WO2017148440A1 - 作为flt3抑制剂的蝶啶酮衍生物及应用 - Google Patents

作为flt3抑制剂的蝶啶酮衍生物及应用 Download PDF

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WO2017148440A1
WO2017148440A1 PCT/CN2017/075628 CN2017075628W WO2017148440A1 WO 2017148440 A1 WO2017148440 A1 WO 2017148440A1 CN 2017075628 W CN2017075628 W CN 2017075628W WO 2017148440 A1 WO2017148440 A1 WO 2017148440A1
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optionally substituted
group
alkyl
hydrogen
disease
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李洪林
徐玉芳
陈卓
孙德恒
吕剑昆
赵振江
宋文琳
周伟
杨宇
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to novel pteridine derivatives, methods for their synthesis and their use as FLT3 inhibitors in the preparation of medicaments for tumors and immune diseases.
  • Protein tyrosine kinase (protein tyrosine kinase) is a class of proteins that catalyze the transfer of ⁇ -phosphate on ATP to specific amino acid residues of proteins. It plays a very important role in the signal transduction pathway in cells and regulates cell growth. A series of physiological processes such as differentiation and death. It has been shown that more than 50% of protooncogenes and their products have protein tyrosine kinase activity, and their abnormal expression will lead to cell cycle life disorder, leading to tumorigenesis. In addition, the abnormal expression of tyrosine kinase is also closely related to tumor metastasis, chemotherapy resistance and the like.
  • FMS-like tyrosine kinase 3 belongs to the family of type III receptor tyrosine kinases. FLT3 plays an important role in the proliferation, differentiation and apoptosis of hematopoietic cells (Oncogene, 1993, 8,815-822). Upon binding to FLT3 ligand, FLT3 activates multiple downstream signaling pathways, including STAT5, Ras/MAPK, and PI3K/AKT pathways.
  • FLT3 mutation in approximately one-third of patients with acute myeloid leukemia (AML) (Blood, 2002, 100, 1532-1542), including the proximal membrane domain 14 and/or exon 15
  • FLT3-ITD an internal tandem repeat
  • FLT3-TKD amino acid deletion or insertion
  • the present invention relates to a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:
  • X is selected from: N, CH;
  • Y is selected from the group consisting of: O, S, and Se;
  • A is selected from various substituted benzene rings, nitrogen-containing five-membered rings, nitrogen-containing six-membered rings, for example
  • R 1 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, fluorine-containing C 1 -C 8 alkyl, optionally substituted phenyl;
  • R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, halogen, optionally substituted C 1 -C 6 alkoxy, amino, -NR a R b , carboxyl, optionally substituted alkoxy Formyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted morpholin-4-yl, optionally substituted piperidin-1-yl, optionally substituted pyrrol-1-yl, Optionally substituted pyrrolidin-1-yl, optionally substituted aryl or optionally substituted arylmethyl, optionally substituted piperidinyloxy, optionally substituted N,N',N'-three Alkyl ethylenediamine;
  • R a and R b are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, -NR c R d , C 1 -C 2 acylamino, optionally substituted C 1 -C 6 alkyl, C 1 -C 3 sulfonylamino, CN, carbamoyl, carboxyl, C1-C6 alkoxycarbonyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted morpholin-4-yl, optionally substituted pyrrol-1- Base, optionally substituted pyrrolidin-1-yl;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is not an amino group.
  • the compound has the structure shown in Formula II:
  • A is selected from various substituted benzene rings
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, halogen, amino, -NR a R b , optionally substituted piperazinyl, optionally Substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R a and R b are each independently selected from the group consisting of: hydrogen, C1-C6 alkyl and alkenyl;
  • n 1, 2, or 3;
  • R 3 is each independently selected from the group consisting of: hydrogen, halogen, C1-C2 acylamino, hydroxy, amino, -NR c R d , methanesulfonylamino, optionally substituted C 1 -C 6 alkyl, optionally substituted piperazine base;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 3 alkyl and alkenyl;
  • n 1, 2, or 3.
  • the compound has the structure shown in Formula III:
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of: an optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R 6 is selected from the group consisting of: an amino group, an optionally substituted piperazinyl group, -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl.
  • R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group; and R 5 is selected from an optionally substituted N-alkylpiperazin-1-yl group.
  • R 6 is selected from an amino group, or -NR e R f ; and R e and R f are each independently selected from hydrogen, and a C 1 -C 3 alkyl group.
  • the invention provides a specific compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or Shape agent.
  • the invention provides the use of a compound of the first or second aspect of the invention for the manufacture of a medicament for the treatment of a FLT3-mediated disease, or for the inhibition of FLT3.
  • the FLT3 mediated disease is a blood disorder, such as a myeloproliferative disorder, a cancer, an immune disease, and a skin disorder such as psoriasis and atopic dermatitis.
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), mixed line leukemia (MLL), T-cell acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic Bone marrow monocytic leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia.
  • AML acute myeloid leukemia
  • MML mixed line leukemia
  • T-ALL T-cell acute leukemia
  • B-ALL B-cell acute leukemia
  • CMML chronic Bone marrow monocytic leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • chronic neutrophilic leukemia chronic neutrophilic leukemia.
  • the immune disease is selected from the group consisting of arthritis, lupus, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis , diabetes, myasthenia gravis, Hashimoto's thyroiditis, Odd thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acutely transmitted encephalomyelitis, Dyson disease, aplastic anemia, autoimmune hepatitis, optic neuritis, silvery disease, graft versus host disease, transplantation, blood transfusion allergy, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis Atopic dermatitis.
  • Figure 1A shows that Western blot analysis determined that compound F-8 autophosphorylates FLT3 and inhibits phosphorylation of downstream signaling pathways;
  • Figure 1B shows compound 20 induction at various concentrations over 48 hours of cell culture. MV4-11 cell apoptosis;
  • Figure 1C shows inhibition of G1 phase cell growth with a specific concentration of compound 20 after 48 hours of culture;
  • Figure 2 shows tumor volume changes in the MV4-11 xenograft model
  • Figure 3 shows tumor weight changes in the MV4-11 xenograft model.
  • the present inventors synthesized a series of pteridinone derivatives which have not been reported in the literature with FLT3 inhibitory activity, and structurally characterized these compounds.
  • a series of compounds were tested for activity at the molecular and cellular levels to obtain a batch of compounds having FLT3 inhibition activity.
  • a plurality of compounds, such as F-8 and F-16 have an inhibitory activity against FLT3 with an IC 50 value of less than 10 nM, which is far superior to the positive control MLN 518.
  • alkyl refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include from 2 to 8 carbon atoms, from 1 to 6, and from 1 to 4 carbon atoms.
  • Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • the alkyl group of the present invention may be substituted with one or more substituents, for example, by halogen or haloalkyl.
  • an alkyl group can be 1-4
  • the fluorine atom-substituted alkyl group or the alkyl group may be an alkyl group substituted by a fluoroalkyl group.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • alkenyl generally denotes a monovalent hydrocarbon radical having at least one double bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, and may be straight or branched.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • halogen atom or halogen means fluoro, chloro, bromo and iodo.
  • Aryl means a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, tetrahydronaphthyl, Indane or the like.
  • the aryl group may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxy a formyl group, a N(CH 3 ) group, a C1-4 acyl group or the like, a heterocyclic group or a heteroaryl group.
  • substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4
  • aralkyl refers to an alkyl group substituted with an aryl group, such as a C1-C6 alkyl group substituted with a phenyl group.
  • aryl groups include, but are not limited to, arylmethyl, arylethyl, and the like, such as benzyl, phenethyl, and the like.
  • an aryl group may be substituted with from 1 to 3 groups selected from the group consisting of halogen, -OH, C1-4 alkoxy, C1-4 alkyl, -NO 2 , -NH 2 , -N(CH 3 ) 2 , carboxyl and ethoxylated groups.
  • 5- or 6-membered heterocyclic ring as used herein includes, but is not limited to, a heterocyclic group containing 1-3 heteroatoms selected from O, S and N, including but not limited to furyl, thienyl, pyrrolyl, Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl and the like.
  • heteroaryl refers to 5-14 ring atoms and 6, 10 or 14 electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur. Heteroaryl groups useful in the present invention include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but It is not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.
  • the heteroaryl or 5- or 6-membered heterocyclic ring may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen, C1-4 aldehyde, C1-6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy) Base), carboxyl group, C1-4 alkoxy group, ethoxylated group, N(CH 3 ) and C1-4 acyl group.
  • 1 to 5 eg, 1, 2, 3, 4 or 5
  • substituents selected from halogen, C1-4 aldehyde, C1-6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy) Base), carboxyl
  • acyloxy refers to a radical of the formula "-O-C(O)-R", wherein R may be selected from alkyl, alkenyl and alkynyl. The R can be optionally substituted.
  • amido refers to a group of the formula "-R'-NH-C(O)-R", wherein R' may be selected from a bond or an alkyl group, and R may be selected from an alkyl group, an alkenyl group. , an alkynyl group, NR a R b is a substituted alkyl group, NR a R b is a substituted alkenyl and NR a R b substituted alkynyl, halogen substituted alkyl, alkenyl substituted with cyano group, Wherein R a and R b may be selected from the group consisting of alkyl and alkenyl.
  • substituent to which it is modified may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a halogen-substituted alkyl group (for example, a trifluoromethyl group), a halogen-substituted alkoxy group ( For example, trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxycarbonyl, N(CH 3 ), and C1-4 acyl.
  • substituents selected from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group,
  • the compound of the present invention is a compound having the structure of the formula I or a pharmaceutically acceptable salt thereof:
  • X is selected from N, CH;
  • Y is selected from the group consisting of O, S and Se;
  • A is selected from various substituted benzene rings, nitrogen-containing five-membered rings, nitrogen-containing six-membered rings, for example
  • R 1 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, fluoro C 1 -C 8 alkyl, optionally substituted phenyl;
  • R 2 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, halogen, optionally substituted C 1 -C 6 alkoxy, amino, —NR a R b , carboxy, optionally substituted alkoxylate Acyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted morpholin-4-yl, optionally substituted piperidin-1-yl (preferably piperazine substituted piperidin-1-yl) , optionally substituted pyrrol-1-yl, optionally substituted pyrrolidin-1-yl, optionally substituted aryl or optionally substituted arylmethyl, optionally substituted piperidinyloxy, any Substituted substituted N,N',N'-trialkylethylenediamine;
  • R a and R b are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, -NR c R d , C1-C2 acylamino, optionally substituted C 1 -C 6 alkyl, C 1 -C 3 sulfonylamino, CN, amino Formyl, carboxyl, C1-C6 alkoxycarbonyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted morpholin-4-yl, optionally substituted pyrrol-1-yl, any Substituted pyrrolidin-1-yl;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is not an amino group.
  • the compound has the structure shown in Formula II:
  • A is selected from various substituted benzene rings
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, halogen, amino, -NR a R b , optionally substituted piperazinyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R a and R b are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and alkenyl;
  • n 1, 2, or 3;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, C1-C2 acylamino, hydroxy, amino, -NR c R d , C1-C3 sulfonylamino (preferably methanesulfonylamino), optionally substituted C 1 -C 6 alkane , optionally substituted piperazinyl, optionally substituted N-alkylpiperazin-1-yl;
  • R c and R d are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl;
  • n 1, 2, or 3.
  • the compound has the structure shown in Formula III:
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of an optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R 6 is selected from the group consisting of amino, optionally substituted piperazinyl, -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl.
  • R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group;
  • R 5 is selected from the group consisting of an optionally substituted N-alkylpiperazin-1-yl
  • R 6 is selected from amino, or -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl.
  • the present inventors synthesized a series of pteridine ketone compounds which have not been reported in the literature; specifically, the present inventors synthesized a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
  • the inventors synthesize a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
  • the inventors synthesize a compound selected from the group consisting of or a pharmaceutically acceptable salt:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient .
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg per kilogram of oral administration.
  • a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial A form of administration, intranasal or topical, for the treatment of tumors and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals is humans.
  • the compounds of the invention or pharmaceutical compositions thereof are useful in the treatment of a variety of diseases mediated by FMS-like tyrosine kinase 3 (FLT3).
  • FLT3-mediated diseases are blood diseases such as myeloproliferative diseases, cancers, immune diseases, and skin diseases such as psoriasis and atopic dermatitis.
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), mixed line leukemia (MLL), T-cell acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic bone marrow Single cell leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia.
  • AML acute myeloid leukemia
  • MML mixed line leukemia
  • T-ALL T-cell acute leukemia
  • B-ALL B-cell acute leukemia
  • CMML chronic bone marrow Single cell leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • chronic neutrophilic leukemia chronic neutrophilic leukemia
  • the immune disease is selected from the group consisting of arthritis, lupus, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes , myasthenia gravis, Hashimoto's thyroiditis, Odd thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acutely transmitted encephalomyelitis, Addison Disease, aplastic anemia, autoimmune hepatitis, optic neuritis, silver disease, graft versus host disease, transplantation, blood transfusion allergy, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, special Shoulder dermatitis.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl
  • disintegrants such as the starch mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Adjuvants especially flow regulators and Lubricants, for example, silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • the invention further provides a method of treating a FLT3-mediated disease comprising administering to a subject in need thereof a compound or pharmaceutical composition of the invention.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the invention also encompasses the use of a compound of the invention in the manufacture of a medicament for the treatment of a FLT3-mediated disease, or inhibition of FLT3.
  • the compound provided by the present invention is a novel pteridine derivative
  • the compound provided by the present invention has excellent inhibitory activity against FLT3;
  • the compound provided by the invention lays a foundation for developing a targeted drug capable of inhibiting FLT3, and has great industrialization and commercialization prospects as well as market value, and the economic benefit is remarkable.
  • R 1 - R 4 are as defined above.
  • One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.
  • P-phenylenediamine (890 mg, 8.23 mmol) was weighed into a 100 mL round bottom flask, 40 mL of dichloromethane was added, and the mixture was stirred in an ice bath, and di-tert-butyl dicarbonate (449 mg, 2.06 mmol) was dissolved in dichloromethane. Among them, it was added dropwise to the above reaction liquid, and then the mixture was further stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness eluted eluted eluted elut elut elut elut elut elut %.
  • the synthesis method is referred to as F-1 to obtain a yellow solid, the yield is 52%, mp 228.9-229.4 ° C.
  • the synthesis method is referred to as F-1, and a yellow solid is obtained in a yield of 70%, mp 262.5-262.9 ° C.
  • the raw material 1 was placed in a 250 ml round bottom flask, dissolved in DCM and MeOH, 100 mg of palladium carbon (10% Pd) was weighed, hydrogen gas was introduced, and the reaction was carried out for about 10 hours at room temperature, followed by suction filtration, and the filtrate was evaporated under reduced pressure to give a solvent. It was used directly in the next step without purification.
  • kinase buffer 50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 2 mM DTT
  • stop buffer 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2
  • %Coating Reagent#3 50 mM EDTA.
  • the compound was diluted to the desired concentration with 100% DMSO, and the formulated compound was transferred to a 96-well plate at a concentration ranging from 20 ⁇ l to 60 ⁇ l and equilibrated to 10 concentrations with a concentration gradient. A 100 ⁇ l concentration of 100% DMSO was used as a blank control.
  • Cell culture Cell lines were obtained from the American Type Culture Collection. The cells were cultured in RPMI-1640 or MEM medium containing 10% fetal bovine serum in 5% CO 2 at 37 °C. MV4-11 cells were cultured in IMDM medium.
  • the activity test of suspension cells is mainly determined by the MTT test method, and the test of adherent cells is mainly the SRB test method.
  • the suspension cells were cultured in 96-well plates of 3-8 x 10 3 cells per well, 100 ⁇ L of the medium was added to each well, and then 10 ⁇ L of the compound (in triplicate) was added, and cultured at 37 ° C for 72 hours. After the cells were cultured, 20 ⁇ L of 5 mg/mL MTT reagent was added to each well plate for further 4 hours, and 50 ⁇ L of three mixed solvents (5% isopropanol-10% SDS-12 mmol/L HCl) were added to dissolve the oxidation product. .
  • the OD value was measured at 570 nm using a multifunction detector Synergy2.
  • the adherent cells were cultured in 96-well plates of 2-7 x 10 3 cells per well for 24 h, and the same equivalent of the compound was also added to the medium. After 72 h of culture, the culture solution was removed, and the strain was fixed with TCA for 1 h. The dried well plates were stained with sulforhodamine B and then 150 ⁇ L of 10 mM Tris-HCl was added. Finally, the light absorption of the lysed cells was detected at 560 nm using a Synergy 2 differential spectrophotometer. All experiments were performed in triplicate.
  • Immunoprecipitation and Western blotting experiments Cells were incubated with different concentrations of compounds for 2 h, then the cells were further solubilized with RIPA lysis buffer, then centrifuged at 4 ° C, and the supernatant was taken for relevant experiments. The protein was separated by SDS-PAGE and then transferred to a nitrocellulose membrane for antibody detection. The primary antibodies act on FLT3, AKT, p-AKT, STAT5, p-STAT5 and p44/42 MAPK, and anti-GAPDH is cultured at the recommended concentrations. The visualized signal was used to detect the elevated ECL matrix using the Tanon 5200 capture system after HRP copolymerization with the antibody.
  • the cell lysate was immunoprecipitated with FLT3 antibody and protein A gel, and the cooked sample was electrophoretically polarized with 6% gel, and then labeled with 4G10 antibody, and the FLT3 phosphorylation level was detected by this method.
  • Flow cytometry Cells were stained with Annexin V and propidium iodide for the detection of apoptotic activity of the compounds.
  • MV4-11 cells were cultured in a 6-well plate at a density of 1 ⁇ 10 5 cells/mL, and then cultured at different concentrations for 48 hours. The cells were divided and washed twice with cold PBS buffer solution. The sample was resuspended in binding buffer and incubated with annexin V and propidium iodide under the protection of light.
  • the cell cycle assay was performed according to the PI/Rnase staining solvent product specification. The dividing cells were fixed in 70% ethanol for 1 h. All cells were then stained with propidium iodide for 30 min under non-illuminated room temperature conditions. Apoptosis and cell cycle were detected by FACS flow cytometry.
  • test results of the compounds are shown in the following table, and the results of the cell test are shown in the attached drawings.
  • the inventors further tested the inhibitory activity of the compounds of the present invention on tumors in the MV4-11 xenograft model.
  • the inventors designed and synthesized a series of pteridinone derivatives that have not been reported in the literature.
  • the obtained compounds were tested at the molecular and cellular levels to obtain a batch of compounds capable of inhibiting FLT3. .
  • the IC 50 value of the inhibitory activity of these compounds on FLT3 reached nM level; the IC 50 value of inhibitory activity against related cells reached the ⁇ M level.
  • a plurality of compounds, such as F-8 and F-16 have an inhibitory activity against FLT3 with an IC 50 value of less than 10 nM, which is far superior to the positive control MLN 518.
  • Further tumor model tests have shown that the compounds of the invention also have excellent tumor suppressor activity in vivo.
  • the non-compounds of the invention may be the target drug for inhibiting FLT3, or the basis for further modification to give compounds that are more active and/or less toxic.

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Abstract

本发明涉及作为FLT3抑制剂的蝶啶酮衍生物及其应用。具体而言，本发明涉及下式I所示的化合物、含有下式I化合物的药物组合物及所述化合物在制备治疗FLT3介导的疾病或抑制FLT3的药物中的用途：(I)。

Description

作为FLT3抑制剂的蝶啶酮衍生物及应用 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及新型的蝶啶酮衍生物，其合成方法及其作为FLT3抑制剂在制备肿瘤、免疫性疾病的药物中的应用。
背景技术
蛋白酪氨酸激酶(protein tyrosine kinase)是一类催化ATP上γ-磷酸转移到蛋白特定氨基酸残基上的蛋白，在细胞内信号转导通路中占有非常重要的地位，并且调节着细胞生长、分化、死亡等一系列生理过程。已有资料表明，超过50％的原癌基因及其产物都具有蛋白酪氨酸激酶活性，它们的异常表达将导致细胞生命周期的紊乱，进而导致肿瘤的发生。此外，酪氨酸激酶的异常表达还与肿瘤的转移、化疗抗性等密切相关。
FMS样酪氨酸激酶3(FMS-like tyrosine kinase 3，FLT3)属于III型受体酪氨酸激酶家族，FLT3在造血细胞的增殖、分化及凋亡过程中起着重要作用(Oncogene,1993,8,815-822)。FLT3与FLT3配体结合之后，激活多个下游信号通路，包括STAT5、Ras/MAPK及PI3K/AKT通路。在大约三分之一的急性髓细胞白血病(acute myeloid leukemia，AML)患者中存在FLT3突变(Blood,2002,100,1532-1542)，包括近膜结构域14和(或)15号外显子的内部串联重复序列(FLT3-ITD)突变、酪氨酸激酶结构域的激活环中氨基酸的缺失或插入(FLT3-TKD)突变。此外，在急性白血病病例中存在FLT3高表达现象(Blood,2004,103,1901)，FLT3的过表达、FLT3-ITD突变及FLT3-TKD突变均会导致AML患者预后不良。因此，FLT3成为AML治疗的重要靶标。到目前为止，尚无FLT3抑制剂被批准用于临床使用，众多处于临床试验阶段的FLT3抑制剂的临床效果仍不够理想。
因此，提高小分子激酶抑制剂临床有效率正成为当前抗肿瘤靶向药物研发的热点，最有前景的策略即为，开发同时靶向多个与疾病(肿瘤)发生相关的激酶的多靶点抑制剂。
发明内容
本发明的目的在于提供一种能够抑制FLT3的化合物，所述化合物或含有所述化合物的药物组合物能够用于制备治疗FLT3介导的疾病或抑制FLT3的药物。
在第一方面，本发明涉及一种具有通式I所示结构的化合物或其药学上可接受的盐：
Figure PCTCN2017075628-appb-000001
式中，
X选自：N、CH；
Y选自：O、S和Se；
A选自各种取代的苯环、含氮五元环、含氮六元环，例如
Figure PCTCN2017075628-appb-000002
R1独立选自：氢、卤素、C1-C8烷基、C3-C6环烷基、含氟C1-C8烷基、任选取代的苯基；
R2选自：氢、任选取代的C1-C6烷基、卤素、任选取代的C1-C6烷氧基、氨基、-NRaRb、羧基、任选取代的烷氧甲酰基、任选取代的N-烷基哌嗪-1-基、任选取代的吗啉-4-基、任选取代的哌啶-1-基、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基、任选取代的芳基或任选取代的芳基甲基、任选取代的哌啶基氧基、任选取代的N,N',N'-三烷基乙二胺基；
Ra和Rb各自独立选自：氢、C1-C6烷基和链烯基；和
n为0、1、2、3或4；
R3各自独立选自：氢、卤素、羟基、氨基、-NRcRd、C1-C2酰基氨基、任选取代的C1-C6烷基、C1-C3磺酰基氨基、CN、氨基甲酰基、羧基、C1-C6烷氧甲酰基、任选取代的苯基、任选取代的哌嗪基、任选取代的吗啉-4-基、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基；
Rc和Rd各自独立选自：氢、C1-C6烷基和链烯基；和
m为0、1、2、3或4；
其中，当n和m均为1时，且R2为C1-C6烷氧基时，R3不为氨基。
在具体的实施方式中，所述化合物具有通式II所示结构：
Figure PCTCN2017075628-appb-000003
式中，
A选自各种取代的苯环；
R1为氢；
R2选自：氢、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、卤素、氨基、-NRaRb、任选取代的哌嗪基、任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
Ra和Rb各自独立选自：氢、C1-C6烷基和链烯基；和
n为1、2、或3；
R3各自独立选自：氢、卤素、C1-C2酰基氨基、羟基、氨基、-NRcRd、甲磺酰氨基、任选取代的C1-C6烷基、任选取代的哌嗪基；
Rc和Rd各自独立选自：氢、C1-C3烷基和链烯基；和
m为1、2、或3。
在具体的实施方式中，所述化合物具有通式III所示结构：
Figure PCTCN2017075628-appb-000004
式中，
R4选自：氢、卤素、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基；
R5选自：任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
R6选自：氨基、任选取代的哌嗪基、-NReRf；
Re和Rf各自独立选自：氢、C1-C3烷基和链烯基。
在具体的实施方式中，R4选自任选取代的C1-C6烷基，优选C1-C3烷基；R5选自任选取代的N-烷基哌嗪-1-基；R6选自氨基、或-NReRf；Re和Rf各自独立选自氢、和C1-C3烷基。
在第二方面，本发明提供选自下组的具体化合物或其药学上可接受的盐：
Figure PCTCN2017075628-appb-000005
Figure PCTCN2017075628-appb-000006
Figure PCTCN2017075628-appb-000007
Figure PCTCN2017075628-appb-000008
在第三方面，本发明提供一种药物组合物，所述药物组合物含有本发明第一或第二方面所述的化合物或其药学上可接受的盐，和药学上可接受的载体或赋形剂。
在第四方面，本发明提供本发明第一或第二方面所述的化合物在制备治疗FLT3介导的疾病，或抑制FLT3的药物中的用途。
在具体的实施方式中，所述FLT3介导的疾病为血液病，如骨髓增殖性疾病，癌症，免疫性疾病，以及皮肤病，如银屑病和特应性皮炎。
在进一步的具体实施方式中，所述癌症选自急性骨髓性白血病(AML)、混合系白血病(MLL)、T-细胞急性白血病(T-ALL)、B细胞急性白血病(B-ALL)、慢性骨髓单细胞性白血病 (CMML)、慢性淋巴细胞白血病、慢性髓细胞白血病、慢性中性粒细胞白血病。
在进一步的具体实施方式中，所述免疫性疾病选自关节炎、狼疮、炎性肠病、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性传播性脑脊髓炎、阿狄森病、再生障碍性贫血、自身免疫性肝炎、视神经炎、银血病、移植物抗宿主病、移植、输血过敏反应、变态反应、I型超敏反应、过敏性结膜炎、过敏性鼻炎、特应性皮炎。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1A显示了用Western blot分析法测定到化合物F-8可以使FLT3自磷酸化并抑制下游信号通路的磷酸化作用；图1B显示了通过48小时的细胞培养，在不同浓度下化合物20诱导的MV4-11细胞凋亡；图1C显示了在48小时培养后，用特定浓度的化合物20来抑制G1期的细胞生长；
图2显示了MV4-11移植瘤模型中的肿瘤体积变化；
图3显示了MV4-11移植瘤模型中的肿瘤重量变化。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一批结构全新的蝶啶酮衍生物，这些衍生物对FLT3的抑制活性IC50值达到nM级别；对相关细胞的抑制活性IC50值达到μM级别。在此基础上完成了本发明。
本发明人合成了一系列具有FLT3抑制活性的未见文献报道的蝶啶酮衍生物，并对这些化合物进行了结构表征。对此系列化合物进行了分子水平和细胞水平的活性测试，得到一批具有抑制FLT3活性的化合物。其中多个化合物，例如F-8和F-16对FLT3的抑制活性IC50值低于10nM，远优于阳性对照MLN518。
术语定义
对于本文中涉及到的一些术语作如下说明：
本文中，“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基，优选的烷基包括长2-8个碳原子、1-6个、1-4个碳原子、3-8个碳原子、1-3个碳原子不等的烷基。烷基的例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。本发明的烷基可以被1个或多个取代基取代，例如被卤素或卤代烷基取代。例如，烷基可以是被1-4 个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。
本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基，更优选为长1-4个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。
本文中，“链烯基”通常表示具有至少一个双键的单价烃基，通常含有2-8个碳原子，优选含有2-6个碳原子，可以是直链或支链。链烯基的例子包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、己烯基等等。
本文中，“卤素原子”或“卤素”指氟、氯、溴和碘。
“芳基”是指含有6到14个碳原子的单环、双环或三环芳族基团，包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
本文中，“芳烷基”指被芳基取代的烷基，例如被苯基取代的C1-C6烷基。芳烷基的例子包括但不限于芳基甲基、芳基乙基等，例如苄基、苯乙基等。
例如，芳基可以被1-3个选自以下的基团取代：卤素、-OH、C1-4烷氧基、C1-4烷基、-NO2、-NH2、-N(CH3)2、羧基和乙氧甲酰基等。
本文所用的“5元或6元杂环”包括但不限于含有1-3个选自O、S和N的杂原子的杂环基团，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。
本文所用“杂芳基”是指含有5-14个环原子，并且有6个、10个或14个电子在环体系上共用。而且所含环原子是碳原子和从氧、氮、硫中任选的1-3个杂原子。可用于本发明的杂芳基包括哌嗪基、吗啉基、哌啶基、吡咯烷基、噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、吡啶基、包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基、吡嗪基、嘧啶基等。
杂芳基或5元或6元杂环可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本文中，“酰氧基”指结构式为“-O-C(O)-R”的基团，其中，R可选自烷基、链烯基和炔基。所述R可任选地被取代。
本文中，“酰氨基”指结构式为“-R’-NH-C(O)-R”的基团，其中，R’可选自键或烷基，R可选自烷基、链烯基、炔基、被NRaRb取代的烷基、被NRaRb取代的链烯基和NRaRb取代的炔基、被卤素取代的烷基、被氰基取代的链烯基、
Figure PCTCN2017075628-appb-000009
其中，Ra和Rb可选自烷基和链烯基。
本文中，“任选取代的”指其所修饰的取代基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、 羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本发明的化合物
本发明的化合物是具有通式I所示结构的化合物或其药学上可接受的盐：
Figure PCTCN2017075628-appb-000010
式中，
X选自N、CH；
Y选自O、S和Se；
A选自各种取代的苯环、含氮五元环、含氮六元环，例如
Figure PCTCN2017075628-appb-000011
R1独立选自氢、卤素、C1-C8烷基、C3-C6环烷基、含氟C1-C8烷基、任选取代的苯基；
R2选自氢、任选取代的C1-C6烷基、卤素、任选取代的C1-C6烷氧基、氨基、-NRaRb、羧基、任选取代的烷氧甲酰基、任选取代的N-烷基哌嗪-1-基、任选取代的吗啉-4-基、任选取代的哌啶-1-基(优选哌嗪取代的哌啶-1-基)、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基、任选取代的芳基或任选取代的芳基甲基、任选取代的哌啶基氧基、任选取代的N,N',N'-三烷基乙二胺基；
Ra和Rb各自独立选自氢、C1-C6烷基和链烯基；和
n为0、1、2、3或4；
R3各自独立选自氢、卤素、羟基、氨基、-NRcRd、C1-C2酰基氨基、任选取代的C1-C6烷基、C1-C3磺酰基氨基、CN、氨基甲酰基、羧基、C1-C6烷氧甲酰基、任选取代的苯基、任选取代的哌嗪基、任选取代的吗啉-4-基、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基；
Rc和Rd各自独立选自：氢、C1-C6烷基和链烯基；和
m为0、1、2、3或4；
其中，当n和m均为1时，且R2为C1-C6烷氧基时，R3不为氨基。
在具体的实施方式中，所述化合物具有通式II所示结构：
Figure PCTCN2017075628-appb-000012
式中，
A选自各种取代的苯环；
R1为氢；
R2选自氢、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、卤素、氨基、-NRaRb、任选取代的哌嗪基、任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
Ra和Rb各自独立选自氢、C1-C6烷基和链烯基；和
n为1、2、或3；
R3各自独立选自氢、卤素、C1-C2酰基氨基、羟基、氨基、-NRcRd、C1-C3磺酰基氨基(优选甲磺酰氨基)、任选取代的C1-C6烷基、任选取代的哌嗪基、任选取代的N-烷基哌嗪-1-基；
Rc和Rd各自独立选自氢、C1-C3烷基和链烯基；和
m为1、2、或3。
在优选的实施方式中，所述化合物具有通式III所示结构：
Figure PCTCN2017075628-appb-000013
式中，
R4选自氢、卤素、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基；
R5选自任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
R6选自氨基、任选取代的哌嗪基、-NReRf；
Re和Rf各自独立选自氢、C1-C3烷基和链烯基。
在进一步优选的实施方式中：
R4选自任选取代的C1-C6烷基，优选C1-C3烷基；
R5选自任选取代的N-烷基哌嗪-1-基；
R6选自氨基、或-NReRf；
Re和Rf各自独立选自氢、和C1-C3烷基。
本发明人合成得到了一系列结构未见文献报道的蝶啶酮类化合物；具体地说，本发明人合成得到了选自下组的化合物或其药学上可接受的盐：
Figure PCTCN2017075628-appb-000014
Figure PCTCN2017075628-appb-000015
Figure PCTCN2017075628-appb-000016
Figure PCTCN2017075628-appb-000017
在优选的实施方式中，本发明人合成得到选自下组的化合物或其药学上可接受的盐：
Figure PCTCN2017075628-appb-000018
在进一步优选的实施方式中，本发明人合成得到选自下组的化合物或其药学上可接受的 盐：
Figure PCTCN2017075628-appb-000019
在本发明的化合物的基础上，本发明提供一种药物组合物，该组合物含有治疗有效量的本发明的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS,胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
虽然每个人的需求各不相同，本领域技术人员可确定本发明药物组合物中每种活性成分的最佳剂量。一般情况下，本发明的化合物或其药学上可接受的盐，对哺乳动物每天口服给药，药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克。例如，单位口服剂量可以包括约0.01到50毫克，最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次，每天为一片或多片，每片含有约0.1到50毫克，合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于治疗肿瘤和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人。
本发明的化合物或其药物组合物可用于治疗各种由FMS样酪氨酸激酶3(FLT3)介导的疾病。在本文中，所述FLT3介导的疾病为血液病，如骨髓增殖性疾病，癌症，免疫性疾病，以及皮肤病，如银屑病和特应性皮炎。
在具体的实施方式中，所述癌症选自急性骨髓性白血病(AML)、混合系白血病(MLL)、T-细胞急性白血病(T-ALL)、B细胞急性白血病(B-ALL)、慢性骨髓单细胞性白血病(CMML)、慢性淋巴细胞白血病、慢性髓细胞白血病、慢性中性粒细胞白血病。
在其它实施方式中，所述免疫性疾病选自关节炎、狼疮、炎性肠病、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性传播性脑脊髓炎、阿狄森病、再生障碍性贫血、自身免疫性肝炎、视神经炎、银血病、移植物抗宿主病、移植、输血过敏反应、变态反应、I型超敏反应、过敏性结膜炎、过敏性鼻炎、特应性皮炎。
本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。
合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠.辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
基于上述化合物和药物组合物，本发明进一步提供一种治疗FLT3介导的疾病的方法，该方法包括给予需要的对象以本发明的化合物或药物组合物。
给药方法包括但不限于本领域周知的各种给药方法，可根据患者的实际情况加以确定。这些方法包括但不限于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药。
本发明也包括本发明化合物在制备治疗FLT3介导的疾病，或抑制FLT3的药物中的用途。
本发明的优点：
1.本发明提供的化合物是一种结构全新的蝶啶酮衍生物；
2.本发明提供的化合物对FLT3具有优异的抑制活性；
3.本发明提供的化合物为开发能抑制FLT3的靶向药物奠定了基础，具备极大的产业化和商品化前景以及市场价值，经济效益显著。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
抑制剂合成部分
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。
Figure PCTCN2017075628-appb-000020
蝶啶酮母核衍生物的合成路线
上述制备流程中，R1-R4的定义如上文所述。本领域技术人员可根据实际制备需要，采用本领域常规获得的各种起始化合物为原料，制备本发明的化合物。
实施例1
1)8-(4-氨基苯基)-2-(4-甲氧基-2-甲基苯基)-7(8H)-蝶啶酮(F-1)的合成
①(4-氨基苯基)氨基甲酸叔丁酯的合成
Figure PCTCN2017075628-appb-000021
称取对苯二胺(890mg，8.23mmol)置于100mL圆底烧瓶中，加入40mL二氯甲烷，冰浴下搅拌，另取二碳酸二叔丁酯(449mg，2.06mmol)溶于二氯甲烷当中，滴加到上述反应液当中，然后继续在室温下搅拌过夜。反应结束，旋转蒸发除溶剂，粗品经硅胶柱层析(石油醚/乙酸乙酯＝3:1，v/v)分离，得到(4-氨基苯基)氨基甲酸叔丁酯398mg，产率93％。
1H NMR(400MHz,CDCl3):δ7.14(d,J＝8.0Hz,2H),6.65(d,J＝8.4Hz,2H),6.26(s,1H),1.52(s,9H).熔点112-113℃，文献值[97]112-114℃。
②(4-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(B-1)的合成
Figure PCTCN2017075628-appb-000022
称取2,4-二氯-5-硝基嘧啶(190mg，0.98mmol)，加入6mL 1,4-二氧六环，置于25mL圆底烧瓶中，室温下搅拌，取(4-氨基苯基)氨基甲酸叔丁酯(200mg，0.96mmol)、N,N-二异丙基乙胺(137mg，1.06mmol)溶于4mL 1,4-二氧六环，缓慢滴加到上述反应液中，滴加完后继续在室温下搅拌1小时左右，TLC监测反应完全转化。旋转蒸发除溶剂，粗品经硅胶柱层析(石油醚/乙酸乙酯＝10:1，v/v)分离，得到(4-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯橙色固体301mg，产率82％。
1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),9.47(s,1H),9.12(s,1H),7.49(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),1.49(s,9H).LC-MS计算值C15H17ClN5O4[M+H]+366.09,实验值366.00。
③(4-(2-(4-甲氧基-2-甲基苯基氨基)-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(C-1)的合成
Figure PCTCN2017075628-appb-000023
称取(4-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(150mg，0.41mmol)、4-甲氧基-2-甲基苯胺(51mg，0.37mmol)、N,N-二异丙基乙胺(145mg，1.12mmol)置于25mL圆底烧瓶中，加入10mL 1,4-二氧六环，室温搅拌过夜。反应结束后，旋转蒸发除去溶剂，粗品经硅胶柱层析(石油醚/乙酸乙酯＝5:1，v/v)纯化，得到(4-(2-(4-甲氧基-2-甲基苯基氨基)-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯黄色固体148mg，产率85％。
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.86(s,1H),9.33(s,1H),9.06(s,1H),7.60(s,1H),7.36(d,J＝8.4Hz,2H),7.27-7.23(m,2H),6.85(s,1H),6.79(d,J＝7.6Hz,1H),3.82(s,3H),2.15(s,3H),1.48(s,9H).ESI计算值C23H27N6O5[M+H]+467.20,实验值467.20。
④(4-(2-(4-甲氧基-2-甲基苯基氨基)-7-氧代-8(7H)-蝶啶基)苯基)氨基甲酸叔丁酯的合成(E-1)的合成
Figure PCTCN2017075628-appb-000024
称取(4-(2-(4-甲氧基-2-甲基苯基氨基)-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(100 mg，0.21mmol)置于250mL圆底烧瓶中，加入100mL甲醇、100mL二氯甲烷和20mg钯碳(10％Pd)，通入氢气，室温搅拌过夜。反应结束后，抽滤，将滤液旋干，得粗产品88mg，产品未经纯化，直接用于下一步反应。
将上一步反应得到的产品置于50mL圆底烧瓶中，加入0.6mL冰醋酸、10mL无水乙醇，然后加入乙醛酸乙酯(50％甲苯溶液)(0.044mL,0.22mmol)，加热至回流搅拌过夜。反应结束后，有固体析出，抽滤，滤饼用乙醇洗涤，烘干。粗产物经硅胶柱层析(二氯甲烷/甲醇＝50:1，v/v)分离纯化，得到(4-(2-(4-甲氧基-2-甲基苯基氨基)-7-氧代-8(7H)-蝶啶基)苯基)氨基甲酸叔丁酯黄色固体61mg，产率64％。
1H NMR(400MHz,DMSO-d6):δ9.55(s,1H),9.17(s,1H),8.76(s,1H),7.98(s,1H),7.56(d,J＝8.8Hz,2H),7.22(d,J＝7.6Hz,2H),7.16(s,1H),6.69(s,1H),6.54(s,1H),3.70(s,3H),2.11(s,3H),1.51(s,9H).ESI计算值C25H27N6O4[M+H]+475.20,实验值475.20。
⑤8-(4-氨基苯基)-2-(4-甲氧基-2-甲基苯基)-7(8H)-蝶啶酮(F-1)的合成
Figure PCTCN2017075628-appb-000025
称取(4-(2-(4-甲氧基-2-甲基苯基氨基)-7-氧代-8(7H)-蝶啶基)苯基)氨基甲酸叔丁酯(50mg,0.11mmol)置于25mL圆底烧瓶中,加入6mL二氯甲烷，0℃下搅拌，加入1.5mL三氟乙酸。继续在0℃下搅拌1小时，后室温下搅拌2小时。反应结束后，加入饱和碳酸氢钠溶液中和至溶液偏碱性，用二氯甲烷萃取，有机相用去离子水洗涤，无水硫酸钠干燥，将溶剂旋干。粗产物经硅胶柱层析(二氯甲烷/甲醇＝30:1，v/v)分离纯化，得到8-(4-氨基苯基)-2-(4-甲氧基-2-甲基苯基)-7(8H)-蝶啶酮黄色固体32mg，产率82％,mp 149.1-149.3℃。
1H NMR(400MHz,DMSO-d6):δ9.13(s,1H),8.72(s,1H),7.95(s,1H),7.21(s,1H),6.94(d,J＝8.0Hz,2H),6.72(s,1H),6.65(d,J＝8.4Hz,2H),6.60(s,1H),5.33(br,2H),3.72(s,3H),2.13(s,3H).HRMS(ESI)计算值C20H19N6O2[M+H]+375.1569,实验值375.1573。HPLC purity:96.0％，retention time＝11.68min.
2)8-(4-氨基苯基)-2-(3-氯-4-甲氧基苯基)-7(8H)-蝶啶酮(F-2)的合成
Figure PCTCN2017075628-appb-000026
合成方法参照F-1，得黄色固体，产率75％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),8.84(s,1H),8.03(s,1H),7.60(s,1H),7.38(s,1H),6.98(d,J＝8.4Hz,2H),6.87(s,1H),6.72(d,J＝8.4Hz,2H),5.39(br,2H),3.79(s,3H).HRMS(ESI)计算值C19H16ClN6O2[M+H]+395.1023,实验值395.1027。HPLC purity:97.0％，retention time＝11.55min.
3)8-(4-氨基苯基)-2-(3-氟-4-甲氧基苯基)-7(8H)-蝶啶酮(F-3)的合成
Figure PCTCN2017075628-appb-000027
合成方法参照F-1，得黄色固体，产率73％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.14(s,1H),8.85(s,1H),8.03(s,1H),7.42(s,1H),7.19(s,1H),6.98(d,J＝8.4Hz,2H),6.89(s,1H),6.72(d,J＝8.4Hz,2H),5.38(br,2H),3.77(s,3H).HRMS(ESI)计算值C19H16FN6O2[M+H]+379.1319,实验值379.1323。HPLC purity:96.3％，retention time＝11.68min.
4)N-(4-(2-(4-甲氧基苯基氨基)-7-氧代-8(7H)-蝶啶基)苯基)乙酰胺(E-4)的合成
Figure PCTCN2017075628-appb-000028
合成方法参照E-1，得黄色固体，产率62％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.23(s,1H),10.10(s,1H),8.85(s,1H),8.04(s,1H),7.78(d,J＝7.2Hz,2H),7.34(d,J＝7.6Hz,4H),6.61(s,2H),3.67(s,3H),2.13(s,3H).HRMS(ESI)计算值C21H19N6O3[M+H]+403.1519,实验值403.1500。HPLC purity:97.5％，retention time＝10.54min.
5)N-(4-(2-((4-甲基苯基)氨基)-7-氧代-8(7H)蝶啶基)苯基)甲基磺酰胺(G-5)的合成
Figure PCTCN2017075628-appb-000029
称取8-(4-氨基苯基)-2-(4-甲氧基苯基)-7(8H)-蝶啶酮(100mg,0.277mmol)，三乙胺(0.232mL，1.662mmol)置于25mL圆底烧瓶中，加入15mL无水二氯甲烷，冰浴下搅拌。称取甲基磺酰氯(0.172mL，2.216mmol)溶于2mL的二氯甲烷中，将其缓慢滴加到上述反应液当中，滴加完后冰浴下继续搅拌1小时，室温搅拌过夜。TLC跟踪至原料完全转化。旋干溶剂，加入饱和碳酸氢钠溶液中和至溶液偏碱性，用二氯甲烷萃取，无水硫酸钠干燥。粗品经硅胶柱层析(二氯甲烷/乙酸乙酯/甲醇＝100:50:1，v/v)纯化，得到N-(4-(2-((4-甲基苯基)氨基)-7-氧代-8(7H)蝶啶基)苯基)甲基磺酰胺黄色固体54mg，产率47％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.11(br,1H),8.84(s,1H),8.03(s,1H),7.40(s,4H),7.31(br,2H),6.66(br,2H),3.69(s,3H),3.12(s,3H).HRMS(ESI)计算值C20H19N6O4S[M+H]+439.1189,实验值439.1187。HPLC purity:95.4％，retention time＝11.70min.
6)8-(4-氨基苯基)-2-((3-氯-4-(4-甲基-1-哌嗪基)苯基)氨基)-7(8H)蝶啶酮(F-6)的合成
Figure PCTCN2017075628-appb-000030
合成方法参照F-1，得黄色固体，产率62％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.13(br,1H),8.85(s,1H),8.03(s,1H),7.60(s,1H),7.37(d,J＝7.6Hz,1H),6.97(d,J＝8.4Hz,2H),6.89(d,J＝7.6Hz,1H),6.71(d,J＝8.4Hz,2H),5.38(s,2H),2.89(br,4H),2.47(br,4H),2.34(s,3H).HRMS(ESI)计算值C23H24ClN8O[M+H]+463.1762,实验值463.1710。HPLC purity:98.7％，retention time＝9.64min.
7)8-(4-氨基苯基)-2-((3-氟-4-(4-甲基-1-哌嗪基)苯基)氨基)-7(8H)蝶啶酮(F-7)的合成
Figure PCTCN2017075628-appb-000031
合成方法参照F-1，得黄色固体，产率64％，mp 238.2-238.7℃。
1H NMR(400MHz,DMSO-d6):δ10.13(br,1H),8.84(s,1H),8.02(s,1H),7.32(d,J＝12.4Hz,1H),7.19(d,J＝7.2Hz,1H),6.97(d,J＝8.4Hz,2H),6.77(br,1H),6.72(d,J＝8.4Hz,2H),5.39(s,2H),2.92-2.90(m,4H),2.45(br,4H),2.22(s,3H).HRMS(ESI)计算值C23H24FN8O[M+H]+447.2057,实验值447.2057。HPLC purity:96.9％,retention time＝9.12min.
8)8-(4-氨基苯基)-2-((3-甲基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7(8H)蝶啶酮(F-8)的合成
Figure PCTCN2017075628-appb-000032
合成方法参照F-1，得黄色固体，产率74％，mp 255.6-256.3℃。
1H NMR(400MHz,DMSO-d6):δ9.94(br,1H),8.80(s,1H),7.99(s,1H),7.36(br,1H),7.18(d,J＝6.4Hz,1H),6.97(d,J＝8.4Hz,2H),6.79(d,J＝8.4Hz,1H),6.71(d,J＝8.4Hz,2H),5.37(s,2H),2.76-2.74(m,4H),2.47(br,4H),2.24(s,3H),2.06(s,3H).HRMS(ESI)计算值C24H27N8O[M+H]+443.2308，实验值443.2301。HPLC purity:99.2％,retention time＝9.44min.
9)8-(4-氨基苯基)-2-((3-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7(8H)蝶啶酮(F-9)的合成
Figure PCTCN2017075628-appb-000033
合成方法参照F-1，得橙黄色固体，产率63％，mp 147.4-147.9℃。
1H NMR(400MHz,DMSO-d6):δ9.94(br,1H),8.81(s,1H),7.99(s,1H),7.09(s,2H),6.97(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,2H),6.60(br,1H),5.41(s,2H),3.56(s,3H),2.87(br,4H),2.43(br,4H),2.21(s,3H).HRMS(ESI)计算值C24H27N8O2[M+H]+459.2257,实验值459.2256。HPLC purity:98.0％,retention time＝8.75min.
10)8-(4-氨基苯基)-2-((3-甲基-4-(1-甲基-4-氧代哌啶基)苯基)氨基)-7(8H)蝶啶酮(F-10)的合成
Figure PCTCN2017075628-appb-000034
合成方法参照F-1，得黄色固体，产率52％，mp 228.9-229.4℃.
1H NMR(400MHz,DMSO-d6):δ9.97(br,1H),8.81(s,1H),7.99(s,1H),7.36(d,J＝2.0Hz,1H),7.16(br,1H),6.97(d,J＝8.8Hz,2H),6.70(d,J＝8.4Hz,3H),5.39(s,2H),4.37(s,1H),2.92(s,2H),2.75(s,2H),2.01(s,6H),1.81-1.71(m,2H),1.34-1.19(m,1H).HRMS(ESI)计算值C25H28N7O2[M+H]+458.2304,实验值458.2289。HPLC purity:99.3％,retention time＝10.29min.
11)N-(4-(2-(4-(4-甲基-1-哌嗪基)氨基)-7-氧代-8(7H)-蝶啶酮)苯基)乙酰胺(E-11)的合成
Figure PCTCN2017075628-appb-000035
合成方法参照E-1，得橙红色固体，产率58％，mp 288.0-288.7℃。
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.05(s,1H),8.82(s,1H),8.02(s,1H),7.80(d,J＝8.0Hz,2H),7.32(d,J＝8.4Hz,2H),7.25(br,2H),6.64(br,2H),3.24(br,4H),3.05(br,4H),2.64(s,3H),2.15(s,3H).HRMS(ESI)计算值C25H27N8O2[M+H]+471.2257,实验值471.2213。HPLC purity:97.3％,retention time＝8.17min.
12)N-(4-(2-((4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-8(7H)蝶啶基)苯基)甲基磺酰胺(G-12)的合成
Figure PCTCN2017075628-appb-000036
合成方法参照F-1，得橙红色固体，产率86％。
1H NMR(400MHz,DMSO-d6):δ9.98(s,1H),8.78(s,1H),7.98(s,1H),7.32(d,J＝6.4Hz,2H),6.97(d,J＝8.8Hz,2H),6.74(d,J＝8.0Hz,2H),6.67(br,2H),3.04-3.02(m,4H),2.45-2.43(m,4H),2.22(s,3H).HRMS(ESI)计算值C23H25N8O[M+H]+429.2151,实验值429.2153。
①N-(4-(2-((4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-8(7H)蝶啶基)苯基)甲基磺酰胺(G-12)的合成
Figure PCTCN2017075628-appb-000037
合成方法参照G-5，得黄色固体，产率50％，mp>300℃。
1H NMR(400MHz,DMSO-d6):δ10.02(s,1H),8.82(s,1H),8.02(s,1H),7.42-7.37(m,4H),7.26(br,2H),6.66(br,2H),3.13(s,3H),3.07(br,4H),2.54(br,4H),2.29(s,3H)。HRMS(ESI)计算值C24H27N8O3S[M+H]+507.1927,实验值507.1926。HPLC purity:99.0％,retention time＝8.53min.
13)8-(4-氨基苯基)-2-((4-(4-甲基-1-哌嗪基)苄基)氨基)-7(8H)蝶啶酮(F-13)的合成
Figure PCTCN2017075628-appb-000038
合成方法参照F-1，得黄色固体，产率65％，mp 216.2-216.8℃。
1H NMR(400MHz,DMSO-d6):δ9.99(s,1H),8.82(s,1H),8.01(s,1H),7.55(d,J＝8.0Hz,2H),7.32(d,J＝8.4Hz,2H),7.20(s,2H),6.59(s,2H),3.86(s,2H),3.00-2.99(m,4H),2.44-2.41(m,4H),2.21(s,3H).HRMS(ESI)计算值C24H27N8O[M+H]+443.2308,实验值443.2304。HPLC purity:97.4％,retention time＝6.92min.
14)2-((4-(4-甲基-1-哌嗪基)苯基)氨基)-8-(4-(1-哌嗪基)苯基)-7(8H)蝶啶酮(F-14)的合成
Figure PCTCN2017075628-appb-000039
合成方法参照F-1，得黄色固体，产率72％，mp 276.6-277.2℃。
1H NMR(400MHz,DMSO-d6):δ10.01(s,1H),8.81(s,1H),8.00(s,1H),7.26(d,J＝6.8Hz,2H),7.20(d,J＝8.8Hz,2H),7.12(d,J＝8.8Hz,2H),6.58(s,2H),3.19-3.17(m,4H),3.02-3.00(m,4H),2.90-2.88(m,4H),2.45-2.43(m,4H),2.22(s,3H).HRMS(ESI)计算值C27H32N9O[M+H]+498.2730,实验值498.2728。HPLC purity:98.6％,retention time＝7.86min.
15)8-(3-氨基苯基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮.(F-15)
Figure PCTCN2017075628-appb-000040
合成方法参照F-1，得黄色固体，收率70％,mp 262.5-262.9℃.
1H NMR(400MHz,DMSO-d6):δ10.01(s,1H),8.81(s,1H),7.99(s,1H),7.35(d,J＝7.2Hz,2H),7.22(t,J＝8.0Hz,1H),6.75(d,J＝7.2Hz,1H),6.66(br,2H),6.52(br,1H),6.48(d,J＝8.0Hz,1H),5.35(s,2H),3.02(br,4H),2.46-2.44(m,4H),2.23(s,3H).HPLC purity:99.5％,retention time＝8.57min.HRMS(ESI)(m/z):[M+H]+calcd for C23H25N8O,429.2151；found,429.2151.
16)8-(4-N,N-二甲氨基苯基)-2-((3-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮.(F-16)
Figure PCTCN2017075628-appb-000041
将原料1置于250ml圆底烧瓶中，加入DCM和MeOH溶解，称取100mg钯碳(10％Pd)，通入氢气，室温下反应约10h后，抽滤，滤液减压蒸去溶剂，产品未经纯化，直接用于下一步。称取原料2(0.3g,0.69mmol)于50ml圆底烧瓶，加入适量乙醇溶解，搅拌下加入乙醛酸乙酯(50％甲苯溶液)0.21ml(1.04mmol)与0.6ml冰醋酸，升温至回流，TLC跟踪反应至原料2转化完全，将反应液冷却至室温后抽滤，滤饼硅胶柱层析(DCM:MeOH＝80:1)，得黄色粉末状固体120mg。
1H NMR(400MHz,DMSO-d6,ppm)δ10.02(br,1H),8.83(s,1H),8.01(s,1H),7.28(s,1H),7.15(d,J＝8.8Hz,3H),6.87(d,J＝8.8Hz,2H),6.69-6.67(m,1H),3.01(s,6H),2.71(m,4H),2.44(m,4H),2.22(s,3H),1.96(s,3H).MS(ESI)(m/z):[M+H]+calcd for C26H30N8O，470.25；found,470.21.
实施例2
化合物1的合成步骤如下所述，而化合物2-31的合成参照化合物1的合成进行：
(S)-3-((2-氯-5-硝基嘧啶)4-氨基)吡咯烷-1-甲酸叔丁酯的合成
Figure PCTCN2017075628-appb-000042
称取2,4-二氯-5-硝基嘧啶(3.23g，16.28mmol)置于250mL低温反应瓶中，加入80mL二氯甲烷溶解，-70℃下搅拌冷却，另取(S)-1-叔丁氧羰基-3-氨基吡咯烷(3.03g，16.28mmol)、N,N-二异丙基乙胺(2.52g，19.53mmol)溶于20mL二氯甲烷，并滴加到上述反应液中，滴加完成后，继续在-70℃下搅拌0.5小时，TLC跟踪至原料完全转化。旋转蒸发除去溶剂，粗品经硅胶柱层析(石油醚/乙酸乙酯＝12:1，v/v)分离，得到S1黄色油状液体5.54g，产率99％。
1H NMR(400MHz,DMSO-d6):δ9.07(s,1H),8.41(d,J＝6.4Hz,1H),4.87-4.84(m,1H),3.81(dd,J＝11.6Hz,6.4Hz,1H),3.54(t,J＝6.4Hz,1H),3.36(br,1H),2.40-2.31(m,1H),2.06-1.98(m,1H),1.48(s,9H).
1-甲基-4-(2-甲基-4-硝基苯基)哌嗪的合成
Figure PCTCN2017075628-appb-000043
称取3-甲基-4-氟-1-硝基苯(2.67g,17.21mmol)以及N-甲基哌嗪(1.72g,17.21mmol)于50ml圆底烧瓶中，加入DMSO溶解，加入K2CO34.76g,90℃加热搅拌9h,TLC跟踪至原料完全转化,抽滤除去K2CO3，乙酸乙酯洗涤后，取滤液加入少量乙酸乙酯稀释，饱和氯化钠萃取，有机层干燥，旋转蒸发除去溶剂，粗品经硅胶柱层析(二氯甲烷/甲醇＝60:1，v/v)分离，得到S2褐色固体3.92g，产率96.8％。
1H NMR(400MHz,DMSO-d6):δ7.88(d,J＝4.8Hz,1H),6.60(dd,J＝9.6Hz,2.4Hz,1H),6.53(s,1H),3.91(s,3H),3.44(br,4H),2.42(br,4H),2.22(s,3H).
3-甲基-4-(4-甲基哌嗪基)苯胺的合成
Figure PCTCN2017075628-appb-000044
称取S2(1.96g,8.33mmol)于250ml圆底烧瓶中，加入乙酸乙酯/甲醇(1:1)溶解，加入100mg10％Pd/C,通入氢气，室温搅拌4h,TLC跟踪至原料完全转化,反应液抽滤后旋转蒸发除去溶剂，得到S3黄色固体1.68g，产率98.2％。产品未经纯化，直接用于下步反应。
(S)-3-((2-((3-甲基-4-(4-甲基-1-哌嗪基)苯基)氨基)-5-硝基-4-嘧啶基)氨基)吡咯烷基-1-叔丁基甲酸酯的合成
Figure PCTCN2017075628-appb-000045
称取S1(2.84g,8.26mmol),S2(1.70g,8.26mmol),DIPEA(2.13g,16.52mmol)于250ml圆底烧瓶中，加入THF溶解，氩气保护下搅拌过夜。TLC跟踪至原料完全转化,，旋转蒸发除去溶剂，加水稀释后用乙酸乙酯萃取(100mL×2)，有机相经饱和氯化铵溶液(50mL×2)、饱和氯化钠溶液洗涤后，加入无水硫酸钠干燥。粗品经硅胶柱层析(二氯甲烷/甲醇＝40:1，v/v)分离，得到S4黄色固体3.45g，产率81.5％。
1H NMR(400MHz,DMSO-d6):δ10.35(s,1H),8.95(s,1H),8.57(s,1H),7.69(s,1H),7.44(d,J＝7.6Hz,1H),6.98(d,J＝8.8Hz,1H),4.65-4.62(m,1H),4.12(s,0.4H),3.72(dd,J＝10.8Hz,6.8Hz),3.57-3.27(m,4.31H),3.18(s,1H),2.80(br,4H),2.45(br,4H),2.22(s,3H),2.21(s,3H),1.42(s,9H)。
(S)-3-((5-氨基-2-((3-甲基-4-(4-甲基-1-哌嗪基苯基)氨基)4-嘧啶基)氨基)吡咯烷基)-1-甲酸叔丁酯
Figure PCTCN2017075628-appb-000046
称取S4(3.45g,6.73mmol)于250ml圆底烧瓶中，加入无水乙醇溶解，加入100mg Pd/C(10％),通入氢气，室温下搅拌过夜8h.反应结束后，抽滤，将滤液旋干，产品未经纯化， 直接用于下一步反应。
(S)-3-(6-异丙基-2-((3-甲基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-8(7H)-蝶啶基)吡咯烷基-1-甲酸叔丁酯
Figure PCTCN2017075628-appb-000047
取上一步产物S5(1.61g,3.33mmol)于25ml圆底烧瓶中，加入10ml无水乙醇，0.6ml冰醋酸，加入二甲基丙酮酸乙酯(721mg,5.00mmol),氩气保护下加热回流，搅拌过夜。TLC跟踪至原料完全转化，旋转蒸发除去溶剂，加水稀释后用二氯甲烷萃取(100mL×2)，有机相经饱和碳酸氢钠溶液(50mL×2)、饱和氯化钠溶液洗涤后，加入无水硫酸钠干燥。粗品经硅胶柱层析(二氯甲烷/甲醇/氨水＝50:1:1，v/v/v)分离，得到S6黄色固体1.34g，产率71.4％。lc-ms
(S)-6-异丙基-2-((3-甲基-4-(4-甲基-1-哌嗪基)苯基)氨基)-8-(3-吡咯烷基)-7(8H)蝶啶酮的合成
Figure PCTCN2017075628-appb-000048
称取S6(1.20g,2.13mmol)于25ml圆底烧瓶中，加入二氯甲烷溶解，在冰浴中冷却后滴加4ml三氟乙酸，室温反应3h,TLC跟踪至原料完全转化,，反应液倒入烧杯，二氯甲烷稀释，边搅拌边滴加氢氧化钠溶液至溶液分层，上层pH约为9，加二氯甲烷稀释，饱和氯化钠溶液萃取，无水硫酸钠干燥。粗品经硅胶柱层析(二氯甲烷/甲醇＝20:1，v/v)分离，得到S7黄色固体0.89g，产率90.2％。
1H NMR(400MHz,DMSO-d6):δ9.85(s,1H),8.74(s,1H),7.51(s,1H),7.43(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),5.85-5.77(m,1H),3.42-3.36(m,1H),2.96-2.91(m,1H),2.82(br,4Hz),2.78-2.73(m,1H),2.47(br,4H),2.24(s,3H),2.23(s,3H),2.17-2.09(m,1H),1.99-1.91(m,1H),1.19(d,J＝6.8Hz,6H)。
实施例3
生物活性测试部分
激酶测试方法
通过Mobility shift assay方法测试而成，激酶缓冲液(50mM HEPES,pH 7.5,0.01％Brij-35,10mM MgCl2,2mM DTT)，终止缓冲液(100mM HEPES,pH 7.5,0.015％Brij-35,0.2％Coating Reagent#3,50mM EDTA)。用100％的DMSO将化合物稀释到所需要的浓度，并将配好的化合物转移到96孔板中，稀释的浓度从20μl至60μl不等并以一定的浓度梯度配成10个浓度。以100μl的100％DMSO浓度作为空白对照。后将96孔板的药物的5μl转移到384孔板中重复试验。激酶在28℃下以特定的方式进行培养。最后通过标准曲线计算出IC50值。
细胞测试方法
细胞培养：细胞株由美国菌种保藏中心获得。细胞在RPMI-1640或者MEM培养基中培养，其在5％的CO2中含10％的胎牛血清，在37℃下进行。MV4-11细胞在IMDM培养基中培养。
细胞活性测定方法：悬浮细胞的活性测试主要是MTT测试方法测定，而贴壁细胞的测试主要是SRB测试方法。悬浮细胞在每孔3-8×103细胞的96孔板上进行培养，每个孔中加入100μL的培养基，然后加入10μL的化合物(一式三份)，在37℃下培养72h。细胞培养完以后，在每一孔板中加入20μL的5mg/mL MTT试剂再继续培养4h，加入50μL三种混合溶剂(5％异丙醇-10％SDS-12mmol/L HCl)来溶解氧化产物。OD值用多功能检测仪Synergy2在570nm处测定。贴壁细胞在每孔2-7×103细胞的96孔板上进行培养24h，同样在培养基中加入相同当量的化合物。72h培养以后，移除培养液，菌种用TCA固定1h。干燥的孔板染上磺酰罗丹明B，然后加入150μL 10mM Tris-HCl。最后，溶解细胞的光吸收用Synergy2微分光光度计在560nm处检测。所有的实验都进行三次平行反应。
免疫沉淀反应和蛋白质印迹实验：用不同浓度的化合物去培养细胞2h，然后用RIPA溶解缓冲液将细胞进一步地溶解，随后在4℃下离心分离，取上清液进行相关实验。蛋白质用SDS-PAGE进行分离，然后转移到硝酸纤维膜中用于抗体的检测。主要抗体作用于FLT3,AKT,p-AKT,STAT5,p-STAT5和p44/42MAPK，抗GAPDH用推荐的浓度进行培养。可视化的信号在用了HRP共聚抗体后用Tanon 5200多捕获系统来检测提高的ECL基质。细胞溶解产物用FLT3抗体和蛋白A凝胶进行免疫沉淀反应，煮熟的样品用6％凝胶进行电泳电极化，然后用4G10抗体进行标记，用此方法来检测FLT3磷酸化水平。
流式细胞实验：细胞用膜联蛋白V和碘化丙啶来染色，用于检测化合物的细胞凋亡活性。MV4-11细胞在6个孔板中用密度为1×105细胞/mL进行培养，然后加入不同浓度的化合物培养48h。将细胞分割并用冷的PBS缓冲溶液洗涤两次。样品在结合缓冲液中重新悬浮，在光照的保护下用膜联蛋白V和碘化丙啶培养。细胞周期试验根据PI/Rnase染色溶剂产品说明书进行操作。分裂细胞在70％的乙醇中固定1h。然后所有的细胞都在非光照室温的条件下用碘化丙啶染色30min。细胞凋亡和细胞周期都用FACS流式细胞仪进行检测。
化合物的测试结果(测试以AC220、MLN518作为阳性对照药)如下表所示，细胞测试结果如附图所示。
表1.化合物的激酶测试和细胞测试结果
Figure PCTCN2017075628-appb-000049
MV4-11移植瘤模型测试
发明人进一步在MV4-11移植瘤模型中测试了本发明化合物对肿瘤的抑制活性。
结果如图2-3所示，本发明化合物对肿瘤体积以及重量的影响与阳性对照AC220相似，从而进一步证实本发明化合物在抑制肿瘤方面的潜能。
讨论：
发明人经过广泛而深入的研究，设计并合成得到了一系列未见文献报道的蝶啶酮衍生物，对得到的化合物进行了分子水平和细胞水平的活性测试，得到一批能够抑制FLT3的化合物。这些化合物对FLT3的抑制活性IC50值达到nM级别；对相关细胞的抑制活性IC50值达到μM级别。其中多个化合物，例如F-8和F-16对FLT3的抑制活性IC50值低于10nM，远优于阳性对照MLN518。而进一步的肿瘤模型测试显示本发明的化合物在体内同样具备优异的抑制肿瘤活性。因此，本发明非化合物有可能成为抑制FLT3的靶向药物，或者作为经进一步修饰得到活性更佳和/或毒性更低的化合物的基础。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 具有通式I所示结构的化合物或其药学上可接受的盐：
    Figure PCTCN2017075628-appb-100001
    式中，
    X选自：N、CH；
    Y选自：O、S和Se；
    A选自各种取代的苯环、含氮五元环、含氮六元环，例如
    Figure PCTCN2017075628-appb-100002
    R1独立选自：氢、卤素、C1-C8烷基、C3-C6环烷基、含氟C1-C8烷基、任选取代的苯基；
    R2选自：氢、任选取代的C1-C6烷基、卤素、任选取代的C1-C6烷氧基、氨基、-NRaRb、羧基、任选取代的烷氧甲酰基、任选取代的N-烷基哌嗪-1-基、任选取代的吗啉-4-基、任选取代的哌啶-1-基、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基、任选取代的芳基或任选取代的芳基甲基、任选取代的哌啶基氧基、任选取代的N,N',N'-三烷基乙二胺基；
    Ra和Rb各自独立选自：氢、C1-C6烷基和链烯基；和
    n为0、1、2、3或4；
    R3各自独立选自：氢、卤素、羟基、氨基、-NRcRd、C1-C2酰基氨基、任选取代的C1-C6烷基、C1-C3磺酰基氨基、CN、氨基甲酰基、羧基、C1-C6烷氧甲酰基、任选取代的苯基、任选取代的哌嗪基、任选取代的吗啉-4-基、任选取代的吡咯-1-基、任选取代的吡咯烷-1-基；
    Rc和Rd各自独立选自：氢、C1-C6烷基和链烯基；和
    m为0、1、2、3或4；
    其中，当n和m均为1时，且R2为C1-C6烷氧基时，R3不为氨基。
  2. 如权利要求1所述的化合物，其特征在于，所述化合物具有通式II所示结构：
    Figure PCTCN2017075628-appb-100003
    式中，
    A选自各种取代的苯环；
    R1为氢；
    R2选自：氢、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、卤素、氨基、-NRaRb、任选取代的哌嗪基、任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
    Ra和Rb各自独立选自：氢、C1-C6烷基和链烯基；和
    n为1、2、或3；
    R3各自独立选自：氢、卤素、C1-C2酰基氨基、羟基、氨基、-NRcRd、甲磺酰氨基、任选取代的C1-C6烷基、任选取代的哌嗪基；
    Rc和Rd各自独立选自：氢、C1-C3烷基和链烯基；和
    m为1、2、或3。
  3. 如权利要求2所述的化合物，其特征在于，所述化合物具有通式III所示结构：
    Figure PCTCN2017075628-appb-100004
    式中，
    R4选自：氢、卤素、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基；
    R5选自：任选取代的N-烷基哌嗪-1-基、任选取代的哌啶基氧基；
    R6选自：氨基、任选取代的哌嗪基、-NReRf；
    Re和Rf各自独立选自：氢、C1-C3烷基和链烯基。
  4. 如权利要求3所述的化合物，其特征在于，
    式中，
    R4选自任选取代的C1-C6烷基，优选C1-C3烷基；
    R5选自任选取代的N-烷基哌嗪-1-基；
    R6选自氨基、或-NReRf；
    Re和Rf各自独立选自氢、和C1-C3烷基。
  5. 选自下组的化合物或其药学上可接受的盐：
    Figure PCTCN2017075628-appb-100005
    Figure PCTCN2017075628-appb-100006
    Figure PCTCN2017075628-appb-100007
    Figure PCTCN2017075628-appb-100008
  6. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-5中任一项所述的化合物或其药学上可接受的盐，和药学上可接受的载体或赋形剂。
  7. 权利要求1-5中任一项所述的化合物在制备治疗FLT3介导的疾病，或抑制FLT3的药物中的用途。
  8. 如权利要求7所述的用途，其特征在于，所述FLT3介导的疾病为血液病，如骨髓增殖性疾病，癌症，免疫性疾病，以及皮肤病，如银屑病和特应性皮炎。
  9. 如权利要求8所述的用途，其特征在于，所述癌症选自急性骨髓性白血病(AML)、混合系白血病(MLL)、T-细胞急性白血病(T-ALL)、B细胞急性白血病(B-ALL)、慢性骨髓单细胞性白血病(CMML)、慢性淋巴细胞白血病、慢性髓细胞白血病、慢性中性粒细胞白血病。
  10. 如权利要求7所述的用途，其特征在于，所述免疫性疾病选自关节炎、狼疮、炎性肠病、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性传播性脑脊髓炎、阿狄森病、再生障碍性贫血、自身免疫性肝炎、视神经炎、银血病、移植物抗宿主病、移植、输血过敏反应、变态反应、I型超敏反应、过敏性结膜炎、过敏性鼻炎、特应性皮炎。
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