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WO2017049462A1 - Nouvel inhibiteur de la kinase flt3 et ses utilisations - Google Patents

Nouvel inhibiteur de la kinase flt3 et ses utilisations Download PDF

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Publication number
WO2017049462A1
WO2017049462A1 PCT/CN2015/090306 CN2015090306W WO2017049462A1 WO 2017049462 A1 WO2017049462 A1 WO 2017049462A1 CN 2015090306 W CN2015090306 W CN 2015090306W WO 2017049462 A1 WO2017049462 A1 WO 2017049462A1
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Prior art keywords
cancer
compound
lymphoma
group
flt3
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PCT/CN2015/090306
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Chinese (zh)
Inventor
刘青松
刘静
李滨华
王傲莉
吴宏
陈程
王文超
胡晨
赵铮
余凯琳
王蓓蕾
王黎
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Precedo Pharmaceuticals Co Ltd
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Precedo Pharmaceuticals Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 FLT3, c-Kit kinase and/or mutant FLT3 kinase in a cell or a subject Activity and use and method of preventing or treating a cell proliferative disorder and/or a FLT3, c-Kit related disorder 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.
  • inhibitors of protein kinases have particular applications in the treatment of human and animal diseases.
  • FLT3 Fms-like tyrosine kinase 3
  • RTK III receptor tyrosine kinase III
  • RTK III type III receptor tyrosine kinase III
  • c-Kit c-FMS and PDGFR.
  • Its protein structure includes an extracellular region consisting of five immunoglobulin (Ig)-like domains, a transmembrane region, a proximal membrane region (JM), and two cytokines separated by a kinase insertion region.
  • Aminokinase (TK) region SDLyman et al, Oncogene, 1993, 8, 815-822).
  • FLT3 mutations were first discovered in AML cells, and the mutation type was internal tandem repeat (FLT3/ITD).
  • FLT3/ITD internal tandem repeat
  • many studies have confirmed that activating mutations in FLT3 play an important pathological role in the pathogenesis and progression of acute myeloid leukemia (AML).
  • AML patients with FLT3/ITD activating mutations usually have unique clinical features such as high peripheral blood leukocyte 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 malignancy is the body's blood formation and immune system, bone marrow and lymphoid tissue Cancer.
  • FLT3 expression is restricted to early progenitor cells in normal bone marrow, in hematological malignancies, 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 granulocytes Leukemia or acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia (CNL), Acute undifferentiated cell leukemia (AUL), degenerative large cell lymphoma (ALCL), adult T cell ALL, AML (AML/TMDS) with mixed lineage dysplasia, mixed lineage leukemia (MLL) , myelodysplastic syndromes (MDSs), myelodysplastic disorders (MPD), multiple myeloma (MM), and myeloma (Kottari
  • 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.
  • the receptor tyrosine kinase c-Kit (also known as CD117) is a type of transmembrane receptor protein with tyrosine kinase activity encoded by the retroviral proto-oncogene c-kit, and a platelet-derived growth factor receptor ( PDGFR), macrophage colony-stimulating factor-1 receptor (CSF-1R) and Fms-like tyrosine kinase receptor 3 (FLT3) together constitute a type III receptor tyrosine kinase superfamily, which is involved in tumorigenesis and progression. It plays a very important role. Therefore, c-Kit is currently swollen One of the hot targets for targeted molecular therapy of tumors.
  • PDGFR platelet-derived growth factor receptor
  • CSF-1R macrophage colony-stimulating factor-1 receptor
  • FLT3 Fms-like tyrosine kinase receptor 3
  • C-Kit is one of the important members of the tyrosine kinase receptor protein family. As a receptor for stem cell factors, C-Kit can participate in the regulation of hematopoietic stem cell proliferation and differentiation through a series of signaling pathways. In recent years, studies have found that mutations in the c-kit gene, especially activating mutations, are closely related to the onset, treatment and prognosis of acute leukemia.
  • Gastrointestinal Stromal Tumors are the most common mesenchymal tumors of the digestive tract.
  • the vast majority of GISTs express the Kit protein (CD117) encoded by the c-kit gene.
  • Kit protein CD117
  • Most of the GISTs have c-kit gene mutations, which leads to the activation of Kit protein, which can stimulate the sustained proliferation of tumor cells and the loss of control of anti-apoptotic signals without the involvement of ligand SCF.
  • Gastrointestinal stromal tumors account for 1 to 3% of gastrointestinal malignancies. The estimated annual incidence rate is about 10-20/1 million. It is more common in middle-aged and elderly patients. Patients under 40 years old are rare, and there is no significant difference in the incidence rate between men and women.
  • 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:
  • Ar 1 and Ar 2 are each independently an aryl or heteroaryl group
  • X is selected from Linking group
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl;
  • R 3 is selected from:
  • R 4 is selected from
  • R 5 is selected from alkyl; alkenyl; alkynyl; haloalkyl; cycloalkyl; aminoalkyl; alkylaminoalkyl; alkylaminoalkenyl; heterocycloalkyl, optionally alkyl, alkyl a carbonyl group, a cycloalkylcarbonyl group, an amino protecting group, or a hetero atom optionally substituted by an alkyl-substituted heterocycloalkyl group; a cycloalkenyl group; a heteroaryl group; a heterocycloalkylalkyl group optionally substituted by an alkyl group; a heteroaryl group optionally substituted by an alkyl group; an aminoacylalkyl group optionally substituted by an amino group and optionally substituted with an amino group; the alkyl group is optionally substituted with an amino group and the nitrogen is optionally protected by an amino group An arylalkyl group substituted with a aryl group
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound provided herein, or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or pre-
  • the drug as well as 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, solvate, isomer, ester, acid, metabolite or prodrug thereof, which reduces or inhibits tyrosine kinase FLT3, in vivo or in vitro, Uses of c-KIT, ABL, EGFR, BMX, BLK, VEGFR, RET, PDGFR, MEK, BCR/ABL, JAK, BRAF activities, particularly FLT3 kinase and/or mutant FLT3 kinase and c-Kit kinase.
  • 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 composition comprising a compound of formula (I), Use in the preparation of a medicament for the treatment of a cell proliferative disorder and/or a FLT3, c-Kit related disorder.
  • condition is responsive to FLT3 or mutant FLT3 kinase inhibition, or in response to c-Kit kinase inhibition.
  • FLT3 mutations include ITD mutations and TKD point mutations, particularly FLT3/ITD mutations.
  • Figures 2a to 2e show the effects of Compound 2-1 and Compound 2-33 of the present invention on apoptosis in MV-4-11, MOLM-14 and MOLM-13 cells, respectively.
  • Figures 3a to 3c show the effects of Compound 2-1 and Compound 2-33 of the present invention on the cell cycle distribution of MV-4-11 and MOLM-14 cell lines, respectively.
  • the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art.
  • naming and laboratory operations and techniques chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and procedures can be carried out by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to a straight or branched chain hydrocarbon radical containing from 1 to 12 carbon atoms.
  • the term “lower alkyl” refers to a C1-C6 alkyl chain.
  • the alkyl group may be optionally substituted with one or more substituents.
  • the alkyl group is preferably a C1-C8 alkyl group, more preferably a C1-C6 alkyl group.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
  • 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.
  • alkenyl refers to an unsaturated hydrocarbon chain which may be straight or branched and which contains from 2 to 12 carbon atoms and at least one carbon-carbon double bond.
  • the alkenyl group may be optionally substituted with one or more substituents.
  • the alkenyl group is preferably a C2-C8 alkenyl group, more preferably a C2-C6 alkenyl group, and even more preferably a C2-C4 alkenyl group.
  • alkynyl refers to an unsaturated hydrocarbon chain which may be straight or branched and which contains from 2 to 12 carbon atoms and at least one carbon-carbon triple bond.
  • An alkynyl group can be optionally substituted with one or more substituents.
  • the alkynyl group is preferably a C2-C8 alkynyl group, more preferably a C2-C6 alkynyl group, more preferably a C2-C4 alkynyl group.
  • the sp 2 or sp carbon of the alkenyl and alkynyl groups may each optionally be the attachment point of an alkenyl or alkynyl group.
  • 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.
  • 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 .
  • aminoalkyl refers to an alkyl 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.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • alkylcarbonylalkyl refers to an alkyl group further substituted with an alkylcarbonyl group.
  • alkoxycarbonyl refers to a carbonyl group further substituted with an alkoxy group.
  • alkylaminoalkyl refers to an alkyl group, as defined herein, substituted by an alkylamino group, as defined herein.
  • alkyl moiety in the alkylamino, aminoalkyl, hydroxyalkyl, cyanoalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, and alkylaminoalkyl groups can be optionally one or Multiple substituents are substituted.
  • 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.
  • 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” means an alkyl group as defined herein Substituted cycloalkyl substituted.
  • 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.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at a position where the heteroalkyl group is attached to the remainder of the molecule.
  • 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 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 Bis-acid, thiobarbituric acid, dioxiperazine, hydantoin, dihydrouracil, aza , homopiperidine, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydr
  • 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.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures 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 A hydroxy group, an alkoxy group, a cyano group, a halogen group, an amide group, a nitro group, a halogenated alkyl group, an amino group, an alkoxycarbonyl group, an alkyl group (heteroaryl group), an alkyl group (heterocycloalkyl group) and the like.
  • Any group may be optionally substituted by one or more Substituent, and the substituent may be at any atom of the group, wherein any group which may be substituted may be optionally substituted by one or more substituents (which may be the same or different), each replacing one A hydrogen atom.
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroarylalkyl, aryl, heteroaryl, halogen, haloalkyl , cyano, nitro, alkoxy, haloalkoxy, aryloxy, hydroxy, hydroxyalkyl, oxygen (ie, carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxy Carbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, decyl, decylalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkane Alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino,
  • the term “inhibiting,” “inhibiting,” or “inhibiting,” a kinase refers to inhibition of phosphotransferase activity.
  • a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
  • the term “metabolized” refers to the sum of the processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • glucosinolate diphosphate catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • modulate refers to interacting directly or indirectly with a target to alter the activity of the target, by way of example only, including enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • 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
  • 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, di-lower alkyls Amides and hydroxyamides.
  • 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.
  • GI50 refers to the concentration of drug required for 50% growth inhibition of cells, i.e., the drug inhibits or controls the growth of 50% of cancer cells, at which time the drug concentration.
  • 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.
  • 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:
  • Ar 1 and Ar 2 are each independently an aryl or heteroaryl group, such as phenyl, thiazolyl, quinazolinyl, benzoxazolyl;
  • X is selected from Linking group
  • R 1 and R 2 are each independently selected from hydrogen; halogen; alkyl, such as methyl; and haloalkyl, such as trifluoromethyl;
  • R 3 is selected from:
  • R 4 is selected from
  • R 5 is selected from alkyl, such as methyl, ethyl, propyl, neopentyl, decyl; alkenyl, such as ethenyl, propenyl; alkynyl, e.g., ethynyl; haloalkyl, e.g., chloroethane Cycloalkyl, such as cyclopropyl; aminoalkyl, such as aminomethyl, aminoethyl; alkylaminoalkyl, such as N,N-dimethylaminomethyl, N,N-dipropylamino Alkylaminoalkenyl, such as N,N-dimethylaminopropenyl; heterocycloalkyl (eg, piperidinyl, pyranyl), optionally substituted with an alkyl group (eg, methyl, ethyl) An alkylcarbonyl group (eg, methylcarbonyl, ethylcarbon
  • amino protecting group is independently selected from the group consisting of tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), benzyl (Bn) and p-methoxyphenyl (PMP).
  • 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
  • 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 the treatment or prevention of cell proliferative disorders and/or FLT3, c-Kit related disorders, particularly diseases responsive to protein tyrosine kinase inhibition, particularly FLT3 or mutant FLT3 kinase inhibition or c-Kit inhibition.
  • FLT3 mutations include ITD mutations and TKD 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 or c-Kit, and particularly preferably treats or prevents a condition associated with mutant FLT3/ITD.
  • a medicament comprising at least one compound of formula (I) can be administered to a patient in need by at least one of injection, oral, inhalation, rectal and transdermal administration.
  • Other therapeutic agents may be selected from the group consisting of immunosuppressive agents (eg, tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, guanidine, mycophenolate mofetil or FTY720), glucocorticoids (eg prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydroxyprednisolone, beclomethasone , fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylate, aryl alkanoic acid, 2-arylpropionic acid, N-aryl anthranilic acid, Oxicam, oxicam or thioanilide, allergy vaccine, antihistamine, anti-leukotriene, beta-agonist
  • therapeutic agents mentioned may also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole.
  • Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this CD, camptothecin, daunorubicin (Daunonibic
  • the other therapeutic agent may also be a cytokine such as G-CSF (granulocyte colony stimulating factor).
  • other therapeutic agents may be, for example but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (Asia) Deriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Aminopterin, 5-fluorouracil and prednisone).
  • Such other therapeutic agents also include, for example, cytostatics, other anti-proliferative agents.
  • anti-proliferative agents include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylation Enzyme inhibitors, farnesyltransferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic antimetabolites, platinum compounds, compounds that reduce protein kinase activity and further anti-angiogenic compounds , gonadotropin-releasing factor agonist, anti-androgen, bengamide, bisphosphonate, steroid, anti-proliferative antibody, 17-(allylamino)-17-demethoxygeldanamycin (17- AAG) and temozolomide (TMEMODAL).
  • aromatase inhibitors include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitor
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, i.e., the conversion of the substrates androstenedione and estradiol.
  • the term includes, but is not limited to, steroids, especially exemestane and formestane, and especially non-steroids, especially aminoglutethimide, vorozole, fadrozole, anastrozole, very 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. under the trademark LENTARON (TM) .
  • 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) .
  • compositions of the invention comprising an aromatase inhibitor as an anti-neoplastic form of the agent are particularly useful for the treatment of hormone receptor positive breast tumors.
  • 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 U.S. Patent 4,695,516, 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 podophyllotoxins 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, Discoder molide and epothilone, such as epothilone B and D.
  • Docetaxel is marketed in the form of, for example, can be administered, eg under the trademark TAXOTERE TM.
  • 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 that inhibits farnesyltransferase and 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 are, in particular, compounds which inhibit the tyrosine kinase activity of VEGF receptors, in particular VEGF receptors, and compounds which bind to VEGF, in particular 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), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0769947; M. Prewett et al. in Cancer Research 59 (1999) 5209-5218, Z. Zhu et al., Cancer Res.
  • 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, WOWO97/38983 and especially WO96/33980.
  • 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 of the particular compound and may further be used in combination with the compounds of the present invention are Imatinib (Gleevec / Glivec), PKC412 , Iressac TM (ZD1839), AEE788 and pharmaceutically acceptable salts thereof (see WO03 / 13541), PTK787 and Its pharmaceutically acceptable salts (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) .
  • Tiluronic 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. under the trademark 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), methylprednisolone, and prednisone.
  • 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 invention relates to a method of treating or preventing a cell proliferative disorder and/or a FLT3, c-Kit related disorder with a substance of the invention.
  • the provided substance of the present invention can be administered to a patient by injection, oral, inhalation, rectal or transdermally during the course of treatment.
  • An effective amount of a compound or pharmaceutical composition comprising at least one formula (I), alone or in combination with one or more other therapeutic agents, may also be used, as appropriate.
  • Other therapeutic agents mentioned are as defined above.
  • Chemotherapy comprising at least one compound of formula (I) or a pharmaceutical composition in combination with radiation therapy can also be administered during the course of treatment.
  • 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, solid tumors (including benign or especially malignant types), sarcomas, gastrointestinal stromal tumors ( Gastrointestinal Stromal Tumors (GIST), Acute Myeloblastic Leukemia (AML), Chronic Myelogenous Leukemia (CML), Leukemia affecting ABL and BCR/ABL tyrosine kinase activity inhibition, B- Cell lymphoma, lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenberg Macroglobulinemia, spleen marginal lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma,
  • the agents of the invention may also be used to treat or prevent c-Kit related disorders, particularly Gastrointestinal Stromal tumors (GIST) or similar diseases or combinations.
  • GIST Gastrointestinal Stromal tumors
  • the agents of the invention are also useful for treating or preventing FLT3-related disorders, particularly mutant FLT3/ITD related disorders including, but not limited to, hematological malignancies including leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin Disease (also known as Hodgkin's lymphoma) and myeloma - for example, acute lymphoblastic leukemia (ALL), 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 large cell lymphoma (ALCL), adult T-cell ALL, with a three-lineage ( Trilineage) AML (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDSs), myelodysplastic (MP
  • compositions for enteral administration to warm-blooded animals, especially humans, such as nasal, buccal, rectal or especially orally, and compositions for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, are preferred.
  • the dosage of the active ingredient will depend on the disease and variety to be treated, its age, weight and individual conditions, individual pharmacokinetic data, and mode of administration.
  • the pharmaceutical composition may optionally be used in combination with known methods of treatment, such as administration of hormones or radiation.
  • the compound of formula (I) can 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, farnesyltransferase 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. It will be understood by those skilled in the art that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted depending on the condition of the patient and in connection with the diagnosis of the physician.
  • 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.
  • Preferred compounds of the invention are as follows:
  • Step 1 Slowly add potassium tert-butoxide (1.2 equivalents) to a reaction flask containing 3-aminophenol (1.2 equivalents) and dimethyl sulfoxide (3 mL), and stir at room temperature for 2 hours before going to 4-Chloro-6,7-dimethoxyquinoline (2.2 mmol) and potassium carbonate (0.6 eq.) were added to the reaction flask. The reaction was heated to 110 ° C and allowed to react overnight.
  • Mass spectrometry was carried out without 4-chloro-6,7-dimethoxyquinoline remaining, the reaction was stopped, cooled to room temperature, and the reaction mixture was diluted with ethyl acetate, then saturated sodium hydrogen carbonate solution was added, and then, ethyl acetate phase was separated.
  • Step 2 4-Chloronitrobenzene (12.69 mmol) and 4-Boc aminopiperidine (1.0 eq.) were dissolved in N,N-dimethylformamide (60 mL). The reaction was heated to 100 ° C for 10 hours. The mass spectrometry detected no raw material remaining and stopped the reaction. After cooling to room temperature, the reaction mixture was diluted with EtOAc EtOAc.
  • Step 3 Compound B (12.96 mmol) was dissolved in methanol (500 mL), and then palladium carbon (2.0 g) was added, and the reaction mixture was reacted under a hydrogen atmosphere for 7 hours. The mass spectrometry detected no raw material remaining and stopped the reaction. The reaction mixture was concentrated and purified by column chromatography to afford Compound C (1.2 g).
  • Step 4 In a argon atmosphere, triphosgene (0.4 eq.) was dissolved in dichloromethane (20 mL), cooled in an ice water bath, then Compound A (1.34 mmol), 4-dimethylaminopyridine (0.1 eq.), A mixture of ethylamine (1.0 eq.) and dichloromethane (5 mL) was slowly dropped into a mixture of triphosgene through a constant pressure low-liquid funnel. After the completion of the dropwise addition, the reaction was carried out for 30 minutes, and then Compound C was added under ice-water bath conditions.
  • Step 5 An ethyl acetate solution (15 mL) was slowly added dropwise to a reaction flask containing Compound D (0.33 mmol), and allowed to react at room temperature for 4 hours. Mass spectrometry detection, the raw material reaction was exhausted, and the reaction was stopped. The reaction solution was filtered to give a white solid, m.
  • Step 6 Compound E (0.078 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), then triethylamine (0.04 mL) was added, cooled to -50 ° C, then propionyl chloride (1.2 equivalents) ) slowly added to the reaction solution. After 5 minutes of reaction, the mass spectrometry was detected and the raw material reaction was exhausted. Saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, and the mixture was washed with chloroform, and then filtered, dried, filtered and concentrated to give compound 1-1 (34 mg).
  • Step 6 The compound 1-(4-(4-aminopiperidin-1-yl)-3-trifluoromethylphenyl)-3-(3-((6,7-dimethoxyquinoline) 4-yl)oxy)phenyl)urea (0.085 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), then triethylamine (0.05 mL) and 4-dimethylaminopyridine ( 0.5 equivalent), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents) and propiolic acid (1.2 equivalents) .
  • N,N-dimethylformamide 0.5 mL
  • 4-dimethylaminopyridine 0.5 equivalent
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, 1.5 equivalents
  • Step 1 Synthesis of Compound F was accomplished by using Step 1 similar to that described in Example 1, except that 2-amino-5-aminophenol was used in place of 3-aminophenol in the reaction.
  • Exact Mass (calculated value): 310.3530; MS (ESI) m/e (M+1) + : 311.2350.
  • Step 2 The synthesis of Compound G was carried out by using Step 4 similar to that described in Example 1, except that 3-nitroaniline was used instead of Compound C in the reaction.
  • Exact Mass (calculated value): 474.4730; MS (ESI) m/e (M+1) + : 478.5112.
  • Step 3 The synthesis of Compound H was carried out by using Step 3 similar to that described in Example 1, except that Compound G was used instead of Compound B in the reaction.
  • Exact Mass (calculated value): 444.4910; MS (ESI) m/e (M+1) + : 445.5609.
  • Step 4 The synthesis of Compound 11-1 was carried out by using Step 6 similar to that described in Example 1, except that Compound H was used instead of Compound E in the reaction.
  • Exact Mass (calculated value): 500.2060; MS (ESI) m/e (M+1) + : 501.5550.
  • Step 1 Slowly add potassium tert-butoxide (1.2 equivalents) to a reaction flask containing 3-aminophenol (1.2 equivalents) and dimethyl sulfoxide (3 mL), and stir at room temperature for 2 hours before going to 4-Chloro-6,7-dimethoxyquinoline (2.2 mmol) and potassium carbonate (0.6 eq.) were added to the reaction flask. The reaction was heated to 110 ° C and allowed to react overnight.
  • Mass spectrometry was carried out without 4-chloro-6,7-dimethoxyquinoline remaining, the reaction was stopped, cooled to room temperature, and the reaction mixture was diluted with ethyl acetate, then saturated sodium hydrogen carbonate solution was added, and then, ethyl acetate phase was separated.
  • Step 2 Methyl 4-chloro-3-trifluoromethylbenzoate (12.69 mmol) and 4-tert-butyl 4-carbamate (1.0 eq.) were dissolved in N,N-dimethylformamide (60 mL) Further, potassium carbonate (3.0 equivalent) was added, and the reaction was heated to 100 ° C for 10 hours. The mass spectrometry detected no raw material remaining and stopped the reaction. After cooling to room temperature, the reaction mixture was diluted with EtOAc EtOAc. Exact Mass (calculated value): 402.4142; MS (ESI) m / e (M + 1) + : 403.1801;
  • Step 3 Compound I (12.96 mmol) was dissolved in methanol (500 mL), and a solution of sodium hydroxide (12.96 mmol) dissolved in water (13 mL) was added to the mixture, and the reaction was heated to reflux for 2 hours. . The mass spectrometry detected no raw material remaining and stopped the reaction. After cooling to room temperature, it was directly concentrated to give Compound J (1.2 g).
  • Step 4 Compound A (1.34 mmol), Compound J (1.34 mmol), HATU (1.89 mmol), and triethylamine (3.01 mmol) were dissolved in DMF (5 mL). The reaction was carried out at room temperature. Mass spectrometry detection, the raw material reaction was exhausted, and the reaction was stopped. The reaction mixture was diluted with EtOAc. EtOAc (EtOAc)EtOAc. Exact Mass (calculated value): 6666982; MS (ESI) m/e (M+1) + : 667.2689.
  • Step 5 An ethyl acetate solution (15 mL) was slowly added dropwise to a reaction flask containing Compound K (0.33 mmol), and the mixture was reacted at room temperature for 4 hours. Mass spectrometry detection, the raw material reaction was exhausted, and the reaction was stopped. The reaction mixture was filtered to give a white solid (yield: 170 mg). Exact Mass (calculated value): 566.5812; MS (ESI) m/e (M+1) + : 567.2173.
  • Step 6 Synthesis of Compound 14-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that Compound L was used instead of Compound E.
  • Exact Mass (calculated value): 622.6452; MS (ESI) m/e (M+1) + : 623.2437.
  • Step 1 Slowly add potassium tert-butoxide (1.2 equivalents) to a reaction flask containing 3-aminophenol (1.2 equivalents) and dimethyl sulfoxide (3 mL), and stir at room temperature for 2 hours before going to 4-Chloro-6,7-dimethoxyquinoline (2.2 mmol) and potassium carbonate (0.6 eq.) were added to the reaction flask. The reaction was heated to 110 ° C and allowed to react overnight.
  • Mass spectrometry was carried out without 4-chloro-6,7-dimethoxyquinoline remaining, the reaction was stopped, cooled to room temperature, and the reaction mixture was diluted with ethyl acetate, then saturated sodium hydrogen carbonate solution was added, and then, ethyl acetate phase was separated.
  • Step 2 Compound A (12.69 mmol), 1-(methoxycarbonyl)cyclopropyl-1-carboxylic acid (12.69 mmol), HATU (15.00 mmol) and triethylamine (15.00 mmol) were dissolved in DMF (15 mL) in. The reaction was carried out at room temperature until mass spectrometry to detect the absence of starting material, and the reaction was stopped. The mixture was diluted with ethyl acetate. The mixture was washed three times with water and brine and brine Exact Mass (calculated value): 422.4370; MS (ESI) m/e (M+1) + : 423.1511.
  • Step 3 Compound M (6.66 mmol) was dissolved in methanol (10 mL), and a solution of sodium hydroxide (6.66 mmol) dissolved in water (7 mL) was added to the mixture, and the reaction was heated to reflux for 2 hours. . The mass spectrometry detected no raw material remaining and stopped the reaction. After cooling to room temperature, it was directly concentrated to give the crude compound N.
  • Step 4 4-Chloronitrobenzene (12.69 mmol) and 4-tert-butyl 4-carbamate (1.0 eq.) were dissolved in N,N-dimethylformamide (60 mL). The reaction was heated to 100 ° C for 10 hours. The mass spectrometry detected no raw material remaining and stopped the reaction. After cooling to room temperature, the reaction mixture was diluted with EtOAc EtOAc.
  • Step 5 Compound B (12.96 mmol) was dissolved in methanol (500 mL), then palladium carbon (2.0 g) was added, and the reaction mixture was reacted under a hydrogen atmosphere for 7 hours. The mass spectrometry detected no raw material remaining and stopped the reaction. The reaction mixture was concentrated and purified by column chromatography to afford Compound C (1.2 g).
  • Step 6 Compound N, Compound C, HATU (15.00 mmol) and triethylamine (15.00 mmol) were dissolved in DMF (15 mL). The reaction was carried out at room temperature until mass spectrometry to detect the absence of starting material, and the reaction was stopped. The mixture was diluted with ethyl acetate. The mixture was washed three times with water and brine and brine Exact Mass (calculated): 681.7900; MS (ESI) m/e (M+1) + : 682.3196.
  • Step 7 An ethyl acetate solution (15 mL) was slowly added dropwise to a reaction flask containing Compound O (0.33 mmol) and allowed to react at room temperature for 4 hours. Mass spectrometry detection, the raw material reaction was exhausted, and the reaction was stopped. The reaction solution was filtered to give a white solid (yield: 170 mg). Exact Mass (calculated value): 581.6730; MS (ESI) m/e (M+1) + : 582.6732.
  • Step 8 Synthesis of Compound 15-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that Compound P was used instead of Compound E.
  • Step 1 The same procedure as described in Step 1 of Example 87 was carried out.
  • Step 2 A procedure similar to that described in Step 4 of Example 87 was carried out except that 2-chloro-5-nitrobenzotrifluoride was used instead of 4-chloronitrobenzene.
  • the solid obtained was AD, Exact Mass (calc.): 389.1562; MS (ESI) m/e (M+1) + : 390.1077.
  • Step 3 A procedure similar to that described in Step 87 of Example 87 was carried out except that AD was used instead of Compound O.
  • the solid obtained was compound AE, Exact Mass (calc.): 289.2582; MS (ESI) m/e (M+1) + : 290.1072.
  • Step 4 A procedure similar to that described in Step 4 of Example 1 was carried out except that AE was used instead of Compound C.
  • the solid obtained was AF, Exact Mass (calculated): 611.5782; MS (ESI) m/e (M+1) + : 612.2025.
  • Step 5 A procedure similar to that described in Step 3 of Example 1 was carried out except that Compound B was replaced by AF.
  • the solid obtained was AG, Exact Mass (calc.): 581.5962; MS (ESI) m/e (M+1) + : 582.2283.
  • Step 6 Synthesis of Compound 20-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that AG was used instead of Compound E.
  • Exact Mass (calculated value): 637.6602; MS (ESI) m/e (M+1) + : 638.6736.
  • Step 1 A procedure similar to that described in Step 1 of Example 1 was carried out using methyl 3-hydroxyphenylacetate and 4-chloro-6,7-dimethylquinoline. The obtained compound was AH, Exact Mass (calc.): 353.3771; MS (ESI) m/e (M+1) + : 354.
  • Step 2 A procedure similar to that described in Step 3 of Example 87 was followed except that Compound M was replaced with AH.
  • the obtained compound was AI, Exact Mass (calc.): 339.3445; MS (ESI) m/e (M+1) + : 340.2025.
  • Step 3 A procedure similar to that described in Step 5 of Example 87 was carried out except that AD was used instead of Compound B.
  • the obtained compound was AJ, Exact Mass (calc.): 359.3932; MS (ESI) m/e (M+1) + : 360.4001.
  • Step 4 A procedure similar to that described in Step 2 of Example 87 was carried out except that Compound A was replaced by AI.
  • the obtained compound was AK, Exact Mass (calc.): 680.7522; MS (ESI) m/e (M+1) + : 681.2225.
  • Step 5 A procedure similar to that described in Step 87 of Example 87 was carried out except that AK was used instead of Compound O.
  • the obtained compound was AL, Exact Mass (calc.): 580.6082; MS (ESI) m/e (M+1) + : 581.2333.
  • Step 6 Synthesis of Compound 21-1 was finally carried out by using a procedure similar to that described in Example 7, except that the compound E was replaced by AL, and the compound 3-(1-methylpiperidin-2-yl)propionic acid was used at the same time. Instead of propiolic acid.
  • Step 1 2-Chloro-7-bromoquinazoline (8.11 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then cuprous bromide (10.16 mmol) was obtained under argon atmosphere. Sodium methoxide (40.54 mmol, 5.4 M in MeOH) was added sequentially to the above solution. The mixture was heated to reflux mass spectrometry until no material remained, and the reaction was stopped. After cooling to room temperature and removing the solvent in vacuo, the residue was crystallised eluted with ethyl acetate. The organic phase was washed three times with water until the solution was light blue, washed with saturated brine and dried over anhydrous magnesium sulfate. Q. Exact Mass (calculated): 194.6186; MS (ESI) m/e (M+1) + : 196.0017.
  • Step 2 The above compound Q (7.98 mmol) was dissolved in dichloromethane (100 mL). After cooling to -78 ° C, a solution of boron trichloride in dichloromethane (1.0 M, 25 mL) was slowly added to the above reaction mixture. In the reaction, the reaction was stopped until the mass of the material was detected, and the reaction was stopped. The reaction mixture was quenched with aq. Exact Mass (calculated value): 180.5898; MS (ESI) m/e (M+1) + : 181.1067.
  • Step 3 A procedure similar to that described in Step 1 of Example 1 was carried out using Compound R and 4-chloro-6,7-dimethoxyquinoline to give Compound S.
  • Exact Mass (calculated value): 367.7681; MS (ESI) m/e (M+1) + : 368.7211.
  • Step 4 Compound S (7.01 mmol) and tert-butyl-(1-(4-amino-2-trifluoromethylphenyl)piperidin-4-yl)carbamate (7.33 mmol) were dissolved in positive In butanol (20 mL), p-toluenesulfonic acid (0.7 mmol) was further added, and the mixture was heated to 80 ° C to react to mass spectrometry to detect no material remaining. The reaction was stopped and cooled to room temperature.
  • Step 5 A procedure similar to that described in Step 5 of Example 1 was carried out except that Compound T was used instead of Compound D to give Compound U.
  • Step 6 Synthesis of Compound 22-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that Compound U was used instead of Compound E.
  • Step 1 The compound 3-((6,7-dimethoxyquinolin-4-yl)oxy)phenylamine (2.11 mmol) was dissolved in anhydrous dichloromethane (10 mL). After slowly adding to room temperature and stirring for 30 minutes, the compound 1,3-dibromopropane (2.11 mmol) was further added to the above mixture, and the mixture was heated to reflux until the mass spectrometry was detected, and the reaction was stopped. The mixture was cooled to room temperature, diluted with methylene chloride, washed with saturated sodium bicarbonate, washed with water, brine, and dried over anhydrous magnesium sulfate. Exact Mass (calculated value): 417.3022; MS (ESI) m/e (M+1) + : 418.0755.
  • Step 2 Step 4 was carried out similarly to Example 1 using Compound V, triphosgene, tert-butyl-(1-(4-amino-2-trifluoromethylphenyl)piperidin-4-yl)carbamate. In the procedure described above, the compound is obtained as W. Exact Mass (calculated): 732.8352; MS (ESI) m/e (M+1) + : 733.3971.
  • Step 3 Compound W (0.88 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (1.34 mmol) was added to the mixture and heated to reflux. The mixture was cooled to room temperature, and the solvent was evaporated in vacuo.
  • Exact Mass (calculated value): 721.7282; MS (ESI) m/e (M+1) + : 723.3971.
  • Step 4 A procedure similar to that described in Step 5 of Example 1 was carried out using Compound X to give Compound Y.
  • Step 5 Synthesis of Compound 25-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that Compound Y was used instead of Compound E.
  • Step 1 The compound 2-aminothiazole-4-carboxylic acid ethyl ester (0.71 mmol) was dissolved in methanol (10 mL), and a solution of sodium hydroxide (1.0 M, 0.71 mmol) was added to the mixture and heated. The mixture was refluxed and reacted to mass spectrometry to detect no residue of the starting material, and the reaction was stopped. After cooling to room temperature, the mixture was concentrated in vacuo, and the obtained residue was a mixture of compound Z and used directly for the next reaction.
  • Step 2 The procedure described in Step 2 of Example 87 was carried out using the mixture Z, 4-Boc aminopiperidine, and the obtained compound was AA.
  • Step 3 using the compound AA, 2-(3-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetic acid, a procedure similar to that described in the second step of Example 87, The resulting compound was AB.
  • Step 4 A procedure similar to that described in Step 5 of Example 1 was carried out using Compound AB to give compound AC.
  • Exact Mass (calculated value): 547.5391; MS (ESI) m/e (M+1) + : 548.2670.
  • Step 5 Synthesis of Compound 27-1 was finally accomplished by using a procedure similar to that described in Step 6 of Example 1, except that Compound AC was used instead of Compound E.
  • Example 111 Effect on cancer cell proliferation
  • human acute monocytic leukemia cell line MV-4-11 (expressing FLT3/ITD mutant gene) and human acute myeloid leukemia cell line MOLM-13 (expressing FLT3/ITD mutant gene and wild) were selected.
  • FLT3 gene human non-small cell lung cancer cell H1975 (expressing EGFR L858R/T790M double mutant gene), blood cancer cell K562, human lung adenocarcinoma cell line A549 (expressing wild-type EGFR gene), prostate cancer C4-2, diffuse Large B cell lymphoma cell line TMD8, prostate cancer RV-1, human Burkitt's lymphoma cell Namalwa, human B cell chronic lymphocytic leukemia cell line MEC-2, MEG-01, chronic myeloid leukemia KU812, human acute myeloid leukemia Cell line MOLM-14 (expressing FLT3/ITD mutant gene and wild-type FLT3 gene), human acute myeloid leukemia cell line U937 (expressing wild-type FLT3 gene), acute myeloid leukemia
  • Mouse BaF3-FLT3-ITD (activated kinase stably expressing FLT3-ITD mutation), mouse BaF3-FLT3-D835Y (activated kinase stably expressing FLT3 D835Y mutation), and mouse BaF3-FLT3-D835V (stable expression) were also selected.
  • FLT3 D835V mutant activated kinase mouse BaF3-FLT3-D835H (activated kinase stably expressing FLT3 D835H mutation), mouse BaF3-FLT3-K663Q (activated kinase stably expressing FLT3 K663Q mutation), mouse TEL-BMX- BaF3 (stable expression of BMX kinase), mouse BaF3-TEL-PDGFRa (stable expression of PDGFRa kinase), mouse BaF3-TEL-VEGFR2 (stable expression of VEGFR2 kinase), mouse TEL-FLT3-BaF3 (stably expressed FLT3 kinase), Mouse BaF3-FLT3-ITD-D835Y (stable expression) FLT3/ITD D835Y mutant activated kinase), mouse BaF3-FLT3-ITD-F691L (activated kinase stably
  • the above cell lines were constructed by our laboratory by PCR to amplify human FLT3/ITD, FLT3 D835Y, FLT3 D835V, FLT3 D835H, BMX, FLT3, FLT3/ITD D835Y, FLT3/ITD F691L, cKIT, cKIT N882K, respectively.
  • the above compounds of different concentrations were separately added to the above cells. And incubated for 72 hours with Cell (Promega, USA) A chemical self-luminescence cell viability assay kit for detecting the number of viable cells by quantitatively measuring ATP in living cells. The experimental results are shown in Table 1.
  • Example 112 In vitro inhibitory activity (enzyme activity) assay
  • Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-11, Compound 2-12, Compound 2-13, Compound 2-14, Compound 2-15, Compound 2- were determined in an in vitro enzyme activity test. 16.
  • the constructed vector was transfected into the SF9 packaging virus, and the SF9 expressing protein was infected with the virus.
  • ADP was converted to ATP by the addition of 10 ⁇ L of kinase assay reagent, and the newly synthesized ATP was detected using a coupled luciferase/luciferin reaction, and the IC50 values were calculated using Envision readings (Table 2).
  • Example 113 Compound 2-1, Compound 2-3, and Compound 2-33 in cells against FLT3 Upstream and downstream signal path effects
  • Human acute myeloid leukemia cell line MV-4-11 (expressing FLT3-ITD mutant gene) carrying human FLT3 gene and/or FLT3-ITD mutant gene, human acute myeloid leukemia cell line MOLM-13 (expressing FLT3) -ITD mutant gene and wild-type FLT3 gene cell line and human acute myeloid leukemia cell line MOLM-14 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene) cell lines, by measuring many cell biochemical endpoints and Functional Endpoints, Compounds 2-1, Compound 2-3, Compound 2-33, and the control compound FLT3 kinase inhibitor AC220 (purchased from Hao Yuan Chemexpress, Shanghai) were tested for FLT3 and/or FLT3-ITD protein in cells.
  • Compound 2-1, Compound 2-3, and Compound 2-33 also inhibited the phosphorylation of protein kinase FLT3 very strongly (its IC50 was less than 10 nM).
  • Compound 2-1, Compound 2-3, and Compound 2-33 also have a very strong inhibitory effect on phosphorylation of FLT3-ITD downstream protein STAT5 in cells.
  • Compound 2-1, Compound 2-3 and Compound 2-33 have a significant inhibitory effect on the phosphorylation of protein kinase ERK, and have a strong degradation effect on the protein C-Myc, which is closely related to FLT3 protein kinase.
  • the same experimental phenomenon was observed in the control compound FLT3 kinase inhibitor AC220.
  • Example 113 shows that Compound 2-1, Compound 2-3, and Compound 2-33 not only strongly inhibited the phosphorylation of protein kinase FLT3, but also strongly inhibited the phosphorylation of the protein STAT5 downstream of the protein kinase FLT3 signaling pathway in cells. It has a strong degrading effect on the protein C-Myc, which is closely related to FLT3 protein kinase, and thus inhibits cell proliferation of acute myeloid leukemia cell lines carrying FLT3 and/or FLT3-ITD genes.
  • Example 114 Effect of Compound 2-1 and Compound 2-33 on Apoptosis on Cells ring
  • human acute myeloid leukemia cell MV-4-11 (expressing FLT3-ITD mutant gene) cell line carrying FLT3 gene and/or FLT3-ITD mutant gene
  • Human acute myeloid leukemia cell line MOLM-13 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene) cell line and human acute myeloid leukemia cell line MOLM-14 (expressing FLT3-ITD mutant gene and wild-type FLT3)
  • the DNA repair enzyme polyadenosine diphosphate-ribose polymerase PARP which contains cysteine, is closely related to apoptosis in compound 2-1 and compound 2-33.
  • Example 114 demonstrates that Compound 2-1 and Compound 2-33 are capable of causing apoptosis in acute myeloid leukemia cells carrying the FLT3 gene and/or the FLT3-ITD mutant gene.
  • Example 115 Effect of Compound 2-1 and Compound 2-33 on Cell Cycle on Cells ring
  • Compound 2-1 was tested on acute myeloid leukemia cells MOLM-14 and MV-4-11 cell lines carrying the FLT3 gene and/or FLT3-ITD mutant gene. The effect of compound 2-33 on the cell cycle distribution of these cell lines.
  • the G0-G1 phase captured by the FLT3 kinase inhibitor AC220 with strong selectivity in the experiment at 0.1 ⁇ M The cells were 88.66%.
  • the cell concentration of the captured G0-G1 phase was also increased as the drug concentration of the compound 2-1 was increased from 0 ⁇ M to 1 ⁇ M.
  • Example 115 demonstrates that Compound 2-1 and Compound 2-33 are capable of blocking acute myeloid leukemia cells MOLM-14 and MV-4-11 cell lines carrying the FLT3 gene and/or FLT3-ITD mutant gene in G0-G1 Period, and has a strong influence on the distribution of cell cycle (Figure 3).
  • the present invention provides a novel FLT3 kinase inhibitor compound which can be used to reduce or inhibit FLT3, c-Kit kinase and/or mutant FLT3 kinase activity of a cell or a subject, and/or to prevent or Treatment of cell proliferative disorders and/or FLT3, c-Kit related disorders.
  • a novel FLT3 kinase inhibitor compound which can be used to reduce or inhibit FLT3, c-Kit kinase and/or mutant FLT3 kinase activity of a cell or a subject, and/or to prevent or Treatment of cell proliferative disorders and/or FLT3, c-Kit related disorders.
  • it can be made into a corresponding drug suitable for industrial applications.

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Abstract

La présente invention concerne un nouvel inhibiteur de kinase, qui comprend un composé représenté par la formule (I) ou un sel, un solvate, un isomère, un ester, un acide, un métabolite pharmaceutiquement acceptables ou un promédicament correspondant. La présente invention concerne également une composition médicamenteuse comprenant le composé représenté par la formule (I) et des utilisations et un procédé pour la prévention ou le traitement de maladies de prolifération cellulaire et/ou de maladies associées à FLT3 et à c-Kit et des utilisations et un procédé pour la prévention ou le traitement de maladies en réponse à une inhibition de la kinase FLT3 (en particulier une kinase de type mutation FLT3/ITD).
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CN114391009A (zh) * 2019-08-08 2022-04-22 Bci制药公司 作为蛋白激酶抑制剂的喹啉衍生物
WO2021023888A1 (fr) 2019-08-08 2021-02-11 B.C.I. Pharma Dérivés d'isoquinoline utilisés comme inhibiteurs de protéine kinase
JP7633702B2 (ja) 2019-08-08 2025-02-20 ビー．シー．アイ．ファーマ プロテインキナーゼ阻害剤としてのイソキノリン誘導体
EP4628083A2 (fr) 2019-08-08 2025-10-08 Hirundo Biosciences Derives de quinoline utilises comme inhibiteurs de proteine kinase
AU2020324561B2 (en) * 2019-08-08 2025-12-18 B.C.I. Pharma Quinoline derivatives as protein kinase inhibitors
CN116763787A (zh) * 2022-03-08 2023-09-19 安徽中科拓苒药物科学研究有限公司 喹啉类化合物的新用途

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