WO2018133716A1 - 杂环脲类化合物及其药物组合物和应用 - Google Patents

杂环脲类化合物及其药物组合物和应用 Download PDF

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WO2018133716A1
WO2018133716A1 PCT/CN2018/072046 CN2018072046W WO2018133716A1 WO 2018133716 A1 WO2018133716 A1 WO 2018133716A1 CN 2018072046 W CN2018072046 W CN 2018072046W WO 2018133716 A1 WO2018133716 A1 WO 2018133716A1
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dmso
nmr
ppm
substituted
cancer
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French (fr)
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蒋晟
涂正超
郝海平
姚和权
邱亚涛
姚毅武
陈东
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
    • 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
    • C07D307/02—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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a heterocyclic urea compound, in particular to a heterocyclic urea compound or a pharmaceutically acceptable salt or stereoisomer thereof and a prodrug molecule thereof, a pharmaceutical composition containing the same, and a compound or composition thereof Preparation in the preparation of drugs.
  • Tryptophan is one of the important amino acids essential in mammals. It plays an important role in the biosynthesis of some important proteins, niacin and some neurotransmitters (such as serotonin, serotonin). Maintain cell activation and proliferation. Tryptophan needs to be ingested in large quantities from food, and its lack can lead to dysfunction of some important cells.
  • Indoleamine-2,3-dioxygenase is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group. Consisting of 403 amino acids with a molecular weight of 45 kDa, it is widely expressed in a variety of mammalian tissues (Hayaishi O. et al Science, 1969, 164, 389-396).
  • IDO is responsible for the cleanup of tryptophan in the human body. It is the first enzyme in the metabolic pathway of tryptophan in the body and is the rate-limiting enzyme. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine by oxidation reaction. When IDO is overexpressed, it will cause a microenvironment in which tryptophan is deleted in vivo. IDO is closely related to a variety of disease pathogenesis and has been shown to be a target for major diseases such as cancer, Alzheimer's disease, depression, and cataract (Swanson et al. Am. J. Respir. Cell Mol. Biol. 2003 30, 311) (Guillemin GJ et al Neuropathol. and Appl. Neurobiol. 2005, 31, 395-404). Finding high-efficiency inhibitors based on IDO targets has become a research hotspot in drug development in recent years.
  • IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in the absence of tryptophan or kynurenine culture conditions, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. However, there is a regulatory point in T cells that is very sensitive to the level of tryptophan. The consumption of tryptophan caused by IDO will cause T cells to arrest in the G1 phase, thereby inhibiting the proliferation of T cells and inhibiting T. The immune response of the cell.
  • T cells stop proliferating, they may not be stimulated any more. This is the mechanism of IDO immunity in vivo (Mellor A. et al Biochem. Biophys. Res. Commun. 2005, 338, 20-24) (LeRond S. Et al J Exp. Med 2002, 196, 447-457). Inhibition of IDO activity can effectively prevent the degradation of tryptophan around tumor cells and promote the proliferation of T cells, thereby enhancing the body's ability to attack tumor cells. IDO inhibitors can also be combined with chemotherapeutic drugs to reduce the resistance of tumor cells, thereby enhancing the anti-tumor activity of conventional cytotoxic therapies. Simultaneous administration of IDO preparations can also improve the efficacy of therapeutic vaccines for cancer patients. The development of IDO inhibitors has become a hot spot for tumor immunotherapy.
  • IDO inhibitors have broad application prospects as drugs, but so far no suitable IDO inhibitors have been marketed as drugs. It is of great theoretical significance and application value to find new and effective IDO inhibitors.
  • the technical problem to be solved by the present invention is to provide a guanamine-2,3-dioxygenase inhibitor of a heterocyclic urea compound for solving the deficiencies in the prior art, and to solve the therapeutic effect of the existing immunotherapy drugs. Weak, toxic side effects and other defects.
  • Another technical problem to be solved by the present invention is to provide a process for preparing a guanamine-2,3-dioxygenase preparation of the above heterocyclic urea compound.
  • a further technical problem to be solved by the present invention is to provide a pharmaceutical use of the above-described heterocyclic urea compound, a guanamine-2,3-dioxygenase preparation or a pharmaceutically acceptable salt thereof.
  • the present invention provides a heterocyclic urea compound having the chemical structure represented by Formula I, and a pharmaceutically acceptable salt, isomer, racemate, prodrug or solvate thereof:
  • X, Y is optionally N or C;
  • Z is optionally O, S, or N;
  • R 1 represents a substituent on the benzene ring selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, dimethylamino, C 1-6 alkyl, C 1-6 perfluoroalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-12 heteroalicyclic or C 1-6 alkoxy;
  • the R 2 group is selected from one of the following:
  • the C 6 -C 12 aryl, heteroaryl, -CH 2 -(C 6 -C 12 aryl) and -CH 2 -heteroaryl groups with or without one or more substitutions
  • the substituent is selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, amino C 1 -C 12 alkyl, C 1 -C 12 acyl, C 1 -C 12 acyloxy, thio C 1 -C 12 alkyl, carboxy or phenyl;
  • the C 3 -C 12 cycloalkyl group with or without one or more substituents selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, amino C 1 -C 12 alkyl, C 1 -C 12 acyl, C 1 -C 12 acyloxy, sulfonyl C 1 -C 12 alkyl, carboxy or phenyl.
  • the invention also provides a preparation method for preparing the heterocyclic urea compound represented by the formula I, which comprises the following steps:
  • the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), ethylene glycol dimethyl ether, 1,2-dichloroethane, and dimethyl phthalate.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • ethylene glycol dimethyl ether 1,2-dichloroethane
  • dimethyl phthalate One or more of ester (DMP), methanol, ethanol, petroleum ether, n-hexane, and diethyl ether.
  • the acid is selected from one or more of the group consisting of acetic acid, trifluoroacetic acid, formic acid, propionic acid, sulfuric acid, nitric acid, and hydrochloric acid.
  • the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide, imidazolium hydroxide, and the like.
  • potassium carbonate sodium carbonate, sodium hydrogencarbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide, imidazolium hydroxide, and the like.
  • the aromatic amine selected from aniline, phenethylamine, halo, nitro, cyano, hydroxy, amino, dimethylamino, C l-6 alkyl, C l-6 perfluoroalkyl, C 2-6 alkenyl
  • aniline phenethylamine
  • halo nitro, cyano, hydroxy, amino, dimethylamino, C l-6 alkyl, C l-6 perfluoroalkyl, C 2-6 alkenyl
  • a mono- or poly-substituted aniline of a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, and a C 3-12 heteroalicyclic group or a C 1-6 alkoxy group a mono- or poly-substituted aniline of a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, and a C 3-12 heteroalicyclic group or a C 1-6 alkoxy group.
  • the isocyanate, or isothiocyanate or isocyanide is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, -CH 2 -O-CH 2 -(C 1 -C 12 alkyl), -CH 2- NH-CH 2 -(C 1 -C 12 alkyl), -CH 2 -S-(C 1 -C 12 alkyl), C 6 -C 12 aryl, heteroaryl, -CH 2 -( C 6 -C 12 aryl) or -CH 2 -heteroaryl, C 3 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl or -CH 2 -NH-SO 2 -NH 2 /CH 3 (C 1 -C 12 alkyl) substituted isocyanate, or isothiocyanate or isocyanide.
  • the present invention also provides an antitumor pharmaceutical composition
  • an antitumor pharmaceutical composition comprising a heterocyclic urea compound of the formula I or a pharmaceutically acceptable salt, isomer, racemate, prodrug or solvent thereof. And a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a heterocyclic urea compound of the formula I and a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof for the preparation of a medicament for treating or preventing a tumor.
  • the application is to treat lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, gastric cancer, colon cancer, colon cancer, kidney cancer, ovarian cancer, pancreas with an effective dose of the compound.
  • the medicament for treating or preventing a tumor includes, but is not limited to, an immunotherapeutic agent for cancer: a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, and any other Chemotherapy or targeted therapy.
  • heterocyclic urea compound and a pharmaceutically acceptable salt thereof can be used for the preparation of a tumor transitional proliferative disease for treating humans and other mammals.
  • the heterocyclic urea compound and the pharmaceutically acceptable salt thereof according to the invention can effectively inhibit the formation of kynurenine in various tumor cells and inhibit the indoleamine-2,3-dioxygenase. It can be used to prepare anti-tumor drugs.
  • heterocyclic urea compounds and pharmaceutically acceptable salts thereof according to the invention include mammalian diseases, including cancer, neurodegenerative diseases, AIDS and old age, which are related to the treatment of guanamine-2,3-dioxygenase dysregulation. dementia.
  • the heterocyclic urea compound represented by the formula I or a salt thereof according to the present invention has an IDO inhibitory action and can be used as an active ingredient for treating or preventing a tumor, and has the advantages of good curative effect and small toxic side effects, and the present invention
  • the heterocyclic urea compounds of formula I are tested by in vitro biological activity assays.
  • any variable e.g., R1, R2, etc.
  • the definition of each occurrence thereof is independent of the definition of each occurrence.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring.
  • alkyl means a straight or branched, C 1 ⁇ n of the aliphatic saturated hydrocarbon alkyl 1-n carbon atoms is represented, including straight and branched chains such as "C 1 ⁇ 12 alkyl group” It is meant that the group is an alkyl group and the number of carbon atoms in the carbon chain of the alkyl group is between 1 and 12. It should be noted that when the number of carbon atoms is not particularly limited, it means only the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group.
  • Cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 6 atoms in the ring or up to 6 atomic bicyclic carbon rings in each ring, at least one of which is an aromatic ring and contains from 1 to 4 Heteroatoms from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, thiazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrole Base, pyridyl.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or a hetero atom-containing ring.
  • salts refers to salts which, within the scope of sound medical judgment, are suitable for contact with mammalian, particularly human, tissues without undue toxicity, irritation, allergic response, etc., and which are commensurate with a reasonable benefit/risk ratio, Pharmaceutically acceptable salts such as amines, carboxylic acids and other types of compounds are well known in the art.
  • isomer refers to two or more compounds that have the same molecular composition but differ in structure and properties.
  • racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. It is composed of the same amount of molecules with opposite optical rotation and the same optical rotation. The optical rotation is due to these molecules. The interaction between the two cancels each other and is therefore not optical.
  • solvate refers to a mixture of a compound and a solvent, for example, a crystalline form is a solvate.
  • prodrug refers to a compound that produces a parent compound of the above formula by rapid conversion in vivo by hydrolysis in blood.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • (C 1 -C 6 )alkyl may be substituted by one, two, or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. Replace.
  • the invention includes the free forms of Formula I, as well as pharmaceutically acceptable salts and stereoisomers.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to an amine compound in a non-salt form. Included are pharmaceutically acceptable salts including not only the exemplary salts of the particular compounds described herein, but also all of the typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the salt is treated by a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of sodium hydroxide, a dilute aqueous solution of sodium carbonate, a dilute aqueous ammonia solution and a dilute aqueous solution of potassium hydrogencarbonate to regenerate the free form.
  • a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of sodium hydroxide, a dilute aqueous solution of sodium carbonate, a dilute aqueous ammonia solution and a dilute aqueous solution of potassium hydrogencarbonate to regenerate the free form.
  • the free form differs somewhat from its respective salt form in the solubility of certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • salts of the compounds are formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, Fumar Salts prepared by acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid.
  • inorganic acids such as hydro
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like.
  • a pharmaceutically acceptable salt of an organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin, such as refined ammonia Acid, beet, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine , N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, methyl glucosamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resin, Rucaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine.
  • a basic ion exchange resin such
  • the present application provides a method for treating a proliferative disease or condition, such as a tumor in a human or other mammal, using a compound of formula (I) and a pharmaceutically acceptable salt thereof.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used to treat or control lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, gastric cancer, pancreatic cancer, Transitional proliferative diseases such as breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, leukemia and cervical cancer.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used with cytotoxic/cytostatics, estrogen receptor modulators, androgen receptor modulators, currently in use or at developmental stages, Retinoid receptor modulators, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, interference Cell cycle checkpoint drugs and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit Inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histone deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibition Agent, MDM2 family protein inhibitor, IAP family protein
  • a method of treating breast cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a method of treating respiratory cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, small cell & non-small cell lung cancer, bronchial adenocarcinoma, and pleural pulmonary blastoma.
  • a method of treating brain cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, brain stem and sub-glial glioma, cerebellum and cerebral astrocytoma, ependymoma, and neuroectoderm and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to, cervical cancer, endometrial cancer, ovarian cancer, vaginal cancer and vulvar cancer, and intrauterine tumors.
  • a method of treating digestive tract cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, anal cancer, colon cancer, colonic straight cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.
  • a method of treating urinary tract cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, and urethral cancer.
  • a method of treating an ocular cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • hepatoma hepatocellular carcinoma with or without fibrotic changes
  • cholangiocarcinoma intrahepatic cholangiocarcinoma
  • mixed hepatocellular cholangiocarcinoma mixed hepatocellular cholangiocarcinoma.
  • a method of treating skin cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • squamous cell carcinoma Kaposi's sarcoma
  • malignant melanoma Merck's cell skin cancer
  • non-melanoma cell carcinoma include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell carcinoma.
  • a method of treating head and neck cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • These include, but are not limited to, laryngeal, hypopharyngeal, nasopharynx, oropharyngeal cancer, and lip and oral cancer.
  • a method of treating lymphoma in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a method of treating a sarcoma of a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as contemplated by the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as contemplated by the present application.
  • these include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • a method of treating leukemia in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • these include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the compounds of the invention may be administered to a mammal, preferably a human, alone or in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, in accordance with standard pharmaceutical techniques.
  • the compound can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, or parenterally.
  • the dosage range is from 0.1 to 500 mg/day/kg body weight orally.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times a day or the like using sustained release techniques.
  • the preferred dosage range is from 0.1 to 1500 mg/day/kg body weight.
  • the dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • the dosage range is from 0.1 to 500 mg/day/kg body weight in an intravenous dose.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times, or the like, or administration using a sustained release technique.
  • the preferred dosage range is from 0.1 to 1500 mg/day/kg body weight.
  • the dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • the pharmaceutical composition containing the active ingredient of the present invention can be formulated into an oral administration form, for example, a tablet, a tablet, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard capsule or Soft capsules, or syrups or elixirs.
  • the composition intended for oral administration can be prepared according to any method known in the art of pharmaceutical composition manufacture, and in order to provide a pharmaceutically refined and palatable preparation, the composition may contain one or more selected from the group consisting of sweetness Agents for flavors, flavors, colorants and preservatives. Tablets contain the active ingredient with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch. Or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to prolong disintegration and absorption in the gastrointestinal tract and thus provide a drug effect that lasts longer.
  • a water-soluble taste-masking raw material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose may be employed, or a delayed starting material such as ethylcellulose or cellulose acetate butyrate may be employed.
  • the dosage form of the tablet may be 0.1 mg/tablet, 0.2 mg/tablet, 0.25 mg/tablet, 0.5 mg/tablet, 1 mg/tablet, 2 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, 50 mg/tablet, 100 mg/tablet, and 250 mg/tablet.
  • Other dosage forms such as capsules can be used for similar dosage references.
  • the preparation for oral use can also be formulated into a hard gelatin capsule in which the active ingredient is mixed in an inert solid diluent such as calcium carbonate, sodium carbonate or kaolin; or a soft gelatin capsule in which the active ingredient is mixed in a water-soluble carrier For example, polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.
  • aqueous suspension contains the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, or gum arabic; such aqueous suspensions may also contain a Or a plurality of preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin Or aspartame.
  • An oily suspension can be prepared by suspending the active ingredient in a vegetable oil, for example, peanut oil, sesame oil, coconut oil, or olive oil, a mineral oil such as liquid paraffin.
  • Such oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol.
  • Sweetening agents and flavoring agents as described above may be added to provide a formulation suitable for oral administration. These compositions can be stored by the addition of an anti-oxidant such as butylated hydroxyanisole or a tocopherol.
  • an anti-oxidant such as butylated hydroxyanisole or a tocopherol.
  • Dispersible powders or granules are suitable for the preparation of aqueous suspensions by the addition of water to provide active ingredients in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by the examples referred to above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be present. These compositions can be stored by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as peanut oil or olive oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or liposomes derived from a mixture of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation of the partial esters and alkylene oxides.
  • the product is, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, antioxidants, and preservatives.
  • Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain wetting agents, flavoring agents, coloring agents, antioxidants, and preservatives.
  • compositions of the invention may be formulated as sterile injectable solutions.
  • Water, Ringer's solution and isotonic sodium chloride solution can be employed in acceptable vehicles and solvents.
  • Such sterile injectables can also be formulated as a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is first dissolved in a mixture of soybean oil and lecithin, and then the oil solution is placed in a mixture of water and glycerin and treated to form a microemulsion.
  • Such pharmaceutical compositions can be formulated in the form of a sterile injectable solution or oily suspension for intramuscular or subcutaneous administration.
  • This suspension can be prepared according to the known techniques using the dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injectable preparation may also be presented as a sterile injectable solution or suspension in a non-pharmaceutically acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • non-volatile oils are conventionally employed as a solvent or suspension medium.
  • any non-irritating, non-volatile oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid have been found to be useful in injectable formulations.
  • Combinations of the compounds of formula (I) may be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • the compound of the formula I is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition comprising both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula I include, but are not limited to, cytotoxin/cytostatics, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, anti-proliferation Agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints, and apoptosis Inducing agents, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibition Agent, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP Family protein inhibitors, ST
  • the drug that can be administered in combination with a compound of formula (I) includes, but is not limited to, adiponectin, alendronate, interferon, atranoxine, allopurinol, sodium allopurinate , palonosetron hydrochloride, hexamethylene melamine, aminoglumidine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arba Nuoxin, 5-azacytidine, azathioprine, BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromide, bortezomib, busulfan , calcitonin, alemzumab injection, capecitabine, carboplatin, cisplatin, constance, cefesone, sir, interleukin
  • the conventional post-treatment method is: after the reaction is completed, an appropriate amount of water is added to the reaction liquid, the organic phase and the aqueous phase are separated, and the organic phase is combined; if necessary, 5% HCl is sequentially used.
  • the solution and/or saturated Na 2 SO 4 are dried, filtered and dried under reduced pressure to give a crude product which is purified by column chromatography to give the final product.
  • HeLa cells were cultured and passaged in DMEM medium supplemented with antibiotics in a 37-degree CO 2 incubator, inoculated into 96-well plates overnight, and then an appropriate concentration of 1 ⁇ l of heterocyclic urea compound was added to each well, followed by 100 ⁇ l of interference. ⁇ (final concentration is 100 ng/ml). After continuing to culture the cells for 72 hours, 70 ⁇ l of the cell culture supernatant was added to a 96-well tip plate, and 5 ⁇ l of trichloroacetic acid (6.1 N) was added to each well, and the cells were incubated at 50 degrees for 30 minutes, and then centrifuged at 25,000 rpm for 10 minutes.
  • DMEM medium supplemented with antibiotics in a 37-degree CO 2 incubator
  • IC50 in Table 1 indicates the drug concentration required for IDO1 enzyme and cell 50% growth inhibition.
  • heterocyclic urea compounds prepared by the present invention each have an IC50 of 1 ⁇ M or less.
  • the heterocyclic urea compound prepared according to the present invention has a significantly inhibited activity of the listed IDO1 enzyme and activity of the Hela cell IDO1 enzyme as compared with the positive control (INCB24360).
  • heterocyclic urea compounds and the pharmaceutical compositions and applications thereof provided by the examples of the present invention are described in detail above, and the principles and embodiments of the present invention are described in the following, and the description of the above embodiments is explained. It is only used to help understand the method of the present invention and its core ideas; at the same time, for those skilled in the art, according to the idea of the present invention, there will be changes in the specific embodiments and application scopes. The contents of this specification are not to be construed as limiting the invention.

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Abstract

本发明提供了杂环脲类化合物的吲哚胺-2,3-双加氧酶抑制剂，其制备方法，以及上述杂环脲类化合物的吲哚胺-2,3-双加氧酶抑制剂或其药学上可接受的盐的在制备治疗或预防肿瘤的药物中的用途。

Description

杂环脲类化合物及其药物组合物和应用 技术领域
本发明涉及杂环脲类化合物，具体涉及杂环脲类化合物或其药学上可接受的盐或立体异构体及其前药分子，含有这种化合物的药物组合物和这些化合物或组合物在制备药物中的应用。
背景技术
色氨酸是哺乳动物体内必须的重要氨基酸之一，它在体内一些重要的蛋白质、烟酸和一些神经递质(如5－羟色胺，即血清素)的生物合成过程中起着重要作用，进而维持细胞活化和增殖。色氨酸需要从食物中大量摄取，它的缺乏会导致一些重要的细胞的功能失常。
吲哚胺-2,3-双加氧酶(Indoleamine-2,3-dioxygenase,简称IDO)是1967年Hayaishi小组首次在细胞内发现的一种含有亚铁血红素的单体酶，cDNA编码蛋白由403个氨基酸组成，分子量为45kDa，在多种哺乳动物的组织中具有广泛的表达(Hayaishi O.et al Science,1969,164,389-396)。
IDO负责清理人体中的色氨酸，它是体内色氨酸代谢途径上的第一个酶并且是限速酶。IDO能催化色氨酸通过氧化反应转化成N-甲酰犬尿氨酸，当IDO过量表达时，会造成体内色氨酸缺失的微环境。IDO与多种疾病发病机制密切相关，己被证实它是癌症、阿尔茨海默病、抑郁症、自内障等重大疾病的靶标(Swanson et al.Am.J.Respir.Cell Mol.Biol.2003 30,311)(Guillemin G.J.et al Neuropathol.and Appl.Neurobiol.2005,31,395-404)。寻找基于IDO靶点的高效抑制剂己成为近年来药物开发的研究热点。
研究表明，IDO在肿瘤微环境中可以通过以下几种方式来抑制局部T细胞免疫反应:色氨酸耗竭、毒性代谢和诱导调节性T细胞增殖。很多情况是在肿瘤中过度表达，从而消耗局部的色氨酸，产生大量的犬尿氨酸等代谢产物。事实上，在缺乏色氨酸或者犬尿氨酸的培养条件下，T细胞会发生增殖抑制、活性降低甚至凋亡。而T细胞中存在一个对色氨酸水平非常敏感的调节点，在IDO的作用下导致的色氨酸消耗，会导致T细胞停滞于Gl期，从而抑制了T细胞的增殖，也抑制了T细胞的免疫应答。而T细胞一旦停止增殖，可能就不会再被刺激作用，这是IDO在体内免疫作用机制(Mellor A.et al Biochem.Biophys.Res.Commun.2005,338,20-24)(LeRond S.et al J Exp.Med 2002,196,447-457)。抑制IDO的活性可以有效地阻止肿瘤细胞周围色氨酸的降解，促进T细胞的增殖，从而增强机体对肿瘤细胞的攻击 能力。IDO抑制剂还可以与化疗药物合用，降低肿瘤细胞的耐药性，从而增强常规细胞毒疗法的抗肿瘤活性。同时服用IDO制剂也可提高癌症病人的治疗性疫苗的疗效。IDO抑制剂的研发已经成为肿瘤免疫疗法的热点领域。
IDO抑制剂作为药物具有广阔的应用前景，但是迄今未有合适的IDO抑制剂作为药物上市，寻找新型高效的IDO抑制剂具有重要的理论意义和应用价值。
发明内容
本发明所要解决的技术问题是针对现有技术中存在的不足，提供一种杂环脲类化合物的吲哚胺-2,3-双加氧酶抑制剂，用以解决现有免疫治疗药物疗效弱、毒副作用较大的缺陷等问题。
本发明所要解决的另一个技术问题是提供上述杂环脲类化合物的吲哚胺-2,3-双加氧酶制剂的制备方法。
本发明所要解决的再一个技术问题是提供了上述杂环脲类化合物的吲哚胺-2,3-双加氧酶制剂或其药学上可接受的盐的药物用途。
本发明所要解决的技术问题是通过以下技术方案来实现的。
本发明提供了具有通式I所示的化学结构的杂环脲类化合物，及其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
Figure PCTCN2018072046-appb-000001
其中，
X,Y任选为N或C；
Z任选为O、S、或N；
R 1表示苯环上的取代基，选自氢、卤素、硝基、氰基、羟基、氨基、二甲氨基、C l-6烷基、C l-6全氟烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-12杂脂环基或C l-6烷氧基；
R 2基团任选自以下的一种:
1)氢；
2)C 1-C 12烷基；
3)-CH 2-O-CH 2-(C 1-C 12烷基)；
4)-CH 2-NH-CH 2-(C 1-C 12烷基)；
5)-CH 2-S-(C 1-C 12烷基)；
6)C 6-C 12芳基；
7)杂芳基；
8)-CH 2-(C 6-C 12芳基)或-CH 2-杂芳基；
9)C 3-C 12环烷基；
10)C 4-C 9杂环烷基；
11)-CH 2-NH-SO 2-NH 2/CH 3(C 1-C 12烷基)；
进一步地，所述的C 6-C 12芳基、杂芳基、-CH 2-(C 6-C 12芳基)和-CH 2-杂芳基，含有或不含有1个或多个取代基，所述取代基选自卤素、氨基、羟基、硝基、氰基、C 1-C 12烷基、C 1-C 12烷氧基、氨基C 1-C 12烷基、C 1-C 12酰基、C 1-C 12酰氧基、硫代C 1-C 12烷基、羧基或苯基；
所述的C 3-C 12环烷基，含有或不含有1个或多个取代基，所述取代基选自卤素、氨基、羟基、硝基、氰基、C 1-C 12烷基、C 1-C 12烷氧基、氨基C 1-C 12烷基、C 1-C 12酰基、C 1-C 12酰氧基、磺酰C 1-C 12烷基、羧基或苯基。
本发明还提供了制备式I所示的杂环脲类化合物的制备方法，该方法包括如下步骤：
(1)将式II化合物在酸和氯代试剂的作用下，在有机溶剂中进行氯代反应，得到式III化合物；反应过程如下所示：
Figure PCTCN2018072046-appb-000002
(2)将式III化合物在在碱的作用下与芳香胺，在有机溶剂中反应，得到式IV化合物；反应过程如下所示：
Figure PCTCN2018072046-appb-000003
(3)将式IV化合物在碳基二咪唑(CDI)作用下，在有机溶剂中反应，得到式V化合物；反应过程如下所示：
Figure PCTCN2018072046-appb-000004
(4)将式V化合物与异氰酸酯、或异硫氰酸酯或异氰亚胺酯，在有机溶剂中反应，得到式VI化合物；反应过程如下所示：
Figure PCTCN2018072046-appb-000005
(5)将式VI化合物在碱的作用下脱保护反应，得到式I化合物；反应过程如下所示：
Figure PCTCN2018072046-appb-000006
进一步地，所述的有机溶剂选自二氯甲烷、四氢呋喃(THF)、二甲基甲酰胺(DMF)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、甲醇、乙醇、石油醚、正己烷和乙醚中的一种或多种。
所述的酸选自乙酸、三氟乙酸、甲酸、丙酸、硫酸、硝酸和盐酸中的一种或多种。
所述的碱选自碳酸钾、碳酸钠、碳酸氢钠、碳酸镁、碳酸钙、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、氢氧化镁、氢氧化咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、N-甲基吗啉、DABCO和吡啶中的一种或多种；
所述的芳香胺选自苯胺、苯乙胺、卤素、硝基、氰基、羟基、氨基、二甲氨基、C l-6烷基、C l-6全氟烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、和C 3-12杂脂环基或C l-6烷氧基单取代或多取代的苯胺的一种或多种。
所述的异氰酸酯、或异硫氰酸酯或异氰亚胺酯选自氢、C 1-C 12烷基、-CH 2-O-CH 2-(C 1-C 12烷基)、-CH 2-NH-CH 2-(C 1-C 12烷基)、-CH 2-S-(C 1-C 12烷基)、C 6-C 12芳基、杂芳基、-CH 2-(C 6-C 12芳基)或-CH 2-杂芳基、C 3-C 9环烷基、C 4-C 9杂环烷基或-CH 2-NH-SO 2-NH 2/CH 3(C 1-C 12烷基)取代的异氰酸酯、或异硫氰酸酯或异氰亚胺酯。
本发明还提供了一种抗肿瘤药物组合物，其中含有通式I所示的杂环脲类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，与药学上可接受的载体。
本发明还提供了通式I所示的杂环脲类化合物及其药学上可接受的盐或立体异构体或其前药分子在制备治疗或预防肿瘤的药物中的应用。
进一步地，所述应用为利用有效剂量的所述化合物治疗淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、结肠癌、大肠癌、肾癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌，包括在其它远离肿瘤原发部位的组织或器官的转移病变。
在另一优选例中，所述治疗或预防肿瘤的药物包括但不限于癌症的免疫治疗药物:PD-1抗体、PD-L1抗体、PD-L2抗体、CTLA-4抗体、以及任何一种其它化疗药物或靶向治疗药物。
进一步地，所述的杂环脲类化合物及其药学上可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤过渡增殖性疾病。本发明涉及的杂环脲类化合物及其药学上可接受的盐，可以有效抑制多种肿瘤细胞中犬尿氨酸的生成，并对吲哚胺-2,3-双加氧酶产生抑制作用，可用于制备抗肿瘤药物。
本发明涉及的杂环脲类化合物及其药学上可接受的盐包括用于治疗吲哚胺-2,3-双加氧酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病和老年痴呆。
本发明所述的通式I所示的杂环脲类化合物或其盐具有IDO抑制作用，可作为有效成分用于治疗或预防肿瘤，具有疗效好、毒副作用小的优点，本发明所述的通式I所示的杂环脲类化合物通过体外生物活性测定实验。
具体实施方式
本发明所述化合物中,当任何变量(例如R1,R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域的普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料,容易的合成目标化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
应当说明的是，本文所使用相关术语诸如“烷基”“芳基”“杂芳基”“卤素”“酰基”等等与所属领域中所述术语的一般含义无明显不同。
例如，术语“烷基”指直链或支链，C 1～n烷基则表示1-n个碳原子的饱和的脂烃基，包括直链和支链，例如“C 1～12烷基”指的是该基团为烷基，且烷基的碳链上碳原子的数量在1-12之间。应当说明的是，当没有特别限制其碳原子数时，仅指其中指明的烷基部分的碳原子数，而并不包括烷基的取代基上碳原子数。“环烷基”指的是具有特定碳原子数的单环饱和的脂烃基。例如“环烷基”包括环丙基,甲基-环丙基,2,2-二甲基-环丁基,2-乙基-环戊基,环己基等。
本文所使用术语“杂芳基”代表环中多达6个原子的稳定的单环或每个环中多达6个原子双环碳环,其中至少一个环为芳香环且含有1-4个选自O，N和S的杂原子。本定义范围内的杂芳基包括但不限于：咪唑基、噻唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、哒嗪基、嘧啶基、吡咯基、吡啶基。对于“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。在杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中,应理解各自经芳香环或含杂原子环连接。
本领域的普通技术人员应当知道下列术语或缩写的含义。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“异构体”是指分子组成相同、但结构和性质不同的两种或多种化合物。
术语“外消旋体”是指一种具有旋光性的手性分子与其对映体的等摩尔混合物，它由旋光方向相反、旋光能力相同的分子等量混合而成，其旋光性因这些分子间的作用而相互抵消，因而是不旋光的。
术语“溶剂合物”是指化合物与溶剂组成的混合物，例如结晶体即是一种溶剂合物。
术语“前体药物”指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化合物的化合物。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氯，氟，溴和碘。
除非另有定义,烷基,环烷基,芳基,杂芳基和杂环基取代基可为未被取代的或取代的。例如,(C 1-C 6)烷基可被一个,两个,或三个选自OH,卤素,烷氧基,二烷基氨基或杂环基例如吗啉基,哌啶基等取代基取代。
本发明包括式I的游离形式,也包括药学上可接受的盐及立体异构体。文中一些特定的示例性化合物为胺类化合物的质子化的盐。术语“游离形式”指以非盐形式的胺类化合物。包括药学上可接受的盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I化合物游离形式的典型的药学上可接收的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,通过适当的碱稀水溶液如氢氧化钠稀水溶液,碳酸钠稀水溶液,稀氨水溶液及碳酸氢钾 稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质如在极性溶剂中的溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成化合物的盐。因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规无毒盐包括得自无机酸例如盐酸、硫酸、氢溴酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、乙酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、2-乙酰氧基-苯甲酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸和三氟乙酸等制备的盐。如果本发明的化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂,例如精氨酸、甜菜、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、甲基葡萄糖胺、组氨酸、赖氨酸、异丙基胺、吗啉、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺和氨基丁三醇等。
在一个实施方案中,本申请提供了一种利用具有式(I)的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
在一个实施方案中,本申请所设计的化合物及其药学可接受的盐可以用于治疗或控制淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等过渡增殖性疾病。
在一个实施方案中,本申请所设计的化合物及其药学可接受的盐可以与目前应用的或处于开发阶段的细胞毒素/细胞抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/ 苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、COX-2抑制剂、整联蛋白阻滞剂、P53激活剂、VEGF抗体、PD-1抗体、PD-L1抗体、PD-L2抗体、CTLA-4抗体和EGF抗体等药物联合用药增加其临床效果。
本申请所涉及的化合物及其药学可接受的盐可根据下面的方法用于治疗下列的疾病以及下面没有列出的其它疾病:
1)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的乳腺癌的方法。包括但不局限于侵袭性导管癌、侵袭性小叶癌、原位管癌和原位小叶癌。
2)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的呼吸道癌的方法。包括但不局限于小细胞&非小细胞肺癌、支气管腺癌和胸膜肺母细胞瘤。
3)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的脑癌的方法。包括但不局限于脑干和眼下神经胶质瘤、小脑和大脑星形细胞瘤、室管膜细胞瘤以及神经外胚层和松果体瘤。
4)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的雌、雄性生殖器官的肿瘤的方法。雄性生殖器官的肿瘤包括但不局限于前列腺和睾丸癌。雌性生殖器官的肿瘤包括但不局限于宫颈癌、子宫内膜癌、卵巢癌、阴道癌和外阴癌以及子宫内瘤。
5)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的消化道癌的方法。包括但不局限于肛门癌、结肠癌、结肠直道癌、食道癌、胃癌、胰腺癌、直肠癌、小肠癌和唾腺癌。
6)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的尿道癌的方法。包括但不局限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌和尿道癌。
7)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的眼癌的方法。包括但不局限于眼内黑素瘤和视网膜细胞瘤。
8)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肝癌的方法。包括但不局限于肝细胞瘤(具有或不具有纤维板变化的肝细胞癌)、胆管癌(肝内胆管癌)和混合的肝细胞性胆管癌。
9)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的皮肤癌的方法。包括但不局限于扁平细胞癌、卡波济氏肉瘤、恶性黑色素瘤、默克氏细胞皮肤癌和非黑素瘤细胞癌。
10)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的头颈癌的方法。包括但不局限于喉、下咽、鼻咽、口咽癌以及唇和口腔癌。
11)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的淋巴瘤的方法。包括但不局限于AIDS相关的淋巴瘤、非何杰金淋巴瘤、皮肤T细胞淋巴瘤、全身T细胞淋巴瘤、何杰金淋巴瘤和中枢神经系统淋巴瘤。
12)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肉瘤的方法。包括但不局限于软组织肉瘤、骨肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
13)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的白血病的方法。包括但不局限于急性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓性白血病以及多毛细胞白血病。
服用方式与剂量范围
根据标准药学技术,本发明化合物可单独偶或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物,优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
在一个实施方案中,利用式(I)化合物治疗或控制癌症等患者时,服用剂量范围为在口服0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日两次、三次、四次等 多次给药或利用缓释技术给药。对于大型哺乳动物,其优选剂量范围为0.1～1500毫克/天/公斤体重。对于平均体重为70公斤的病人,其剂量为1～500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
在一个实施方案中,利用式(I)化合物治疗或控制癌症等患者时,服用剂量范围为在静脉注射0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日两次、三次、四次等多次给药或利用缓释技术给药。对于大型哺乳动物,其优选剂量范围为0.1～1500毫克/天/公斤体重。对于平均体重为70公斤的病人,其剂量为1～500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
剂型
本发明含有活性成分的药用组合物可制成适于口服给药形式,例如片剂、含片、锭剂、水或油混悬液、可分散粉剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、或糖浆剂或酊剂。可根据药用组合物制造领域中任何已知方法制备预期口服给以予的组合物,并且为提供药学上精制的及适口的制剂,这种组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的药剂。片剂含有活性成分与无毒的适用于制造片剂的药学上可接受的辅料。这些辅料可为例如,惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；制粒剂(granulating)和崩解剂如微晶纤维素、交联羧甲纤维素钠、玉米淀粉或海藻酸；粘合剂例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；及润滑剂例如硬脂酸镁、硬脂酸或滑石粉。片剂可不包衣或通过已知技术包衣从而掩盖药物的不良味道或延长在胃肠道中崩解和吸收且因而提供持续更长时间的药物效应。例如,可采用水溶性掩盖味道的原料例如羟丙基-甲基纤维素或羟丙纤维素,或采用延时原料例如乙基纤维素、醋酸丁酸纤维素。片剂剂型可为0.1毫克/片、0.2毫克/片、0.25毫克/片、0.5毫克/片、1毫克/片、2毫克/片、5毫克/片、10毫克/片、25毫克/片、50毫克/片、100毫克/片、和250毫克/片。其它剂型如胶囊等可作相似剂量参考。
口服使用的制剂也可制成硬明胶胶囊剂,其中活性成分混合于惰性固体稀释剂,例如碳酸钙、碳酸钠或白陶土中；或制成软明胶胶囊剂,其中活性成分混合于水溶性载体例如聚乙烯二醇或油性介质如花生油、液体石蜡或橄榄油中。水混悬液含有与适于制造水混悬液的辅料混合的活性材料。这种辅料为助悬剂例如羧甲纤维素钠、甲基纤维素、羟丙基-甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、或阿拉伯胶；此水混悬液也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种 甜味剂例如蔗糖、糖精或阿司帕坦。可通过将活性成分混悬与植物油例如,花生油、麻油、椰子油、或橄榄油中,矿物油例如液体石蜡制备油性混悬液。这种油性混悬液可含有增稠剂例如蜂蜡、固体石蜡或鲸蜡醇。
可加入上文所述的甜味剂和调味剂以提供适合口服的制剂。可通过加入抗氧化剂例如丁羟茴醚或a生育酚储存这些组合物。
可分散粉剂或颗粒剂适于通过加入水制备水混悬液而提供与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适当的分散剂或湿润剂及助悬剂已通过上文涉及的例子说明。也可存在其他辅料例如甜味剂、调味剂和着色剂。这些组合物可通过加入抗氧化剂例如抗坏血酸而储存。
本发明组合物可制成水包油乳状液的形式。油相可为植物油例如花生油或橄榄油,或矿物油例如液体石蜡或其混合物。适当的乳化剂可为天然存在的磷脂例如大豆卵磷脂及酯类或得自脂肪酸和己糖醇酐混合的偏脂例如脱水山梨糖醇单油酸酯,及所述偏酯和烯化氧的缩合产物例如聚氧乙烯脱水山梨糖醇单油酸酯。此乳剂也可含甜味剂、调味剂、抗氧化剂和防腐剂。可使用甜味剂例如甘油、丙二醇、山梨醇、或蔗糖制备糖浆剂和酊剂。这种制剂也可含有湿润剂、调味剂、着色剂、抗氧化剂和防腐剂。
本发明组合物可制成无菌注射的水溶液。在可接受的载体和溶剂中可采用水、林格氏液和等渗氯化钠溶液。
这种无菌可注射剂也可制成活性成分溶于油相中的无菌可注射水包油微乳剂。例如,首先将活性成分溶于豆油和卵磷脂的混合物中,然后将油溶液放入水和甘油的混合物中并处理而制成微乳剂。
这种药用组合物可制成用于肌内或皮下给药的无菌可注射溶液或油状混悬液形式。可根据已知技术使用上文中提到的分散剂或湿润剂及助悬剂制备这种混悬液。无菌可注射制剂也可制成在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。另外,常规采用非挥发油作为溶剂或混悬介质。为此目的,可采用任何无刺激性的非挥发油包括合成的甘油一酯或甘油二酯。另外,发现在可注射制剂中使用脂肪酸例如油酸。
药物代谢物及前药
本申请所涉及的化合物及其药学上可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学上可接受的盐的结构的前药,也包括本申请的专利要求中。
联合用药式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式(I)化合物。当式I化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行联用时,式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I化合物进行药物联用的药物或活性成分包括但不局限为：细胞毒素/细胞抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、COX-2抑制剂、整联蛋白阻滞剂、P53激活剂、VEGF抗体、PD-1抗体、PD-L1抗体、PD-L2抗体、CTLA-4抗体、EGF抗体等。
在一个实施方案中,可以与式(I)化合物进行药物联用的药物包括但不局限为：阿地白介素、阿仑瞵酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射液、卡培他滨、卡铂、顺铂、康士德、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米送、磷酸地塞米送、戊酸雌二醇、地尼白介素2、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、壳聚糖复合物、拉步立酶、盐酸表柔比星、阿瑞吡坦、表 阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃胞塞啶-5’-硬脂磷酸酯、福莫司汀、氟维司群、丙钟球蛋白、吉西他滨、吉妥单抗、伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素α2、干扰素α-2A、干扰素α-2B、干扰素α-n1、干扰素α-n3、干扰素β、干扰素γ-1a、白细胞介素-2、内含子A、易瑞沙、依立替康凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-巯基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢化可的松口服溶液剂、奥沙利铂、紫杉醇、多西他塞、卡巴他塞、泼尼松磷酸钠、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸皮鲁卡品、毗柔比星、普卡霉素、卜吩姆钠、泼尼莫司汀、泼尼松、司替泼尼松龙、倍美力、丙卡巴齐、重组人类红细胞生成素、雷替曲塞、利比、依替瞵酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、沙莫司亭、司莫司汀、西佐喃、奥布佐生、唬钠甲强龙、帕福斯酸、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁瞵酸、拓扑替康、托瑞米芬、托西莫单抗、曲瑞妥珠单抗、曲奥舒凡、维甲酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、吉西他滨、阿霉素-MTC、伊班瞵酸、兰乐肽、拉索昔芬、米泼昔芬、米诺屈酸酯、脂质体MTP-PE、那法瑞林、诺拉曲特、紫杉醇聚谷氨酸酯、西奥骨化醇、埃罗替尼、紫杉醇脂质体、tipifarnib、SAHA、替拉扎明、伐普肽、vatalanib、维替泊芬、长春氟宁或它们的组合。
为了更好的说明本发明的技术内容，下面结合具体实例对本发明作进一步阐述,但该实施例并非用于限制本发明的保护范围。
应当说明的是，下述实施例中，常规后处理方法是：反应完成后，在反应液中加入适量的水，分离有机相和水相，合并有机相；如有需要，依次使用5％HCl溶液和/或饱和Na 2SO 4干燥，过滤之后减压选干，得到粗产物，再经过柱层析分离纯化之后得到最终产物。
实施例1
Figure PCTCN2018072046-appb-000007
步骤1.(Z)-4-氨基-N’-羟基-N-(3-溴-4-氟苯基)-1,2,5-噁二唑-3-甲脒
Figure PCTCN2018072046-appb-000008
在0℃，向原料(5g,34.96mmol)中依次滴入醋酸(5mL)，盐酸(4N)(5mL)，NaNO 2(2.42g，34.96mmol)的水(5mL)溶液，升温至室温反应18h，加入乙酸乙酯(25ml)，分层，水相用乙酸乙酯(2*25ml)萃取，合并有机相，用饱和食盐水(25mL)洗，无水硫酸钠干燥，浓缩得中间体(4.5g)。在氩气保护下，向中间体(4.5g)和3-溴-4-氟苯胺(11.8g，62.0mmol)的甲醇(20ml)溶液中加入NaHCO 3(7.8g，93.0mmol)的水(20ml) 溶液，50℃反应12小时，TLC检测反应完全，浓缩，加入乙酸乙酯(20mL)，分层，水相用乙酸乙酯(2*20mL)萃取，合并有机相，用饱和食盐水(20mL)洗，无水硫酸钠干燥，浓缩，柱层析得化合物目标物(7.32g，75％)。 1H NMR(400MHz,DMSO):δ8.08(dd,J＝3.6,2.4Hz,1H),7.71(m,1H),7.60(t,J＝8.8Hz,1H),6.59(s,2H)ppm.
步骤2. 3-(4-氨基-1,2,5-噁二唑-3-取代)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)羰基
Figure PCTCN2018072046-appb-000009
向原料(3.8g，12.1mmol)的乙酸乙酯(10ml)溶液中加入CDI(8.0g，36.3mmol),加热到70℃反应5小时，TLC检测反应完全，加入水(20ml)分层，水相用乙酸乙酯(2*20mL)萃取，合并有机相，用饱和食盐水(10mL)洗，无水硫酸钠干燥，浓缩，柱层析得化合物(3.3g，81％)。 1H NMR(400MHz,DMSO):δ11.42(s,1H),8.85(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝3.2and 2.8Hz 1H),6.76(m,1H),6.24(s,2H)ppm.
步骤3. 1-(4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-取代)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000010
在0℃，在氩气保护下，将对甲氧基苯异氰(14.4mg，0.0965mmol)的四氢呋喃溶液(1mL)慢慢滴加到原料(30mg，0.0877mmol)的四氢呋喃溶液(1mL)中，升温至室温反应16h，浓缩，加入水(1mL)，再加入乙酸乙酯(1mL)，分层，水相用乙酸乙酯(2*2mL)萃取，合并有机相，用饱和食盐水(2mL)洗，无水硫酸钠干燥，浓缩，柱层析得目标物(24.92mg，58％)。MS(EI,m/z):492(M ++1).
步骤4.(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000011
将上述原料(20mg)溶于乙酸乙酯(1mL)，加入NaOH水溶液(0.2mL,2M)反应5h，加入水(1mL)，乙酸乙酯(5mL)，分层，水相用乙酸乙酯(2*5mL)萃取，合并有机相，用饱和食盐水(2mL)洗，无水硫酸钠干燥，浓缩，柱层析得目标化合物1-1(16.7mg，88％)。 1H NMR(400MHz,DMSO):δ11.44(s,1H),8.85(s,1H),7.18(t,J＝8.8Hz,1H),7.10(m,1H),6.78(m,1H),6.25(s,1H),3.57(m,1H),1.85-1.81(m,2H),1.63-1.59(m,2H),1.46-1.19(m,4H)ppm. 13C NMR(125MHz,DMSO):δ162.1,158.1,154.1,150.2,148.3,139.5,133.6,130.6,120.1,119.6,119.1,118.9,114.9,113.6,54.6ppm.MS(EI,m/z):466(M ++1).
实施例2
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-乙基苯基)脲
Figure PCTCN2018072046-appb-000012
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.43(s,1H),8.85(s,1H),7.37-7.36(m,2H),7.18-7.16(m,2H),7.12-7.09(m,1H),6.79-6.59(m,2H),6.25(s,1H),6.11(s,1H),3.76(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.4,159.1,155.1,151.3,146.2, 139.9,136.2,133.9,129.8,121.1,119.9,119.1,116.1,115.7,113.1,110.1,54.2ppm.MS(EI,m/z):465(M ++1).
实施例3
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环己基脲
Figure PCTCN2018072046-appb-000013
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.44(s,1H),8.85(s,1H),7.18(t,J＝8.8Hz,1H),7.10(m,1H),6.79-6.75(m,1H),6.25(s,1H),3.58-3.52(m,1H),1.85-1.81(m,2H),1.63-1.59(m,2H),1.46-1.19(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.1,159.2,154.4,149.2,145.7,135.1,134.6,112.6,107.4,100.3,52.1,31.9,25.9,24.8ppm.MS(EI,m/z):442(M ++1).
实施例4
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环戊基脲
Figure PCTCN2018072046-appb-000014
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.13-7.01(m,1H),6.77-6.61(m,1H),6.14(s,1H),3.61-3.58(m,1H),1.85-1.62 (m,4H),1.56-1.48(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.8,158.2,153.9,148.1,145.9,135.2,134.3,112.3,107.5,101.1,58.1,32.4,24.6ppm.MS(EI,m/z):428(M ++1).
实施例5
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(四氢-2H-吡喃-4-取代)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000015
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.85(s,1H),7.19(t,J＝8.8Hz,1H),7.13(m,1H),6.85-6.75(m,1H),6.29(s,1H),3.66-3.58(m,4H),3.55(m,1H),1.68-1.56(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.3,159.5,154.5,149.3,145.7,135.3,134.8,112.7,107.5,100.6,63.9,52.8,32.6ppm.MS(EI,m/z):444(M ++1).
实施例6
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(哌啶-4-取代)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000016
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.11(m,1H),6.85(m,1H),6.28(s,1H),3.56(m,1H),2.79-2.69(m,4H),1.67-1.55 (m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.3,159.5,154.5,149.3,145.7,135.3,134.8,112.7,107.5,100.6,51.8,42.6,32.0ppm.MS(EI,m/z):443(M ++1).
实施例7
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1(甲磺酰基)哌啶-4-取代)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000017
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.85(s,1H),7.19(t,J＝8.8Hz,1H),7.13(m,1H),6.88(m,1H),6.29(s,1H),3.59(m,1H),2.86(s,3H),2.81-2.72(m,4H),1.71-1.63(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.3,159.5,154.5,149.3,145.7,135.3,134.8,112.7,107.5,100.6,52.9,38.6,33.7,28.5ppm.MS(EI,m/z):521(M ++1).
实施例8
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-羟基丙烷)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000018
1H NMR(400MHz,DMSO):δ11.51(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.10(m,1H),6.83(m,1H),6.27(s,1H),3.56(t,J＝6.8Hz,2H),3.15(t,J＝6.6Hz,,2H),1.79(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.2,154.3,149.2,145.5,135.1,134.8,112.6,107.3,100.5,59.9,39.3,31.6ppm.MS(EI,m/z):418(M ++1).
实施例9
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-胺基丙烷)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000019
1H NMR(400MHz,DMSO):δ11.50(s,1H),8.82(s,1H),7.15(t,J＝8.8Hz,1H),7.09(m,1H),6.82(m,1H),6.26(s,1H),3.13(t,J＝6.8Hz,,2H),2.56(t,J＝6.6Hz,2H),1.76(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.1,159.3,154.2,149.1,145.3,135.2,134.6,112.5,107.2,100.3,39.9,38.6,30.7ppm.MS(EI,m/z):417(M ++1).
实施例10
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1(氨基磺酰基)哌啶-4-取代)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000020
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.83(s,1H),7.18(t,J＝8.8Hz,1H),7.12(m,1H),6.87(m,1H),6.28(s,1H),3.58(m,1H),2.80-2.70(m,4H),1.85-1.66(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.3,154.2,149.1,145.6,135.2,134.6,112.6,107.3,100.5,46.1,38.9,28.3ppm.MS(EI,m/z):522(M ++1).
实施例11
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-胺基乙基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000021
1H NMR(400MHz,DMSO):δ11.48(s,1H),8.81(s,1H),7.12(t,J＝8.8Hz,1H),7.05(m,1H),6.80(m,1H),6.23(s,1H),3.36(t,J＝6.8Hz,,2H),2.86(t,J＝6.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.1,154.1,149.0,145.1,135.0,134.3,112.3,107.0,100.1,43.7,39.6,ppm.MS(EI,m/z):403(M ++1).
实施例12
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-甲磺酰氨基-丙基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000022
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.83(s,1H),7.16(t,J＝8.8Hz,1H),7.09(m,1H),6.83(m,1H),6.26(s,1H),3.18(t,J＝6.8Hz,,2H),2.88(s,3H),2.66(t,J＝6.6Hz,2H),1.83(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.5,154.2,149.2,145.3,135.1,134.6,112.6,107.3,100.4,42.1,39.7,38.8,27.9ppm.MS(EI,m/z):495(M ++1).
实施例13
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-氨基磺酰氨基-丙基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000023
1H NMR(400MHz,DMSO):δ11.51(s,1H),8.84(s,1H),7.16(t,J＝8.8Hz,1H),7.08(m,1H),6.82(m,1H),6.25(s,1H),3.16(t,J＝6.8Hz,,2H),2.65(t,J＝6.6Hz,2H),1.81(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.1,159.2,154.0-,149.2,145.3,135.0,134.3,112.2,107.3,100.3,39.5,37.2,27.3ppm.MS(EI,m/z):496(M ++1).
实施例14
(Z)-1-(4-(N-(4-溴-3-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-苯基脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000024
1H NMR(400MHz,DMSO):δ11.46(s,1H),8.80(s,1H),7.83(d,J＝8.4Hz,1H),7.18-7.12(m,2H),7.14-7.01(m,4H),6.73-6.52(m,3H),6.21(s,1H),6.07(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.6,160.0,154.0,151.4,148.1,140.3,135.1,134.8,121.7,120.6,119.0,118.6,115.7,114.6ppm.MS(EI,m/z):436(M ++1).
实施例15
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧-2-氟苯基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000025
1H NMR(400MHz,DMSO):δ11.47(s,1H),8.89(s,1H),7.57(s,1H),7.25-7.21(m,2H),7.21(d,J＝8.8Hz,1H),7.11(m,1H),6.77-6.52(m,1H),6.21(s,1H),6.10(s,1H),3.76(s,3H)ppm. 13C NMR(125MHz,DMSO):δ162.3,154.0,151.1,147.2,140.1,136.3,134.6,139.3,120.8,119.6,119.3,118.7,114.3,54.8ppm.MS(EI,m/z):484(M ++1).
实施例16
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧-2-三氟甲基苯基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000026
1H NMR(400MHz,DMSO):δ11.49(s,1H),8.89(s,1H),7.59(s,1H),7.28-7.23(m,2H),7.23(d,J＝8.8Hz,1H),7.15(m,1H),6.79-6.55(m,1H),6.23(s,1H),6.13(s,1H),3.78(s,3H)ppm. 13C NMR(125MHz,DMSO):δ162.5,154.3,151.2,147.3,140.2,136.5,134.8,139.5,120.9,119.7,119.4,118.7,114.5,54.9ppm.MS(EI,m/z):534(M ++1).
实施例17
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000027
1H NMR(400MHz,DMSO):δ11.42(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.08(m,1H),6.76(m,1H),6.23(s,1H),3.56(m,1H),1.84-1.80(m,2H),1.61-1.58(m,2H),1.45-1.16(m,4H)ppm. 13C NMR(125MHz,DMSO):δ162.0,158.1,153.9,150.1,148.3,139.3,133.5,130.6,120.1,119.3,119.0,118.7,114.7,113.6,54.5ppm.MS(EI,m/z):421(M ++1).
实施例18
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-羟基苯基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000028
1H NMR(400MHz,DMSO):δ11.41(s,1H),8.80(s,1H),7.15(t,J＝8.8Hz,1H),7.06(m,1H),6.75(m,1H),6.23(s,1H),3.53(m,1H)ppm. 13C NMR(125MHz,DMSO):δ162.0,158.0,153.7,150.1,148.2,139.1,133.3,130.6,120.1,119.3,119.0,118.5,114.3,113.2ppm.MS(EI,m/z):407(M ++1).
实施例19
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基苯基)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000029
1H NMR(400MHz,DMSO):δ11.38(s,1H),8.79(s,1H),7.13(t,J＝8.8Hz,1H),7.03(m,1H),6.72(m,1H),6.21(s,1H),ppm. 13C NMR(125MHz,DMSO):δ161.8,157.8,153.7,150.0,148.1,139.0,133.2,130.3,120.0,119.2,119.0,118.3,114.2,113.1ppm.MS(EI,m/z):406(M ++1).
实施例20
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环己基脲
Figure PCTCN2018072046-appb-000030
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.42(s,1H),8.84(s,1H),7.17(t,J＝8.8Hz,1H),7.10(m,1H),6.78-6.75(m,1H),6.23(s,1H),3.57-3.51(m,1H),1.84-1.80(m,2H),1.62-1.57(m,2H),1.45-1.17(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.1,154.2,149.1,145.5,135.0,134.3,112.5,107.3,100.2,52.0,31.8,25.8,24.7ppm.MS(EI,m/z):397(M ++1).
实施例21
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基环己基)脲
Figure PCTCN2018072046-appb-000031
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.47(s,1H),8.82(s,1H),7.11(t,J＝8.8Hz,1H),7.14-7.07(m,1H),6.81-6.70(m,1H),6.22(s,1H),3.55-3.50(m,1H),2.86(m,1H),1.83-1.81(m,2H),1.64-1.55(m,2H),1.47-1.21(m,5H)ppm. 13C NMR(125MHz,DMSO):δ164.1,159.0,153.5,149.1,145.2,135.0,133.8,112.5,107.0,100.5,53.1,33.8,33.8,32.2,31.3ppm.MS(EI,m/z):412(M ++1).
实施例22
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基环己基)脲
Figure PCTCN2018072046-appb-000032
1H NMR(400MHz,DMSO):δ11.49(s,1H),8.85(s,1H),7.13(t,J＝8.8Hz,1H),7.13-7.06(m,1H),6.83-6.72(m,1H),6.25(s,1H),3.57-3.53(m,1H),3.39(m,1H),1.85-1.82(m,2H),1.66-1.56(m,2H),1.48-1.23(m,5H)ppm. 13C NMR(125MHz,DMSO):δ164.3,159.2,153.7,149.3,145.3,135.3,133.9,112.8,107.3,100.7,53.5,51.9,33.9,32.6,31.5ppm.MS(EI,m/z):413(M ++1).
实施例23
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(23-羟基乙烷)脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000033
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.85(s,1H),7.19(t,J＝8.8Hz,1H),7.13(m,1H),6.85(m,1H),6.28(s,1H),3.58(t,J＝6.8Hz,2H),3.19(t,J＝6.8Hz,,2H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.3,154.6,149.5,145.7,135.3,134.9,112.8,107.5,100.6,59.9,39.8ppm.MS(EI,m/z):359(M ++1).
实施例24
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-甲磺酰氨基-乙基)脲
Figure PCTCN2018072046-appb-000034
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.85(s,1H),7.18(t,J＝8.8Hz,1H),7.09(m,1H),6.84(m,1H),6.27(s,1H),3.41(t,J＝6.8Hz,,2H),2.93(t,J＝6.8Hz,2H),2.83(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.2,154.1,149.2,145.1,135.0,134.3,112.5,107.2,100.3,42.3,41.7,40.2ppm.MS(EI,m/z):436(M ++1).
实施例25
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-甲磺酰氨基-乙基)脲
Figure PCTCN2018072046-appb-000035
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.54(s,1H),8.86(s,1H),7.19(t,J＝8.8Hz,1H),7.09(m,1H),6.83(m,1H),6.28(s,1H),3.43(t,J＝6.8Hz,,2H),2.95(t,J＝6.8Hz,2H),2.03(s,2H)ppm. 13C NMR(125MHz,DMSO):δ163.1,159.3,154.3,149.4,145.1,135.1,134.3,112.6,107.3,100.4,40.7,39.6ppm.MS(EI,m/z):437(M ++1).
实施例26
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环丁基脲
Figure PCTCN2018072046-appb-000036
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.14-7.02(m,1H),6.77-6.62(m,1H),6.15(s,1H),4.09(m,1H),2.33-2.08(m,4H),2.02-1.93(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,112.3,107.6,101.2,48.3,31.2,16.6ppm.MS(EI,m/z):414(M ++1).
实施例27
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环丙基脲
Figure PCTCN2018072046-appb-000037
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.51(s,1H),8.80(s,1H),7.15(t,J＝8.8Hz,1H),7.13-7.01(m,1H),6.75-6.60(m,1H),6.13(s,1H),3.33(m,1H),1.25-1.03(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.3,158.0,153.6,148.0,145.5,135.1,134.2,112.3,107.2,101.0,38.3,11.2ppm.MS(EI,m/z):400(M ++1).
实施例28
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环庚基脲
Figure PCTCN2018072046-appb-000038
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.42(s,1H),8.84(s,1H),7.16(t,J＝8.8Hz,1H),7.10(m,1H),6.77-6.73(m,1H),6.24(s,1H),3.57(m,1H),1.68-1.41(m,4H),1.38-1.28(m,4H),1.30-1.25(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.2,154.4,149.2,145.7,135.1,134.6,112.6,107.4,100.3,49.9,31.7,29.1,23.8ppm.MS(EI,m/z):456(M ++1).
实施例29
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1H-吲哚4-取代)脲
Figure PCTCN2018072046-appb-000039
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.43(s,1H),10.2(s,1H),8.82(s,1H),7.39(d,J＝8.6Hz,1H),7.28(d,J＝8.8Hz,1H),7.17(t,J＝8.8Hz,1H),7.14(d,J＝8.6Hz,1H),7.09(m,1H),7.05(m,1H),6.78(m,1H),6.55d,J＝8.6Hz,1H),6.24(s,1H)ppm. 13C NMR(125MHz,DMSO):δ162.1,158.2,153.8,150.2,148.5,139.4, 135.8,133.5,130.7,130.3,124.3,120.3,120.1,119.3,119.0,118.7,114.7,113.6,112.4,106.7,102.3ppm.MS(EI,m/z):475(M ++1).
实施例30
(Z)-1-(4-(N-(4-溴-3-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(吡啶-4-取代)脲
Figure PCTCN2018072046-appb-000040
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.54(s,1H),8.85(s,1H),8.45(d,J＝7.6Hz,2H),7.17(t,J＝8.8Hz,1H),7.15-7.03(m,1H),6.78-6.62(m,1H),6.60(d,J＝7.6Hz,2H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,155.3,153.9,150.3,148.2,145.9,135.3,134.4,112.3,109.1,107.6,101.2,ppm.MS(EI,m/z):437(M ++1).
实施例31
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1H-吲哚7-取代)脲
Figure PCTCN2018072046-appb-000041
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.46(d,J＝7.8Hz,1H),7.29(d,J＝7.6Hz,1H),7.25(d,J＝7.8Hz,1H),7.17(t,J＝8.8Hz,1H),7.14-7.02(m,1H),6.98(m,1H),6.77-6.62(m,1H),6.46(d,J＝7.8Hz,1H),6.15(s,1H), ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,140.5,135.3,134.4,128.3,124.3,122.4,120.7,114.6,112.7,112.3,107.6,102.3,101.2ppm.MS(EI,m/z):475(M ++1).
实施例32
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1H-吲哚3-取代)脲
Figure PCTCN2018072046-appb-000042
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),10.2(s,1H),8.83(s,1H),7.61(d,J＝7.8Hz,1H),7.40(d,J＝7.2Hz,1H),7.32(s,1H),7.17(t,J＝8.8Hz,1H),7.14-7.03(m,2H),7.01(m,1H),6.77(m,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.6,135.3,134.4,124.0,122.2,120.5,120.1,119.0,112.3,111.1,107.6,102.3,101.2ppm.MS(EI,m/z):475(M ++1).
实施例33
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(苯并呋喃-3-取代)脲
Figure PCTCN2018072046-appb-000043
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.54(s,1H),8.83(s,1H),7.55(d,J＝7.6Hz,1H),7.50(s,1H),7.42(d,J＝7.6Hz,1H),7.25(m,1H),7.17(t,J＝8.8Hz,1H),7.14-7.02 (m,2H),6.75(m,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,156.4,153.9,148.2,145.9,145.0,135.3,134.4,124.7,123.9,123.3,121.2,112.3,111.6,107.6,107.0,101.2ppm.MS(EI,m/z):476(M ++1).
实施例34
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(苯并噻吩-3-取代)脲
Figure PCTCN2018072046-appb-000044
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.86(d,J＝7.2Hz,1H),7.78(d,J＝7.2Hz,1H),7.33-7.30(m,2H),7.17(t,J＝8.8Hz,1H),7.13(m,1H),6.77(m,1H),6.30(s,1H),6.15(s,1H),ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,139.5,136.0,135.3,134.4,127.2,124.4,124.3,123.3,122.8,112.3,109.7,107.6,101.2ppm.MS(EI,m/z):492(M ++1).
实施例35
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(1H-吡咯-3-取代)脲
Figure PCTCN2018072046-appb-000045
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.12(m,1H),6.74(m,1H),6.63(s,1H),6.59(d,J＝6.8Hz,1H),6.15(s,1H),6.10 (d,J＝6.8Hz,1H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,131.9,112.3,117.5,109.3,108.0,107.6,101.2,ppm.MS(EI,m/z):425(M ++1).
实施例36
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(呋喃-3-取代)脲
Figure PCTCN2018072046-appb-000046
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.45(s 1H),7.40(d,J＝7.0Hz,1H),7.17(t,J＝8.8Hz,1H),7.13(m,1H),6.76(m,1H),6.33(d,J＝7.0Hz,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,144.2,141.6,135.3,134.4,130.4,124.7,112.3,107.6,101.2ppm.MS(EI,m/z):426(M ++1).
实施例37
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(四氢呋喃-3-取代)脲
Figure PCTCN2018072046-appb-000047
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.15(m,1H),6.77(m,1H),6.15(s,1H),4.10-3.93(m,2H),3.90(m,1H),3.80-3.70 (m,2H),2.19-1.95(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,112.3,107.6,101.2,77.6,67.9,51.8,51.5ppm.MS(EI,m/z):430(M ++1).
实施例38
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)哌嗪-1-氨甲酰
Figure PCTCN2018072046-appb-000048
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.13(m,1H),6.75(m,1H),6.15(s,1H),3.28(t,J＝7.8Hz,2H),2.81(t,J＝7.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,112.3,107.6,101.2,51.8,45.3ppm.MS(EI,m/z):429(M ++1).
实施例39
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)吗啉-1-氨甲酰
Figure PCTCN2018072046-appb-000049
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.12(m,1H),6.75(m,1H),6.15(s,1H),3.68(t,J＝7.8Hz,2H),3.48(t,J＝7.8 Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,112.3,107.6,101.2,65.9,47.7ppm.MS(EI,m/z):430(M ++1).
实施例40
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-4-(甲磺酰基)-哌嗪-1-氨甲酰
Figure PCTCN2018072046-appb-000050
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.13(m,1H),6.76(m,1H),6.15(s,1H),3.28(t,J＝7.8Hz,2H),2.88(s,3H),2.85(t,J＝7.8Hz,2H),ppm. 13C NMR(125MHz,DMSO):δ163.9,158.3,153.9,148.2,145.9,135.3,134.4,112.3,107.6,101.2,48.6,45.7,39.8ppm.MS(EI,m/z):507(M ++1).
实施例41
(Z)-1-(4-(N-(4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-苯基脲
Figure PCTCN2018072046-appb-000051
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.46(s,1H),8.80(s,1H),7.83(d,J＝8.4Hz,1H),7.18-7.12(m,2H),7.14-7.01(m,4H),6.73-6.52(m,4H),6.21(s,1H),6.07(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.7,160.1,154.0,151.3,148.2,140.3,135.2,134.8,121.8,120.6,119.1,118.6,115.7,114.7ppm.MS(EI,m/z):357(M ++1).
实施例42
(Z)-1-(4-(N-(4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环己基脲
Figure PCTCN2018072046-appb-000052
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.44(s,1H),8.85(s,1H),6.79(d,J＝8.2Hz,2H),6.53(d,J＝8.2Hz,2H),6.15(s,1H),3.55(m,1H),1.83-1.79(m,2H),1.60-1.54(m,2H),1.46-1.19(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.1,154.3,149.2,145.7,135.2,134.5,117.6,107.3,100.3,52.1,31.9,25.9,24.8ppm.MS(EI,m/z):363(M ++1).
实施例43
(Z)-1-(4-(N-(4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-4-(甲磺酰基)-哌嗪-1-氨甲酰
Figure PCTCN2018072046-appb-000053
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.83(s,1H),6.75(d,J＝8.0Hz,2H),6.50(d,J＝8.0Hz,2H),6.14(s,1H),3.28(t,J＝7.8Hz,2H),2.87(s,3H),2.83(t,J＝7.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.6,158.1,153.8,148.2,145.9,135.2,134.3,116.3,107.6,101.2,48.2,45.5,39.7ppm.MS(EI,m/z):428(M ++1).
实施例44
(Z)-1-(4-(N-(4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000054
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.42(s,1H),8.83(s,1H),7.53(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),6.74(d,J＝8.0Hz,2H),6.51(d,J＝8.0Hz,2H),6.20(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ162.1,158.1,154.1,150.2,148.3,139.5,133.6,130.6,120.1,119.6,119.1,115.6 54.6ppm.MS(EI,m/z):387(M ++1).
实施例45
(Z)-1-(4-(N-(4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基环己基)脲
Figure PCTCN2018072046-appb-000055
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.48(s,1H),8.83(s,1H),6.76(d,J＝8.0Hz,2H),6.52(d,J＝8.0Hz,2H),6.25(s,1H),3.55(m,1H),3.29(m,1H),1.80-1.75(m,2H),1.66-1.56(m,2H)ppm. 13C NMR(125MHz,DMSO):δ164.3,159.2,153.7,149.3,145.3,135.3,133.9,112.9,107.3,72.8,49.8,31.0,27.1ppm.MS(EI,m/z):379(M ++1).
实施例46
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-4-(氨基磺酰基)-哌嗪-1-氨甲酰
Figure PCTCN2018072046-appb-000056
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),8.83(s,1H),6.70(d,J＝7.8Hz,2H),6.45(d,J＝7.8Hz,2H),6.15(s,1H),3.29(t,J＝7.6Hz,2H),2.83(t,J＝7.6Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.8,158.3,153.9,148.2,145.9,135.3,110.3,107.6,47.9,42.9ppm.MS(EI,m/z):429(M ++1).
实施例47
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000057
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.33(s,1H),8.80(s,1H),7.53(d,J＝8.6Hz,2H),7.44(s,1H),7.41(s,1H),6.86(d,J＝8.6Hz,2H),6.73(s,1H),6.63(d,J＝8.0Hz,1H),6.43(d,J＝8.0Hz,1H),6.15(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.7,152.0,150.1,146.1,142.8,141.7,141.3,139.0,134.3,131.7,120.6,120.1,118.7,118.5,115.6,55.9ppm.MS(EI,m/z):464(M ++1).
实施例48
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-环己基脲
Figure PCTCN2018072046-appb-000058
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.76(s,1H),7.41(s,1H),7.39(s,1H),6.76(s,1H),6.66(d,J＝6.8Hz,1H),6.46(d,J＝6.8Hz,1H),6.12(s,1H),1.83-1.78(m,2H),1.63-1.56(m,2H),1.43-1.19(m,6H)ppm. 13C NMR(125MHz,DMSO):δ161.7,152.1,150.0,146.1,142.7,141.5,141.1,138.9,134.0,131.4,120.3,120.0,118.6,118.1,115.2,49.5,33.6,28.1,22.5ppm.MS(EI,m/z):440(M ++1).
实施例49
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-环戊基脲
Figure PCTCN2018072046-appb-000059
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.40(s,1H),7.38(s,1H),6.75(s,1H),6.64(d,J＝6.8Hz,1H),6.43(d,J＝6.8Hz,1H),6.12(s,1H),3.61(m,1H),1.86-1.68(m,4H),1.59-1.49(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.2,142.8,141.6,141.1,138.9,134.1,131.5,120.3,120.1,118.7,118.2,115.2,56.2,34.6,24.9ppm.MS(EI,m/z):426(M ++1).
实施例50
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(4-羟基环己基)脲
Figure PCTCN2018072046-appb-000060
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.32(s,1H),8.78(s,1H),7.43(s,1H),7.40(s,1H),6.76(s,1H),6.65(d,J＝6.8Hz,1H),6.44(d,J＝6.8Hz,1H),6.15(s,1H),3.60(m,1H),3.19(m,1H),1.80-1.70(m,4H),1.55-1.49(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.8,152.4,150.3,146.3,142.8,141.7,141.1,138.9,134.2,131.6,120.4,120.1,118.9,118.3,115.3,72.7,49.8,31.6,27.0ppm.MS(EI,m/z):456(M ++1).
实施例51
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(哌啶-4-取代)脲
Figure PCTCN2018072046-appb-000061
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.31(s,1H),8.77(s,1H),7.42(s,1H),7.40(s,1H),6.75(s,1H),6.63(d,J＝6.6Hz,1H),6.43(d,J＝6.6Hz,1H),6.14(s,1H),3.59(m,1H),2.79-2.69(m,4H),1.85-1.63(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.7,152.2,150.2,146.3,142.7,141.6,141.1,138.8,134.2,131.5,120.3,120.0,118.8,118.3,115.2,46.0,42.8,32.0ppm.MS(EI,m/z):441(M ++1).
实施例52
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-环戊基脲
Figure PCTCN2018072046-appb-000062
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.20(s,1H),8.72(s,1H),7.39(s,1H),7.36(s,1H),6.73(s,1H),6.62(d,J＝6.6Hz,1H),6.41(d,J＝6.6Hz,1H),6.11(s,1H),2.32(m,1H),0.59-0.39(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.0,150.0,145.9,142.5,141.3,140.8,138.7,134.0,131.2,120.3,119.8,118.5,118.0,115.0,26.5,7.9ppm.MS(EI,m/z):398(M ++1).
实施例53
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(4-氨基环己基)脲
Figure PCTCN2018072046-appb-000063
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.30(s,1H),8.76(s,1H),7.42(s,1H),7.40(s,1H),6.73(s,1H),6.63(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.14(s,1H),3.55(m,1H),2.57(m,1H),1.80-1.70(m,4H),1.65-1.53(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,134.1,131.5, 120.3,120.0,118.8,118.1,115.1,50.3,49.6,31.0,28.3ppm.MS(EI,m/z):455(M ++1).
实施例54
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(3-氨基丙基)脲
Figure PCTCN2018072046-appb-000064
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.30(s,1H),8.76(s,1H),7.42(s,1H),7.40(s,1H),6.73(s,1H),6.63(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.14(s,1H),3.18(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),1.81(m,2H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,134.1,131.5,120.3,120.0,118.8,118.1,115.1,50.3,49.6,31.0,28.3ppm.MS(EI,m/z):415(M ++1).
实施例55
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(2-羟基乙基)脲
Figure PCTCN2018072046-appb-000065
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.32(s,1H),8.76(s,1H),7.43(s,1H),7.41(s,1H),6.75(s,1H),6.64(d,J＝6.8Hz,1H),6.43(d,J＝6.8Hz,1H),6.16(s,1H),3.79(t,J＝6.8Hz,2H),3.35(t,J＝6.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ161.7,152.3,150.2,146.2,142.6,141.7,141.2,138.7,134.2,131.6,120.4,120.1,118.9,118.2,115.2,60.6,43.7ppm.MS(EI,m/z):402(M ++1).
实施例56
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(2-氨基乙基)脲
Figure PCTCN2018072046-appb-000066
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.75(s,1H),7.42(s,1H),7.40(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.15(s,1H),3.42(t,J＝6.6Hz,2H),2.91(t,J＝6.6Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,134.1,131.5,120.3,120.0,118.8,118.1,115.1,45.0,40.1ppm.MS(EI,m/z):401(M ++1).
实施例57
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-丙脲
Figure PCTCN2018072046-appb-000067
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.75(s,1H),7.41(s,1H),7.39(s,1H),6.72(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.13(s,1H),3.15(t,J＝6.6Hz,2H),1.59(m,2H),0.97(t,J＝6.6Hz,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.0,150.0,145.8,142.2,141.3,140.8,138.5,134.0,131.2,120.0,119.7,118.5,117.8,115.0,44.7,22.7,10.8ppm.MS(EI,m/z):400(M ++1).
实施例58
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-异丙脲
Figure PCTCN2018072046-appb-000068
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.75(s,1H),7.41(s,1H),7.39(s,1H),6.72(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.13(s,1H),3.94(m,2H),1.25(d,J＝6.8Hz,6H)ppm. 13C NMR(125MHz,DMSO):δ161.4,152.1,150.0,145.9,142.3,141.3,140.9,138.6,134.1,131.3,120.1,119.8,118.6,117.9,115.1,43.2,22.8ppm.MS(EI,m/z):400(M ++1).
实施例59
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(2-甲磺酰氨基乙基)脲
Figure PCTCN2018072046-appb-000069
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.76(s,1H),7.43(s,1H),7.41(s,1H),6.74(s,1H),6.63(d,J＝6.8Hz,1H),6.43(d,J＝6.8Hz,1H),6.16(s,1H),3.45(t,J＝6.8Hz,2H),2.94(t,J＝6.8Hz,2H),2.83(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,134.1,131.5,120.3,120.0,118.8,118.1,115.1,42.9,41.7,40.3ppm.MS(EI,m/z):479(M ++1).
实施例60
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(4-氨基吲哚)脲
Figure PCTCN2018072046-appb-000070
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.75(s,1H),7.42(s,1H),7.40(s,1H),7.38(d,J＝7.6Hz,1H),7.27(d,J＝7.0Hz,1H),7.14(d,J＝7.6Hz,1H),7.06(m,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.49(d,J＝7.0Hz,1H),6.42(d,J＝6.8Hz,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,135.7,134.1,131.5,130.2,124.3,120.5,120.3,120.0,118.8,118.1,115.1,114.7,112.3,106.7,102.5ppm.MS(EI,m/z):473(M ++1).
实施例61
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(3-氨基吲哚)脲
Figure PCTCN2018072046-appb-000071
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),10.11(s,1H),8.75(s,1H),7.60(d,J＝6.6Hz,1H),7.45(d,J＝6.6Hz,1H),7.42(s,1H),7.40(s,1H),7.37(s,1H),7.12-7.07(m,2H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.7,135.6,134.1,131.5,124.1,12.2,120.6,120.3,120.0,119.0,118.8,118.1,115.1,111.1ppm.MS(EI,m/z):473(M ++1).
实施例62
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(3-氨基吡啶)脲
Figure PCTCN2018072046-appb-000072
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.75(s,1H),8.53(s,1H),8.23(d,J＝6.6Hz,1H),7.42(s,1H),7.40(s,1H),7.37(m,1H),7.26(d,J＝6.6Hz,1H),6.72(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.14(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.6,152.2,150.1,146.1,142.5,141.6,141.1,138.9,138.7,137.6,134.4,134.1,131.5,124.7,122.8,120.3,120.0,118.7,118.1,115.0ppm.MS(EI,m/z):435(M ++1).
实施例63
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000073
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.53(d,J＝7.2Hz,2H),7.48(s,1H),6.78(d,J＝7.2Hz,2H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,156.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,128.2,122.6,120.3,120.0,118.6,118.0,115.1,114.5,57.8ppm.MS(EI,m/z):465(M ++1).
实施例64
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-苯基脲
Figure PCTCN2018072046-appb-000074
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),7.43-7.22(m,5H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,135.9,134.1,131.2,129.0,124.5,121.6,120.3,120.0,118.6,118.0,115.1ppm.MS(EI,m/z):435(M ++1).
实施例65
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(环己基)脲
Figure PCTCN2018072046-appb-000075
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.54(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,49.6,33.3,28.0,22.5ppm.MS(EI,m/z):441(M ++1).
实施例66
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-羟基环己基)脲
Figure PCTCN2018072046-appb-000076
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.76(s,1H),7.49(s,1H),6.74(s,1H),6.63(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.13(s,1H),3.59(m,1H),3.22(m,1H),1.77-1.49(m,8H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1, 150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,72.9,49.8,31.0,27.1ppm.MS(EI,m/z):457(M ++1).
实施例67
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(哌啶-4-取代)脲
Figure PCTCN2018072046-appb-000077
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.61(m,1H),2.79-2.69(m,4H),1.85-1.60(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,46.0,42.9,32.0ppm.MS(EI,m/z):442(M ++1).
实施例68
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-氨基环己基)脲
Figure PCTCN2018072046-appb-000078
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.58(m,1H), 2.59(m,1H),1.80-1.53(m,8H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.0,50.3,49.6,31.0,28.3ppm.MS(EI,m/z):456(M ++1).
实施例69
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(3-丙基)脲
Figure PCTCN2018072046-appb-000079
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.16(d,J＝6.8Hz,2H),2.66(d,J＝6.6Hz,1H),1.82(m,2H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,39.6,38.8,31.0ppm.MS(EI,m/z):416(M ++1).
实施例70
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(2-羟基乙基)脲
Figure PCTCN2018072046-appb-000080
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.79(d,J＝6.8Hz,2H),3.63(d,J＝6.8Hz,1H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,60.6,43.8ppm.MS(EI,m/z):403(M ++1).
实施例71
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(2-氨基乙基)脲
Figure PCTCN2018072046-appb-000081
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.42(d,J＝6.6Hz,2H),2.91(d,J＝6.6Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,45.1,40.2ppm.MS(EI,m/z):402(M ++1).
实施例72
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(丙基)脲
Figure PCTCN2018072046-appb-000082
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.16(d,J＝6.6Hz,2H),1.59(m,2H),0.96(d,J＝6.7Hz,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,44.7,22.7,10.8ppm.MS(EI,m/z):401(M ++1).
实施例73
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(异丙基)脲
Figure PCTCN2018072046-appb-000083
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.95(m,1H),1.25(d,J＝6.8Hz,6H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,43.2,22.8ppm.MS(EI,m/z):401(M ++1).
实施例74
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(2-甲磺酰氨基乙基)脲
Figure PCTCN2018072046-appb-000084
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.43(d,J＝6.6Hz,2H),2.91(d,J＝6.6Hz,6H),2.81(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,41.9,41.3,40.2ppm.MS(EI,m/z):480(M ++1).
实施例75
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-氨基吲哚)脲
Figure PCTCN2018072046-appb-000085
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),7.37(d,J＝7.2Hz,1H),7.26(d,J＝7.0Hz,1H),7.15(d,J＝7.2Hz,1H),7.06(m,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.45(d,J＝7.0Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,135.7,134.1,131.2,130.2,124.3,120.3,120.0,118.6,118.0,115.1,114.7,112.3,106.7,102.3ppm.MS(EI,m/z):474(M ++1).
实施例76
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(3-氨基吲哚)脲
Figure PCTCN2018072046-appb-000086
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),10.10(s,1H),8.75(s,1H),7.62(d,J＝7.6Hz,1H),7.48(s,1H),7.43(d,J＝7.2Hz,1H),7.33(d,J＝7.0Hz,1H),7.13(m 1H),7.05(m 1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.12(s,1H),ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,135.5,134.1,131.2,124.1,122.2,120.5,120.2,120.0,119.1,118.6,118.0,115.1,111.1,102.3ppm.MS(EI,m/z):474(M ++1).
实施例77
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(3-氨基吡啶)脲
Figure PCTCN2018072046-appb-000087
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),8.53(s,1H),8.23(d,J＝6.6Hz,1H),7.48(s,1H),7.40(m,1H),7.26(d,J＝6.6Hz,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H)ppm. 13C NMR(125 MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.9,138.5,137.6,134.5,134.1,131.2,124.7,122.8,120.3,120.0,118.6,118.0,115.1,ppm.MS(EI,m/z):436(M ++1).
实施例78
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-甲氧基苯基)脲
Figure PCTCN2018072046-appb-000088
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.53(d,J＝6.8Hz,1H),7.48(s,1H),6.79(d,J＝6.8Hz,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),ppm. 13C NMR(125MHz,DMSO):δ161.3,156.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,128.2,122.6,120.3,120.0,118.6,118.0,115.1,114.5,55.9ppm.MS(EI,m/z):420(M ++1).
实施例79
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(苯基)脲
Figure PCTCN2018072046-appb-000089
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.64-7.24(m,5H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5, 135.9,134.1,131.2,129.0,124.4,121.6,120.3,120.0,118.6,118.0,115.1ppm.MS(EI,m/z):390(M ++1).
实施例80
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(环己基)脲
Figure PCTCN2018072046-appb-000090
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.57(m,1H),1.79-1.57(m,4H),1.49-1.39(m,6H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,49.5,33.3,28.0,22.5ppm.MS(EI,m/z):396(M ++1).
实施例81
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000091
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.51(d,J＝7.2Hz,2H),7.48(s,1H),6.77(d,J＝7.2Hz,2H),6.73(s,1H),6.61(d,J＝6.8Hz,1H),6.40 (d,J＝6.8Hz,1H),6.13(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,156.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,128.2,122.6,120.3,120.0,118.6,118.0,115.1,114.5,57.8ppm.MS(EI,m/z):465(M ++1).
实施例82
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(3-甲氧苯基)脲
Figure PCTCN2018072046-appb-000092
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.48(s,1H),7.19(d,J＝6.6Hz,1H),7.16(s,1H),7.13(m,1H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.51(d,J＝6.6Hz,1H),6.40(d,J＝6.8Hz,1H),6.13(s,1H),3.71(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.3,160.9,152.8,152.1,150.1,146.0,141.1,138.5,136.9,134.1,131.2,130.1,120.3,120.0,118.5,118.0,115.1,113.8,109.7,104.7,55.7ppm.MS(EI,m/z):465(M ++1).
实施例83
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-苯基脲
Figure PCTCN2018072046-appb-000093
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.48(s,1H),7.43-7.21(m,5H),6.71(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.10(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.1,152.6,152.1,150.1,146.0,141.1,138.3,135.6,134.1,131.2,129.0,124.3,121.4,120.3,120.0,118.3,118.0,115.1ppm.MS(EI,m/z):435(M ++1).
实施例84
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(环己基)脲
Figure PCTCN2018072046-appb-000094
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.47(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.54(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.1,138.5,134.1,131.2,120.3,120.0,118.6,118.0,115.1,49.8,33.6,28.1,22.6ppm.MS(EI,m/z):441(M ++1).
实施例85
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-羟基环己基))脲
Figure PCTCN2018072046-appb-000095
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.30(s,1H),8.77(s,1H),7.49(s,1H),6.75(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.58(m,1H),3.23(m,1H),1.76-1.49(m,8H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.2,150.1,146.1,141.2,138.5,134.2,131.3,120.3,120.0,118.6,118.0,115.2,72.8,49.9,31.1,27.2ppm.MS(EI,m/z):457(M ++1).
实施例86
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(哌啶-4-取代))脲
Figure PCTCN2018072046-appb-000096
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.47(s,1H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.13(s,1H),3.62(m,1H),2.78-2.68(m,4H),1.86-1.61(m,4H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.2,138.6,134.0,131.1,120.3,120.1,118.5,118.1,115.1,46.1,42.8,32.1ppm.MS(EI,m/z):442(M ++1).
实施例87
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-氨基环己基))脲
Figure PCTCN2018072046-appb-000097
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.47(s,1H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.13(s,1H),3.56(t,J＝6.6Hz,1H),2.56(t,J＝6.8Hz,1H),1.80-1.53(m,8H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.1,150.1,146.0,141.2,138.6,134.0,131.1,120.3,120.1,118.5,118.1,115.1,50.3,49.6,31.0,28.2ppm.MS(EI,m/z):456(M ++1).
实施例88
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(3-羟基丙基))脲
Figure PCTCN2018072046-appb-000098
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.76(s,1H),7.48(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.14(s,1H),3.53(t,J＝6.6Hz,2H),3.16(t,J＝6.5Hz,2H),1.73(m,2H)ppm. 13C NMR(125MHz,DMSO):δ161.3,152.8,152.2,150.3,146.1,141.2,138.7,134.1,131.2,120.3,120.2,118.6,118.1,115.1,59.6,38.7,31.7ppm.MS(EI,m/z):417(M ++1).
实施例89
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(2-羟基乙基))脲
Figure PCTCN2018072046-appb-000099
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.76(s,1H),7.48(s,1H),6.73(s,1H),6.63(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.15(s,1H),3.79(t,J＝6.8Hz,2H),3.36(t,J＝6.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ161.4,152.9,152.2,150.4,146.1,141.3,138.7,134.2,131.2,120.4,120.2,118.7,118.1,115.2,60.6,43.7ppm.MS(EI,m/z):403(M ++1).
实施例90
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(2-氨基乙基))脲
Figure PCTCN2018072046-appb-000100
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.76(s,1H),7.47(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.14(s,1H),3.43(t,J＝6.6Hz,2H),2.92(t,J＝6.6Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ161.4,152.9, 152.2,150.3,146.1,141.2,138.7,134.2,131.1,120.3,120.2,118.6,118.1,115.1,45.6,40.2ppm.MS(EI,m/z):402(M ++1).
实施例91
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-甲氧苯基)脲
Figure PCTCN2018072046-appb-000101
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.72(s,1H),7.50(d,J＝7.2Hz,2H),7.48(s,1H),6.75(d,J＝7.2Hz,2H),6.71(s,1H),6.61(d,J＝6.8Hz,1H),6.39(d,J＝6.8Hz,1H),6.11(s,1H),3.72(s,3H)ppm. 13C NMR(125MHz,DMSO):δ161.1,156.2,152.8,152.0,150.1,146.1,141.0,138.3,134.1,131.1,128.0,122.5,120.2,120.0,118.5,118.0,115.0,114.5,55.9ppm.MS(EI,m/z):420(M ++1).
实施例92
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-苯基脲
Figure PCTCN2018072046-appb-000102
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.48(s,1H),7.43-7.20(m,5H),6.71(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.10(s,1H)ppm. 13C NMR(125MHz,DMSO):δ161.1,152.6,152.1,150.1,146.2,141.1,138.1, 135.6,134.1,131.2,129.0,124.3,121.4,120.3,120.0,118.3,118.0,115.0ppm.MS(EI,m/z):390(M ++1).
实施例93
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(环己基)脲
Figure PCTCN2018072046-appb-000103
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.26(s,1H),8.74(s,1H),7.46(s,1H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.11(s,1H),3.52(m,1H),1.78-1.53(m,4H),1.497-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ161.2,152.7,152.1,150.0,146.0,141.1,138.4,134.1,131.1,120.2,120.0,118.5,118.0,115.1,49.5,33.3,28.0,22.3ppm.MS(EI,m/z):396(M ++1).
实施例94
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)硫脲
Figure PCTCN2018072046-appb-000104
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.36(s,1H),8.85(s,1H),7.17(t,J＝8.8Hz,1H),7.10(m,1H),6.77(m,1H),6.24(s,1H),3.56(m,1H),1.84-1.80(m,2H),1.63-1.58 (m,2H),1.45-1.18(m,4H)ppm. 13C NMR(125MHz,DMSO):δ179.6,158.0,154.1,150.2,148.2,139.5,133.5,130.4,120.1,119.5,119.1,118.8,114.7,113.6,54.6ppm.MS(EI,m/z):482(M ++1).
实施例95
(Z)-1-(4-(N-(4-溴-3-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-苯基硫脲
Figure PCTCN2018072046-appb-000105
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.81(s,1H),7.83(d,J＝8.4Hz,1H),7.19-7.15(m,2H),7.15-7.02(m,4H),6.73-6.52(m,3H),6.21(s,1H),6.07(s,1H)ppm. 13C NMR(125MHz,DMSO):δ179.5,160.1,154.0,151.3,148.1,140.2,135.3,134.8,121.5,120.6,119.0,118.5,115.5,114.3ppm.MS(EI,m/z):452(M ++1).
实施例96
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-羟基苯基)硫脲
Figure PCTCN2018072046-appb-000106
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.22(s,1H),8.79(s,1H),7.16(t,J＝8.8Hz,1H),7.08(m,1H),6.76(m,1H),6.23(s,1H),3.53(m,1H)ppm. 13C NMR(125MHz,DMSO):δ178.9,158.0,153.7,150.1,148.3,139.1,133.6,130.6,120.1,119.5,119.0,118.6,114.5,113.3ppm.MS(EI,m/z):468(M ++1).
实施例97
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基苯基)硫脲
Figure PCTCN2018072046-appb-000107
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.39(s,1H),8.81(s,1H),7.16(t,J＝8.8Hz,1H),7.05(m,1H),6.74(m,1H),6.23(s,1H),ppm. 13C NMR(125MHz,DMSO):δ179.6,157.9,153.7,150.3,148.2,139.0,133.4,130.5,120.0,119.5,119.0,118.5,114.2,113.3ppm.MS(EI,m/z):467(M ++1).
实施例98
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(环己基)硫脲
Figure PCTCN2018072046-appb-000108
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.46(s,1H),8.85(s,1H),7.19(t,J＝8.8Hz,1H),7.12(m,1H),6.81-6.77(m,1H),6.27(s,1H),3.59-3.53(m,1H),1.85-1.81(m,2H), 1.63-1.59(m,2H),1.46-1.21(m,6H)ppm. 13C NMR(125MHz,DMSO):δ179.8,159.3,154.5,149.2,145.8,135.1,134.6,112.7,107.6,100.4,52.3,31.9,26.3,24.9ppm.MS(EI,m/z):458(M ++1).
实施例99
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-羟基环己基)硫脲
Figure PCTCN2018072046-appb-000109
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.48(s,1H),8.84(s,1H),7.13(t,J＝8.8Hz,1H),7.12-7.06(m,1H),6.83-6.72(m,1H),6.23(s,1H),3.57-3.53(m,1H),3.37(m,1H),1.85-1.82(m,2H),1.66-1.56(m,2H),1.47-1.21(m,5H)ppm. 13C NMR(125MHz,DMSO):δ179.9,159.2,153.8,149.3,145.4,135.3,133.9,112.9,107.3,100.8,53.6,51.9,33.9,32.7,31.6ppm.MS(EI,m/z):474(M ++1).
实施例100
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(哌啶-4-取代)硫脲
合成方法如实施例1。
Figure PCTCN2018072046-appb-000110
1H NMR(400MHz,DMSO):δ11.51(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.11(m,1H),6.84(m,1H),6.28(s,1H),3.55(m,1H),2.79-2.67(m,4H),1.67-1.55(m,4H)ppm. 13C NMR(125MHz,DMSO):δ179.6,159.3,154.4,149.3,145.6,135.3,134.7,112.7,107.3,100.6,51.6,42.5,32.0ppm.MS(EI,m/z):459(M ++1).
实施例101
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基环己基)硫脲
Figure PCTCN2018072046-appb-000111
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.45(s,1H),8.81(s,1H),7.10(t,J＝8.8Hz,1H),7.13-7.07(m,1H),6.81-6.70(m,1H),6.21(s,1H),3.54-3.50(m,1H),2.85(m,1H),1.82-1.81(m,2H),1.63-1.55(m,2H),1.46-1.21(m,5H)ppm. 13C NMR(125MHz,DMSO):δ179.5,159.0,153.4,149.1,145.1,135.0,133.6,112.5,107.0,100.3,53.0,33.6,32.1,31.2ppm.MS(EI,m/z):473(M ++1).
实施例102
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-羟基丙基)硫脲
Figure PCTCN2018072046-appb-000112
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.50(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.10(m,1H),6.82(m,1H),6.26(s,1H),3.55(t,J＝6.8Hz,2H),3.14(t,J＝6.6Hz,,2H),1.78(m,2H)ppm. 13C NMR(125MHz,DMSO):δ179.7,159.2,154.2,149.2,145.3,135.1,134.7,112.6,107.2,100.5,59.8,39.3,31.5ppm.MS(EI,m/z):434(M ++1).
实施例103
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-羟基乙基)硫脲
Figure PCTCN2018072046-appb-000113
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.52(s,1H),8.84(s,1H),7.19(t,J＝8.8Hz,1H),7.13(m,1H),6.83(m,1H),6.28(s,1H),3.57(t,J＝6.8Hz,2H),3.17(t,J＝6.8Hz,,2H)ppm. 13C NMR(125MHz,DMSO):δ179.9,159.3,154.5,149.5,145.6,135.3,134.8,112.8,107.4,100.6,59.8,39.6ppm.MS(EI,m/z):420(M ++1).
实施例104
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-氨基乙基)硫脲
Figure PCTCN2018072046-appb-000114
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.46(s,1H),8.80(s,1H),7.12(t,J＝8.8Hz,1H),7.03(m,1H),6.80(m,1H),6.22(s,1H),3.34(t,J＝6.8Hz,,2H),2.85(t,J＝6.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ179.6,159.1,154.0,149.0,144.9,135.0,134.2,112.3,106.9,100.1,43.6,39.5,ppm.MS(EI,m/z):419(M ++1).
实施例105
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-甲氧苯基)硫脲
Figure PCTCN2018072046-appb-000115
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.51(d,J＝7.2Hz,2H),7.48(s,1H),6.77(d,J＝7.2Hz,2H),6.73(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.13(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ179.3,156.3,152.7,152.1,150.0,146.0,140.8,138.5,134.0,131.2,128.1,122.5,120.3,118.5,118.0,115.0,114.3,57.6ppm.MS(EI,m/z):436(M ++1).
实施例106
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(苯基)硫脲
Figure PCTCN2018072046-appb-000116
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.26(s,1H),8.73(s,1H),7.46(s,1H),7.43-7.21(m,5H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.38(d,J＝6.8Hz,1H),6.10(s,1H)ppm. 13C NMR(125MHz,DMSO):δ179.6,152.5,150.0,146.0,141.0,138.2,135.4,134.1,131.1,129.0,124.2,121.3,120.3,119.8,118.2,115.0ppm.MS(EI,m/z):406(M ++1).
实施例107
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(环己基)硫脲
Figure PCTCN2018072046-appb-000117
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.47(s,1H),6.73(s,1H),6.62(d,J＝6.8Hz,1H),6.41(d,J＝6.8Hz,1H),6.12(s,1H),3.54(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ179.6,152.7,152.1,150.1,145.8,141.1,138.3,134.1,131.1,120.2,118.5,118.0,115.0,49.7,33.5,28.1,22.5ppm.MS(EI,m/z):412(M ++1).
实施例108
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-甲氧苯基)硫脲
Figure PCTCN2018072046-appb-000118
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.74(s,1H),7.50(d,J＝7.2Hz,2H),7.48(s,1H),6.76(d,J＝7.2Hz,2H),6.73(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.12(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ179.4,156.3,152.7,152.1,150.1,146.0,140.8,138.5,134.0,131.3,128.1,122.5,120.2,118.5,118.1,115.0,114.4,57.6ppm.MS(EI,m/z):481(M ++1).
实施例109
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(苯基)硫脲
Figure PCTCN2018072046-appb-000119
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.73(s,1H),7.47(s,1H),7.43-7.21(m,5H),6.73(s,1H),6.61(d,J＝6.8Hz,1H),6.39(d,J＝6.8Hz,1H),6.10(s,1H)ppm. 13C NMR(125MHz,DMSO):δ179.6,152.6,150.0,146.1,141.0,138.3,135.4,134.2,131.1,129.1,124.2,121.5,120.3,119.9,118.2,115.1ppm.MS(EI,m/z):451(M ++1).
实施例110
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(环己基)硫脲
Figure PCTCN2018072046-appb-000120
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.75(s,1H),7.47(s,1H),6.74(s,1H),6.63(d,J＝6.8Hz,1H),6.42(d,J＝6.8Hz,1H),6.13(s,1H),3.55(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ179.7,152.7,152.2,150.1,145.9,141.1,138.4,134.1,131.2,120.2,118.6,118.0,115.1,49.8,33.5,28.2,22.6ppm.MS(EI,m/z):457(M ++1).
实施例111
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-苯基硫脲
Figure PCTCN2018072046-appb-000121
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.30(s,1H),8.78(s,1H),7.60-7.28(m,5H),7.42(s,1H),7.39(s,1H),6.78(s,1H),6.69(d,J＝6.8Hz,1H),6.49(d,J＝6.8Hz,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ178.7,152.1,149.8,146.1,142.5,141.3,141.0,138.8,134.0,131.3,120.2,120.0,118.5,118.1,115.0ppm.MS(EI,m/z):450(M ++1).
实施例112
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-环己基硫脲
Figure PCTCN2018072046-appb-000122
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.73(s,1H),7.40(s,1H),7.39(s,1H),6.76(s,1H),6.65(d,J＝6.8Hz,1H),6.43(d,J＝6.8Hz,1H),6.11(s,1H),1.83-1.78(m,2H),1.63-1.56(m,2H),1.43-1.19(m,6H)ppm. 13C NMR(125MHz,DMSO):δ178.3,152.0,148.9,146.1,142.5,141.5,141.0,138.7,134.0,131.3,120.2,118.5,118.1,115.1,49.3,33.5,28.1,22.3ppm.MS(EI,m/z):456(M ++1).
实施例113
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-甲氧苯基)胍
Figure PCTCN2018072046-appb-000123
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.41(s,1H),9.05(s,1H),8.83(s,1H),7.17(t,J＝8.8Hz,1H),7.09(m,1H),6.77(m,1H),6.25(s,1H),3.56(m,1H),1.85-1.81(m,2H),1.63-1.59(m,2H),1.46-1.19(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.1,157.1,153.1,150.2,148.2,139.2,133.5,130.6,120.0,119.3,119.0,118.8,114.8,113.5,54.5ppm.MS(EI,m/z):465(M ++1).
实施例114
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-苯基胍
Figure PCTCN2018072046-appb-000124
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.40(s,1H),9.03(s,1H),8.78(s,1H),7.82(d,J＝8.4Hz,1H),7.16-7.12(m,2H),7.13-7.01(m,4H),6.73-6.52(m,3H),6.21(s,1H),6.06(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.2,154.0,151.3,148.1,140.2,135.1,134.7,121.6,120.5,119.0,118.5,115.6,114.3ppm.MS(EI,m/z):435(M ++1).
实施例115
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-羟基苯基)胍
Figure PCTCN2018072046-appb-000125
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.38(s,1H),9.05(s,1H),8.78(s,1H),7.13(t,J＝8.8Hz,1H),7.05(m,1H),6.75(m,1H),6.22(s,1H),3.52(m,1H)ppm. 13C NMR(125MHz,DMSO):δ162.8,157.6,153.7,150.0,148.1,139.1,133.2,130.5,120.1,119.2,119.0,118.3,114.2,113.1ppm.MS(EI,m/z):406(M ++1).
实施例116
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基苯基)胍
Figure PCTCN2018072046-appb-000126
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.35(s,1H),9.04(s,1H),8.76(s,1H),7.12(t,J＝8.8Hz,1H),7.03(m,1H),6.71(m,1H),6.21(s,1H)ppm. 13C NMR(125MHz,DMSO):δ162.8,157.5,153.5,150.0,148.1,138.9,133.2,130.1,120.0,119.1,119.0,118.2,114.1,113.0ppm.MS(EI,m/z):405(M ++1).
实施例117
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-氟-4-三甲氧基苯基)胍
Figure PCTCN2018072046-appb-000127
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.43(s,1H),9.05(s,1H),8.85(s,1H),7.56(s,1H),7.25-7.21(m,2H),7.20(d,J＝8.8Hz,1H),7.11(m,1H),6.76-6.51(m,1H),6.21(s,1H),6.10(s,1H),3.75(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.3,154.0,150.9,147.1,140.1,136.2,134.5,139.3,120.6,119.5,119.3,118.6,114.2,54.7ppm.MS(EI,m/z):483(M ++1).
实施例118
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-环己基胍
Figure PCTCN2018072046-appb-000128
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.41(s,1H),9.01(s,1H),8.83(s,1H),7.16(t,J＝8.8Hz,1H),7.10(m,1H),6.78-6.73(m,1H),6.24(s,1H),3.58-3.52(m,1H),1.85-1.81(m,2H),1.63-1.59(m,2H),1.46-1.19(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.0,159.1,154.2,149.2,145.6,135.1,134.5,112.5,107.3,100.3,52.1,31.8,25.6,24.7ppm.MS(EI,m/z):441(M ++1).
实施例119
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-羟基环己基)胍
Figure PCTCN2018072046-appb-000129
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.51(s,1H),9.05(s,1H),8.87(s,1H),7.16(t,J＝8.8Hz,1H),7.13-7.06(m,1H),6.84-6.73(m,1H),6.26(s,1H),3.57-3.53(m,1H),3.39(m,1H),1.85-1.82(m,2H),1.68-1.56(m,2H),1.48-1.23(m,5H)ppm. 13C NMR(125MHz,DMSO):δ163.9,159.1,153.6,149.3,145.2,135.1,133.8,112.7,107.3,100.6,53.4,51.8,33.8,32.5,31.3ppm.MS(EI,m/z):412(M ++1).
实施例120
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(哌啶-4-取代)胍
Figure PCTCN2018072046-appb-000130
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.48(s,1H),9.02(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.10(m,1H),6.84(m,1H),6.27(s,1H),3.55(m,1H),2.79-2.69(m,4H),1.68-1.54(m,4H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.4,154.3,149.2,145.6,135.2,134.7,112.6,107.4,100.5,51.7,42.5,32.0ppm.MS(EI,m/z):442(M ++1).
实施例121
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(4-氨基环己基)胍
Figure PCTCN2018072046-appb-000131
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.45(s,1H),9.03(s,1H),8.83(s,1H),7.13(t,J＝8.8Hz,1H),7.15-7.08(m,1H),6.82-6.70(m,1H),6.23(s,1H),3.56-3.50(m,1H),2.87(m,1H),1.83-1.81(m,2H),1.65-1.55(m,2H),1.48-1.21(m,5H)ppm. 13C  NMR(125MHz,DMSO):δ163.2,159.0,153.4,149.0,145.1,134.8,133.7,112.4,107.0,100.3,53.1,33.7,32.1,31.2ppm.MS(EI,m/z):411(M ++1).
实施例122
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(3-羟基丙基)胍
Figure PCTCN2018072046-appb-000132
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.50(s,1H),9.05(s,1H),8.82(s,1H),7.16(t,J＝8.8Hz,1H),7.10(m,1H),6.82(m,1H),6.26(s,1H),3.56(t,J＝6.8Hz,2H),3.13(t,J＝6.6Hz,,2H),1.79(m,2H)ppm. 13C NMR(125MHz,DMSO):δ163.2,159.1,154.3,149.1,145.3,135.1,134.6,112.5,107.3,100.4,59.8,39.3,31.5ppm.MS(EI,m/z):417(M ++1).
实施例123
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-羟基乙基)胍
Figure PCTCN2018072046-appb-000133
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.53(s,1H),9.08(s,1H),8.84(s,1H),7.18(t,J＝8.8Hz,1H),7.12(m,1H),6.84(m,1H),6.28(s,1H),3.79(t,J＝6.8Hz,2H), 2.87(t,J＝6.6Hz,,2H),ppm. 13C NMR(125MHz,DMSO):δ163.2,159.3,154.5,149.3,145.5,135.3,134.8,112.7,107.5,100.6,59.9,39.6,31.8ppm.MS(EI,m/z):403(M ++1).
实施例124
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-1,2,5-噁二唑-3-取代)-3-(2-羟基乙基)胍
Figure PCTCN2018072046-appb-000134
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ11.47(s,1H),9.05(s,1H),8.80(s,1H),7.11(t,J＝8.8Hz,1H),7.04(m,1H),6.80(m,1H),6.22(s,1H),3.35(t,J＝6.8Hz,,2H),2.86(t,J＝6.8Hz,2H)ppm. 13C NMR(125MHz,DMSO):δ163.1,159.0,153.9,148.8,145.1,134.9,134.1,112.2,106.9,100.0,43.6,39.5,ppm.MS(EI,m/z):402(M ++1).
实施例125
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-(4-甲氧苯基)胍
Figure PCTCN2018072046-appb-000135
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.96(s,1H),8.753(s,1H),7.50(d,J＝7.2Hz,2H),7.47(s,1H),6.76(d,J＝7.2Hz,2H),6.72(s,1H),6.60(d,J ＝6.8Hz,1H),6.39(d,J＝6.8Hz,1H),6.12(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.0,156.2,152.7,152.0,150.0,145.8,140.9,138.4,134.0,131.1,128.1,122.5,120.2,120.0,118.5,118.0,115.0,114.4,57.7ppm.MS(EI,m/z):419(M ++1).
实施例126
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-苯基胍
Figure PCTCN2018072046-appb-000136
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.26(s,1H),8.97(s,1H),8.73(s,1H),7.47(s,1H),7.42-7.21(m,5H),6.70(s,1H),6.61(d,J＝6.8Hz,1H),6.39(d,J＝6.8Hz,1H),6.09(s,1H)ppm. 13C NMR(125MHz,DMSO):δ162.9,152.5,152.0,149.9,146.0,140.8,138.2,135.5,134.0,131.1,128.9,124.2,121.3,120.2,118.2,117.9,115.1ppm.MS(EI,m/z):389(M ++1).
实施例127
(Z)-1-(4-(N-(3-氯-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-4-环己基胍
Figure PCTCN2018072046-appb-000137
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.23(s,1H),8.95(s,1H),8.72(s,1H),7.46(s,1H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.11(s,1H), 3.53(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.0,152.7,152.0,150.1,145.9,141.1,138.4,134.1,131.1,120.2,118.5,118.0,115.0,49.7,33.5,28.0,22.5ppm.MS(EI,m/z):395(M ++1).
实施例128
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-(4-甲氧苯基)胍
Figure PCTCN2018072046-appb-000138
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.97(s,1H),8.74(s,1H),7.52(d,J＝7.2Hz,2H),7.47(s,1H),6.76(d,J＝7.2Hz,2H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.11(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.1,156.2,152.7,152.1,150.0,145.9,141.0,138.4,134.0,131.2,128.1,122.5,120.2,118.5,117.9,115.0,114.5,57.7ppm.MS(EI,m/z):464(M ++1).
实施例129
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-苯基胍
Figure PCTCN2018072046-appb-000139
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.26(s,1H),8.95(s,1H),8.74(s,1H),7.47(s,1H),7.42-7.22(m,5H),6.72(s,1H),6.61(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.11(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.0,152.7,152.1,149.9,145.8, 141.0,138.4,135.8,134.0,131.1,128.8,124.3,121.5,120.2,118.5,117.8,115.0ppm.MS(EI,m/z):434(M ++1).
实施例130
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-异噁唑-3-取代)-3-环己基胍
Figure PCTCN2018072046-appb-000140
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.27(s,1H),8.92(s,1H),8.73(s,1H),7.47(s,1H),6.72(s,1H),6.62(d,J＝6.8Hz,1H),6.40(d,J＝6.8Hz,1H),6.12(s,1H),3.52(m,1H),1.79-1.55(m,4H),1.49-1.38(m,6H)ppm. 13C NMR(125MHz,DMSO):δ162.9,152.7,152.1,150.0,145.8,141.0,138.3,133.9,131.1,120.2,119.9,118.5,117.8,115.0,49.5,33.2,27.9,22.4ppm.MS(EI,m/z):440(M ++1).
实施例131
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-(4-甲氧苯基)胍
Figure PCTCN2018072046-appb-000141
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.32(s,1H),8.94(s,1H),8.79(s,1H),7.52(d,J＝8.6Hz,2H),7.43(s,1H),7.40(s,1H),6.85(d,J＝8.6Hz,2H),6.73(s,1H),6.62(d,J＝8.0Hz,1H),6.42(d,J＝8.0Hz,1H),6.15(s,1H),3.73(s,3H)ppm. 13C NMR(125MHz,DMSO):δ163.1,152.0,149.8,146.0,142.6,141.6,141.3,138.9,134.2,131.7,120.5,120.0,118.6,118.3,115.5,55.8ppm.MS(EI,m/z):463(M ++1).
实施例132
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-苯基胍
Figure PCTCN2018072046-appb-000142
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.29(s,1H),8.95(s,1H),8.77(s,1H),7.60-7.27(m,5H),7.41(s,1H),7.38(s,1H),6.76(s,1H),6.68(d,J＝6.8Hz,1H),6.48(d,J＝6.8Hz,1H),6.15(s,1H)ppm. 13C NMR(125MHz,DMSO):δ163.2,152.0,150.0,145.8,142.6,141.4,140.9,138.8,134.0,131.2,120.1,118.5,118.0,115.1ppm.MS(EI,m/z):433(M ++1).
实施例133
(Z)-1-(4-(N-(3-溴-4-氟苯基)-N’-羟基氨基亚氨甲基)-呋喃-3-取代)-3-环己基胍
Figure PCTCN2018072046-appb-000143
合成方法如实施例1。
1H NMR(400MHz,DMSO):δ10.28(s,1H),8.93(s,1H),8.75(s,1H),7.40(s,1H),7.38(s,1H),6.75(s,1H),6.65(d,J＝6.8Hz,1H),6.43(d,J＝6.8Hz,1H),6.11(s,1H),1.83-1.78(m,2H),1.63-1.56(m,2H),1.42-1.18(m,6H)ppm. 13C NMR(125MHz,DMSO):δ163.1,152.0,149.8,146.1,142.5,141.4,140.8,138.7,133.8, 131.2,120.3,118.5,118.0,115.1,49.4,33.5,28.0,22.4ppm.MS(EI,m/z):439(M ++1).
试验例体外生化活性的测定
(1)IDO1酶生化活性的测定方法
首先在微孔板孔内加入15μl磷酸氢钠的缓冲液(PH:7-8)，加入5μl含有适量IDO-1酶的反应缓冲液和本发明制备的杂环脲类化合物，混匀，室温反应3小时后，用PE公司的Envision MultilabelReader多功能酶标仪进行检测320nm波长光吸收值，根据吸收比值计算杂环脲类化合物对酶反应的抑制率，用GraphPad软件进行分析计算出杂环脲类化合物的IC50值。
(2)细胞活性的测试方法
在37度CO 2培养箱中，用添加抗生素的DMEM培养基培养及传代Hela细胞，接种到96孔板中过夜培养，然后每孔加入适当浓度的1μl杂环脲类化合物，再加入100μl的干扰素γ(终浓度为100ng/ml)。继续培养细胞72h后，取70μl细胞培养上清液加入96孔尖底板，每孔加入5μl三氯乙酸(6.1N)，50度孵化30min后取出，25000rpm离心10min。将上述离心后的上清20μl/孔转移入384微孔板，然后每孔加入20μl的2％二甲氨基苯甲醛乙酸溶液，震荡混匀后，480nm下测光吸收,并测定数值。
各个杂环脲类化合物的IDO1酶抑制活性和细胞抑制活性的测定结果如表1所示。
B:IC 50＝100nM-1μM；A:IC 50<1nM；
表1 IDO1酶和细胞抑制活性测定结果
Figure PCTCN2018072046-appb-000144
Figure PCTCN2018072046-appb-000145
Figure PCTCN2018072046-appb-000146
Figure PCTCN2018072046-appb-000147
Figure PCTCN2018072046-appb-000148
Figure PCTCN2018072046-appb-000149
Figure PCTCN2018072046-appb-000150
Figure PCTCN2018072046-appb-000151
表1中IC50表示的是IDO1酶和细胞50％生长抑制所需的药物浓度。
从表1中结果可以看出：本发明所制备的杂环脲类化合物的IC50均在1μM以下。本发明所制备的杂环脲类化合物与阳性对照(INCB24360)相比，具有显著的抑制所列IDO1酶的活性和Hela细胞IDO1酶的活性。
以上对本发明实施例所提供的杂环脲类化合物及其药用组合物和应用，进行了详细介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想；同时，对于本领域的一般技术人员，依据本发明的思想，在具体实施方式及应用范围上均会有改变之处，综上所述，本说明书内容不应理解为对本发明的限制。

Claims (10)

  1. 具有通式I所示的化学结构的杂环脲类化合物，或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
    Figure PCTCN2018072046-appb-100001
    其中，
    X,Y任选为N或C；
    Z任选为O、S、或N；
    R 1表示苯环上的取代基，选自氢、卤素、硝基、氰基、羟基、氨基、二甲氨基、C l-6烷基、C l-6全氟烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-12杂脂环基或C l-6烷氧基；
    R 2基团任选自以下的一种：
    1)氢；
    2)C 1-C 12烷基；
    3)-CH 2-O-CH 2-(C 1-C 12烷基)；
    4)-CH 2-NH-CH 2-(C 1-C 12烷基)；
    5)-CH 2-S-(C 1-C 12烷基)；
    6)C 6-C 12芳基；
    7)杂芳基；
    8)-CH 2-(C 6-C 12芳基)或-CH 2-杂芳基；
    9)C 3-C 12环烷基；
    10)C 4-C 9杂环烷基；
    11)-CH 2-NH-SO 2-NH 2/CH 3(C 1-C 12烷基)；
  2. 权利要求1所述的杂环脲类化合物，或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，其中所述的C 6-C 12芳基、杂芳基、-CH 2-(C 6-C 12芳基)和-CH 2-杂芳基，含有或不含有1个或多个取代基，所述取代基选自卤素、氨基、羟基、硝基、氰基、C 1-C 12烷基、C 1-C 12烷氧基、氨基C 1-C 12烷基、C 1-C 12酰基、C 1-C 12酰氧基、硫代C 1-C 12烷基、羧基或苯基；
    所述的C 3-C 12环烷基，含有或不含有1个或多个取代基，所述取代基选自卤素、氨基、羟基、硝基、氰基、C 1-C 12烷基、C 1-C 12烷氧基、氨基C 1-C 12烷基、C 1-C 12酰基、C 1-C 12酰氧基、磺酰C 1-C 12烷基、羧基或苯基。
  3. 权利要求1所述的杂环脲类化合物的制备方法，其中包括如下步骤：
    (1)将式II化合物在酸和氯代试剂的作用下，在有机溶剂中进行氯代反应，得到式III化合物；反应过程如下所示：
    Figure PCTCN2018072046-appb-100002
    (2)将式III化合物在在碱的作用下与芳香胺，在有机溶剂中反应，得到式IV化合物；反应过程如下所示：
    Figure PCTCN2018072046-appb-100003
    (3)将式IV化合物在碳基二咪唑(CDI)作用下，在有机溶剂中反应，得到式V化合物；反应过程如下所示：
    Figure PCTCN2018072046-appb-100004
    (4)将式V化合物与异氰酸酯、或异硫氰酸酯或异氰亚胺酯，在有机溶剂中反应，得到式VI化合物；反应过程如下所示：
    Figure PCTCN2018072046-appb-100005
    (5)将式VI化合物在碱的作用下脱保护反应，得到式I化合物；反应过程如下所示：
    Figure PCTCN2018072046-appb-100006
  4. 权利要求3所述的制备方法，其中所述的有机溶剂选自二氯甲烷、四氢呋喃、二甲基甲酰胺、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯、甲醇、乙醇、石油醚、正己烷和乙醚中的一种或多种；
    所述的酸选自乙酸、三氟乙酸、甲酸、丙酸、硫酸、硝酸和盐酸中的一种或多种；
    所述的碱选自碳酸钾、碳酸钠、碳酸氢钠、碳酸镁、碳酸钙、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、氢氧化镁、氢氧化咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、N-甲基吗啉、DABCO和吡啶中的一种或多种；
    所述的芳香胺选自苯胺、苯乙胺、卤素、硝基、氰基、羟基、氨基、二甲氨基、C l-6烷基、C l-6全氟烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、和C 3-12杂脂环基或C l-6烷氧基单取代或多取代的苯胺的一种或多种；
    所述的异氰酸酯、或异硫氰酸酯或异氰亚胺酯选自氢、C 1-C 12烷基、-CH 2-O-CH 2-(C 1-C 12烷基)、-CH 2-NH-CH 2-(C 1-C 12烷基)、-CH 2-S-(C 1-C 12烷基)、C 6-C 12芳基、杂芳基、-CH 2-(C 6-C 12芳基)或-CH 2-杂芳基、C 3-C 9环烷基、C 4-C 9杂环烷基或-CH 2-NH-SO 2-NH 2/CH 3(C 1-C 12烷基)取代的异氰酸酯、或异硫氰酸酯或异氰亚胺酯。
  5. 抗肿瘤药物组合物，其中含有权利要求1或2的通式I所示的杂环脲类化合物或其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物，与药学上可接受的载体。
  6. 权利要求1或2的通式I所示的化学结构的杂环脲类化合物及其药学上可接受的盐或立体异构体或其前药分子在制备治疗或预防肿瘤的药物中的应用。
  7. 权利要求6所述的应用，其中利用有效剂量的所述化合物治疗淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、结肠癌、大肠癌、肾癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌，包括在其它远离肿瘤原发部位的组织或器官的转移病变。
  8. 权利要求6所述的应用，其中所述治疗或预防肿瘤的药物包括但不限于癌症的免疫治疗药物:PD-1抗体、PD-L1抗体、PD-L2抗体、CTLA-4抗体、以及任何一种其它化疗药物或靶向治疗药物。
  9. 权利要求6所述的应用，其中所述的杂环脲类化合物及其药学上可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤过渡增殖性疾病。
  10. 权利要求6所述的应用，其中所述的杂环脲类化合物及其药学上可接受的盐包括用于治疗吲哚胺-2,3-双加氧酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病和老年痴呆。
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