WO2013075596A1 - 作为dhodh抑制剂的五元二氢杂环酮类衍生物及应用 - Google Patents

作为dhodh抑制剂的五元二氢杂环酮类衍生物及应用 Download PDF

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WO2013075596A1
WO2013075596A1 PCT/CN2012/084556 CN2012084556W WO2013075596A1 WO 2013075596 A1 WO2013075596 A1 WO 2013075596A1 CN 2012084556 W CN2012084556 W CN 2012084556W WO 2013075596 A1 WO2013075596 A1 WO 2013075596A1
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group
optionally substituted
compound
alkyl
alkoxy
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李洪林
赵振江
黄瑾
徐玉芳
许鸣豪
刁妍妍
周洪昌
金黄涛
高瑞
朱俊生
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华东理工大学
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Priority to CH00795/14A priority Critical patent/CH707498B1/de
Priority to CN201280048200.3A priority patent/CN103842350B/zh
Priority to DE201211004878 priority patent/DE112012004878T8/de
Publication of WO2013075596A1 publication Critical patent/WO2013075596A1/zh

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    • 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
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • 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
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the invention belongs to the field of malaria treatment, and particularly relates to the synthesis and application of a dihydrothiophenone derivative as a DHODH inhibitor. Background technique
  • Malaria is an insect-borne disease caused by the infection of malaria parasites by mosquito bites and is still one of the global problems affecting human health.
  • drugs for the treatment of malaria include chloroquine, artemisinin, pyrimethamine and the like.
  • drugs for the treatment of malaria include chloroquine, artemisinin, pyrimethamine and the like.
  • quinine, chloroquine, and mequitine drugs for the treatment of malaria.
  • malaria parasites chloroquine, nuclear fragmentation of malaria parasites
  • the cytoplasm appears vacuoles, and the malaria pigments aggregate into clumps.
  • Chloroquine does not kill Plasmodium directly, but it can interfere with its reproduction.
  • Artemisinin is the only anti-malarial drug that has not been reported to have extensive and severe drug resistance. However, it has been reported in recent years that there are malaria parasites with anti-artemisinin-resistant Plasmodium in the border area of Thailand and Cambodia. The findings also deepen the growing anxiety about the increasing resistance of artemisinin therapy (Eastman, RT; Fidock, DA, Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Micro 2009, 7 (12 ), 864-874).
  • early malaria drugs such as pyrimethamine can inhibit the folate reductase of Plasmodium, and thus interfere with the normal generation of folate of the malaria parasite, which is effective for the pre-stage of Plasmodium falciparum cells, and thus is used as a preventive for etiology.
  • it also inhibits the development of Plasmodium in mosquitoes, thus blocking transmission (McKie, JH; Douglas, KT; Chan, C; Roser, SA; Yates, R.; Read, M.; Hyde, JE; Dascombe, MJ; Yuthavong, Y.; Sirawaraporn, W., Rational Drug Design Approach for Overcoming Drug Resistance: Application to Pyrimethamine Resistance in Malaria.
  • Dihydroorotate dehydrogenase is an iron-containing flavin-dependent mitochondrial enzyme (McConkey.A; Fishwick CW G; Johnson AP; The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase [J].Bioorganic & Medicinal Chemistry Letters. 2006, 16: 88-92) is an enzyme that catalyzes the dehydrogenation of dihydroorotate to convert it to orotic acid.
  • This process belongs to the fourth step of the pyrimidine de novo synthesis pathway, so DHODH is The key enzyme of nucleoside pyrimidine synthesis, and also the only catalyzed dihydroorotate-forming orotate in parasites, is mainly involved in the fourth step of catalyzing the de novo biosynthesis pathway of pyrimidine.
  • Human and Plasmodium dihydroorotate dehydrogenase are located on the inner mitochondrial membrane, and the catalytic process requires the participation of other cofactors.
  • DHODH is mainly divided into two parts, namely the N-terminal ⁇ -helical structure region and the C-terminal ⁇ / ⁇ barrel structure.
  • DHODH is attached to the inner mitochondrial membrane through a unique structure at the N-terminus, while the C-terminal region is the major site for catalysis. There is a binding site for both substrate and cofactor flavin mononucleotide (FMN) and coenzyme Q (CoQ) on DHODH. Its main catalytic process is completed in two steps: First-dihydro-orotate to orotate is reduced, while the oxidation of the hydrogen atom FMN receiving process is off after FMNH 2 under the effect of CoQ, dehydrogenation occurs FMNH 2 Revert to FMN. Any compound that can compete with the substrate or cofactor for binding can block the action of DHODH, thereby blocking the synthesis of DNA or RNA.
  • P. falciparum DHODH inhibitors mainly achieve the treatment of malaria by blocking the synthesis of biopyrimidine in Plasmodium and inhibiting the reproduction and growth of Plasmodium.
  • pyrimidine bases can be obtained through de novo synthesis and salvage pathways, but rapidly differentiated human cells, such as activated T-lymphocytes, B-lymphocytes, and tumor cells, also need to rely on pyrimidine.
  • the de novo synthesis pathway to meet its growth needs. This allows DHODH inhibitors to be used as anti-cell proliferative agents for the treatment of tumors and certain immunosuppressive responses. Due to the universal mechanism of action of DHODH on DNA and RNA synthesis, its inhibition also affects many other downstream signaling pathways. The study (Proceedings of the National Academy of Sciences 2010, 107 (29), 12828) showed that inhibition of DHODH in mitochondria causes a p53 stress response and can be used to treat tissue damage.
  • Leflunomide was launched in 1998 and has strong inhibitory effects on various autoimmune diseases, acute and chronic reactions caused by organ transplantation, and xenogeneic rejection. It has been used clinically to treat lupus erythematosus and rheumatoid arthritis. Prevention of graft rejection.
  • rheumatoid arthritis Herrmann, ML, Schleyerbach, R. and Kirschbaum, BJ, Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and Other autoimmune diseases. Immunopharmacology 2000, 47 (2-3), 273-289 ), colitis (Fitzpatrick, LR, Demi, L., Hofmann, C.; > Small, JS, Groeppel, M., Hamm, S.
  • psoriatic arthritis Kaltwasser, JP, Nash, P., Gladman, D., Rosen, CF, Behrens, F., Jones, P., Wollenhaupt, J., Falk, FG and Mease, P., Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: A multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis & Rheumatism 2004, 50 (6), 1939-1950), Psoriasis (White, RM, Cech, J., Ratanasirintrawoot, S.
  • Inhibitor based on the principle of binding of a DHODH inhibitor to a coenzyme binding pocket located at the N-terminus of the DHODH enzyme Both have a polar head and a hydrophobic tail that allows them to be effectively incorporated into the Coenzyme Q binding pocket (Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W. Malmquist, NA; Goldsmith, EJ; Rathod, PK; Phillips, MA Structural plasticity of malaria
  • Dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. [J]. J. Biol. Chem. 2009, 284, 26999-27009). Accordingly, the inventors have comprehensively applied computer drug design, medicinal chemistry, and molecular biology methods and techniques in the preliminary work, and found a series of five-membered dihydroheterocyclic ketone derivatives that meet the above structural requirements, and the structural skeleton is completely different. A highly active Plasmodium falciparum DHODH inhibitor reported in the literature. Some of these compounds have significant inhibition of the activity and immunological activity of Plasmodium cell lines at the cellular level, and have good prospects for drug discovery. For the series of lead compounds, the inventors designed and synthesized a series of five-membered dihydroheterocyclic ketone derivatives having the following structural formula:
  • Xi is selected from the group consisting of 0, S, NH and CH 2 ;
  • X 2 is selected from the group consisting of 0, S, NH, N0H, C1-C6 imino;
  • R 1 is selected from the group consisting of H, C1-C10 alkyl, an unsaturated hydrocarbon group below CIO, an optionally substituted aryl group, a nitro group, an amino group, NR 4 R 5 , a halogen;
  • R 2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 unsaturated hydrocarbon group, C1-C6 alkylcarbonyl group, optionally substituted benzoyl group, carboxyl group, aminocarbonyl group, C1-C6 alkoxycarbonyl group, C1-C6 Alkylaminocarbonyl, hydroxy, C1-C6 alkoxy, C3-C8 cycloalkylaminocarbonyl, C3-C8 cycloalkyl-C1-C6 alkylaminocarbonyl, C3-C8 cycloalkyl-C1-C6 alkoxy Alkylcarbonyl;
  • R 3 is selected from the group consisting of H, C1-C6 alkyl, optionally substituted C2-C6 unsaturated hydrocarbon group, C1-C6 alkylcarbonyl group, optionally substituted benzoyl group, carboxyl group, aminocarbonyl group, C1-C6 alkoxycarbonyl group , C1-C6 aminocarbonyl, hydroxy, C1-C6 alkoxy;
  • R 4 and R 5 are independently selected from the group consisting of H, C1-C6 alkyl, -C(0)NHR 6 , C1-C6 alkoxycarbonyl, halogen-substituted alkyl, C2-C6 unsaturated hydrocarbon, optionally substituted Aryl, C1-C6 alkylcarbonyl, optionally substituted benzoyl, optionally substituted heterocyclic, optionally substituted heterocyclylcarbonyl, C1-C6 alkoxycarbonyl;
  • R 6 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heterocyclic group.
  • the compound is selected from the group consisting of the compounds of formula II: In the formula,
  • Xi is selected from O, S, NH and CH 2 ;
  • R 2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 unsaturated hydrocarbon group, C1-C6 alkylcarbonyl group, optionally substituted benzoyl group, carboxyl group, aminocarbonyl group, C 1 -C6 alkoxycarbonyl group, C 1-C6 alkylaminocarbonyl, hydroxy, C 1 -C6 alkoxy, C3-C8 cycloalkylaminocarbonyl, C3-C8 cycloalkyl-C 1-C6 alkylaminocarbonyl, C3-C8 cycloalkyl- C 1-C6 alkoxycarbonyl;
  • R 7 is selected from an optionally substituted aryl group, an optionally substituted arylcarbonyl group, an optionally substituted nitrogen-containing heterocyclic carbonyl group, an optionally substituted heterocyclic group, and an optionally substituted aryloxy group, C 1- C3 alkylcarbonyl;
  • alkyl generally refers to saturated branched and straight-chain alkyl groups having a carbon chain length of from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 or 1-3.
  • Cycloalkyl means a cyclic alkyl group which usually has 3 to 8 ring carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl and the like.
  • alkenyl means a radical or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains a double bond.
  • Preferred alkenyl groups are alkenyl groups having 2 to 4 carbon atoms.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl means a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains a hydrazone bond.
  • Preferred alkynyl groups are alkynyl groups having 2 to 4 carbon atoms.
  • Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic radical containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, tetrahydronaphthalene. Base, indanyl group, and the like.
  • the aryl group may be optionally substituted by 1 to 5 (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C 1-C4 aldehyde group, C 1-C6 linear or Branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (eg trifluoromethyl), halogen-substituted alkoxy (eg trifluoromethoxy), carboxyl, C1 -C4 alkoxy, fluorenyl, C 1-C4 alkyl fluorenyl, -SF 5 , morpholinyl, optionally substituted aryl (eg, optionally substituted phenyl), optionally substituted aryloxy (eg, any A substituted phenoxy group and an optionally substituted benzyloxy group are selected.
  • 1 to 5 for example, 1, 2, 3, 4 or 5
  • substituents selected from the group consisting of halogen, C
  • an aryl group may be substituted with from 1 to 3 groups selected from the group consisting of: fluorine, chlorine, bromine, C1-C4 alkyl, trifluoromethyl, morpholinyl, methoxy, phenyl, methoxy Substituted phenyl, phenoxy, benzyloxy, benzyloxy substituted by halogen, ethoxy, nitro and the like.
  • heterocyclyl refers to a single or fused ring structure, which may be aromatic or non-aromatic in nature, and which preferably contains from 3 to 20 ring atoms, more preferably from 5 to 14 Ring atoms, wherein at least one and preferably up to 4 are heteroatoms selected from the group consisting of 0, S and N.
  • heterocyclic group examples include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, Isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridyl, decyl, tridecyl, quinolinyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazole Base, benzothienyl, benzofuranyl, morpholinyl, oxazolyl, dibenzothiophene, coumarinyl and 1,2-methylenedioxyphenyl.
  • a heterocyclic group may be optionally substituted with from 1 to 3 substituents as described herein.
  • heteroatom as used herein includes 0, S and N.
  • the N atom may be further substituted with a group such as hydrogen or a C1-C10 alkyl group.
  • the hetero atom is S
  • the S atom may be further substituted by a group such as a C1-C10 alkyl group.
  • heteroaryl or “aromatic heterocyclic” as used herein, refers to those heterocyclic groups having aromatic character as described above, including but not limited to furyl, thienyl, pyrrolyl, pyridyl, oxazolyl. , pyridinyl, fluorenyl, pyrimidinyl and the like.
  • halogen as used herein includes fluoro, chloro, bromo and iodo.
  • optionally substituted means that the group to which it is modified may be optionally substituted with from 1 to 5 (typically 1, 2 or 3) substituents selected from the group consisting of: C1-C4 alkyl, carboxy, halogen, C1-C4 alkoxy, cyano, nitro, amino, hydroxy, aldehyde, C1-C6 acyl, hydroxymethyl, halogen-substituted C1-C4 alkyl (eg three Fluoromethyl), C1-C10 thioalkyl (eg pentafluorothiomethyl), C1-C10 thioalkoxy (eg pentafluorothiomethoxy), halogen-substituted C1-C4 alkoxy (eg Trifluoromethoxy), fluorenyl and C1-C4 acyl.
  • substituents selected from the group consisting of: C1-C4 alkyl, carboxy, halogen, C1-C4 alkoxy,
  • the amide group (aminocarbonyl group) itself or as part of another group means a "C1-C6 alkyl-CO-NH-" group, "C3-C8 cycloalkyl-CO-NH-" or "C3" -C8 cycloalkyl-C1-C6 alkyl-CO-NH-”.
  • exemplary amide groups include, but are not limited to, formamide groups, acetamido groups, propionamide groups, butanamide groups, cyclopropionamido groups, cyclopropionamide groups, and the like.
  • acyl group itself or as a part of other groups may have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • exemplary acyl groups include, but are not limited to, formyl, acetyl, and the like.
  • Preferred compounds of the invention include those wherein S and 0, X 2 are zero.
  • Preferred compounds of the invention include those wherein R 3 is H.
  • the compounds of the invention do not include Compound 14-21.
  • Preferred compounds of the invention include R 2 as a C1-C6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, etc.), C1-C6 aminocarbonyl (e.g., A compound of a carboxamide group, an acetamido group, a propionamide group, a butyramide group, a cyclopropionamido group, a cyclopropionamide group or the like.
  • C1-C6 alkoxycarbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, etc.
  • C1-C6 aminocarbonyl e.g., A compound of a carboxamide group, an acetamido group, a propionamide group, a butyramide group,
  • Preferred compounds of the invention include R 1 which is -NH-optionally substituted phenyl, -NH-optionally substituted naphthyl, -NH-optionally substituted indanyl, -NH-optionally substituted tetrahydrogenate A compound of naphthyl or -NH-optionally substituted quinolyl.
  • Preferred compounds of the invention include a substituent on the optionally substituted phenyl or naphthyl group in R 1 which is halogen, halogen substituted C 1-C4 alkyl, C 1 -C4 alkyl, C 1-C4 alkoxy compound of.
  • the invention includes that 1 is 8 and 0, X 2 is 0, R 3 is H, and R 2 is a C 1-C6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, cyclopropane An oxycarbonyl group, a cyclopropylmethoxycarbonyl group, etc., a C 1 -C6 aminocarbonyl group (for example, a carboxamide group, an acetamido group, a propionamide group, a butyramido group, a cyclopropionamido group, a cyclopropylamido group, etc.), R 1 is -NH-optionally substituted phenyl, -NH-optionally substituted naphthyl, -NH-optionally substituted indanyl, -NH-optionally substituted tetrahydronaphthyl or -NH- An optionally substituted quinolyl compound.
  • R 1 is -NH
  • the substituent on the optionally substituted phenyl or naphthyl group in R 1 is halogen, halogen-substituted C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy.
  • 1 is 8 and 0, X 2 is 0, R 3 is H, and R 2 is a C1-C6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), R 1 An optionally substituted phenyl group, -NH-optionally substituted naphthyl group, -NH-optionally substituted indanyl group, -NH-optionally substituted tetrahydronaphthyl group or -NH-option Substituted quinolyl; phenyl preferably has no substituent or has one to three substituents selected from the group consisting of halogen, trifluoromethyl, methyl, nitro and methoxy. Preferably, the substituent is at the 3, 4 and/or 5 position.
  • the compound does not include compound 14-21.
  • 1 is 8 and 0, X 2 is 0, R 3 is H, and R 2 is a C2-C4 alkoxycarbonyl group (e.g., ethoxycarbonyl, cyclopropoxycarbonyl, cyclopropylidene).
  • R 1 is -NH-optionally substituted phenyl, -NH-optionally substituted naphthyl, -NH-optionally substituted indanyl, -NH-optionally substituted tetrahydrogen Naphthyl or -NH- optionally substituted quinolyl; phenyl preferably has no substituent or has 2 to 3 substituents selected from halogen and C 1 -C 4 alkyl.
  • the compound does not include compound 14-21.
  • the compounds of the present invention include -11-optionally substituted naphthyl, -NH-optionally substituted indanyl, -NH-optionally substituted tetrahydronaphthyl or -NH- An optionally substituted quinolyl compound.
  • the present invention is preferably a compound of Nos. 1 to 67 shown in Table 1 below, and those having a inhibition ratio of 50% or more are particularly preferable.
  • the compounds of the invention include compounds 1, 2, 4, 6, 7, 10, 22-25, 35, 38, 39, 44, 61 and 62.
  • the compound of the present invention can be obtained by the following method.
  • R 1 is a substituent on the phenyl group in the final product, and its definition is the same as defined above for the aryl substituent.
  • Those skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as raw materials according to actual preparation needs. For example, the method of synthesizing the present invention can be carried out by referring to the method described in Du Xiaohua et al. (Synthesis of some phenyl isothiocyanates which are difficult to synthesize by non-sulfur phosgene method [J]. Pesticide, 2004, 43 (2), 78-79). Formula compound.
  • R 1 is a substituent on the phenyl group in the final product, which is defined as the definition of the above aryl substituent C1-C6
  • R 1 is a substituent on the phenyl group in the final product, and its definition is the same as defined above for the aryl substituent.
  • R 3 is the same as the above C1-C6 alkoxycarbonyl group.
  • a second aspect of the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic base salt. While the needs of each individual are varied, one skilled in the art can determine the optimal dosage of each active ingredient in the pharmaceutical compositions of the present invention.
  • inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic base salt. While the needs of each individual
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg per kilogram of oral administration.
  • 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, conveniently 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 for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, cranial A form of administration, intranasal or topical, 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 a dose sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such a dose can be administered as a single dose or can be administered according to an effective treatment regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. It is generally necessary to repeat the medication 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 benefit.
  • 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.
  • DHODH-mediated diseases mainly include: parasitic diseases, including falciparum malaria, vivax malaria, ovarian malaria, three-day malaria, trichomoniasis and dengue fever; diseases caused by rapid proliferation of certain types of cells, Such as cancer; inflammatory response; and various autoimmune diseases.
  • DHODH-mediated diseases also include host rejection caused by transplantation of the same or xenogeneic organs.
  • DHODH-mediated diseases include, but are not limited to, Trypanosoma cruzi, falciparum malaria, dengue fever, vivax malaria, ovarian malaria, three-day malaria, rheumatoid arthritis, colitis, lupus erythematosus (including systems) Lupus erythematosus, glomerular disease (including multiple secondary and primary glomerular diseases), anti-organ transplant rejection, melanoma, psoriatic arthritis and psoriasis.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by conventional mixing, granulating, tableting, dissolving, or freeze drying processes. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding appropriate amounts of auxiliaries, the granule mixture is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, Sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, Sodium carboxymethylcellulose, or poly
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dose of an active ingredient.
  • a third aspect of the present invention provides a method of treating or preventing a DHODH-mediated disease, which comprises administering a subject of the formula I or a hydrazine compound or a pharmaceutical composition of the present invention to a subject in need thereof.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the invention includes the use of a Formula I or a guanidine compound of the invention in the manufacture of a medicament for the treatment or prevention of a DHODH mediated disease.
  • the invention also encompasses the use of a Formula I or a guanidine compound of the invention in the manufacture of a medicament for the treatment or prevention of a Plasmodium DHODH mediated disease.
  • the present invention also encompasses the use of a compound of formula I or hydrazine of the present invention for the manufacture of a medicament for inhibiting the activity of Plasmodium DHODH.
  • the above therapeutic and prophylactic methods and uses are carried out using Compounds 1-4, 6, 7, 10, 12, 16-18, 20-25 35, 38, 39, 44, 61 and 62. detailed description
  • the intermediate was directly added to the flask, 10 mL of chloroform was added, and suspended, and 10 mmol of chloroform solution in which 1 mmol of triphosgene was dissolved was added dropwise, and the reaction was filtered overnight to obtain a mother liquor, which was directly subjected to spin-drying chromatography.
  • the substituted phenyl isothiocyanate has a yield of about 45%.
  • Synthetic method Add 3 mmol of 60% sodium hydrogen to about 240 mg and 1.8 mL of anhydrous THF in a 50 mL flask, and add 1.8 mL of an anhydrous THF solution containing 6 mmol of diethyl malonate in an ice water bath, 10 After the minute, 3 mL of 3 mmol of chloroacetyl chloride solution was added dropwise, and the ice bath was maintained for one hour, and the reaction was carried out for 40 hours at 40-45 ° C. The substituted aromatic amine was added dropwise at normal temperature. After normal temperature overnight, TLC showed a small amount of starting material, and refluxed for 2 hours.
  • DHODH dihydroorotate dehydrogenase
  • IPTG IPTG was added to the medium to make the final concentration of IPTG 0.5 mM, and induced at 25 °C for 4-6 h.
  • the cells were collected by centrifugation at 4000 °C for 20 min at 4 °C, and the cells were resuspended in 15 ml of deionized water and centrifuged at 10,000 rpm for 30 min to collect the cell pellet. After storage at -80 °C overnight, 20 ml of lysate was used.
  • DCIP is reduced in the reaction, is the final electron acceptor of DHO (dihydroorotate), so the degree of hydrolysis of the substrate DHO can be judged according to the rate of decrease of absorbance of DCIP at 600 nm.
  • the culture process was as follows. The initial infection rate was 1%, 2% blood pressure, and cultured in the presence or absence of a series of drugs, with a final volume of 100 L. Each compound was diluted in a ratio ranging from 0.15625 ⁇ m to 20 ⁇ . 0.2% DMSO was used as a negative control, different concentrations of chloroquine were used as positive controls, 100 L, 2% blood pressure of uninfected red blood cells were used as background control, and cultured at 37 ° C for 72 hours; 3 parallel controls were set for each of the above designs. The above cultures were all carried out in 96-well cell culture plates.
  • SYBR Green I-containing erythrocyte lysate 8.26 g/L NH4C1, 1 g/L KHC03, 0.037 g/L EDTA and 5 X SYBR Green
  • the dishes were placed in a dark room at room temperature for 1 hour, and all samples were transferred to a black ELISA plate (Coring 3925) and fluorescently detected by Biotek's Synergy MX Multi-Purpose Plate Detector at 485/520 nm. reading. This experiment was repeated twice.
  • the fluorescence data obtained from the negative control treatment group minus the background fluorescence data generated by the uninfected red blood cell group represents the maximum amount of DNA in the normal cultured Plasmodium falciparum in this experiment, and is recorded as the fluorescence data of the negative control well.
  • the fluorescence data of each test group and positive control group were corrected as such.
  • the inhibition rate at different concentrations was calculated from the following formula: Inhibition rate (%) 1 - (average fluorescence count in the test well / average fluorescence count in the negative control well)] X 100%.
  • the curves were fitted by the Growth/Sigmoidal program in the software Origin 8.0 and calculated to obtain the half-inhibition rate (IC50 values), and the mean and standard deviation were calculated by Microsoft Excel.

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Abstract

本发明涉及通式I的作为恶性疟原虫DHODH抑制剂的五元二氢杂环酮类衍生物的合成及应用，本发明所涉及的化合物能用于与DHODH相关疾病的治疗和预防，包括疟疾等由疟原虫引起的寄生虫病的治疗。

Description

作为 DHODH 抑制剂的五元二氢杂环酮类衍生物及应用 技术领域
本发明属于疟疾治疗领域， 具体涉及作为 DHODH 抑制剂的二氢噻吩酮衍生物 的合成及应用。 背景技术
疟疾 (Malaria)是经蚊叮咬而感染疟原虫所引起的虫媒传染病， 目前仍然是全球影 响人类健康的问题之一。目前典型的治疗疟疾的药物中已上市药物包括氯喹，青蒿素， 乙胺嘧啶等。 近几十年来， 越来越多的耐药问题在许多一度非常有效的药物中产生， 如奎宁， 氯喹， 和梅尔喹啉等等； 疟原虫经氯喹作用， 疟原虫的核碎裂， 细胞浆出现 空泡， 疟色素聚成团块。 氯喹并不能直接杀死疟原虫， 但能干扰它的繁殖。 它与核蛋 白有较强的结合力， 通过喹啉环上带负电的 7-氯与疟原虫 DNA上的鸟嘌吟上的 2-氨 基接近，使氯喹插入到 DNA的双螺旋两股之间，与 DNA形成复合物，从而阻止 DNA 的复制与 RNA转录。 氯喹还能抑制磷酸掺入疟原虫的 DNA与 RNA， 由于核酸的合 成减少， 而干扰疟原虫的繁殖。 但是， 最近许多年， 有报道证实氯喹及其衍生物作为 抗疟药物的药效正在快速消失， 有些地区的病人中甚至出现了对氯喹的完全抗性， 同 时导致寄生虫的清除需要更长的治疗周期和反复发作 (Wu, T.; S. Nagle, A.; K.
Chatterjee, A., Road Towards New Antimalarials - Overview of the Strategies and their Chemical Progress. Current Medicinal Chemistry 2011, 18 (6), 853-871)。
青蒿素是唯一没有被报道有广泛， 严重耐药性的抗疟疾药物， 但是近年有报道 称在泰柬边界地区出现了体内带有抗青蒿素抗性的疟原虫的疟蚊，相关后续研究结果 也加深了人们对青蒿素疗法不断加剧抗性的急迫忧虑 (Eastman, R. T.; Fidock, D. A., Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Micro 2009, 7 (12), 864-874)。
另外， 早期疟疾药物如乙胺嘧啶能抑制疟原虫的叶酸还原酶， 进而干扰疟原虫 的叶酸正常代射， 对恶性疟原虫细胞前期有效， 因此用作病因性预防药。 此外， 它也 能抑制疟原虫在蚊体内的发育， 故可阻断传播 (McKie, J. H.; Douglas, K. T.; Chan, C; Roser, S. A.; Yates, R.; Read, M.; Hyde, J. E.; Dascombe, M. J.; Yuthavong, Y.; Sirawaraporn, W., Rational Drug Design Approach for Overcoming Drug Resistance: Application to Pyrimethamine Resistance in Malaria. Journal of Medicinal Chemistry 1998, 41 (9), 1367-1370)。临床上用于预防疟疾和休止期抗复发治疗。但随着使用多年 后酶的突变导致药物脱靶现象的不断凸显及上述药物或多或少均存在腹泻、 皮疹、 高 血压以及肝酶系统的紊乱等毒副作用， 因此， 寻找新的高选择性， 高效， 安全及成药 性好的的恶性疟原虫二氢乳清酸脱氢酶抑制剂具有重要的学术价值及应用价值。
二氢乳清酸脱氢酶是一种含铁的黄素依赖的线粒体酶（McConkey.A; Fishwick C. W. G; Johnson A. P.; The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase [J].Bioorganic & Medicinal Chemistry Letters. 2006， 16： 88-92) ， 是催化二氢乳清酸脱氢作用使其转化为乳清酸的一种酶， 该过程属于嘧啶 从头合成途径的第四步反应， 因而 DHODH是核酸嘧啶合成的关键酶， 同时也是寄生 虫体内唯一催化二氢乳清酸生成乳清酸盐，主要参与催化嘧啶从头生物合成途径中的 第四步反应。人类及疟原虫二氢乳清酸脱氢酶位于线粒体内膜上， 其催化过程需要其 它辅因子的参与。 从结构上讲， DHODH主要分为两部分， 即 N-末端的 α -螺旋结构 区域和 C-末端的 α / β桶状结构。 DHODH通过 N-末端的独特结构附着在线粒体内膜 上， 而 C-末端区域则是催化作用的主要位点。 在 DHODH 上同时具有底物和辅因子 黄素单核苷酸 （Flavin mononucleotide, FMN) 以及辅酶 Q ( CoQ) 的结合位点。 其催 化过程主要通过两步反应完成： 首先二氢乳清酸被还原为乳清酸， 同时 FMN接受该 过程脱下的氢原子氧化为 FMNH2之后在 CoQ的作用下， FMNH2发生脱氢作用重新 还原为 FMN。 任何可以与底物或辅因子竞争性结合的化合物都可以阻断 DHODH的 作用， 从而阻断 DNA或 RNA的合成。 恶性疟原虫 DHODH抑制剂主要通过阻断疟 原虫体内生物嘧啶的合成， 抑制疟原虫的繁殖和生长达到治疗疟疾的作用。
此外， 对于大部分生物来说， 嘧啶碱基可以通过从头合成途径和补救途径得到， 但是快速分化的人类细胞， 例如激活的 T-淋巴细胞、 B-淋巴细胞以及肿瘤细胞， 也 需要依赖于嘧啶的从头合成途径来满足其生长需求。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。由于 DHODH对 DNA和 RNA 合成的普遍作用机制， 也使得它的抑制对下游许多其它的信号通路产生影响。 研究 ( Proceedings of the National Academy of Sciences 2010, 107 (29), 12828 ) 表明， 线粒 体内 DHODH的抑制会引起 p53应激反应， 可用于治疗组织损伤。 另有文献 （Annals of the Rheumatic Diseases 2006, 65 (6), 728-735 ) 报导， DHODH的抑制可以阻止 TNF 诱导的转录因子 NF- κ B磷酸化， 抑制 AP-1和 c-jun N-末端蛋白激酶的激活， 最终抑 制 TNF诱导的细胞凋亡反应。
以二氢乳清酸类似物作为 DHODH抑制剂的研究早期曾有过报导 （Biochemical pharmacology 1988, 37 (20), 3807-3816 )现在对 DHODH抑制剂的研究主要是针对 CoQ 结合位点进行的， 其中 Brequinar和 Leflunomide 已经应用于临床。 Brequinar用于抗 肿瘤和器官移植引起的宿主免疫反应， 但 Brequinar治疗窗窄， 且联合顺铂或环孢菌 素 A 口服给药时， 容易引起血小板减少、 黏膜炎的副作用， 限制了其在临床中的广 泛应用。 Leflunomide于 1998年上市， 对多种自身免疫疾病、 器官移植引起的急慢性 反应和异种排斥反应均有很强的抑制作用， 临床上已用于治疗红斑狼疮、 类风湿性关 节炎， 并可用于防治移植物排异反应。
其它可使用 DHODH抑制剂进行治疗的疾病及相关文献还可参见， 包括类风湿 性关节炎 ( Herrmann, M. L.、 Schleyerbach, R.禾口 Kirschbaum, B. J.， Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 2000, 47 (2-3), 273-289 ) 、 结肠炎 ( Fitzpatrick, L. R.、 Demi, L.、 Hofmann, C.; > Small, J. S.、 Groeppel, M.、 Hamm, S.、 Lemstra, S.、 Leban, J. 禾口 Ammendola, A.， 4SC-101 , a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease. Inflammatory bowel diseases 2010, 16 (10), 1763-1777 ) 、 系统性红斑狼疮 ( Kulkami, O. P.、 Sayyed, S. G.、 Kantner, C.、 Ryu, M.、 Schnurr, M.、 Sardy, M.、 Leban, J.、 Jankowsky, R.、 Ammendola, A.禾口 Doblhofer, R.， 4SC-101 , A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas) lpr Mice. Am. J. Pathol. 2010, 176 (6), 2840-2847 )、银屑病关节炎（Kaltwasser, J. P.、 Nash, P.、 Gladman, D.、 Rosen, C. F.、 Behrens, F.、 Jones, P.、 Wollenhaupt, J.、 Falk, F. G. 禾口 Mease, P. , Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: A multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis & Rheumatism 2004, 50 (6), 1939-1950 ) 、 银屑病 （White, R. M.、 Cech, J.、 Ratanasirintrawoot, S. > Lin, C. Y.、 Rahl, P. B.、 Burke, C. J.、 Langdon, E. > Tomlinson, M. L.、 Mosher, J.禾口 Kaufman, C.， DHODH modulates transcriptional elongation in the neural crest and melanoma, Nature 2011 , 471 (7339), 518-522 ) 、 移植排斥 ( Makowka, L.; Sher, L.; Cramer, D. The development of Brequinar as an immunosuppressive drug for transplantation. Immunological reviews 1993, 136, 51 )、 肾小球疾病（曾健英， 张建林， 来氟米特用于肾小球疾病的临床观察， 实用医学杂志， 2006(15) ) ； 等。 发明内容
根据 DHODH抑制剂与位于 DHODH酶 N末端的辅酶结合口袋结合的原理，抑制剂 都会具有一个极性的头部和一个疏水的尾部，这种结构使它们可以有效地结合在辅酶 Q结合口袋中（Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W.; Malmquist,N. A.; Goldsmith, E. J.; Rathod, P. K.; Phillips, M. A. Structural plasticity of malaria
dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. [J]. J. Biol. Chem. 2009, 284, 26999-27009)。 据此， 本发明人在前期工作中综合运用计算机 药物设计、 药物化学和分子生物学方法和技术， 发现了符合上述结构要求的一系列五 元二氢杂环酮类衍生物， 结构骨架完全不同于以往文献报道过的高活性恶性疟原虫 DHODH抑制剂。 其中的一些化合物在细胞水平具有显著的抑制疟原虫细胞株的活性 和免疫活性， 具有良好的成药前景。 针对该系列先导化合物， 本发明人设计合成了一 系列五元二氢杂环酮衍生物， 结构通式如下：
Figure imgf000005_0001
式中：
Xi选自 0， S， NH禾口 CH2 ;
X2选自 0， S， NH, N0H， C1-C6亚氨基；
R1选自 H， C1-C10烷基， CIO以下不饱和烃基， 任选取代的芳基， 硝基， 氨基， NR4R5， 卤素；
R2选自 H， C1-C6烷基， C2-C6不饱和烃基， C1-C6烷基羰基， 任选取代的苯甲 酰基， 羧基， 氨基羰基， C1-C6烷氧基羰基， C1-C6烷基氨基羰基， 羟基， C1-C6烷 氧基， C3-C8环烷基氨基羰基， C3-C8环烷基 -C1-C6烷基氨基羰基， C3-C8环烷基 -C1-C6烷氧基羰基；
R3选自 H， C1-C6烷基， 任选取代的 C2-C6不饱和烃基， C1-C6烷基羰基， 任 选取代的苯甲酰基， 羧基， 氨基羰基， C1-C6烷氧基羰基， C1-C6氨基羰基， 羟基， C1-C6烷氧基；
R4和 R5独立的选自 H， C1-C6烷基， -C(0)NHR6， C1-C6烷氧基羰基， 卤素取 代的烷基， C2-C6不饱和烃基， 任选取代的芳基， C1-C6烷基羰基， 任选取代的苯甲 酰基， 任选取代的杂环基， 任选取代的杂环基羰基， C1-C6烷氧基羰基；
R6选自任选取代的芳基和任选取代的杂环基。
在优选实施例中， 所述化合物选自下式 II的化合物：
Figure imgf000005_0002
式中，
Xi选自 O, S, NH禾 Π CH2 ;
R2选自 H， C1-C6烷基， C2-C6不饱和烃基， C 1-C6烷基羰基， 任选取代的苯甲 酰基， 羧基， 氨基羰基， C 1 -C6烷氧基羰基， C 1-C6烷基氨基羰基， 羟基， C 1 -C6烷 氧基， C3-C8环烷基氨基羰基， C3-C8环烷基 -C 1-C6烷基氨基羰基， C3-C8环烷基 -C 1-C6烷氧基羰基；
R7选自任选取代的芳基， 任选取代的芳基羰基， 任选取代的含氮杂环基羰基， 任选取代的杂环基， 和任选取代的芳氧基， C 1-C3烷基羰基；
本文中， "烷基 "通常指碳链长度为 1-10个碳原子的饱和的支链和直链烷基， 优 选长 1-6个碳原子、 更优选长 1-4个或 1-3个碳原子的烷基。 "环烷基"指环状烷基， 其成 环碳原子数通常为 3-8个。 示例性的环烷基包括环丙基、 环丁基、 环戊基、 环庚基和 环己基等。
本文中， "不饱和烃基"包括链烯基和炔基。 "链烯基"指直链或支链含有 2-10 个碳原子、 其中至少是链中的两个碳原子之间含有一个双键的基团。优选的烯基是含 有 2-4个碳原子的烯基。 典型的链烯基包括乙烯基、 1-丙烯基、 2-甲基 -1-丙烯基、 1- 丁烯基 和 2-丁烯基。
本文所用 "炔基"是指直链或支链含有 2-10个碳原子， 其中至少是链中的两个碳 原子之间含有一个叁键的基团。 优选的炔基是含有 2-4个碳原子的炔基。 典型的炔基 包括乙炔基、 1-丙炔基、 1-甲基 -2-丙炔基、 2-丙炔基、 1 -丁炔基和 2-丁炔基。
本文中， "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、 弗基、 四氢化萘基、 二氢化茚基等。 芳基可任选地被 1 -5个 （例如， 1、 2、 3、 4或 5个） 选自以下的取代基取代： 卤素、 C 1-C4醛基、 C 1-C6 的直链或支链烷基、 氰基、 硝基、 氨基、 羟基、 羟甲基、 卤素取代的烷基 （例如三氟 甲基） 、 卤素取代的烷氧基 （例如三氟甲氧基） 、 羧基、 C1-C4烷氧基、 巯基、 C 1-C4 烷基巯基、 -SF5、 吗啉基、 任选取代的芳基 （例如任选取代的苯基） 、 任选取代的芳 氧基 （例如任选取代的苯氧基） 和任选取代的苄氧基。 例如， 芳基可以被 1-3个选自 以下的基团取代： 氟、 氯、 溴、 C 1-C4烷基、 三氟甲基、 吗啉基、 甲氧基、 苯基、 甲 氧基取代的苯基、 苯氧基、 苄氧基、 被卤素取代的苄氧基、 乙氧基和硝基等。
本文所使用的术语 "杂环基"指单一或稠合的环结构， 在性质上可以是芳族或 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个环原子， 其中至少 1个并且优选最多可至 4个是选自 0、 S和 N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、 三唑基、 噻唑基、 四唑基、 噁唑基、 异噁唑基、 吡唑基、 吡啶基、 嘧啶基、 吡嗉基、 哒嗉基、 三嗉基、 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、 香豆素基和 1,2-亚甲基二氧苯基。 本文中， 杂环基可任选地被 1-3个本 文所述的取代基取代。
本文所使用的术语 "杂原子 "包括 0、 S和N。 当杂原子是 N时， 此 N原子可 以进一步由例如氢或 C1-C10烷基的基团所取代。 当杂原子是 S时， 此 S原子可以进 一步由例如 C1-C10烷基的基团所取代。
本文所使用的术语 "杂芳基" 或 "芳香杂环基"指如上所述具有芳族特性的那 些杂环基， 包括但不限于呋喃基、 噻吩基、 吡咯基、 吡啶基、 噁唑基、 吡嗉基、 哒嗉 基、 嘧啶基等。
本文所使用的术语 "卤素" 包括氟、 氯、 溴和碘。
除非另有说明， 本文所使用的术语 "任选取代的" 指其所修饰的基团可任选地 被 1-5个 （通常为 1、 2或 3个） 选自以下的取代基取代： C1-C4 烷基、 羧基、 卤素、 C1-C4 烷氧基、 氰基、 硝基、 氨基、 羟基、 醛基、 C1-C6酰基、 羟甲基、 卤素取代的 C1-C4 烷基 （例如三氟甲基） 、 C1-C10硫代烷基 （例如五氟硫甲基） ， C1-C10硫代 烷氧基 （例如五氟硫甲氧基） ， 卤素取代的 C1-C4 烷氧基 （例如三氟甲氧基） 、 巯 基和 C1-C4 酰基。
本文中， 酰胺基 （氨基羰基） 自身或作为其它基团的一部分， 指 " C1-C6烷基 -CO-NH-"基团、 " C3-C8环烷基 -CO-NH-"或 " C3-C8环烷基 -C1-C6烷基 -CO-NH-" 。 示例性的酰胺基包括但不限于甲酰胺基、 乙酰胺基、 丙酰胺基、 丁酰胺基、 环丙酰胺 基、 环丙甲酰胺基等。
本文中， 酰基自身或作为其它基团的一部分， 可含有 1-6个碳原子， 优选 1-4个碳 原子。 示例性的酰基包括但不限于甲酰基、 乙酰基等。
本发明优选的化合物包括那些 为 S和 0， X2为 0的化合物。
本发明优选的化合物包括那些 R3为 H的化合物。
在某些实施方式中， 本发明的化合物不包括化合物 14一 21。
本发明优选的化合物包括 R2为 C1-C6烷氧基羰基（例如甲氧基羰基、乙氧基羰基， 环丙氧基羰基， 环丙甲氧基羰基等） 、 C1-C6氨基羰基 （例如甲酰胺基， 乙酰胺基， 丙酰胺基， 丁酰胺基， 环丙酰胺基， 环丙甲酰胺基等） 的化合物。
本发明优选的化合物包括 R1为 -NH-任选取代的苯基、 -NH-任选取代的萘基、 -NH- 任选取代的二氢化茚基、 -NH-任选取代的四氢化萘基或 -NH-任选取代的喹啉基的化 合物。 本发明优选的化合物中包括 R1中任选取代的苯基或萘基上的取代基为卤素、 卤 素取代的 C 1-C4烷基、 C 1 -C4烷基、 C 1-C4烷氧基的化合物。
在优选实施例中， 本发明包括 1为8和 0， X2为 0， R3为 H， R2为 C 1-C6烷氧基羰 基 （例如甲氧基羰基、 乙氧基羰基， 环丙氧基羰基， 环丙甲氧基羰基等） 、 C 1 -C6氨 基羰基 （例如甲酰胺基， 乙酰胺基， 丙酰胺基， 丁酰胺基， 环丙酰胺基， 环丙甲酰胺 基等） ， R1为 -NH-任选取代的苯基、 -NH-任选取代的萘基、 -NH-任选取代的二氢化 茚基、 -NH-任选取代的四氢化萘基或 -NH-任选取代的喹啉基的化合物。 更优选地， R1中任选取代的苯基或萘基上的取代基为卤素、 卤素取代的 C1 -C4烷基、 C 1 -C4烷基、 C 1 -C4烷氧基。
在更优选的实施例中， 1为8和 0， X2为 0， R3为 H， R2为 C1 -C6烷氧基羰基 （例 如甲氧基羰基、 乙氧基羰基等） ， R1为 -NH-任选取代的苯基、 -NH-任选取代的萘基、 -NH-任选取代的二氢化茚基、 -NH-任选取代的四氢化萘基或 -NH-任选取代的喹啉基； 苯基优选没有取代基， 或者具有 1一 3个选自卤素、 三氟甲基、 甲基、 硝基和甲氧基的 取代基。 优选的， 取代基位于 3、 4和 /或 5位。 优选的， 所述化合物不包括化合物 14一 21。
在其它优选的实施例中， 1为8和 0， X2为 0， R3为 H， R2为 C2-C4烷氧基羰基（例 如乙氧基羰基，环丙氧基羰基，环丙甲氧基羰基等）， R1为 -NH-任选取代的苯基、 -NH- 任选取代的萘基、 -NH-任选取代的二氢化茚基、 -NH-任选取代的四氢化萘基或 -NH- 任选取代的喹啉基； 苯基优选没有取代基， 或者具有 2— 3个选自卤素和 C 1 -C4烷基的 取代基。 优选地， 所述化合物不包括化合物 14一 21。
在其它优选实施例中， 本发明的化合物包括 为^11-任选取代的萘基、 -NH-任 选取代的二氢化茚基、 -NH-任选取代的四氢化萘基或 -NH-任选取代的喹啉基的化合 物。
本发明优选下文表 1中所示的编号 1 -67的化合物， 尤其优选抑制率在 50 %以上 的那些化合物。 尤其是， 本发明化合物包括化合物 1、 2、 4、 6、 7、 10、 22-25、 35、 38、 39、 44、 61禾 Π 62。 本发明的化合物可采用以下方法制备获得
-NH; -NHCSH
丙酮， 18h ' 氯仿，12h
Figure imgf000008_0001
Figure imgf000008_0002
上述制备流程中， R1为最终产物中苯基上的取代基， 其定义与上文的芳基取代 基的定义相同。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。 例如， 可参考杜晓华等 （非硫光气法合成一 些难合成的苯基异硫氰酸酯 . [J]. 农药， 2004， 43 (2)， 78-79)) 所述的方法合成本发 明式 Π化合物。
Figure imgf000009_0001
上述制备流程中， R1为最终产物中苯基上的取代基， 其定义与上文的芳基取代 基的定义 C1-C6
Figure imgf000009_0002
上述制备流程中， R1为最终产物中苯基上的取代基， 其定义与上文的芳基取代 基的定义相同。 R3的定义与上文中 C1-C6烷氧基羰基相同。
Figure imgf000009_0003
上述制备流程中， R1为最终产物中苯基上的取代基， 其定义与上文的芳基取代 基的定义相同。 本发明第二方面包括一种药物组合物， 该组合物含有治疗有效量的本发明式 I、 II的化合物或其药学上可接受的盐， 以及药学上可接受的载体或赋形剂。
本发明化合物的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 盐酸盐、 氢溴酸盐、 硫酸盐、 柠檬酸盐、 乳酸盐、 酒石酸盐、 马来酸盐、 富马酸盐、 扁桃酸盐和草酸盐； 以及与碱例如钠羟基、 三 （羟基甲基）胺基甲烷 （TRIS， 胺丁三 醇） 和 N-甲基葡糖胺形成的无机和有机碱盐。 虽然每个人的需求各不相同， 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， 药量按照约 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， 合宜地约 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 被配制成用于肠外， 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， 用于治疗肿瘤和其他疾病。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， 健康与体重， 并行治疗的种 类， 治疗的频率， 以及所需治疗效益来决定。
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。
本发明的化合物或其药物组合可用于治疗与预防各种 DHODH介导的疾病， 尤其 与 DHODH的抑制相关的疾病。 本文中， DHODH介导的疾病主要包括： 寄生虫病， 包 括恶性疟疾、 间日疟、 卵形疟疾、 三日疟、 克氏锥虫病和登革热等； 由某类细胞快速 增殖引起的疾病， 如癌症； 炎症反应； 以及各种自身免疫疾病。 DHODH介导的疾病 还包括由同种或异种器官移植引起的宿主排斥反应。
具体地讲， DHODH介导的疾病包括但不限于克氏锥虫病、 恶性疟疾、 登革热、 间日疟、 卵形疟疾、 三日疟、 类风湿性关节炎、 结肠炎、 红斑狼疮 （包括系统性红斑 狼疮） 、 肾小球疾病 （包括多种继发性和原发性肾小球疾病） 、 抗器官移植物排异反 应、 黑色素瘤、 银屑病关节炎和银屑病等。
本发明的药物制剂可用已知的方式制造。 例如， 由传统的混合， 制粒， 制锭， 溶解， 或冷冻干燥过程制造。 制造口服制剂时， 可结合固体辅料和活性化合物， 选择 性研磨混合物。 如果需要或必要时加入适量助剂后， 加工颗粒混合物， 获得片剂或锭 剂芯。
合适的辅料特别是填料， 例如糖类如乳糖或蔗糖， 甘露醇或山梨醇； 纤维素制 剂或钙磷酸盐， 例如磷酸三钙或磷酸氢钙； 以及粘结剂， 例如淀粉糊， 包括玉米淀粉， 小麦淀粉， 大米淀粉， 马铃薯淀粉， 明胶， 黄芪胶， 甲基纤维素， 羟丙基甲基纤维素， 羧甲基纤维素钠， 或聚乙烯吡咯烷酮。 如果需要， 可增加崩解剂， 比如上面提到的淀 粉， 以及羧甲基淀粉， 交联聚乙烯吡咯烷酮， 琼脂， 或褐藻酸或其盐， 如海藻酸钠。 辅助剂特别是流动调节剂和润滑剂， 例如， 硅石， 滑石， 硬脂酸盐类， 如镁硬脂酸钙， 硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此， 可以应用浓缩糖类溶液。 这个溶液可以含有阿拉伯树胶， 滑石， 聚乙烯吡咯烷酮， 聚 乙二醇和 /或二氧化钛， 漆溶液和合适的有机溶剂或溶剂混合物。 为了制备耐胃液的 包衣， 可使用适当的纤维素溶液， 例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻 苯二甲酸。 可向药片或锭剂核芯的包衣加入染料或色素。 例如， 用于识别或为了表征 活性成分剂量的组合。
因此， 本发明第三方面提供一种治疗或预防 DHODH介导的疾病的方法， 该方法 包括给予需要的对象以本发明的式 I或 Π化合物或药物组合物。
给药方法包括但不限于本领域周知的各种给药方法， 可根据患者的实际情况加 以确定。 这些方法包括但不限于肠外， 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。
本发明包括本发明式 I或 Π化合物在制备治疗或预防 DHODH介导的疾病用的药 物中的用途。
本发明也包括本发明式 I或 Π化合物在制备治疗或预防疟原虫 DHODH介导的疾 病用的药物中的用途。
本发明还包括本发明式 I或 Π化合物在制备抑制疟原虫 DHODH活性用的药物中 的用途。
优选的， 使用化合物 1-4、 6、 7、 10、 12、 16-18、 20-25 35、 38、 39、 44、 61 和 62实施上述治疗和预防方法和用途。 具体实施方式
在以下的实施例中将进一步举例说明本发明。 这些实施例仅用于说明本发明， 但不以任何方式限制本发明。 合成部分：
2-取代苯胺基 -4 ,5-二氢噻 -3-羧酸乙酯系列化合物合成通则:
Figure imgf000011_0001
合成方法： 将 3 mmol的取代苯胺溶于 3 mL的丙酮中， 加入 9 mmol的三乙烯二 胺， 滴加 15 mL的二硫化碳， 常温搅拌 24小时， 析出黄色固体， 抽滤烘干得中间体， 将中间体直接加入烧瓶中， 加入 10 mL的三氯甲烷,， 悬浮状，滴加溶解有 1 mmol三 光气的 10 mL三氯甲烷溶液， 反应过夜， 抽滤得母液， 直接旋干柱层析得取代苯基异 硫氰酸酯,收率 45%左右。
乙基 2-取代苯胺基 -4-羰基 -4,5-二氢噻吩 -3-羧基系列化合物合成通则：
(Faull.W.A.; Hull.R.; Some Reactions of Ethyl 2-Anil ino-4-oxo-4,5-di hydrothiophen -3-carboxylate [J].J. Chem. Society. Perkin. 1981 , 1078-1082)。
Figure imgf000012_0001
合成方法： 现制 0.55 mmol的甲醇钠固体和干燥的 DME 10mL， 取 0.55 mmol 的 4-氯乙酰乙酸乙酯， 常温搅拌 1小时， 另取 0.5 mmol的取代苯异硫氰酸酯溶于 10 mL的 DME， 氩气保护下缓慢滴加， 反应 6小时结束， 选干 DME， 用稀盐酸中和， 饱和食盐水洗涤乙酸乙酯萃取， 有机层浓缩干燥柱层析得产品。 上述流程中， R为最 终产物中苯基上的取代基， 其定义与前文的芳基取代基的定义相同。
Figure imgf000012_0002
合成方法： 冰浴下， 取 2- ( 4-三氟甲基苯胺基） -4-羰基 -4,5-二氢噻吩 -3-羧酸乙 酯 3 mmol， 溶于甲醇-水 =5 : 1 (总 18 mL) 的混合溶液中， 加入 5 eq的一水合氢氧 化锂， 搅拌半小时后撤去冰浴， 加热至 60度反应过夜， 旋干甲醇， 加少许水和 10% 的稀盐酸调节 pH =2,析出大量米白色固体， 抽滤干燥得产品。
Figure imgf000012_0003
合成方法： 取干燥的对应酸 （lmmol, 285mg) ， 取代胺 （1.2 mmol) 于圆底 烧瓶中， 加入 5 mL的二氯甲烷， HOBt ( 1.2 mmol， 260 mg) ， EDC ( 1.2 mmol, 330 mg) ， 常温搅拌过夜， TLC显示原料仍有， 新点明显， 依次直接加入饱和氯化铵， 饱和碳酸钠， 食盐水洗涤， 有机层浓缩， 干燥， 柱层析 （PE:EA=5 : 1， v/v) 提纯， 得淡黄色固体。
Figure imgf000013_0001
合成方法： 将干燥的酸 （l mmol) ， 醇 （l mmol) ， 三苯基膦 （1.1 mmol) 力口 入至 5 mL的甲苯中， 氩气保护下滴加偶氮二甲酸二乙酯 （1.2 mmol) ， 反应半小时 后升温至 50度， 过夜反应， 饱和食盐水洗涤， 柱层析 （PE:EA=3 : 1， v/v ) 提纯， 得
Figure imgf000013_0002
合成方法： 在 50 mL烧瓶中加入 3 mmol的 60%钠氢约 240 mg和 1.8 mL的无水 THF, 冰水浴下滴加 1.8 mL含有 6mmol的丙二酸二乙酯的无水 THF溶液， 10分钟 后滴加 3 mL含有 3 mmol的氯乙酰氯溶液， 维持冰浴一小时， 40-45摄氏度反应 1小 时， 常温下滴加取代芳香胺， 常温过夜后 TLC显示原料少量存在， 回流 2小时 TLC 显示原料仍存， 停止反应， 用稀 HC1调节 pH至 7， 乙酸乙酯萃取， 食盐水洗涤 2次， 有机层浓缩， 干燥， 柱层析 （PE:EA=2: 1， v/v) ， 柱层析得纯品， 白色粉末， 收率 35-40%。 目标化合物谱图数据
2-取代苯胺基 -4-羰基 -4,5-二氢噻吩 -3-羧酸乙酯系列化合物
2-(4-氯苯胺基) -4-羰基 -4,5- 物 1 )
Figure imgf000013_0003
1H NMR(400MHz, DMSO-t¾)S( ppm ): 1 1.12(s, 1H), 7.55(d, J = 8.8 Hz, 2H), 7.47(d, J = 8.4 Hz, 2H), 4.25-4.19(q, J= 7.2 Hz, 2H)， 3.68(s, 2H), 1.25(t, J= 7.2 Hz, 3H); HRMS (ESI) calcd for C13H12C1N03S[M+H+] 298.0305, found 298.0307;
2-(4-三氟甲基苯胺基) -4- （化合物 2 )
Figure imgf000013_0004
1H NMR(400MHz, DMSO-t¾)S( ppm ): 1 1.34(s, 1H), 7.86(d, J = 8.4 Hz, 2H), 7.68(d, J = 8.4 Hz, 2H), 4.26-4.21(q, J= 7.2 Hz, 2H)， 3.74(s, 2H), 1.26(t, J= 7.2 Hz, 3H); HRMS (ESI) calcd for C14H12F3N03S [M+H ] 332.0568, found 332.0559;
2-(4-溴 -3-甲基苯胺基) -4-羰 （化合物 3)
Figure imgf000014_0001
1H NMR(400MHz, DMSO-t5)5( ppm ): 10.91(s, 1H), 7.49(d, J= 8.4 Hz, 1H), 7.29(d J= 8.4 Hz, 2H), 4.24-4.19(q,J= 6.8 Hz, 2H)， 3.32(s, 2H), 2.22(s, 3H), 1.25(t,J= 6.8 Hz, 3H); HRMS (ESI) calcd for C14H14BrN03S [M+H+] 355.9956, found 355.9955;
2-(3,5-二氯苯胺基) -4-羰基 -4 （化合物 4)
Figure imgf000014_0002
ΉΝΜΚ(400ΜΗζ, DMSO-t6)5( ppm ): 11.12(s, 1H), 7.66(s, 1H), 7.61(s, 2H), 4.25-4.20(q, J= 7.2 Hz, 2H)， 3.71(s, 2H), 1.27(t, J= 7.2 Hz, 3H); HRMS (ESI) calcd for CnHnC NOsS [M+H+] 331.9915, found331.9916;
2-(4-甲基 -3-氟苯胺基) -4- （化合物 5)
Figure imgf000014_0003
Ή NMR(400MHz, DMSO-t5)5( ppm ): 11.10(s, 1H), 7.39(t,J= 8.4 Hz, 1H), 7.30(d, J= 10.8 Hz, 1H), 7.19(t,J= 8.0 Hz, 1H), 4.25-4.19(q, J= 7.2 Hz, 2H)， 3.68(s, 2H), 2.26(s, 3H), 1.25(t,J= 7.2 Hz, 3H); HRMS (ESI) calcd for C14H14FN03S [M+H+] 296.0757, found 296.0757;
2-(3,4-甲基苯胺基) -4-羰基 （化合物 6)
Figure imgf000014_0004
Ή NMR(400MHz, DMSO-t¾S( ppm ): 11.36(s, IH), 7.21(d, J = 7.6 Hz, IH), 7.13-7.10(m, 2H), 4.42-4.37(q, J = 7.2 Hz, 2H)， 3.63(s, 2H), 2.31(s, 6H), 1.42(t, J = 7.2 Hz, 3H); HRMS (ESI) calcd for C15H17N03S [M+H+] 292.1007, found 292.1007;
2-(9-乙基 -9H-咔唑 -3-氨基 -4-羰基 -4,5-二氢噻吩 -3-羧酸乙酯 （化合物 7)
Figure imgf000015_0001
Ή ΝΜΚ(400ΜΗζ, CDC13)5( ppm ): 11.42(s, IH), 8.10(d, J = 7.6 Hz, 2H), 7.55(t, J = 7.2 Hz, IH), 7.48-7.41(m, 3H), 7.30(d, J = 7.2 Hz, IH), 4.46-4.39(m, 4H)， 3.64(s, 2H), 1.51-1.48(m, 6H); HRMS (ESI) calcd for C21H20N2O3S [M+H+] 381.1273, found
381.1274;
2-(4-溴 -3-三氟甲基苯胺基) 酸乙酯 （化合物 8 )
Figure imgf000015_0002
Ή ΝΜΚ(400ΜΗζ, DMSO-t 5)5( ppm ): 11.66(s, IH), 7.73(s, IH), 7.61(d, J = 8.4 Hz IH), 7.53(t, J = 8.4 Hz, IH), 4.43-4.37(q, J = 7.2 Hz, 2H)， 3.70(s, 2H), 1.42(t, J = 7.2 Hz, 3H); HRMS (ESI) calcd for CnHnBrFsNOsS [M+H+] 409.9673, found 409.9675;
2—(4-氯 -3-三氟甲基苯胺基) 酸乙酯 （化合物 9)
Figure imgf000015_0003
1H NMR(400MHz, DMSO-t¾)S( ppm ): 11.67(s, IH), 7.81(d, J= 8.4 Hz, IH), 7.73(s IH), 7.45(d, J = 8.4 Hz, IH), 4.43-4.36(q, J = 6.8 Hz, 2H)， 3.71(s, 2H), 1.42(t, J = 6.8 Hz 3H); HRMS (ESI) calcd for CHHHCIFSNOSS [M+H+]366.0179, found 366.0177;
2-(2-萘胺基 )-4-羰基 -4,5-二氢噻吩 -3-羧酸乙酯 （化合物 10)
Figure imgf000016_0001
Ή NMR(400MHz, DMSO-t5)5( ppm ): 11.34(s, IH), 8.05-7.96(m, 4H), 7.60-7.54(m: 3H), 4.28-4.22(q, J= 7.2 Hz, 2H)， 3.70(s, 2H), 1.27(t,J= 7.2 Hz, 3H); HRMS (ESI) calcd for C17H15N03S [M+H+] 314.0851, found 314.0849;
2-0-蒽胺基 -羰基 -4,5- 11)
Figure imgf000016_0002
ΉΝΜΚ(400ΜΗζ, OMSO-d6) δ( ppm ): 8.46(d,J= 12.8Hz, 2H), 8.10(d, J= 9.2Hz IH), 8.04(s, 2H), 8.02(s,lH), 7.53(t,J= 4.8Hz, 2H), 7.40(d,J= 8.4Hz, IH), 4.44(q,J = 7.2Hz, 2H), 3.76(s, 2H), 1.45(t,J= 7.2Hz, 3H). HRMS (ESI) calcd for C21H18N03S
[M+H+] 364.1007, found 364.1005;
2- (苯胺基) -4-羰基 -4,5-二氢噻 12)
Figure imgf000016_0003
Ή NMR(400MHz, DMSO-t¾S( ppm ): 7.47(t, J= 8.0 Hz, 2H), 7.37(d, J= 8.0 Hz, 2H), 7.34(s, IH), 4.39(q,J= 7.2 Hz, 2H), 3.67(s, 2H), 1.42(t, J= 7.2Hz, 3H) HRMS (ESI) calcd for C13H14N03S [M+H+] 264.0694, found 264.0694;
2-(6-二苯并噻吩胺基) -4-羰 （化合物 13)
Figure imgf000016_0004
ΉΝΜΚ(400ΜΗζ, OMSO-d6) 5(ppm ): 11.27(s, IH), 8.49 (d,J= 2.0Hz, IH), 8.42(dd, Ji = 2.0 Hz, J2= 1.6 Hz, IH), 8.15 (d,J= 8.4 Hz, IH), 8.08 (dd, Ji=1.6 Hz, J2= 2.4 Hz, IH), 7.56(m, 3H), 4.25(q, Ji = 7.2Hz, 2H), 3.67(s, 2H), 1.28(t, J= 7.2Hz, 3H) ·
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■ZL£0'0L£ P^noj 'ZLiO'OLi [+H+W] ¾εΟ 9ΐΗ6ΐ3∞J P。I 。 (isa) SW&R 9SS1780/Z10ZN3/X3d 96SS.0/CT0Z OAV 4.22 (q, J= 7.2 Hz, 2H), 3.67 (s, 2H), 2.74 (t, J = 9.6 Hz, 4H), 1.75 (t, J = 3.2 Hz, 4H), 1.26 (t, J = 7.0 Hz, 3H). HRMS (ESI) calcd for C17H19N03S [M+H+] 318.1164, found 318.1168.
2-(4-叔丁基苯胺基 )-4-羰基 -4,5-二氢噻吩 -3-羧酸乙酯 （化合物 26)
Figure imgf000018_0001
1H NMR (400 MHz, CDC13): δ 11.44 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 9.6 Hz, 2H), 4.40 (q, J= 6.8 Hz, 2H), 3.66 (s, 2H), 1.43 (t, J= 6.8 Hz 3H), 1.36 (s, 9H). HRMS (ESI) calcd for C17H21N03S [M+H+] 320.1320 found 320.1318.
2-(4-三氟甲基苯胺基) -4-羰基 酰胺 （化合物 27)
Figure imgf000018_0002
'HNMR (400 MHz, DMSO-t6): δ 12.81 (s, 1Η), 8.89 (t,J= 5.2 Hz, 1H), 7.77 (d,J = 8.4 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 3.95 (s, 2H), 3.17 (t, J= 6.4 Hz, 2H), 1.08-0.98 (m, 1H), 0.46 (d, J = 6.8 Hz, 2H), 0.23 (d, J = 4.8 Hz, 2H). HRMS (ESI) calcd for C16H15F3N202S [M+H+] 357.0885, found 357.0885
2-(4-三氟甲基苯胺基) -4-羰基 胺 （化合物 28)
Figure imgf000018_0003
'HNMR (400 MHz, DMSO-t6): δ 12.73 (s, 1Η), 8.75 (t,J=3.6Hz, 1H), 7.87 (d,J = 8.4 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 3.94 (s, 2H), 2.80-2.74 (m, 1H), 0.75-0.73 (m, 2H), 0.50 (d,J= 1.6 Hz, 2H). HRMS (ESI) calcd for C15H13F3N2O2S [M-H+] 341.0572, found 341.0565 2-(3,4-二甲基苯胺基 )-4-羰基 - 甲酰胺 （化合物 29)
Figure imgf000019_0001
'H NMR (400 MHz, DMSO-t 6): δ 12.34 (s, IH), 8.88 (t, J = 9.6 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.20 (s, IH), 7.15 (dd, Ji = 2.4 Hz, J2 = 8.0 Hz, IH), 3.85 (s, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.24 (d, J = 3.2 Hz, 6H), 1.02-0.97 (m, IH), 0.48-0.43 (m, 2H), 0.23-0.19 (m, 2H). HRMS (ESI) calcd for C17H20N2O2S [M+H+] 317.1316, found 317.1324.
2-P,4-二甲基苯胺基 )-4-羰基 - 酰胺 （化合物 30)
Figure imgf000019_0002
Ή NMR (400 MHz, DMSO-t 6): δ 12.27 (s, IH), 8.75 (d, J = 7.6 Hz, IH), 7.25 (d, J = 8.0 Hz, IH), 7.20 (d, J = 2.0 Hz, IH), 7.15 (dd, Ji = 2.0 Hz, J? = 8.0 Hz, IH), 3.83 (s, 2H), 2.77-2.73 (m, IH), 2.24 (d, J = 1.6 Hz, 6H), 0.75-0.70 (m, 2H), 0.50-0.48 (m, 2H). HRMS (ESI) calcd for C16H18N202S [M+H+] 303.1 158, found 303.1167.
2-(3,4-二甲基苯胺基 )-4-羰基 -4,5-二氢噻吩 -3-甲酰胺 （化合物 31 )
Figure imgf000019_0003
Ή NMR (400 MHz, DMSO-t 6): δ 10.92 (s, IH), 8.92 (s, IH), 7.88 (s, IH), 7.26 (d, J = 8.0 Hz, IH), 7.13 (s, IH), 7.06 (dd, Ji = 2.0 Hz, J2 = 8.0 Hz, IH), 3.81 (s, 2H), 2.25 (s, 6H). HRMS (ESI) calcd for C13H14N2O2S [M+H+] 263.0853, found 263.0854.
2-(2,3-二氢化 -IH印胺基 )-4- 丙甲酰胺 （化合物 32)
Figure imgf000019_0004
Ή NMR (400 MHz, DMSO-t 6): δ 12.33 (s, IH), 8.88 (t, J = 5.2 Hz, IH), 7.33-7.26 (m, 2H), 7.16 (d, J= 8.0 Hz, IH), 3.85 (s, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.88 (q, J = 6.8 Hz 4H), 2.09-2.02 (m, 2H), 1.03-0.97 (m, IH), 0.45 (d, J = 7.6 Hz, 2H), 0.22 (d, J = 4.8 Hz, 2H). HRMS (ESI) calcd for C18H20N2O2S [M+H+] 329.1342, found 329.1315.
2-(2,3-二氢化 -IH印胺基 )-4- 丙酰胺 （化合物 33 )
Figure imgf000020_0001
Ή NMR (400 MHz, DMSO-t 6): δ 12.27 (s, IH), 8.76 (s, IH), 7.34-7.28 (m, 2H), 7.17 (d, J = 8.0 Hz, IH), 3.83 (s, 2H), 2.89 (d, J = 5.6 Hz, 4H), 2.75 (d, J = 3.6 Hz, IH), 2.05 (t, J = 7.2 Hz, IH), 2.05 (t, J = 7.2 Hz, 2H), 0.73 (d, J = 5.6 Hz, 2H), 0.49 (s, 2H). HRMS (ESI) calcd for C17H18N202S [M+H+] 315.1 167, found 315.1174 萘胺基 )-4-羰基 -4,5-二氢 合物 34)
Figure imgf000020_0002
Ή NMR (400 MHz, CDC13): δ 12.92 (s, IH), 8.89 (s, IH), 7.91-7.82 (m, 4H), 7.56-7.42 (m, 3H), 3.73 (s, 2H), 3.28 (t, J = 6.4 Hz, 2H), 1.07 (m, IH), 0.59-0.54 (m, 2H), 0.31-0.27 (m, 2H). HRMS (ESI) calcd for C19H18N202S [M+Na+] 361.0987, found 361.0997
2-(2-萘胺基 )-4-羰基 -4,5-二氢 物 35 )
Figure imgf000020_0003
Ή NMR (400 MHz, CDC13): δ 12.92 (s, IH), 8.89 (s, IH), 7.92-7.83 (m, 4H), 7.54-7.43 (m, 3H), 3.73 (s, 2H), 2.83 (s, IH), 0.90-0.84 (m, 2H), 0.67-0.63 (m, 2H). HRMS (ESI) calcd for C18H16N202S [M+Na+] 347.0830, found 347.0834. 2-(2-萘胺基 )-4-羰基 -4,5-二氢 36)
Figure imgf000021_0001
1H NMR (400MHz, CDC13): δ 10.47 (s, 1H), 7.96 (m, 4H), 7.62 (dd, Ji = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.54 (m, 2H), 4.75 (s, 2H), 4.25 (q, J = 6.8 Hz, 2H), 1.28 (t, J = 6.4 Hz, 3H). HRMS (ESI) calcd for C17H15N04 [M+Na+] 320.0899, found 320.0897.
2-(3,4-二甲基苯胺基 )-4-羰 -4,5-二氢噻吩 -3-乙酰胺 （化合物 37)
Figure imgf000021_0002
Ή NMR (400 MHz, CDC13): δ 12.38 (s, 1H), 8.77 (t, J = 5.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (dd, Ji = 2.0 Hz, J2 = 7.6 Hz, 1H), 3.84 (s, 2H), 3.27 (q, J = 6.8 Hz, 2H), 2.25 (s, 3H), 2.24 (s, 3H), l . l l(t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C15H18N202S [M+H+] 291.1 167, found 291.1169.
2-(3,4-二甲基苯胺基 )-4-羰基 （化合物 38 )
Figure imgf000021_0003
'H NMR (400 MHz, DMSO-t 6): δ 12.36 (s, 1Η), 8.82 (t, J = 5.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (dd, Ji = 2.0 Hz, J2 = 7.6 Hz, 1H), 3.85 (s, 2H), 3.23 (q, J = 6.8 Hz, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.53-1.48 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C16H20N2O2S [M+Na+] 327.1143, found 327.1 134.
2-(3,4-二甲基苯胺基 )-4-羰 （化合物 39)
Figure imgf000021_0004
O NMR (400 MHz, DMSO-t 6): δ 12.36 (s, 1Η), 8.80 (t, J = 5.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (dd, Ji = 2.0 Hz, J2 = 7.6 Hz, 1H), 3.84 (s, 2H), 3.27 (q, J = 6.8 Hz, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.51-1.44 (m, 2H), 1.37-1.28 (m, 3H), 0.91(t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C17H22N2O2S [M+Na+] 341.1300, found 341.1305.
2-(2-萘胺基 )-4-羰基 -4,5-二氢噻吩 -3-乙酰胺 （化合物 40)
Figure imgf000022_0001
1H NMR (400 MHz, DMSO-t 6): δ 12.71 (s, 1H), 8.80 (d, J = 5.6 Hz, 1H), 8.05-7.95 (m, 4H), 7.60-7.53 (m, 3H), 3.90 (s, 2H), 3.31 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C17H16N202S [M+H+] 313.1011, found 313.1022.
2-(2-萘胺基 )-4-羰基 -4,5-二 41 )
Figure imgf000022_0002
Ή NMR (400 MHz, CDC13): δ 12.95 (s, 1H), 8.91 (s, 1H), 7.92-7.84 (m, 4H), 7.56-7.29 (m, 3H), 3.75 (s, 2H), 1.66 (q, J = 6.8 Hz, 2H), 1.36-1.28 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C18H18N202S [M+H+] 327.1167, found 327.1165.
2-(2-萘胺基 )-4-羰基 -4,5- 42)
Figure imgf000022_0003
Ή NMR (400 MHz, CDCI3): δ 12.94 (s, 1H), 8.89 (s, 1H), 7.93-7.84 (m, 4H): 7.58-7.44 (m, 3H), 3.75 (s, 2H), 1.66-1.59 (m, 2H), 1.45 (q, J = 7.2 Hz, 2H), 1.36-1.28 (m: 2H), 0.99 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C19H20N2O2S [M+H+] 341.1324 found 341.1320.
2—(3,4-二甲基苯胺基 )-4-羰基 -4,5-二氢噻吩 -3-羧酸 （化合物 43 ) π COOH
1H NMR (400MHz, DMSO-t 6): δ 7.26 (d, J = 8.0 Hz, IH), 7.23 (s, IH), 7.17 (d, J = 8.0 Hz, IH), 4.02 (s, 2H), 2.26 (s, 6H). HRMS (ESI) calcd for C13H13N03S [M+H+] 264.0694, found 264.0690.
2-(2-萘胺基 )-4-羰基 -4,5-二氢 44)
Figure imgf000023_0001
'H NMR (400MHz, DMSO-t 6):S 10.55 (s, IH), 8.08-7.89 (m, 4H), 7.62-7.40 (m, 3H), 4.07 (s, 2H), HRMS (ESI) calcd for Ci5HuN03S [M+H+] 286.0538, found 286.0541.
2-(3,4-二甲基苯胺基 )-4-羰基 酯 （化合物 45 )
Figure imgf000023_0002
1H NMR (400MHz, DMSO-t 6): δ 11.03 (s, IH), 7.25 (d, J = 8.0 Hz, IH), 7.21 (s, IH), 7.15 (d, J = 8.0 Hz, IH), 3.72 (s, 3H), 3.67 (s, 2H), 2.26 (s, 6H). HRMS (ESI) calcd for C15H17NO3S [M+H+] 292.1007, found 292.1007.
2-(3,4-二甲基苯胺基 )-4-羰基 酯 （化合物 46)
Figure imgf000023_0003
Ή NMR (400MHz, DMSO-t 6): δ 11.07 (s, IH), 7.24 (d, J = 8.0 Hz, IH), 7.20 (s, IH), 7.15 (d, J = 8.0 Hz, IH), 4.13 (t, J = 6.8 Hz, 2H), 3.66 (s, 2H), 2.26 (s, 6H), 1.68-1.61 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C16H19N03S [M+H+] 306.1164, found 306.1170
2-(3,4-二甲基苯胺基 )-4-羰基 -4,5-二氢噻吩 -3-羧酸丙酯 （化合物 47) S爾 H "(H£ 'ZH Z'L =/"'!) 90Ί '(Ηζ '^) ζ8Ή8·Ι '(Ηζ 's) \L'£ ΉΖ 8·9 = '0 £1'1 '(Η£ '^) WL- i'L '(Hl7 'ra '(HI 's) L9'\\ 9 -(£\DQD 'ZH则 0l) 麵 HT
Figure imgf000024_0001
(05呦 驅¾1邈！ ^-£-^難¾二- -¾羅卞(¾¾ |-乙)-乙
'6690O0£ Ρ画 J
'17690"00£ [+H+W] S£O nH9I3 p B。 (isa) SW&R Wi 's) \ i '(He 'S) 9L'i '(He ra) W L—99' L '^) 6 —90·8 '(HI 's) 0£'Π § :(9P-OS顯 则 0l) 麵 HT
Figure imgf000024_0002
(617呦 驅 ώ邈！ ^-£-^難¾二-^-¾羅卞(¾¾ |-乙)-乙
'89ΙΓ8ΚΡ画 J '17911"81£
[+α+ν s£O 6laLlD P。JB。 dsa) sw a '(az 1 = 'ρ) oi-o m 8·9 =
P) 19Ό '(HI '^) LZ'l-0£'l '(Ηζ 's) W£ ΉΖ 8·9 = "' ) LVV '(HI 8·8 = " 'Ρ) 01^ '(HI 's) £VL '(HI 'ZH 8"8 = 'V) OZ'L '(HI 's) ζ£·Π § (HJ j 'mViOO ) ¾W HT
Figure imgf000024_0003
(817呦 驅 ώ¾1 ^邈凝 -£-^難¾二- -¾羅 -
S£0 T¾IT3 p 。 (isa) S爾 H "(H£ 'ZH Z'L = 'l) S6'0 '(Ηζ '^) 9£'WI Wi '^) 65Ί-99Ί '(H9 's) ςΖ'Ζ '(Ηζ 's) 9'£ ΉΖ Y9 = "' ) LVV '(HI 0·8 = " 'Ρ) SVL (HI 's) OZ'L '(HI
Figure imgf000024_0004
PZ'L '(HI 's) 90· Π 9 (9P-QSViQ 则 Ot) ¾W HT
Figure imgf000024_0005
9SS1780/Z10ZN3/X3d 96SS.0/CT0Z OAV 7
Figure imgf000025_0001
。 εΐΓ6εερ画 εΐΠ·6εε + [¾ +w]sso^ om^i3 p 。 dsa) s爾 H m 'ZH VL = r Ί)ΟΟΊ '(Η^) W\ m ~z 'ΖΗ τ L
= Γ 'b) 6'Z XUZ 'ZH Z'L = Γ 'b) ς£·£ '(Ηζ 's) \ £ '(HI 'ZH 0"8 = Γ 'P) ZVL '(HI 's) IT L '(HI 'ZH 8"01 =Γ 'P) LZL '(HI 's ·8 '(HI 's) ςς'ΖΙ 9： tod 'z謂 00 ¾麵 Ητ
Figure imgf000025_0002
p 。 dsa) s爾 H 'to 'ZH YL = r Ί)ΟΟΊ '(Η^) W\ m VL = r Ί) 'ZH Z'L = " 'b) WZ '(Hf ra) ZV£ ΉΖ 'S) 0 £ '(HI 0"8 = Γ 'V) ZVL '(HI 's) ZZ L '(HI 'ZH 8"01 =Γ 'P) LZ'L '(HI 's '(HI 's) ςς'ΖΙ 9 :( (Ί 'z謂 00 ¾麵 Ητ
Figure imgf000025_0003
ζς
-1660"l79£ P画 J '£860"l79£ [+¾ +W] S£O 6IH6I3 J。J P 。 (isa) S爾 H "(H£ 'ΖΗ 8·8
=r Ί) oo'i m '^) ςγ\-ςς·\ nz '^) L \-i '\ m 's) 69·ε ΉΖ 'ΖΗ 8·9 = ' ςί'Ρ
(Η£ '^) WL-Li'L '(Ηΐ7 'ra) 9 'L-i6'L '(HI 's) 99'Π 9 -(£\DQD 'zHW00l)¾W HT
Figure imgf000025_0004
(\ξ呦 驅丄邈凝-£-^難¾二-^-¾羅卞(¾¾ |-乙)-乙
•££80-05£ P画 J '^80Ό5£ [ ¾ +W] S£O iTH8I3 J。J Ρ。Ι 。 (isa)
9SS1780/Z10ZN3/X3d 96SS.0/CT0Z OAV 1H NMR (400 MHz, DMSO-t¾: δ 11.38 (s, IH), 7.88 (d, J = 8.4 Hz, IH), 7.55 (d, J = 2.0 Hz, IH), 7.49 (dd, Ji = 2.0 Hz, J2 = 8.4 Hz, IH), 6.45 (s, IH), 4.25 (q, J = 6.8 Hz,2H), 3.76 (s, 2H), 2.47 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C17H15N05S[M+H]+ 346.0749, found 346.0746。 化合物 55
Figure imgf000026_0001
'H NMR (400MHz, DMSO-t 6): δ 11.23 (s, IH), 7.86 (s, IH), 7.78-7.72 (m, 3H) 4.24 (q, J = 6.8 Hz, 2H), 3.71 (s, 2H), 1.26 (t, J = 6.8 Hz, 3H). HRMS (ESI) calcd for C14H12F3N03S [M+H+] 332.0568, found 332.0572. 化合物 56
Figure imgf000026_0002
'H NMR (400 MHz, DMSO-t¾: δ 11.14 (s, IH), 8.11 (d, J = 9.6 Hz, IH), 7.85 (d, J = 2.8 Hz, IH), 7.67 (dd, Ji = 2.4 Hz, J2 = 8.8 Hz, IH), 7.52 (d, J = 8.8 Hz, IH), 6.59 (d, J = 9.2 Hz, IH), 4.23 (q, J = 7.2 Hz, 2H), 3.69 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C16H13N05S [M+H+] 332.0593, found 332.0603. 化合物 57
Figure imgf000026_0003
'H NMR (400MHz, DMSO-t 6): δ 11.17 (s, IH), 9.11 (s, IH), 8.27 (s, IH), 7.85 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 3.84 (s, 2H) HRMS (EI) m/z calcd for
C12H9F3N2O2S [M+] 302.0337, found 302.0338. 化合物 58
Figure imgf000026_0004
H NMR (400MHz, DMSO-t 6): δ 7.88 (d, J = 8.0 Hz, 2H), 7.71 (d, J= 8.0 Hz, 2H) 4.04 (s, 2H) HRMS (EI) m/z calcd for C12¾F3N03S [M+] 303.0177, found 303.0175 化合物 59
Figure imgf000027_0001
'HNMR (400MHz, DMSO-t6): δ 7.33 (d,J= 8.0 Hz, IH), 7.28 (s,lH), 7.18 (d,J = 8.0 Hz, IH), 4.00 (s, 2H), 2.87 (q, J= 7.2 Hz, 4H), 2.06-2.00 (m,2H). HRMS (EI) m/z calcd for C14H13N03S [M+] 275.0616, found 275.0617 化合物 60
Figure imgf000027_0002
'HNMR (400 MHz, DMSO-t¾): δ 11.21 (s, IH), 7.64 (s, IH), 7.54 (d,J= 7.2 Hz, 2H), 7.48 (t,J= 7.2 Hz, 2H), 7.43 (d,J= 7.2 Hz, IH), 7.30-7.24 (m, 3H), 4.29 (q,J= 7.2 Hz, 2H), 2.28 (s, 6H), 1.31 (t,J= 7.2 Hz, 3H). HRMS (EI) m/z calcd for C22H21N03S [M+ 379.1242, found 379.1245 化合物 61
Figure imgf000027_0003
H NMR (400MHz, CDC13): δ 10.47 (s, IH), 7.96 (m, 4H), 7.62 (dd, Ji = 2.0 Hz, J2 = 8.8 Hz, IH), 7.54 (m, 2H), 4.75 (s, 2H), 4.25 (q, J= 6.8 Hz, 2H), 1.28 (t, J= 6.4 Hz, 3H). HRMS (ESI) calcd for C17H15N04 [M+Na+] 320.0899, found 320.0897. 化合物 62
Figure imgf000027_0004
1H NMR (400MHz, CDC13) δ 10.15 (s, IH), 7.22 (s, IH), 7.17 (s, 2H), 4.66 (s, 2H), 4.22 (q, J= 7.1 Hz, 2H), 2.23 (s, 3H), 2.22 (s, 3H), 1.26 (t,J= 7.2 Hz, 3H). HRMS (ESI) calcd for C15H17N04 [M+Na+] 298.1055, found 298.1059. 化合物 63
Figure imgf000028_0001
'HNMR (400 MHz, DMSO-t6): δ 10.62 (s, IH), 8.99 (d,J= 2.4Hz, IH), 8.44 (d, J = 2.4 Hz, IH), 8.04 (d, J = 8.0 Hz, IH), 7.99 (d, J = 8.0 Hz, IH), 7.79-7.75 (m, IH), 7.67-7.63 (m, IH), 4.75 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C16H14N202 [M+Na+] 321.0843, found 321.0851. 化合物 64
Figure imgf000028_0002
H NMR (400 MHz, DMSO-t6): δ 10.16 (s, IH), 7.15 (d,J= 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, IH), 4.68 (s, 2H), 4.22 (q,J= 6.8 Hz, 2H), 2.71 (s, 4H), 1.73 (s, 4H), 1.26 (t,J = 6.8 Hz, 3H) HRMS (ESI) calcd for C17H19N04 [M+Na+] 324.1027, found 324.1212. 化合物 65
Figure imgf000028_0003
'HNMR (400 MHz, DMSO-t6): δ 10.19 (s, IH), 7.31 (s, IH), 7.25 (d, J= 8.0 Hz, IH), 7.18 (d, J= 8.0 Hz, IH), 4.66 (s, 2H), 4.22 (q, J= 6.8 Hz, 2H), 2.86 (q, J= 7.2 Hz, 4H), 2.04 (t, J= 7.2 Hz, 2H), 1.26 (t, J= 6.8 Hz, 3H) HRMS (ESI) calcd for C16H17N04 [M+Na+] 310.1056, found 310.1055. 化合物 66
Figure imgf000028_0004
1HNMR (400 MHz, DMSO-t6): δ 10.52 (s, IH), 7.93 (d,J= 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 4.76 (s, 2H), 4.24 (q,J= 7.2 Hz, 2H), 1.26 (t,J= 7.2 Hz, 3H). HRMS (ESI) calcd for C13H12F5N04S [M+H+] 374.0485, found 374.0490. 化合物 67
Figure imgf000029_0001
Ή NMR (400 MHz, DMSO-t 6): δ 10.49 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 4.75 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd for C14H13F3N04 [M+Na+] 338.0607, found 338.0616.
DHODH活性测试部分
实施例 1
本发明提供的化合物对二氢乳清酸脱氢酶 （DHODH) 活性的体外抑制效果： 将 PfDHODH ( Plasmodium falciparum dihydroorotate dehydrogenase)的催化区域 159-565克隆到载体 pET101/D中 （The Journal of Biological Chemistry, 2008 , 283 , 35078-35085 ) ， 转入表达菌株 E.coli BL21， 将 1.5 ml pET101/D- PfDHODH菌液接 种 500mL含 250 μΜ氨苄青霉素的 2xYT培养基中， 37°C、 230rpm摇床培养约 4 h。 待菌体 OD值达到 0.8-1时， 向培养基中加入 IPTG， 使 IPTG终浓度为 0.5 mM, 25°C 诱导 4-6 h。 4°C、 4000 rpm离心 20 min收集诱导后菌体， 用 15 ml去离子水重悬菌体 后 10000 rpm离心 30 min收集菌体沉淀， -80°C过夜保存后，用 20 ml 裂解液 50 mM HEPES (pH 7.5), 500 mM NaCl, 40 mM imidazole, 0.1 % Triton X-100重悬，超声破碎裂 解菌体。 用含 300 mM咪唑的裂解液洗脱蛋白后， 50 mM HEPES (pH 7.5), 150 mM NaCl, 10% glycerol,0.1% Triton X-100过夜透析后用于后续的酶活测定及抑制剂筛选。
抑制剂筛选使用 DCIP比色法， DCIP在反应中被还原， 是 DHO (二氢乳清酸） 最终的电子受体， 因此根据 DCIP在 600nm处吸光度的减弱速率可以判断底物 DHO 的水解程度， 光吸收值减弱的速率越快， 表明酶的活性越高， 即化合物对其抑制作用 越小 （以同体积的 DMSO为阴性对照， 等量的 A77 1726为阳性对照） ， 具体见文献 ( The Immunosuppressive Metabolite of Lef unomide Is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase)。
所有试剂， 包括氨苄青霉素、 YT培养基、 IPTG、 咪唑、 HEPES、 Triton X-100 NaCl、 DCIP、 DHO等均购自 sigma公司。 化合物 14_ 21购自荷兰 SPECS化合物库。 实施例 2
本发明化合物对两种恶性疟原虫细胞株的体外活性的抑制效果： 氯喹购于 Sigma公司， SYBR Green购于 Invitrogen公司， 氯喹敏感的恶性疟原 虫 3D7细胞株和氯喹抗性的恶性疟原虫 Dd2细胞株用于体外测试抗疟活性， 以 0.5% Albumax II ( Invitrogen公司）代替人血清，其他按 Trager and Jensen的培养方法培养。 两种恶性疟原虫虫株均来自美国的 MR4 ( Malaria Research and Reference Reagent Resource Center) 。
实验中使用 SYBR Green为荧光探针， 通过测定荧光数据的方法来测定抗疟活 性。 培养过程如下， 起始感染率为 1%， 2%血压积， 与一系列的药物存在或不存在的 条件下培养， 终体积为 100 L。 每种化合物经倍比稀释， 浓度范围为 0.15625 μ Μ到 20 μ Μ。 以 0.2% DMSO作为阴性对照， 不同浓度的氯喹作为阳性对照， 以 100 L， 2%血压积的未感染红细胞作为背景对照， 37 ° C下培养 72小时； 以上每种设计均设 置 3个平行对照； 以上培养均在 96孔细胞培养板中进行。 培养 72小时后， 离心， 弃 去上清液，每孔加入 100 μ L含 SYBR Green I 的红细胞裂解液 (8.26 g/L NH4C1, 1 g/L KHC03, 0.037 g/L EDTA and 5 X SYBR Green 1)。 培养皿在避光环境中室温放置 1小 时，将所有样品转移到黑色酶标板中（ Corning 3925 )，通过 Biotek公司的 Synergy MX 多功能微孔板检测仪进行荧光检测， 在 485/520 nm下读数。 本实验重复两次。
数据分析是根据 Michael等报道的方法进行改进获得。简述如下， 阴性对照处理 组获得的荧光数据减去未感染红细胞组所产生的背景荧光数据，代表本次实验中正常 培养的恶性疟原虫中的 DNA最大量， 记为阴性对照孔的荧光数据， 各测试组及阳性 对照组的荧光数据均如此校正。 不同浓度下抑制率的计算由下式所得： 抑制率 （％) 1— (测试孔中平均荧光计数 /阴性对照孔中平均荧光计数） 〕 X 100%。 通过软 件 Origin 8.0中的 Growth/Sigmoidal 程序拟合曲线并计算获得半数抑制率 （IC50 values) ， 通过 Microsoft Excel 计算平均值和标准差。
实施例 1和 2的结果如下表所示：
噻吩酮衍生物的抑制率和活性化合物的 IC
Figure imgf000030_0001
Figure imgf000031_0001
0/Z10ZN3/X3d 96SS.0/CT0Z OAV 4.73749994
30.2244076 8.47004 6.62546
58.24222769 4.73106±0.19 2.69638 2.77772
63.78877439 5.73275 + 0.2855 3.17317 3.926755
40.99553838 11.14765 8.491925
44.62101375
59.45378691 1.23842±0.011 1.86025 1.04883
20.56110617 17.14 15.31
26.62551656
6.74 4.87
36.46239003 14.35 13.59
37.76443461 >20 >20
5.043710956 >20 >20
9.195823097 >20 >20
29.6098525 13.82 10.42
91.59259371 0.00597±5.8E-06 0.01567 0.01842
82.10318913 0.69764±0.01335 0.372205 0.485605

Claims

1 . 下式 I化合物:
Figure imgf000033_0001
式中，
Xi选自 O, S, NH禾 Π CH2;
X2选自 0， S， NH, NOH， NHR， R为 C1-C6烷基；
R1选自 H， C1-C10烷基， CIO以下不饱和烃基， 任选取代的芳基， 硝基， 氨基， NR4R5， 卤素；
R2选自 H， C1-C6烷基， C2-C6不饱和烃基， C1-C6烷基羰基， 任选取代的苯甲 酰基， 羧基， 氨基羰基， C1-C6烷氧基羰基， C1-C6烷基氨基羰基， 羟基， C1-C6烷 氧基， C3-C8环烷基氨基羰基， C3-C8环烷基 -C1-C6烷基氨基羰基， C3-C8环烷基 -C1-C6烷氧基羰基；
R3选自 H， C1-C6烷基， 任选取代的 C2-C6不饱和烃基， C1-C6烷基羰基， 任 选取代的苯甲酰基， 羧基， 氨基羰基， C1-C6烷氧基羰基， C1-C6氨基羰基， 羟基， C1-C6烷氧基；
R4和 R5独立选自 H， C1-C6烷基， -C(0)NHR6， C1-C6烷氧基羰基， 卤素取代 的烷基， C2-C6不饱和烃基， 任选取代的芳基， C1-C6烷基羰基， 任选取代的苯甲酰 任选取代的杂环基， 任选取代的杂环基羰基， C1-C6烷氧基羰基；
R6选自任选取代的芳基和任选取代的杂环基 (
2. 如权利要求 1所述的化合 其特征在于， 所述化合物选自下式 II的化合物：
Figure imgf000033_0002
式中，
Xi选自 0, S, NH禾 Π CH2;
R2选自 H， C1-C6焼基， C2-C6不饱和烃基， C1-C6烷基羰基， 任选取代的苯甲 酰基， 羧基， 氨基羰基， C1-C6烷氧基羰基， C1-C6烷基氨基羰基， 羟基， C1-C6烷 氧基， C3-C8环烷基氨基羰基， C3-C8环烷基 -C1-C6烷基氨基羰基， C3-C8环烷基 -C1-C6烷氧基羰基；
R7选自任选取代的芳基， 任选取代的杂环基， 任选取代的芳基羰基， 任选取代 的含氮杂环基羰基， 和任选取代的芳氧基， C1-C3烷基羰基。
3. 如权利要求 2所述的化合物， 其特征在于， 所述芳基和杂环基任选地被 1一 5 个选自以下的基团取代： C1-C10烷基， C3-C8环烷基， C1-C4烷氧基， 任选取代的 苯基， 任选取代的苯氧基， 苄氧基， CF3， F， CI, Br和 I。
4. 如权利要求 2所述的化合物， 其特征在于， R2选自 H， C1-C6烷基， C2-C6 不饱和烃基， C1-C3烷基羰基， 任选取代的苯甲酰基， 羧基， 氨基羰基， C1-C6烷氧 基羰基， C1-C6氨基羰基， 羟基， C1-C6烷氧基；
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0003
Figure imgf000036_0001
6. 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 1一 5中任一 项所述的化合物或其药学上可接受的盐， 和药学上可接受的载体或赋形剂。
7. 权利要求 1一 5中任一项所述的化合物在制备治疗或预防二氢乳清酸脱氢酶 介导的疾病用的药物中的用途。
8. 如权利要求 7所述的用途， 其特征在于， 所述二氢乳清酸脱氢酶介导的疾病 选自恶性疟疾， 间日疟， 卵形疟疾， 三日疟， 克氏锥虫病， 登革热等寄生虫病；
9. 如权利要求 7所述的用途， 其特征在于， 所述二氢乳清酸脱氢酶介导的疾病 选自类风湿性关节炎、 结肠炎、 银屑病关节炎、 红斑狼疮、 肾小球疾病和抗器官移植 物排异反应。
10. 如权利要求 7所述的用途， 其特征在于， 所述二氢乳清酸脱氢酶介导的疾病 选自黑色素瘤和同种或异种器官移植引起的宿主排斥反应。
1 1 . 权利要求 1一 5中任一项所述的化合物在制备抑制二氢乳清酸脱氢酶活性用 的药物中的用途。
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