WO2020147097A1 - Nouvel inhibiteur de kinase liposome - Google Patents

Nouvel inhibiteur de kinase liposome Download PDF

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Publication number
WO2020147097A1
WO2020147097A1 PCT/CN2019/072281 CN2019072281W WO2020147097A1 WO 2020147097 A1 WO2020147097 A1 WO 2020147097A1 CN 2019072281 W CN2019072281 W CN 2019072281W WO 2020147097 A1 WO2020147097 A1 WO 2020147097A1
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compound
acid
pyridin
pharmaceutically acceptable
ester
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PCT/CN2019/072281
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English (en)
Chinese (zh)
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刘青松
刘静
梁小飞
李凤
胡晨
蒋宗儒
汪文亮
陈程
王蓓蕾
王黎
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中国科学院合肥物质科学研究院
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Priority to PCT/CN2019/072281 priority Critical patent/WO2020147097A1/fr
Publication of WO2020147097A1 publication Critical patent/WO2020147097A1/fr

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • 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

  • This application relates to a new type of kinase inhibitor compounds, pharmaceutical compositions containing these compounds, and the use of these compounds and compositions for the treatment of diseases mediated by PI3K kinase or PfPI4K kinase activation, especially malaria, cancer and others Uses and methods for cell proliferative diseases.
  • Phosphoinositide is a type of phospholipids involved in the above several cellular processes.
  • Phosphatidylinositol is the basic backbone of PI.
  • the 3, 4, and 5 hydroxyl groups are reversibly phosphorylated by kinases to obtain a total of 7 PIs, including phosphatidylinositol-3-phosphate.
  • PI3P is distributed in the early and late endosomes
  • PI4P is mainly distributed on the Golgi apparatus
  • PI(3,4)P2, PI(4,5)P2, PI(3,4,5)P3 are mainly located in the plasma membrane
  • PI (3,5) P2 is mainly distributed in synaptic secretory vesicles, and a small amount is also distributed in the late endosome.
  • PIs are negatively charged phospholipids that are widely present in cell membranes. Although their content is low in biological membranes, they are an important part of biological membranes. It plays an important role in membrane permeability, vesicle transport, membrane transfer, cytoskeleton adjustment and signal transduction pathways.
  • PI4K phosphatidylinositol 4-kinases
  • This patent mainly relates to a new type of kinase inhibitor. Its target is mainly Plasmodium falciparum PI4K (Plasmodium falciparum phosphatidylinositol 4-kinase, PfPI4K) and phosphatidylinositol 3-kinases (PI3K) , But has no obvious inhibitory effect on human PI4K, so as to achieve the effect of treating malaria. Since the compound of the present patent also has a significant inhibitory effect on PI3K protein, it can also be used to treat diseases mediated by PI3K.
  • PI4K Plasmodium falciparum PI4K
  • PfPI4K phosphatidylinositol 4-kinase
  • PI3K phosphatidylinositol 3-kinases
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • X is selected from CH or N;
  • the A ring is selected from the group consisting of pyridyl, pyrrolyl, pyrrolopyridyl, pyrazolyl, pyrazolopyridyl, tetrahydropyridyl, isoquinolyl, phenyl, and indolyl, and the nitrogen atom of the A ring Optionally substituted by an amino protecting group;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, halogen, and C 1-6 haloalkyl;
  • R 3 is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkanoyl, C 1-6 alkylaminocarbonyl, C 3-6 ring Alkylaminocarbonyl, C 1-6 alkanoylamino, C 1-6 alkylamino C 1-6 alkanoylamino, amino C 1-6 alkylaminocarbonyl, phenylalkyl, phenylaminocarbonyl, phenylalkane
  • the above substituents are optionally substituted with an amino group, an amino group substituted with an amino protecting group, a hydroxyl group, or a halogen.
  • the A ring is selected from pyridin-3-yl, pyridin-4-yl, pyrrol-3-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrazole-4-yl Group, pyrazolo[3,4-b]pyridin-5-yl, tetrahydropyridin-4-yl, isoquinolin-4-yl, phenyl, and indol-2-yl, the A ring is The nitrogen atom is optionally selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and an amino protecting group of trifluoroacetyl replace.
  • At least one of R 1 and R 2 is H.
  • R 3 is selected from chlorine, methyl, and methoxy.
  • R 4 is selected from C 1-6 alkylaminocarbonyl, C 1-6 alkanoylamino, C 1-6 alkylamino C 1-6 alkanoylamino, amino C 1-6 alkyl
  • the aminocarbonyl group, the phenylaminocarbonyl group, the phenylalkylaminocarbonyl group, and the pyridylaminocarbonyl group are optionally substituted by an amino group, an amino group substituted with an amino protecting group, a hydroxyl group or a halogen.
  • R 4 is selected from methylaminocarbonyl, ethylaminocarbonyl, acetamido, dimethylaminoacetamido, phenylaminocarbonyl, fluorophenylaminocarbonyl, benzylaminocarbonyl, and 2-pyridyl Aminocarbonyl.
  • the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • X is selected from CH or N;
  • At least one of R 1 and R 2 is H, and the other is selected from H, C 1-6 alkyl, halogen, and C 1-6 haloalkyl;
  • R 3 is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 4 is selected from H, C 1-6 alkylaminocarbonyl optionally substituted by amino, C 1-6 alkanoylamino, C 1-6 alkylamino C 1-6 alkanoylamino, amino C 1-6 Alkylaminocarbonyl, phenylaminocarbonyl optionally substituted with halogen, phenylalkylaminocarbonyl, and pyridylaminocarbonyl.
  • At least one of R 1 and R 2 is H, and the other is selected from H, methyl, 2-propyl, fluorine, chlorine, and trifluoromethyl.
  • R 3 is selected from chlorine, methyl, and methoxy.
  • R 4 is selected from methylaminocarbonyl, ethylaminocarbonyl, acetylamino, dimethylaminoacetamido, phenylaminocarbonyl, fluorophenylaminocarbonyl, benzylaminocarbonyl, and 2- Pyridylaminocarbonyl.
  • the application 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, ester, acid, metabolite, or prodrug thereof, and a pharmaceutical Acceptable carriers or excipients, and optionally other therapeutic agents.
  • the present application relates to methods and uses for inhibiting the activity of PI3K and/or PfPI4K, including administering the compound of the present invention or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or Pharmaceutical compositions including the compounds of the invention.
  • this application relates to methods and uses for treating, preventing or ameliorating diseases mediated by PI3K and/or PfPI4K, especially methods and uses for treating, preventing or ameliorating malaria, including for subjects
  • the compound of the present invention or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition including the compound of the present invention is administered.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology
  • nomenclature and laboratory operations and techniques related to the analytical chemistry, synthetic organic chemistry, and medicine and medicinal chemistry described herein are known to those skilled in the art.
  • the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general documents and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. According to the structure, the alkyl group may be a monovalent group or a divalent group (ie, an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include but are not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl and the like.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • butyl includes n-butyl.
  • Pentyl includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
  • cycloalkyl refers to a monocyclic or polycyclic group, which contains only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • aryl refers to a planar ring having a delocalized ⁇ electron system and containing 4n+2 ⁇ electrons, where n is an integer.
  • the aromatic ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aromatic groups may be optionally substituted.
  • aryl includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl” or “heteroaryl”) groups (e.g., 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 atom of the aromatic ring is a carbon atom.
  • the aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and indenyl.
  • the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • the N-containing “heteroaryl” moiety means that at least one backbone atom in the aromatic ring is a nitrogen atom.
  • the heteroaryl group may be a monovalent group or a divalent group (ie, heteroarylene).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole Group, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoindyl Dolyl, pterridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , Naphthyridiny
  • alkyl(aryl) or “aralkyl” means that an alkyl group as defined herein is substituted with an aryl group as defined herein.
  • Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
  • heteroalkyl as used herein means that one or more of the backbone chain atoms in the alkyl group as defined herein is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof.
  • the heteroatom(s) can be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is connected to the rest of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein means that one or more of the atoms constituting the ring in the non-aromatic ring are heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocycloalkyl ring can be composed of three, four, five, six, seven, eight, nine, or more than nine atoms.
  • the heterocycloalkyl ring may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-Dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiolan, 1,4- Oxythiolan, 1,4-oxathiolane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, Pakistan Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene,
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include structures of alkyl, alkoxy, or heteroalkyl in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are the same or different from each other.
  • amino refers to the group -NH 2.
  • aminoacyl refers to -CO-NH 2 .
  • amido or “amido” refers to -NR-CO-R', where R and R'are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted by one or two alkyl groups, specifically referring to the group -NRR', wherein R and R'are each independently selected from hydrogen or lower alkyl, with the condition of- NRR' is not -NH 2 .
  • Alkylamino includes groups of compounds in which the nitrogen of -NH 2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • arylamino and diarylamino refer to amino substituents further substituted with one or two aryl groups, specifically referring to the group -NRR', wherein R and R'are each independently selected from hydrogen, Lower alkyl, or aryl, where N is connected to at least one or two aryl groups, respectively.
  • cycloalkylamino refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.
  • aralkylamino herein refers to a group -NRR' in which R is lower aralkyl and R'is hydrogen, lower alkyl, aryl, or lower aralkyl.
  • heteroarylamino refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.
  • alkylaminoalkyl means that an alkyl group as defined herein is substituted with an alkylamino group as defined herein.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • hydroxy refers to a group of formula -OH.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted with one or more hydroxy groups.
  • acyl refers to the monovalent atomic group left after the hydroxyl group is removed from an organic or inorganic oxyacid.
  • the general formula is R-M(O)-, where M is usually C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
  • alkylaminocarbonyl cycloalkylaminocarbonyl
  • arylaminocarbonyl arylaminocarbonyl
  • aralkylaminocarbonyl heteroarylaminocarbonyl
  • optional means that one or more events described later may or may not occur, and include both events that occur and events that do not occur.
  • the term “optionally substituted” or “substituted” means that the mentioned group may be substituted by one or more additional groups, which are each and independently selected from alkyl, cycloalkyl , Aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
  • inhibitor of a kinase as used herein refers to the 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.
  • metabolized refers to the total number of processes in which a specific substance is changed by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions. Therefore, enzymes can produce specific structures and convert them into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucosyltransferase 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 a tissue sample from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both of these methods are known in the art.
  • the metabolites of the compound are formed through an oxidation process and correspond to the corresponding hydroxyl-containing compound.
  • the compound is metabolized into a pharmaceutically active metabolite.
  • modulation refers to directly or indirectly interacting with a target to change the activity of the target. For example, it includes enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
  • 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.
  • the GI 50 used herein refers to the concentration of the drug required for 50% inhibition of cell growth, that is, the drug concentration at which the drug inhibits or controls the growth of 50% of cancer cells.
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • X is selected from CH or N;
  • Ring A is selected from pyridyl (e.g. pyridin-3-yl, pyridin-4-yl), pyrrolyl (e.g. pyrrol-3-yl), pyrrolopyridyl (e.g. pyrrolo[2,3-b]pyridine-5 -Base), pyrazolyl (e.g. pyrazol-4-yl), pyrazolopyridyl (e.g. pyrazolo[3,4-b]pyridin-5-yl), tetrahydropyridyl (e.g. tetrahydropyridine -4-yl), isoquinolinyl (e.g.
  • ring A is particularly preferably pyridin-3-yl;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, halogen, and C 1-6 haloalkyl, preferably at least one of R 1 and R 2 is H, more preferably both are H;
  • R 3 is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy, preferably selected from chlorine, methyl, and methoxy;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkanoyl, C 1-6 alkylaminocarbonyl, C 3-6 ring Alkylaminocarbonyl, C 1-6 alkanoylamino, C 1-6 alkylamino C 1-6 alkanoylamino, amino C 1-6 alkanoylamino, amino C 1-6 alkylaminocarbonyl, hydroxy C 1 -6 alkylaminocarbonyl, phenylalkyl, phenylaminocarbonyl, phenylalkylaminocarbonyl, pyridylaminocarbonyl, and amino protecting groups, wherein the amino group is optionally substituted with an amino protecting group, and the above substituents are optionally An amino group, an amino group substituted with an amino protecting group, a hydroxy group or a halogen substitution, R 4 is preferably selected from C 1-6 alkylaminocarbony
  • the amino protecting group in the present invention is selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
  • the present invention further relates to a compound of formula (II) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • X is selected from CH or N;
  • At least one of R 1 and R 2 is H, the other is selected from H, C 1-6 alkyl, halogen, and C 1-6 haloalkyl, more preferably selected from H, methyl, 2-propyl, fluorine, Chlorine, and trifluoromethyl, most preferably R 1 and R 2 are both H;
  • R 3 is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy, preferably selected from chlorine, methyl, and methoxy;
  • R 4 is selected from H, C 1-6 alkylaminocarbonyl optionally substituted by amino, C 1-6 alkanoylamino, C 1-6 alkylamino C 1-6 alkanoylamino, amino C 1-6 Alkylaminocarbonyl, phenylaminocarbonyl optionally substituted by halogen, phenylalkylaminocarbonyl, and pyridylaminocarbonyl are preferably selected from preferably selected from methylaminocarbonyl, ethylaminocarbonyl, acetylamino , Dimethylaminoacetamido, phenylaminocarbonyl, fluorophenylaminocarbonyl, benzylaminocarbonyl, and 2-pyridylaminocarbonyl.
  • the chiral compound involved in the present invention can have any configuration or a mixed racemate.
  • the compounds described herein can be formulated and/or used as pharmaceutically acceptable salts.
  • the types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids 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, ethanesulfonic acid Acid, 1,2-ethanedisulfonic acid, 2-
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various 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, solvent evaporation, or lyophilization in the case of an aqueous solution.
  • Screening and characterizing 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 methods, and elemental analysis.
  • the various spectroscopic 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.
  • This application provides a pharmaceutical composition formulated for administration by an appropriate route and mode, the pharmaceutical composition comprising an effective concentration of one or more of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, ester, Acids, metabolites or prodrugs, and pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents.
  • compositions of formula (I) or (II) in free form or salt form are also referred to as "substances of the present invention" hereinafter, due to their inhibitory effect on phosphatidylinositol 3-kinase, free form or pharmaceutically acceptable salt
  • the compound of formula (I) or formula (II) in form can be used to treat diseases, disorders, or disorders mediated by the activation of one or more members of the PI3K kinase family (including normal activity, especially excessive activation), such as proliferation Diseases, cancer, inflammatory diseases or allergic diseases, obstructive respiratory diseases and/or transplant-related disorders.
  • the compound of formula (I) or formula (II) in free form or pharmaceutically acceptable salt form can be used It is used to treat diseases, disorders, or conditions mediated by the activation of one or more members of the PfPI4K kinase family (including normal activity, especially overactivation), such as falciparum malaria.
  • treatment of the present invention can be therapeutic (such as symptomatic treatment) and/or prophylactic.
  • said proliferative diseases are selected from benign or malignant tumors, including but not limited to: brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, lymphoma, gastric cancer, Stomach cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, pancreatic cancer, thyroid cancer, neck cancer, CNS cancer, malignant glioma, myelodysplastic disease, sarcoma, gelatinization Plasma cell tumor, multiple myeloma, gastrointestinal cancer, head and neck tumor, brain tumor, epidermal hyperplasia, psoriasis, prostate hyperplasia, neoplasia, epithelial characteristic neoplasia, lymphoma, or leukemia.
  • benign or malignant tumors including but not limited to: brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, lymphoma, gastric cancer, Stomach cancer, esoph
  • Cowden syndrome Cowden syndrome
  • Lhermitte-Dudos disease Bannayan-Zonana syndrome
  • diseases in which the PI3K/PKB pathway is abnormally activated Preferably treat colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, neck cancer, CNS cancer, malignant glioma, myelodysplasia, Leukemia and lymphoma.
  • the substance of the present invention can be used for the treatment of inflammatory or obstructive airway diseases, resulting in, for example, tissue damage, airway inflammation, bronchial hyperreaction, remodeling or reduction of disease development.
  • the inflammatory or obstructive airway diseases applicable to the present invention include asthma of any type or cause, including endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, Severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced by bacterial infection.
  • the treatment of asthma should also be understood to include the treatment of individuals, such as individuals younger than 4 or 5 years old, who show symptoms of wheezing and are diagnosed or can be diagnosed as "whez infants", which is a kind of
  • the categories of patients that have been identified as major medical concerns are now generally identified as early or early asthma. For convenience, this particular asthma condition is called "wheezing baby syndrome”.
  • the preventive effect in the treatment of asthma will be manifested as a reduction in the frequency or severity of symptoms, such as a reduction in the frequency or severity of acute asthma or bronchoconstriction, improvement in lung function, or improvement in airway hyperactivity.
  • the efficacy is also manifested as a reduction in the need for treatment of other symptoms, which are used or intended to limit or stop the onset of symptoms when they occur, such as anti-inflammatory drugs (such as corticosteroids) or bronchiectasis medicine.
  • anti-inflammatory drugs such as corticosteroids
  • bronchiectasis medicine such as bronchiectasis medicine.
  • the prevention benefits of asthma may be particularly obvious in individuals with a tendency to "morning dipping".
  • “Morning drop” is a recognized asthma syndrome, which usually accounts for a large proportion of asthma, and is characterized by, for example, onset between about 4 and 6 in the morning, that is, any asthma symptoms usually administered at a distance before The onset of treatment is longer.
  • inflammatory or obstructive airway diseases and disorders to which the present invention is applicable include acute lung injury (ALI), adult type/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung diseases (COPD, COAD or COLD), including chronic bronchitis or related dyspnea, emphysema, and deterioration of airway hyperactivity caused by other medications, especially other inhaled medications.
  • the present invention is also suitable for the treatment of bronchitis of any type or origin, including, for example, acute bronchitis, arachidic inhalation bronchitis, catarrhal bronchitis, fibrinous bronchitis, chronic bronchitis or tuberculous bronchitis.
  • inflammatory or obstructive airway diseases include pneumoconiosis of any type or origin (an inflammatory, usually occupational lung disease, whether chronic or acute, often accompanied by airway obstruction, and caused by repeated inhalation Dust caused), including, for example, alumina lung, carbon lung, asbestos lung, stone end lung, ostrich pneumoconiosis, iron sinking lung, silicosis, smoke pneumoconiosis, and cotton pneumoconiosis.
  • pneumoconiosis of any type or origin (an inflammatory, usually occupational lung disease, whether chronic or acute, often accompanied by airway obstruction, and caused by repeated inhalation Dust caused), including, for example, alumina lung, carbon lung, asbestos lung, stone end lung, ostrich pneumoconiosis, iron sinking lung, silicosis, smoke pneumoconiosis, and cotton pneumoconiosis.
  • the substance of the present invention is also used to treat the following diseases, disorders or conditions mediated by phosphatidylinositol 3-kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis Disease, ulcerative colitis, Crohn's disease, septic shock, proliferative disorder, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, interstitial Tumor, thyroid cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, lung Hypertension, Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial
  • the substance of the present invention can also be used to treat diseases related to eosinophils, such as eosinophilia, especially airway diseases related to eosinophils (for example, lung tissues involving diseased eosinophil infiltration), Including eosinophilia, because it affects the airways and/or lungs, and, for example, infection by Loewler syndrome, eosinophilic pneumonia, parasites (especially metazoans) (including tropical eosinophilia) Disease), bronchopulmonary aspergillosis, nodular polyarteritis (including Chu-S syndrome), eosinophilic granuloma caused by or concurrent with eosinophil-related airway disorders, and drug reactions caused An eosinophil-related disorder affecting the airway.
  • diseases related to eosinophils such as eosinophilia, especially airway diseases related to eosinophils (for example, lung tissues
  • the substance of the present invention can also be used to treat inflammatory or allergic disorders of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, Allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, acquired epidermolysis bullosa and other inflammatory or allergic conditions of the skin.
  • inflammatory or allergic disorders of the skin such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, Allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus,
  • the substance of the present invention can also be used to treat other diseases or conditions, especially diseases or conditions with inflammatory components, such as the treatment of ocular diseases and conditions, such as conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis; diseases affecting the nose , Including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or autoimmune components or etiology, including autoimmune hematological disorders (such as hemolytic anemia, aplastic anemia, pure red blood cell anemia and special (Idiopathic thrombocytopenia), systemic lupus erythematosus, polychondrosis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, S-Jow syndrome, idiopathic oral Inflammatory diarrhea, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), endocrine
  • Other diseases or conditions that can be treated with the substance of the present invention include septic shock, rheumatoid arthritis, osteoarthritis, proliferative diseases such as cancer, atherosclerosis, allograft rejection after transplantation, stroke , Obesity, restenosis, diabetes such as type I diabetes (juvenile diabetes) and type II diabetes, diarrhea diseases, ischemia/reperfusion injury, retinopathy such as diabetic retinopathy or hyperbaric oxygen induced retinopathy, and A condition characterized by increased intraocular pressure or secretion of aqueous humor, such as glaucoma.
  • the effectiveness of the substance of the present invention in inhibiting inflammatory conditions such as inflammatory airway diseases can be demonstrated in animal models, such as mouse or rat models of airway inflammation or other inflammatory conditions, such as Szarka et al., J Immunol. Methods (1997) 202:49-57; Renzi et al., Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. Clin. 1nvest. (1995) 96: 2924-2931 ; And Cernadas et al., Am. J. Respir. Cell Mol. Biol. (1999) 20:1-8.
  • the substance of the present invention can also be used as a combination therapeutic agent for use in combination with other drug substances, such as anti-inflammatory drugs, bronchodilators or antihistamine drug substances, especially for the treatment of obstructive or inflammatory airway diseases, Such as those mentioned above, for example, as a potentiator of the therapeutic activity of these drugs or as a means to reduce the required dosage or potential side effects of these drugs.
  • the substance of the present invention can be mixed with other drug substances in a fixed drug composition, or can be administered separately before, at the same time or after administration of other drug substances.
  • the present invention includes a combination of the above-mentioned substance of the present invention and an anti-inflammatory drug, bronchodilator or antihistamine drug substance.
  • the substance of the present invention and the drug substance may be in the same or different drugs.
  • anti-inflammatory drugs include steroids, particularly glucocorticoids such as budesonide, beclomethasone dipropionate, fluticasone propionate, cyclic pine or sauerkraut methasone, and WO 0200679, WO 0288167, WO 0212266 and Compounds described in WO 02100879, LTB4 antagonists such as those described in US5451700, LTD4 antagonists such as montelukast and zafirukast, dopamine receptor agonists such as cabergoline, bromocriptine, repiled Luohe 4-hydroxy 7-[2-[[2-[[[3-(2-phenylethoxy)-propyl]-sulfonyl]-ethyl]-amino]ethyl]-2(3H) -Benzothiazolone and its pharmaceutically acceptable salts (hydrochloride -AstraZeneca), and
  • Such bronchodilators include anticholinergics or antimuscarinic drugs, especially ipratropium, ethosamine bromide and tiotropium salts, as well as WO 01/04118, WO 02/51841, WO 02/53564 , WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US 5171744, US 3714357 and WO 03/33495, and ⁇ -2 adrenal glands Receptor agonists such as salbutamol, terbutaline, salmeterol and formoterol and their pharmaceutically acceptable salts, and the compound of formula I in PCT International Patent Publication WO 00/75114 (this document is incorporated herein by reference) ( Free form or salt form or solvate form), preferably the antihistamine drug substance of the compound combination treatment of the embodiments includes cetirizine hydrochloride, paracetamol, clemastine fumarate, promethaz
  • the combination of the substance of the present invention with steroids, ⁇ -2 agonists, PDE4 inhibitors or LTD4 antagonists can be used, for example, to treat COPD or especially asthma.
  • the combination of the substance of the present invention with anticholinergic or antimuscarinic drugs, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists can be used, for example, for the treatment of asthma or particularly COPD.
  • chemokine receptor antagonists such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7 , CCR-8, CCR-9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly a combination of antagonists of CCR-5, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]hydroxy]amino ]Phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770), and US6166037 (especially claims 18 and 19), WO 00/ The CCR-5 antagonist described in 66558 (in particular claim 8) and WO
  • the substance of the present invention can be administered by any suitable route, such as oral administration, such as oral administration in the form of tablets or capsules; parenteral, such as intravenous administration; administration by inhalation, such as in inflammatory or obstructive airway diseases.
  • oral administration such as oral administration in the form of tablets or capsules
  • parenteral such as intravenous administration
  • administration by inhalation such as in inflammatory or obstructive airway diseases.
  • intranasal administration for example, in the treatment of allergic rhinitis
  • topical administration to the skin for example, in the treatment of atopic dermatitis
  • rectal administration for example, in the treatment of inflammatory bowel disease.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention in free form or in a pharmaceutically acceptable salt form, optionally together with a suitable pharmaceutically acceptable diluent or carrier.
  • the composition may contain a combined therapeutic agent, such as an anti-inflammatory drug, bronchodilator or antihistamine as described above.
  • a combined therapeutic agent such as an anti-inflammatory drug, bronchodilator or antihistamine as described above.
  • Such compositions can be prepared using conventional diluents or excipients and techniques known in the galenic field. Therefore, oral dosage forms may include tablets and capsules.
  • Formulations for topical application may take the form of creams, ointments, gels, or transdermal delivery systems such as patches.
  • the composition for inhalation may include an aerosol or other atomizable formulation or dry powder formulation.
  • the composition when it includes an aerosol formulation, it preferably contains, for example, a hydrogen-fluoro-alkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol ( Up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan triolease, and/or one or more fillers such as lactose.
  • HFA hydrogen-fluoro-alkane
  • the composition when the composition includes a dry powder, it preferably contains, for example, a compound of the present invention having a particle size of not more than 10 microns, optionally with a diluent or carrier such as lactose having a desired particle size distribution, and helps prevent product properties A compound that becomes worse due to moisture.
  • a spray formulation it preferably contains, for example, the compound of the present invention dissolved or suspended in a medium containing water, a co-solvent such as ethanol or propylene glycol, and a stabilizer, which may be a surfactant.
  • the dosage of the substance of the present invention used in the practice of the present invention will vary according to, for example, the specific condition to be treated, the desired effect and the way of administration. Generally, the appropriate dose for oral administration is in the order of 0.1 to 10 mg/kg.
  • the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, depending on the specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dosage may be known in the art
  • the method is routinely decided.
  • the administered dose is typically in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose can conveniently be expressed as one dose, or simultaneous (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the doctor's diagnosis.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are subsequently added by the methods described herein and/or methods known in the art.
  • provided herein are methods of preparing the PI3K and/or PfPI4K kinase inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic schemes. A method similar to that described below can be used to synthesize the compound by using suitable optional starting materials.
  • the starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
  • the general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
  • reaction product can be separated and purified using conventional techniques, including but not limited to methods such as filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.
  • the organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate.
  • the organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product.
  • the crude product was purified by pressurized silica gel column chromatography to obtain compound (2), LC/MS: M+H 320.12.
  • the organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate.
  • the organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product.
  • the crude product was purified by pressurized silica gel column chromatography to obtain compound (3), LC/MS: M+H 460.11.
  • N-(5-(4-Aminophenyl)-2-chloropyridin-3-yl)benzenesulfonamide (4) In a round bottom flask, add (4-(6-chloro-5-(phenylsulfonyl) Amino)pyridin-3-yl)phenyl)tert-butyl carbamate (100 mg) was added to a solution of hydrochloric acid in ethyl acetate (4 mL) and methanol (1 mL). The reaction system reacted at room temperature for 0.5 hours. After the reaction, the solvent was evaporated to dryness under reduced pressure to obtain compound (4), LC/MS: M+H 360.06.
  • the reaction system was stirred at room temperature for 14 hours under argon protection. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound (5), LC/MS: M+H 559.18.
  • the reaction system was heated to 80°C for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound (9), LC/MS: M+H 287.16.
  • N-(2-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)benzenesulfonamide (11) In a round bottom flask, add 2-chloro- 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-amine (300 mg) followed by pyridine (8 mL) and benzenesulfonyl chloride (0.25 mL). The reaction system was reacted at room temperature for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate.
  • the reaction system was stirred at room temperature for 14 hours under argon protection. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound (12), LC/MS: M+H 584.18.
  • 5-(5-Amino-6-chloropyridin-3-yl)-N-methylnicotinamide Put 5-bromo-2-chloropyridin-3-amine (90 mg) in a round bottom flask and add 1, 4-Dioxane (4ml), water (1ml), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -Based) nicotinamide (135 mg), Pd(PPh 3 ) 4 (16 mg), potassium carbonate (155 mg). The reaction system was reacted at 80°C for 14 hours under argon protection.
  • N-(5-Bromo-2-chlorophenyl)benzenesulfonamide (26) Put 5-bromo-2-chloroaniline (3.0g) in a round bottom flask, then add pyridine (15ml) and benzenesulfonyl chloride ( 2.8g). The reaction system was reacted at room temperature for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound (26), LC/MS: M+H 345.93.
  • N-methyl-5-(6-methyl-5-(phenylsulfonylamino)pyridin-3-yl)nicotinamide (32) add 5-(6-methyl-5- (Phenylsulfonylamino)pyridin-3-yl)nicotinic acid (50mg) and then add anhydrous tetrahydrofuran (2ml), oxalyl chloride (140mg), N,N-dimethylformamide (1 drop), The reaction system was reacted for 2 hours at room temperature under argon protection. Then, methylamine (360 mg) was added to the system and stirred at room temperature for 1 hour.
  • N-(5-Bromo-2-fluoropyridin-3-yl)benzenesulfonamide (38) Put 5-bromo-2-fluoropyridin-3-amine (2.0g) in a round bottom flask and then add pyridine (10 ML) and benzenesulfonyl chloride (1.5 mL). The reaction system was reacted at room temperature for 20 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound (38), LC/MS: M+H 330.96.
  • N-(5-(6-Chloro-5-(phenylsulfonylamino)pyridin-3-yl)pyridin-3-yl)-2-(dimethylamino)acetamide (56): in a round bottom flask Add N-(5-(5-aminopyridin-3-yl)-2-chloropyridin-3-yl)benzenesulfonamide (35 mg), then add tetrahydrofuran (1 ml), 2-(dimethylamino)acetic acid ( 18 mg), HATU (67 mg) and N,N-diisopropylethylamine (0.1 mL). The reaction system was stirred at room temperature for 14 hours under argon protection.
  • N-(5-(4-Chloro-3-(phenylsulfonylamino)phenyl)pyridin-3-yl)acetamide 80: Add N-(5-bromo-2-chloride to a round bottom flask Phenyl)benzenesulfonamide (63 mg) was added with 1,4-dioxane (1 ml), N-(5-(4,4,5,5-tetramethyl-1,3,2-bis Oxaborane-2-yl)pyridin-3-yl)acetamide (50 mg), PdCl 2 (dppf) 2 (15 mg), potassium acetate (42 mg). The reaction system was reacted at 80°C for 14 hours under argon protection.
  • Example 57 The synthesis of the compound of Example 57 was accomplished by using procedures similar to those described in Example 54. MS(ESI) m/z(M+1) + : 410.16.
  • Example 58 The synthesis of the compound of Example 58 was accomplished by using procedures similar to those described in Example 54. MS(ESI) m/z(M+1) + : 424.17.
  • Example 63 The synthesis of the compound of Example 63 was accomplished by using procedures similar to those described in Example 42. MS(ESI) m/z(M+1) + : 450.11.
  • Example 66 The synthesis of the compound of Example 66 was accomplished by using procedures similar to those described in Example 42. MS(ESI) m/z(M+1) + : 424.17.
  • Example 74 The synthesis of the compound of Example 74 was accomplished by using procedures similar to those described in Example 42. MS(ESI) m/z(M+1) + : 410.16.
  • Example 76 The synthesis of the compound of Example 76 was accomplished by using procedures similar to those described in Example 42. MS(ESI) m/z(M+1) + : 416.09.
  • Example 77 The synthesis of the compound of Example 77 was accomplished by using procedures similar to those described in Example 42. MS(ESI) m/z(M+1) + : 410.16.
  • Protein kinases PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , VPS34, PI4KB were purchased from Invitrogen (USA); protein kinase PI3K ⁇ was purchased from Sigma (USA); PfPI4K was expressed by our laboratory, and the expression steps are as follows.
  • the Bac-to-Bac expression system (Thermo Fisher, USA) was used to construct the PfPI4K protein expression system. According to the instructions of the Bac-to-Bac expression system, the recombinant baculovirus was first constructed, and then 1000 mL of SF9 cells (purchased from ATC in the United States) were cultured in large quantities. The constructed recombinant baculovirus was infected with SF9 cells and centrifuged at 1000 rpm for 5 minutes after 72 hours. The cell pellet was collected, the cells were lysed by ultrasound, and the supernatant was collected at 12,000 revolutions for 10 minutes. First use his-beads for preliminary purification, and then use FPLC protein purification instrument (AKTA, US GE) for further purification. The three substrates PIP2: PS, PI and PI: PS were purchased from Invitrogen (USA).
  • PI3K ⁇ 5.4 ⁇ L Dilute to a certain concentration of protein kinase PI3K ⁇ 5.4 ⁇ L (final concentration is 0.16ng/ ⁇ L), PI3K ⁇ 5.4 ⁇ L (final concentration is 6ng/ ⁇ L), PI3K ⁇ 5.4 ⁇ L (final concentration is 1ng/ ⁇ L), PI3K ⁇ 5.4 ⁇ L ( The final concentration is 5ng/ ⁇ L), VPS34 5.4 ⁇ L (final concentration is 1.2ng/ ⁇ L), PI4KB 5.4 ⁇ L (final concentration is 5ng/ ⁇ L), and PfPI4K 5.4 ⁇ L (final concentration is 5ng/ ⁇ L) respectively with gradient dilutions Each 1 ⁇ L of the test drug compound was reacted at room temperature for 1 h (final drug concentrations were 10 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M, respectively).
  • reaction buffer 50 mM Hepes (pH 7.5), 0.1% CHAPS, and 1 mM EGTA.
  • reaction buffer 20mM Tris (pH 7.5), 0.5mM EGTA and 0.4% Triton X-100.
  • reaction kinase solution Take 5 ⁇ L of the reaction kinase solution in a 384-well plate (Corning, USA), add 5 ⁇ L of ADP-Glo TM (Promega, USA) reagent, and react at room temperature for 40 minutes to stop the kinase reaction and consume the remaining ATP.
  • ADP-Glo TM Promega, USA
  • Example 1 Compound PIK3 ⁇ / ⁇ M PIK3 ⁇ / ⁇ M Example 1 - 5.37 Example 3 - 2.09 Example 4 - 2.08 Example 5 - 0.43 Example 6 0.33 0.22 Example 7 0.14 0.19 Example 8 0.018 0.28 Example 12 3.54 - Example 13 - 1.23 Example 14 2.09 - Example 15 0.025 0.024 Example 16 0.048 0.026 Example 17 0.91 2.54
  • Example 18 0.046 0.34
  • Example 19 - 0.50
  • Example 20 2.76
  • Example 21 - 0.072
  • Example 22 0.063 0.83
  • Example 23 0.028 0.089
  • Example 24 0.073 0.045
  • Example 25 0.090 5.84
  • Example 26 0.36 2.64
  • Example 27 0.029 2.10
  • Example 28 1.78
  • Example 31 0.68 -
  • Example 32 0.11 -
  • Example 33 1.99 -
  • Example 34 0.075 1.37
  • Example 35 0.082 0.66
  • Example 36 0.11 6.26
  • Example 37 0.16 -
  • Example 38 0.18 3.46
  • Example 39 0.30 0.25
  • Example 40 0.73 -
  • Example 41 - 1.18
  • Example 42 - 0.17
  • Example 43 0.085 0.17
  • Example 45 0.19 1.13
  • Example 46 6.61 1.47
  • Example 48 - 2.19
  • Example 49 0.067 0.13
  • Example 50 0.040 0.040
  • Example 51 0.73 1.99
  • Example 52 0.61 0.23
  • Example 53 0.25
  • Example 55 8.66 -
  • Example 57 8.20 -
  • White blood cells (separated from normal human blood) and ficoll reagent were added to 10ml pbs, red blood cells were washed twice, and each time was 2000RPM for 5 minutes. Aspirate the supernatant and leave the precipitate for later use. Aspirate 3 ⁇ l of the bottom cell pellet in a culture dish with infected red blood cells, drop it on a glass slide to make a blood slice, stain with Giemsa stain for 19 minutes, wash off the stain with double distilled water, and count the infection rate. Transfer the infected red blood cell culture to a 15ml disposable centrifuge tube. Turn at 2000RPM for 5 minutes and remove the culture supernatant.
  • the 96-well plate was shaken on a shaker for 14 seconds, and 30 ⁇ l of lysate was added and shaken for another 10 seconds. Place on a shaker at room temperature for 120 revolutions for 10 minutes. Envision reading, the absorption wavelength is about 497nm, the emission wavelength is about 520nm, and the GI 50 value is calculated with Graphpad 7.0.
  • Example 2 Compound Plasmodium ( ⁇ M) Example 2 2.34 Example 3 2.65 ⁇ 1.10 Example 4 0.36 Example 6 0.11 ⁇ 0.039 Example 7 1.05 ⁇ 0.27 Example 8 1.49 ⁇ 0.15 Example 13 0.13 ⁇ 0.051 Example 14 0.14 ⁇ 0.041 Example 15 5.27 ⁇ 2.77 Example 16 4.67 ⁇ 1.58 Example 18 3.94 ⁇ 1.85 Example 19 5.23 ⁇ 4.17 Example 22 4.71 ⁇ 1.20 Example 23 7.92 Example 25 8.08 Example 27 0.42 ⁇ 0.32 Example 28 0.54 ⁇ 0.17 Example 29 1.68 ⁇ 1.17 Example 30 6.62 ⁇ 4.25 Example 31 3.56 ⁇ 1.26
  • Example 32 0.47 ⁇ 0.13 Example 34 3.68 Example 35 3.57 ⁇ 2.19 Example 37 4.04 Example 38 7.59 Example 39 0.16 ⁇ 0.063 Example 40 7.24 Example 41 3.32 ⁇ 2.56 Example 42 0.11 ⁇ 0.047 Example 43 2.01 ⁇ 1.47 Example 44 0.13 ⁇ 0.049 Example 45 0.11 ⁇ 0.063 Example 46 2.44 ⁇ 0.97 Example 47 0.085 ⁇ 0.043 Example 48 2.58 ⁇ 1.15 Example 49 1.04 ⁇ 1.13 Example 50 0.19 ⁇ 0.053 Example 51 0.63 ⁇ 0.28 Example 52 1.02 ⁇ 0.52 Example 53 1.86 ⁇ 1.42 Example 59 2.53
  • the present invention provides a new type of kinase inhibitor compounds, which can be used to treat diseases mediated by PI3K kinase or PfPI4K kinase activation, especially malaria, cancer and other cell proliferative diseases. Therefore, it can be made into corresponding drugs, suitable for industrial applications.

Abstract

L'invention concerne un nouvel inhibiteur de kinase, comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable, un solvate, un ester, un acide, un métabolite ou un promédicament de celui-ci. L'invention concerne également une composition pharmaceutique comprenant le composé de formule (I) et l'utilisation de celui-ci et un procédé d'utilisation d'un tel composé et d'une composition pour traiter des états pathologiques médiés par l'activation de la kinase PI3K ou PfPI4K, en particulier le paludisme, les cancers et d'autres maladies prolifératives cellulaires.
PCT/CN2019/072281 2019-01-18 2019-01-18 Nouvel inhibiteur de kinase liposome WO2020147097A1 (fr)

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CN113214247A (zh) * 2021-01-14 2021-08-06 复旦大学 氮杂吲哚衍生物髓细胞增殖抑制剂及其制备方法与在制药中的应用
US11912668B2 (en) 2020-11-18 2024-02-27 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof

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CN103539777A (zh) * 2012-07-13 2014-01-29 广东东阳光药业有限公司 Pi3激酶调节剂及其使用方法和用途
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US11912668B2 (en) 2020-11-18 2024-02-27 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof
CN113214247A (zh) * 2021-01-14 2021-08-06 复旦大学 氮杂吲哚衍生物髓细胞增殖抑制剂及其制备方法与在制药中的应用
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