WO2019196714A1 - 作为dhodh抑制剂的n-取代丙烯酰胺衍生物及其制备和用途 - Google Patents

作为dhodh抑制剂的n-取代丙烯酰胺衍生物及其制备和用途 Download PDF

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WO2019196714A1
WO2019196714A1 PCT/CN2019/081066 CN2019081066W WO2019196714A1 WO 2019196714 A1 WO2019196714 A1 WO 2019196714A1 CN 2019081066 W CN2019081066 W CN 2019081066W WO 2019196714 A1 WO2019196714 A1 WO 2019196714A1
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compound
group
substituted
unsubstituted
reacted
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French (fr)
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徐晓勇
李洪林
李忠
李诗良
曾凡勋
王蕊
章乐天
朱丽丽
齐甜甜
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华东理工大学
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry and pharmacotherapy, and in particular to N-substituted acrylamide derivatives as DHODH inhibitors, and their preparation and use.
  • Dihydroorotate dehydrogenase is an iron-containing flavin-dependent mitochondrial enzyme that is the intracellular rate-limiting enzyme in the synthesis of nucleoside pyrimidines and catalyzes the fourth step in the biosynthesis pathway from cephalin. . Inhibition of DHODH can block the synthesis of neonatal pyrimidines, resulting in DNA and RNA synthesis barriers. There are two ways to synthesize pyrimidine in most organisms: the salvage pathway and de novo synthesis from small molecules.
  • the demand for pyrimidine in an organism depends on the cell type and the stage of differentiation in which the cells in the resting and differentiated phases acquire only a small fraction of the pyrimidines through the de novo synthesis pathway, and rely mainly on the salvage pathway.
  • rapidly differentiated human cells such as activated T-lymphocytes, B-lymphocytes, and tumor cells need to rely on pyrimidine de novo synthesis to satisfy them.
  • Leflunomide marketed in 1998, is a new type of isoxazole immunomodulator, which is mainly used for the treatment of autoimmune diseases such as rheumatoid arthritis and lupus erythematosus and acute and chronic anti-organ transplantation. Rejection and prevention of xenogeneic rejection. It was later discovered that leflunomide is a prodrug that is rapidly converted to the active metabolite A771726 (MI) via the cytoplasm and microsomes of the liver and intestinal wall after oral administration. MI is a good human dihydroorotate dehydrogenase inhibitor that blocks the de novo biosynthesis of pyrimidines and thus the synthesis of DNA and RNA. Studies have shown that MI can be used to prevent, treat or inhibit a variety of autoimmune diseases, acute and chronic rejection of organ transplantation and xenogeneic rejection, skin diseases such as psoriasis, and diversity hardening.
  • autoimmune diseases such as rheumatoid arthritis and l
  • Buquina originally developed as an anticancer drug, is one of the most potent DHODH inhibitors, but clinical phase II experiments have demonstrated its anti-tumor effect, and the compound continues to be developed as an immunosuppressive agent. 4SC-101 has been shown to have a good inhibitory effect on lupus erythematosus and enteritis, and is in the clinical development stage.
  • a first aspect of the invention provides a compound of formula I, or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or Crystal form:
  • A is an unsubstituted or substituted C 3-7 cycloalkyl group, an unsubstituted or substituted C 5-7 cycloalkenyl group, an unsubstituted or substituted C 6 -C 10 aryl group, or an unsubstituted or substituted 5-10 a heterocyclic group; said substituted means substituted with a group selected from the group consisting of halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-7 cycloalkyl, C 5-7 cycloalkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-NH-CO-, -O-(CH 2 )mO-, -(CH 2 ) n-; wherein m or n
  • B is an unsubstituted or substituted C 3-7 cycloalkyl group, a C 5-7 cycloalkenyl group, a C 6 -C 10 aryl group, a 5-10 membered heterocyclic group;
  • the substituted group means selected from the group consisting of Substituted by: a halogen, a cyano group (-CN), a nitro group, a carboxyl group (-COOH), an amide group (-CONH 2 ), a sulfonic acid group, a sulfonamide, a C 1-6 sulfonate group, a hydroxyl group, C 1-6 alkylcarbonyl, C 1-6 haloalkylcarbonyl, C 1-6 aldehyde, C 1-6 ester, C 1-6 hydrazide, fluorenyl, C 1-6 alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl.
  • the compound is selected from the group consisting of the compounds of formula II:
  • a and R 2 are defined as before;
  • X represents a nitrogen atom or a group CY, wherein Y is selected from the group consisting of a carboxyl group, an amide group, a sulfonic acid group, a sulfonamide group, a C 1-6 sulfonate group, a hydroxyl group, a C 1-6 alkylcarbonyl group, and C 1- 6 haloalkylcarbonyl, C 1-6 aldehyde, C 1-6 ester, C 1-6 hydrazide, cyano, nitro, fluorenyl;
  • R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 2 -6 alkenyl, C 1-6 alkoxy, hydroxy, C 1-6 haloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-NH- CO-, -O-CH 2 -O-, -(CH 2 )n-; wherein n is an integer of 2 to 4.
  • the Y is selected from the group consisting of a carboxyl group, an amide group, and a cyano group.
  • A is an unsubstituted or substituted phenyl group, an unsubstituted or substituted pyridyl group, an unsubstituted or substituted indenyl group, an unsubstituted or substituted naphthyl group, an unsubstituted or substituted thienyl group, Unsubstituted or substituted benzothienyl, unsubstituted or substituted furyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted quinoline or unsubstituted or substituted isoquinolyl.
  • A is selected from the group consisting of:
  • R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl, cyclopropyl.
  • R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 halogenated alkane, C 3-7 cycloalkane.
  • Base C 1-4 alkoxy group, hydroxyl group.
  • each of R 3 , R 4 and R 5 is independently hydrogen, fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, methoxy, cyclopropyl or hydroxy.
  • the compound is selected from the group consisting of compounds of formula III:
  • R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 halogenated alkane, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6 -C 10 aryl, C 6 - C 10 aryloxy, 5- or 6-membered heterocyclic group, hydroxy group, C 6 -C 10 aryl-NH-CO-;
  • B is selected from unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heterocyclic groups, or unsubstituted or substituted C 5-7 cycloalkenyl.
  • the 5- or 6-membered heterocyclic group is selected from the group consisting of pyridyl, thienyl, and furyl.
  • B is selected from the group consisting of:
  • a second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect, or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof or a pharmaceutically acceptable salt or solvate or crystalline form thereof; and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is an injection, a capsule (such as a hard and soft gelatin capsule), a tablet, a coated tablet, a pill, a powder, a granule, a sugar-coated tablet, a solution, a syrup Agents, emulsions, suspensions, aerosols, suppositories, infusions, ointments, creams and elixirs.
  • a capsule such as a hard and soft gelatin capsule
  • a tablet such as a hard and soft gelatin capsule
  • a tablet such as a hard and soft gelatin capsule
  • a coated tablet such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill such as a coated tablet
  • a pill
  • a third aspect of the invention provides the compound of the first aspect, or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof Or a use of the pharmaceutical composition of the second aspect, for the preparation of a dihydroorotate dehydrogenase inhibitor; for the preparation of a pyrimidine biosynthetic enzyme inhibitor; and/or for the preparation of a prophylactic or therapeutic Inhibition of hydrogen orotate dehydrogenase and/or inhibition of pyrimidine biosynthetic enzymes to improve pathological conditions or diseases.
  • the pathological condition or disease is selected from the group consisting of cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular disease, anti-organ transplant rejection, melanoma, silver shavings Disease, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia and malaria.
  • a fourth aspect of the invention provides the compound of the first aspect, or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof Type preparation method,
  • the method is method 1, comprising the steps of:
  • method 4 including the steps of:
  • the compound 12 is subjected to a hydrolysis reaction to form a compound 13;
  • the compound 17 is subjected to a hydrolysis reaction to form a compound 18;
  • the compound 24 is subjected to a hydrolysis reaction to form a compound 25;
  • the present invention provides a method of treatment or prevention comprising administering to a subject in need thereof the compound of the present invention, or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof or A pharmaceutically acceptable salt or solvate or crystalline form thereof or a pharmaceutical composition of the invention.
  • the compound is a compound of Formula I, Formula II, or Formula III.
  • C 1-6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, A sec-butyl group, a tert-butyl group, or the like.
  • C 2-6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, propenyl, isopropenyl, 1-butenyl, 2- Butenyl, or a similar group.
  • C 2-6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, or the like.
  • C 3-7 cycloalkyl refers to a cyclic alkyl group having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
  • C 5-7 cycloalkenyl refers to a cyclic alkenyl group having from 5 to 7 carbon atoms having one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1 , 3-cyclohexadienyl, 1,4-cyclohexadienyl, or the like.
  • C1-6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen means fluoro, chloro, bromo, or iodo.
  • C 1-6 haloalkane refers to a straight or branched chain alkane having from 1 to 6 carbon atoms which is substituted by the same or different one or more of the above halogen atoms, such as trifluoromethyl, pentafluoroethyl, Heptafluoroisopropyl, or a similar group.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, tetrahydronaphthyl, Indane or the like.
  • an aryl group can be optionally substituted with one or more substituents as described herein.
  • aryloxy refers to aryl-O-, for example phenoxy (
  • the curve mark is the substitution position, the same as above and below.
  • heterocyclyl refers to a single or fused ring structure, which may be aromatic and non-aromatic in nature, and which preferably contains from 3 to 20 ring atoms, more preferably from 5 to 14 or 5 to 10
  • One or more ring atoms, at least one and preferably up to 4 are heteroatoms selected from nitrogen, oxygen or sulfur.
  • examples of the heterocyclic group include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridine , pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuran , morpholinyl, oxazolyl, dibenzothiophenyl, 1,2-methylenedioxyphenyl, fluorenyl, oxazolyl, benzimidazolyl, benzo[d][1,2 , 3] thiadiazolyl, imidazo[1,2-a]pyridyl, porphyrinyl,
  • 5- or 6-membered heterocyclyl refers to a five- or six-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, such as pyridinyl, thiazolyl, thienyl, furanyl, pyrrolyl , pyrazolyl, pyrimidinyl, tetrahydrofuranyl, oxazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl, and the like.
  • C1-6 aldehyde group refers to -C1-5 alkyl-CHO.
  • the groups described in the present invention can be 0 to more (usually 0, 1, 2 or 3, whether or not specifically stated as “unsubstituted or optionally substituted” or not specifically stated as “unsubstituted or optionally substituted”. Substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, carboxy, decyl, hydroxy, hydroxymethyl, C 1-4 aldehyde, C 1-6 alkyl, C 1-6 Haloalkyl (such as trifluoromethyl), halogen-substituted alkoxy (such as trifluoromethoxy), C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 5- 7 cycloalkenyl, C 1-6 alkoxy (such as methoxy), C 1-6 thioalkyl (such as pentafluorothiomethyl), C 1-6 thioalkoxy (such as pentafluorosulfur Methoxy),
  • the compounds of the present invention can be prepared by the following methods:
  • the starting aldehyde-based compound used can be purchased directly from the reagent company or by the following method:
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the starting aldehyde-based compound can be directly purchased from a reagent company or synthesized by the following method.
  • the substituted aromatic acid (10 mmol) was weighed and dissolved in 25 mL of anhydrous THF, and argon gas was added thereto, and LiAlH 4 (20 mmol) was slowly added thereto in portions under ice-cooling. After reacting for 10 minutes in an ice bath, the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the mixture was cooled in an ice bath, and 0.76 g of ice water, 0.76 g of a 15% aqueous NaOH solution, and 2.28 g of water were slowly added thereto in this order.
  • the substituted benzyl alcohol obtained in the previous step was dissolved in 100 mL of DCM, 70 mmol of MnO 2 was added under stirring, and reacted at room temperature for 4 h, filtered, and the filtrate was concentrated by spin-drying, and purified by column to obtain substituted aryl formaldehyde, the yield was 85-95%.
  • the substituted arylmethyl compound (5 mmol) was dissolved in 10 mL of CCl 4 , 10 mmol of NBS, 0.1 mmol of BPO was added, and the mixture was refluxed for 5 h, cooled to room temperature, filtered, and the filter cake was washed with an appropriate amount of petroleum ether and concentrated to dryness.
  • the obtained concentrate was dissolved in 10 mL of dioxane, added with 10 mL of water, 20 mmol of CaCO 3 , refluxed for 10 h, filtered, and extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate The yield is about 80%.
  • the substituted benzyl alcohol (4 mmol) obtained in the previous step was dissolved in 40 mL of DCM, 28 mmol of MnO 2 was added under stirring, and reacted at room temperature for 4 h, filtered, and the filtrate was concentrated by spin-drying, and purified by column to obtain substituted aryl formaldehyde.
  • the yield was about 90. %.
  • the substituted aldehyde compound (5 mmol) was dispersed into 15 mL of DCM, and 9 mmol of ethoxyformylethylenetriphenylphosphine was added. The reaction was carried out for 12 h at room temperature, a part of the solvent was removed, and the column was purified to obtain 2-methyl-3-substituted acrylic acid.
  • the ethyl ester intermediate has a yield of about 95%.
  • the 2-methyl 3-substituted ethyl acrylate (4 mmol) obtained in the previous step was dissolved in 12 mL of THF and 12 mL of MeOH, and 16 mL of 2M aqueous NaOH solution was added.
  • the reaction was carried out at 40 ° C for 5 h. It was acidified with 1 M HCl, precipitated as a white solid, suction filtered, washed with an appropriate amount of water, and dried to give 2-methyl 3-substituted acrylic acid in a yield of about 95%.
  • the amino compound (1.2 mmol) was dissolved in 2 mL of DCM, 1.5 mmol of TEA and 0.1 mmol of DMAP were added and cooled in an ice bath.
  • the obtained acid chloride was dissolved in 1 mL of DCM, added dropwise to the reaction liquid, and reacted at room temperature until the end of the reaction. Acidified with 1 M HCl, solid precipitated, suction filtered, and recrystallized from ethanol to give the final product. The yield is about 70%.
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the preparation of the starting material 2-methyl 3-substituted acrylic acid is similar to the preferred examples described above. Add 1 mmol of 2-methyl 3-substituted acrylic acid, 1.1 mmol of TsCl, 5 mL of DCE, 0.1 mmol of DMAP, 1.5 mmol of TEA, and react at 35 ° C for 1 h, add 1 mmol of amino compound, and react at 60 ° C for 10 h. Acidified with 1 M HCl, suction filtered to give a solid, washed with water, dried, and purified by column to give the desired product.
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the compound of the present invention can be synthesized by a method comprising the following steps:
  • the compound of the present invention is a compound represented by the formula I or II or III or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof. Or crystal form.
  • Examples of the pharmaceutically acceptable salts of the present invention include, but are not limited to, inorganic and organic acid salts such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, formic acid, acetic acid, propionic acid, oxalic acid. , malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid and other organic acids; and aspartic acid Acidic amino acids such as glutamic acid.
  • Another preferred class of salts are the salts of the compounds of the invention with bases, such as the alkali metal salts, especially the sodium and potassium salts.
  • the compound of the present invention has excellent DHODH inhibitory activity and can be used for the preparation of a medicament for treating or preventing DHODH-mediated diseases.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the invention together with a pharmaceutically acceptable carrier or excipient.
  • each active ingredient in the pharmaceutical compositions of the present invention can be determined by those skilled in the art, although the dosage of the drug required by each individual is different.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal daily, in an amount of from 0.0025 to 50 mg/kg body weight, preferably from about 0.01 to 10 mg per kg orally.
  • a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, more preferably from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes including, but not limited to, being formulated into parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, A form of nasal or topical administration for the treatment of tumors and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined by the age, health and weight of the patient, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic effect.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals is humans.
  • the medicament of the present invention or a pharmaceutical composition thereof can be used for treating or preventing DHODH-mediated diseases including cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular disease, anti-organ transplant rejection, melanoma , psoriasis, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, malaria, etc.
  • DHODH-mediated diseases including cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular disease, anti-organ transplant rejection, melanoma , psoriasis, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, malaria, etc.
  • cancers include, but are not limited to, breast cancer, prostate cancer, head and neck squamous cell carcinoma
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of blending with the compounds of the invention and with each other without significantly reducing the potency of the compound.
  • Pharmaceutically acceptable carriers include: fillers, bulking agents, disintegrating agents, binding agents, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or flavoring agents, A buffer substance or the like, and a solvent, a solubilizing agent or a reagent for obtaining a storage effect, a salt for changing the osmotic pressure, a coating reagent or an antioxidant, and the like.
  • examples of pharmaceutically acceptable carriers include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as Stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), a wetting agent (such as sodium lauryl sulfate), pyrogen-free water, and the like.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as Stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive
  • Solid dosage forms for oral administration include capsules (such as hard or soft gelatin capsules), tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or solubilizer, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example , glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) slow solvent, such as paraffin; (f) absorption acceleration Agents, for example, quaternary ammonium compounds;
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, especially cottonseed oil, peanut oil
  • compositions may contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, etc. .
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, for example, in combination with existing drugs for the treatment of the aforementioned diseases. In the latter case, an increase in efficacy can be observed.
  • Anthranilic acid (1.2 mmol) was dissolved in 2 mL of DCM, 1.5 mmol of TEA and 0.1 mmol of DMAP were added and cooled in an ice bath.
  • the obtained acid chloride was dissolved in 1 mL of DCM, added dropwise to the reaction liquid, and reacted at room temperature until the end of the reaction. Acidified with 1 M HCl, solid precipitated, suction filtered, and recrystallized from ethanol to give the final product. The yield was 70%.
  • the preparation method was similar to that of Example 1, except that 4-trifluoromethylbenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 6-trifluoromethylpyridine-3-carbaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 4-methoxybenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 4-tert-butylbenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 4-chloro-3-trifluoromethylbenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3-chloro-4-methylbenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3,4-dichlorobenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3,5-dichlorobenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3,4-dimethylbenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3,4-dimethoxybenzaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1,3-benzodioxan-5-formaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 2,3-dihydro-1H-indole-5-formaldehyde was used as a starting material.
  • the prepared substituted benzyl alcohol was dissolved in 100 mL of DCM, 70 mmol of MnO 2 was added under stirring, and reacted at room temperature for 4 h, filtered, and the filtrate was concentrated by spin-drying and purified by column to obtain 5,6,7,8-tetrahydronaphthalene-2. - Formaldehyde, yield 90%.
  • the subsequent step of preparing the target compound is similar to that of Example 1.
  • the preparation method was similar to that of Example 1, except that 6-methoxy-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 6-bromo-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 5-ben-2-naphthaldehyde was replaced with 5-chloro-2-naphthaldehyde.
  • the 5-chloro-2-naphthaldehyde is obtained by the main method as follows:
  • 5-Bromo-2 naphthoic acid (0.75 g, 3 mmol) was dispersed in 10 mL of methanol, and cooled in an ice bath. 1 mL of concentrated sulfuric acid was slowly added dropwise to the reaction mixture, and the mixture was refluxed for 2 hours, and 20 mL of water was added thereto, followed by extraction with DCM. The organic phase was washed successively with a saturated aqueous sodium hydrogen sulfate solution and brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to give methyl 5-bromo-2-naphthoate.
  • Methyl 5-chloro-2 naphthoate (0.44 g, 2 mmol) was dissolved in 10 mL of anhydrous THF, and then argon gas was applied, and LiAlH 4 (0.1 g, 2.6 mmol) was slowly added thereto in portions under ice bath. After reacting for 10 minutes in an ice bath, it was kept at room temperature for 12 hours, cooled in an ice bath, and 0.1 g of ice water, 0.1 g of a 15% aqueous NaOH solution, and 0.3 g of water were slowly added thereto in this order.
  • Phenol (705 mg, 7.5 mmol), p-fluorobenzaldehyde (625 mg, 5.0 mmol) and K 2 CO 3 (1.38 g, 10.0 mmol) were dispersed in 5 mL DMSO, argon-protected and reacted at 110 ° C overnight. After cooling to room temperature, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The subsequent preparation of the final product was the same as in Example 1.
  • the preparation method was similar to that of Example 14, except that [1,1'-biphenyl]-4-carboxylic acid was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1H-indole-6-formaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1-methyl-1H-indole-6-formaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3-quinolinaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 3-isoquinolinecarboxaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 7-quinolinaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 6-isoquinolinecarboxaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that benzothiophene-2-carbaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that benzothiophene-6-formaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that benzofuran-2-carbaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that benzofuran-6-formaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 35 except that triethyl phosphonoacetate was replaced with 2-phosphonopropionic acid triethyl ester.
  • the preparation method was similar to that of Example 35, except that 1-(naphthalen-2-yl)-1-ethanone was replaced with 2-naphthaldehyde, and phosphorus oxyacetate was replaced with 2-phosphonobutyrate triethyl acrylate. Ethyl ester.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-chlorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-bromobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-trifluoromethylbenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-methylbenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-methoxybenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-fluoro-2-naphthaldehyde was used as a raw material.
  • the 1-fluoro-2-naphthaldehyde can be prepared as follows:
  • 2-methyl-1-naphthylamine (1.57 g, 10 mmol) was added to a 100 mL eggplant-shaped flask, and fluoroboric acid (15 mL) was added dropwise to the reaction flask, and the mixture was cooled in an ice bath, and 10 mL of NaNO 2 was slowly added dropwise to the reaction solution.
  • the solution (2.76 g, 40 mmol) was reacted for 0.5 h in an ice bath, suction filtered, and the filter cake was dried to give diazonium salt.
  • the obtained diazonium salt was added to 50 mL of toluene, reacted at 90 ° C for 1 h, and refluxed for 2 h.
  • the reaction solution was washed successively with a saturated NaHCO 3 solution and brine, dried over anhydrous sodium sulfate, and evaporated.
  • the obtained concentrate was dissolved in 10 mL of dioxane, 10 mL of water, 20 mmol of CaCO 3 was added , refluxed for 10 h, filtered, ethyl acetate was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, 1-fluoronaphthalen-2-yl)methanol, yield 80%.
  • the preparation method was similar to that of Example 37 except that 1-fluoro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-fluoro-2-naphthaldehyde was used as a raw material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-chloro-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1-chloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 37 except that 1-chloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-bromo-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 37 except that 1-bromo-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-bromo-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 1-fluoro-6-methoxy-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 6-bromo-1-fluoro-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1,6-dichloro-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 1,6-dichloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 5-chloro-1-fluoro-2-naphthaldehyde was used as a starting material.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-3-thiophenecarboxylic acid.
  • the 2-amino-3-thiophenecarboxylic acid can be obtained by the main method as follows:
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4-methylthiophene-3-carboxylic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4,5-dimethylthiophene-3-carboxylic acid.
  • the preparation method of the raw material (E)-2-methyl-3-(naphthalen-2-yl)acrylic acid is similar to the synthesis method of (E)-2-methyl-3-phenylacrylic acid in Example 1, except that the difference lies in 2-naphthaldehyde is used as a starting material.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with o-cyanobenzoic acid.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-aminobenzamide.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-aminopyridine.
  • the preparation method was similar to that of Example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 1-amino-2-cyano-1-cyclopentene.
  • DHODH can catalyze the oxidation of its natural substrate DHO (dihydroorotate) to Orotate under certain conditions.
  • DHODH dihydroorotate
  • the two H + and e - of the substrate DHO are first transferred to the coenzyme FMN, and then the reduced FMNH 2 transfers electrons to the free coenzyme Q.
  • the free coenzyme Q eventually delivers electrons to the chromogenic substrate DCIP, which is reduced.
  • DCIP has maximum light absorption at 600 nm, while the reduced DCIP has no light absorption at 600 nm.
  • the degree to which the substrate DHO is oxidized can be judged based on the degree of decrease in absorbance.
  • the degree of oxidation of the substrate DHO per unit time is the initial rate of the enzymatic reaction. After the addition of the inhibitor, the initial rate of the enzymatic reaction is lowered.
  • the 96-well plate was used for the measurement, and the absorbance at 600 nm was read by a BioTek microplate reader. 199 ⁇ L of assay buffer (50 mM HEPES (pH 8.0), 0.15 M KCl, 0.1% Triton X-100, 100 ⁇ M CoQ, 100 ⁇ M DCIP) was added to each well. Add 0.4 ⁇ L of compound, incubate for 5 min at room temperature, then add 1 ⁇ L of substrate DHO (final concentration of 500 ⁇ M) to each well and mix well.
  • assay buffer 50 mM HEPES (pH 8.0), 0.15 M KCl, 0.1% Triton X-100, 100 ⁇ M CoQ, 100 ⁇ M DCIP

Abstract

一种作为DHODH抑制剂的通式I所示的N-取代丙烯酰胺衍生物及其制备和用途。其具有优异的DHODH抑制活性，从而能用于治疗或预防DHODH介导的各种疾病，包括但不限于癌症，类风湿性关节炎、红斑狼疮和器官移植排斥等自身免疫性疾病，结肠炎和鼻炎等炎症性疾病。

Description

作为DHODH抑制剂的N-取代丙烯酰胺衍生物及其制备和用途 技术领域
本发明属于药物化学和药物治疗学领域，具体涉及作为DHODH抑制剂的N-取代丙烯酰胺衍生物及其制备和用途。
背景技术
二氢乳清酸脱氢酶(Dihydroorotate dehydrogenase，DHODH)是一种含铁的黄素依赖的线粒体酶，是核酸嘧啶合成中细胞内限速酶，催化从头嘧啶生物合成途径中的第四步反应。抑制DHODH，可以阻断新生嘧啶合成，致使DNA和RNA合成障碍。在大部分有机体中嘧啶合成有两种方式：补救途径和由小分子从头合成。生物体对嘧啶的需求取决于细胞类型和所处的分化阶段，处于休息期和分化期的细胞通过从头合成途径获取嘧啶只占小部分，而主要依靠补救途径。与此相反，为了满足生物体对核苷酸前体和其它细胞成分的需要，激活的T-淋巴细胞、B-淋巴细胞和肿瘤细胞等快速分化的人类细胞需要依赖嘧啶的从头合成来满足其生长需要，这使得DHODH抑制剂可以作为抗细胞增殖剂用于肿瘤以及某些免疫抑制反应的治疗。
1998年上市的来氟米特(leflunomide，LEF)是一种新型的异噁唑类免疫调节剂，临床上主要用于治疗风湿性关节炎、红斑狼疮等自身免疫疾病和抗器官移植的急慢性排斥反应及异种排斥反应的防治。后来发现来氟米特是个前药，其口服后经肝脏和肠壁的细胞质和微粒体迅速转化为活性的代谢产物A771726(MI)。MI是很好的人体二氢乳清酸脱氢酶抑制剂，可以阻断嘧啶的从头生物合成，进而影响DNA和RNA的合成。研究表明MI可以运用于预防、治疗或抑制多种自身免疫性疾病、抗器官移植的急慢性排斥反应及异种排斥反应、牛皮癣等皮肤病、多样性硬化等。
Figure PCTCN2019081066-appb-000001
最初作为抗癌药来研究的布喹那是最强有力的DHODH抑制剂之一，但是临床II期实验证明其抗肿瘤作用一般，该化合物继续作为免疫抑制剂开发。4SC-101被证明对红斑狼疮和肠炎有较好的抑制作用，正处于临床开发阶段。
由于来氟米特的长期使用会产生抗药性和肝酶异常、高血压或皮疹等副作用，寻找新型、高效和副作用小的DHODH抑制剂仍然是免疫相关疾病和肿瘤治疗中的研究热点。
发明内容
本发明的目的是提供一类结构新颖的可作为DHODH抑制剂的化合物及其制备方法和用途。
本发明第一方面提供了一种式I所示化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型：
Figure PCTCN2019081066-appb-000002
式中，
A为未取代或取代的C 3-7环烷基、未取代或取代的C 5-7环烯基、未取代或取代的C 6-C 10芳基、或未取代或取代的5-10元杂环基；所述取代的是指被选自下组的基团所取代：卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 5-7环烯基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、C 6-C 10芳基-NH-CO-、-O-(CH 2)m-O-、-(CH 2)n-；其中，m或n为1～4的整数；
B为未取代或取代的C 3-7环烷基、C 5-7环烯基、C 6-C 10芳基、5-10元杂环基；所述取代的是指被选自下组的基团所取代：卤素、氰基(-CN)、硝基、羧基(-COOH)、酰胺基(-CONH 2)、磺酸基、磺酰胺、C 1-6磺酸酯基、羟基、C 1-6烷羰基、C 1-6卤代烷羰基、C 1-6醛基、C 1-6酯基、C 1-6酰肼基、胍基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 2-6烯基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、C 6-C 10芳基-NH-CO-、-O-CH 2-O-、-(CH 2)n-；其中，n为2～4的整数；
R 1选自下组：氢、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 5-7环烯基；
R 2选自下组：氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 5-7环烯基。
在另一优选例中，所述化合物选自式II所示的化合物：
Figure PCTCN2019081066-appb-000003
式中，
A和R 2定义同前；
X代表氮原子或基团CY，其中Y选自下组：羧基、酰胺基、磺酸基、磺酰胺基、C 1-6磺酸酯基、羟基、C 1-6烷羰基、C 1-6卤代烷羰基、C 1-6醛基、C 1-6酯基、C 1-6酰肼基、氰基、 硝基、胍基；
R 3、R 4、R 5各自独立地选自下组：氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 2-6烯基、C 1-6烷氧基、羟基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、C 6-C 10芳基-NH-CO-、-O-CH 2-O-、-(CH 2)n-；其中，n为2～4的整数。
在另一优选例中，所述Y选自下组：羧基、酰胺基、氰基。
在另一优选例中，A为未取代或取代的苯基、未取代或取代的吡啶基、未取代或取代的吲哚基、未取代或取代的萘基、未取代或取代的噻吩基、未取代或取代的苯并噻吩基、未取代或取代的呋喃基、未取代或取代的苯并呋喃基、未取代或取代的喹啉或未取代或取代的异喹啉基。
在另一优选例中，A选自下组：
Figure PCTCN2019081066-appb-000004
在另一优选例中，R 2选自下组：氢、氟、氯、溴、三氟甲基、甲基、乙基、丙基、环丙基。
在另一优选例中，R 3、R 4、R 5各自独立地选自氢、卤素、氰基、硝基、C 1-4烷基、C 1-4卤代烷烃、C 3-7环烷基、C 1-4烷氧基、羟基。
在另一优选例中，R 3、R 4、R 5各自独立地为氢、氟、氯、氰基、三氟甲基、甲基、乙基、甲氧基、环丙基、羟基。
在另一优选例中，所述化合物选自式III所示的化合物：
Figure PCTCN2019081066-appb-000005
式中，
B和R 2定义同前；
R 6、R 7、R 8、R 9、R 10各自独立地选自氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷烃、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 5-7环烯基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10 芳基、C 6-C 10芳氧基、5元或6元杂环基、羟基、C 6-C 10芳基-NH-CO-；
或者R 6、R 7、R 8、R 9、R 10中的任意两个可以连接形成-O-(CH 2)m-O-、-(CH 2)n-、-CH＝CH-；其中，m或n为1～4的整数。
在另一优选例中，B选自未取代或取代的苯基、未取代或取代的5元或6元杂环基、或未取代或取代的C 5-7环烯基。
在另一优选例中，所述5元或6元杂环基选自下组：吡啶基、噻吩基、呋喃基。
在另一优选例中，B选自下组：
Figure PCTCN2019081066-appb-000006
在另一优选例中，R 8和R 9可以连接形成-O-(CH 2)m-O-、-(CH 2)n-、-CH＝CH-；其中，m或n为1～4的整数。
本发明第二方面提供了一种药物组合物，所述药物组合物含有第一方面所述的化合物或其立体异构体、顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型；和药学上可接受的载体或赋形剂。
在另一优选例中，所述的药物组合物为注射剂、囊剂(如硬和软明胶胶囊)、片剂、包被的片剂、丸剂、散剂、颗粒剂、糖衣片、溶液剂、糖浆剂、乳剂、悬浮液剂、气雾剂、栓剂、输注剂、软膏、乳膏和酊剂。
本发明第三方面提供了第一方面所述化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型或第二方面所述药物组合物的用途，用于制备二氢乳清酸脱氢酶抑制剂；用于制备嘧啶生物合成酶抑制剂；和/或用于制备用于预防或治疗由二氢乳清酸脱氢酶的抑制和/或嘧啶生物合成酶的抑制来改善的病理学病状或疾病。
在另一优选例中，所述的病理学病状或疾病选自下组：癌症、类风湿性关节炎、结肠炎、红斑狼疮、肾小球疾病、抗器官移植排斥反应、黑色素瘤、银屑病、关节炎、纤维病变、鼻炎、牛皮癣、多发性硬化、眼色素层炎、哮喘、白血病和疟疾。
本发明第四方面提供了第一方面所述化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型的制备方法，
所述方法为方法1，包括步骤：
Figure PCTCN2019081066-appb-000007
(1)在惰性溶剂中，化合物1和化合物2进行反应，从而形成化合物3；
(2)在惰性溶剂中，化合物3进行水解反应，从而形成化合物4；
(3)在惰性溶剂中，化合物4先后和草酰氯和化合物5进行反应，从而形成化合物6；
或所述方法为方法2，包括步骤：
Figure PCTCN2019081066-appb-000008
(1)在惰性溶剂中，化合物7和TsCl进行反应，从而形成化合物8；
(2)在惰性溶剂中，化合物8和化合物5进行反应，从而形成化合物6；
或所述方法为方法3，包括步骤：
Figure PCTCN2019081066-appb-000009
(1)在惰性溶剂中，化合物1和化合物9进行反应，从而形成化合物10；
(2)在惰性溶剂中，化合物10先后和草酰氯和化合物5进行反应，从而形成化合物6；
或所述方法为方法4，包括步骤：
Figure PCTCN2019081066-appb-000010
(1)在惰性溶剂中，化合物1和化合物11以及NCS或NBS进行反应，从而形成化合物12；
(2)在惰性溶剂中，化合物12进行水解反应，从而形成化合物13；
(3)在惰性溶剂中，化合物13先后和草酰氯和化合物5进行反应，从而形成化合物6；
或所述方法为方法5，包括步骤：
Figure PCTCN2019081066-appb-000011
(1)在惰性溶剂中，化合物15和化合物16进行反应，从而形成化合物17；
(2)在惰性溶剂中，化合物17进行水解反应，从而形成化合物18；
(3)在惰性溶剂中，化合物18先后和草酰氯和化合物5进行反应，从而形成化合物19；
或所述方法为方法6，包括步骤：
Figure PCTCN2019081066-appb-000012
(1)在惰性溶剂中，化合物1和化合物20进行反应，从而形成化合物21；
(2)在惰性溶剂中，化合物21先后和草酰氯和化合物5进行反应，从而形成化合物22；
或所述方法为方法7，包括步骤：
Figure PCTCN2019081066-appb-000013
(1)在惰性溶剂中，化合物1和化合物23进行反应，从而形成化合物24；
(2)在惰性溶剂中，化合物24进行水解反应，从而形成化合物25；
(3)在惰性溶剂中，化合物25先后和草酰氯和化合物5进行反应，从而形成化合物26；
上述各式中，除了给出定义的基团，其它基团定义同前。
本发明提供了一种治疗或预防方法，该方法包括给需要的对象施用本发明的所述化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型或本发明的药物组合物。
在另一优选例中，所述化合物为式I、式II、或式III化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此 不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地发现一类结构新颖、性能优异的DHODH抑制剂。在此基础上完成了本发明。
术语
本文所用术语“C 1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“C 2-6烯基”指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
术语“C 2-6炔基”是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、或类似基团。
术语“C 3-7环烷基”指具有3-7个碳原子的环状烷基，例如环丙基、环丁基、环戊基、环己基、环庚基、或类似基团。
术语“C 5-7环烯基”指具有5-7个碳原子的、具有一个或多个双键的环状烯基，例如环戊烯基、环己烯基、环庚烯基、1,3-环己二烯基、1,4-环己二烯基、或类似基团。
如本文所用，术语“C 1-6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“卤素”指氟、氯、溴、或碘。
术语“C 1-6卤代烷烃”指被相同或不同的一个或多个上述卤原子取代的具有1-6个碳原子的直链或支链烷烃，例如三氟甲基、五氟乙基、七氟异丙基、或类似基团。
术语“芳基”指含有6到14个碳原子的单环、双环或三环芳族基团，包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。本文中，芳基可任选地被一个或多个本文所述的取代基取代。
术语“芳氧基”指芳基-O-，例如苯氧基(
Figure PCTCN2019081066-appb-000014
曲线标记处为取代位，上下同)。
术语“杂环基”指单一或稠合的环结构，在性质上可以是芳族和非芳族的，并且其优选含有3-20个成环原子，更优选含有5-14或5-10个环原子，其中至少1个并且优选最多可至4个是选自氮、氧或硫的杂原子。本文中，杂环基的例子包括呋喃基、噻吩基、吡咯基、吡咯烷基、咪唑基、***基、噻唑基、四唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、喹啉基、异喹啉基、喹喔啉基、苯并噻唑基、苯并噁唑基、苯并噻吩基、苯并呋喃基、吗啉基、咔唑基、二苯并噻吩基、1,2-亚甲基二氧苯基、吲哚基、吲唑基、苯并咪唑基、苯并[d][1,2,3]噻二唑基、咪唑并[1,2-a]吡啶基、噌啉基、酞嗪基、1,8-萘啶基、或苯并[d][1,2,3]三嗪-4(3H)-3-基等。本文中，杂环基可任选地被一个或多个本文所述的取代基取代。
术语“5元或6元杂环基”指含一个或多个选自氮、氧或硫的杂原子的五元或六元环，例如吡啶基、噻唑基、噻吩基、呋喃基、吡咯基、吡唑基、嘧啶基、四氢呋喃基、噁唑基、1,2,3-噻二唑基、1,3,4-噻二唑基、或1,3,4-噁二唑基等。
本文所用术语“C 1-6磺酸酯基”是指具有1-6个碳原子的磺酸酯基(C 1-6烷基-S(＝O) 2O-)。
本文所用术语“C 1-6烷羰基”是指C 1-6烷基-C＝O-。
本文所用术语“C 1-6酯基”是指C 1-5烷基-C(＝O)O-)。
本文所用术语“C 1-6酰肼基”是指-C 1-6烷基-C＝O-NHNH 2或C 1-6烷基-C＝O-NHNH-。
本文所用术语“C 1-6醛基”是指-C 1-5烷基-CHO。
本发明所述的基团无论是特别说明“未取代或任选取代的”还是未特别说明是“未取代或任选取代的”均可被0至多个(通常0、1、2或3个)被选自下组的取代基所取代：卤素、氰基、硝基、氨基、羧基、巯基、羟基、羟甲基、C 1-4醛基、C 1-6烷基、C 1-6卤代烷基(如三氟甲基)、卤素取代的烷氧基(如三氟甲氧基)、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 5-7环烯基、C 1-6烷氧基(如甲氧基)、C 1-6硫代烷基(例如五氟硫甲基)、C 1-6硫代烷氧基(例如五氟硫甲氧基)、卤代烷羰基(例如三氟乙酰基)、C 1-4的酰基、吗啉基，任选取代的芳基、任选取代的杂环基、任选取代的芳氧基(例如任选取代的苯氧基)、任选取代的苄氧基、任选取代的芳甲酰胺基和任选取代的芳胺甲酰基。
制备方法
本发明的化合物可采用以下方法制备获得:
方法1：
Figure PCTCN2019081066-appb-000015
方法2：
Figure PCTCN2019081066-appb-000016
方法3：
Figure PCTCN2019081066-appb-000017
方法4：
Figure PCTCN2019081066-appb-000018
方法5：
Figure PCTCN2019081066-appb-000019
方法6：
Figure PCTCN2019081066-appb-000020
方法7：
Figure PCTCN2019081066-appb-000021
Figure PCTCN2019081066-appb-000022
所用的原料醛基化合物可直接从试剂公司购买或由以下方法制得:
1.由取代甲酸制得：
Figure PCTCN2019081066-appb-000023
2.由含甲基的原料制得：
Figure PCTCN2019081066-appb-000024
上述制备流程中，A和B的定义如上文所述。本领域技术人员可根据实际制备需要，采用本领域常规获得的各种起始化合物为原料，制备本发明的化合物。
在一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
原料醛基化合物可直接从试剂公司购买或用以下方法合成。
1.由取代甲酸制得：
Figure PCTCN2019081066-appb-000025
称取取代芳甲酸(10mmol)溶解在25mL无水THF中，氩气保护，冰浴条件下向其中分批缓慢加入LiAlH 4(20mmol)。冰浴反应10min后室温反应4h，反应结束后冰浴冷却，依次向其中缓慢滴加0.76g冰水、0.76g 15％NaOH水溶液和2.28g水。搅拌片刻后加入20mL水，过滤，用少量乙酸乙酯洗涤，滤液减压旋干浓缩。向浓缩液中加入适量水，乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干即得取代苄醇粗品，收率90-95％，直接用于下一步反应。
将上一步制得的取代苄醇溶解在100mL DCM中，搅拌条件下加入70mmol MnO 2，室温下反应4h，过滤，滤液旋干浓缩，过柱纯化得取代芳甲醛，收率85-95％。
2.由芳甲基制得：
Figure PCTCN2019081066-appb-000026
将取代芳甲基化合物(5mmol)溶于10mL CCl 4，加入10mmol NBS，0.1mmol BPO，回流反应5h，冷却至室温，过滤，用适量石油醚洗涤滤饼，旋干浓缩。将所得浓缩液溶解在10mL dioxane中，加入10mL水，20mmol CaCO 3，回流10h，过滤，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，旋干浓缩，过柱纯化得取代苄醇，收率约80％。
将上一步制得的取代苄醇(4mmol)溶解在40mL DCM中，搅拌条件下加入28mmol MnO 2，室温下反应4h，过滤，滤液旋干浓缩，过柱纯化得取代芳甲醛，收率约90％。
Figure PCTCN2019081066-appb-000027
上述各式中，A和B如上文中所定义；
将取代醛基化合物(5mmol)分散至15mL DCM中，加入9mmol乙氧甲酰基亚乙基三苯基膦，室温反应12h，旋除部分溶剂，过柱纯化得2-甲基-3-取代丙烯酸乙酯中间体，收率约95％。
将上一步制得的2-甲基3-取代丙烯酸乙酯(4mmol)溶解在12mL THF和12mL MeOH中，加入16mL 2M NaOH水溶液。40℃反应5h。1M HCl酸化，有白色固体析出，抽滤，用适量水洗，固体烘干得2-甲基3-取代丙烯酸，收率约95％。
将制得的2-甲基3-取代丙烯酸(1mmol)分散在3mL干燥DCM中，冰浴滴加草酰氯(3mmol)，滴加一滴DMF做催化剂，套上干燥管，室温反应3h，减压旋除溶剂浓缩即得酰氯中间体。
将氨基化合物(1.2mmol)溶解在2mL DCM中，加入1.5mmol TEA和0.1mmol DMAP，冰浴冷却。将制得的酰氯溶解在1mL DCM中，滴加至反应液中，室温反应至反应结束。用1M HCl酸化，有固体析出，抽滤，乙醇重结晶得终产物。收率约70％。
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000028
上述各式中，A和B如上文中所定义；
原料2-甲基3-取代丙烯酸的制备方法和上文所述优选例类似。向套有干燥管的25mL反应瓶中加入1mmol 2-甲基3-取代丙烯酸，1.1mmol TsCl，5mL DCE，0.1mmol DMAP， 1.5mmol TEA，35℃反应1h，加入1mmol氨基化合物，60℃反应10h，用1M HCl酸化，抽滤得固体，水洗，干燥，过柱纯化得目标产物，收率约50％。
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000029
上述各式中，A和B如上文中所定义；
将2mmol取代醛基化合物和6mmol丙二酸分散在1.2mL DMF中，加入2mmol吡啶，90℃反应5h，冷却至室温，加入1.2mL水，1M HCl酸化至PH为2，抽滤，水洗两次，滤饼干燥即得3-取代丙烯酸中间体，收率约80％。后续制备目标化合物的步骤和上文以2-甲基-3-取代丙烯酸乙酯为原料制备终产物的方法类似。
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000030
上述各式中，A和B如上文中所定义；
向反应瓶中加入9mmol乙氧甲酰基亚甲基三苯基膦和15mL DCM，氩气保护，-20℃下分批加入9mmol NCS或NBS，-20℃下反应1h，室温下加入5mmol醛基化合物和12.5mmol K 2CO 3，室温反应10h，反应液用水洗，有机相用无水硫酸钠干燥，旋干浓缩，过柱纯化得2-卤代-3-取代丙烯酸乙酯。后续制备目标化合物的步骤和上文以2-甲基-3-取代丙烯酸乙酯为原料制备终产物的方法类似。
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000031
上述各式中，A和B如上文中所定义；
在50mL三口烧瓶中加入4.2mmol NaH，氩气保护，加入24mL无水THF，加入3.9mmol 2-膦酰基三乙脂类化合物，室温下搅拌0.5h，将12mL羰基化合物(3mmol)的THF溶液滴加到反应液中，室温反应12h，2M HCl酸化，旋掉THF，加入适量水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，旋除溶剂浓缩，过柱纯化得丙烯酸乙酯中间体。后续制备目标化合物的步骤和上文以2-甲基-3-取代丙烯酸乙酯为原料制备终产物的方法类似。
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000032
在反应瓶中依次加入6mmol醛基化合物、4mmol 3,3,3-三氟丙酸、20mL THF和8mL1M的TiCl 4二氯甲烷溶液，室温搅拌0.5h，向反应液中滴加16mmol三乙胺。室温反应40h后向反应瓶中缓慢加入30mL水，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋干并用硅胶柱分离纯化(二氯甲烷：甲醇＝10：1)，得2-三氟甲基丙烯酸中间体。后续制备目标化合物的步骤和上文以2-甲基-3-取代丙烯酸乙酯为原料制备终产物的方法类似
在另一优选例中，本发明的化合物可通过包括如下步骤的方法合成：
Figure PCTCN2019081066-appb-000033
将5mmol醛基化合物分散在7.5mL甲醇中，加入5mmol氰基乙酸甲酯和0.5mmol哌啶，回流反应至反应完全。冷却至室温，固体析出，抽滤，滤饼用适量甲醇洗涤，滤饼烘干即得2-氰基-3-取代丙烯酸甲酯中间体。后续制备目标化合物的步骤和上文以2-甲基-3-取代丙烯酸乙酯为原料制备终产物的方法类似。
活性成分
本发明化合物为通式I或II或III所示的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型。
本发明所述药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐，尤其是钠盐和钾盐。
药物组合物
本发明化合物具有优异的DHODH抑制活性，可用于制备治疗或预防DHODH介导的疾病用的药物中。
本发明的药物组合物含有治疗有效量的本发明化合物以及药学上可接受的载体或赋形剂。
虽然每个人所需的药物剂量不同，本领域技术人员可确定本发明药物组合物中每种活性成分的最佳剂量。一般情况下，本发明的化合物或其药学上可接受的盐，对哺乳动物每天口服给药，药量按照0.0025到50毫克/公斤体重，但最好是每公斤口服给药约0.01到10毫克。例如，单位口服剂量可以包括约0.01到50毫克，最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次，每天为一片或多片，每片含有约0.1到50毫克，更佳为含有约0.25到10毫克的本发明化合物或其溶剂化物。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药的形式，用于***和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可以治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康状况与体重，并行治疗的种类，治疗的频率，以及所需治疗效果来决定。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类。
本发明的药物或其药物组合物可用于治疗或预防DHODH介导的各种疾病，包括癌症、类风湿性关节炎、结肠炎、红斑狼疮、肾小球疾病、抗器官移植排斥反应、黑色素瘤、银屑病、关节炎、纤维病变、鼻炎、牛皮癣、多发性硬化、眼色素层炎、哮喘、白血病、疟疾等。所述癌症包括但不限于乳腺癌，***癌，头颈部鳞状细胞癌和多发性骨髓癌。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体包括：填充剂、膨胀剂、崩解剂、结合剂、助流剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、调味剂或香料、缓冲物质等，以及用于获得贮存效果的溶剂、增溶剂或试剂，以及用于改变渗透压的盐，包被试剂或抗氧剂等。具体地，药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019081066-appb-000034
)、润湿剂(如十二烷基硫酸钠)、无热原水等。
用于口服给药的固体剂型包括：胶囊剂(如硬或软明胶胶囊剂)、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季铵化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油，或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂和香料。除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂，或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌水或无水溶液、分散液、悬浮液 或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂，包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药，例如与现有的用于治疗前述疾病的药物联合给药。在后一情况下可观察到疗效的增强。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1(E)-2-(2-甲基-3-苯基丙烯酰胺基)苯甲酸(化合物1)
Figure PCTCN2019081066-appb-000035
将苯甲醛(5mmol)分散至15mL DCM中，加入9mmol乙氧甲酰基亚乙基三苯基膦，室温反应4h，旋除部分溶剂，过柱纯化得(E)-2-甲基3-苯基丙烯酸乙酯，收率95％。
将上一步制得的(E)-2-甲基3-苯基丙烯酸乙酯(4mmol)溶解在12mL THF和12mL MeOH中，加入16mL 2M NaOH水溶液。40℃反应5h。1M HCl酸化，有白色固体析出，抽滤，用适量水洗，固体烘干得(E)-2-甲基3-苯基丙烯酸，收率95％。
将制得的(E)-2-甲基3-苯基丙烯酸(1mmol)分散在3mL干燥DCM中，冰浴滴加草酰氯(3mmol)，滴加一滴DMF做催化剂，套上干燥管，室温反应3h，减压旋除溶剂浓缩即得酰氯中间体。
将邻氨基苯甲酸(1.2mmol)溶解在2mL DCM中，加入1.5mmol TEA和0.1mmol DMAP，冰浴冷却。将制得的酰氯溶解在1mL DCM中，滴加至反应液中，室温反应至反应结束。用1M HCl酸化，有固体析出，抽滤，乙醇重结晶得终产物。收率70％。
熔点：179.1-181.6℃； 1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.84(s,1H),8.70(d,J＝8.0Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.68-7.62(m,1H),7.53(d,J＝0.8Hz,1H),7.50-7.43(m,4H),7.40-7.35(m,1H),7.22-7.16(m,1H),2.19(d,J＝1.2Hz,3H)ppm； 13C  NMR(100MHz,DMSO-d6):δ169.91,166.89,141.25,135.57,134.54,134.26,132.50,131.21,129.43,128.51,128.20,122.68,119.73,116.22,13.87ppm；HRMS(EI)calc.for C 17H 15NO 3 + 281.1052,found 281.1053。
实施例2(E)-2-(2-甲基-3-(4-三氟甲基苯基)丙烯酰胺基)苯甲酸(化合物2)
制备方法与实施例1的方法类似，不同点在于，以4-三氟甲基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000036
熔点：211.6-212.3℃； 1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.88(s,1H),8.69(dd,J＝8.4,0.8Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.67-7.63(m,1H),7.57(s,1H),7.23-7.18(m,1H),2.20(d,J＝1.2Hz,3H)ppm； 19F NMR(376MHz,DMSO-d6):δ-61.05(s,3F)ppm；HRMS(EI)calc.for C 18H 14F 3NO 3 + 349.0926,found 349.0925。
实施例3(E)-2-(2-甲基-3-(6-三氟甲基吡啶-3-基)丙烯酰胺基)苯甲酸(化合物3)
制备方法与实施例1的方法类似，不同点在于，以6-三氟甲基吡啶-3-甲醛为起始原料。
Figure PCTCN2019081066-appb-000037
熔点：267.6-268.3℃； 1H NMR(400MHz,DMSO-d6):δ13.81(s,1H),11.90(s,1H),8.87(d,J＝1.6Hz,1H),8.69(d,J＝7.6Hz,1H),8.19(dd,J＝8.0,1.6Hz,1H),8.06(dd,J＝8.0,1.6Hz,1H),7.98(d,J＝8.4Hz,1H),7.70-7.63(m,1H),7.60(s,1H),7.24-7.18(m,1H),2.23(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.86,165.99,150.47,145.19(q, 2J CF＝33.8Hz),140.93,138.40,136.66,135.05,134.26,131.22,129.85,124.36(q, 1J CF＝264.8Hz),122.97,120.47(q, 3J CF＝2.7Hz),119.86,116.49,13.90ppm； 19F NMR(376MHz,DMSO-d6):δ-66.40(s,3F)ppm；HRMS(EI)calc.for C 17H 13F 3N 2O 3 + 350.0878,found 350.0879。
实施例4(E)-2-(3-(4-甲氧基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物4)
制备方法与实施例1的方法类似，不同点在于，以4-甲氧基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000038
熔点：191.4-192.3℃； 1H NMR(400MHz,DMSO-d6):δ13.73(s,1H),11.81(s,1H),8.70(d,J＝8.4Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.67-7.60(m,1H),7.49-7.42(m,3H),7.20-7.14(m,1H),7.02(d,J＝8.8Hz,2H),3.80(s,3H),2.19(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.93,167.14,159.21,141.39,134.37,134.24,131.18,130.26,127.93,122.53,119.67,116.09,114.01,55.19,13.89ppm；HRMS(EI)calc.for C 18H 17NO 4 + 311.1158,found 311.1159。
实施例5(E)-2-(3-(4-叔丁基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物5)
制备方法与实施例1的方法类似，不同点在于，以4-叔丁基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000039
熔点：179.9-180.9℃； 1H NMR(400MHz,DMSO-d6):δ13.74(s,1H),11.84(s,1H),8.71(d,J＝8.0Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.68-7.61(m,1H),7.50(s,1H),7.47(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.21-7.16(m,1H),2.20(d,J＝1.2Hz,3H),1.31(s,9H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.92,166.96,150.86,141.33,134.45,134.24,132.74,131.71,131.20,129.32,125.28,122.59,119.69,116.12,34.39,30.96,13.90ppm；HRMS(EI)calc.for C 21H 23NO 3 + 337.1678,found 337.1680。
实施例6(E)-2-(3-(4-氯-3-三氟甲基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物6)
制备方法与实施例1的方法类似，不同点在于，以4-氯-3-三氟甲基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000040
熔点：192.4-193.3℃； 1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.87(s,1H),8.69(dd,J＝8.0,0.6Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.91(s,1H),7.81(s,2H),7.69-7.62(m,1H),7.56(s,1H),7.22-7.17(m,1H),2.19(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.86,166.37,141.03,135.32,134.99,134.57,134.26,131.92,131.78,131.22,130.08(q, 3J CF＝1.5Hz),128.64(q, 3J CF＝5.2Hz),126.75(q, 2J CF＝30.6Hz),124.04,122.68(q, 1J CF＝271.5Hz),119.78,116.37,13.80ppm； 19F NMR(376MHz,DMSO-d6):δ-61.33(s,3F)ppm；HRMS(EI)calc.for C 18H 13 35ClF 3NO 3 + 383.0536,found 383.0542；calc.for C 18H 13 37ClF 3NO 3 + 385.0507,found 385.0515。
实施例7(E)-2-(3-(3-氯-4-甲基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物7)
制备方法与实施例1的方法类似，不同点在于，以3-氯-4-甲基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000041
熔点：225.6-226.3℃； 1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.84(s,1H),8.69(dd,J＝8.0,0.4Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.68-7.61(m,1H),7.51(d,J＝1.6Hz,1H),7.46(s,1H),7.43(d,J＝8.0Hz,1H),7.36(dd,J＝8.0,1.2Hz,1H),7.22-7.16(m,1H),2.36(s,3H),2.18(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.89,166.68,141.17,135.46,135.17,134.24,133.36,133.24,132.98,131.26,131.20,129.47,128.06,122.72,119.72,116.26,19.39,13.86ppm；HRMS(EI)calc.for C 18H 16 35ClNO 3 + 329.0819,found329.0823；calc.for C 18H 16 37ClNO 3 + 331.0789,found 331.0791。
实施例8(E)-2-(3-(3,4-二氯苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物8)
制备方法与实施例1的方法类似，不同点在于，以3,4-二氯苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000042
熔点：211.8-212.5℃； 1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.85(s,1H),8.68(d,J＝8.4Hz,1H),8.04(dd,J＝7.8,1.4Hz,1H),7.74(d,J＝1.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.68-7.62(m,1H),7.50-7.46(m,2H),7.22-7.17(m,1H),2.18(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.87,166.42,141.06,136.37,134.55,134.26,132.07,131.24,131.22,131.14,130.63,130.62,129.51,122.85,119.76,116.36,13.85ppm；HRMS(EI)calc.for C 17H 13 35Cl 2NO 3 + 349.0272,found 349.0274；calc.for C 17H 13 35Cl 37ClNO 3 + 351.0243,found 351.0253；calc.for C 17H 13 37Cl 2NO 3 + 353.0214,found 353.0196。
实施例9(E)-2-(3-(3,5-二氯苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物9)
制备方法与实施例1的方法类似，不同点在于，以3,5-二氯苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000043
熔点：222.5-223.3℃； 1H NMR(400MHz,DMSO-d6):δ13.79(s,1H),11.85(s,1H),8.67(d,J＝8.0Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.68-7.63(m,1H),7.62(t,J＝2.0Hz,1H),7.53(d,J＝1.6Hz,2H),7.46(s,1H),7.23-7.17(m,1H),2.18(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.84,166.27,140.99,139.25,135.34,134.27,134.16,131.80,131.23,127.79,127.50,122.91,119.78,116.41,13.86ppm；HRMS(EI)calc.for  C 17H 13 35Cl 2NO 3 + 349.0272,found 349.0278；calc.for C 17H 13 35Cl 37ClNO 3 + 351.0243,found 351.0251；calc.for C 17H 13 37Cl 2NO 3 + 353.0214,found 353.0206。
实施例10(E)-2-(3-(3,4-二甲基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物10)
制备方法与实施例1的方法类似，不同点在于，以3,4-二甲基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000044
熔点：221.4-222.3℃； 1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H),8.71(d,J＝8.0Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.67-7.61(m,1H),7.46(s,1H),7.25(s,1H),7.21(s,2H),7.20-7.15(m,1H),2.26(s,3H),2.25(s,3H),2.19(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.94,167.03,141.36,136.62,136.34,134.64,134.23,133.08,131.45,131.20,130.61,129.58,126.91,122.54,119.66,116.08,19.33,19.18,13.92ppm；HRMS(EI)calc.for C 19H 19NO 3 + 309.1365,found 309.1368。
实施例11(E)-2-(3-(3,4-二甲氧基苯基)-2-甲基丙烯酰胺基)苯甲酸(化合物11)
制备方法与实施例1的方法类似，不同点在于，以3,4-二甲氧基苯甲醛为起始原料。
Figure PCTCN2019081066-appb-000045
熔点：170.0-170.9℃； 1H NMR(400MHz,DMSO-d6):δ13.74(s,1H),11.81(s,1H),8.71(d,J＝8.4Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.67-7.60(m,1H),7.48(s,1H),7.18(t,J＝7.4Hz,1H),7.09-7.02(m,3H),3.80(s,3H),3.80(s,3H),2.22(d,J＝1.2Hz,1H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.91,167.16,148.94,148.46,141.40,134.74,134.23,131.20,130.42,128.17,122.61,122.52,119.68,116.09,113.21,111.58,55.49,13.96ppm；HRMS(EI)calc.for C 19H 19NO 5 + 341.1263,found 341.1262。
实施例12(E)-2-(3-(1,3-苯并二恶茂-5-基)-2-甲基丙烯酰胺基)苯甲酸(化合物12)
制备方法与实施例1的方法类似，不同点在于，以1,3-苯并二恶茂-5-甲醛为起始原料。
Figure PCTCN2019081066-appb-000046
HRMS(EI)calc.for C 18H 15NO 5 + 325.0950,found 325.0952。
实施例13(E)-2-(3-(2,3-二氢-1H-茚-5-基)-2-甲基丙烯酰胺基)苯甲酸(化合物13)
制备方法与实施例1的方法类似，不同点在于，以2,3-二氢-1H-茚-5-甲醛为起始原料。
Figure PCTCN2019081066-appb-000047
熔点：185.4-186.3℃； 1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H),8.71(d,J＝7.6Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.67-7.59(m,1H),7.50(s,1H),7.33(s,1H),7.30(d,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),7.20-7.15(m,1H),2.89(q,J＝6.8Hz,4H),2.19(d,J＝1.2Hz,3H),2.08-1.99(m,2H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.94,167.05,144.17,144.09,141.36,135.07,134.24,133.51,131.37,131.20,127.69,125.25,124.28,122.55,119.64,116.08,32.19,24.97,13.94ppm；HRMS(EI)calc.for C 20H 19NO 3 + 321.1365,found 321.1366。
实施例14(E)-2-(2-甲基-3-(5,6,7,8-四氢萘-2-基)丙烯酰胺基)苯甲酸(化合物14)
Figure PCTCN2019081066-appb-000048
将5,6,7,8-四氢萘-2-甲酸(10mmol)溶解在25mL无水THF中，氩气保护，冰浴条件下向其中分批缓慢加入LiAlH 4(20mmol)。冰浴反应10min后室温反应4h，反应结束后冰浴冷却，依次向其中缓慢滴加0.76g冰水、0.76g 15％NaOH水溶液和2.28g水。搅拌片刻后加入20mL水，过滤，用少量乙酸乙酯洗涤，滤液减压旋干浓缩。向浓缩液中加入适量水，乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干即得取代苄醇粗品，收率98％。
将制得的取代苄醇溶解在100mL DCM中，搅拌条件下加入70mmol MnO 2，室温下反应4h，过滤，滤液旋干浓缩，过柱纯化得5,6,7,8-四氢萘-2-甲醛，收率90％。后续制备目标化合物的步骤与实施例1类似。熔点：232.3-233.3℃； 1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H),8.70(d,J＝8.4Hz,1H),8.04(dd,J＝7.8,1.4Hz,1H),7.67-7.61(m,1H),7.44(s,1H),7.22-7.10(m,4H),2.75(d,J＝3.6Hz,4H),2.18(d,J＝0.8Hz,3H),1.79-1.72(m,4H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.94,167.05,141.35, 141.09,137.11,136.77,134.67,134.24,132.71,131.48,131.21,130.11,129.04,126.59,122.56,119.64,116.11,28.71,28.62,22.58,13.93ppm；HRMS(EI)calc.for C 21H 21NO 3 + 335.1521,found 335.1522。
实施例15(E)-2-(3-(6-甲氧基萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物15)
制备方法与实施例1的方法类似，不同点在于，以6-甲氧基-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000049
熔点：206.8-207.3℃； 1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.90(s,1H),8.74(d,J＝7.6Hz,1H),8.06(dd,J＝7.8,1.4Hz,1H),7.98(s,1H),7.89(t,J＝8.8Hz,2H),7.69-7.63(m,2H),7.58(dd,J＝8.4,1.6Hz,1H),7.36(d,J＝2.4Hz,1H),7.23-7.16(m,2H),3.90(s,3H),2.29(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.96,167.03,157.96,141.36,134.77,134.27,133.85,131.82,131.23,130.75,129.81,128.86,128.15,127.63,126.82,122.61,119.70,119.09,116.15,105.83,55.25,14.07ppm；HRMS(EI)calc.for C 22H 19NO 4 + 361.1314,found 361.1312。
实施例16(E)-2-(3-(6-溴萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物16)
制备方法与实施例1的方法类似，不同点在于，以6-溴-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000050
熔点：213.8-214.4℃； 1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.93(s,1H),8.74(d,J＝8.4Hz,1H),8.24(s,1H),8.07(s,2H),7.97(dd,J＝8.4,5.8Hz,2H),7.70-7.63(m,4H),7.20(t,J＝7.6Hz,1H),2.28(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.94,166.76,141.24,134.25,134.19,133.76,133.44,133.28,131.25,131.22,130.38,129.46,129.44,128.73,128.27,127.16,122.70,119.89,119.74,116.24,14.05ppm；HRMS(EI)calc.for C 21H 16 79BrNO 3 + 409.0314,found 409.0313；calc.for C 21H 16 81BrNO 3 + 411.0293,found 411.0291。
实施例17(E)-2-(3-(5-氯萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物17)
制备方法与实施例1的方法类似，不同点在于，以5-氯-2-萘甲醛替换苯甲醛。
Figure PCTCN2019081066-appb-000051
熔点：232.8-233.6℃； 1H NMR(400MHz,DMSO-d6):δ13.79(s,1H),11.92(s,1H),8.72(d,J＝7.6Hz,1H),8.23(d,J＝8.8Hz,1H),8.15(s,1H),8.06(dd,J＝8.0,1.6Hz,1H),8.02(d,J＝8.4Hz,1H),7.79(dd,J＝8.8,1.6Hz,1H),7.74(dd,J＝7.2,0.8Hz,1H),7.69(s,1H),7.68-7.64(m,1H),7.56(t,J＝8.0Hz,1H),7.23-7.18(m,1H),2.29(d,J＝0.8Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.93,166.73,141.20,134.28,134.25,134.06,133.85,133.77,131.23,130.44,129.24,129.18,128.73,127.97,126.93,126.82,123.82,122.78,119.79,116.33,14.05ppm；HRMS(EI)calc.for C 21H 16 35ClNO 3 + 365.0819,found 365.0815；calc.for C 21H 16 37ClNO 3 + 367.0789,found 367.0783。
其中，所述5-氯-2-萘甲醛可由主要步骤如下的方法制得：
Figure PCTCN2019081066-appb-000052
将5-溴-2萘甲酸(0.75g，3mmol)分散在10mL甲醇中，冰浴冷却，向反应液中缓慢滴加1mL浓硫酸，回流反应2h，加入20mL水，用DCM萃取。有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得5-溴-2萘甲酸甲酯，收率97％。
将所得的5-溴-2-萘甲酸甲酯、CuCl(0.45g,4.5mmol)和12mL N,N-二甲基甲酰胺(DMF)分散在50mL茄形瓶中，氩气保护，回流反应过夜。冷却至室温，加入25mL水，抽滤，滤饼干燥。将所得滤饼分散在10mL DCM中，过滤除去不溶杂质，用适量DCM洗涤，滤液浓缩得5-氯-2萘甲酸甲酯，收率97％。
将5-氯-2萘甲酸甲酯(0.44g,2mmol)溶解在10mL无水THF中，氩气保护，冰浴条件下向其中分批缓慢加入LiAlH 4(0.1g,2.6mmol)。冰浴反应10min后在室温状态保持12h，冰浴冷却，依次向其中缓慢滴加0.1g冰水、0.1g的15％NaOH水溶液和0.3g水。搅拌片刻后加入10mL水，过滤，用少量乙酸乙酯洗涤，滤液减压旋干浓缩。向浓缩液中加入适量水，乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干即得(5-氯萘-2-基)甲醇粗品，收率90％。
将上述制得的(5-氯萘-2-基)甲醇溶解在20mL的DCM中，搅拌条件下加入14mmol的MnO 2，室温下反应4h，过滤，滤液旋干浓缩，过柱纯化得5-氯-2-萘甲醛，收率90％。
实施例18(E)-2-(2-甲基-3-(4-苯氧基苯基)丙烯酰胺基)苯甲酸(化合物18)
Figure PCTCN2019081066-appb-000053
将苯酚(705mg，7.5mmol)、对氟苯甲醛(625mg，5.0mmol)和K 2CO 3(1.38g，10.0mmol)分散在5mL DMSO中，氩气保护，110℃反应过夜。冷却至室温，加入适量的水，乙酸乙酯萃取，合并有机相，饱和食盐水洗三次，无水硫酸钠干燥，旋干浓缩，过柱纯化得4-苯氧基苯甲醛。后续制备终产物的方法同实施例1。熔点：184.4-185.2℃； 1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H),8.71(d,J＝8.4Hz,1H),8.05(dd,J＝7.6,1.2Hz,1H),7.67-7.61(m,1H),7.53(s,1H),7.51(s,2H),7.44(t,J＝8.0Hz,2H),7.19(q,J＝7.2Hz,2H),7.09(d,J＝8.0Hz,2H),7.06(d,J＝8.8Hz,2H),2.21(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.93,166.95,156.80,155.96,141.32,134.24,133.90,131.53,131.44,131.20,130.53,130.13,123.94,122.60,119.69,119.17,118.10,116.14,13.88ppm；HRMS(EI)calc.for C 23H 19NO 4 + 373.1314,found 373.1316。
实施例19(E)-2-(2-甲基-3-(3-苯氧基苯基)丙烯酰胺基)苯甲酸(化合物19)
Figure PCTCN2019081066-appb-000054
将间溴苯甲醛(5mmol)分散至15mL DCM中，加入9mmol乙氧甲酰基亚乙基三苯基膦，室温反应4h，旋除部分溶剂，过柱纯化得(E)-3-(3-溴苯基)-2-甲基丙烯酸乙酯，收率94％。
在反应瓶中加入苯酚(6mmol)、(E)-3-(3-溴苯基)-2-甲基丙烯酸乙酯(5mmol)、K 2CO 3(10mmol)、CuCl(0.25mmol)、N-丁基咪唑(2.5mmol)和5mL邻二甲苯，氩气保护，140℃反应16h。过滤，滤液依次用稀盐酸和饱和食盐水洗，无水硫酸钠干燥，旋干浓缩，过柱纯化得(E)-2-甲基-3-(3-苯氧基苯基)丙烯酸乙酯。后续制备终产物的方法同实施例1。熔点：158.6-159.3℃； 1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.82(s,1H),8.68(d,J＝8.0Hz,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.66-7.61(m,1H),7.50-7.45(m,2H),7.45-7.39(m,2H),7.25(d,J＝7.6Hz,1H),7.21-7.15(m,2H),7.09-7.07(m,2H),7.07-7.05(m,1H),7.01(dd,J＝8.0,2.0Hz,1H),2.15(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.86,166.72,156.78,156.37,141.16,137.51,134.22,133.76,133.30,131.19,130.16,130.09,124.49,123.66,122.71,119.75,119.20,118.80,118.22,116.29,13.89ppm；HRMS(EI)calc.for C 23H 19NO 4 + 373.1314,found 373.1313。
实施例20(E)-2-(2-甲基-3-(4-苯氨甲酰基苯基)丙烯酰胺基)苯甲酸(化合物20)
Figure PCTCN2019081066-appb-000055
将4-醛基苯甲酸(10mmol)、EDCI(11mmol)和HOBT(1.1mmol)加入30mL DCM中，室温下搅拌反应。TLC跟踪反应，待4-醛基苯甲酸反应完全，加入(10mmol)苯胺，室温下继续反应。反应结束后，旋掉部分溶剂，过柱纯化得4-甲酰基-N-苯基苯甲酰胺。后续制备终产物的方法同实施例1。HRMS(EI)calc.for C 24H 20N 2O 4 + 400.1423,found 400.1418。
实施例21(E)-2-(3-([1,1'-联苯]-4-基)-2-甲基丙烯酰胺基)苯甲酸(化合物21)
制备方法与实施例14的方法类似，不同点在于，以[1,1'-联苯]-4-甲酸为起始原料。
Figure PCTCN2019081066-appb-000056
熔点：241.3-242.2℃； 1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.87(s,1H),8.71(d,J＝8.4Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.77(d,J＝8.0Hz,2H),7.73(d,J＝6.8Hz,2H),7.68-7.63(m,1H),7.60(s,1H),7.58(s,1H),7.57(s,1H),7.50(t,J＝7.6Hz,2H),7.40(t,J＝7.2Hz,1H),7.19(t,J＝7.6Hz,1H),2.25(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.92,166.91,141.27,139.81,139.38,134.70,134.26,134.13,132.56,131.22,130.17,129.00,127.73,126.71,126.63,122.68,119.74,116.26,14.02ppm；HRMS(EI)calc.for C 23H 19NO 3 + 357.1365,found 357.1363。
实施例22(E)-2-(3-(1H-吲哚-6-基)-2-甲基丙烯酰胺基)苯甲酸(化合物22)
制备方法与实施例1的方法类似，不同点在于，以1H-吲哚-6-甲醛为起始原料。
Figure PCTCN2019081066-appb-000057
HRMS(EI)calc.for C 19H 16N 2O 3 + 320.1161,found 320.1165。
实施例23(E)-2-(2-甲基-3-(1-甲基-1H-吲哚-6-基)丙烯酰胺基)苯甲酸(化合物23)
制备方法与实施例1的方法类似，不同点在于，以1-甲基-1H-吲哚-6-甲醛为起始原料。
Figure PCTCN2019081066-appb-000058
HRMS(EI)calc.for C 20H 18N 2O 3 + 334.1317,found 334.1312。
实施例24(E)-2-(2-甲基-3-(1-甲基-1H-吲哚-2-基)丙烯酰胺基)苯甲酸(化合物24)
Figure PCTCN2019081066-appb-000059
原料(E)-2-甲基-3-(1-甲基-1H-吲哚-2-基)丙烯酸的合成方法同实施例14，不同点在于，用1-甲基-1H-吲哚-2-甲酸代替5,6,7,8-四氢萘-2-甲酸。
向套有干燥管的25mL反应瓶中依次加入(E)-2-甲基-3-(1-甲基-1H-吲哚-2-基)丙烯酸(215mg，1.0mmol)、对甲苯磺酰氯(209mg，1.1mmol)、1,2-二氯乙烷(5mL)、4-二甲氨基吡啶(12mg，0.1mmol)和三乙胺(152mg，1.5mmol)，35℃反应1小时，加入邻氨基苯甲酸(137mg，1.0mmol)，60℃反应10小时，用1M的HCl酸化，抽滤得固体，水洗，干燥，乙醇重结晶，收率：50％。熔点：243.3-244.1℃； 1H NMR(400MHz,DMSO-d6):δ13.82(s,1H),11.98(s,1H),8.73(d,J＝8.4Hz,1H),8.06(dd,J＝8.0,1.2Hz,1H),7.69-7.62(m,3H),7.53(d,J＝8.4Hz,1H),7.25-7.17(m,2H),7.08(t,J＝7.4Hz,1H),6.87(s,1H),3.84(s,3H),2.33(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ170.03,166.61,141.50,141.35,137.40,134.47,134.30,132.73,131.27,127.23,122.87,122.66,120.73,119.75,119.62,116.21,110.00,104.77,29.74,14.68ppm；HRMS(EI)calc.for C 20H 18N 2O 3 + 334.1317,found 334.1312。
实施例25(E)-2-(2-甲基-3-(喹啉-3-基)丙烯酰胺基)苯甲酸(化合物25)
制备方法与实施例1的方法类似，不同点在于，以3-喹啉甲醛为起始原料。
Figure PCTCN2019081066-appb-000060
HRMS(EI)calc.for C 20H 16N 2O 3 + 332.1161,found 332.1159。
实施例26(E)-2-(3-(异喹啉-3-基)-2-甲基丙烯酰胺基)苯甲酸(化合物26)
制备方法与实施例1的方法类似，不同点在于，以3-异喹啉甲醛为起始原料。
Figure PCTCN2019081066-appb-000061
熔点：252.6-253.2℃； 1H NMR(400MHz,DMSO-d6):δ13.86(s,1H),11.96(s,1H),9.41(s,1H),8.75(d,J＝8.4Hz,1H),8.16(d,J＝8.0Hz,1H),8.08-8.04(m,2H),8.02(d,J＝8.4Hz,1H),7.82(t,J＝7.6Hz,1H),7.73(t,J＝7.4Hz,1H),7.69-7.62(m,2H),7.20(t,J＝7.6Hz,1H),2.61(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.94,167.14,152.15,148.44,141.26,135.43,134.45,134.23,133.35,131.22,130.99,128.19,127.61,127.13,126.95,123.11,122.72,119.78,116.33,13.93ppm；HRMS(EI)calc.for C 20H 16N 2O 3 + 332.1161,found 332.1160。
实施例27(E)-2-(2-甲基-3-(喹啉-7-基)丙烯酰胺基)苯甲酸(化合物27)
制备方法与实施例1的方法类似，不同点在于，以7-喹啉甲醛为起始原料。
Figure PCTCN2019081066-appb-000062
HRMS(EI)calc.for C 20H 16N 2O 3 + 332.1161,found 332.1158。
实施例28(E)-2-(3-(异喹啉-6-基)-2-甲基丙烯酰胺基)苯甲酸(化合物28)
制备方法与实施例1的方法类似，不同点在于，以6-异喹啉甲醛为起始原料。
Figure PCTCN2019081066-appb-000063
HRMS(EI)calc.for C 20H 16N 2O 3 + 332.1161,found 332.1163。
实施例29(E)-2-(3-(苯并噻吩-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物29)
制备方法与实施例1的方法类似，不同点在于，以苯并噻吩-2-甲醛为起始原料。
Figure PCTCN2019081066-appb-000064
HRMS(EI)calc.for C 19H 15NO 3S + 337.0773,found 337.0771。
实施例30(E)-2-(3-(苯并噻吩-6-基)-2-甲基丙烯酰胺基)苯甲酸(化合物30)
制备方法与实施例1的方法类似，不同点在于，以苯并噻吩-6-甲醛为起始原料。
Figure PCTCN2019081066-appb-000065
HRMS(EI)calc.for C 19H 15NO 3S + 337.0773,found 337.0774。
实施例31(E)-2-(3-(苯并呋喃-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物31)
制备方法与实施例1的方法类似，不同点在于，以苯并呋喃-2-甲醛为起始原料。
Figure PCTCN2019081066-appb-000066
HRMS(EI)calc.for C 19H 15NO 4 + 321.1001,found 321.1003。
实施例32(E)-2-(3-(苯并呋喃-6-基)-2-甲基丙烯酰胺基)苯甲酸(化合物32)
制备方法与实施例1的方法类似，不同点在于，以苯并呋喃-6-甲醛为起始原料。
Figure PCTCN2019081066-appb-000067
HRMS(EI)calc.for C 19H 15NO 4 + 321.1001,found 321.1006。
实施例33(E)-2-(3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物33)
Figure PCTCN2019081066-appb-000068
将2mmol 2-萘甲醛和6mmol丙二酸分散在1.2mL DMF中，加入2mmol吡啶，90℃反应5h，冷却至室温，加入1.2mL水，1M HCl酸化，抽滤，水洗两次，滤饼干燥即得(E)-3-(萘-2-基)丙烯酸，收率80％，后续制备终产物的方法同实施例1。熔点：241.9-242.7℃； 1H NMR(400MHz,DMSO-d6):δ13.65(s,1H),11.41(s,1H),8.66(d,J＝8.4Hz,1H),8.23(s,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.99-7.92(m,4H),7.80(d,J＝15.6Hz,1H),7.68-7.61(m,1H),7.60-7.54(m,2H),7.23-7.18(m,1H),7.04(d,J＝15.6Hz,1H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.44,163.79,141.34,140.85,134.00,133.60,132.94,132.01,131.13,129.48,128.47,128.40,127.66,127.15,126.71,124.09,122.88,122.73,120.41,116.82ppm；HRMS(EI)calc.for C 20H 15NO 3 + 317.1052,found 317.1055。
实施例34(E)-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物34)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000069
熔点：231.5-232.3℃； 1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.92(s,1H),8.74(d,J＝8.0Hz,1H),8.07(dd,J＝8.0,1.6Hz,1H),8.05(s,1H),8.00-7.94(m,3H),7.70-7.64(m,2H),7.62(dd,J＝8.8,1.6Hz,1H),7.60-7.54(m,2H),2.30(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.95,166.90,141.29,134.54,134.28,133.14,132.87,132.74,132.37,131.23,128.81,128.19,127.92,127.52,127.09,126.71,126.50,122.69,119.74,116.22,14.05ppm；HRMS(EI)calc.for C 21H 17NO 3 + 331.1208,found 331.1204。
实施例35(E)-2-(3-(萘-2-基)-2-丁烯酰胺基)苯甲酸(化合物35)
Figure PCTCN2019081066-appb-000070
在50mL三口烧瓶中加入4.2mmol NaH，氩气保护，加入24mL无水THF，加入3.9mmol 2-磷酰基乙酸三乙酯，室温下搅拌0.5h，将12mL 1-(萘-2-基)-1-乙酮(3mmol)的THF溶液滴加到反应液中，室温反应12h，2M HCl酸化，旋掉THF，加入适量水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，旋除溶剂浓缩，过柱纯化得2-(萘-2-基亚甲基)丁烯酸乙酯，收率50％。后续制备终产物的方法同实施例1。HRMS(EI)calc.for C21H17NO3+ 331.1208,found 331.1206。
实施例36(E)-2-(2-甲基-3-(萘-2-基)-2-丁烯酰胺基)苯甲酸(化合物36)
制备方法与实施例35的方法类似，不同点在于，以2-膦酰丙酸三乙脂替换磷酰基乙酸三乙酯。
Figure PCTCN2019081066-appb-000071
HRMS(EI)calc.for C 22H 19NO 3 + 345.1365,found 345.1361。
实施例37(Z)-2-(2-氯-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物37)
Figure PCTCN2019081066-appb-000072
向反应瓶中加入9mmol乙氧甲酰基亚甲基三苯基膦和15mL DCM，氩气保护，-20℃下分批加入9mmol NCS，-20℃下反应1h，室温下加入5mmol 2-萘醛和12.5mmol K 2CO 3，室温反应10h，反应液用水洗，有机相用无水硫酸钠干燥，旋干浓缩，过柱纯化得(Z)-2-氯-3-(萘-2-基)丙烯酸乙酯。后续制备终产物的方法同实施例1。熔点：236.1-237.0℃； 1H NMR(400MHz,DMSO-d6):δ13.92(s,1H),12.53(s,1H),8.74(d,J＝8.0Hz,1H),8.49(s,1H),8.24(s,1H),8.09(dd,J＝7.8,1.2Hz,1H),8.03(s,3H),7.97(d,J＝7.2Hz,1H),7.70(t,J＝7.4Hz,1H),7.66-7.56(m,2H),7.27(t,J＝7.4Hz,1H)ppm. 13C NMR(100MHz,DMSO-d6):δ169.61,160.22,140.24,134.39,134.29,133.26,132.53,131.29,130.97,130.23,128.66,128.11,127.66,127.56,126.77,126.71,123.65,123.60,119.86,116.90ppm；HRMS(EI)calc.for C 20H 14 35ClNO 3 + 351.0662,found 351.0664；calc.for C 20H 14 37ClNO 3 + 353.0633,found 353.0643。
实施例38(Z)-2-(2-溴-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物38)
Figure PCTCN2019081066-appb-000073
向反应瓶中加入9mmol乙氧甲酰基亚甲基三苯基膦和15mL DCM，氩气保护，-20℃下分批加入9mmol NBS，-20℃下反应1h，室温下加入5mmol 2-萘醛和12.5mmol K 2CO 3，室温反应10h，反应液用水洗，有机相用无水硫酸钠干燥，旋干浓缩，过柱纯化得(Z)-2-溴-3-(萘-2-基)丙烯酸乙酯。后续制备终产物的方法同实施例1。熔点：233.9-234.7℃； 1H NMR(400MHz,DMSO-d6):δ13.89(s,1H),12.36(s,1H),8.69(d,J＝8.0Hz,1H),8.48(s,1H),8.45(s,1H),8.08(dd,J＝8.0,1.6Hz,1H),8.04-7.99(m,3H),7.97(d,J＝7.6Hz,1H),7.75-7.66(m,1H),7.66-7.55(m,2H),7.27(t,J＝7.6Hz,1H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.49,160.86,140.26,138.03,134.20,133.21,132.43,131.27,131.25,130.35,128.55,127.95,127.61,127.56,126.77,126.39,123.62,119.97,117.08,115.82ppm；HRMS(EI)calc.for C 20H 14 79BrNO 3 + 395.0157,found 395.0158；calc.for C 20H 14 81BrNO 3 + 397.0137,found 397.0132。
实施例39(E)-2-(2-(萘-2-基亚甲基)丁烯酰胺基)苯甲酸(化合物39)
制备方法与实施例35的方法类似，不同点在于，用2-萘甲醛替换1-(萘-2-基)-1-乙酮，用2-膦酰丁酸三乙脂替换磷酰基乙酸三乙酯。
Figure PCTCN2019081066-appb-000074
熔点：184.6-185.2℃； 1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.91(s,1H),8.74(d,J＝8.4Hz,1H),8.06(dd,J＝7.8,1.4Hz,1H),8.02-7.93(m,4H),7.70-7.63(m,1H),7.62-7.55(m,4H),7.21(t,J＝7.4Hz,1H),2.71(q,J＝7.2Hz,2H),1.23(t,J＝7.4Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.96,166.76,141.22,139.76,134.28,133.60,133.05,132.79,132.40,131.23,128.24,128.21,128.11,127.51,126.70,126.56,126.55,122.72,119.77,116.26,20.47,13.53ppm；HRMS(EI)calc.for C 22H 19NO 3 + 345.1365,found 345.1363。
实施例40(Z)-2-(3-(萘-2-基)-2-三氟甲基丙烯酰胺基)苯甲酸(化合物40)
Figure PCTCN2019081066-appb-000075
在反应瓶中依次加入6mmol 2-萘甲醛、4mmol 3,3,3-三氟丙酸、20mL THF和8mL 1M的TiCl 4二氯甲烷溶液，室温搅拌0.5h，向反应液中滴加16mmol三乙胺。室温反应40h后向反应瓶中缓慢加入30mL水，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋干并用硅胶柱分离纯化(二氯甲烷：甲醇＝10：1)，得(Z)-3-(萘-2-基)-2-(三氟甲基)丙烯酸。后续制备终产物的方法同实施例1。HRMS(EI)calc.for C 21H 14F 3NO 3 + 385.0926,found 385.0922。
实施例41(E)-2-(2-氰基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物41)
Figure PCTCN2019081066-appb-000076
将5mmol 2-萘甲醛分散在7.5mL甲醇中，加入5mmol氰基乙酸甲酯和0.5mmol哌啶，回流反应至反应完全。冷却至室温，固体析出，抽滤，滤饼用适量甲醇洗涤，滤饼烘干即得(E)-2-氰基-3-(萘-2-基)丙烯酸甲酯中间体。收率90％。后续制备终产物的方法同实施例1。HRMS(EI)calc.for C 21H 14N 2O 3 + 342.1004,found 342.1007。
实施例42(E)-5-氟-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物42)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000077
熔点：237.4-238.2℃； 1H NMR(400MHz,DMSO-d6):δ14.11(s,1H),11.71(s,1H),8.73(dd,J＝9.2,5.2Hz,1H),8.03(s,1H),8.01-7.92(m,3H),7.76(dd,J＝9.2,3.2Hz,1H),7.68(s,1H),7.61(dd,J＝8.6,1.2Hz,1H),7.59-7.52(m,3H),2.28(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.74,166.79,156.70(d, 1J CF＝239.4Hz),137.71(d, 4J CF＝2.3Hz),134.61,133.10,132.69(d, 3J CF＝8.3Hz),132.36,128.82,128.18,127.91,127.51,127.07,126.71,126.50,121.99(d, 3J CF＝7.4Hz),121.08(d, 2J CF＝21.9Hz),118.33,118.26,116.94(d, 2J CF＝23.7Hz),14.01ppm； 19F NMR(376MHz,DMSO-d6):δ-118.88--118.96(m,1F)ppm；HRMS(EI)calc.for C 21H 16FNO 3 + 349.1114,found 349.1113。
实施例43(E)-4-氟-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物43)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-4-氟苯甲酸。
Figure PCTCN2019081066-appb-000078
熔点：238.6-239.2℃； 1H NMR(400MHz,DMSO-d6):δ13.96(s,1H),12.17(s,1H),8.58(dd,J＝12.4,2.4Hz,1H),8.13(dd,J＝8.6,7.0Hz,1H),8.04(s,1H),8.00-7.93(m,3H),7.70(s,1H),7.61(dd,J＝8.6,1.0Hz,1H),7.59-7.55(m,2H),7.03(td,J＝8.6,2.4Hz,1H),2.29(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.27,167.18,165.00(d, 1J CF＝247.8Hz),143.43(d, 3J CF＝13.0Hz),135.11,133.96(d, 3J CF＝11.2Hz),132.98,132.72,132.43,132.42,128.92,128.20,127.94,127.51,127.04,126.77,126.52,112.73(d, 4J CF＝2.4Hz),109.65(d, 2J CF＝22.1Hz),106.15(d, 2J CF＝28.1Hz),13.92ppm； 19F NMR(376MHz,DMSO-d6):δ-102.67--102.97(m,1F)ppm；HRMS(EI)calc.for C 21H 16FNO 3 + 349.1114,found 349.1115。
实施例44(E)-5-氯-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物44)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氯苯甲酸。
Figure PCTCN2019081066-appb-000079
熔点：251.5-252.2℃； 1H NMR(400MHz,DMSO-d6):δ14.18(s,1H),11.83(s,1H),8.74(d,J＝9.2Hz,1H),8.03(s,1H),8.00-7.92(m,4H),7.72(dd,J＝9.0,2.6Hz,1H),7.69(s,1H),7.61(dd,J＝8.6,1.6Hz,1H),7.59-7.53(m,2H),2.28(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.69,166.90,140.05,134.86,133.83,133.04,132.72,132.56,132.39,130.32,128.87,128.19,127.92,127.51,127.05,126.74,126.51,126.24,121.58,118.12,13.99ppm；HRMS(EI)calc.for C 21H 16 35ClNO 3 + 365.0819,found 365.0816；calc.for C 21H 16 37ClNO 3 + 367.0789,found 367.0789。
实施例45(E)-5-溴-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物45)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-溴苯甲酸。
Figure PCTCN2019081066-appb-000080
熔点：256.9-257.6℃； 1H NMR(400MHz,DMSO-d6):δ14.18(s,1H),11.83(s,1H),8.69(d,J＝8.8Hz,1H),8.11(d,J＝2.8Hz,1H),8.02(s,1H),8.00-7.92(m,3H),7.82(dd,J＝8.8,2.4Hz,1H),7.68(s,1H),7.60(dd,J＝8.6,1.4Hz,1H),7.58-7.53(m,2H),2.28(d,J＝0.8Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.62,166.88,140.44,136.67,134.88,133.21,133.04,132.71,132.55,132.38,128.87,128.19,127.91,127.50,127.03,126.73,126.49,121.81,118.34,114.01,13.98ppm；HRMS(EI)calc.for C 21H 16 79BrNO 3 + 409.0314,found 409.0312；calc.for C 21H 16 81BrNO 3 + 411.0293,found 411.0308。
实施例46(E)-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)-5-三氟甲基苯甲酸(化合物46)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-三氟甲基苯甲酸。
Figure PCTCN2019081066-appb-000081
熔点：228.7-229.4℃； 1H NMR(400MHz,DMSO-d6):δ12.20(s,1H),8.92(d,J＝8.8Hz,1H),8.28(d,J＝2.0Hz,1H),8.04(s,1H),8.02-7.93(m,4H),7.72(s,1H),7.62(dd,J＝8.6,1.4Hz,1H),7.59-7.54(m,2H),2.30(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.77,167.27,144.37,135.28,132.95,132.71,132.48,132.43,130.66(q, 3J CF＝3.4Hz),128.96,128.21,127.94,127.91(q, 3J CF＝3.5Hz),127.51,127.02,126.79,126.52,123.83(q, 1J CF＝270Hz),122.49(q, 2J CF＝32.6Hz),120.16,116.86,13.99ppm； 19F NMR (376MHz,DMSO-d6):δ-60.79(s,3F)ppm；HRMS(EI)calc.for C 22H 16F 3NO 3 + 399.1082,found 399.1088。
实施例47(E)-5-甲基-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物47)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-甲基苯甲酸。
Figure PCTCN2019081066-appb-000082
熔点：194.6-195.3℃； 1H NMR(400MHz,DMSO-d6):δ13.73(s,1H),11.81(s,1H),8.63(d,J＝8.4Hz,1H),8.03(s,1H),8.00-7.92(m,3H),7.87(s,1H),7.67(s,1H),7.61(d,J＝8.4Hz,1H),7.58-7.53(m,2H),7.47(dd,J＝8.4,1.2Hz,1H),2.33(s,3H),2.28(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.96,166.66,138.93,134.80,134.34,133.19,132.88,132.74,132.34,131.76,131.23,128.77,128.17,127.89,127.51,127.09,126.68,126.48,119.78,116.12,20.20,14.03ppm；HRMS(EI)calc.for C 22H 19NO 3 + 345.1365,found 345.1367。
实施例48(E)-5-甲氧基-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸(化合物48)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-甲氧基苯甲酸。
Figure PCTCN2019081066-appb-000083
熔点：218.6-219.3℃； 1H NMR(400MHz,DMSO-d6):δ13.70(s,1H),11.60(s,1H),8.65(d,J＝9.2Hz,1H),8.02(s,1H),7.99(t,J＝2.8Hz,1H),7.97-7.92(m,2H),7.67(s,1H),7.61(dd,J＝8.4,1.6Hz,1H),7.57(d,J＝3.2Hz,1H),7.55(d,J＝3.6Hz,1H),7.53(d,J＝2.8Hz,1H),7.28(dd,J＝9.2,3.2Hz,1H),3.81(s,3H),2.28(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.49,166.44,154.16,134.67,134.15,133.25,132.87,132.75,132.32,128.72,128.15,127.88,127.49,127.08,126.64,126.46,121.63,120.23,117.74,114.89,55.37,14.02ppm；HRMS(ES+)calcd for C 22H 19NO 4Na(M+Na) +,384.1212；found,384.1213。
实施例49(E)-2-(3-(1-氟萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物49)
制备方法与实施例1的方法类似，不同点在于，以1-氟-2-萘甲醛为原料。
Figure PCTCN2019081066-appb-000084
熔点：247.3-248.2℃； 1H NMR(400MHz,DMSO-d6):δ13.83(s,1H),11.98(s,1H),8.74(d,J＝8.0Hz,1H),8.14-8.09(m,1H),8.07(dd,J＝8.0,1.4Hz,1H),8.05-8.01(m,1H),7.85(d,J＝8.8Hz,1H),7.71-7.65(m,4H),7.62(t,J＝8.0Hz,1H),7.24-7.18(m,1H),2.19(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.99,166.14,154.97(d, 1J CF＝252.1Hz),141.14,135.12,134.30,134.08(d, 3J CF＝5.8Hz),131.23,127.68,127.40(d, 3J CF＝3.0Hz),127.23(d, 4J CF＝1.4Hz),126.71(d, 3J CF＝3.2Hz),123.71(d, 3J CF＝4.1Hz),122.83,122.58(d, 2J CF＝16.6Hz),120.23,120.17,119.77,117.85(d, 2J CF＝12.7Hz),116.30,14.25ppm； 19F NMR(376MHz,DMSO-d6):δ-122.81(d,J＝7.2Hz,1F)ppm；HRMS(EI)calc.for C 21H 16FNO 3 + 349.1114,found 349.1120。
其中，所述的1-氟-2-萘甲醛可按下列方法制备：
Figure PCTCN2019081066-appb-000085
将2-甲基-1-萘胺(1.57g，10mmol)加入到100mL茄形瓶中，向反应瓶中滴加氟硼酸(15mL)，冰浴冷却，向反应液中缓慢滴加10mL NaNO 2溶液(2.76g，40mmol)，冰浴反应0.5h，抽滤，滤饼干燥得重氮盐。将所得重氮盐加入到50mL甲苯中，90℃反应1h，回流反应2h。依次用饱和NaHCO 3溶液和饱和食盐水洗涤反应液，用无水硫酸钠干燥，浓缩反应液，过柱纯化得1-氟-2-甲基萘，收率67％。
将制得的1-氟-2-甲基萘(5mmol)溶于10mL CCl 4，加入10mmol NBS，0.1mmol过氧化二苯甲酰(BPO)，回流反应5h，冷却至室温，过滤，用适量石油醚洗涤滤饼，浓缩。将所得浓缩液溶解在10mL二氧六环中，加入10mL水，20mmol CaCO 3，回流10h，过滤，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，旋干浓缩，过柱纯化得(1-氟萘-2-基)甲醇，收率80％。
将制得的(1-氟萘-2-基)甲醇(4mmol)溶解在40mL的DCM中，搅拌条件下加入28mmol的MnO 2，室温下反应4h，过滤，滤液旋干浓缩，过柱纯化得1-氟-2-萘甲醛(起始原料)，收率90％。
实施例50(Z)-2-(2-氯-3-(1-氟萘-2-基)丙烯酰胺基)-5-氟苯甲酸(化合物50)
制备方法与实施例37的方法类似，不同点在于，以1-氟-2-萘甲醛为原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000086
1H NMR(400MHz,DMSO-d 6):δ14.21(s,1H),12.53(s,1H),8.73(dd,J＝9.2,5.2Hz,1H),8.06(dd,J＝8.0,1.4Hz,1H),8.05-8.01(m,1H),7.81(d,J＝8.8Hz,1H),7.71-7.63(m,4H),7.62(t,J＝8.0Hz,1H),7.25-7.20(m,1H),ppm；HRMS(EI)calc.for C 20H 12ClF 2NO 3 +387.0474,found 387.0471；HRMS(EI)calc.for C 20H 12 37ClF 2NO 3 + 389.0445,found 389.0447.
实施例51(E)-5-氟-2-(3-(1-氟萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物51)
制备方法与实施例1的方法类似，不同点在于，以1-氟-2-萘甲醛为原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000087
熔点：250.8-251.7℃； 1H NMR(400MHz,DMSO-d6):δ14.13(s,1H),11.76(s,1H),8.72(dd,J＝9.2,5.2Hz,1H),8.14-8.09(m,1H),8.06-8.01(m,1H),7.85(d,J＝8.4Hz,1H),7.77(dd,J＝9.2,3.2Hz,1H),7.70-7.64(m,3H),7.61(d,J＝8.0Hz,1H),7.59-7.53(m,1H),2.17(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.76,166.07,156.80(d, 1J CF＝239.8Hz),154.97(d, 1J CF＝252.3Hz),137.54(d, 4J CF＝2.3Hz),134.94,134.08(d, 3J CF＝5.0Hz),127.69,127.67,127.47(d, 4J CF＝3.2Hz),127.23(d, 4J CF＝1.3Hz),126.69(d, 3J CF＝3.4Hz),123.71(d, 3J CF＝4.2Hz),122.59(d, 2J CF＝16.5Hz),122.07(d, 3J CF＝7.4Hz),121.09(d, 2J CF＝22.1Hz),120.20(d, 3J CF＝5.6Hz),118.46(d, 3J CF＝6.7Hz),117.82(d, 2J CF＝12.6Hz),116.97(d, 2J CF＝23.5Hz),14.22ppm； 19F NMR(376MHz,DMSO-d6):δ-118.53--119.11(m,1F),-122.80(d,J＝6.6Hz,1F)ppm；HRMS(EI)calc.for C 21H 15F 2NO 3 + 367.1020,found 367.1018。
实施例52(E)-2-(3-(1-氯萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物52)
制备方法与实施例1的方法类似，不同点在于，以1-氯-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000088
熔点：240.3-241.2℃； 1H NMR(400MHz,DMSO-d6):δ13.82(s,1H),11.99(s,1H),8.75(d,J＝8.0Hz,1H),8.28(d,J＝8.4Hz,1H),8.08-8.05(m,2H),8.02(d,J＝8.4Hz,1H),7.78(s,1H),7.77-7.71(m,1H),7.71-7.65(m,2H),7.62(d,J＝8.4Hz,1H),7.22(t,J＝7.2Hz,1H),2.13(d,J＝0.8Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.96,166.11,141.11,134.80,134.31,133.50,132.21,131.74,131.26,130.17,130.07,128.40,128.04,127.38,127.22, 127.07,123.76,122.87,119.78,116.29,14.02ppm；HRMS(EI)calc.for C 21H 16 35ClNO 3 +365.0819,found 365.0824；calc.for C 21H 16 37ClNO 3 + 367.0789,found 367.0827。
实施例53(E)-2-(3-(1-氯萘-2-基)-2-甲基丙烯酰胺基)-5-氟苯甲酸(化合物53)
制备方法与实施例1的方法类似，不同点在于，以1-氯-2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000089
熔点：255.8-256.7℃； 1H NMR(400MHz,DMSO-d6):δ14.15(s,1H),11.79(s,1H),8.75(dd,J＝9.2,5.2Hz,1H),8.27(d,J＝5.6Hz,1H),8.08-7.98(m,2H),7.80-7.65(m,4H),7.63-7.52(m,2H),2.12(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.76,165.99,156.79(d, 1J CF＝239.6Hz),137.52(d, 4J CF＝2.4Hz),134.60,133.49,132.28,131.69,130.18,130.06,128.38,128.02,127.36,127.18,127.05,123.75,122.00(d, 3J CF＝6.6Hz),121.11(d, 2J CF＝22.3Hz),118.35(d, 3J CF＝5.4Hz),116.99(d, 2J CF＝24.0Hz),13.98ppm； 19F NMR(376MHz,DMSO-d6):δ-118.64--118.74(m,1F)ppm；HRMS(EI)calc.for C 21H 15 35ClFNO 3 + 383.0724,found 383.0724。
实施例54(Z)-2-(2-氯-3-(1-氯萘-2-基)丙烯酰胺基)-5-氟苯甲酸(化合物54)
制备方法与实施例37的方法类似，不同点在于，以1-氯-2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000090
1H NMR(400MHz,DMSO-d 6):δ14.23(s,1H),12.32(s,1H),8.72(dd,J＝9.2,5.2Hz,1H),8.05-7.96(m,3H),7.71(dd,J＝9.2,3.2Hz,1H),7.63(s,1H),7.61(dd,J＝8.6,1.2Hz,1H),7.58-7.49(m,3H)ppm；HRMS(EI)calc.for C 20H 12 35Cl 2FNO 3 + 403.0178,found403.0176。
实施例55(E)-2-(3-(1-溴萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物55)
制备方法与实施例1的方法类似，不同点在于，以1-溴-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000091
熔点：235.6-236.2℃； 1H NMR(400MHz,DMSO-d6):δ13.83(s,1H),11.99(s,1H),8.76(d,J＝8.4Hz,1H),8.27(d,J＝8.4Hz,1H),8.09-8.01(m,3H),7.76-7.71(m,2H),7.70- 7.63(m,2H),7.61-7.55(m,1H),7.22(t,J＝7.6Hz,1H),2.10(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ169.95,166.04,141.11,134.85,134.32,134.28,134.22,133.45,131.41,131.27,128.45,128.27,127.80,127.46,127.33,126.40,123.41,122.86,119.77,116.25,13.92ppm；HRMS(EI)calc.for C 21H 16 79BrNO 3 + 409.0314,found 409.0316；calc.for C 21H 16 81BrNO 3 + 411.0293,found 411.0302。
实施例56(Z)-2-(3-(1-溴萘-2-基)-2-氯丙烯酰胺基)-5-氟苯甲酸(化合物56)
制备方法与实施例37的方法类似，不同点在于，以1-溴-2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000092
1H NMR(400MHz,DMSO-d 6):δ14.24(s,1H),12.22(s,1H),8.71(dd,J＝9.2,5.2Hz,1H),8.01-7.93(m,3H),7.74(dd,J＝9.2,3.2Hz,1H),7.63(s,1H),7.61(dd,J＝8.6,1.2Hz,1H),7.59-7.49(m,3H)ppm；HRMS(EI)calc.for C 20H 12 79Br 35ClFNO 3 + 446.9673,found446.9678。
实施例57(E)-2-(3-(1-溴萘-2-基)-2-甲基丙烯酰胺基)-5-氟苯甲酸(化合物57)
制备方法与实施例1的方法类似，不同点在于，以1-溴-2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000093
熔点：261.9-262.7℃； 1H NMR(400MHz,DMSO-d6):δ14.17(s,1H),11.79(s,1H),8.76(dd,J＝9.2,5.2Hz,1H),8.27(d,J＝8.4Hz,1H),8.07-8.03(m,2H),7.77(dd,J＝9.2,3.2Hz,1H),7.75-7.71(m,2H),7.69-7.65(m,1H),7.60-7.54(m,2H),2.09(d,J＝1.6Hz,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ168.72,165.94,156.79(d, 1J CF＝239.9Hz),137.55(d, 4J CF＝2.2Hz),134.91,134.24,134.04,133.45,131.41,128.44,128.26,127.79,127.42,127.32,126.40,123.40,122.00(d, 3J CF＝7.2Hz),121.12(d, 2J CF＝21.6Hz),118.31(d, 3J CF＝6.8Hz),116.99(d, 2J CF＝23.6Hz),13.88ppm； 19F NMR(376MHz,DMSO-d6):δ-118.64--118.72(m,1F)ppm；HRMS(EI)calc.for C 21H 15 79BrFNO 3 + 427.0219,found 427.0216；calc.for C 21H 15 81BrFNO 3 + 429.0199,found 429.0189。
实施例58(E)-2-(3-(1-氟-6-甲氧基萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物58)
制备方法与实施例1的方法类似，不同点在于，以1-氟-6-甲氧基-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000094
HRMS(EI)calc.for C 22H 18FNO 4 + 379.1220,found 379.1226。
实施例59(E)-2-(3-(6-溴-1-氟萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物59)
制备方法与实施例1的方法类似，不同点在于，以6-溴-1-氟-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000095
HRMS(EI)calc.for C 21H 15 79BrFNO 3 + 427.0219,found 427.0217；calc.for C 21H 15 81BrFNO 3 + 429.0199,found 429.0192。
实施例60(E)-2-(3-(1,6-二氯萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物60)
制备方法与实施例1的方法类似，不同点在于，以1,6-二氯-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000096
HRMS(EI)calc.for C 21H 15 35Cl 2NO 3 + 399.0429,found 399.0427；calc.for C 21H 15 35Cl 37ClNO 3 + 401.0399,found 401.0392；calc.for C 21H 15 37Cl 2NO 3 + 403.0396,found 403.0394。
实施例61(E)-2-(3-(1,6-二氯萘-2-基)-2-甲基丙烯酰胺基)-5-氟苯甲酸(化合物61)
制备方法与实施例1的方法类似，不同点在于，以1,6-二氯-2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-5-氟苯甲酸。
Figure PCTCN2019081066-appb-000097
HRMS(EI)calc.for C 21H 15 35Cl 2FNO 3 + 417.0335,found 417.0336；calc.for C 21H 15 35Cl 37ClFNO 3 + 419.0305,found 419.0302；calc.for C 21H 15 37Cl 2FNO 3 + 421.0275,found 421.0277。
实施例62(E)-2-(3-(5-氯-1-氟萘-2-基)-2-甲基丙烯酰胺基)苯甲酸(化合物62)
制备方法与实施例1的方法类似，不同点在于，以5-氯-1-氟-2-萘甲醛为起始原料。
Figure PCTCN2019081066-appb-000098
HRMS(EI)calc.for C 21H 15 35ClFNO 3 + 383.0724,found 383.0722；calc.for C 21H 15 37ClFNO 3 + 385.0694,found 385.0692。
实施例63(E)-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)噻吩-3-甲酸(化合物63)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-3-噻吩甲酸。
Figure PCTCN2019081066-appb-000099
熔点：219.0-219.9℃； 1H NMR(400MHz,DMSO-d6):δ13.36(s,1H),11.93(s,1H),8.07(s,1H),8.04-7.93(m,3H),7.76(s,1H),7.64(d,J＝8.4Hz,1H),7.57(s,2H),7.23(d,J＝5.6Hz,1H),7.04(d,J＝5.6Hz,1H),2.31(s,3H)ppm； 13C NMR(100MHz,DMSO-d6):δ166.75,164.77,147.92,136.27,132.76,132.70,132.51,130.01,129.14,128.26,127.98,127.54,127.06,126.89,126.56,124.30,116.68,114.14,13.69ppm；HRMS(ES+)calcd for C 19H 15NO 3SNa(M+Na) +,360.0670；found,360.0672。
所述2-氨基-3-噻吩甲酸可由主要步骤如下的方法制得：
Figure PCTCN2019081066-appb-000100
将2-氨基-3-噻吩甲酯(314mg，2.0mmol)分散在10mL水和10mL甲醇混合溶剂中，加入氢氧化钠(1.6g，40.0mmol)，氩气保护，回流反应2小时，冷却，旋除甲醇，1M HCl酸化，乙酸乙酯萃取，饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱分离纯化(二氯甲烷：甲醇＝10：1)，得2-氨基-3-噻吩甲酸，收率46％。
实施例64(E)-4-甲基-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)噻吩-3-甲酸(化合物64)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-4-甲基噻吩-3-甲酸。
Figure PCTCN2019081066-appb-000101
HRMS(EI)calc.for C 20H 17NO 3S + 351.0929,found 351.0926。
实施例65(E)-4,5-二甲基-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)噻吩-3-甲酸(化合物65)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基-4,5-二甲基噻吩-3-甲酸。
Figure PCTCN2019081066-appb-000102
HRMS(EI)calc.for C 21H 19NO 3S + 365.1086,found 365.1081。
实施例66(E)-4-(2-甲基-3-(萘-2-基)丙烯酰胺基)烟酸(化合物66)
Figure PCTCN2019081066-appb-000103
原料(E)-2-甲基-3-(萘-2-基)丙烯酸的制备方法与实施例1中(E)-2-甲基-3-苯基丙烯酸的合成方法类似，不同点在于，以2-萘甲醛为起始原料。
将(E)-2-甲基-3-(萘-2-基)丙烯酸(212mg,1.0mmol)分散在干燥的二氯甲烷(3mL)中，冰浴冷却，向其中滴加草酰氯(381mg，3.0mmol)，滴加一滴二甲基甲酰胺，套上干燥管，室温反应3h，减压旋除溶剂，即得酰氯中间体，将其溶于1mL吡啶。
将4-氨基烟酸(138mg，1.0mmol)分散在2mL吡啶中，冰浴冷却，向其中滴加上述酰氯吡啶溶液，室温反应过夜。向反应液中滴加5mL水，抽滤，滤饼用适量水洗涤，烘干，硅胶柱分离纯化(二氯甲烷：甲醇＝3：1)，得化合物66，收率30％。熔点：303.3-304.2℃； 1H NMR(400MHz,DMSO-d6):δ14.55(s,1H),9.11(s,1H),8.51(d,J＝5.6Hz,1H),8.46(d,J＝5.6Hz,1H),8.02(s,1H),7.97(d,J＝8.4Hz,2H),7.94(d,J＝5.2Hz,1H),7.69(s,1H),7.61(d,J＝8.4Hz,1H),7.58-7.52(m,2H),2.27(s,3H)ppm. 13C NMR(100MHz,DMSO-d6):δ169.28,167.65,152.54,151.23,147.21,134.69,133.23,133.02,132.73,132.35,128.82,128.17,127.88,127.51,127.08,126.70,126.49,118.00,112.44,14.09ppm.HRMS(ES+)calcd for C 20H 17N 2O 3(M+H) +,333.1239；found,333.1241。
实施例67(E)-N-(2-氰基苯基)-2-甲基-3-(萘-2-基)丙烯酰胺(化合物67)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为邻氰基苯甲酸。
Figure PCTCN2019081066-appb-000104
HRMS(EI)calc.for C 21H 16N 2O + 312.1263,found 312.1266。
实施例68(E)-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酰胺(化合物68)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基苯甲酰胺。
Figure PCTCN2019081066-appb-000105
熔点：169.8-170.6℃； 1H NMR(400MHz,DMSO-d6):δ12.57(s,1H),8.69(d,J＝8.0Hz,1H),8.39(s,1H),8.03(s,1H),8.00-7.93(m,3H),7.89(dd,J＝7.6,1.2Hz,1H),7.83(s,1H),7.64(s,1H),7.61(dd,J＝8.4,1.2Hz,1H),7.59-7.54(m,3H),7.20-7.14(m,1H),2.27(d,J＝0.8Hz,1H)ppm； 13C NMR(100MHz,DMSO-d6):δ171.07,166.67,140.14,134.17,133.24,133.05,132.75,132.42,132.33,128.73,128.66,128.17,127.89,127.51,127.09,126.66,126.48,122.42,120.06,119.25,14.05ppm；HRMS(EI)calc.for C 21H 18N 2O 2 + 330.1368,found 330.1371。
实施例69(E)-2-(2-甲基-3-(萘-2-基)丙烯酰胺基)苯甲酸甲酯(化合物69)
Figure PCTCN2019081066-appb-000106
将化合物34(1.0mmol)和5mL二氯甲烷依次加入到套有干燥管的反应瓶中，冰浴冷却，向反应液中滴加3mmol草酰氯、一滴DMF和1.5mmol甲醇。室温下反应12h，将反应液旋干浓缩，硅胶柱分离纯化(石油醚：乙酸乙酯＝3：1)，得化合物64，收率40％。熔点：113.4-114.2℃； 1H NMR(400MHz,CDCl 3):δ11.71(s,1H),8.90(d,J＝8.4Hz,1H),8.08(dd,J＝8.0,1.6Hz,1H),7.89-7.83(m,4H),7.78(s,1H),7.63-7.58(m,1H),7.54(dd,J＝8.6,1.4Hz,1H),7.52-7.48(m,2H),7.14-7.09(m,1H),3.95(s,3H),2.37(d,J＝1.2Hz,3H)ppm； 13C NMR(100MHz,CDCl 3):δ168.93,167.99,141.92,135.71,134.76,133.76,133.16,132.99,132.81,130.94,128.99,128.23,127.92,127.68,127.19,126.52,126.39,122.52,120.62,115.24,52.42,14.31ppm；HRMS(EI)calc.for C 22H 19NO 3 + 345.1365,found 345.1366。
实施例70(E)-2-甲基-3-(萘-2-基)-N-(吡啶-2-基)丙烯酰胺(化合物70)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为2-氨基吡啶。
Figure PCTCN2019081066-appb-000107
HRMS(EI)calc.for C 19H 16N 2O + 288.1263,found 288.1261。
实施例71(E)-N-(2-氰基-1-环戊烯-1-基)-2-甲基-3-(萘-2-基)丙烯酰胺(化合物71)
制备方法与实施例1的方法类似，不同点在于，以2-萘甲醛为起始原料，将邻氨基苯甲酸替换为1-氨基-2-氰基-1-环戊烯。
Figure PCTCN2019081066-appb-000108
HRMS(EI)calc.for C 20H 18N 2O + 302.1419,found 302.1415。
实施例72本发明化合物的DHODH抑制活性测试
DHODH在一定条件下能催化其天然底物DHO(二氢乳清酸)氧化为Orotate。在DHODH的催化下，首先将底物DHO的两个H +及e -转移到辅酶FMN上，随后还原态的FMNH 2将电子传递给游离辅酶Q。游离辅酶Q最终将电子传递给显色底物DCIP，DCIP被还原。DCIP在600nm处有最大光吸收，而还原态的DCIP在600nm处没有光吸收。根据吸光度的减弱程度即可判断底物DHO被氧化的程度。单位时间内底物DHO被氧化程度即为酶促反应初速度，加入抑制剂后，酶促反应初速度降低。测定时采用96孔板，由BioTek酶标仪读取600nm处吸光值。每孔加入199μL测活缓冲液(50mM HEPES(pH8.0)，0.15M KCl，0.1％Triton X-100，100μM辅酶Q，100μM DCIP)。加入0.4μL化合物，室温孵育5min，然后每孔加入1μL底物DHO(终浓度为500μM)并混匀，然后立刻用酶标仪测定600nm处吸光值，每隔30s读取一次数据，共读6min。每个实验至少设3个平行。最后计算不同浓度化合物的抑制率，通过Origin8.0计算出半数有效抑制浓度IC 50值。具体参考文献Sci.Rep.,2015.5:14836。
表1 代表性化合物1-71的活性列表
Figure PCTCN2019081066-appb-000109
Figure PCTCN2019081066-appb-000110
Figure PCTCN2019081066-appb-000111
Figure PCTCN2019081066-appb-000112
Figure PCTCN2019081066-appb-000113
Figure PCTCN2019081066-appb-000114
Figure PCTCN2019081066-appb-000115
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型：
    Figure PCTCN2019081066-appb-100001
    式中，
    A为未取代或取代的C 3-7环烷基、未取代或取代的C 5-7环烯基、未取代或取代的C 6-C 10芳基、或未取代或取代的5-10元杂环基；所述取代的是指被选自下组的基团所取代：卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 5-7环烯基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、C 6-C 10芳基-NH-CO-、-O-(CH 2)m-O-、-(CH 2)n-；其中，m或n为1～4的整数；
    B为未取代或取代的C 3-7环烷基、C 5-7环烯基、C 6-C 10芳基、5-10元杂环基；所述取代的是指被选自下组的基团所取代：卤素、氰基(-CN)、硝基、羧基(-COOH)、酰胺基(-CONH 2)、磺酸基、磺酰胺、C 1-6磺酸酯基、羟基、C 1-6烷羰基、C 1-6卤代烷羰基、C 1-6醛基、C 1-6酯基、C 1-6酰肼基、胍基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 2-6烯基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、C 6-C 10芳基-NH-CO-、-O-CH 2-O-、-(CH 2)n-；其中，n为2～4的整数；
    R 1选自下组：氢、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 5-7环烯基；
    R 2选自下组：氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 5-7环烯基。
  2. 如权利要求1所述的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型，其特征在于，所述化合物选自式II所示的化合物：
    Figure PCTCN2019081066-appb-100002
    式中，
    A和R 2定义同前；
    X代表氮原子或基团CY，其中Y选自下组：羧基、酰胺基、磺酸基、磺酰胺基、C 1-6磺酸酯基、羟基、C 1-6烷羰基、C 1-6卤代烷羰基、C 1-6醛基、C 1-6酯基、C 1-6酰肼基、氰基、硝基、胍基；
    R 3、R 4、R 5各自独立地选自下组：氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、C 2-6烯基、C 1-6烷氧基、羟基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、 C 6-C 10芳基-NH-CO-、-O-CH 2-O-、-(CH 2)n-；其中，n为2～4的整数。
  3. 如权利要求1或2所述的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型，其特征在于，A为未取代或取代的苯基、未取代或取代的吡啶基、未取代或取代的吲哚基、未取代或取代的萘基、未取代或取代的噻吩基、未取代或取代的苯并噻吩基、未取代或取代的呋喃基、未取代或取代的苯并呋喃基、未取代或取代的喹啉或未取代或取代的异喹啉基。
  4. 如权利要求1或2所述的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型，其特征在于，R 2选自下组：氢、氟、氯、溴、三氟甲基、甲基、乙基、丙基、环丙基。
  5. 如权利要求1所述的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型，其特征在于，所述化合物选自式III所示的化合物：
    Figure PCTCN2019081066-appb-100003
    式中，
    B和R 2定义同前；
    R 6、R 7、R 8、R 9、R 10各自独立地选自氢、卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷烃、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 5-7环烯基、C 1-6烷氧基、C 1-6卤代烷氧基、C 6-C 10芳基、C 6-C 10芳氧基、5元或6元杂环基、羟基、C 6-C 10芳基-NH-CO-；
    或者R 6、R 7、R 8、R 9、R 10中的任意两个可以连接形成-O-(CH 2)m-O-、-(CH 2)n-、-CH＝CH-；其中，m或n为1～4的整数。
  6. 如权利要求1或5所述的化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型，其特征在于，B选自未取代或取代的苯基、未取代或取代的5元或6元杂环基、或未取代或取代的C 5-7环烯基。
  7. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-6中任一项所述的化合物或其立体异构体、顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型；和药学上可接受的载体或赋形剂。
  8. 如权利要求1-6中任一项所述化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型或权利要求7所述药物组合物的用途，其特征在于，
    用于制备二氢乳清酸脱氢酶抑制剂；
    用于制备嘧啶生物合成酶抑制剂；和/或
    用于制备用于预防或治疗由二氢乳清酸脱氢酶的抑制和/或嘧啶生物合成酶的抑制来 改善的病理学病状或疾病。
  9. 如权利要求所述8所述的用途，其特征在于，所述的病理学病状或疾病选自下组：癌症、类风湿性关节炎、结肠炎、红斑狼疮、肾小球疾病、抗器官移植排斥反应、黑色素瘤、银屑病、关节炎、纤维病变、鼻炎、牛皮癣、多发性硬化、眼色素层炎、哮喘、白血病和疟疾。
  10. 如权利要求1-6中任一项所述化合物或其立体异构体、其顺反异构体、其互变异构体、其前药或其药学上可接受的盐或溶剂化物或晶型的制备方法，其特征在于，
    所述方法为方法1，包括步骤：
    Figure PCTCN2019081066-appb-100004
    (1)在惰性溶剂中，化合物1和化合物2进行反应，从而形成化合物3；
    (2)在惰性溶剂中，化合物3进行水解反应，从而形成化合物4；
    (3)在惰性溶剂中，化合物4先后和草酰氯和化合物5进行反应，从而形成化合物6；
    或所述方法为方法2，包括步骤：
    Figure PCTCN2019081066-appb-100005
    (1)在惰性溶剂中，化合物7和TsCl进行反应，从而形成化合物8；
    (2)在惰性溶剂中，化合物8和化合物5进行反应，从而形成化合物6；
    或所述方法为方法3，包括步骤：
    Figure PCTCN2019081066-appb-100006
    (1)在惰性溶剂中，化合物1和化合物9进行反应，从而形成化合物10；
    (2)在惰性溶剂中，化合物10先后和草酰氯和化合物5进行反应，从而形成化合物6；
    或所述方法为方法4，包括步骤：
    Figure PCTCN2019081066-appb-100007
    (1)在惰性溶剂中，化合物1和化合物11以及NCS或NBS进行反应，从而形成化合物12；
    (2)在惰性溶剂中，化合物12进行水解反应，从而形成化合物13；
    (3)在惰性溶剂中，化合物13先后和草酰氯和化合物5进行反应，从而形成化合物6；
    或所述方法为方法5，包括步骤：
    Figure PCTCN2019081066-appb-100008
    (1)在惰性溶剂中，化合物15和化合物16进行反应，从而形成化合物17；
    (2)在惰性溶剂中，化合物17进行水解反应，从而形成化合物18；
    (3)在惰性溶剂中，化合物18先后和草酰氯和化合物5进行反应，从而形成化合物19；
    或所述方法为方法6，包括步骤：
    Figure PCTCN2019081066-appb-100009
    (1)在惰性溶剂中，化合物1和化合物20进行反应，从而形成化合物21；
    (2)在惰性溶剂中，化合物21先后和草酰氯和化合物5进行反应，从而形成化合物22；
    或所述方法为方法7，包括步骤：
    Figure PCTCN2019081066-appb-100010
    (1)在惰性溶剂中，化合物1和化合物23进行反应，从而形成化合物24；
    (2)在惰性溶剂中，化合物24进行水解反应，从而形成化合物25；
    (3)在惰性溶剂中，化合物25先后和草酰氯和化合物5进行反应，从而形成化合物26；
    上述各式中，除了给出定义的基团，其它基团定义同前。
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