WO2020147097A1 - 一种新型的脂质体激酶抑制剂 - Google Patents

一种新型的脂质体激酶抑制剂 Download PDF

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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)
French (fr)
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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/zh
Publication of WO2020147097A1 publication Critical patent/WO2020147097A1/zh

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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.

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Abstract

一种新型的激酶抑制剂，其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药。还提供包括式(I)化合物的药物组合物以及使用这些化合物和组合物用于治疗由PI3K激酶或PfPI4K激酶活化介导的病症，特别是疟疾、癌症和其它的细胞增殖性疾病的用途和方法。

Description

一种新型的脂质体激酶抑制剂 技术领域
本申请涉及一类新型的激酶抑制剂的化合物、包含这些化合物的药物组合物、以及使用这些化合物和组合物用于治疗由PI3K激酶或PfPI4K激酶活化介导的病症，特别是疟疾、癌症和其它的细胞增殖性疾病的用途和方法。
背景技术
诸多病毒对宿主脂质代谢、脂质膜的运输以及脂质介导的信号转导均会产生影响。磷酸肌醇(phosphoinositide，PI)是一类参与以上几种细胞过程的磷脂。磷脂酰肌醇是PI的基本骨架，磷脂酰肌醇的5个羟基中，3、4、5位羟基被激酶可逆地磷酸化后总共可得到7种PIs，包括磷脂酰肌醇-3-磷酸(phosphatidylinositol 3-phosphate，PI3P)、磷脂酰肌醇-4-磷酸(phosphatidylinositol 4-phosphate，PI4P)、磷脂酰肌醇-5-磷酸(phosphatidylinositol 5-phosphate，PI5P)、磷脂酰肌醇-3,4-二磷酸盐(phosphatidylinositol 3,4-biphosphate，PI(3,4)P2)、磷脂酰肌醇-3,5-二磷酸盐(phosphatidylinositol 3,5-bisphosphate，PI(3,5)P2)、磷脂酰肌醇-4,5-二磷酸盐(phosphatidylinositol 4,5-bisphosphate，PI(4,5)P2)和磷脂酰肌醇-3,4,5-三磷酸盐(phosphatidylinositol 3,4,5-triphosphate，PI(3,4,5)P3)。这7种PIs可以相互间进行转换，不同类型的磷酸酶和激酶参与其相互转换的过程。这些PIs在亚细胞膜中的分布各不相同。PI3P在早晚期内体上都有分布，PI4P主要分布在高尔基体上；PI(3,4)P2、PI(4,5)P2、PI(3,4,5)P3主要位于血浆膜；PI(3,5)P2主要分布于突触分泌小泡，晚期内体上也有少量分布。
PIs是广泛存在于细胞膜中带负电荷的一种磷脂，虽然在生物膜中含量较低，却是生物膜中重要的组成部分。其在膜的通透性、囊泡的运输、膜的转移、细胞骨架调整及信号传导通路中均发挥着重要作用。
最近研究发现，磷脂酰肌醇-4-激酶(phosphatidylinositol 4-kinases，PI4K)是针对恶性疟原虫的主要靶标，通过选择性地抑制恶性疟原虫的PI4K蛋白，而不抑制人的PI4K蛋白，能够达到治疗疟疾的效果 (Nature,2013，504,248–253)。
本专利主要涉及一种新型的激酶抑制剂，它的作用靶点主要是恶性疟原虫PI4K(Plasmodium falciparum phosphatidylinositol 4-kinase，PfPI4K)以及磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases，PI3K)，而对人的PI4K没有明显的抑制作用，从而达到治疗疟疾的效果。由于本专利的化合物对PI3K蛋白也有明显的抑制效果，因而也能用于治疗由PI3K所介导的病症。
发明内容
本发明涉及一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
Figure PCTCN2019072281-appb-000001
其中：
X选自CH或N；
A环选自吡啶基、吡咯基、吡咯并吡啶基、吡唑基、吡唑并吡啶基、四氢吡啶基、异喹啉基、苯基、和吲哚基，所述A环的氮原子任选被氨基保护基取代；
R 1和R 2各自独立地选自H、C 1-6烷基、卤素、和C 1-6卤代烷基；
R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基；
R 4选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷酰基、C 1-6烷基氨基羰基、C 3-6环烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、苯烷基、苯基氨基羰基、苯基烷基氨基羰基、吡啶基氨基羰基、和氨基保护基，上述取代基任选地被氨基、氨基保护基取代的氨基、羟基或卤素取代。
在优选的方面，所述的A环选自吡啶-3-基、吡啶-4-基、吡咯-3-基、吡咯并[2,3-b]吡啶-5-基、吡唑-4-基、吡唑并[3,4-b]吡啶-5-基、四氢吡啶-4-基、异喹啉-4-基、苯基、和吲哚-2-基，所述A环的氮原子任选被选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧 苄基、烯丙氧羰基、和三氟乙酰基的氨基保护基取代。
另外优选地，R 1和R 2中至少一个是H。
另外优选地，R 3选自氯、甲基、和甲氧基。
在优选的实施方式中，R 4选自C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基，上述取代基任选地被氨基、氨基保护基取代的氨基、羟基或卤素取代。进一步优选地，R 4选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
在又一方面，本发明涉及式(II)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
Figure PCTCN2019072281-appb-000002
其中：
X选自CH或N；
R 1和R 2中至少一个为H，另一个选自H、C 1-6烷基、卤素、和C 1-6卤代烷基；
R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基；
R 4选自H、任选地被氨基取代的C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、任选地被卤素取代的苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基。
优选地，R 1和R 2中至少一个为H，另一个选自H、甲基、2-丙基、氟、氯、和三氟甲基。
另外优选地，R 3选自选自氯、甲基、和甲氧基。
在其它实施方式中，R 4选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
在另一方面，本申请提供一种药物组合物，其包括治疗有效量的至少一种本文提供的化合物或其药学可接受的盐、溶剂化物、酯、酸、 代谢物或前药，以及药学可接受的载体或赋形剂，以及任选的其它治疗剂。
在另一方面，本申请涉及用于抑制PI3K和/或PfPI4K活性的方法和用途，包括施用本发明的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或包括本发明化合物的药物组合物。
在另一方面，本申请涉及用于治疗、预防或改善由PI3K和/或PfPI4K介导的疾病的方法和用途，特别是用于治疗、预防或改善疟疾的方法和用途，包括对受试者施用本发明的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或包括本发明化合物的药物组合物。
具体实施方式
术语
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷 氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“芳香基”是指平面环具有离域的π电子***并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个 骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷、吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
术语“氨基”是指基团-NH 2。
术语“氨酰基”是指-CO-NH 2。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH 2。“烷基氨基”包括其中-NH 2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH 2的氮连接至少两个其 它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。
术语“芳基氨基”和“二芳基氨基”是指进一步被一个或两个芳基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢、低级烷基、或芳基，其中N分别连接至少一个或两个芳基基团。
术语“环烷基氨基”是指进一步被一个或两个本文所定义的环烷基取代的氨基取代基。
本文的术语“芳烷基氨基”是指其中R是低级芳烷基且R’是氢、低级烷基、芳基或低级芳烷基的基团-NRR’。
术语“杂芳基氨基”是指进一步被一个或两个本文所定义的杂芳基取代的氨基取代基。
术语“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。
术语“羟基”是指式-OH基团。
术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。
术语“烷基氨基羰基”、“环烷基氨基羰基”、“芳基氨基羰基”、“芳烷基氨基羰基”、“杂芳基氨基羰基”分别是指本文定义的羰基分别被本文定义的烷基氨基、环烷基氨基、芳基氨基、芳烷基氨基、或杂芳基氨基取代。
术语“砜基”或“磺酰基”是指磺酸失去羟基后的官能团，具体 是指-S(＝O) 2-基团。
术语“氨基砜基”或“氨基磺酰基”是指-S(＝O) 2-NH 2基团。
术语“烷基砜基”或“烷基磺酰基”是指-S(＝O) 2-R，其中R为烷基。
术语“任选”指后面描述的一个或多个事件可以或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和，包括但不限于水解反应和由酶催化的反应，例如氧化反应。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶 标的活性。
本文使用的IC 50是指在测量这样的效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。
本文使用的GI 50是指细胞50％生长抑制所需的药物浓度，即药物使50％癌细胞的生长得到抑制或控制，此时的药物浓度。
本发明的新型激酶抑制剂
本发明涉及一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
Figure PCTCN2019072281-appb-000003
其中，X选自CH或N；
A环选自吡啶基(例如吡啶-3-基、吡啶-4-基)、吡咯基(例如吡咯-3-基)、吡咯并吡啶基(例如吡咯并[2,3-b]吡啶-5-基)、吡唑基(例如吡唑-4-基)、吡唑并吡啶基(例如吡唑并[3,4-b]吡啶-5-基)、四氢吡啶基(例如四氢吡啶-4-基)、异喹啉基(例如异喹啉-4-基)、芳基(例如苯基)、和吲哚基(例如吲哚-2-基)，上述取代基的氮原子任选被氨基保护基取代，A环特别优选为吡啶-3-基；
R 1和R 2各自独立地选自H、C 1-6烷基、卤素、和C 1-6卤代烷基、，优选R 1和R 2中至少一个是H，更优选两个都是H；
R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基，优选地选自氯、甲基、和甲氧基；
R 4选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷酰基、C 1-6烷基氨基羰基、C 3-6环烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、羟基C 1-6烷基氨基羰基、苯烷基、苯基氨基羰基、苯基烷基氨基羰基、吡啶基氨基羰基、和氨基保护基，其中氨基任选被氨基保护基取代，上述取代基任选地被氨基、氨基保护基取代的氨基、羟基或卤素取代，R 4优选地选自C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷 基氨基羰基、苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基，更优选地选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
本发明所述的氨基保护基选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基。
本发明进一步涉及一种式(II)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
Figure PCTCN2019072281-appb-000004
其中，X选自CH或N；
R 1和R 2至少一个为H，另一个选自H、C 1-6烷基、卤素、和C 1-6卤代烷基，更优选地选自H、甲基、2-丙基、氟、氯、和三氟甲基，最优选R 1和R 2都是H；
R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基，优选地选自氯、甲基、和甲氧基；
R 4选自H、任选地被氨基取代的C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、任选地被卤素取代的苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基，优选地选自优选地选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
本发明所涉及含有手性的化合物，其构型可以是任意构型或者混合的外消旋体。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐、通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙 二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱或无机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺，等等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发、或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物组合物及其用途
本申请提供配制用于通过适当的途径和方式给药的药物组合物，该药物组合物包含有效浓度的本文提供的一种或多种化合物、或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，以及药学可接受的载体或赋形剂，以及任选的其它治疗剂。
游离形式或盐形式的式(I)或式(II)的化合物在下文中又称为“本发明的物质”，由于它们对磷脂酰肌醇3-激酶的抑制作用，游离形式或可药用盐形式的式(I)或式(II)的化合物可用于治疗由PI3K激酶家族的一个或多个成员的激活(包括正常活性，尤其是过度活化)所介导的疾病、障碍或病症，例如增殖性疾病、癌症、炎性疾病或过敏性 疾病、阻塞性呼吸道疾病和/或与移植有关的病症。
由于游离形式或盐形式的“本发明的物质”对恶性疟原虫的磷脂酰肌醇4-激酶的抑制作用，游离形式或可药用盐形式的式(I)或式(II)的化合物可用于治疗由PfPI4K激酶家族的一个或多个成员的激活(包括正常活性，尤其是过度活化)所介导的疾病、障碍或病症，例如恶性疟疾。
本发明的“治疗”可以是治疗性的(如对症治疗)和/或预防性的。
优选用于治疗增殖性疾病的用途，所述的增殖性疾病选自良性或恶性肿瘤，包括但不限于：脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、淋巴癌、胃癌、胃肿瘤、食道癌、卵巢癌、结直肠癌、***癌、胰腺癌、肺癌、***癌、膜腺癌、甲状腺癌、颈癌、CNS癌症、恶性胶质瘤、骨髓增生病、肉瘤、成胶质细胞瘤、多发性骨髓瘤、胃肠癌、头颈肿瘤、脑瘤、表皮过度增生、银屑病、***增生、瘤形成、上皮特征的瘤形成、淋巴瘤、或白血病。其它疾病包括考登综合征(Cowden syndrome)、莱尔米-杜伯斯(Lhermitte-Dudos)疾病和Bannayan-Zonana综合征或其中PI3K/PKB通路被异常激活的疾病。优选地治疗结直肠癌、胃癌、乳腺癌、肺癌、肝癌、***癌、膜腺癌、甲状腺癌、膀胱癌、肾癌、脑瘤、颈癌、CNS癌症、恶性胶质瘤、骨髓增生病、白血病和淋巴癌。
本发明的物质可用于治疗炎性或阻塞性气道疾病，导致例如组织损伤、气道炎症、支气管反应过度、重塑或疾病发展的减轻。本发明适用的炎性或阻塞性气道疾病包括任何类型或起因的哮喘，包括内源性(非变应性)哮喘和外源性(变应性)哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管炎性哮喘、运动诱发的哮喘、职业性哮喘和细菌感染后诱发的哮喘。哮喘的治疗还应理解为包括对个体的治疗，例如小于4或5岁的个体，其显示出喘鸣症状，被诊断为或可诊断为“喘鸣婴儿(wheezy infant)”，这是一种已确定的主要医疗关注中的患者分类，现在通常鉴定为初期或早期哮喘。为方便，这种特殊的哮喘病症被称为“喘鸣婴儿综合征”。
在哮喘治疗中的预防功效将表现为症状发作频率的减少或严重程度的减轻，例如急性哮喘或支气管收缩发作频率的减少或严重程度的 减轻、肺功能改善或气道过度活动改善。所述功效还表现为对其它症状治疗需求的减少，所述的其它症状治疗即用于或旨在在其发生时限制或中止症状发作的治疗，例如抗炎药(例如皮质类固醇)或支气管扩张药。在有“晨降(morning dipping)”倾向的个体中对哮喘的预防益处可能特别明显。“晨降”是一种公认的哮喘综合征，通常在哮喘中占很大比例，其特征是例如在早晨约4至6点之间发作，即，通常在距离以前施用的任意针对哮喘症状的治疗较远的时间发作。
本发明适用的其它炎性或阻塞性气道疾病和病症包括急性肺损伤(ALI)、成人型/急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺病、气道或肺疾病(COPD、COAD或COLD)，包括慢性支气管炎或与之有关的呼吸困难、肺气肿，以及由其它药物治疗、特别是其它吸入药物治疗导致的气道过度活动恶化。本发明还适于治疗任何类型或起因的支气管炎，包括例如急性支气管炎、花生仁吸入性支气管炎、卡他性支气管炎、纤维蛋白性支气管炎、慢性支气管炎或结核性支气管炎。本发明适用的其它炎性或阻塞性气道疾病包括任何类型或起因的尘肺(一种炎性、通常为职业性的肺病，不论是慢性还是急性的经常伴有气道阻塞，且由重复吸入灰尘引起)，包括例如矾土肺、炭肺、石棉肺、石末肺、驼鸟毛尘肺、铁沉肺、矽肺、烟尘肺和棉尘肺。
本发明的物质还用于治疗由磷脂酰肌醇3-激酶介导的下述疾病、障碍或病症：呼吸***疾病、***反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、***性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、***瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、***状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、***癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、 肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、***癌、***、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
本发明的物质还可用于治疗与嗜酸粒细胞相关的病症，例如嗜酸粒细胞增多，特别是与嗜酸粒细胞相关的气道病症(例如涉及病态嗜酸粒细胞浸润的肺组织)，包括嗜酸细胞过多，因为其影响气道和/或肺，以及例如由勒夫勒综合征、嗜酸细胞性肺炎、寄生虫(特别是后生动物)侵染(包括热带嗜酸粒细胞增多症)、支气管肺曲霉病、结节性多动脉炎(包括丘-斯综合征)、嗜酸细胞肉芽肿引起的或与其相并行的与嗜酸粒细胞相关的气道病症，和药物反应导致的影响气道的与嗜酸粒细胞相关的病症。
本发明的物质还可用于治疗皮肤的炎性或变应性病症，例如银屑病、接触性皮炎、特应性皮炎、局限性脱发、多形红斑、疱疹样皮炎、硬皮病、白斑、变应性血管炎、荨麻疹、大疱性类天疱疮、红斑狼疮、天疱疮(pemphisus)、获得性大疱性表皮松解症和其它皮肤的炎性或变应性病症。
本发明的物质还可用于治疗其它疾病或病症，特别是具有炎性成份的疾病或病症，例如治疗眼的疾病和病症，如结膜炎、干燥性角膜结膜炎和春季结膜炎；影响鼻的疾病，包括变应性鼻炎；以及其中涉及自身免疫反应或具有自身免疫性成份或病因学的炎性疾病，包括自身免疫性血液学病症(例如溶血性贫血、再生障碍性贫血、纯红细胞贫血和特发性血小板减少)、***性红斑狼疮、多发性软骨炎、硬皮病、韦格纳肉芽肿病、皮肌炎、慢性活动性肝炎、重症肌无力、斯-约综合征、特发性口炎性腹泻、自身免疫性炎性肠病(例如溃疡性结肠炎和局限性回肠炎)、内分泌性眼病、格雷夫斯病、结节病、肺泡炎、慢性变应性肺炎、多发性硬化症、原发性胆汁性肝硬化、眼色素层炎(前眼色素层炎和后眼色素层炎)、干燥性角膜结膜炎和春季角膜结膜炎、间质性肺纤维化、银屑病关节炎和肾小球肾炎(伴有和不伴有肾病综合征，例如包括特发性肾病综合征或微小病变肾病)。
其它可以用本发明的物质治疗的疾病或病症包括败血症性休克、类风湿性关节炎、骨关节炎、增殖性疾病如癌、动脉粥样硬化、移植 后的同种异体移植物排斥反应、中风、肥胖症、再狭窄、糖尿病例如I型糖尿病(幼年型糖尿病)和II型糖尿病、腹泻疾病、局部缺血/再灌注损伤、视网膜病变如糖尿病性视网膜病变或高压氧诱发的视网膜病变，以及以眼内压升高或眼房水分泌为特征的病症，如青光眼。
本发明的物质在抑制炎性病症例如炎性气道疾病方面的有效性可以在动物模型中得到证明，例如气道炎症或其它炎性病症的小鼠或大鼠模型，例如如Szarka等,J.Immunol.Methods(1997)202:49-57；Renzi等,Am.Rev.Respir.Dis.(1993)148:932-939；Tsuyuki等,J.Clin.1nvest.(1995)96:2924-2931；和Cernadas等,Am.J.Respir.Cell Mol.Biol.(1999)20:1-8中所述。
本发明的物质还可作为联用治疗剂用于与其它药物物质组合使用，如抗炎药、支气管扩张药或抗组胺药药物物质，特别是用于治疗阻塞性或炎性气道疾病，如上文所提及的那些，例如作为这些药物治疗活性的增效剂或作为减少这些药物所需给药剂量或潜在副作用的手段。本发明的物质可以与其它药物物质在固定药物组合物中混合，或者可以在其它药物物质施用之前、同时或之后单独施用。本发明包括上文所述的本发明的物质与抗炎药、支气管扩张药或抗组胺药药物物质的组合，所述的本发明的物质和所述的药物物质可以在相同或不同的药物组合物中。这样的抗炎药包括类固醇，特别是糖皮质类固醇如布地缩松、丙酸倍氯米松、丙酸氟地松、环缩松或糠酸菜米他松、以及WO 0200679、WO 0288167、WO 0212266和WO 02100879中所述的化合物、LTB4拮抗剂如US5451700中所述的那些、LTD4拮抗剂如孟鲁司特和扎鲁司特、多巴胺受体激动剂如卡麦角林、溴隐亭、累匹利洛和4-羟基7-[2-[[2-[[3-(2-苯基乙氧基)-丙基]-磺酰基]-乙基]-氨基]乙基]-2(3H)-苯并噻唑酮及其可药用盐(盐酸盐为
Figure PCTCN2019072281-appb-000005
-AstraZeneca)，和PDE4抑制剂如
Figure PCTCN2019072281-appb-000006
(GlaxoSmithKline)、罗氟司特(Byk Gulden)、V-11294A(Napp)、BAY19-8004(Bayer)、SCH-351591(Schering-Plough)、阿罗茶碱(AlmirallProdesfarma)、PD189659(Parke-Davis)、AWD-12-281(AstaMedica)、CDC-801(Celgene)和KW-4490(Kyowa Hakko Kogyo)以及WO 98/18796和WO 03/39544中所述的那些。这样的支气管扩张药包括抗胆碱能药或抗毒蕈碱药，特别是异丙托品、溴乙东莨菪碱和 噻托铵盐，还有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和WO 03/33495中所述的那些，以及β-2肾上腺素受体激动剂如沙丁胺醇、特布他林、沙美特罗和福莫特罗及其可药用盐，和PCT国际专利公布WO 00/75114(将该文献引入本文作为参考)中的式I化合物(游离形式或盐形式或溶剂合物形式)，优选其实施例的化合物联用治疗的抗组胺药药物物质包括盐酸西替利嗪、扑热息痛、富马酸氯马斯丁、异丙嗪、氯雷他定、地氯雷他定(desloratidine)、苯海拉明和盐酸非索那丁。本发明的物质与类固醇、β-2激动剂、PDE4抑制剂或LTD4拮抗剂的组合可用于例如治疗COPD或特别是哮喘。本发明的物质与抗胆碱能药或抗毒蕈碱药、PDE4抑制剂、多巴胺受体激动剂或LTB4拮抗剂的组合可用于例如治疗哮喘或特别是COPD。本发明的物质与抗炎药的其它有用的组合是与趋化因子受体拮抗剂例如CCR-l、CCR-2、CCR-3、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9、CCR10、CXCRl、CXCR2、CXCR3、CXCR4、CXCR5、特别是CCR-5的拮抗剂的组合，所述拮抗剂例如Schering-Plough拮抗剂SC-351125、SCH-55700和SCH-D，Takeda拮抗剂如N-[[4-[[[6,7-二氢-2-(4-甲基苯基)-5H-苯并环庚烯-8-基]羟基]氨基]苯基]-甲基]四氢-N,N-二甲基-2H-吡喃-4-氯化铵(TAK-770)，和US6166037(特别是权利要求18和19)、WO 00/66558(特别是权利要求8)和WO 00/66559(特别是权利要求9)中所述的CCR-5拮抗剂。
本发明的物质可以通过任何适当的途径施用，例如口服施用，如以片剂或胶囊剂形式口服施用；胃肠外例如静脉内施用；通过吸入施用，例如在炎性或阻塞性气道疾病的治疗中；鼻内施用，例如在变应性鼻炎的治疗中；对皮肤局部施用，例如在特应性皮炎的治疗中；或直肠施用，例如在炎性肠病的治疗中。
本发明还提供了药物组合物，其包含游离形式或可药用盐形式的本发明化合物，任选地以及合适的可药用的稀释剂或载体。该组合物可以含有联用治疗剂，如上文所述的抗炎药、支气管扩张药或抗组胺药。这样的组合物可以使用常规的稀释剂或赋形剂和盖伦制剂领域中已知的技术制备。因此，口服剂型可以包括片剂和胶囊剂。
用于局部施用的制剂可以采用乳膏剂、软膏剂、凝胶剂或透皮递送***例如贴剂的形式。用于吸入的组合物可以包括气雾剂或其它可雾化的制剂或干粉制剂。
当组合物包括气雾剂制剂时，其优选含有例如氢-氟-烷烃(HFA)抛射剂如HFA134a或HFA227或这些的混合物，可以含有一种或多种本领域已知的助溶剂如乙醇(以重量计至多20％)，和/或一种或多种表面活性剂如油酸或脱水山梨糖醇三油酸酶，和/或一种或多种填充剂如乳糖。当组合物包括干粉剂时，其优选含有例如具有不超过10微米粒径的本发明化合物，任选地和具有所需粒径分布的稀释剂或载体如乳糖，以及有助于防止产品性质因受潮而变差的化合物。当组合物包括喷雾制剂时，其优选含有例如溶解或混悬在介质中的本发明化合物，所述介质含有水、助溶剂如乙醇或丙二醇以及稳定剂，其可以是表面活性剂。
在实施本发明中所用的本发明物质的剂量将根据例如所治疗的具体病症、所希望的效果和施用方式的不同而变化。通常，口服施用的合适剂量为0.1至10毫克/kg级别。
在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)和式(II)的化合物。另 外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中，本文提供的是本文描述的PI3K和/或PfPI4K激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
制备的本发明的化合物的非限制性实施例参见表1。
表1.实施例化合物的结构
Figure PCTCN2019072281-appb-000007
Figure PCTCN2019072281-appb-000008
Figure PCTCN2019072281-appb-000009
Figure PCTCN2019072281-appb-000010
Figure PCTCN2019072281-appb-000011
实施例
以下具体的非限制性实施例将被解释为仅仅是说明性的，并不以任何方式限制本公开。虽然无需进一步详细描述，但是可以相信本领域技术人员能基于本文的描述，完全利用本公开。
实施例1：(S)-(1-((4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸叔丁酯
Figure PCTCN2019072281-appb-000012
(4-(5-氨基-6-氯吡啶-3-基)苯基)氨基甲酸叔丁酯(2)：在圆底烧瓶中加入5-溴-2-氯吡啶-3-胺(219毫克)后加入1,4-二氧六环(8毫升)、水(4毫升)、(4-((叔丁氧基羰基)氨基)苯基)硼酸(300毫克)、Pd(PPh 3) 4(37毫克)、碳酸钾(300毫克)。反应体系在氩气保护下80度反应14 小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(2)，LC/MS：M+H 320.12。
(4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)氨基甲酸叔丁酯(3)：在圆底烧瓶中加入(4-(5-氨基-6-氯吡啶-3-基)苯基)氨基甲酸叔丁酯(240毫克)后加入吡啶(2毫升)和苯磺酰氯(0.57毫升)。反应体系在氩气保护下常温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(3)，LC/MS：M+H 460.11。
N-(5-(4-氨基苯基)-2-氯吡啶-3-基)苯磺酰胺(4)：在圆底烧瓶中加入(4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)氨基甲酸叔丁酯(100毫克)后加入盐酸的乙酸乙酯(4毫升)和甲醇(1毫升)溶液。反应体系常温反应0.5小时。反应结束后，体系在减压下蒸干溶剂得到化合物(4)，LC/MS：M+H 360.06。
(S)-(1-((4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸叔丁酯(5)：在圆底烧瓶中加入N-(5-(4-氨基苯基)-2-氯吡啶-3-基)苯磺酰胺(60毫克)后加入N,N-二甲基甲酰胺(2毫升)、(叔丁氧羰基)-L-缬氨酸(38毫克)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU(78毫克)和N,N-二异丙基乙胺(0.2毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(5)，LC/MS：M+H 559.18。
实施例2：(S)-2-氨基-N-(4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)-3-甲基丁酰胺
Figure PCTCN2019072281-appb-000013
在圆底烧瓶中加入(S)-(1-((4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)苯基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸叔丁酯(50毫克)后加入盐酸的乙酸乙酯(2毫升)和甲醇(1毫升)溶液。反应体系常温反应0.5小时。反应结束后，体系在减压下蒸干溶剂得到实施例2的化合物(6)，LC/MS：M+H 459.13。
实施例3：(S)-(1-(5-(6-氯-5-(苯基磺酰胺)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-1-基)-3-甲基-1-氧代丁-2-基)氨基甲酸叔丁酯
Figure PCTCN2019072281-appb-000014
1-(5-溴-1H-吡咯并[2,3-b]吡啶-1-基)乙-1-酮(8)：在圆底烧瓶中加入5-溴-1H-吡咯并[2,3-b]吡啶(5.0克)后加入无水二氯甲烷(80毫升)、三乙胺(3.6毫升)，然后用冰水浴使体系冷却到0度。接着缓慢加入乙酰氯。反应体系在室温下、氩气保护反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用二氯甲烷萃取。有机相用分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得化合物(8)，LC/MS：M+H 238.98。
1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-基)乙-1-酮(9)：在圆底烧瓶中加入1-(5-溴-1H-吡咯并[2,3-b]吡啶-1-基)乙-1-酮(2.5g)后加入1,4-二氧六环(80毫升)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼烷)(5.3g)、PdCl 2(dppf) 2(257毫克)和醋酸钾(3.1g)。反应体系在氩气保护下加热至80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提 纯后得化合物(9)，LC/MS：M+H 287.16。
2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)吡啶-3-胺(10)：在圆底烧瓶中加入5-溴-2-氯吡啶-3-胺(1.5g)后加入1,4-二氧六环(80毫升)、水(15毫升)、1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-基)乙-1-酮(2.5g)、Pd(PPh 3) 4(200毫克)、碳酸钾(2.5g)。反应体系在氩气保护下80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(10)，LC/MS：M+H 245.06。
N-(2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)吡啶-3-基)苯磺酰胺(11)：在圆底烧瓶中加入2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)吡啶-3-胺(300毫克)后加入吡啶(8毫升)和苯磺酰氯(0.25毫升)。反应体系在氩气保护下常温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(11)，LC/MS：M+H 385.05。
(S)-(1-(5-(6-氯-5-(苯基磺酰胺)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-1-基)-3-甲基-1-氧代丁-2-基)氨基甲酸叔丁酯(12)：在圆底烧瓶中加入N-(2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)吡啶-3-基)苯磺酰胺(80毫克)后加入N,N-二甲基甲酰胺(3毫升)、(叔丁氧羰基)-L-缬氨酸(48毫克)、HATU(95毫克)和N,N-二异丙基乙胺(0.25毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(12)，LC/MS：M+H 584.18。
实施例4：4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯
Figure PCTCN2019072281-appb-000015
实施例4化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1) +：450.13。
实施例5：N-(2-氯-5-(1,2,3,6-四氢吡啶-4-基)吡啶-3-基)苯磺酰胺盐酸盐
Figure PCTCN2019072281-appb-000016
在圆底烧瓶中加入4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(100毫克)后加入盐酸的乙酸乙酯(3毫升)和甲醇(1毫升)溶液。反应体系常温反应0.5小时。反应结束后，体系在减压下蒸干溶剂得到实施例5的化合物，LC/MS：M+H 350.08。
实施例6：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基烟酰胺
Figure PCTCN2019072281-appb-000017
5-(5-氨基-6-氯吡啶-3-基)-N-甲基烟酰胺：在圆底烧瓶中加入5-溴-2-氯吡啶-3-胺(90毫克)后加入1,4-二氧六环(4毫升)、水(1毫升)、N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)烟酰胺(135毫克)、Pd(PPh 3) 4(16毫克)、碳酸钾(155毫克)。反应体系在氩气保护下80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得5-(5-氨基-6-氯吡啶-3-基)-N-甲基烟酰胺，LC/MS：M+H 263.07。
5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基烟酰胺：在圆底烧瓶中加入5-(5-氨基-6-氯吡啶-3-基)-N-甲基烟酰胺(41毫克)后加入吡啶(2毫升)和苯磺酰氯(0.15毫升)。反应体系在氩气保护下常温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得实施例6的化合物，LC/MS：M+H 403.06。
实施例7：N-(5-(1-乙酰基-1H-吡咯并[2,3-b]吡啶-5-基)-2-氯吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000018
实施例7的化合物的合成通过使用类似于实施例3中所述的步骤完成。MS(ESI)m/z(M+1) +：427.07。
实施例8：N-(2-氯-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000019
实施例8的化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1) +：349.05。
实施例9：N-(2-氯-5-(异喹啉-4-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000020
实施例9的化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1) +：396.06。
实施例10：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N,N-二甲基烟酰胺
Figure PCTCN2019072281-appb-000021
实施例10的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：417.08。
实施例11：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-环丙基烟酰胺
Figure PCTCN2019072281-appb-000022
实施例11的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：429.08。
实施例12：N-叔丁基-5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺
Figure PCTCN2019072281-appb-000023
实施例12的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：445.11。
实施例13：5-(4-氯-3-(苯基磺酰氨基)苯基)-N-甲基烟酰胺
Figure PCTCN2019072281-appb-000024
N-(5-溴-2-氯苯基)苯磺酰胺(26)：在圆底烧瓶中加入5-溴-2-氯苯胺(3.0g)后加入吡啶(15毫升)和苯磺酰氯(2.8g)。反应体系在氩气保护下常温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(26)，LC/MS：M+H 345.93。
5-(4-氯-3-(苯基磺酰氨基)苯基)烟酸(27)：在圆底烧瓶中加入N-(5-溴-2-氯苯基)苯磺酰胺(690毫克)后加入1,4-二氧六环(5毫升)、水 (5毫升)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)烟酸乙酯(500毫克)、Pd(PPh 3) 4(200毫克)、碳酸钾(570毫克)。反应体系在氩气保护下80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(27)，LC/MS：M+H 389.04。
5-(4-氯-3-(苯基磺酰氨基)苯基)-N-甲基烟酰胺(28)：在圆底烧瓶中加入5-(4-氯-3-(苯基亚磺酰氨基)苯基)烟酸(50毫克)后加入无水四氢呋喃(2毫升)、草酰氯(140毫克)、N,N-二甲基甲酰胺(1滴)，反应体系在氩气保护下室温反应2小时。然后，向体系中加入甲胺(360毫克)，室温下搅拌1小时。体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(28)，LC/MS：M+H 402.07。
实施例14：N-甲基-5-(6-甲基-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺
Figure PCTCN2019072281-appb-000025
N-(5-溴-2-甲基吡啶-3-基)苯磺酰胺(30)：在圆底烧瓶中加入5-溴-2-甲基吡啶-3-胺(1.5g)后加入吡啶(10毫升)和苯磺酰氯(1.56g)。反应体系在氩气保护下常温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(30)，LC/MS：M+H 326.99。
5-(6-甲基-5-(苯基磺酰氨基)吡啶-3-基)烟酸(31)：在圆底烧瓶中加 入N-(5-溴-2-甲基吡啶-3-基)苯磺酰胺(650毫克)后加入1,4-二氧六环(5毫升)、水(5毫升)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)烟酸甲酯(500毫克)、Pd(PPh 3) 4(200毫克)、碳酸钾(570毫克)。反应体系在氩气保护下80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(31)，LC/MS：M+H 370.09。
N-甲基-5-(6-甲基-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺(32)：在圆底烧瓶中加入5-(6-甲基-5-(苯基磺酰氨基)吡啶-3-基)烟酸(50毫克)后加入无水四氢呋喃(2毫升)、草酰氯(140毫克)、N,N-二甲基甲酰胺(1滴)，反应体系在氩气保护下室温反应2小时。然后，向体系中加入甲胺(360毫克)，室温下搅拌1小时。体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(32)，LC/MS：M+H 383.12。
实施例15：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-甲酸叔丁酯
Figure PCTCN2019072281-appb-000026
实施例15的化合物的合成通过使用类似于实施例3中所述的步骤完成。MS(ESI)m/z(M+1) +：486.10。
实施例16：N-(2-氯-5-(1H-吡唑并[3,4-b]吡啶-5-基)吡啶-3-基)苯磺酰胺盐酸盐
Figure PCTCN2019072281-appb-000027
实施例16的化合物的合成通过使用类似于实施例15中所述的步骤完成。MS(ESI)m/z(M+1) +：386.05。
实施例17：3-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基苯甲酰胺
Figure PCTCN2019072281-appb-000028
实施例17的化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1) +：402.07。
实施例18：N-(2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000029
实施例18的化合物的合成通过使用类似于实施例7中所述的步骤完成。MS(ESI)m/z(M+1) +：385.05。
实施例19：5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基烟酰胺
Figure PCTCN2019072281-appb-000030
N-(5-溴-2-氟吡啶-3-基)苯磺酰胺(38)：在圆底烧瓶中加入5-溴-2-氟吡啶-3-胺(2.0g)后加入吡啶(10毫升)和苯磺酰氯(1.5毫升)。反应体系在氩气保护下常温反应20小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(38)，LC/MS：M+H 330.96。
5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)烟酸乙酯(39)：在圆底烧瓶中加入N-(5-溴-2-氟吡啶-3-基)苯磺酰胺(331毫克)后加入1,4-二氧六环(1毫升)、5-(乙氧基羰基)吡啶-3-基硼酸(332毫克)、PdCl 2(dppf) 2(81.6毫克)、乙酸钾(294毫克)。反应体系在氩气保护下100℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(39)，LC/MS：M+H 402.09。
5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)烟酸(40)：在圆底烧瓶中加入5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)烟酸乙酯(100毫克)后加入乙醇(4毫升)和水(1毫升)，反应体系在氩气保护下室温反应5小时。然后，向体系中加入氢氧化钠(360毫克)，室温下搅拌1小时。体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(40)，LC/MS：M+H 383.12。
5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基烟酰胺(41)：在圆底烧瓶中加入5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)烟酸(40毫克)后加入无水四氢呋喃(1毫升)、甲胺盐酸盐(14毫克)、HATU(76毫克)、N,N-二异丙基乙胺(0.1毫升)。反应体系在氩气保护下室温反应14小时。体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(41)，LC/MS：M+H 387.09。
实施例20：4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基苯甲酰胺
Figure PCTCN2019072281-appb-000031
实施例20的化合物的合成通过使用类似于实施例18中所述的步骤完成。MS(ESI)m/z(M+1) +：402.07。
实施例21：4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基吡啶酰氨
Figure PCTCN2019072281-appb-000032
实施例21的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：403.07。
实施例22：N-(2-氯-5-(吡啶-3-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000033
实施例22的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：346.04。
实施例23：N-(2-氯-5-(吡啶-4-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000034
实施例23的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：346.04。
实施例24：N-(2-氯-5-(6-甲氧基吡啶-3-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000035
实施例24的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：376.05。
实施例25：N-(5-(1-苄基-1H-吡唑-4-基)-2-氯吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000036
实施例25的化合物的合成通过使用类似于实施例8中所述的步骤完成。MS(ESI)m/z(M+1) +：425.09。
实施例26：N-(2-氯-5-(2-甲氧基吡啶-3-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000037
实施例26的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：376.05。
实施例27：N-(5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)-2-(二甲氨基)乙酰胺
Figure PCTCN2019072281-appb-000038
N-(5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺(54)：在圆底烧瓶中加入N-(5-溴-2-氯吡啶-3-基)苯磺酰胺(200毫克)后加入1,4-二氧六环(5毫升)、N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)乙酰胺(165毫克)、PdCl 2(dppf) 2(47毫克)和醋酸钾(134毫克)。反应体系在氩气保护下加热至80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(54)，LC/MS： M+H 403.07。
N-(5-(5-氨基吡啶-3-基)-2-氯吡啶-3-基)苯磺酰胺(55)：在圆底烧瓶中加入N-(5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺(150毫克)后加入甲醇(5毫升)和6M盐酸溶液(2毫升)。反应体系在氩气保护下加热至80℃反应6小时。反应结束后，体系在减压下蒸干溶剂得到固体化合物(55)。LC/MS：M+H 361.05。
N-(5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)-2-(二甲氨基)乙酰胺(56)：在圆底烧瓶中加入N-(5-(5-氨基吡啶-3-基)-2-氯吡啶-3-基)苯磺酰胺(35毫克)后加入四氢呋喃(1毫升)、2-(二甲氨基)乙酸(18毫克)、HATU(67毫克)和N,N-二异丙基乙胺(0.1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(56)，LC/MS：M+H 446.11。
实施例28：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-乙基烟酰胺
Figure PCTCN2019072281-appb-000039
5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酸乙酯(57)：在圆底烧瓶中加入N-(5-溴-2-氯吡啶-3-基)苯磺酰胺(1.0g)后加入1,4-二氧六环(10毫升)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)烟酸乙酯(0.84g)、PdCl 2(dppf) 2(0.23g)和醋酸钾(0.68g)。反应体系在氩气保护下加热至80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无 水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(57)，LC/MS：M+H 418.07。
5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酸(58)：在圆底烧瓶中加入5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酸乙酯(1.2g)后加入乙醇(5毫升)和1M氢氧化钠溶液(5毫升)。反应体系在氩气保护下加热至80℃反应10小时。反应结束后，体系在减压下蒸干溶剂，所得物用水(50毫升)稀释后用1M盐酸调节pH到3。沉淀物过滤干燥得到化合物(58)，LC/MS：M+H 390.03。
5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-乙基烟酰胺(59)：在圆底烧瓶中加入5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酸(50毫克)后加入四氢呋喃(1毫升)、乙胺盐酸盐(21毫克)、HATU(99毫克)和N,N-二异丙基乙胺(0.11毫升)。反应体系在氩气保护下室温反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(59)，LC/MS：M+H 417.08。
实施例29：2-(3-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰氨基)乙基氨基甲酸叔丁酯
Figure PCTCN2019072281-appb-000040
实施例29的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：532.14。
实施例30：(R)-2-(3-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰氨基)丙基氨基甲酸叔丁酯
Figure PCTCN2019072281-appb-000041
实施例30的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：546.16。
实施例31：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-(2-羟基-2-甲基丙基)烟酰胺
Figure PCTCN2019072281-appb-000042
实施例31的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：461.11。
实施例32：N-(2-氨基乙基)-5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺盐酸盐
Figure PCTCN2019072281-appb-000043
实施例32的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：468.07。
实施例33：N-((R)-1-氨基丙-2-基)-5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺盐酸盐
Figure PCTCN2019072281-appb-000044
实施例33的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：482.08。
实施例34：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-苯基烟酰胺
Figure PCTCN2019072281-appb-000045
实施例34的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：465.08。
实施例35：N-苄基-5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)烟酰胺
Figure PCTCN2019072281-appb-000046
实施例35的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：479.10。
实施例36：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-(4-氟苯基)烟酰胺
Figure PCTCN2019072281-appb-000047
实施例36的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：483.07。
实施例37：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-(3-氟苯基)烟酰胺
Figure PCTCN2019072281-appb-000048
实施例37的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：483.07。
实施例38：5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-(吡啶-2-基)烟酰胺
Figure PCTCN2019072281-appb-000049
实施例38的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：466.08。
实施例39：N-(5-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000050
实施例39的化合物的合成通过使用类似于实施例27中所述的步骤完成。MS(ESI)m/z(M+1) +：403.07。
实施例40：4-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-N-甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019072281-appb-000051
实施例40的化合物的合成通过使用类似于实施例28中所述的步骤完成。MS(ESI)m/z(M+1) +：391.07。
实施例41：5-(5-(4-(叔丁基)苯基磺酰氨基)-6-氯吡啶-3-基)-N-甲基烟酰胺
Figure PCTCN2019072281-appb-000052
实施例41的化合物的合成通过使用类似于实施例6中所述的步骤完成。MS(ESI)m/z(M+1) +：459.13。
实施例42：N-(5-(4-氯-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000053
N-(5-(4-氯-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺(80)：在圆底烧瓶中加入N-(5-溴-2-氯苯基)苯磺酰胺(63毫克)后加入1,4-二氧六环(1毫升)、N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)乙酰胺(50毫克)、PdCl 2(dppf) 2(15毫克)、乙酸钾(42毫克)。反应体系在氩气保护下80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(80)，LC/MS：M+H 402.07。
实施例43：N-(5-(6-氟-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000054
实施例43的化合物的合成通过使用类似于实施例39中所述的步骤完成。MS(ESI)m/z(M+1) +：387.09。
实施例44：N-(5-(6-甲基-5-(苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000055
实施例44的化合物的合成通过使用类似于实施例39中所述的步骤完成。MS(ESI)m/z(M+1) +：383.12。
实施例45：5-(6-氯-5-(4-(异丙基)苯基磺酰氨基)吡啶-3-基)-N-甲基烟酰胺
Figure PCTCN2019072281-appb-000056
实施例45的化合物的合成通过使用类似于实施例41中所述的步骤完成。MS(ESI)m/z(M+1) +：445.11。
实施例46：N-(5-(4-氟-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000057
实施例46的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：386.10。
实施例47：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000058
实施例47的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：382.12。
实施例48：N-(5-(3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000059
实施例48的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：368.11。
实施例49：N-(5-(6-氯-5-(2,6-二氟苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000060
实施例49的化合物的合成通过使用类似于实施例39中所述的步骤完成。MS(ESI)m/z(M+1) +：439.05。
实施例50：N-(5-(6-氯-5-(2-氟苯基磺酰氨基)吡啶-3-基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000061
实施例50的化合物的合成通过使用类似于实施例39中所述的步骤完成。MS(ESI)m/z(M+1) +：421.06。
实施例51：N-(5-(4-甲氧基-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000062
实施例51的化合物的合成通过使用类似于实施例39中所述的步骤完成。MS(ESI)m/z(M+1)+:398.12。
实施例52：N-(5-(4-氯-3-(2,6-二氟苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000063
实施例52的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：438.05。
实施例53：N-(5-(4-氯-3-(2-氟苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000064
实施例53的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：420.06。
实施例54：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)丙酰胺
Figure PCTCN2019072281-appb-000065
N-(5-(5-氨基吡啶-3-基)-2-甲基苯基)苯磺酰胺(93)：在圆底烧瓶中加入N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺(1.7克)后加入甲醇(20毫升)和盐酸(20毫升)。反应体系在氩气保护下80℃反应4小时。反应结束后，体系在减压下蒸干溶剂得到固体化合物(93)。LC/MS：M+H 340.11。
N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)丙酰胺(94)：在圆底烧瓶中加入N-(5-(5-氨基吡啶-3-基)-2-甲基苯基)苯磺酰胺(30毫克)后加入丙酸酐(0.5毫升)。反应体系在氩气保护下85℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物(94)，LC/MS：M+H 396.14。
实施例55：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)新戊酰胺
Figure PCTCN2019072281-appb-000066
实施例55的化合物的合成通过使用类似于实施例54中所述的步骤完成。MS(ESI)m/z(M+1) +：424.17。
实施例56：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)异丁酰胺
Figure PCTCN2019072281-appb-000067
实施例56的化合物的合成通过使用类似于实施例54中所述的步骤完成。MS(ESI)m/z(M+1) +：410.16。
实施例57：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)丁酰胺
Figure PCTCN2019072281-appb-000068
实施例57的化合物的合成通过使用类似于实施例54中所述的步骤完成。MS(ESI)m/z(M+1) +：410.16。
实施例58：N-(5-(4-甲基-3-(苯基磺酰氨基)苯基)吡啶-3-基)戊酰胺
Figure PCTCN2019072281-appb-000069
实施例58的化合物的合成通过使用类似于实施例54中所述的步骤完成。MS(ESI)m/z(M+1) +：424.17。
实施例59：2-(6-氯-5-(苯基磺酰氨基)吡啶-3-基)-1H-吲哚-1-羧酸叔丁酯
Figure PCTCN2019072281-appb-000070
实施例59的化合物的合成通过使用类似于实施例4中所述的步骤完成。MS(ESI)m/z(M+1) +：484.11。
实施例60：N-(2-氯-5-(1H-吲哚-2-基)吡啶-3-基)苯磺酰胺盐酸盐
Figure PCTCN2019072281-appb-000071
实施例60的化合物的合成通过使用类似于实施例5中所述的步骤完成。MS(ESI)m/z(M+1) +：384.06。
实施例61：N-(2-氯-5-(4-(三氟甲氧基)苯基)吡啶-3-基)苯磺酰胺
Figure PCTCN2019072281-appb-000072
实施例61的化合物的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1) +：429.03。
实施例62：N-(5-(4-甲基-3-(3-甲基-苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000073
实施例62的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：396.14。
实施例63：N-(5-(4-甲基-3-(3-三氟甲基-苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000074
实施例63的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：450.11。
实施例64：N-(5-(4-甲基-3-(4-甲基-苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000075
实施例64的化合物的合成通过使用类似于实施例42中所述的步 骤完成。MS(ESI)m/z(M+1) +：396.14。
实施例65：N-(5-(4-甲基-3-(2-甲基-苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000076
实施例65的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1)+：396.14。
实施例66：N-(5-(3-(4-异丙基-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000077
实施例66的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：424.17。
实施例67：N-(5-(3-(3,4-二氯-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000078
实施例67的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：450.05。
实施例68：N-(5-(4-甲基-3-(2-三氟甲基-苯基磺酰氨基)苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000079
实施例68的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：450.11。
实施例69：N-(5-(3-(2,4-二氟-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000080
实施例69的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：418.11。
实施例70：N-(5-(3-(2,3-二氯-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000081
实施例70的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：450.05。
实施例71：N-(5-(3-(3-氯-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000082
实施例71的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：416.09。
实施例72：N-(5-(3-(2,5-二甲基-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000083
实施例72的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：410.16。
实施例73：N-(5-(3-(2-氯-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000084
实施例73的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：416.09。
实施例74：N-(5-(3-(2,4-二甲基-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000085
实施例74的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：410.16。
实施例75：N-(5-(3-(3,4-二氟-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000086
实施例75的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：418.11。
实施例76：N-(5-(3-(4-氯-苯基磺酰氨基)-4-甲基苯基)吡啶-3-基)乙酰胺
Figure PCTCN2019072281-appb-000087
实施例76的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：416.09。
实施例77：N-(5-(3-(3,4-二甲基-苯基磺酰氨基)-4-甲基苯基)吡啶-3- 基)乙酰胺
Figure PCTCN2019072281-appb-000088
实施例77的化合物的合成通过使用类似于实施例42中所述的步骤完成。MS(ESI)m/z(M+1) +：410.16。
实施例78
体外抑制活性(酶活)测定
体外酶活实验测定化合物对PI3K家族Ⅰ型激酶(PI3Kα、PI3Kβ、PI3Kδ、PI3Kγ)、Ⅲ型激酶(VPS34)、和PI4K家族的激酶(PfPI4K、PI4KB(人源))的IC 50值。蛋白激酶PI3Kα、PI3Kδ、PI3Kγ、VPS34、PI4KB均购自Invitrogen(美国)；蛋白激酶PI3Kβ购自Sigma(美国)；PfPI4K由本实验室表达，表达步骤如下。使用Bac-to-Bac表达***(Thermo Fisher，美国)构建PfPI4K蛋白表达***。按照Bac-to-Bac表达***使用说明书首先构建重组杆状病毒，然后大量培养1000mL SF9细胞(购自美国ATC)，将构建的重组杆状病毒感染SF9细胞，72小时之后以1000转5分钟离心收集细胞沉淀，超声裂解细胞，以12000转10分钟收集上清。先使用his-beads初步纯化，再使用FPLC蛋白纯化仪(AKTA，美国GE)进一步纯化。三种底物PIP2:PS、PI和PI:PS均购自Invitrogen(美国)。
分别取稀释至一定浓度的蛋白激酶PI3Kα 5.4μL(终浓度为0.16ng/μL)、PI3Kβ 5.4μL(终浓度为6ng/μL)、PI3Kδ 5.4μL(终浓度为1ng/μL)、PI3Kγ 5.4μL(终浓度为5ng/μL)、VPS34 5.4μL(终浓度为1.2ng/μL)、PI4KB 5.4μL(终浓度为5ng/μL)、和PfPI4K 5.4μL(终浓度为5ng/μL)分别与梯度稀释的测试药物化合物各1μL室温反应1h(药物终浓度分别为10μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM)。
向上述PI3K家族Ⅰ型激酶各反应管中加入ATP和底物PIP2:PS混合物共6μL(激酶PI3Kα、PI3Kβ反应体系中ATP终浓度为10μM，激酶PI3Kδ、PI3Kγ反应体系中ATP终浓度为50μM，底物PIP2:PS终浓度均 为50μM)，37℃反应1h。反应缓冲液为50mM HEPES(pH 7.5)、3mM MgCl 2、1mM EGTA、100mM NaCl、和0.03％CHAPS。
向上述PI3K家族Ⅲ型激酶各反应管中加入ATP和底物PI:PS混合物共6μL(终浓度分别为50μM和100μM)，37℃反应1h。反应缓冲液为50mM Hepes(pH 7.5)、0.1％CHAPS、和1mM EGTA。
向上述PI4K家族激酶各反应管中加入ATP和底物PI:PS混合物共6μL(终浓度分别为50μM和100μM)，37℃反应1h。反应缓冲液为20mM Tris(pH 7.5)、0.5mM EGTA和0.4％Triton X-100。
取5μL反应后的激酶溶液于384孔板(Corning，美国)中，加入5μL ADP-Glo TM(Promega，美国)试剂，室温反应40min以终止激酶反应并消耗完剩余的ATP。
加入10μL激酶检测试剂将ADP转化成ATP，使用偶联的萤光素酶/萤光素反应检测新合成的ATP，利用Envision读数后作图，计算Graphpad 7.0IC 50值，实验结果见表2。
表2.体外抑制活性(酶活)的测定结果(“-”表示未检测)
化合物 PIK3δ/μM PIK3γ/μM
实施例1 - 5.37
实施例3 - 2.09
实施例4 - 2.08
实施例5 - 0.43
实施例6 0.33 0.22
实施例7 0.14 0.19
实施例8 0.018 0.28
实施例12 3.54 -
实施例13 - 1.23
实施例14 2.09 -
实施例15 0.025 0.024
实施例16 0.048 0.026
实施例17 0.91 2.54
实施例18 0.046 0.34
实施例19 - 0.50
实施例20 - 2.76
实施例21 - 0.072
实施例22 0.063 0.83
实施例23 0.028 0.089
实施例24 0.073 0.045
实施例25 0.090 5.84
实施例26 0.36 2.64
实施例27 0.029 2.10
实施例28 - 1.78
实施例31 0.68 -
实施例32 0.11 -
实施例33 1.99 -
实施例34 0.075 1.37
实施例35 0.082 0.66
实施例36 0.11 6.26
实施例37 0.16 -
实施例38 0.18 3.46
实施例39 0.30 0.25
实施例40 0.73 -
实施例41 - 1.18
实施例42 - 0.17
实施例43 0.085 0.17
实施例44 - 2.70
实施例45 0.19 1.13
实施例46 6.61 1.47
实施例48 - 2.19
实施例49 0.067 0.13
实施例50 0.040 0.040
实施例51 0.73 1.99
实施例52 0.61 0.23
实施例53 - 0.25
实施例55 8.66 -
实施例57 8.20 -
实施例61 - 2.66
续表2.
IC 50(μM) 实施例6 实施例47
PIK3α 0.20 0.35
PIK3β 0.31 5.41
PIK3δ 0.33 >10
PIK3γ 0.22 >10
VPS34 0.20 4.14
PfPI4K 0.0015 0.0029
PI4KB(人源) 1.42 >10
实施例79
恶性疟原虫GI50检测方法
将吉姆萨染液(购自sigma，美国)用双蒸水1:20稀释待用，每次要现配现用。裂解液含有3x SYBR Green I(购自invitrogen，美国)，1.5％triton-x-100。将未感染的红细胞(正常人血液中分离)转移到15ml离心管中以2000RPM转5分钟，去除上清，将沉淀缓慢加入ficoll溶液(北京，索莱宝)上层，以800g离心20分钟，去除上清。将白细胞(正常人血液中分离)和ficoll试剂加入10ml pbs，洗涤红细胞2次，每次2000RPM转5分钟。吸去上清留下沉淀待用。在培养感染红细胞的培养皿中吸出3μl底部细胞沉淀，滴在载玻片上制作血薄片，用吉姆萨染液染色19分钟，双蒸水洗去染液，计数感染率。将感染的红细胞培养物转移到15ml一次性离心管中。2000RPM转5分钟，去除培养上清。混匀感染的红细胞沉淀，加入未感染的红细胞，把感染率调整在1.8～2.4％。 在感染的红细胞中加入培养基(美国，Gibcol)，把红细胞积压调整到4.8～5％。将感染的红细胞悬液以100μl/孔加入96孔板中。各孔依次加入10、3、1、0.3、0.1、0.03、0.01、0.003、0μM的药物终浓度，每块96孔板设置3个孔积压相同的未感染红细胞100μl。蜡烛缸培养法培养72小时。72小时后，96孔板在震荡器上震荡14秒，加入裂解液30μl后再震荡10秒。室温置于摇床上120转，10分钟。Envision读数，吸收波长约497nm，发射波长约520nm，用Graphpad 7.0计算GI 50值。
表3
化合物 疟原虫(μM)
实施例2 2.34
实施例3 2.65±1.10
实施例4 0.36
实施例6 0.11±0.039
实施例7 1.05±0.27
实施例8 1.49±0.15
实施例13 0.13±0.051
实施例14 0.14±0.041
实施例15 5.27±2.77
实施例16 4.67±1.58
实施例18 3.94±1.85
实施例19 5.23±4.17
实施例22 4.71±1.20
实施例23 7.92
实施例25 8.08
实施例27 0.42±0.32
实施例28 0.54±0.17
实施例29 1.68±1.17
实施例30 6.62±4.25
实施例31 3.56±1.26
实施例32 0.47±0.13
实施例34 3.68
实施例35 3.57±2.19
实施例37 4.04
实施例38 7.59
实施例39 0.16±0.063
实施例40 7.24
实施例41 3.32±2.56
实施例42 0.11±0.047
实施例43 2.01±1.47
实施例44 0.13±0.049
实施例45 0.11±0.063
实施例46 2.44±0.97
实施例47 0.085±0.043
实施例48 2.58±1.15
实施例49 1.04±1.13
实施例50 0.19±0.053
实施例51 0.63±0.28
实施例52 1.02±0.52
实施例53 1.86±1.42
实施例59 2.53
工业应用性
本发明提供一类新型的激酶抑制剂的化合物，其可以用于治疗由PI3K激酶或PfPI4K激酶活化介导的病症，特别是疟疾、癌症和其它的细胞增殖性疾病。因而，可将其制成相应的药物，适于工业应用。
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。

Claims (17)

  1. 一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药：
    Figure PCTCN2019072281-appb-100001
    其中：
    X选自CH或N；
    A环选自吡啶基、吡咯基、吡咯并吡啶基、吡唑基、吡唑并吡啶基、四氢吡啶基、异喹啉基、苯基、和吲哚基，所述A环的氮原子任选被氨基保护基取代；
    R 1和R 2各自独立地选自H、C 1-6烷基、卤素、和C 1-6卤代烷基；
    R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基；
    R 4选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷酰基、C 1-6烷基氨基羰基、C 3-6环烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、苯烷基、苯基氨基羰基、苯基烷基氨基羰基、吡啶基氨基羰基、和氨基保护基，上述取代基任选地被氨基、氨基保护基取代的氨基、羟基或卤素取代。
  2. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中所述的A环选自吡啶-3-基、吡啶-4-基、吡咯-3-基、吡咯并[2,3-b]吡啶-5-基、吡唑-4-基、吡唑并[3,4-b]吡啶-5-基、四氢吡啶-4-基、异喹啉-4-基、苯基、和吲哚-2-基，所述A环的氮原子任选被选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基的氨基保护基取代。
  3. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 1和R 2中至少一个是H。
  4. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 3选自氯、甲基、和甲氧基。
  5. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 4选自C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基，上述取代基任选地被氨基、氨基保护基取代的氨基、羟基或卤素取代。
  6. 如权利要求5所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 4选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
  7. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中所述化合物具有以下式(II)的结构：
    Figure PCTCN2019072281-appb-100002
    其中：
    X选自CH或N；
    R 1和R 2中至少一个为H，另一个选自H、C 1-6烷基、卤素、和C 1-6卤代烷基；
    R 3选自H、卤素、C 1-6烷基、和C 1-6烷氧基；
    R 4选自H、任选地被氨基取代的C 1-6烷基氨基羰基、C 1-6烷酰氨基、C 1-6烷基氨基C 1-6烷酰氨基、氨基C 1-6烷基氨基羰基、任选地被卤素取代的苯基氨基羰基、苯基烷基氨基羰基、和吡啶基氨基羰基。
  8. 如权利要求7所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 1和R 2中至少一个为H，另一个选自H、甲基、 2-丙基、氟、氯、和三氟甲基。
  9. 如权利要求7所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 3选自选自氯、甲基、和甲氧基。
  10. 如权利要求7所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中R 4选自甲基氨基羰基、乙基氨基羰基、乙酰氨基、二甲氨基乙酰氨基、苯基氨基羰基、氟代苯基氨基羰基、苯甲基氨基羰基、和2-吡啶基氨基羰基。
  11. 如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中所述的化合物是选自下表的化合物。
    Figure PCTCN2019072281-appb-100003
    Figure PCTCN2019072281-appb-100004
    Figure PCTCN2019072281-appb-100005
    Figure PCTCN2019072281-appb-100006
    Figure PCTCN2019072281-appb-100007
  12. 一种药物组合物，其包括如权利要求1-11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，和药学上可接受的载体或赋形剂，以及任选的其它治疗剂。
  13. 如权利要求1-11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备PI3K激酶抑制剂中的用途。
  14. 如权利要求1-11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备针对恶性疟原虫的PfPI4K激酶抑制剂中的用途。
  15. 如权利要求1-11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于治疗、预防或改善由PI3K激酶介导的病症的药物中的用途。
  16. 如权利要求1-11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于治疗、预防或改善由PfPI4K激酶介导的病症的药物中的用途。
  17. 如权利要求16所述的用途，其中所述由PfPI4K激酶介导的病症为疟疾。
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