835Y or FLT3 [D835Y].
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides a novel FLT3 kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite, or prodrug thereof:
  • X and Y is C and the other is selected from C and N;
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 alkylamino, C 1-8 haloalkoxy, C 1-8 Aminoalkyl, C 1-8 aminoalkoxy, C 1-8 alkylamino C 1-8 alkoxy, quaternary ammonium C 1-8 alkoxy, C 1-8 alkanoyl C 1-8 alkyl, Arylcarbonyl C 1-8 alkyl, C 1-8 alkanoyl C 1-8 alkoxy, arylcarbonyl C 1-8 alkoxy, aminosulfonyl, C 1-8 alkylaminosulfonyl, C 3-6 heterocycloalkyl, aminoacyl, C 1-8 alkylaminocarbonyl, C 3-6 heterocycloalkylcarbonyl, C 3-6 cycloalkyl, C 1-8 alkyl (C 3-6 hetero Cycloalkyl), C 1-8 alk
  • R 2 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkylamino C 1-8 alkyl, aryl and heteroaryl, wherein aryl and heteroaryl are optionally 1-3 R 4 groups are substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, and C 1-8 haloalkyl;
  • R 4 is independently selected from halogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 aminoalkyl, C 1-8 Alkanoyl, C 1-8 alkylsulfonyl, and aminoacyl.
  • both X and Y are C.
  • R 1 is a substituent on X or Y, and more preferably a substituent on Y.
  • the alkyl group described in the substituents of R 1 , R 2 , R 3 and R 4 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
  • the aryl group is preferably a phenyl group
  • the heteroaryl group is preferably an isoxazolyl group or a thiazolyl group
  • the heterocycloalkyl group is preferably a 6-membered heterocycloalkyl group such as morpholine Or a piperidinyl group, a piperazinyl group or a tetrahydropyranyl group
  • the alkanoyl group is preferably an acetyl group or a propionyl group
  • the alkylamino group is preferably a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group or a methyl ethyl group
  • the alkyl sulfone group is preferably a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group,
  • the invention provides a novel FLT3 kinase inhibitor comprising a compound of formula (II), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite, or prodrug thereof:
  • R 1 is selected from the group consisting of hydrogen, a C 1-8 alkylamino group (e.g., dimethylamino group, etc.), and a C 1-8 alkylamino C 1-8 alkoxy group (e.g., 2-two).
  • C 1-8 alkoxy C 3- 6 heterocycloalkyl
  • C 3- 6 heterocycloalkyl eg 2-morpholinomethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, (2-piperidin-1-yl)ethoxy, 2 -(4-(methylsulfonyl)piperazin-1-yl)ethoxy, (4-methylpiperazin-1-yl)ethoxy, etc.
  • C3-6 heterocycloalkyl Carbonyl C 1-8 alkyl (eg 2-morpholino-2-oxoethyl, 3-morpholino-3-oxopropyl, 3-(4-ethylpiperazin-1-yl)- 3-oxopropyl, etc.
  • Alkylaminocarbonyl eg (tetrahydropyran-4-yl)aminocarbonyl, morpholinoaminocarbonyl, etc.
  • amide C 1-8 alkylamino C 1-8 alkyl) (eg 2-(di) methylamino) acetamido, etc.)
  • C 1-8 alkylamino C 1-8 alkylamino (e.g., (2- (dimethylamino) ethyl) methyl Amino, etc.).
  • R 1 is most preferably C 1-8 alkoxy (C 3-6 heterocycloalkyl), especially 2-morpholinomethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy And (2-piperidin-1-yl)ethoxy and the like.
  • R 2 is selected from a C 1-8 alkyl group (e.g., isobutyl group, etc.), a C 1-8 alkylamino C 1-8 alkyl group (e.g., 2-(dimethylamino).
  • phenyl eg 4-(tert-butyl)phenyl, 4-methyl-3-(trifluoromethyl)phenyl, 4-chloro-3-(trifluoromethyl) a phenyl group, a 3,4,5-trimethoxyphenyl group, etc.
  • heteroaryl group eg, isoxazol-3-yl, 5-(methyl)isoxazol-3-yl, 5-(tert-butyl)isoxazol-3-yl, 4-(tert-butyl)thiazol-2-yl, 4-(trifluoromethyl)thiazol-2-yl, etc.
  • R 2 is 5-(tert-butyl)isoxazol-3-yl.
  • R 3 is selected from the group consisting of hydrogen and a C 1-8 alkyl group (e.g., methyl group, etc.). R 3 is most preferably hydrogen.
  • preferred FLT3 kinase inhibitors include the following compounds of Table 1 and pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites, or prodrugs thereof:
  • the present invention relates to chiral compounds which may be in any configuration or in a mixed racemate.
  • kinase inhibitors Described herein are novel kinase inhibitors.
  • Pharmaceutically acceptable salts, solvates, isomers, 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
  • Acceptable 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 invention also relates to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier or Excipients, and optionally other therapeutic agents.
  • the compound of the formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof and a pharmaceutical composition comprising the same are hereinafter also referred to as "the substance of the present invention".
  • the agents of the invention are useful for treating or preventing a disorder associated with FLT3, particularly a disease responsive to protein tyrosine kinase inhibition, particularly wild-type FLT3 or mutant FLT3 kinase inhibition.
  • FLT3 mutations include ITD mutations and point mutations, especially ITD mutations.
  • "Treatment" of the invention can be therapeutic (eg, symptomatic treatment) and/or prophylactic.
  • the substance of the present invention preferably treats or prevents a condition associated with FLT3, and particularly preferably treats or prevents a condition associated with mutant FLT3/ITD.
  • the agents of the invention are useful for treating or preventing a cell proliferative disorder selected from benign or malignant tumors including, but not limited to, the presence or development of a solid tumor, a sarcoma, a lymphoma (eg, B-cell lymphoma, diffuseness) Severe B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia Acroglobulinemia), spleen marginal zone lymphoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymus) large B-cell lymphoma, intravascular large B Cellular lymphoma, primary exudative lymphoma, Burkitt lymphoma, leukemia (eg chronic lymphocytic leukemia, B-cell prolymphocytic leukemia
  • the agents of the invention preferably treat or prevent FLT3-related disorders, particularly preferably to treat or prevent disorders associated with mutant FLT3/ITD, including but not limited to: hematological malignancies, including leukemias, lymphomas (eg, non-Hodgkin) Lymphoma, Hodgkin's lymphoma) and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic granules Cellular leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated cell leukemia (AUL), degenerative large cell lymphoma (ALCL), adult T-cell ALL, with trilineage spinal cord Dysplastic AML (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myelodysplastic (MPD), multiple myelo
  • the warm-blooded animal can be administered by at least one of injection, oral, inhalation, rectal and transdermal administration.
  • the dosage of the active ingredient will be determined based on the individual characteristics (e.g., age, weight, medical history, individual pharmacokinetic data, etc.) to be treated, the type of disease, and the mode of administration.
  • agents of the invention may optionally be used in combination with known methods of treatment, such as administration of other therapeutic agents or radiation therapy.
  • Other therapeutic agents include, for example, cytostatics, other anti-proliferative agents, and the like.
  • antiproliferative agents include, but are not limited to, aromatase inhibitors, antiestrogens, topologies Isomerase I inhibitor, topoisomerase II inhibitor, microtubule active agent, alkylating agent, histone deacetylase inhibitor, farnesyl transferase inhibitor, COX-2 inhibitor, MMP inhibitor , mTOR inhibitors, anti-neoplastic antimetabolites, platinum compounds, compounds that reduce protein kinase activity and further anti-angiogenic compounds, gonadotropin-releasing factor agonists, antiandrogens, bengamide, bisphosphonates, Steroids, anti-proliferative antibodies, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) and temozolomide (TMEMODAL).
  • aromatase inhibitors include, but are not limited to, aromatase inhibitors, antiestrogens, topologies Isomerase I inhibitor, topoisomerase II inhibitor, microtubule active agent, al
  • aromatase inhibitor as used herein relates to a compound which inhibits the production of estrogen by an aromatase which prevents the conversion of androstenedione and estradiol.
  • the term includes, but is not limited to, steroids such as exemestane and formestane, and non-steroids such as aminoglutethimide, vorozole, fadrozole, anastrozole, letrozole, especially letrozole.
  • Exemestane can be administered, for example, in the form as it is marketed, for example under the trademark AROMASIN (TM) .
  • Formestane can be administered, e.g., in the form as it is marketed, e.g.
  • Fadrozole may be administered in the form as it is marketed, e.g. under the trademark AFEMA TM.
  • the aminoglutethimide can be administered, for example, in the form as it is marketed, e.g. under the trademark ORIMETEN (TM) .
  • the agents of the invention are particularly useful in the treatment of hormone receptor positive breast tumors when used in combination with aromatase inhibitors.
  • antiestrogens as used herein relates to compounds which antagonize the effects of estrogen at the level of estrogen receptors.
  • the term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
  • Tamoxifen for example, can be administered in the form as it is marketed, eg under the trademark NOLVADEX TM.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA (TM) .
  • Fulvestrant can be formulated as described in US 4,659,516, or can be administered, for example, in the form as it is marketed, for example under the trademark FASLODEX (TM) .
  • topoisomerase I inhibitor includes, but is not limited to, topotecan, irinotecan, 9-nitrocamptothecin conjugate PNU-166148 (compound A1 in WO 99/17804).
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark CAMPTOSAR (TM) .
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN (TM) .
  • topoisomerase II inhibitors includes but is not limited to anthracycline-based (antracycline) doxorubicin (including liposomal formulation, e.g. CAELYX TM), epirubicin, idarubicin and Nye Nemorubin, mitoxantrone and rosin, and podophyllotoxin etoposide and teniposide.
  • Etoposide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ETOPOPHOS (TM) .
  • Teniposide can be, for example, drug delivery marketed, e.g. under the trademark VM 26-BRISTOL TM.
  • Doxorubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ADRIBLASTIN (TM) .
  • Idarubicin may be administered in the form as it is marketed, e.g. under the trademark ZAVEDOS TM.
  • Mitoxantrone may be administered in the form as it is marketed, e.g. under the trademark NOVANTRON TM.
  • microtubule active agent relates to microtubule stabilizing agents, including but not limited to paclitaxel and docetaxel, vinca alkaloids such as vinblastine, especially vinblastine sulfate, spongolactone ( Discodermolide) and epothilone, such as epothilone B and D.
  • Docetaxel can be administered, for example, in the form as it is marketed, for example under the trademark TAXOTERETM.
  • Vinblastine sulfate can be administered in the form as it is marketed, e.g. under the trademark VINBLASTIN RP TM.
  • Vincristine sulfate can be administered, for example, in the form as it is marketed, e.g. under the trademark FARMISTION (TM) .
  • Spongolactones can be obtained, for example, as described in US 5010099.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, and melphalan.
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN (TM) .
  • Ifosfamide can be administered in the form as it is marketed, e.g. under the trademark HOLOXAN TM.
  • histone deacetylase inhibitor relates to a compound that inhibits histone deacetylase and possesses anti-proliferative activity. This includes the compounds disclosed in WO 02/22577, especially N-hydroxy-3-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl -2E-2-acrylamide, N-hydroxy-3-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]- 2E-2-acrylamide and a pharmaceutically acceptable salt thereof. Further especially includes suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • farnesyl transferase inhibitor relates to a compound which inhibits farnesyl transferase and which possesses anti-proliferative activity.
  • COX-2 inhibitor relates to compounds which inhibit the cyclooxygenase type 2 enzyme (COX-2) and possess anti-proliferative activity, such as Celebrex, Viofx and Quamila. Cox (COX189).
  • MMP inhibitor relates to a compound that inhibits matrix metalloproteinase (MMP) and possesses anti-proliferative activity.
  • mTOR inhibitors relates to inhibit the mammalian target of rapamycin (of mTOR) and have antiproliferative activity of the compounds, such as sirolimus (Rapamune), everolimus (Certican TM ), CCI-779 and ABT578.
  • anti-neoplastic antimetabolite includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine , 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of such compounds, in addition to ZD1694 (rALTITREXED TM), LY231514 ( ALIMTA TM), LY264618 (LOMOTREXOL TM) and OGT719.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cisplatin, and oxaliplatin.
  • Carboplatin can be administered in the form as it is marketed, e.g. under the trademark CARBOPLAT TM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN (TM) .
  • a compound that reduces protein kinase activity and a further anti-angiogenic compound includes, but is not limited to, compounds that reduce activity such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), c-Src, protein.
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • c-Src protein.
  • Kinase C platelet-derived growth factor (PDGF), Bcr-Abl, c-Kit, FLT3, insulin-like growth factor I receptor (IGF-IR), and cyclin-dependent kinase (CDK), which differ from reduced protein kinases
  • IGF-IR insulin-like growth factor I receptor
  • CDK cyclin-dependent kinase
  • Compounds which reduce VEGF activity include compounds which inhibit the tyrosine kinase activity of VEGF receptors, particularly VEGF receptors, and compounds which bind to VEGF, particularly those compounds, proteins and monoclonal antibodies which are generally and specifically disclosed in the following literature: WQ98/35958 (description of the compound of formula I), WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819, WO01/55114, WO01/58899 and EP0769947; M. Prewett et al. in Cancer Research 59 ( 1999) 5209-5218, Z. Zhu et al., in Cancer Res. 58, 1998, 3209-3214 and J.
  • Compounds which reduce EGF activity are, in particular, compounds which inhibit EGF binding, in particular those which are generally and specifically disclosed in the following documents: WO97/02266 (description of the compound of formula IV), EP0564409, WO99/03854, EP0520722, EP0566226, EP0787722, EP0837063 , WO98/10767, WO97/30034, WO97/49688, WO WO 97/38983 and in particular WO 96/33980.
  • Compounds that reduce c-Src activity include, but are not limited to, compounds that inhibit c-Src protein tyrosine kinase activity and SH2 interaction inhibitors, such as those disclosed in WO97/07131 and WO97/08193, as defined below.
  • Compounds that inhibit c-Src protein tyrosine kinase activity include, but are not limited to, compounds belonging to the following structural classes: pyrrolopyrimidins, especially pyrrolo[2,3-d]pyrimidines; purines; pyrazolopyrimidines, especially Pyrrolo[3,4-d]pyrimidine; pyrazolopyrimidines, especially pyrazolopyrrolo[3,4-d]pyrimidines and pyridopyrimidines, especially pyridopyrrolo[2,3-d]pyrimidines .
  • the term relates to those compounds disclosed in WO 96/10028, WO 97/28161, WO 97/32879 and WO 97/49706.
  • Compounds which reduce the activity of IGF-IR are especially those compounds disclosed in WO 02/92599.
  • Decreasing the protein kinase activity and may further particular compound of the present invention in combination with the material used are Imatinib (Gleevec / Glivec), PKC412 , Iressac TM (ZD1839), AEE788 and pharmaceutically acceptable salts thereof (see WO03 / 13541), PTK787 And pharmaceutically acceptable salts thereof (see also WO 98/35958), ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632, KRN-633 and SU5416.
  • Anti-angiogenic compounds having mechanisms of action different from those that reduce protein kinase activity include, but are not limited to, for example, thalidomide (THALOMID), celecoxib (Celebrex), and ZD6126.
  • Goserelin-releasing factor agonist includes, but is not limited to,jurixix, serotonin, and acetate-containing relin.
  • Goserelin disclosed in US4100274 for example, may be administered in the form as it is marketed, e.g. under the trademark ZOLADEX TM.
  • Abarelix can be formulated, for example, as described in US 5,743,901.
  • antiandrogen as used herein includes, but is not limited to, bicalutamide (CASODEX (TM )) which can be formulated, for example, as described in US 4,634,505.
  • bengamide relates to bengamide and its derivatives having anti-proliferative properties.
  • bisphosphonate as used herein includes, but is not limited to, pamidronic acid, alendronic acid.
  • Estrogenic acid can be administered, for example, in the form as it is marketed, e.g. under the trademark DIDRINEL (TM) .
  • the clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS (TM) .
  • the tiludronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID (TM) .
  • Pamidronic acid can be administered, e.g., in the form as it is marketed, e.g.
  • AREDIA TM
  • Alendronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX (TM) .
  • Ibandronic acid may be, for example, be administered in the form as it is marketed, e.g. under the trademark BONDRANAT TM.
  • Risedronic acid can be administered, for example, in the form as it is marketed, for example under the trademark ACTONOL (TM) .
  • Zoledronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOMETA (TM) .
  • steroid includes hydrocortisone, dexamethasone (Decadron), methylhydronenisone, and prednisolone.
  • antiproliferative antibodies includes, but is not limited to trastuzumab (Trastuzumab) (Herceptin TM), trastuzumab -DM1, erlotinib (Terceva TM), bevacizumab (Avastin TM), rituximab (of Rituxan) , PRO64553 (anti-CD40) and 2C4 antibodies.
  • the compounds of formula (I) can be used in combination with standard leukemia therapies, especially for the treatment of AML.
  • the compounds of formula (I) may be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful in the treatment of AML, such as daunorubicin, doxorubicin, Ara-C, VP-16. , teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.
  • the structure of the active ingredient as determined by the code, generic name or trade name may be from the current version of the standard work "Merck Index” or from a database, such as Patents International (eg IMS World Publications).
  • 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.
  • appropriate intervals such as two, three, four or more divided doses per day.
  • provided herein are methods of making the 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.
  • Step 3 Combination of the compound 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine c to make:
  • the inhibitory effect of the compounds of the present invention on cancer cell proliferation and their selectivity for inhibiting cancer cell proliferation were evaluated by testing the effects of the compounds of the present invention on cancer cell growth (Table 2).
  • human acute myeloid leukemia cell line MV-4-11 (expressing FLT3[ITD] mutant gene), human acute myeloid leukemia cell line MOLM-13 (expressing FLT3[ITD] mutant gene and wild type were selected.
  • FLT3 gene human acute myeloid leukemia cell line MOLM-14 (expressing FLT3 [ITD] mutant gene and wild-type FLT3 gene), human acute myeloid leukemia cell line OCI-AML3 (expressing FLT3 [A680V] mutant gene )
  • Myeloid leukemia cell line U937 (expressing wild-type FLT3 gene) and mouse proB cell BaF3, all of which were purchased from ATCC.
  • Mouse BaF3-FLT3[ITD] (activated kinase stably expressing FLT3[ITD] mutation), mouse tel-BaF3-FLT3-D835Y (activated kinase stably expressing FLT3[D835Y] mutation), mouse tel- was also selected.
  • BaF3-BMX stabilized expression of BMX kinase
  • mouse tel-FLT3-BaF3 stable expression of FLT3 kinase
  • mouse BaF3-FLT3-ITD-D835Y activated kinase stably expressing FLT3 [ITD+D835Y] mutation
  • mouse BaF3-FLT3-ITD-F691L activated kinase stably expressing FLT3[ITD+F691L] mutation
  • mouse tel-cKIT-BaF3 stable expression of cKIT kinase
  • mouse BaF3-tel-cKit-N882K stable expression of cKIT- N882K mutant activated kinase
  • mouse BaF3-tel-cKit-D816V activateated kinase stably expressing cKIT-D816V mutation
  • mouse BaF3-tel-cKit-T670I activated kinas
  • the above cell lines were constructed by our laboratory by PCR to amplify human FLT3/ITD, FLT3D835Y, BMX, FLT3, FLT3[ITD+D835Y], FLT3[ITD+F691L], cKIT, cKIT[N882K], respectively.
  • cKIT[D816V], cKIT[T670I], MET, EGFR, EGFR[L858R], BLK, JAK1, FLT3[K663Q], FLT3[D835V], FLT3[D835H], PDGFRa, PEGFRb, VEGFR2, JAK2, JAK3, ABL kinase Sequences were inserted into MSCV-Puro vectors (purchased from Clontech) with N-terminal TEL or TPR fragments, and stably transferred into mouse BaF3 cells (purchased from ATCC) by retrovirus method, and IL-3 was removed.
  • the three cell lines (MOLM-13 and MOLM-14 and MV-4-11) were used to add the different concentrations of FLT3 ligand FL to the compounds of the invention. 1 In vitro experiments were performed.
  • the IC50 value of Compound 1 measured with the addition of 10 ng/ml FLT3 ligand FL was compared with the addition of FLT3 ligand FL.
  • the IC50 values measured were similar, indicating the proliferation of compound 1 in human acute myeloid leukemia cell lines in the presence of drug-resistant FL ligand overexpression. The activity is basically unaffected.
  • MOLM-14 0.36 MOLM-14+FL (1ng/mL) 0.87 MOLM-14+FL (5ng/mL) 1.0 MOLM-14+FL (10ng/mL) 1.0 MOLM-13 0.27 MOLM-13+FL (1ng/mL) 1.1 MOLM-13+FL (5ng/mL) 1.3 MOLM-13+FL (10ng/mL) 1.1 MV-4-11 0.4 MV-4-11+FL (10ng/mL) 0.38
  • Example 70 Effect of Compound 1 on Upstream and Downstream Signaling Pathway of FLT3 in Cells
  • Human acute myeloid leukemia cell line MV-4-11 (expressing FLT3[ITD] mutant gene), human acute myeloid leukemia cell line MOLM-13 (expressing FLT3[ITD] mutant gene and wild-type FLT3 gene)
  • human acute myeloid leukemia cell line MOLM-14 (expressing FLT3 [ITD] mutant gene and wild-type FLT3 gene) cell line
  • compound 1 and control compound FLT3 were tested by measuring many cell biochemical endpoints and functional endpoints.
  • kinase inhibitor AC220 AC220 from Hao Yuan Chemexpress, Shanghai
  • AC220 AC220 from Hao Yuan Chemexpress, Shanghai
  • compound 1 and Effect of AC220 on phosphorylation of other related protein kinases ERK and AKT AC220 from Hao Yuan Chemexpress, Shanghai
  • Compound 1 and AC220 on c-Myc degradation and phosphorylation of the transcription factor NF- ⁇ B subunit p65 were also examined, with glycerate-3-phosphate dehydrogenase (GAPDH) as an internal standard protein.
  • GPDH glycerate-3-phosphate dehydrogenase
  • control compound FLT3 kinase inhibitor AC220 was also able to inhibit protein kinase FLT3 and phosphorylation of protein STAT5, which is closely related to FLT3/ITD, and degradation of protein c-Myc, and its inhibitory effect was comparable to that of compound 1 at 0.001 ⁇ M. .
  • Example 70 demonstrates that Compound 1 is capable of strongly inhibiting phosphorylation of protein kinase FLT3, affecting phosphorylation of the protein STAT5 downstream of the signaling pathway of protein kinase FLT3 in cells. Based on such results, it is presumed that Compound 1 inhibits cell proliferation of an acute myeloid leukemia cell line carrying the FLT3 and/or FLT3/ITD gene by inhibiting a protein such as protein kinase FLT3.
  • Apoptosis is closely related to the DNA repair enzyme polyadenylation diphosphate-ribose polymerase PARP, cysteine-containing aspartate proteolytic enzyme Caspase 3 protein cleavage effect.
  • MOLM-13, MOLM-14, MV- were treated with different concentrations (0 ⁇ M, 0.003 ⁇ M, 0.01 ⁇ M, 0.03 ⁇ M, 0.1 ⁇ M in DMSO) of Compound 1, 0.1 ⁇ M (in DMSO) of FLT3 kinase inhibitor AC220, respectively.
  • the 4-11 cell line was then harvested after 12 hours, 24 hours, and 48 hours, respectively.
  • Western Blot was used to detect the DNA repair enzyme polyadenylation diphosphate-ribose polymerase PARP and cysteine-containing aspartate proteolytic enzyme Caspase 3 at different time points.
  • GPDH glycerate-3-phosphate dehydrogenase
  • Fig. 2 The experimental results are shown in Fig. 2.
  • MOLM-13 For the acute myeloid leukemia cell line MOLM-13, when the concentration of compound 1 is 0.003 ⁇ M, the obvious DNA repair enzyme polyadenosine diphosphate-ribose can be seen after 12 hours of action. Shearing of the polymerase PARP, as well as the cleaving of the cysteine-containing aspartate proteolytic enzyme Caspase 3. Similar results were observed for the MOLM-14 cell line after 48 hours of Compound 1 administration. For the MV-4-11 cell line, similar results were observed even after 24 hours of administration of Compound 1, and the DNA repair enzyme polyadenosine diphosphate-ribose polymerase PARP was more markedly cleaved.
  • Compound 1 is capable of causing apoptosis of acute myeloid leukemia cells carrying the FLT3 gene and/or the FLT3/ITD mutant gene.
  • the cells were collected, washed twice with 1 ⁇ PBS buffer, fixed with 75% ethanol at -20 ° C for 24 hours, washed twice with 1 ⁇ PBS buffer, and added 0.5 mL 1 ⁇ PBS buffer and 0.5 mL of PI staining solution (purchased from BD Bioscience, USA) were added to the cells and the cells were stained in the dark at 37 ° C for 15 minutes, and the cell cycle distribution was measured by flow cytometry (BD FACS Calibur). 3).
  • Example 72 demonstrates that Compound 1 is capable of blocking the acute myeloid leukemia cells MOLM-13, MOLM-14, and MV-4-11 cells carrying the FLT3/ITD mutant gene in the G0-G1 phase, and has a strong distribution of cell cycle. Impact ( Figure 3).
  • a vehicle ie, methyl fiber.
  • Susie-based aqueous suspension (purchased from Sinopharm Chemical Reagent Co., Ltd.); the second group was orally administered with 3.75 mg/kg of methylcellulose-based aqueous suspension of Compound 1 per day; the third group was orally administered 7.5 per day.
  • the experimental results are shown in Fig. 4.
  • the dose of Compound 1 was 3.75 mg/kg, the tumor growth of the mice was significantly inhibited after 28 days of treatment, and the body weight of the mice did not decrease, and the tumor inhibition rate was as high as possible. 75%.
  • the dose of Compound 1 was 7.5 mg/kg, the tumor of the mice was basically inhibited 28 days after the administration, and the body weight of the mice did not decrease, and the tumor inhibition rate was as high as 92%.
  • the dose of Compound 1 was 15 mg/kg, the tumor of the mice was completely inhibited after administration, and the body weight of the mice did not decrease, and the tumor inhibition rate was as high as 97%.
  • the data of the tumor-transplanted mouse model in this example demonstrate that Compound 1 can significantly inhibit the growth of acute myeloid leukemia (AML) tumors in mice.
  • AML acute myeloid leukemia
  • the present invention provides a novel FLT3 kinase inhibitor compound which can be used to reduce or inhibit wild-type FLT3 kinase and/or mutant FLT3 kinase activity in a cell or in a subject, and/or to prevent or Treating conditions associated with FLT3.
  • a novel FLT3 kinase inhibitor compound which can be used to reduce or inhibit wild-type FLT3 kinase and/or mutant FLT3 kinase activity in a cell or in a subject, and/or to prevent or Treating conditions associated with FLT3.
  • it can be made into a corresponding drug suitable for industrial applications.

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Abstract

本发明提供FLT3激酶的新型抑制剂，其包括式（I）的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药。本发明还提供包括式（I）化合物的药物组合物，以及其用于预防或治疗与FLT3相关的病症的用途和方法，特别是与突变型FLT3激酶（尤其是FLT3/ITD突变型激酶）相关的病症。

Description

FLT3激酶的新型抑制剂及其用途 技术领域
本发明涉及一种新型的FLT3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和组合物来降低或抑制细胞中或受试者中的野生型FLT3激酶和/或突变型FLT3激酶的活性、以及在受试者中预防或治疗与FLT3相关的病症的用途和方法。
背景技术
蛋白激酶是信号转导途径的酶组分，其催化ATP的末端磷酸酯转移到蛋白质的酪氨酸、丝氨酸和/或苏氨酸残基的羟基。在哺乳动物中正常或突变的蛋白激酶的超量表达或不当表达已经成为广泛研究的主题，并且已经证明在许多疾病的发展中起到重要作用，所述疾病包括糖尿病、血管生成、银屑病、再狭窄(restenosis)、眼病、精神分裂症、类风湿性关节炎、动脉粥样硬化、心血管疾病和癌症。因此，蛋白激酶的抑制剂在治疗人类和动物疾病中有特殊的应用。
FLT3(Fms-like tyrosine kinase 3)即FMS样酪氨酸激酶3，它与c-Kit、c-FMS和PDGFR同属于III型受体酪氨酸激酶(receptor tyrosine kinase III，RTK III)家族成员，其蛋白结构包括5个免疫球蛋白(Ig)样结构域组成的胞外区，1个跨膜区，1个近膜区(JM)，以及胞内由激酶插入区分隔而成的2个酪氨酸激酶(TK)区(S.D.Lyman等,Oncogene,1993,8,815-822)。1996年首先在急性髓细胞白血病(AML)细胞中发现了FLT3突变，其突变类型是内部串联重复(FLT3/ITD)。近年来，许多研究已经证实FLT3的激活突变在AML的发生及疾病的进展中起到十分重要的病理作用。具有FLT3/ITD激活突变的AML患者通常具有外周血白细胞计数高、临床预后较差、易复发等独特的临床特征，并且由于FLT3激活突变的检测方法简单易行，故越来越多的研究者致力于将FLT3发展成为AML的常规检测手段用来指导AML患者的治疗和预后的判断以及作为微小残留白血病的检测手段，并将其作为白血病患者化疗药物的又一新的靶点。
血液恶性肿瘤是身体的血液形成和免疫系统、骨髓和淋巴组织的癌症。尽管在正常的骨髓中，FLT3表达只限于早期祖细胞，但在血液 恶性肿瘤中，FLT3以高水平表达或者FLT3突变引起不受控制的FLT3受体和下游分子通道诱导、可能的RAS活化。血液恶性肿瘤包括白血病、淋巴瘤(非霍奇金淋巴瘤)、霍奇金病(也称为霍奇金淋巴瘤)和骨髓瘤——例如，急性淋巴细胞白血病(ALL)、急性粒细胞白血病或急性髓性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、慢性嗜中性细胞白血病(CNL)、急性未分化细胞白血病(AUL)、退行发育性大细胞性淋巴瘤(ALCL)、成人T细胞ALL、伴有三谱系(trilineage)脊髓发育不良的AML(AML/TMDS)、混合型谱系白血病(MLL)、脊髓发育不良综合征(MDSs)、骨髓增生异常(MPD)、多发性骨髓瘤(MM)和脊髓肉瘤(Kottaridis,P.D.,R.E.Gale等人,FLT3mutations and leukaemia,British Journal of Haematology,2003,122(4):523-38；Ansari-Lari,Ali等人,FLT3mutations in myeloid sarcoma,British Journal of Haematology,2004,126(6):785-91.)。
现已证实FLT3的激活突变主要有两种：内部串联重复(internal tandem duplication，ITD)和活化环中的点突变(point mutation in the activation loop，PM点突变)。FLT3的这两种激活突变均能引起FLT3发生自动磷酸化进而导致FLT3发生配体非依赖性的组成性激活，进一步激活其下游异常的信号转导，从而起到促进增殖和抑制凋亡的作用，使得具有此突变表型的白血病患者临床预后较差。
目前对野生型FLT3及突变型FLT3的靶向抑制成为研究热点，主要为开发小分子酪氨酸激酶抑制剂，通过与FLT3酪氨酸激酶竞争ATP结合位点而抑制其活性。目前已经进入临床的抑制FLT3的激酶抑制剂有AC220等。然而，发现使用现有药物进行治疗的一些患者(如AML患者)在治疗后期会对治疗药物产生耐药性。目前已有研究表明，这类耐药性是由与FLT3共表达的配体FL(FLT3Ligand)的高表达而引起的。
发明内容
本发明提供了一种新型FLT3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、异构体、酯、酸、代谢物、或前 药：
Figure PCTCN2017087159-appb-000001
其中，X和Y中的至少一个为C，另一个选自C和N；
R1选自氢、卤素、C1-8烷基、C1-8卤代烷基、C1-8烷氧基、C1-8烷基氨基、C1-8卤代烷氧基、C1-8氨基烷基、C1-8氨基烷氧基、C1-8烷基氨基C1-8烷氧基、季铵基C1-8烷氧基、C1-8烷酰基C1-8烷基、芳基羰基C1-8烷基、C1-8烷酰基C1-8烷氧基、芳基羰基C1-8烷氧基、氨基砜基、C1-8烷基氨基砜基、C3-6杂环烷基、氨酰基、C1-8烷基氨基羰基、C3-6杂环烷基羰基、C3-6环烷基、C1-8烷基(C3-6杂环烷基)、C1-8烷氧基(C3-6杂环烷基)、C3-6杂环烷基羰基C1-8烷基、芳氧基、C1-8烷基砜基、C1-8烷基砜基氨基、C3-6环烷基砜基氨基、C3-6杂环烷基氨基羰基、酰胺基(C1-8烷基氨基C1-8烷基)、和C1-8烷基氨基(C1-8烷基氨基)，其中芳基和杂环烷基任选地被1-3个R4基团取代；
R2选自C1-8烷基、C1-8卤代烷基、C1-8烷基氨基C1-8烷基、芳基和杂芳基，其中芳基和杂芳基任选地被1-3个R4基团取代；
R3选自氢、卤素、C1-8烷基和C1-8卤代烷基；
R4独立地选自卤素、C1-8烷基、C1-8烷氧基、C1-8卤代烷基、C1-8羟基烷基、C1-8氨基烷基、C1-8烷酰基、C1-8烷基砜基、和氨酰基。
在另一方面，本发明提供一种药物组合物，其包括治疗有效量的至少一种本文提供的式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，以及药学可接受的载体或赋形剂，以及任选的其它治疗剂。
在又一方面，本发明提供一种制备本发明的式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药的方法。
在又一方面，本发明涉及式(I)的化合物或其药学可接受的盐、 溶剂化物、异构体、酯、酸、代谢物或前药在体内或体外降低或抑制野生型FLT3激酶和/或突变型FLT3激酶活性的用途。
在又一方面，本发明涉及式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药、或包括式(I)的化合物的药物组合物在制备用于治疗与FLT3相关的病症的药物中的用途。
特别地，所述病症响应于野生型FLT3或突变型FLT3激酶抑制。FLT3突变包括ITD突变和点突变，尤其是FLT3/ITD突变。
附图说明
图1示出化合物1在三种细胞中对FLT3上下游信号通路的影响，其中图1a、图1b和图1c分别显示MOLM-14、MOLM-13和MV-4-11细胞中的结果；
图2示出化合物1在三种细胞中对与细胞凋亡密切相关的蛋白酶的影响，其中图1a、图1b和图1c分别显示MOLM-13、MV-4-11和MOLM-14细胞中的结果；
图3a、3b和3c分别示出化合物1对MOLM-13、MOLM-14和MV-4-11细胞系的细胞周期的影响；
图4示出化合物1在裸鼠皮下荷瘤模型中对肿瘤的抑制效果，其中图4a显示小鼠体重随着化合物用药天数变化的曲线图；图4b显示肿瘤相对大小随着化合物用药天数变化的曲线图；图4c显示不同剂量给药组中的抑瘤率。
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。
“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、异丙基、丁基、异丁基、叔丁基、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“丁基”包括正丁基、异丁基和叔丁基。
“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。
“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。
本文使用的术语“氰基”是指式-CN基团。
术语“砜基”是指-S(＝O)2-基团。术语“氨基砜基”是指-S(＝O)2-NH2基团，术语“烷基砜基”或“磺酰基”是指-S(＝O)2-R，其中R为烷基。
术语“氨基”是指基团-NH2。术语“氨酰基”是指-CO-NH2。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“季铵基”是指-N+RR’R”，其中R、R’和R”各自独立地选自C1-8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-NH2。本文的术语“芳烷基氨基”是指其中R是低级芳烷基且R’是氢、低级烷基、芳基或低级芳烷基的基团-NRR’。术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。术语“氨基烷氧基”是指进一步被一个或多个氨基取代的烷氧基取代基。术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。术语“烷基羰基”或“烷酰基”是指进一步被一个烷基取代的羰基。术语“烷基羰基烷基”或“烷酰基烷基”是指进一步被一个烷基羰基取代的烷基。术语“烷基羰基烷氧基”或“烷酰基烷氧基”是指进一步被一个烷基羰基取代的烷氧基。术语“烷氧基羰基”是指进一步被一个烷氧基取代的羰 基。
“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
“烷基氨基砜基”是指本文定义的砜基被本文定义的烷基氨基取代。
“烷基氨基羰基”是指本文定义的羰基被本文定义的烷基氨基取代。
“烷基砜基氨基”或“环烷基砜基氨基”是指本文定义的氨基被本文定义的烷基砜基或环烷基砜基取代。
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)。
“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“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“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-8个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。
“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的烷基(环烷基)包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
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。
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、呋喃基、苯并呋喃基、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。
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、环亚胶、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。
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“杂环烷基羰基”是指本文定义的羰基被本文定义的杂环烷基取代。术语“杂环烷基氨基”是指本文定义的氨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“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“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、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、烷基羰基、烷氧基羰基、烷基(杂芳基)、烷基(杂环烷基)、烷基砜基、氨酰基等。
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。
术语“前药”包括具有可以在体内代谢的部分的化合物。通常，前药通过酯酶或通过其它机理在体内代谢成活性药物。前药及其用途的例子在本领域内公知(参见例如Berge等人(1977)“Pharmaceutical Salts”,J.Pharm.Sci.66:1-19)。可以在化合物最终分离和纯化期间原位制备前药，或者通过单独地使纯化的化合物以其游离酸形式或羟基与合适的酯化剂反应来制备。羟基可以经羧酸处理而转换成酯。前药部分的实例包括取代和未被取代的、支链或无支链的低级烷基酯部分(例如丙酸酯)、低级烯基酯、二-低级烷基-氨基低级烷基酯(例如二甲基氨基乙基酯)、酰基氨基低级烷基酯(例如乙酰氧基甲基酯)、酰氧基低级烷基酯(例如新戊酰氧基甲基酯)、芳基酯(苯基酯)、芳基低级烷基酯(例如苄基酯)、取代的(例如被甲基、卤素或甲氧基取代基取代的)芳基和芳基低级烷基酯、酰胺、低级烷基酰胺、二低级烷基酰胺和羟基酰胺。优选的前药部分为丙酸酯和酰基酯。也包括在体内通过其它机理转化成活性形式的前药。在一些方面，本发明的化合物是任意本文通式的前药。
术语“异构体”是指化学组成相同但是原子或基团在空间排列上不同的化合物，意在包括非对映异构体、对映异构体、区域异构体(regioisomers)、结构异构体、旋转异构体、互变异构体等。对于含有一个或多个立体中心(stereogenic center)的化合物，例如手性化合物，可以使用对映异构富集化合物、外消旋体、或非对映异构体混合物来实施本发明的方法。
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FLT3。
“耐药性”(drug resistance)是指微生物、寄生虫以及肿瘤细胞等对于化疗药物作用的耐受性，耐药性一旦产生，药物的化疗作用就明显下降。耐药性根据其发生原因可分为获得耐药性和天然耐药性。对于抗肿瘤药物，肿瘤细胞对抗恶性肿瘤药物产生不敏感现象即耐药性，是肿瘤化疗失败的重要原因，亦是肿瘤化疗急需解决的难题。本发明所涉及的耐药性总体是指患有与FLT3相关的疾病的患者在经历本发 明化合物以外的药物治疗之后所产生的耐药性。
本文使用的IC50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EC50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。
本说明书中使用的术语“EGFR”是指表皮生长因子受体。
本说明书中使用的术语“BMX”是指染色体X上的骨骼酪氨酸激酶(Bone Marrow X kinase)。
本说明书中使用的术语“ABL”是指由Abelson鼠白血病病毒致癌基因表达的蛋白。
本说明书中使用的术语“MET”是指肝细胞生长因子受体，也称为HGFR。
对于氨基酸取代来说，使用以下命名规则：原始氨基酸、位置、取代的氨基酸。例如，第835位天门冬氨酸(Asp835)残基突变为酪氨酸(Tyr)，简写为D835Y。
在说明书中，携带某一具体突变的蛋白用以下方式表示：在发生突变的蛋白名称之后用“/”、“-”或“[]”来连接其具体的突变。例如，具有内部串联重复的FLT3突变激酶被简写为FLT3/ITD、FLT3-ITD或者FLT3[ITD]；具有D835Y的FLT3突变激酶被简写为FLT3/D835Y、FLT3/D835Y或者FLT3[D835Y]。
本发明新型的激酶抑制剂
本发明提供了一种新型FLT3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、异构体、酯、酸、代谢物、或前药：
Figure PCTCN2017087159-appb-000002
其中，X和Y中的至少一个为C，另一个选自C和N；
R1选自氢、卤素、C1-8烷基、C1-8卤代烷基、C1-8烷氧基、C1-8烷基氨基、C1-8卤代烷氧基、C1-8氨基烷基、C1-8氨基烷氧基、C1-8烷基氨基C1-8烷氧基、季铵基C1-8烷氧基、C1-8烷酰基C1-8烷基、芳基羰基C1-8烷基、C1-8烷酰基C1-8烷氧基、芳基羰基C1-8烷氧基、氨基砜基、C1-8烷基氨基砜基、C3-6杂环烷基、氨酰基、C1-8烷基氨基羰基、C3-6杂环烷基羰基、C3-6环烷基、C1-8烷基(C3-6杂环烷基)、C1-8烷氧基(C3-6杂环烷基)、C3-6杂环烷基羰基C1-8烷基、芳氧基、C1-8烷基砜基、C1-8烷基砜基氨基、C3-6环烷基砜基氨基、C3-6杂环烷基氨基羰基、酰胺基(C1-8烷基氨基C1-8烷基)、和C1-8烷基氨基(C1-8烷基氨基)，其中芳基和杂环烷基任选地被1-3个R4基团取代；
R2选自C1-8烷基、C1-8卤代烷基、C1-8烷基氨基C1-8烷基、芳基和杂芳基，其中芳基和杂芳基任选地被1-3个R4基团取代；
R3选自氢、卤素、C1-8烷基和C1-8卤代烷基；
R4独立地选自卤素、C1-8烷基、C1-8烷氧基、C1-8卤代烷基、C1-8羟基烷基、C1-8氨基烷基、C1-8烷酰基、C1-8烷基砜基、和氨酰基。
在优选的实施方式中，X和Y均为C。
在另一优选的实施方式中，R1为X或Y上的取代基，更优选为Y上的取代基。
在本发明的实施方式中，R1、R2、R3和R4取代基中所述的烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；所述的芳基优选为苯基；所述的杂芳基优选为异噁唑基或噻唑基；所述的杂环烷基优选为6元杂环烷基，例如吗啉基、哌啶基、哌嗪基或四氢吡喃基；所述的烷酰基优选为乙酰基或丙酰基；所述的烷基氨基优选 为甲基氨基、乙基氨基、二甲基氨基、二乙基氨基或甲基乙基氨基；所述的烷基砜基优选为甲砜基、乙砜基、丙砜基、正丁基砜基、异丁基砜基或叔丁基砜基；所述的卤代烷基优选为三氟甲基；所述的烷氧基优选为甲氧基、乙氧基、或丙氧基。
另一方面，本发明提供了一种新型FLT3激酶抑制剂，其包括式(II)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药：
Figure PCTCN2017087159-appb-000003
其中，X、R1、R2、R3和R4取代基如上文所定义。
在本实施方式中，更优选地，R1选自氢、C1-8烷基氨基(例如二甲氨基等)、C1-8烷基氨基C1-8烷氧基(例如2-二甲氨基-乙氧基、2-二乙氨基-乙氧基等)、季铵基C1-8烷氧基(例如三甲基铵甲氧基等)、C1-8烷基氨基砜基(例如二甲氨基磺酰基等)、任选取代的C3-6杂环烷基(例如吗啉代、哌啶-1-基、哌嗪-1-基4-乙酰基哌嗪-1-基、4-甲基哌嗪-1-基、4-乙基哌嗪-1-基、哌啶-4-基、1-甲基哌啶-4-基、1-乙基哌啶-4-基、1-(2-羟基乙基)-哌啶-4-基、4-(2-羟乙基)-哌嗪-1-基、4-(2-氨基乙基)-哌嗪-1-基等)、氨酰基、C1-8烷基氨基羰基(例如甲氨基羰基、二甲氨基羰基等)、任选取代的C3-6杂环烷基羰基(例如哌啶-1-羰基、4-氨酰基哌啶-1-羰基、吗啉-4-羰基、4-乙基哌嗪-1-羰基、4-异丙基哌嗪-1-羰基等)、任选取代的C1-8烷基(C3-6杂环烷基)(例如吗啉代甲基、(4-甲基哌啶-1-基)甲基、(4-甲基哌嗪-1-基)甲基、(4-乙基哌嗪-1-基)甲基、(4-乙酰基哌嗪-1-基)甲基等)、任选取代的C1-8烷氧基(C3-6杂环烷基)(例如2-吗啉代甲氧基、2-吗啉代乙氧基、3-吗啉代丙氧基、(2-哌啶-1-基)乙氧基、2-(4-(甲磺酰基)哌嗪-1-基)乙氧基、(4-甲基哌嗪-1-基)乙氧基 等)、任选取代的C3-6杂环烷基羰基C1-8烷基(例如2-吗啉代-2-氧代乙基、3-吗啉代-3-氧代丙基、3-(4-乙基哌嗪-1-基)-3-氧代丙基等)、任选取代的苯氧基、C1-8烷基砜基(例如甲磺酰基、异丙基磺酰基、异丁基磺酰基等)、C1-8烷基砜基氨基(例如甲磺酰基氨基、异丙基磺酰基氨基等)、C3-6环烷基砜基氨基(例如环丙基砜基氨基)、任选取代的C3-6杂环烷基氨基羰基(例如(四氢吡喃-4-基)氨基羰基、吗啉代氨基羰基等)、酰胺基(C1-8烷基氨基C1-8烷基)(例如2-(二甲基氨基)乙酰胺基等)、和C1-8烷基氨基(C1-8烷基氨基)(例如(2-(二甲基氨基)乙基)甲基氨基等)。R1最优选为C1-8烷氧基(C3-6杂环烷基)，特别是2-吗啉代甲氧基、2-吗啉代乙氧基、3-吗啉代丙氧基、和(2-哌啶-1-基)乙氧基等。
在本实施方式中，更优选地，R2选自C1-8烷基(例如异丁基等)、C1-8烷基氨基C1-8烷基(例如2-(二甲氨基)乙基等)、任选取代的苯基(例如4-(叔丁基)苯基、4-甲基-3-(三氟甲基)苯基、4-氯-3-(三氟甲基)苯基、3,4,5-三甲氧基苯基等)、和任选取代的杂芳基(例如异噁唑-3-基、5-(甲基)异噁唑-3-基、5-(叔丁基)异噁唑-3-基、4-(叔丁基)噻唑-2-基、4-(三氟甲基)噻唑-2-基等)。R2最优选为5-(叔丁基)异噁唑-3-基。
在本实施方式中，更优选地，R3选自氢、和C1-8烷基(例如甲基等)。R3最优选为氢。
在本发明中，优选的FLT3激酶抑制剂包括表1的以下化合物及其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药：
表1
Figure PCTCN2017087159-appb-000004
Figure PCTCN2017087159-appb-000005
Figure PCTCN2017087159-appb-000006
Figure PCTCN2017087159-appb-000007
本发明所涉及带有手性的化合物，其构型可以是任意构型或者混合的外消旋体。
一方面，本文优选提供选下列的化合物，这些优选化合物的结构如表1所示。
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、异构体、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及其用途
本发明也涉及药物组合物，它们包含式(I)化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药作为活性成分，以及药学可接受的载体或赋形剂，以及任选的其它治疗剂。
式(I)化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药以及包括其的药物组合物在下文中又称为“本发明的物质”。
本发明的物质可用于治疗或预防与FLT3相关的病症，特别是响应于蛋白酪氨酸激酶抑制、尤其野生型FLT3或突变型FLT3激酶抑制的疾病。FLT3突变包括ITD突变和点突变，尤其是ITD突变。本发明的“治疗”可以是治疗性的(如对症治疗)和/或预防性的。本发明的物质优选可治疗或预防与FLT3相关的病症，特别优选治疗或预防与突变型FLT3/ITD相关的病症。
具体而言，本发明的物质可用于治疗或预防细胞增殖性病症，选自良性或恶性肿瘤，包括但不限于：实体肿瘤的存在或发展、肉瘤、淋巴瘤(例如B-细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症 (
Figure PCTCN2017087159-appb-000008
acroglobulinemia)、脾边缘区淋巴瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤(mantle cell lymphoma)、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma))、白血病(例如慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病)、浆细胞性骨髓瘤、浆细胞瘤、淋巴瘤样肉芽肿病、黑色素瘤、B细胞增生性疾病、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌(例如乳腺导管癌、小叶癌)、胃肿瘤(包括但不限于胃癌)、食道癌、卵巢癌、结直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、膜腺癌、甲状腺癌、颈癌、CNS的癌症、恶性胶质瘤、骨髓增生病、成胶质细胞瘤、多发性骨髓瘤、胃肠癌、结肠直肠癌、头颈肿瘤、脑瘤、表皮过度增生、银屑病、前列腺增生、瘤形成、上皮特征的瘤形成、或类似疾病、或其组合。
本发明的物质优选可治疗或预防与FLT3相关的病症，特别优选治疗或预防与突变型FLT3/ITD相关的病症，包括但不限于：血液恶性肿瘤，包括白血病、淋巴瘤(如非霍奇金淋巴瘤、霍奇金淋巴瘤)和骨髓瘤，例如急性淋巴细胞白血病(ALL)、急性粒细胞白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、慢性嗜中性粒细胞白血病(CNL)、急性未分化细胞白血病(AUL)、退行发育性大细胞性淋巴瘤(ALCL)、成人T细胞ALL、伴有三谱系(trilineage)脊髓发育不良的AML(AML/TMDS)、混合型谱系白血病(MLL)、脊髓发育不良综合征(MDS)、骨髓增生异常(MPD)、多发性骨髓瘤(MM)和脊髓肉瘤、或类似疾病、或其组合。
优选可以通过注射、口服、吸入、直肠和经皮施用中的至少一种对温血动物、尤其是人类进行给药。活性成分的剂量需基于所要治疗的个体特征(如年龄、体重、病史、个体药动学数据等)、疾病类型和给药方式来加以确定。
本发明的物质可以任选地与已知治疗方法联合使用，例如其它治疗剂或放射疗法的施用。其它治疗剂包括，例如细胞抑制剂、其他抗增殖剂等。
其他抗增殖剂包括但不限于：芳构化酶抑制剂、抗雌激素、拓扑 异构酶I抑制剂、拓扑异构酶II抑制剂、微管活性剂、烷基化剂、组蛋白去乙酰酶抑制剂、法呢基转移酶抑制剂、COX-2抑制剂、MMP抑制剂、mTOR抑制剂、抗瘤形成性抗代谢物、铂化合物、降低蛋白激酶活性的化合物与进一步的抗血管生成化合物、促性腺激素释放因子激动剂、抗雄激素、bengamide、双膦酸类化合物、类固醇、抗增殖性抗体、17-(烯丙胺基)-17-去甲氧基格尔德霉素(17-AAG)和替莫唑胺(TMEMODAL)。
本文所用术语“芳构化酶抑制剂”涉及抑制芳构化酶产生雌激素的化合物，其可以阻止雄烯二酮和雌二酮的转化。该术语包括但不限于类固醇，例如依西美坦和福美坦，以及非类固醇，例如氨鲁米特、伏罗唑、法倔唑、阿那曲唑、来曲唑，特别是来曲唑。依西美坦例如可以以其市售形式给药，例如商标为AROMASINTM。福美坦例如可以以其市售形式给药，例如商标为LENTARONTM。法倔唑例如可以以其市售形式给药，例如商标为AFEMATM。氨鲁米特例如可以以其市售形式给药，例如商标为ORIMETENTM。
本发明的物质在联合芳构化酶抑制剂使用时特别可用于治疗激素受体阳性乳腺肿瘤。
本文所用的术语“抗雌激素”涉及在雌激素受体水平上拮抗雌激素效应的化合物。该术语包括但不限于他莫昔芬、氟维司群(fulvestrant)、雷洛昔芬和盐酸雷洛昔芬。他莫昔芬例如可以以其市售形式给药，例如商标为NOLVADEXTM。盐酸雷洛昔芬例如可以以其市售形式给药，例如商标为EVISTATM。氟维司群可以如US4659516所述配制，或者例如可以以其市售形式给药，例如商标为FASLODEXTM。
本文所用的术语“拓扑异构酶I抑制剂”包括但不限于拓扑替康、伊立替康、9-硝基喜树碱缀合物PNU-166148(WO99/17804中的化合物A1)。伊立替康例如可以以其市售形式给药，例如商标为CAMPTOSARTM。拓扑替康例如可以以其市售形式给药，例如商标为HYCAMTINTM。
本文所用的术语“拓扑异构酶II抑制剂”包括但不限于蒽环素类(antracycline)阿霉素(包括脂质体制剂，例如CAELYXTM)、表柔比星、伊达比星和奈莫比星(nemorubin)，蒽醌类米托蒽醌和洛素蒽醌， 和鬼臼毒素类依托泊苷和替尼泊苷。依托泊苷例如可以以其市售形式给药，例如商标ETOPOPHOSTM。替尼泊苷例如可以以其市售式给药，例如商标为VM 26-BRISTOLTM。阿霉素例如可以以其市售形式给药，例如商标为ADRIBLASTINTM。伊达比星例如可以以其市售形式给药，例如商标为ZAVEDOSTM。米托蒽醌例如可以以其市售形式给药，例如商标为NOVANTRONTM。
术语“微管活性剂”涉及微管稳定化剂，包括但不限于紫杉醇(paclitaxel)和多西他赛(docetaxel)，长春花属生物碱，例如长春碱，尤其硫酸长春碱，海绵内酯(discodermolide)和埃坡霉素(epothilone)，例如埃坡霉素B和D。多西他赛例如可以以其市售形式给药，例如商标为TAXOTERETM。硫酸长春碱可以以其市售形式给药，例如商标为VINBLASTIN R.P.TM。硫酸长春新碱例如可以以其市售形式给药，例如商标为FARMISTIONTM。海绵内酯例如可以如US 5010099所述得到。
本文所用的术语“烷基化剂”包括但不限于环磷胺、异环磷酰胺和美法仑。环磷酰胺例如可以以其市售形式给药，例如商标为CYCLOSTINTM。异环磷酰胺例如可以以其市售形式给药，例如商标为HOLOXANTM。
术语“组蛋白去乙酰酶抑制剂”涉及抑制组蛋白去乙酰酶并且具备抗增殖活性的化合物。这包括WO 02/22577所公开化合物，尤其N-羟基-3-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺、N-羟基-3-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺和其药学上可接受的盐。进一步尤其包括辛二酰苯胺异羟肟酸(SAHA)。
术语“法呢基转移酶抑制剂”涉及抑制法呢基转移酶并且具备抗增殖活性的化合物。
术语“COX-2抑制剂”涉及抑制环加氧酶2型酶(COX-2)并且具备抗增殖活性的化合物，例如塞来昔布(Celebrex)、洛芬昔布(Vioxx)和鲁米拉考昔(COX189)。
术语“MMP抑制剂”涉及抑制基质金属蛋白酶(MMP)并且具备抗增殖活性的化合物。
术语“mTOR抑制剂”涉及抑制哺乳动物雷帕霉素靶(mTOR)并且具备抗增殖活性的化合物，例如西罗莫司(Rapamune)、everolimus(CerticanTM)、CCI-779和ABT578。
术语“抗瘤形成性抗代谢物”包括但不限于5-氟尿嘧啶、替加氟、卡培他滨、克拉屈滨、阿糖胞苷、磷酸氟达拉滨、氟脲苷(fluorouridine)、吉西他滨、6-巯基嘌呤、羟基脲、甲氨喋呤、依达曲沙和这类化合物的盐，此外还有ZD1694(RALTITREXEDTM)、LY231514(ALIMTATM)、LY264618(LOMOTREXOLTM)和OGT719。
本文所用的术语“铂化合物”包括但不限于卡铂、顺铂和奥沙利铂。卡铂例如可以以其市售形式给药，例如商标为CARBOPLATTM。奥沙利铂例如可以以其市售形式给药，例如商标为ELOXATINTM。
本文所用的术语“降低蛋白激酶活性的化合物与进一步的抗血管生成化合物”包括但不限于降低下列活性的化合物，例如血管内皮生长因子(VEGF)、表皮生长因子(EGF)、c-Src、蛋白激酶C、血小板衍生生长因子(PDGF)、Bcr-Abl、c-Kit、FLT3、胰岛素样生长因子I受体(IGF-IR)和细胞周期蛋白依赖性激酶(CDK)，具有不同于降低蛋白激酶活性的作用机理的抗血管生成化合物。
降低VEGF活性的化合物包括抑制VEGF受体、尤其VEGF受体的酪氨酸激酶活性的化合物和与VEGF结合的化合物，特别是在下列文献中一般和具体公开的那些化合物、蛋白质和单克隆抗体：WQ98/35958(描述式I化合物)、WO00/09495、WO00/27820、WO00/59509、WO98/11223、WO00/27819、WO01/55114、WO01/58899和EP0769947；M.Prewett等人在Cancer Research 59(1999)5209-5218中、Z.Zhu等人在Cancer Res.58,1998,3209-3214中和J.Mordenti等人在Toxicologic Pathology,vol.27,no.1,14-21,1999中所述的那些；WO00/37502和WO94/10202；AngiostatinTM，如M.S.O’Reilly等人，Cell 79,1994,315-328所述。
降低EGF活性的化合物尤其是抑制EGF结合的化合物，特别是在下列文献中一般与具体公开的那些化合物：WO97/02266(描述式IV化合物)、EP0564409、WO99/03854、EP0520722、EP0566226、EP0787722、EP0837063、WO98/10767、WO97/30034、WO97/49688、 WOWO97/38983和尤其WO96/33980。
降低c-Src活性的化合物包括但不限于如下所定义的抑制c-Src蛋白酪氨酸激酶活性的化合物和SH2相互作用抑制剂，例如公开在WO97/07131和WO97/08193中的那些。
抑制c-Src蛋白酪氨酸激酶活性的化合物包括但不限于属于下列结构种类的化合物：吡咯并嘧啶类、尤其吡咯并[2,3-d]嘧啶；嘌呤类；吡唑并嘧啶类、尤其吡咯并[3,4-d]嘧啶；吡唑并嘧啶类、尤其吡唑并吡咯并[3,4-d]嘧啶和吡啶并嘧啶类、尤其吡啶并吡咯并[2,3-d]嘧啶。优选地，该术语涉及公开在WO96/10028、WO97/28161、WO97/32879和WO97/49706中的那些化合物。
降低IGF-IR活性的化合物尤其是公开在WO02/92599中的那些化合物。
降低蛋白激酶活性并且也可以与本发明的物质联合使用的进一步具体化合物有Imatinib(Gleevec/Glivec)、PKC412、IressacTM(ZD1839)、AEE788和其药学可接受盐(另见WO03/13541)、PTK787和其药学上可接受的盐(另见WO98/35958)、ZD6474、GW2016、CHIR-200131、CEP-7055/CEP-5214、CP-547632、KRN-633和SU5416.
具有不同于降低蛋白激酶活性的作用机理的抗血管生成化合物包括但不限于例如沙利度胺(THALOMID)、塞来昔布(Celebrex)和ZD6126。
本文所用的术语“促性腺激素释放因子激动剂”包括但不限于abarelix、性瑞林和乙酸性瑞林。性瑞林公开在US4100274中，例如可以以其市售形式给药，例如商标为ZOLADEXTM。Abarelix例如可以如US5843901所述配制。
本文所用的术语“抗雄激素”包括但不限于比卡鲁胺(CASODEXTM)，它例如可以如US4636505所述配制。
术语“bengamide”涉及bengamide和其具有抗增殖性质的衍生物。
本文所用的术语“双膦酸类化合物”包括但不限于依曲膦酸(pamidronic acid)、阿仑膦酸(alendronic acid)。依曲膦酸例如可以以其市售形式给药，例如商标为DIDRINELTM。氯膦酸例如可以以其市售形式给药，例如商标为BONEFOSTM。替鲁膦酸例如可以以其市售形 式给药，例如商标为SKELIDTM。帕米膦酸例如可以以其市售形式给药，例如商标为AREDIATM。阿仑膦酸例如可以以其市售形式给药，例如商标为FOSAMAXTM。伊班膦酸例如可以以其市售形式给药，例如商标为BONDRANATTM。利塞膦酸例如可以以其市售形式给药，例如商标为ACTONELTM。唑来膦酸例如可以以其市售形式给药，例如商标为ZOMETATM。
术语“类固醇”包括氢化可的松、地塞米松(Decadron)、甲基氢化波尼松龙和波尼松龙。
本文所用的术语“抗增殖性抗体”包括但不限于司徒曼布(Trastuzumab)(HerceptinTM)、司徒曼布-DM1、erlotinib(TercevaTM)、bevacizumab(AvastinTM)、利妥希玛(Rituxan)、PRO64553(抗-CD40)和2C4抗体。
就急性髓性白血病AML的治疗而言，式(I)化合物可以与标准白血病疗法联合使用，尤其用于治疗AML的疗法。确切而言，式(I)化合物可以与例如法呢基转移酶抑制剂和/或其他可用于治疗AML的药物联合给药，例如柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、卡铂和PKC412。
由代码、通用名称或商品名称所确定的活性成分的结构可以来自标准著作“默克索引”的现行版本或者来自数据库，例如Patents International(例如IMS World Publications)。
上述可以与式(I)化合物联合使用的化合物可以如本领域例如上面引用的文献所述制备和给药。
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。
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)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。
在某些实施方式中，本文提供的是本文描述的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。
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。
制备式(I)的化合物的合成方案的非限制性实施例参见方案I。
实施例1
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲1
Figure PCTCN2017087159-appb-000009
步骤1.化合物2-吗啉-乙基甲基砜a的合成：
将化合物2-吗啉乙醇(5g,1eq)、N,N-二异丙基乙胺(6.4g，1eq)和四氢呋喃(20mL)混合，于氮气保护下在0℃滴加甲基磺酰氯(5.3g，1eq)。滴毕，室温反应3h，然后加乙酸乙酯(400mL)稀释，水洗，饱和食盐水洗，后浓缩得化合物a直接用于下一步反应。
步骤2.化合物4-((2-吗啉)乙氧基)苯硼酸频哪醇酯b的合成：
将化合物a(5g，1eq)、对羟基苯硼酸频哪醇酯(6.3g，1.2eq)、碳酸钾(6.6g，2eq)和N,N-二甲酰胺(50mL)混合于60℃下搅拌6h，后加乙酸乙酯(400mL)稀释，水洗，饱和食盐水洗，后浓缩经柱层析得固体化合物b 5.5克。
步骤3.化合物3-碘-1-(4-硝基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺c的合 成：
将3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(5g，1eq)、对氟硝基苯(2.8g，1.05eq)、碳酸钾(7.9g，3eq)和N,N-二甲酰胺(50mL)于氮气保护下混合，并在100℃下搅拌过夜，然后冷却，倒入水中(200mL)，固体过滤烘干得化合物c 6克。
步骤4.化合物3-(4-(2-吗啉代乙氧基)苯基)-1-(4-硝基苯基)-1H-吡唑并 [3,4-d]嘧啶-4-胺d的合成：
将化合物c(5g，1eq)、化合物b(4.8g，1.1eq)、Pd(PPh3)4(0.75g,0.05eq)、碳酸钾(3.6g,2eq)、1,4-二氧六环/H2O(60mL,5/1)，于氮气中混合并在90℃搅拌过夜，然后冷却，倒入水中(150mL)，固体过滤烘干得化合物d 5.2g。
步骤5.化合物3-(4-(2-吗啉代乙氧基)苯基)-1-(4-氨基苯基)-1H-吡唑并 [3,4-d]嘧啶-4-胺e的合成：
将化合物d(5g，1eq)溶于50mL的甲醇中，加入Pd/C(2g，5％)，在氢气氛中搅拌过夜，后过滤，并用含10％甲醇的二氯甲烷洗涤，浓缩得化合物e直接进行下一步。
步骤6.化合物N-(5-(叔丁基)异噁唑-3-基)-1H-咪唑-1-甲酰胺f的合成：
将羰基咪唑(8.7g，1eq)和1,2-二氯乙烷(50mL)混合，于氮气保护下在50℃加入3-氨基-5-叔丁基异噁唑(5g，1eq)，并在此温度下搅拌过夜，后冰水浴冷却，固体过滤得化合物f 7g。
步骤7.化合物1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并 [3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲1的合成：
将化合物f(0.1g，2eq)和三氯甲烷(4mL)混合，于50℃下加入化合物e(0.1g，1eq)，并在此温度下搅拌0.5h，后冷却至0℃并搅拌1h，后固体过滤得化合物1，共60mg。
Figure PCTCN2017087159-appb-000010
Exact Mass(计算值):597.28；MS(ESI)m/z(M+1)+:598.2836。
实施例2
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(甲基)异噁唑-3-基)脲2
Figure PCTCN2017087159-appb-000011
化合物2的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):555.23；MS(ESI)m/z(M+1)+:556.2415。
实施例3
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(异噁唑-3-基)脲3
Figure PCTCN2017087159-appb-000012
化合物3的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):541.22；MS(ESI)m/z(M+1)+:542.2245。
实施例4
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-异丁基脲4
Figure PCTCN2017087159-appb-000013
化合物4的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):530.28；MS(ESI)m/z(M+1)+:531.2865。
实施例5
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(2-(二甲氨基)乙基)脲5
Figure PCTCN2017087159-appb-000014
化合物5的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):545.29；MS(ESI)m/z(M+1)+:546.2943。
实施例6
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-甲基苯)-3-(5-(叔丁基)异噁唑-3-基)脲6
Figure PCTCN2017087159-appb-000015
化合物6的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):611.30；MS(ESI)m/z(M+1)+:612.3059。
实施例7
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-甲基苯)-3-(5-(叔丁基)异噁唑-3-基)脲7
Figure PCTCN2017087159-appb-000016
化合物7的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):611.30；MS(ESI)m/z(M+1)+:612.3055。
实施例8
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(4-(叔丁基)噻唑-2-基)脲8
Figure PCTCN2017087159-appb-000017
化合物8的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):613.26；MS(ESI)m/z(M+1)+:614.2615。
实施例9
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(4-(三氟甲基)噻唑-2-基)脲9
Figure PCTCN2017087159-appb-000018
化合物9的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):625.18；MS(ESI)m/z(M+1)+:626.1865。
实施例10
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(4-(叔丁基)苯基)脲10
Figure PCTCN2017087159-appb-000019
化合物10的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):606.31；MS(ESI)m/z(M+1)+:607.3124。
实施例11
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(4-甲基-3-(三氟甲基)苯基)脲11
Figure PCTCN2017087159-appb-000020
化合物11的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):632.25；MS(ESI)m/z(M+1)+:633.2536。
实施例12
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲12
Figure PCTCN2017087159-appb-000021
化合物12的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):652.19；MS(ESI)m/z(M+1)+:653.1928。
实施例13
1-(4-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(3,4,5-三甲氧基苯基)脲13
Figure PCTCN2017087159-appb-000022
化合物13的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):640.28；MS(ESI)m/z(M+1)+:641.2860。
实施例14
1-(4-(4-氨基-3-(4-(3-吗啉代丙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲14
Figure PCTCN2017087159-appb-000023
化合物14的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):611.30；MS(ESI)m/z(M+1)+:612.3064。
实施例15
1-(4-(4-氨基-3-(4-(2-哌啶-1-基)乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲15
Figure PCTCN2017087159-appb-000024
化合物15的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):595.30；MS(ESI)m/z(M+1)+:596.3075。
实施例16
1-(4-(4-氨基-3-(3-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲16
Figure PCTCN2017087159-appb-000025
化合物16的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):597.28；MS(ESI)m/z(M+1)+:598.2862。
实施例17
1-(3-(4-氨基-3-(4-(2-吗啉代乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲17
Figure PCTCN2017087159-appb-000026
化合物17的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):597.28；MS(ESI)m/z(M+1)+:598.2858。
实施例18
1-(4-(4-氨基-3-苯基-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲18
Figure PCTCN2017087159-appb-000027
化合物18的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):468.20；MS(ESI)m/z(M+1)+:469.2136。
实施例19
1-(4-(4-氨基-3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲19
Figure PCTCN2017087159-appb-000028
化合物19的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):566.29；MS(ESI)m/z(M+1)+:567.2944。
实施例20
1-(4-(4-氨基-3-(4-((4-乙基哌嗪-1-基)甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲20
Figure PCTCN2017087159-appb-000029
化合物20的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):594.32；MS(ESI)m/z(M+1)+:595.3266。
实施例21
1-(4-(3-(4-((4-乙酰基哌嗪-1-基)甲基)苯基)-4氨基-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲21
Figure PCTCN2017087159-appb-000030
化合物21的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):608.30；MS(ESI)m/z(M+1)+:609.3078。
实施例22
1-(4-(4-氨基-3-(4-(2-(4-(甲基磺酰基)哌嗪-1-基)乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲22
Figure PCTCN2017087159-appb-000031
化合物22的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):674.27；MS(ESI)m/z(M+1)+:675.2754。
实施例23
1-(4-(4-氨基-3-(4-(吗啉代甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲23
Figure PCTCN2017087159-appb-000032
化合物23的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):567.27；MS(ESI)m/z(M+1)+:568.2748。
实施例24
1-(4-(4-氨基-3-(4-(吗啉-4-羰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲24
Figure PCTCN2017087159-appb-000033
化合物24的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):581.25；MS(ESI)m/z(M+1)+:582.2563。
实施例25
1-(4-(4-氨基-3-(4-(2-吗啉代-2-氧乙基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲25
Figure PCTCN2017087159-appb-000034
化合物25的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):595.27；MS(ESI)m/z(M+1)+:596.2715。
实施例26
1-(4-(4-氨基-3-(吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲26
Figure PCTCN2017087159-appb-000035
化合物26的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):469.20；MS(ESI)m/z(M+1)+:467.2061。
实施例27
N-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)甲磺酸酰胺27
Figure PCTCN2017087159-appb-000036
化合物27的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):561.19；MS(ESI)m/z(M+1)+:562.1976。
实施例28
1-(4-(4-氨基-3-(6-吗啉代吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲28
Figure PCTCN2017087159-appb-000037
化合物28的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):554.25；MS(ESI)m/z(M+1)+:555.2578。
实施例29
1-(4-(4-氨基-3-(4-吗啉代苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲29
Figure PCTCN2017087159-appb-000038
化合物29的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):553.25；MS(ESI)m/z(M+1)+:554.2561。
实施例30
1-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲30
Figure PCTCN2017087159-appb-000039
化合物30的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):561.23；MS(ESI)m/z(M+1)+:562.2379。
实施例31
1-(4-(4-氨基-3-(吡啶-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲31
Figure PCTCN2017087159-appb-000040
化合物31的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):469.20；MS(ESI)m/z(M+1)+:470.2026。
实施例32
1-(4-(4-氨基-3-(4-(甲基磺酰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲32
Figure PCTCN2017087159-appb-000041
化合物32的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):546.18；MS(ESI)m/z(M+1)+:547.1538。
实施例33
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯磺酰胺33
Figure PCTCN2017087159-appb-000042
化合物33的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):547.18；MS(ESI)m/z(M+1)+:548.1856。
实施例34
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N,N-二甲基苯磺酰胺34
Figure PCTCN2017087159-appb-000043
化合物34的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):575.21；MS(ESI)m/z(M+1)+:576.2176。
实施例35
1-(4-(4-氨基-3-(4-(异丁基磺酰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲35
Figure PCTCN2017087159-appb-000044
化合物35的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):588.23；MS(ESI)m/z(M+1)+:589.2355。
实施例36
1-(4-(4-氨基-3-(4-(哌嗪-1-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲36
Figure PCTCN2017087159-appb-000045
化合物36的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):552.27；MS(ESI)m/z(M+1)+:553.2782。
实施例37
1-(4-(3-(4-(4-乙基哌嗪-1-基)苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲37
Figure PCTCN2017087159-appb-000046
化合物37的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):580.30；MS(ESI)m/z(M+1)+:581.3067。
实施例38
1-(4-(3-(4-(4-乙酰基哌嗪-1-基)苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲38
Figure PCTCN2017087159-appb-000047
化合物38的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):594.28；MS(ESI)m/z(M+1)+:595.2877。
实施例39
1-(4-(4-氨基-3-(4-(3-吗啉代-3-氧代丙基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲39
Figure PCTCN2017087159-appb-000048
化合物39的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):609.28；MS(ESI)m/z(M+1)+:610.2875。
实施例40
1-(4-(4-氨基-3-(4-(3-(4-乙基哌嗪-1-基)-3-氧代丙基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲40
Figure PCTCN2017087159-appb-000049
化合物40的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):636.33；MS(ESI)m/z(M+1)+:637.3389。
实施例41
1-(4-(4-氨基-3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲41
Figure PCTCN2017087159-appb-000050
化合物41的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):580.30；MS(ESI)m/z(M+1)+:581.3056。
实施例42
1-(4-(4-氨基-3-(4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲42
Figure PCTCN2017087159-appb-000051
化合物42的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):610.31；MS(ESI)m/z(M+1)+:611.3191。
实施例43
1-(4-(4-氨基-3-(4-(2-吗啉代甲氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲43
Figure PCTCN2017087159-appb-000052
化合物43的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):583.27；MS(ESI)m/z(M+1)+:584.2748。
实施例44
1-(4-(4-氨基-3-(4-((4-甲基哌啶-1-基)甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲44
Figure PCTCN2017087159-appb-000053
化合物44的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):579.31；MS(ESI)m/z(M+1)+:580.3172。
实施例45
1-(4-(4-氨基-3-(4-(4-乙基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲45
Figure PCTCN2017087159-appb-000054
化合物45的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):608.30；MS(ESI)m/z(M+1)+:609.3044。
实施例46
1-(4-(4-氨基-3-(4-(哌啶-1-羰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲46
Figure PCTCN2017087159-appb-000055
化合物46的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):579.27；MS(ESI)m/z(M+1)+:580.2749。
实施例47
1-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苄基)哌啶-4-甲酰胺47
Figure PCTCN2017087159-appb-000056
化合物47的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):622.28；MS(ESI)m/z(M+1)+:623.2867。
实施例48
1-(4-(4-氨基-3-(4-(4-异丙基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲48
Figure PCTCN2017087159-appb-000057
化合物48的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):622.31；MS(ESI)m/z(M+1)+:623.3172。
实施例49
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺49
Figure PCTCN2017087159-appb-000058
化合物49的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):595.27；MS(ESI)m/z(M+1)+:596.2748。
实施例50
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-吗啉苯甲酰胺50
Figure PCTCN2017087159-appb-000059
化合物50的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):596.26；MS(ESI)m/z(M+1)+:597.2638。
实施例51
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯甲酰胺51
Figure PCTCN2017087159-appb-000060
化合物51的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):511.21；MS(ESI)m/z(M+1)+:512.2178。
实施例52
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-甲基苯甲酰胺52
Figure PCTCN2017087159-appb-000061
化合物52的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):525.22；MS(ESI)m/z(M+1)+:526.2294。
实施例53
4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-二甲基苯甲酰胺53
Figure PCTCN2017087159-appb-000062
化合物53的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):539.24；MS(ESI)m/z(M+1)+:540.2466。
实施例54
1-(4-(4-氨基-3-(4-(二甲氨基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲54
Figure PCTCN2017087159-appb-000063
化合物54的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):511.24；MS(ESI)m/z(M+1)+:512.2485。
实施例55
N-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-2-(二甲基氨基)乙酰胺55
Figure PCTCN2017087159-appb-000064
化合物55的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):568.27；MS(ESI)m/z(M+1)+:569.2754。
实施例56
1-(4-(4-氨基-3-(4-((2-(二甲基氨基)乙基)甲基氨基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲56
Figure PCTCN2017087159-appb-000065
化合物56的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):568.30；MS(ESI)m/z(M+1)+:569.3062。
实施例57
1-(4-(4-氨基-3-(4-(4-(2-羟乙基)哌嗪-1-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲57
Figure PCTCN2017087159-appb-000066
化合物57的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):596.30；MS(ESI)m/z(M+1)+:597.3032。
实施例58
1-(4-(4-氨基-3-(4-(4-(2-氨基乙基)哌嗪-1-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲58
Figure PCTCN2017087159-appb-000067
化合物58的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):595.31；MS(ESI)m/z(M+1)+:596.3148。
实施例59
1-(4-(4-氨基-3-(4-(1-(2-羟乙基)哌啶-4-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲59
Figure PCTCN2017087159-appb-000068
化合物59的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):595.30；MS(ESI)m/z(M+1)+:596.3059。
实施例60
1-(4-(4-氨基-3-(4-(哌啶-4-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲60
Figure PCTCN2017087159-appb-000069
化合物60的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):551.28；MS(ESI)m/z(M+1)+:552.2830。
实施例61
1-(4-(4-氨基-3-(4-(1-甲基哌啶-4-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲61
Figure PCTCN2017087159-appb-000070
化合物61的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):565.29；MS(ESI)m/z(M+1)+:566.2946。
实施例62
1-(4-(4-氨基-3-(4-(1-乙基哌啶-4-基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲62
Figure PCTCN2017087159-appb-000071
化合物62的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):579.31；MS(ESI)m/z(M+1)+:580.3166。
实施例63
1-(4-(4-氨基-3-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲63
Figure PCTCN2017087159-appb-000072
化合物63的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):555.27；MS(ESI)m/z(M+1)+:556.2786。
实施例64
1-(4-(4-氨基-3-(4-(2-(二乙基氨基)乙氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲64
Figure PCTCN2017087159-appb-000073
化合物64的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):583.30；MS(ESI)m/z(M+1)+:584.3076。
实施例65
N-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)环丙基磺酰胺65
Figure PCTCN2017087159-appb-000074
化合物65的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):587.21；MS(ESI)m/z(M+1)+:588.2178。
实施例66
N-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)异丙基磺酰胺66
Figure PCTCN2017087159-appb-000075
化合物66的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):589.22；MS(ESI)m/z(M+1)+:590.2238。
实施例67
1-(4-(4-氨基-3-(4-(异丙基磺酰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5-(叔丁基)异噁唑-3-基)脲67
Figure PCTCN2017087159-appb-000076
化合物67的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):574.21；MS(ESI)m/z(M+1)+:575.2193。
实施例68
N,N,N-三甲基1-(4-(4-氨基-1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯氧基)甲基碘化铵68
Figure PCTCN2017087159-appb-000077
化合物68的合成通过使用类似于实施例1中所述的步骤完成。
Exact Mass(计算值):556.28；MS(ESI)m/z(M+1)+:557.2864。
实施例69：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)，来评估本发明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急性髓性白血病细胞株MV-4-11(表达FLT3[ITD]突变型基因)、人急性髓性白血病细胞株MOLM-13(表达FLT3[ITD]突变型基因及野生型FLT3基因)、人急性髓性白血病细胞株MOLM-14(表达FLT3[ITD]突变型基因及野生型FLT3基因)、人急性髓性白血病细胞株OCI-AML3(表达FLT3[A680V]突变型基因)、人急 性髓性白血病细胞株U937(表达野生型FLT3基因)、小鼠原B细胞BaF3，以上细胞均购自ATCC。
还选用了小鼠BaF3-FLT3[ITD](稳定表达FLT3[ITD]突变的活化激酶)、小鼠tel-BaF3-FLT3-D835Y(稳定表达FLT3[D835Y]突变的活化激酶)、小鼠tel-BaF3-BMX(稳定表达BMX激酶)、小鼠tel-FLT3-BaF3(稳定表达FLT3激酶)、小鼠BaF3-FLT3-ITD-D835Y(稳定表达FLT3[ITD+D835Y]突变的活化激酶)、小鼠BaF3-FLT3-ITD-F691L(稳定表达FLT3[ITD+F691L]突变的活化激酶)、小鼠tel-cKIT-BaF3(稳定表达cKIT激酶)、小鼠BaF3-tel-cKit-N882K(稳定表达cKIT-N882K突变的活化激酶)、小鼠BaF3-tel-cKit-D816V(稳定表达cKIT-D816V突变的活化激酶)、小鼠BaF3-tel-cKit-T670I(稳定表达cKIT-T670I突变的活化激酶)、小鼠TPR-MET-BaF3(稳定表达MET激酶)、小鼠tel-BaF3-EGFR(稳定表达EGFR激酶)、小鼠BaF3-FL-EGFR-L858R(稳定表达EGFR[L858R]突变的活化激酶)、小鼠tel-BaF3-BLK(稳定表达BLK激酶)、小鼠tel-JAK1-BaF3(稳定表达JAK1激酶)等细胞(具体参见下表2)。上述细胞株均由本实验室构建，构建方法为：通过PCR分别扩增人类FLT3/ITD、FLT3D835Y、BMX、FLT3、FLT3[ITD+D835Y]、FLT3[ITD+F691L]、cKIT、cKIT[N882K]、cKIT[D816V]、cKIT[T670I]、MET、EGFR、EGFR[L858R]、BLK、JAK1、FLT3[K663Q]、FLT3[D835V]、FLT3[D835H]、PDGFRa、PEGFRb、VEGFR2、JAK2、JAK3、ABL激酶区序列，并分别插入到带有N端TEL或者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(购自ATCC)，并且撤除IL-3生长因子，最终得到依赖FLT3/ITD、FLT3D835Y、BMX、FLT3、FLT3[ITD D835Y]、FLT3[ITD+F691L]、cKIT、cKIT[N882K]、cKIT[D816V]、cKIT[T670I]、MET、EGFR、EGFR[L858R]、BLK、JAK1、FLT3[K663Q]、FLT3[D835V]、FLT3[D835H]、PDGFRa、PEGFRb、VEGFR2、JAK2、JAK3、ABL转入蛋白的细胞株。
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)的化合物1-30、36-37和57分别加入到上述细胞中， 并孵育72小时，用Cell
Figure PCTCN2017087159-appb-000078
(Promega，美国)化学自发光法细胞活力检测试剂盒，通过对活细胞中的ATP进行定量测定来检测活细胞数目，并在此基础上确定GI50值。实验结果见表2。
表2.不同的化合物对各癌细胞生长的影响(结果示为GI50值，单位为 μM)
细胞名称 化合物1 化合物2 化合物3 化合物4 化合物5 化合物6
MV-4-11 <0.3nM 0.069 0.26 2.8 0.082 ＜0.0003
MOLM-13 <0.3nM         <0.3nM
MOLM-14 <0.3nM 0.1 0.44 2.5 0.13 ＜0.0003
BaF3-TEL-FLT3 <0.3nM 0.36 0.84 5.4 0.32 ＜0.0003
BaF3-FLT3[ITD] <0.3nM 0.056 0.24 1.1 0.1 0.002
BaF3-TEL-FLT3[D835Y] 0.012 3.5 4.2 ＞10 1.3 0.02
BaF3-FLT3[ITD+D835Y] 0.002 3.5 4.2 ＞10 1.3 0.055
BaF3-FLT3[ITD+F691L] 0.002         0.013
BaF3-TEL-FLT3[K663Q] 3.5 6.2 8 ＞10 3.7 2.6
BaF3-TEL-FLT3[D835V] 0.003 3.5 4.7 >10 1.7 0.004
BaF3-TEL-FLT3[D835H] <0.0003         ＜0.0003
BaF3-TEL-PDGFRa <0.0003         0.003
BaF3-TEL-PEGFRb <0.0003         0.004
BaF3   ＞10 ～10 ＞10 3.8 5.5
U937 4.2 4.7 3.8 ＞10 9.2 1.3
OCI-AML3 6.3          
BaF3-TEL-BMX 1.1         1.9
BaF3-TEL-cKIT 0.001 3.9 ＞10 ＞10 3.5 0.14
BaF3-TEL-cKit[N882K]   7.6 6.7 ＞10 3.3 0.033
BaF3-TEL-cKit[D816V] 3.5 9.5 3.8 ＞10 8.3 1.6
BaF3-TEL-cKit[T670I]           0.007
TPR-MET-BaF3 9.8          
BaF3-TEL-EGFR >10          
BaF3-FL-EGFR[L858R]            
BaF3-TEL-BLK 3.6          
BaF3-TEL-JAK1 3.8          
BaF3-TEL-JAK2            
BaF3-TEL-JAK3 8.3          
BaF3-TEL-ABL            
BaF3-TEL-VEGFR2 0.002          
续表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值，单位为 μM)
Figure PCTCN2017087159-appb-000079
Figure PCTCN2017087159-appb-000080
续表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值，单位为 μM)
Figure PCTCN2017087159-appb-000081
Figure PCTCN2017087159-appb-000082
续表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值，单位为 μM)
细胞名称 化合物19 化合物20 化合物21 化合物22 化合物24
MV-4-11 <0.0003 <0.0003 ＜0.0003 ＜0.0003 0.002
MOLM-13          
MOLM-14 0.0009 <0.0003 ＜0.0003 ＜0.0003 0.002
BaF3-TEL-FLT3 0.001 0.002 0.001 0.001 0.001
BaF3-FLT3[ITD] 0.0006 0.0009 ＜0.0003 ＜0.0003 ＜0.0003
BaF3-TEL-FLT3[D835Y] 0.57 0.24 0.009 0.02 0.12
BaF3-FLT3[ITD+D835Y] 0.57 0.24 0.059 0.1 0.26
BaF3-FLT3[ITD+F691L]     0.12 0.039 1.2
BaF3-TEL-FLT3[K663Q] 1.8 1.6 3.6 3.8 ＞10
BaF3-TEL-FLT3[D835V] 0.023 0.008 0.004 0.017 0.095
BaF3-TEL-FLT3[D835H]     ＜0.0003 0.004 ＜0.0003
BaF3-TEL-PDGFRa     0.002 0.002 0.006
BaF3-TEL-PEGFRb     0.01 0.012 0.012
BaF3 3.3 2.5 ～10 6.5 ＞10
U937 4.0 1.7 2.3 8.5 ＞10
OCI-AML3          
BaF3-TEL-BMX     5.3 2.0 7.0
BaF3-TEL-cKIT 0.04 0.04 0.031 0.04 0.12
BaF3-TEL-cKit[N882K] 0.018 0.009 0.010 0.015 0.016
BaF3-TEL-cKit[D816V] 2.9 1.9 1.8 2.2 6.8
BaF3-TEL-cKit[T670I]     0.004 0.013 0.024
续表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值，单位为 μM)
细胞名称 化合物25 化合物26 化合物27 化合物29 化合物30
MV-4-11 0.0005 <0.0003 0.0006 0.0005 0.021
MOLM-13         0.032
MOLM-14 0.0004 0.001 0.001 0.0004 0.032
BaF3-TEL-FLT3 0.003 0.001 0.002 0.002  
BaF3-FLT3[ITD] 0.002 0.0007 0.001 0.0007 0.001
BaF3-TEL-FLT3[D835Y] 0.25 0.61 0.6 0.44 0.014
BaF3-FLT3[ITD+D835Y] 0.25 0.61 0.6 0.44 3.7
BaF3-FLT3[ITD+F691L]          
BaF3-TEL-FLT3[K663Q] ～10 ＞10 ＞10 6.5  
BaF3-TEL-FLT3[D835V] 0.009 0.02 0.022 0.022 0.033
BaF3-TEL-FLT3[D835H]         0.19
BaF3-TEL-PDGFRa          
BaF3-TEL-PEGFRb         0.29
BaF3 ＞10 ＞10 ＞10 ＞10  
U937 9.9 ＞10 ＞10 3.7  
OCI-AML3         1.9
BaF3-TEL-BMX         1.1
BaF3-TEL-cKIT 0.041 0.038 0.12 0.041  
BaF3-TEL-cKit[N882K] 0.018 0.029 0.051 0.053  
BaF3-TEL-cKit[D816V] 3.6 7.6 ＞10 3.2 >10
续表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值，单位为 μM)
细胞名称 化合物23 化合物28 化合物36 化合物37 化合物57
MOLM-14 <0.0003 0.002 <0.0003 0.0009 0.001
MV-4-11 <0.0003 0.001 <0.0003 <0.0003 ＜0.0003
BaF3-FLT3[ITD]   0.002 <0.0003 <0.0003 ＜0.0003
BaF3-TEL-FLT3[D835Y] 0.001 0.003 0.003 0.002 0.005
BaF3-TEL-FLT3[K663Q] 5.4 ＞10 1.4 0.93 1.2
BaF3-TEL-FLT3 <0.0003 0.004 0.001 <0.0003  
BaF3 5.9 6.9 2.8 1.9 2.5
BaF3-TEL-cKIT 0.012 0.041 0.027 0.015 0.012
U937 4.1 ＞10 2.8 1.8  
此外，为了模拟受试者产生耐药性的情形，使用三种细胞株(MOLM-13和MOLM-14以及MV-4-11)在添加不同浓度的FLT3配体FL的情况下对本发明的化合物1进行了体外实验。
在添加FLT3配体FL的试验中(如下表3所示)，可以明显看到，在携带FLT3-ITD突变型基因及野生型FLT3基因的人急性髓性白血病细胞株MOLM-13和MOLM-14细胞中分别加入1ng/ml、5ng/ml、10ng/ml的FLT3配体FL之后，在细胞株MOLM-13和MOLM-14中，随着加入的FLT3配体FL量的增加，化合物1的IC50变化不大。对于仅携带FLT3突变型基因的人急性髓性白血病细胞株MV-4-11，在加入10ng/ml FLT3配体FL的情况下测得的化合物1的IC50值与在不添加FLT3配体FL的情况下测得的IC50值相近，这表明在引起耐药性的FL配体过表达的情况下，化合物1对人急性髓性白血病细胞株的增殖 活性基本不受影响。
表3的结果表明，化合物1的活性作用基本不受FL配体存在的影响。基于这样的结果可以推测，即使是在携带FLT3突变型基因的急性髓性白血病细胞由于配体FL分泌增加而产生耐药性的情况下，化合物1对其也能发挥明显的抑制作用。这意味着，化合物1能够应用于治疗具有与FL配体的高表达相关联的耐药性的携带FLT3突变型基因的急性髓细胞白血病。
表3
  化合物1的IC50(nM)
MOLM-14 0.36
MOLM-14+FL(1ng/mL) 0.87
MOLM-14+FL(5ng/mL) 1.0
MOLM-14+FL(10ng/mL) 1.0
MOLM-13 0.27
MOLM-13+FL(1ng/mL) 1.1
MOLM-13+FL(5ng/mL) 1.3
MOLM-13+FL(10ng/mL) 1.1
MV-4-11 0.4
MV-4-11+FL(10ng/mL) 0.38
实施例70：化合物1在细胞中对FLT3上下游信号通路的影响
在人急性髓性白血病细胞MV-4-11(表达FLT3[ITD]突变型基因)细胞株、人急性髓性白血病细胞株MOLM-13(表达FLT3[ITD]突变型基因及野生型FLT3基因)以及人急性髓性白血病细胞株MOLM-14(表达FLT3[ITD]突变型基因及野生型FLT3基因)细胞株中，通过测定许多细胞生物化学终点和功能性终点，测试了化合物1及对照化合物FLT3激酶抑制剂AC220(AC220购自Hao Yuan Chemexpress公司，上海)对细胞中的FLT3、FLT3/ITD蛋白激酶的磷酸化及与之密切相关的信号通路下游STAT5蛋白的磷酸化的影响，以及化合物1和AC220对其它相关的蛋白激酶ERK、AKT磷酸化的影响。另外，还检测了化合物1和AC220对c-Myc降解以及转录因子NF-κB亚单位p65磷酸化的影响，其中以甘油酸-3-磷酸脱氢酶(GAPDH)作为内标蛋白。
用不同浓度(0μM、0.001μM、0.003μM、0.01μM、0.03μM、0.1μM、0.3μM于DMSO中)的化合物1及0.1μM(于DMSO中)的FLT3激酶抑制剂AC220分别处理携带FLT3和/或FLT3/ITD基因的急性髓性白血病细胞MV-4-11、MOLM-13和MOLM-14细胞株4小时，收集样品。测定化合物对细胞中的STAT5、ERK、NF-κB p65、AKT等蛋白磷酸化以及c-Myc蛋白降解均有影响，结果见图1。
实验结果如图1所示：在MV-4-11、MOLM-13及MOLM-14细胞株中，化合物1能够强烈地抑制蛋白激酶FLT3的磷酸化。此外，在急性髓性白血病细胞MV-4-11、MOLM-13及MOLM-14细胞株中，化合物1对细胞中FLT3/ITD下游蛋白STAT5的磷酸化也具有明显的抑制作用，且对与FLT3蛋白激酶密切相关的蛋白c-Myc有明显的降解作用。作为参照，对照化合物FLT3激酶抑制剂AC220也能够抑制蛋白激酶FLT3及与FLT3/ITD密切相关的蛋白STAT5的磷酸化以及蛋白c-Myc的降解，其抑制效果与化合物1在0.001μM时的效果相当。
实施例70表明化合物1能够强烈地抑制蛋白激酶FLT3的磷酸化，影响细胞中蛋白激酶FLT3的信号通路下游蛋白STAT5的磷酸化。基于这样的结果可以推测，化合物1通过对蛋白激酶FLT3等相关蛋白的抑制，进而抑制携带FLT3和/或FLT3/ITD基因的急性髓性白血病细胞株的细胞增殖。
实施例71：化合物1在细胞上对细胞凋亡的影响
为了证明用药以后细胞的死亡是凋亡还是坏死，在急性髓性白血病细胞MOLM-13、MOLM-14、MV-4-11细胞株中，检测了化合物1以及对照药AC220在细胞中对与细胞凋亡密切相关的DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP、含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3蛋白剪切的影响。用不同浓度(0μM、0.003μM、0.01μM、0.03μM、0.1μM于DMSO中)的化合物1、0.1μM(于DMSO中)的FLT3激酶抑制剂AC220分别处理MOLM-13、MOLM-14、MV-4-11细胞株，然后分别在12小时、24小时、48小时后收集细胞。用Western Blot检测不同浓度的药在不同时间段对DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP和含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切 蛋白的影响，其中以甘油酸-3-磷酸脱氢酶(GAPDH)作为内标蛋白。
实验结果如图2所示：对于急性髓性白血病细胞株MOLM-13，当化合物1的用药浓度为0.003μM时，作用12小时后就能够看到明显的DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP的剪切，以及明显的含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切。对于MOLM-14细胞株，在化合物1给药48小时之后也观察到相似的结果。对于MV-4-11细胞株，在化合物1给药24小时之后也观察到相似的结果，并且DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP的剪切更为显著。
这样的结果表明，化合物1能够引起携带FLT3基因和/或FLT3/ITD突变型基因的急性髓性白血病细胞的凋亡。
实施例72：化合物1在细胞上对细胞周期的影响
为了研究用药后细胞被阻止在哪个生长周期，在急性髓性白血病细胞MOLM-13、MOLM-14、MV-4-11细胞株中，测试了化合物1对这些细胞株的细胞周期分布的影响。用不同浓度的0μM、0.01μM、0.03μM、0.1μM(于DMSO中)的化合物1，0.1μM的FLT3激酶抑制剂AC220作用于MOLM-13、MOLM-14、MV-4-11细胞株中，作用12或24小时后，收集细胞，在用1×PBS缓冲液洗涤两次之后，用75％的乙醇于-20℃固定24小时，用1×PBS缓冲液再洗涤两次，加0.5mL1×PBS缓冲液和0.5mL的PI染色液(购自美国BD Bioscience)到细胞中并将细胞放置于黑暗避光37℃染色15分钟，用流式细胞仪(BD FACS Calibur)检测细胞周期分布(图3)。
实验结果如图3所示：在携带FLT3/ITD突变型基因的急性髓性白血病细胞株MOLM-13、MOLM-14、MV-4-11细胞株中，化合物1能够将细胞阻止在G0-G1期，这与AC220的作用效果一致。
实施例72证明了化合物1能够将携带FLT3/ITD突变基因的急性髓性白血病细胞MOLM-13、MOLM-14、MV-4-11细胞阻止在G0-G1期，对细胞周期的分布有强烈的影响(图3)。
实施例73：使用化合物1治疗急性髓性白血病
为了检测化合物1在体内对肿瘤的抑制效果，引入了裸鼠皮下荷 瘤模型。对25只5周大的小鼠(Balb/c-nu雌性小鼠，购自上海斯莱克实验动物有限责任公司)皮下接种MOLM-14细胞1×107个/只，每日记录小鼠的体重变化及肿瘤体积(肿瘤体积＝肿瘤长×肿瘤宽2/2)。10天后，小鼠肿瘤体积达到200-400mm3，将小鼠随机分成4组，每组6只或7只，分别进行如下治疗：第一组每天口服灌胃溶媒(vehicle)，即甲基纤维素基水混悬液(购自国药集团化学试剂有限公司)；第二组每天口服灌胃3.75mg/kg化合物1的甲基纤维素基水混悬液制剂；第三组每天口服灌胃7.5mg/kg化合物1的甲基纤维素基水混悬液制剂；第四组每天口服灌胃15mg/kg化合物1的甲基纤维素基水混悬液制剂；第一次给药当天记为第0天，连续给药观察28天(参见图4)。
实验结果如图4所示，当化合物1的用药剂量为3.75mg/kg时，给小鼠进行治疗28天后，小鼠的肿瘤生长已经受到显著抑制，小鼠体重没有下降，同时抑瘤率高达75％。当化合物1的用药剂量在7.5mg/kg时，用药28天后小鼠肿瘤基本得到抑制，小鼠体重没有下降，抑瘤率高达92％。当化合物1的用药剂量在15mg/kg时，用药后小鼠肿瘤完全得到抑制，并且小鼠体重没有下降，抑瘤率高达97％。本实施例中肿瘤移植小鼠模型的数据证明，化合物1在小鼠体内能起到显著的抑制急性髓性白血病(AML)肿瘤生长的作用。
工业应用性
本发明提供一种新型FLT3激酶抑制剂化合物，其可以用于降低或抑制细胞中或受试者中的野生型FLT3激酶和/或突变型FLT3激酶活性，并且/或者在受试者中预防或治疗与FLT3相关的病症。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 (21)

  1. 一种式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，其具有以下结构：
    Figure PCTCN2017087159-appb-100001
    其中，X和Y中的至少一个为C，另一个选自C和N；
    R1选自氢、卤素、C1-8烷基、C1-8卤代烷基、C1-8烷氧基、C1-8烷基氨基、C1-8卤代烷氧基、C1-8氨基烷基、C1-8氨基烷氧基、C1-8烷基氨基C1-8烷氧基、季铵基C1-8烷氧基、C1-8烷酰基C1-8烷基、芳基羰基C1-8烷基、C1-8烷酰基C1-8烷氧基、芳基羰基C1-8烷氧基、氨基砜基、C1-8烷基氨基砜基、C3-6杂环烷基、氨酰基、C1-8烷基氨基羰基、C3-6杂环烷基羰基、C3-6环烷基、C1-8烷基(C3-6杂环烷基)、C1-8烷氧基(C3-6杂环烷基)、C3-6杂环烷基羰基C1-8烷基、芳氧基、C1-8烷基砜基、C1-8烷基砜基氨基、C3-6环烷基砜基氨基、C3-6杂环烷基氨基羰基、酰胺基(C1-8烷基氨基C1-8烷基)、和C1-8烷基氨基(C1-8烷基氨基)，其中芳基和杂环烷基任选地被1-3个R4基团取代；
    R2选自C1-8烷基、C1-8卤代烷基、C1-8烷基氨基C1-8烷基、芳基和杂芳基，其中芳基和杂芳基任选地被1-3个R4基团取代；
    R3选自氢、卤素、C1-8烷基和C1-8卤代烷基；
    R4独立地选自卤素、C1-8烷基、C1-8烷氧基、C1-8卤代烷基、C1-8羟基烷基、C1-8氨基烷基、C1-8烷酰基、C1-8烷基砜基、和氨酰基。
  2. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，其中X和Y均为C。
  3. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，其中R1为X或Y上的取代基。
  4. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，其中所述化合物为式(II)的化合物
    Figure PCTCN2017087159-appb-100002
    其中X、R1、R2、R3和R4取代基如权利要求1中所定义。
  5. 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、异构体、酯、酸、代谢物或前药，其中R1选自氢、C1-8烷基氨基、C1-8烷基氨基C1-8烷氧基、季铵基C1-8烷氧基、C1-8烷基氨基砜基、任选被R4基团取代的C3-6杂环烷基、氨酰基、C1-8烷基氨基羰基、任选被R4基团取代的C3-6杂环烷基羰基、任选被R4基团取代的C1-8烷基(C3-6杂环烷基)、任选被R4基团取代的C1-8烷氧基(C3-6杂环烷基)、任选被R4基团取代的C3-6杂环烷基羰基C1-8烷基、任选被R4基团取代的苯氧基、C1-8烷基砜基、C1-8烷基砜基氨基、C3-6环烷基砜基氨基、任选被R4基团取代取代的C3-6杂环烷基氨基羰基、酰胺基(C1-8烷基氨基C1-8烷基)、和C1-8烷基氨基(C1-8烷基氨基)。
  6. 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、异构体、酯、酸、代谢物或前药，其中R2选自C1-8烷基、C1-8烷基氨基C1-8烷基、任选被R4基团取代的苯基、和任选被R4基团取代的杂芳基。
  7. 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、异构体、酯、酸、代谢物或前药，其中R2为5-(叔丁基)异噁唑-3-基。
  8. 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、异构体、酯、酸、代谢物或前药，其中R3为氢。
  9. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2017087159-appb-100003
    Figure PCTCN2017087159-appb-100004
    Figure PCTCN2017087159-appb-100005
  10. 一种药物组合物，包括根据权利要求1-9中任一项所述的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，和药学上可接受的载体或赋形剂，以及任选的其它治疗剂。
  11. 根据权利要求1-9中任一项所述的化合物在制备用于治疗与FLT3相关的病症的药物中的用途。
  12. 根据权利要求11所述的用途，其中所述病症与突变型FLT3激酶有关。
  13. 根据权利要求12所述的用途，其中所述突变型FLT3激酶是FLT3/ITD、FLT3/835Y、FLT3/F691L、FLT3/K663Q、FLT3/D835V和FLT3/D835H突变型激酶中的一种或多种。
  14. 根据权利要求11所述的用途，其中所述与FLT3相关的病症为增殖性疾病，其选自：实体肿瘤的存在或发展、肉瘤、淋巴瘤、B-细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤、白血病、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、浆细胞性骨髓瘤、浆细胞瘤、淋巴瘤样肉芽肿病、黑色素瘤、B细胞增生性疾病、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、乳腺导管癌、小叶癌、胃肿瘤、胃癌、食道癌、卵巢癌、结直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、膜腺癌、甲状腺癌、颈癌、CNS的癌症、恶性胶质瘤、骨髓增生病、成胶质细胞瘤、多发性骨髓瘤、胃肠癌、结肠直肠癌、头颈肿瘤、脑瘤、表皮过度增生、银屑病、前列腺增生、瘤形成、上皮特征的瘤形成、以及它们的组合。
  15. 根据权利要求11所述的用途，其中所述与FLT3相关的病症是血液恶性肿瘤，其选自：骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、急性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性嗜中性粒细胞白血病、急性未分化细胞白血病、退行发育性大细胞性淋巴瘤、成人T细胞急性淋巴细胞白血病、伴有三谱系脊髓发育不良的急性粒细胞白血病、混合型谱系白血病、脊髓发育不良综合征、骨髓增生异常、多发性骨髓瘤、脊髓肉瘤、以及它们的组合。
  16. 根据权利要求11所述的用途，其中所述与FLT3相关的病症是急性粒细胞白血病。
  17. 根据权利要求1-9中任一项所述的化合物在制备用于降低或抑制细胞中或受试者中野生型FLT3激酶和/或突变型FLT3激酶的活性的药物中的用途。
  18. 根据权利要求17所述的用途，其中所述受试者具有由FL配体高表达引起的耐药性，或所述细胞过表达FL配体或处于FL配体高表达的环境下。
  19. 根据权利要求17所述的用途，其中所述受试者或所述细胞表达FLT3/ITD、FLT3/835Y、FLT3/F691L、FLT3/K663Q、FLT3/D835V和FLT3/D835H突变型激酶中的一种或多种。
  20. 根据权利要求17-19中任一项所述的用途，其中所述受试者是急性粒细胞白血病患者，或所述细胞是急性粒细胞白血病细胞。
  21. 一种非治疗目的地降低或抑制细胞中或受试者中的野生型FLT3激酶和/或突变型FLT3激酶的活性的方法，包括对所述细胞或受试者施用有效量的权利要求1-9中任一项所述的化合物或权利要求10所述的药物组合物。
PCT/CN2017/087159 2016-06-03 2017-06-05 Flt3激酶的新型抑制剂及其用途 WO2017206962A1 (zh)

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WO2014017659A1 (ja) * 2012-07-27 2014-01-30 独立行政法人理化学研究所 急性骨髄性白血病の治療又は再発抑制剤
WO2014015673A1 (zh) * 2012-07-27 2014-01-30 四川大学 4位有取代的吡唑并嘧啶衍生物及其在药物制备中的用途
WO2015043492A1 (en) * 2013-09-26 2015-04-02 Sunshine Lake Pharma Co., Ltd. Substituted urea derivatives and uses thereof in medicine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014017659A1 (ja) * 2012-07-27 2014-01-30 独立行政法人理化学研究所 急性骨髄性白血病の治療又は再発抑制剤
WO2014015673A1 (zh) * 2012-07-27 2014-01-30 四川大学 4位有取代的吡唑并嘧啶衍生物及其在药物制备中的用途
WO2015043492A1 (en) * 2013-09-26 2015-04-02 Sunshine Lake Pharma Co., Ltd. Substituted urea derivatives and uses thereof in medicine

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