WO2019218998A1 - 一种丙烯酸酯化合物及其用途 - Google Patents

一种丙烯酸酯化合物及其用途 Download PDF

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WO2019218998A1
WO2019218998A1 PCT/CN2019/086792 CN2019086792W WO2019218998A1 WO 2019218998 A1 WO2019218998 A1 WO 2019218998A1 CN 2019086792 W CN2019086792 W CN 2019086792W WO 2019218998 A1 WO2019218998 A1 WO 2019218998A1
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unsubstituted
pharmaceutically acceptable
substituted
acceptable salt
compound
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PCT/CN2019/086792
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French (fr)
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廖杰远
陈先红
邹德超
季鸣
孙志国
谈敦潮
王珂
陈晓光
杜立民
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北京微医智慧信息技术有限责任公司
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to an acrylate compound and its use.
  • the interleukin 17, IL-17 family includes six interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F) and their receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE and IL-17RF) (Gaffen, SL et al., Nature reviews. Immunology, 2009, (9): 556-567) , IF-17F, also known as IL-24 or ML-1, is a member of the IL-17 cytokine family.
  • IF-17F is about 55% identical to IL-17A and is thought to share the same receptor as IL-17A (Kolls and Linden 2004, Immunity, 21, 467-476; Hymowitz et al, EMBO J., 2001, 20 (19), 5332-5341; Kuestner et al, Journal of Immunology, 2007, 179, 5462-5473). Both can form homodimeric and heterodimeric proteins, both produced by activated human CD4+ T cells (Wright et al, J Biol Chem. 2007, 282(18), 13447-13455).
  • IL-17F can be associated with the development of a variety of diseases, including diseases mediated by abnormal immune responses, such as rheumatoid arthritis and airway inflammation, as well as organ transplant rejection and tumors or cancer; correspondingly IL -17F inhibitors may be promising therapeutic agents for these diseases (Huichao Yan et al, Immuno-Gastroenterology, 2012, 1:100-103; Yuting Ma et al, Journal of Experimental Medicine, 2011, 208(3): 491- 503).
  • IL-17F is associated with autoimmune diseases (Iwakura, Y., H. Ishigame et al, Immunity, 2011, 34(2): 149-162).
  • IL-17F antagonism is associated with protection against asthma (Kawaguchi et al, 2006, J. Allergy Clin. Immunol. 117 (4); 795-801), and IL-17F also plays a role in arthritis pathology (Lubberts) , Current Opinion in Investigational Drugs, 2003, 4(5): 572-577).
  • IL-17F inhibitors have been reported in the prior art.
  • some WO2014065413 reports triazole derivatives and isoxazole derivatives as ROR gamma receptor inhibitors, thereby inhibiting the differentiation and activation of Th17 cells, and IL-17 produces an inhibitory effect.
  • WO201400944 and WO2016014918 report on aryl sultam derivatives and benzimidazole derivatives as RORc modulators, such compounds are mainly used for the treatment of autoimmune diseases.
  • WO2016213676 reports a substituted 2,3-dihydro-inden-1-ones -1H- structure as ROR ⁇ t / ROR ⁇ receptor antagonists, such compounds are useful for modulating ROR ⁇ t / ROR ⁇ activity and for treatment ROR ⁇ t / ROR ⁇ Mediated diseases and conditions.
  • WO2016072402 reports a cyclic amine derivative ⁇ t on inhibit cell receptor ROR TH17, TH17 thereby inhibiting cell differentiation, reduced IL-17 secretion.
  • WO2016120849 reports the use of methoxy substituted pyrrolopyridines for ROR gamma receptor inhibitors, thereby reducing the amount of IL-17.
  • the inhibition of these compounds is still not satisfactory, or there are selectivity problems. Therefore, there is still an urgent need in the art to develop novel IL-17 inhibitors, particularly IL-17F inhibitors, for the prevention of related diseases. / or treatment.
  • the inventors have unexpectedly discovered through research that the compound of formula I or a pharmaceutically acceptable salt thereof has unexpected IL-17F inhibition:
  • Q is selected from O and N;
  • X, Y, Z are each independently selected from C, O, S and N;
  • R 1 and R 2 are the same or different and are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted Or a substituted arylalkyl group, an unsubstituted or substituted acyl group; or, R 1 and R 2 form an acetal with an adjacent oxygen;
  • R 3 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted acyl;
  • R 4 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl;
  • R 5 is selected from hydrogen, halogen, cyano, nitro, unsubstituted or substituted hydroxy, unsubstituted or substituted alkyl.
  • At least one of X, Y, Z is N, but is not N at the same time.
  • Q is selected from O, and R 3 and R 4 form a lactone with its adjacent oxygen.
  • R 1 and R 2 form an acetal with their adjacent oxygen.
  • R 1 and R 2 are the same.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, and C1-C5 alkyl acyl.
  • R 1 and R 2 form an acetal of the formula:
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl and phenyl C2-C5 alkenyl.
  • R 6 , R 7 form a 3 to 6 membered ring with its adjacent C.
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo and iodo.
  • X, Y, Z are C or N.
  • the compound of formula I of the invention is a specific compound selected from the group consisting of:
  • the invention provides a compound of formula I above, or a pharmaceutically acceptable salt thereof.
  • the salt when QR4 is a hydroxyl group, the salt may be a salt of a compound of formula I with an alkali metal, alkaline earth metal, transition metal or amine; when there are N atoms in X, Y or Z, the salt may be of formula I a salt of a compound with an organic or inorganic acid.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I according to the invention or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.
  • the present invention provides the use of a compound of the above formula I of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the secretion and activity of IL-17F.
  • the present inventors have surprisingly found that the compound of the formula I and a pharmaceutically acceptable salt thereof have an action of inhibiting the secretion of interleukin 17F, and thus can be used as a modulator of interleukin 17F.
  • the invention provides a method of inhibiting secretion and activity of IL-17F comprising administering a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present application also demonstrates that the compound of the formula I and its pharmaceutically acceptable salt also have the effect of preventing and treating tumors, and thus can be used as a medicament for the prevention and treatment of tumors.
  • the tumor includes solid tumors and non-solid tumors, including but not limited to melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple Myeloma, lymphoma, leukemia, bladder cancer, prostate cancer, cholangiocarcinoma, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, head and neck cancer, gallbladder cancer, kidney cancer, etc.
  • the tumor is colorectal cancer, gastric cancer, bladder cancer and breast cancer. Accordingly, the invention provides a method of preventing and/or treating a tumor comprising administering a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof has an action of preventing and treating an autoimmune disease, and therefore, can be used as a drug for preventing and treating an autoimmune disease.
  • the autoimmune diseases include, but are not limited to, lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like.
  • the autoimmune disease is selected from the group consisting of lupus erythematosus and psoriasis.
  • the present invention provides a method of preventing and/or treating an autoimmune disease comprising administering a compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the pharmaceutically acceptable salt of the compound of the formula I means that it is suitable for contact with human body and lower animal tissues within a reasonable medical judgment, without undue toxicity, irritation, allergic reaction, etc., and reasonable The benefit/risk ratio is commensurate.
  • Salts of the compounds of the invention include those derived from suitable inorganic and organic bases.
  • the inorganic base salts include salts with ammonia, alkali metals, alkaline earth metals or transition metals, such as ammonium salts and lithium, sodium, potassium, calcium, zinc, iron, ferrous salts and the like.
  • the organic base salt includes an amine salt, including a salt of a compound of formula I with a primary, secondary or tertiary amine, which may be selected from salts with the following organic bases: for example arginine, ethylenediamine, triethylamine, caffeine, beets Base, ethanolamine, trimethylamine, piperidine, and the like.
  • Q is selected from the group consisting of O.
  • X, Y, Z are selected from C or N.
  • R 1 and R 2 are the same; particularly preferably, R 1 and R 2 are independently selected from hydrogen, C1-C3 alkyl or C1-C5 alkyl acyl.
  • R 1 and R 2 form an acetal of the formula:
  • R 6 and R 7 are independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, phenyl C2-C5 alkenyl; or R 6 , R 7 and its The adjacent C forms a 3 to 6 membered ring.
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl.
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl.
  • R 3 and R 4 form a lactone with its adjacent oxygen.
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo.
  • R 1 or R 2 are the same, independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C1-C5 alkyl
  • An acyl group R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl
  • R 5 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • Base propyl, isopropyl, nitro, fluoro, chloro, bromo and iodo.
  • R 1 and R 2 do not form an acetal, and R 3 and R 4 also do not form a lactone.
  • the compounds of formula I of the invention have the structure of formula I-2 below:
  • R 1 and R 2 may be the same, independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C1-C5 alkyl acyl;
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, and iodine.
  • R 3 and R 4 form a lactone.
  • the compound of Formula I has the structure of Formula I-3 below:
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, phenyl C2-C5 alkenyl;
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl;
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 1 and R 2 form an acetal.
  • the compound of Formula I has the structure of Formula I-4 below:
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl;
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl;
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl;
  • n is selected from 1, 2, 3 and 4.
  • R 1 and R 2 form an acetal, and the substituent thereon forms a 3- to 6-membered ring.
  • the compound of Formula I has the structure of Formula I-5 below:
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, phenyl C2-C5 alkenyl;
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 1 and R 2 form an acetal
  • R 3 and R 4 form a lactone
  • the compound of Formula I has the structure of Formula I-6 below:
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl;
  • n is selected from 1, 2, 3 or 4.
  • R 1 and R 2 form an acetal, the substituent thereon forms a 3- to 6-membered ring, and at the same time, R 3 and R 4 form a lactone.
  • the compound of formula I can be prepared as follows:
  • the starting material D-(-)-quinic acid is lactone in the presence of a catalyst, and a protecting group is introduced at the 3,4 position to obtain intermediate 1, and intermediate 1 and intermediate 2 are esterified to obtain an intermediate. 3.
  • Intermediate 3 is subjected to ester hydrolysis under basic conditions to give intermediate 4, which is further deprotected under acidic conditions to give the compound of formula I.
  • the reaction process is as follows:
  • ⁇ R 1 , ⁇ R 2 , ⁇ R 3 , ⁇ R 4 , ⁇ R 5 are defined as in the formula I, R 1 , R 2 , R 3 , R 4 , R 5 , respectively , and other variables X, Y, Z is the same as defined in formula I; L is a halogen or a hydroxyl group selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • the method of ester formation in the preparation of the intermediate 3, generally has two methods: when the intermediate 2 is a carboxylic acid, it can be used in a conventional condensing agent (for example, N, N'-dicyclohexyl group).
  • a conventional condensing agent for example, N, N'-dicyclohexyl group.
  • the ester is directly esterified under basic conditions (for example, pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, etc.).
  • the base used for the ester hydrolysis of the intermediate 3 may be lithium hydroxide, sodium hydroxide, potassium hydroxide or the like;
  • the acid used for the deprotection of the intermediate 4 may be an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, or the like.
  • Aqueous fluoroacetic acid or the like may be lithium hydroxide, sodium hydroxide, potassium hydroxide or the like;
  • alkyl means a saturated straight or branched hydrocarbon group of 1 to 12 carbon atoms, preferably a saturated linear or branched hydrocarbon group of 1 to 6 carbon atoms, more preferably 1 to 5
  • the saturated linear or branched hydrocarbon group of the carbon atom is particularly preferably a saturated linear or branched hydrocarbon group of 1 to 4 carbon atoms, and particularly preferably a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl Base, neopentyl, hexyl, heptyl, octyl.
  • alkenyl group means a monovalent group derived from a hydrocarbon moiety by removing a single hydrogen atom, wherein the hydrocarbyl moiety has at least one carbon-carbon double bond and contains 2 to 12 carbon atoms, respectively.
  • a preferred alkenyl group is a C2-C6 alkenyl group, more preferably a C2-C5 alkenyl group.
  • Representative alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and the like.
  • cycloalkyl means that the saturated carbocyclic compound has 3 to 12 ring atoms, preferably the cycloalkyl group has 3 to 6 carbon atoms, more preferably a cycloalkyl group having 3 to 5 carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • acyl includes residues derived from an acid including, but not limited to, a carboxylic acid, a carbamic acid, a carbonic acid, a sulfonic acid, and a phosphoric acid.
  • examples include aliphatic carbonyl groups, aromatic carbonyl groups, aliphatic sulfonic acid groups.
  • aliphatic carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, and the like.
  • Preferred acyl groups in the present invention are alkyl acyl groups, especially C1-C6 alkyl acyl groups.
  • halogen means fluorine, chlorine, bromine or iodine.
  • aryl means a monocyclic, bicyclic or tricyclic carbocyclic ring system having 1 to 3 aromatic rings, preferably an aryl group having 6 to 14 carbon atoms, including but not limited to, phenyl group. , naphthyl, tetrahydronaphthyl, anthracenyl and the like.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecule through an alkyl group, as defined herein. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • substituted means that one, two or three or more hydrogen atoms thereof are independently substituted with a substituent including, but not limited to, halogen, -OH, protected hydroxyl group, -NO 2 , -CN, -NH 2 , protected amino group, alkoxy group, and the like.
  • substituents include halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, -NO 2, acetyl.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable adjuvant (excipient or diluent).
  • composition in the context of the present invention means any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, etc., which are suitable for the particular dosage form desired. Thick or emulsifier, preservative, solid binder, lubricant, etc.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Maetin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation.
  • materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer materials such as: phosphate; glycine; sorbic acid or potassium sorbate a mixture of fatty acid esters of saturated plant fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; Acrylates; saccharides such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; gelatin; talc; Excipients such as waxes for cocoa butter and suppositories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil
  • the present invention also provides a pharmaceutical preparation comprising a compound of the formula I or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or diluent, which can be used according to a conventional preparation method. It is formulated into a conventional pharmaceutical preparation such as a capsule, a tablet, a pill, a granule, an emulsion, a flocculant, an injection, a drop, and the like.
  • the present inventors have found that the compound of the formula I of the present invention and a pharmaceutically acceptable salt thereof have an action of inhibiting the secretion of interleukin 17, particularly interleukin 17F, and are capable of preventing and treating tumors.
  • the experimental results show that some compounds in the compound of formula I have an inhibition rate of interleukin-17F at a concentration of 0.5 ⁇ M/L, which is close to 70%; at a dose of 20 mg/kg, for melanoma, pancreatic cancer, colorectal cancer, lung cancer, etc. Tumors have a good inhibitory effect, both exceeding 50%.
  • (2E)-3-(2-pyrimidinyl)acrylic acid (18.0 g, 0.12 mol) was added to the reaction flask, dichloromethane (200.0 ml) was added, the solid was not completely dissolved, and thionyl chloride (40.0 ml) was added. Heated to reflux for 3 h. The reaction of the starting material was completed, and the reaction system was directly evaporated to give a white solid (2E)-3-(2-pyrimidinyl)-propionyl chloride hydrochloride ( Intermediate 1-14b), which was directly used for the next reaction.
  • the intermediate 1-14e (6.0 g, 19.59 mmol) was added to the reaction flask, dissolved in anhydrous DMF (60.0 ml), the system was cooled to 0 ° C, and sodium hydride (2.0 g, 48.98 mmol) was added portionwise. , 60% mineral oil), stirred for 30 min, slowly added dropwise containing methyl iodide (6.2 g, 43.68 mmol), and naturally raised to room temperature for 1 h. 2N ammonium chloride aqueous solution was added to the reaction system, and the organic phase was extracted with ethyl acetate.
  • Example 10 Preparation of Compound 3-1
  • Compound 1-1d prepared in Example 1 was Compound 3-1.
  • Step A Following the procedure of Step A in Example 11, wherein cyclohexanone was used in place of methyl isobutyl ketone.
  • Step C Following the procedure of Step C in Example 1, wherein the esterification was carried out using 1-14b instead of 1-1b to afford Intermediate 4-8c.
  • Step D An operation was carried out in accordance with Step D of Example 1, wherein 1-1c was replaced by 4-8c.
  • MS (ESI + ): m/z 404.1.
  • sample loading separate blank holes (the blank control hole except the sample and the enzyme standard reagent, the other steps are the same as the standard hole and the sample hole to be tested), the standard hole, the sample hole to be tested.
  • sample loading separate blank holes (the blank control hole except the sample and the enzyme standard reagent, the other steps are the same as the standard hole and the sample hole to be tested), the standard hole, the sample hole to be tested.
  • adding enzyme adding enzyme labeling reagent to each well, except for blank holes.
  • color development first add coloring agent A to each well, then add coloring agent B, gently shake and mix, and develop color at 37 ° C for 10 minutes.
  • termination stop solution is added to each well to terminate the reaction (at this time, the blue color turns yellow).
  • GI (growth inhibition rate) (1-OD drug group / OD control group ) ⁇ 100%.
  • Table 7 is the result of in vitro activity test of the compounds provided by the present invention.
  • Mouse pancreatic cancer PAN02 tumor fluid was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissue with good growth was taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to prepare a tumor cell suspension with a concentration of 1.2 ⁇ 10 7 /mL, which was small in C57BL/6. Rats were inoculated with 0.2 mL/only on the right side of the arm. The animals were randomly divided into the next day after inoculation, and 6 rats in each group were weighed and administered with the test compound for 13 consecutive administrations. The positive control drug cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • Mouse colorectal cancer MC38 tumor fluid was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissues with good growth were taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to prepare a suspension of tumor cells at a concentration of 1.2 ⁇ 10 7 cells/mL in C57BL/6 mice. The right axilla was inoculated with 0.2 mL/head. The animals were randomly divided into the next day after inoculation, and 6 rats in each group were weighed and administered with the test compound for 13 consecutive administrations. The positive control drug cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • Mouse Lewis lung carcinoma virus solution was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissue with good growth was taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to prepare a tumor cell suspension with a concentration of 1.2 ⁇ 10 7 /mL, which was small in C57BL/6. Rats were inoculated with 0.2 mL/only on the right side of the arm. The animals were randomly divided into the next day after inoculation, and 6 rats in each group were weighed and administered with the test compound for 13 consecutive administrations. Cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • TGI (1-T/C) ⁇ 100.
  • T tumor weight in the treatment group
  • C tumor weight in the negative control group.
  • Compound 1-1 has an inhibitory effect on interleukin-17F, and the inhibition rate is close to 70%; Compound 1-1 has a dose of 20 mg/kg against melanoma, pancreatic cancer, colorectal cancer, lung cancer and the like. Good inhibition is more than 50%.
  • the derivatives also have a good inhibitory effect on tumors such as melanoma, pancreatic cancer, colorectal cancer and lung cancer.
  • Imiquimod model Dosage Mode of administration Animals only Control group - - - 10 Model group + - - 10 Imiquimod group + 1.5mg/kg Stomach 10 Compound 1-1 + 20mg/kg Tail vein injection 8
  • the pet hair clipper and hair removal cream were used to depilate the back of the mouse, and the area was about 1.5 ⁇ 2 cm 2 . Except for the negative control animals, each group of animals was modeled with imiquimod cream, that is, 50 mg of imiquimod cream was applied to the skin of the back hair removal part of the mice every day, and it was applied once a day for 7 consecutive times. day. The compound was injected intraperitoneally on the day of modeling, and the animals were treated on the 8th day. The animals were scored daily for psoriasis-like lesions and severity of disease (PASI, psoriasis area and severity index) on the first day of the first modeling. According to the PASI scoring standard, the scores of 0-4 in the erythema, scales and infiltration thickening of the mouse lesions were respectively given, and the three points were added to obtain the total score.
  • PASI psoriasis-like lesions and severity of disease
  • PASI scoring criteria 0, none; 1, mild; 2, moderate; 3, severe; 4, very severe.
  • Day 7 the mice were sacrificed by cervical dislocation, the skin thickness was measured with a vernier caliper, and the skin of the animal's back hair removal was removed and fixed with 4% paraformaldehyde for pathological analysis.
  • the PASI score results are shown in Table 1.3 below and the results are expressed as mean ⁇ standard deviation.
  • Control group Module MTX Compound 1-1 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 1 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 2 0 ⁇ 0 1.1 ⁇ 0 0.8 ⁇ 0.7 0.6 ⁇ 0.5 3 0 ⁇ 0 2.2 ⁇ 0 2.0 ⁇ 0.3 1.5 ⁇ 0.5 4 0 ⁇ 0 1.9 ⁇ 0 1.8 ⁇ 0.4 1.7 ⁇ 0.5 5 0 ⁇ 0 2 ⁇ 0 1.3 ⁇ 0.5 1.3 ⁇ 0.5 6 0 ⁇ 0 1.3 ⁇ 0.5 1.3 ⁇ 0.5 1 ⁇ 0
  • Control group Module MTX Compound 1-1 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 1 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 2 0 ⁇ 0 0.4 ⁇ 0.5 0.2 ⁇ 0.3 0.1 ⁇ 0 3 0 ⁇ 0 1.5 ⁇ 0.5 1.9 ⁇ 0.3 1.5 ⁇ 0.5 4 0 ⁇ 0 1.9 ⁇ 0.4 1.6 ⁇ 0.7 1.6 ⁇ 0.4 5 0 ⁇ 0 2.4 ⁇ 0.7 1.7 ⁇ 0.7 1.8 ⁇ 0.5 6 0 ⁇ 0 2.5 ⁇ 0.5 2.4 ⁇ 1.0 2.4 ⁇ 0.9
  • Control group Module MTX Compound 1-1 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 1 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 2 0 ⁇ 0 1 ⁇ 0 0.9 ⁇ 0.3 1 ⁇ 0 3 0 ⁇ 0 2.3 ⁇ 0.6 2.3 ⁇ 0.5 2 ⁇ 0 4 0 ⁇ 0 2.4 ⁇ 0.5 2.3 ⁇ 0.5 2.1 ⁇ 0.5 5 0 ⁇ 0 2.8 ⁇ 0.4 2.1 ⁇ 0.7 2.3 ⁇ 0.5 6 0 ⁇ 0 3.5 ⁇ 0.5 3.1 ⁇ 0.9 3.3 ⁇ 0.7
  • Control group Module MTX Compound 1-1 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 1 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 0 ⁇ 0 2 0 ⁇ 0 2.5 ⁇ 0.5 1.9 ⁇ 0.6 1.7 ⁇ 0.5
  • Compound 1-1 improved the pathological erythema better than the improvement of scale and thickening. At different times of the disease, there are certain improvements in different pathological conditions, which are basically equivalent to the positive compound MTX.
  • mice 10 weeks old MRL/lpr self-exposure lupus mice were intragastrically or intraperitoneally injected once a day for 3 months. Skin pathology, degree of joint swelling and pathology, blood/urinary creatinine urea nitrogen, and blood dsDNA and ANA antibodies were observed and detected during the administration period and at the end of the experiment. The results indicate that the compounds of the invention have a significant improvement in lupus erythematosus.

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Abstract

本发明涉及式I所示的丙烯酸酯化合物及其在制备用于预防或治疗与IL-17F相关疾病或症状的药物中的用途。

Description

一种丙烯酸酯化合物及其用途
本申请要求于2018年5月18日提交到中国专利局的发明名称为“一种丙烯酸酯化合物及其用途”的中国专利申请201810481958.5的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于药物化学技术领域，具体地涉及一种丙烯酸酯化合物及其用途。
背景技术
白细胞介素17(the interleukin 17，IL-17)家族包括6种白细胞介素(IL-17A，IL-17B，IL-17C，IL-17D，IL-17E和IL-17F)及其受体(IL-17RA，IL-17RB，IL-17RC，IL-17RD，IL-17RE和IL-17RF)(Gaffen，S.L.等，免疫学通讯(Nature reviews.Immunology)，2009，(9)：556-567)，其中IF-17F也称为IL-24或ML-1，是IL-17细胞因子家族的成员。IF-17F与IL-17A大约55％相同，并且被认为与IL-17A共享相同的受体(Kolls和Linden 2004,Immunity，21,467-476；Hymowitz等，EMBO J.，2001，20(19),5332-5341；Kuestner等，Journal of Immunology，2007，179,5462-5473)。二者都可以形成同型二聚体和杂二聚体蛋白，均由激活的人CD4+T细胞产生(Wright等，J Biol Chem.2007，282(18)，13447-13455)。
现有技术已表明：IL-17F可与多种疾病的发生相关，包括由异常免疫反应介导的疾病，如类风湿性关节炎和呼吸道炎症，以及器官移植排斥和肿瘤或癌症；相应地IL-17F抑制剂有可能成为这些疾病的有前景的治疗剂(Huichao Yan等，Immuno-Gastroenterology，2012，1:100-103；Yuting Ma等，Journal of Experimental Medicine，2011,208(3)：491-503)。现有技术已经表明，IL-17F与自身免疫疾病相关(Iwakura，Y.,H.Ishigame等，Immunity，2011，34(2)：149-162)。IL-17F拮抗作用与对抗哮喘的保护作用相关(Kawaguchi等，2006，J.Allergy Clin.Immunol.117(4)；795-801)，并且IL-17F在关节炎病理学中也起作用(Lubberts，Current Opinion in Investigational Drugs，2003，4(5)：572-577)。
现有技术已经报道了一些IL-17F抑制剂，例如，一些WO2014065413报道了三唑类衍生物和异噁唑类衍生物作为RORγ受体抑制剂，从而可以抑制Th17细胞的分化和活化，并且对IL-17产生抑制作用。WO201400944和WO2016014918报道了关于芳基磺内酰胺衍生物和苯并咪唑类衍生物作为RORc 调节剂，此类化合物主要用于治疗自身免疫疾病。
WO2016213676报道了取代2,3-二氢-1H-茚-1-酮类结构作为ROR γt/ROR γ受体拮抗剂，此类化合物可用于调节RORγt/RORγ活性和用于治疗ROR γt/ROR γ介导的疾病和病症。WO2016072402报道了关于环状胺衍生物对TH17细胞受体ROR γt有抑制作用，从而抑制TH17细胞分化，降低IL-17分泌。WO2016120849报道了甲氧基取代的吡咯并吡啶类化合物用于ROR γ受体抑制剂，从而减少IL-17的量。然而，这些化合物的抑制作用仍不够令人满意，或者存在选择性问题，因此，现有技术中仍迫切需要开发新型的IL-17抑制剂特别是IL-17F抑制剂用于相关疾病的预防和/或治疗。
发明内容
本发明人通过研究出乎意料地发现，式I所示的化合物或其药学上可接受的盐具有出乎意料的IL-17F抑制作用：
Figure PCTCN2019086792-appb-000001
其中，Q选自O和N；X、Y、Z各自独立地选自C、O、S和N；
R 1和R 2相同或不同，独立地选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的芳基烷基、未取代或取代的酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
R 3选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的酰基；
R 4选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的芳基烷基；
R 5选自氢、卤素、氰基、硝基、未取代或取代的羟基、未取代或取代的烷基。
在一些优选的实施方案中，X、Y、Z中至少有一个为N，但不同时为N。
在一些优选的实施方案中，Q选自O，R 3和R 4与其相邻的氧形成内酯。
在一些优选的实施方案中，R 1和R 2与其相邻的氧形成缩醛。
在一些优选的实施方案中，R 1和R 2相同。
在一些优选的实施方案中，R 1和R 2独立地选自氢、C1-C3烷基和C1-C5烷基酰基。
在一些优选的实施方案中，R 1和R 2与其相邻的氧形成下式所示的缩醛：
Figure PCTCN2019086792-appb-000002
其中，R 6、R 7独立地选自氢、C1-C5烷基、C2-C5烯基、取代或未取代的苯基和苯基C2-C5烯基。
在一些优选的实施方案中，R 6、R 7与其相邻的C形成3～6元环。
在一些优选的实施方案中，R 5选自氢、甲基、乙基、丙基、异丙基、氟、氯、溴和碘。
在一些优选的实施方案中，X、Y、Z为C或N。
在一些特别优选的实施方案中，本发明的式I化合物为选自以下的具体化合物：
Figure PCTCN2019086792-appb-000003
Figure PCTCN2019086792-appb-000004
因此，在第一方面，本发明提供了上述式I化合物或其药学上可接受的盐。例如，当QR4为羟基时，所述盐可以是式I化合物与碱金属、碱土金属、过渡金属或胺形成的盐；当X、Y或Z中有N原子时，所述盐可以是式I化合物与有机酸或无机酸所形成的盐。
在另一方面，本发明提供了一种药物组合物，其包含本发明的式I化合物或 其药学上可接受的盐，以及任选的药学上可接受的载体或赋形剂。
在又一方面，本发明还提供了本发明的上述式I化合物或其药学上可接受的盐在制备用于抑制IL-17F的分泌和活性的药物中的用途。
本发明人惊讶地发现，式I的化合物及其药学上可接受的盐具有抑制白介素17F的分泌的作用，因此能够作为白介素17F的调节剂使用。
相应地，在另一方面，本发明提供了一种抑制IL-17F的分泌和活性的方法，包括向有此需要的对象施用本发明的式I化合物或其药学上可接受的盐。
本申请还证实，如式I的化合物及其药学上可接受的盐还具有预防和治疗肿瘤的作用，因此能够作为预防和治疗肿瘤的药物应用。具体而言，所述肿瘤包括实体瘤和非实体瘤，所述肿瘤包括但不限于黑色素瘤、胰腺癌、结直肠癌、肺癌、肝癌、胃癌、喉癌、鼻咽癌、食道癌、多发性骨髓瘤、淋巴癌、白血病、膀胱癌、前列腺癌、胆管癌、宫颈癌、卵巢癌、乳腺癌、子宫内膜癌、皮肤癌、头颈癌、胆囊癌、肾癌等。特别优选地，所述肿瘤为结直肠癌、胃癌、膀胱癌和乳腺癌。相应地，本发明提供了一种预防和/或治疗肿瘤的方法，包括向有此需要的对象施用本发明的式I化合物或其药学上可接受的盐。
另一方面本发明的式I化合物或其药学上可接受的盐在还具有预防和治疗自身免疫疾病的作用，因此，能够作为预防和治疗自身免疫疾病的药物应用。具体而言，所述自身免疫疾病包括但不限于红斑狼疮、银屑病、类风湿性关节炎、硬皮病等。特别优选地，所述自身免疫疾病选自红斑狼疮和银屑病。相应地，本发明提供了一种预防和/或治疗自身免疫疾病的方法，包括向有此需要的对象施用本发明的式I化合物或其药学上可接受的盐。
本发明中，式I化合物的药学上可接受的盐意味着在合理的医学判断范围内适合用于与人体和低等动物组织接触，没有不适当的毒性、刺激性、变态反应等，与合理的利益/风险比相称。
药学上可接受的盐是本领域熟知的。例如，S.M.Berge等在J.Pharmaceutical Sciences,1977,66,1-19中详细描述了药学上可接受的盐，在此并入本文作为参考。本发明化合物的盐包括从适合的无机与有机碱衍生的那些。无机碱盐包括与氨、碱金属、碱土金属或过渡金属形成的盐，例如铵盐以及锂盐、钠盐、钾盐、钙盐、锌盐、铁盐、亚铁盐等。有机碱盐包括胺盐，包括式I化合物与伯、仲或叔胺形成的盐，可以选自与下列有机碱形成的盐：例如精氨酸、乙二胺、三乙胺、咖啡因、甜菜碱、乙醇胺、三甲胺、哌啶等。
具体实施方式
在本发明中，式I化合物如下所示：
Figure PCTCN2019086792-appb-000005
在一些优选的实施方案中，Q选自O。在一些优选的实施方案中，X，Y，Z选自C或N。
在一些优选的实施方案中，R 1和R 2相同；特别优选地，R 1和R 2独立地选自氢、C1-C3烷基或C1-C5烷基酰基。
在一些优选的实施方案中，R 1和R 2与其相邻的氧形成下式所示的缩醛：
Figure PCTCN2019086792-appb-000006
其中，R 6、R 7独立地选自氢、C1-C5烷基、C2-C5烯基、取代或未取代的苯基、苯基C2-C5烯基；或者，R 6、R 7与其相邻的C形成3～6元环。
在一些优选的实施方案中，R 3选自氢、甲基、乙基、丙基、异丙基。
在一些优选的实施方案中，R 4选自氢、甲基、乙基、丙基、异丙基。
在一些优选实施方案中，R 3和R 4与其相邻的氧成内酯。
在一些优选实施方案中，R 5选自氢、甲基、乙基、丙基、异丙基、氟、氯、溴、碘。
在优选的实施方案中，提供了以下的式I化合物：
Figure PCTCN2019086792-appb-000007
其中，X、Y、Z中至少一个为N，但不同时为N；R 1或R 2相同，独立地选自氢、 甲基、乙基、丙基、异丙基或C1-C5烷基酰基；R 3选自氢、甲基、乙基、丙基、异丙基；R 4选自氢、甲基、乙基、丙基、异丙基；R 5选自氢、甲基、乙基、丙基、异丙基、硝基、氟、氯、溴和碘。在上述情况下的式I化合物中，R 1和R 2未形成缩醛，并且R 3和R 4也未形成内酯。
上述典型化合物见表1。
表1
Figure PCTCN2019086792-appb-000008
Figure PCTCN2019086792-appb-000009
在一些具体的方面，本发明的式I化合物具有下述式I-2结构：
Figure PCTCN2019086792-appb-000010
其中，R 1与R 2可以相同，独立的选自氢、甲基、乙基、丙基、异丙基或C1-C5烷基酰基；
R 5选自氢、甲基、乙基、丙基、异丙基、氟、氯、溴、碘。
即，在上述情况下的式I化合物中，R 3和R 4形成内酯。
式I-2所示的典型化合物见表2。
表2
Figure PCTCN2019086792-appb-000011
Figure PCTCN2019086792-appb-000012
在一些具体的方面，式I化合物具有以下式I-3结构：
Figure PCTCN2019086792-appb-000013
其中，R 6、R 7独立地选自氢、C1-C5烷基、C2-C5烯基、取代或未取代的苯基、苯基C2-C5烯基；
R 3选自氢、甲基、乙基、丙基、异丙基；
R 4选自氢、甲基、乙基、丙基、异丙基。
R 5选自氢、甲基、乙基、丙基、异丙基。
即，在上述情况下的式I化合物中，R 1和R 2形成缩醛。
式I-3所示的典型化合物见表3。
表3
Figure PCTCN2019086792-appb-000014
Figure PCTCN2019086792-appb-000015
在一些具体的方面，式I化合物具有以下式I-4结构：
Figure PCTCN2019086792-appb-000016
其中，R 3选自氢、甲基、乙基、丙基、异丙基；
R 4选自氢、甲基、乙基、丙基、异丙基；
R 5选自氢、甲基、乙基、丙基、异丙基；
n选自1、2、3和4。
即，在上述情况下的式I化合物中，R 1和R 2形成缩醛，且其上的取代基形成3～6元环。
式I-4所示的典型化合物见表4。
表4
Figure PCTCN2019086792-appb-000017
Figure PCTCN2019086792-appb-000018
在一些具体的方面，式I化合物具有以下式I-5结构：
Figure PCTCN2019086792-appb-000019
其中，R 6、R 7独立地选自氢、C1-C5烷基、C2-C5烯基、取代或未取代的苯基、苯基C2-C5烯基；
R 5选自氢、甲基、乙基、丙基、异丙基。
即，在上述情况下的式I化合物中，R 1和R 2形成缩醛，并且R 3和R 4形成内酯。
式I-5所示的典型化合物见表5。
表5
Figure PCTCN2019086792-appb-000020
Figure PCTCN2019086792-appb-000021
在一些具体的方面，式I化合物具有以下式I-6结构：
Figure PCTCN2019086792-appb-000022
其中，R 5选自氢、甲基、乙基、丙基、异丙基；
n选自1、2、3或4。
即，在上述情况下的式I化合物中，R 1和R 2形成缩醛，其上的取代基形成3～6元环，并且同时R 3和R 4形成内酯。
式I-6所示的典型化合物见表6。
表6
Figure PCTCN2019086792-appb-000023
Figure PCTCN2019086792-appb-000024
在本发明中，式I化合物可以按照以下方法制备：
首先，起始原料D-(-)-奎宁酸在催化剂存在下成内酯，同时在3,4位引入保护基得到中间体1，中间体1与中间体2进行酯化反应得到中间体3，中间体3在碱性条件下，进行酯水解得到中间体4，中间体4在酸性条件下，进一步脱保护基得到式Ⅰ化合物。
反应过程如下：
Figure PCTCN2019086792-appb-000025
其中：
`R 1、`R 2、`R 3、`R 4、`R 5的定义分别与式I中R 1、R 2、R 3、R 4、R 5、定义相同，其它变量X、Y、Z的定义与式I中相同；L为选自氟、氯、溴、碘的卤素或羟基。
在本发明的合成路线中，在制备中间体3时，成酯的方法通常有两种方法即：当中间体2为羧酸时，可在常规缩合剂(例如N,N`-二环己基碳二亚胺(DCC)、1-乙基-(3-二甲基氨基丙基)碳二亚胺(EDC)等)存在下成酯；当中间体2为相应的酰卤时，可在碱性条件下(例如吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂环[5,4,0]十一烯-7等)直接成酯。
本发明合成方法中，将中间体3进行酯水解所使用的碱可为氢氧化锂、氢氧化钠、氢氧化钾等；中间体4脱保护所使用的酸可为盐酸水溶液、硫酸水溶液、三氟乙酸水溶液等。
在本发明中，术语“烷基”表示1至12个碳原子的饱和直链或支链烃基，优选为1至6个碳原子的饱和直链或支链烃基，更优选为1至5个碳原子的饱和直链或支链烃基，特别优选为1至4个碳原子的饱和直链或支链烃基，尤其优选甲基、乙基、丙基、异丙基。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、2-甲基丁基、新戊基、己基、庚基、辛基。
在本发明中，术语“烯基”表示通过去除单个氢原子衍生自烃部分的单价基 团，其中烃基部分分别具有至少一个碳碳双键并且包含2至12个碳原子。优选的烯基为C2-C6烯基，更优选C2-C5烯基。代表性烯基包括但不限于乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基及类似基团。
在本发明中，术语“环烷基”表示饱和碳环化合物具有3至12个环原子，优选的环烷基具有3至6个碳原子，更优选具有3至5个碳原子的环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基。
在本发明中，术语“酰基”包括衍生至酸的残基，该酸包括但不限于羧酸、氨基甲酸、碳酸、磺酸和磷酸。实例包括脂肪族羰基、芳族羰基、脂肪族磺酸基。脂肪族羰基的实例包括但不限于，乙酰基、丙酰基、丁酰基及类似基团。本发明中优选的酰基是烷基酰基，尤其是C1-C6烷基酰基。
在本发明中，术语“卤素”指氟、氯、溴、碘。
在本发明中，术语“芳基”是指具有1至3个芳环的单环、双环或三环碳环系统，优选碳原子数为6至14的芳基，包括但不限于，苯基、萘基、四氢萘基、蒽基及类似基团。
在本发明中，术语“芳基烷基”如本文所用，是指通过如本文定义的烷基附于母体分子的如本文定义的芳基。实例包括但不限于，苄基、苯乙基及类似基团。
在本发明中，术语“取代”是指其上一个、两个或三个或更多个氢原子被取代基独立地取代，该取代基包括但不限于，卤素、-OH、被保护羟基、-NO 2、-CN、-NH 2、被保护的氨基、烷氧基等。优选的取代基包括卤素、-OH、C1-C4烷基、C1-C4烷氧基、-NO 2、乙酰基。
本发明还提供了一种药物组合物，包含式I化合物或其药学上可接受的盐以及任选的药学上可接受的辅料(赋形剂或稀释剂)。
在本发明中术语“药物组合物”是指包括适合于所需的特定剂型的任意和所有溶剂、稀释剂或其他液体赋形剂、分散或悬浮助剂、表面活性剂、等渗剂、增稠或乳化剂、防腐剂、固体粘合剂、润滑剂等。Remington`s Pharmaceutical Sciences,Sixteenth Edition,E.W.Maetin(Mack Publishing Co.,Easton,Pa.,1980)公开了用于配制药学上可接受的组合物的各种载体和用于其制备的已知技术。除了任何常规载体介质与本发明化合物不相容以外，例如产生任何不可取得生物学效应或者以有害方式相互作用于药学上可接受的组合物的任何其他组分，它的使用涵盖在本发明的范围内。能够充当药学上可接受的载体的材料的一些 实例包括，但不限于，离子交换剂；氧化铝；硬脂酸铝；卵磷脂；缓冲物质，例如：磷酸盐；甘氨酸；山梨酸或山梨酸钾；饱和植物脂肪酸的偏苷油酯混合物；水；盐或电解质，例如：磷酸氢二钠、磷酸氢钾、氯化钠、锌盐；胶体二氧化硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸酯；糖类，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；明胶；滑石；赋形剂，例如可可脂和栓剂用蜡；油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇，例如丙二醇或聚乙二醇；酯类，例如油酸乙酯和月桂酸乙酯；琼脂；无热原的水；等渗盐水；乙醇；以及其他无毒的可相容的润滑剂，例如月桂基硫酸钠和硬脂酸镁；根据制剂人员的判断，在组合物中也可以存在着色剂、释放剂、包衣剂、甜味剂、调味剂和香料、防腐剂和抗氧化剂。
本发明还提供了一种药物制剂，包含式I化合物或其药学上可接受的盐以及任选的药学上可接受的赋形剂或稀释剂，可以按照常规制备方法将本发明化合物或其盐配制为常规药物制剂，例如胶囊剂、片剂、丸剂、颗粒剂、乳剂、混浮剂、注射剂、滴剂等。
本发明人发现，本发明的式I化合物及其药学上可接受的盐具有抑制白介素17，尤其是白介素17F的分泌的作用，并且能够预防和治疗肿瘤。实验结果表明，式I化合物中有部分化合物在浓度为0.5μM/L时对白介素17F的抑制率接近70％；在20mg/kg的剂量下对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤有较好的抑制作用，均超过50％。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：化合物1-1的制备
Figure PCTCN2019086792-appb-000026
步骤A：
将D-(-)-奎宁酸(40.0g，0.208mol，、对甲苯磺酸一水合物(0.8g，4.16mmol)、丙酮(200.0ml)、2,2-二甲氧基丙烷(75.8g，0.728mol)投入反应口瓶中，，加热回流反应4h。体系开始反应时为固液混合相，随着反应的不断进行，全部溶解。反应完毕，40℃，减压浓缩干，剩余物中加入乙酸乙酯(300.0ml)、加入5％NaHCO 3水溶液(300.0ml)搅拌，分液，水相用乙酸乙酯(100.0ml)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，旋干，得浅黄色固体。用乙酸乙酯/石油醚体系重结晶，得36.2g类白色固体3,4-氧-异丙叉奎宁酸-1,5-内酯(中间体1-1a)，收率：81.2％。mp：131～133℃；
Figure PCTCN2019086792-appb-000027
(c＝1，CH 3OH)。
步骤B：
将(E)-3(3-吡啶基)烯丙酸(20g，0.134mol)加入到反应瓶中，加入二氯甲烷(200.0ml)，固体未完全溶解，加入氯化亚砜(40.0ml)，加热回流反应3h。原料反应完全，反应体系直接减压旋蒸得类白色固体(E)-3-(3-吡啶基)烯丙酰氯盐酸盐(中间体1-1b)，直接用于下一步反应。
步骤C：
向反应瓶中依次加入中间体1-1a(23.6g，0.11mol)，无水二氯甲烷(240.0ml)，N,N-二异丙基乙胺(56.9g，0.44mol)，4-二甲氨基吡啶(4.0g，0.033mol)，体系用冰浴降温到0℃，滴加(E)-3-(3-吡啶基)烯丙酰氯盐酸盐(中间体1-1b)(27.3g，0.134mol)的N,N-二甲基乙酰胺(110.0ml)溶液，滴加完，体系升温至25℃反应1h，原料反应完全。向体系中加入水，分液，水相用二氯甲烷萃取两次，合并有机相分别用水、1N HCl洗涤，再用饱和氯化钠洗涤，无水硫酸钠干燥，抽滤，滤液减压旋蒸除去溶剂，得淡黄色油状物。用二氯甲烷/石油醚结晶，过滤得到淡黄色固体31.5g(中间体1-1c)，收率：82.8％。MS(ESI +)：m/z＝345.2步骤D：
向反应瓶中加入中间体1-1c(4.0g，11.58mmol)，加入四氢呋喃(80.0ml)、H 2O(20.0ml)，室温下搅拌溶清。体系用冰浴降温到0℃，滴加1mol/L LiOH水溶液(17.4ml，17.4mmol)，滴加完毕，室温搅拌反应1h。TLC(PE:EA＝1:1)显示原料反应完全，体系用0.5N柠檬酸水溶液调pH值至6左右，减压浓缩至干，得到固体用四氢呋喃(60.0ml×3)提取，合并有机相用无水硫酸钠干燥，过滤，滤液旋蒸得2.41g固体(中间体1-1d)，收率：57.3％。MS(ESI +)：m/z＝363.1步骤E：
将中间体1-1d(1.0g，2.75mmol)加入到反应瓶中，加入二氯甲烷(20.0ml)溶解，加入水(1.0ml)，体系用冰浴降温到0℃，滴加三氟乙酸(2.0ml)，滴加完毕，体系升温至25℃反应0.5h，原料反应完全，将体系直接减压浓缩，得到类白色固体(化合物1-1)0.77g，收率：86.5％。MS(ESI +)：m/z＝323.3。
实施例2：化合物1-5的制备
Figure PCTCN2019086792-appb-000028
步骤E：
向三口瓶中依次加入中间体1-1c(10.0g，28.96mmol)、DCM(100.0ml)，搅拌溶清，再加入H 2O(10.0ml)，体系用冰浴降温到0℃，缓慢滴加三氟乙酸(20.0ml)，滴毕，体系升温至25℃反应0.5h，原料反应完全，将反应体系室温下用油泵减压浓缩，得7.2g类白色泡沫状固体1-5e，收率：81.5％。MS(ESI +)：m/z＝305.1。
步骤F：
氮气保护下，将中间体1-5e(5.0g，16.38mmol)加入到反应瓶中，加入无水DMF(50.0ml)溶解，体系降温至0℃，分批加入氢化钠(1.64g，40.95mmol，60％矿物油)，搅拌30min，缓慢滴加含有溴乙烷(3.9g，35.79mmol)的DMF溶液(10.0ml)，自然升至室温反应2h。向反应体系中加入饱和氯化铵水溶液，用乙酸乙酯萃取三次，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，减压下旋蒸得粗品，粗品经柱层析纯化，得1.3g标题化合物1-5f，收率：22.0％。MS(ESI +)：m/z＝361.2。
步骤G：
将中间体1-5f(1.0g，2.77mmol)加入到反应瓶中，加入甲醇(10.0ml)，室温下搅拌溶清。将甲醇钠(0.18g，3.33mmol)加入到反应体系中，室温搅拌反应1h。原料反应完全。向反应体系中加入饱和氯化铵水溶液(10.0ml)，减压浓缩，剩余物用乙酸乙酯萃取三次，合并有机相，用饱和氯化钠洗涤，无水硫 酸钠干燥，抽滤，减压下旋蒸得粗品，粗品经柱层析纯化，得0.35g标题化合物1-5，收率：32.1％。MS(ESI +)：m/z＝393.3。
实施例3：化合物1-8的制备
Figure PCTCN2019086792-appb-000029
步骤B：
将(E)-3-(6-甲基-3-吡啶基)烯丙酸(15g，0.092mol)加入到反应瓶中，加入二氯甲烷(150.0ml)，固体未完全溶解，加入氯化亚砜(30.0ml)，加热回流反应3h。原料反应完全，反应体系直接减压旋蒸得类白色固体(E)-3-(6-甲基-3-吡啶基)烯丙酰氯盐酸盐(中间体1-8b)，直接用于下一步反应。
步骤C：
向反应瓶中依次加入中间体1-1a(16.5g，0.077mol)，无水二氯甲烷(170.0ml)，N,N-二异丙基乙胺(39.8g，0.308mol)，4-二甲氨基吡啶(2.8g，0.023mol)，体系用冰浴降温到0℃，滴加(E)-3-(6-甲基-3-吡啶基)烯丙酰氯盐酸盐(中间体1-8b)(20.1g，0.092mol)的N,N-二甲基乙酰胺(80.0ml)溶液，滴加完，体系升温至25℃反应1h，原料反应完全。向体系中加入水，分液，水相用二氯甲烷萃取两次，合并有机相分别用水、1N HCl洗涤，再用饱和氯化钠洗 涤，无水硫酸钠干燥，抽滤，滤液减压旋蒸除去溶剂，得淡黄色油状物。用二氯甲烷/石油醚结晶，过滤得到淡黄色固体21.80g(中间体1-8c)，收率：78.8％。MS(ESI +)：m/z＝359.2
步骤D：
向反应瓶中加入中间体1-8c(10.0g，0.028mol)，加入四氢呋喃(200.0ml)、H 2O(50.0ml)，室温下搅拌溶清。体系用冰浴降温到0℃，滴加1mol/L LiOH水溶液(42.0ml，0.042mol)，滴加完毕，室温搅拌反应1h。TLC(PE:EA＝1:1)显示原料反应完全，体系用0.5N柠檬酸水溶液调pH值至6左右，减压浓缩至干，得到固体用四氢呋喃(80.0ml×3)提取，合并有机相用无水硫酸钠干燥，过滤，滤液旋蒸得6.48g固体(中间体1-8d)，收率：61.7％。MS(ESI +)：m/z＝377.1
步骤E：
将中间体1-8d(1.0g，2.65mmol)加入到反应瓶中，加入二氯甲烷(20.0ml)溶解，加入水(1.0ml)，体系用冰浴降温到0℃，滴加三氟乙酸(2.0ml)，滴加完毕，体系升温至25℃反应0.5h，原料反应完全，将体系直接减压浓缩，得到类白色固体(化合物1-8)0.69g，收率：77.2％。MS(ESI +)：m/z＝337.3。
实施例4：化合物1-9的制备
Figure PCTCN2019086792-appb-000030
按照实施例1工艺描述的操作条件制备，首先，用(E)-3-(2-氯-3-吡啶基)烯丙酸代替(E)-3-(3-吡啶基)烯丙酸成酰氯，得到中间体1-9b，然后，中间体1-9b与1-1a在碱性条件下酯化反应，再经水解、脱保护得到标题化合物1-9。MS(ESI +)：m/z＝357.0。
实施例5：化合物1-10的制备
Figure PCTCN2019086792-appb-000031
按照实施例1工艺描述的操作条件制备，首先，用(E)-3-(5-硝基-3-吡啶基)烯丙酸代替(E)-3-(3-吡啶基)烯丙酸成酰氯，得到中间体1-10b，然后中间体1-10b与1-1a在碱性条件下酯化反应，再经水解、脱保护得到标题化合物1-10。MS(ESI +)：m/z＝368.1。
实施例6：化合物1-11的制备
Figure PCTCN2019086792-appb-000032
按照实施例1工艺描述的操作条件制备，首先，用(E)-3-(2-吡啶基)丙烯酸代替(E)-3-(3-吡啶基)烯丙酸成酰氯，得到中间体1-11b，然后，中间体1-11b与1-1a在碱性条件下酯化反应，再经水解、脱保护得到标题化合物1-11。
MS(ESI +)：m/z＝323.1。
实施例7：化合物1-14的制备
Figure PCTCN2019086792-appb-000033
步骤B：
将(2E)-3-(2-嘧啶基)丙烯酸(18.0g，0.12mol)加入到反应瓶中，加入二氯甲烷(200.0ml)，固体未完全溶解，加入氯化亚砜(40.0ml)，加热回流反应3h。原料反应完全，反应体系直接减压旋蒸得类白色固体(2E)-3-(2-嘧啶基)烯丙酰氯盐酸盐(中间体1-14b)，直接用于下一步反应。
步骤C:
向反应瓶中依次加入中间体1-1a(21.4g，0.1mol)，无水二氯甲烷(220.0ml)，N,N-二异丙基乙胺(51.7g，0.4mol)，4-二甲氨基吡啶(3.7g，0.03mol)，体系用冰浴降温到0℃，滴加(2E)-3-(2-嘧啶基)烯丙酰氯盐酸盐(中间体1-14b)(24.6g，0.12mol)的N,N-二甲基乙酰胺(100.0ml)溶液，滴加完，体系升温至25℃反应1h，原料反应完全。向体系中加入水，分液，水相用二氯甲烷萃取 两次，合并有机相分别用水、1N HCl洗涤，再用饱和氯化钠洗涤，无水硫酸钠干燥，抽滤，滤液减压旋蒸除去溶剂，得淡黄色油状物。用二氯甲烷/石油醚结晶，过滤得到淡黄色固体24.2g(中间体1-14c)，收率：69.9％。MS(ESI +)：m/z＝346.2
步骤E：
向三口瓶中依次加入中间体1-14c(10.0g，28.87mmol)、DCM(100.0ml)，再加入H 2O(10.0ml)，冰水浴中缓慢滴加三氟乙酸(20.0ml)，滴毕室温搅拌0.5h，取样TLC监控反应完全。将反应体系室温下用真空油泵减压浓缩，得6.6g淡黄色泡沫状固体1-14e，收率：74.6％。MS(ESI +)：m/z＝306.0。
步骤F：
氮气保护下，将中间体1-14e(6.0g，19.59mmol)加入到反应瓶中，加入无水DMF(60.0ml)溶解，体系降温至0℃，分批加入氢化钠(2.0g，48.98mmol，60％矿物油)，搅拌30min，缓慢滴加含有碘甲烷(6.2g，43.68mmol)，自然升至室温反应1h。向反应体系中加入2N氯化铵水溶液，用乙酸乙酯萃取三次，合并有机相，用饱和氯化钠洗涤，无水硫酸钠干燥，抽滤，滤液减压下旋蒸得粗品，粗品经柱层析纯化，得2.4g标题化合物1-14f，收率：36.6％。MS(ESI +)：m/z＝334.2。
步骤G：
将中间体1-14f(1.5g，4.49mmol)加入到反应瓶中，加入甲醇(15.0ml)，室温下搅拌溶清。将甲醇钠(0.3g，5.55mmol)加入到反应体系中，室温搅拌反应0.5h。原料反应完全。向反应体系中加入饱和氯化铵水溶液(15.0ml)，减压浓缩，剩余物用乙酸乙酯萃取三次，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，减压下旋蒸得粗品，粗品经柱层析纯化，得0.57g标题化合物1-14，收率：34.7％。MS(ESI +)：m/z＝366.3。
实施例8：化合物2-1的制备
实施例2制备的化合物1-5e即化合物2-1。
实施例9：化合物2-3的制备
Figure PCTCN2019086792-appb-000034
步骤F：
按照实施例2步骤F描述的操作制备得到化合物2-3。MS(ESI +)：m/z＝485.3。
实施例10：化合物3-1的制备实施例1制备的化合物1-1d即化合物3-1。
实施例11：化合物3-4的制备
Figure PCTCN2019086792-appb-000035
步骤A：
向500ml单口瓶中依次加入D-(-)-奎宁酸(20.0g，0.10mol)、甲苯(120ml)、甲基异丁烯甲酮(100.0ml)、对甲苯磺酸一水合物(2.0g，0.01mol)，加毕升温至回流，架分水器，体系呈黄色浑浊液，回流后分水2h、继续回流反应2h。体系变澄清，有少量黄色不溶物贴于瓶壁，TLC监控反应完全。50℃减压浓缩，剩余物中加入H 2O(80.0ml)、，用饱和NaHCO 3调pH为7～8，水相用二氯甲烷(100.0ml×2)萃取，合并有机相，用brine(100.0ml)洗涤，无水Na 2SO 4干燥， 过滤浓缩，得23.70g黄色固体。用乙酸乙酯\石油醚体系重结晶，析晶过夜，0℃析晶2h，抽滤，滤饼真空干燥得13.71g白色晶体，即中间体3-4a。收率：53.92％。MS(ESI +)：m/z＝254.1。
步骤C：
按照实施例1中步骤C的操作进行，其中将1-1a用3-4a代替。
步骤D：
按照实施例1中步骤D进行操作，其中用3-4c代替1-1c。MS(ESI +)：m/z＝403.2。
实施例12：化合物4-8的制备
Figure PCTCN2019086792-appb-000036
步骤A：按照实施例11中步骤A的操作进行，其中用环己酮代替甲基异丁烯甲酮。
步骤C：按照实施例1中步骤C的操作进行，其中用1-14b代替1-1b进行酯化得到中间体4-8c。
步骤D：按照实施例1中步骤D进行操作，其中用4-8c代替1-1c。MS(ESI +)：m/z＝404.1。
实施例13：化合物5-1的制备
实施例1制备的化合物1-1c即化合物5-1。
实施例14：化合物6-3的制备
Figure PCTCN2019086792-appb-000037
步骤C：按照实施例1中步骤C的操作进行，其中将中间体1-1a用4-8a替代。MS(ESI +)：m/z＝385.4。
实施例15 本发明提供的化合物的生物活性实验
1、体外活性研究：利用白介素17F(IL17F)检测试剂盒，通过ELISA法检测式I所示的化合物作用24h对U87-Luc细胞IL17F分泌的影响。
操作步骤如下：
(1)、加样：分别设空白孔(空白对照孔除不加样品及酶标试剂外，其余各步操作与标准孔和待测样品孔相同)、标准孔、待测样品孔。在酶标包被板上标准品准确加样，待测样品孔中先加样品稀释液，然后再加待测样品。加样时将样品加于酶标板孔底部，尽量不触及孔壁，轻轻晃动混匀。
(2)、温育：用封板膜封板后置37℃温育30分钟。
(3)、配液：将30倍浓缩洗涤液用蒸馏水30倍稀释后备用。
(4)、洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，在吸水纸上轻拍酶标板来移除孔内所有液体。如此重复5次，最后一次洗涤后，吸取或倒出剩余的洗涤缓冲液，将酶标板倒扣在吸水纸上，将残留在孔内的液体全部吸干。
(5)、加酶：每孔加入酶标试剂，空白孔除外。
(6)、显色：每孔先加入显色剂A，再加入显色剂B，轻轻震荡混匀，37℃避光显色10分钟。
(7)、终止：每孔加终止液，终止反应(此时蓝色立转黄色)。
(8)、测定：以空白孔调零，在450nm波长下依序测量各孔的吸光度(OD值)。 测量应在加终止液后15分钟以内进行。
计算方法：
GI(生长抑制率)＝(1-OD 药物组/OD 对照组)×100％。                     测试结果见表7，表7为本发明提供的化合物的体外活性测试结果。
表7 本发明化合物的体外活性测试结果
Figure PCTCN2019086792-appb-000038
Figure PCTCN2019086792-appb-000039
2、体内效力研究：
2.1小鼠黑色素瘤体内模型
无菌条件下将1×10 7个B16-F10细胞接种到C57BL/6小鼠腋下。10天后，无菌条件下获取肿瘤组织，匀浆用生理盐水稀释后计数，制成浓度为1×10 6个/mL的肿瘤细胞悬液，于小鼠右侧腋下接种0.2mL/只。接种后次日(24小时后)动物随机分组，称重后给药，待测化合物每天1次，连续腹腔给药13次。阳性对照药环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织，称重并进行拍照。最后计算肿瘤增殖抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.2小鼠胰腺癌PAN02体内模型
无菌条件下将小鼠胰腺癌PAN02瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数，制成浓度为1.2×10 7个/mL的肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给予待测化合物，连续给药13次。阳性对照药环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.3小鼠结直肠癌MC38体内模型
无菌条件下将小鼠结直肠癌MC38瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数，制成浓度为1.2×107个/mL的肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给予待测化合物，连续给药13次。阳性对照药环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.4小鼠Lewis肺癌体内模型
无菌条件下将小鼠Lewis肺癌瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数，制成浓度为1.2×10 7个/mL的肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给予待测化合物，连续 给药13次。环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
计算方法：
肿瘤增殖抑制率TGI(％)：TGI＝(1-T/C)×100。(T：治疗组肿瘤重量；C：阴性对照组肿瘤重量)。测试结果见表8。
表8 本发明部分化合物的体内活性测试结果
Figure PCTCN2019086792-appb-000040
Figure PCTCN2019086792-appb-000041
由表7可知，化合物1-1对白介素17F具有抑制作用，抑制率接近70％；化合物1-1在20mg/kg的剂量下对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤有较好的抑制作用，均超过50％。而其衍生物对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤也具有较好的抑制作用。
实施例16 自身免疫疾病动物模型
1.咪喹莫特诱导的小鼠银屑病模型
1.1动物分组
  咪喹莫特造模 给药剂量 给药方式 动物只数
对照组 - - - 10
模型组 + - - 10
咪喹莫特组 + 1.5mg/kg 灌胃 10
化合物1-1 + 20mg/kg 尾静脉注射 8
1.2造模及评价方式
用宠物电推剪及脱毛膏给小鼠背部去毛，面积约为1.5×2cm 2。除了阴性对照组动物外，每组动物均用咪喹莫特乳膏进行造模，即每天给予小鼠背部去毛部位的皮肤涂抹50mg的咪喹莫特乳膏，每天涂抹1次，连续7天。造模当天腹腔注射化合物，每天1次，第8天处理动物。首次造模次日开始每天对动物进行银屑病样皮损面积和疾病严重程度(PASI，psoriasis area and severity index)评分。依据PASI评分标准，对小鼠皮损处红斑、鳞屑以及浸润增厚程度分别给予0-4的积分，将三者积分相加即得到总分。
PASI评分标准：0，无；1，轻度；2，中度；3，重度；4，极重度。实验结束(第7天)时，将小鼠脱颈椎处死，用游标卡尺测量皮肤厚度，并将动物背部脱毛处的皮肤取下，用4％多聚甲醛固定，进行病理分析。PASI评分结果见以下表1.3，结果以平均值±标准差表示。
1.3 PASI评分
红斑
天数 对照组 造模组 MTX 化合物1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 1.1±0 0.8±0.7 0.6±0.5
3 0±0 2.2±0 2.0±0.3 1.5±0.5
4 0±0 1.9±0 1.8±0.4 1.7±0.5
5 0±0 2±0 1.3±0.5 1.3±0.5
6 0±0 1.3±0.5 1.3±0.5 1±0
鳞屑
天数 对照组 造模组 MTX 化合物1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 0.4±0.5 0.2±0.3 0.1±0
3 0±0 1.5±0.5 1.9±0.3 1.5±0.5
4 0±0 1.9±0.4 1.6±0.7 1.6±0.4
5 0±0 2.4±0.7 1.7±0.7 1.8±0.5
6 0±0 2.5±0.5 2.4±1.0 2.4±0.9
增厚
天数 对照组 造模组 MTX 化合物1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 1±0 0.9±0.3 1±0
3 0±0 2.3±0.6 2.3±0.5 2±0
4 0±0 2.4±0.5 2.3±0.5 2.1±0.5
5 0±0 2.8±0.4 2.1±0.7 2.3±0.5
6 0±0 3.5±0.5 3.1±0.9 3.3±0.7
总分
天数 对照组 造模组 MTX 化合物1-1
0 0±0 0±0 0±0 0±0
1 0±0 0±0 0±0 0±0
2 0±0 2.5±0.5 1.9±0.6 1.7±0.5
3 0±0 6±0.6 6.2±0.5 5.0±0.5
4 0±0 6.3±0.7 5.7±1.0 5.4±0.6
5 0±0 7.3±0.8 5.1±1.2 5.4±0.5
6 0±0 7.3±1.1 6.8±1.9 6.7±1.5
从PASI评分上看，化合物1-1对病理红斑的改善程度好于对鳞屑及增厚的改善。在疾病的不同时间，对不同病理情况均有一定的改善作用，与阳性化合物MTX基本相当。
2.红斑狼疮动物模型
10周龄MRL/lpr自发型狼疮性小鼠，灌胃或腹腔注射化合物，每天1次，连续3个月。给药期间及实验结束时观察并检测皮肤病理、关节肿胀程度及病理、血/尿肌酐尿素氮以及血dsDNA和ANA抗体。结果表明本发明的化合物对红斑狼疮有明显改善。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (16)

  1. 式I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2019086792-appb-100001
    其中，Q选自O和N；X、Y、Z各自独立地选自C、O、S和N；
    R 1和R 2相同或不同，独立地选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的芳基烷基、未取代或取代的酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
    R 3选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的酰基；
    R 4选自氢、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的环烷基、未取代或取代的芳基、未取代或取代的芳基烷基；
    R 5选自氢、卤素、氰基、硝基、未取代或取代的羟基、未取代或取代的烷基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中X、Y、Z中至少有一个为N，但不同时为N。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中Q选自O，R 3和R 4与其相邻的氧形成内酯。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中R 1和R 2与其相邻的氧形成缩醛。
  5. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐，其中R 1和R 2相同。
  6. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中R 1和R 2独立地选自氢、C1-C3烷基和C1-C5烷基酰基。
  7. 根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐，其中R 1和R 2与其相邻的氧形成下式所示的缩醛：
    Figure PCTCN2019086792-appb-100002
    其中，R 6、R 7独立地选自氢、C1-C5烷基、C2-C5烯基、取代或未取代的苯基、苯基C2-C5烯基。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中R 6、R 7与其相邻的C形成3～6元环。
  9. 根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐，其中R 5选自氢、甲基、乙基、丙基、异丙基、硝基、氰基、氟、氯、溴和碘。
  10. 根据权利要求1至9中任一项所述的化合物或其药学上可接受的盐，其中X、Y、Z为C或N。
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其为选自以下结构的化合物或其药学上可接受的盐：
    Figure PCTCN2019086792-appb-100003
    Figure PCTCN2019086792-appb-100004
  12. 根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐，其中所述盐为与碱金属、碱土金属、过渡金属或胺形成的盐。
  13. 一种药物组合物，其包含权利要求1至12中任一项所述的化合物或其药学上可接受的盐，以及任选的药学上可接受的载体或稀释剂。
  14. 权利要求1至12中任一项所述的化合物或其药学上可接受的盐在制备用于抑制IL-17F的分泌和活性的药物中的用途。
  15. 根据权利要求14的用途，其中所述药物用于预防或治疗肿瘤。
  16. 根据权利要求14的用途，其中所述药物用于预防或治疗炎性疾病或自身免疫疾病。
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