WO2019120237A1 - 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 - Google Patents

一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 Download PDF

Info

Publication number
WO2019120237A1
WO2019120237A1 PCT/CN2018/122247 CN2018122247W WO2019120237A1 WO 2019120237 A1 WO2019120237 A1 WO 2019120237A1 CN 2018122247 W CN2018122247 W CN 2018122247W WO 2019120237 A1 WO2019120237 A1 WO 2019120237A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
aryl
alkyl
compound
alkoxy
Prior art date
Application number
PCT/CN2018/122247
Other languages
English (en)
French (fr)
Inventor
杜武
艾朝武
李宇
温坤
吕海斌
任闻
何锦云
秦德锟
李兴海
陈元伟
Original Assignee
成都海创药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都海创药业有限公司 filed Critical 成都海创药业有限公司
Priority to EP18890728.1A priority Critical patent/EP3730484B1/en
Priority to JP2020533145A priority patent/JP2021509399A/ja
Priority to US16/956,581 priority patent/US11447477B2/en
Publication of WO2019120237A1 publication Critical patent/WO2019120237A1/zh

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of medical chemistry and relates to an extremely preparation method and use of a guanamine-2,3-dioxygenase inhibitor.
  • Malignant tumors are one of the major diseases that currently threaten human health and life. According to statistics from the National Health and Family Planning Commission, the incidence of cancer in mainland China is about 235/100,000, and the mortality rate is about 144.3/100,000.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.
  • Indoleamine 2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folded alpha-helical structures.
  • the domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is the only rate-limiting enzyme outside the liver that catalyzes the metabolism of tryptophan, which causes it to decompose along the kynurenine pathway to produce a series of metabolites including quinolinic acid.
  • tryptophan-2,3-dioxygenase Another class of enzymes that catalyze the metabolism of tryptophan are tryptophan-2,3-dioxygenase, which has a similar heme active site as IDO, but only about 10% of the amino acid sequences are identical.
  • About 95% of free L-tryptophan in the human body can be metabolized by the kynurenine pathway and produce a variety of biologically active metabolites, including kynurenine, kynuric acid, 3-hydroxy kynurenine. , 3-hydroxyanthronic acid, picolinic acid, quinolinic acid, and oxidized coenzyme A.
  • IDO has a low expression level under normal conditions, and a significant increase in expression during inflammation or infection, and lipopolysaccharide and cytokines can induce expression of IDO.
  • lipopolysaccharide and cytokines can induce expression of IDO.
  • the intermediate metabolites of tryptophan, 3-hydroxyanthronic acid and quinolinic acid can also induce T lymphocyte apoptosis in mouse thymocytes in vitro. Tumor cells can induce local immunity by depleting local tryptophan and producing metabolites, while the level of local invasive T lymphocytes in the tumor is significantly decreased.
  • IDO can inhibit local immunity of tumors by several ways: 1 tryptophan depletion mechanism: through the transient expression of IDO, resulting in the lack of tryptophan necessary for T cell proliferation, affecting the effective proliferation of T cells, It is clear that T cells are prone to apoptosis; 2 Toxic mechanism of tryptophan metabolites: IDO catalyzes the degradation of tryptophan to inhibit the function of activated T cells and even induce T cell apoptosis; 3IDO can also be induced Proliferation of regulatory T cells inhibits the immune function of activated T cells. Therefore, IDO is a potential target for tumor immunotherapy.
  • Inhibitors of the disclosed selective inhibitors of IDO include WO2010005958, WO2013174947, WO2014066834, WO2016155545, CN201610059454.5, CN201710060610.4, and the like.
  • 1-Methyl-tryptophan is an oral small molecule IDO inhibitor developed by Newlink Genetics for the treatment of metastatic breast cancer and solid tumors. It is currently in the clinical phase II trial.
  • Incyte is developing a series of oral IDO small molecule inhibitors, INCB-24360 is also undergoing clinical phase III trials, mainly for the treatment of a variety of cancers including myelodysplastic syndrome, but in clinical trials A certain problem of toxicity of drug metabolism stability.
  • the present invention provides a compound represented by the formula (I), or an optical isomer thereof, or a cis-trans isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or a mesogenic thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or Its metabolites, or their metabolic precursors:
  • X is an amino group, oxygen, or sulfur
  • R 1 is hydrogen, -(CH 2 ) m COR 5 , -(CH 2 ) m SO 2 R 6 , -(CH 2 ) m COOR 7 , alkyl, haloalkyl, alkoxy, cycloalkyl, substituted ring
  • m is selected from 0 to 5 integers;
  • R 5 , R 6 and R 7 are each independently selected from alkyl, amino, hydroxy, cycloalkyl, alkoxy, heterocycloalkyl, -CONR 8 R 9 , -NR 8 R 9 , aryl, aromatic Ring base
  • R 8 and R 9 are each independently selected from hydrogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 8 and R 9 are linked into a ring;
  • R 2 is hydrogen, alkyl, hydroxy, amino, alkoxy, alkylamino, halogen
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, carboxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl ;
  • hydrogen refers to hydrogen (H) or isotope ⁇ (D);
  • R 6 is selected from the group consisting of alkyl, amino, hydroxy, cycloalkyl, alkoxy, heterocycloalkyl, -CONR 8 R 9 , -NR 8 R 9 , aryl, aromatic heterocyclic;
  • R 8 and R 9 are each independently selected from hydrogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 8 and R 9 are linked into a ring;
  • R 5 is selected from the group consisting of alkyl, amino, hydroxy, cycloalkyl, alkoxy, heterocycloalkyl, -CONR 8 R 9 , -NR 8 R 9 , aryl, aromatic heterocyclic;
  • R 8 and R 9 are each independently selected from hydrogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 8 and R 9 are linked into a ring.
  • R 1 is hydrogen, -COR 5 , -SO 2 R 6 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3 -C8 unsaturated heterocyclic group, aryl group, substituted aryl group, aromatic heterocyclic group, substituted heteroaryl group;
  • R 5 and R 6 are each independently selected from the group consisting of alkyl, hydroxy, C3-C8 cycloalkyl, alkoxy, C3-C8 heterocycloalkyl, -CONR 8 R 9 , -NR 8 R 9 , aryl, hetero Aryl;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, amino, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl;
  • R 2 is hydrogen, C1-C8 alkyl, hydroxy, amino, C1-C8 alkoxy, C1-C8 alkylamino, halogen;
  • R 3 and R 4 are each selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C1-C8 alkoxy, amino, carboxyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl.
  • R 1 is hydrogen, -COR 5 , -SO 2 R 6 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3 -C8 unsaturated heterocyclic group, aryl group, substituted aryl group, aromatic heterocyclic group, substituted heteroaryl group;
  • R 5 and R 6 are each independently selected from the group consisting of alkyl, hydroxy, C3-C8 cycloalkyl, alkoxy, C3-C8 heterocycloalkyl, -CONR 8 R 9 , -NR 8 R 9 , aryl, hetero Aryl;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, amino, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, substituted aryl a heteroaryl group, a substituted heteroaryl group, or a link of R 8 and R 9 to form a ring;
  • R 2 is hydrogen, C1-C8 alkyl, hydroxy, amino, C1-C8 alkoxy, C1-C8 alkylamino, halogen;
  • R 3 and R 4 are each selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C1-C8 alkoxy, amino, carboxyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl.
  • the compound is one of the following compounds, but is not limited to the following compounds:
  • the present invention also provides the aforementioned compound, or an optical isomer thereof, or a cis-trans isomer thereof or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, prepared for prevention and/or Use in the treatment of a medicament having a disease characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.
  • the present invention also provides the aforementioned compound, or an optical isomer thereof, or a cis-trans isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or tautomer thereof , or a mesogen thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a metabolite thereof, or a metabolic precursor thereof, are prepared Use in IDO inhibitors
  • the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, Psychological disorders and AIDS; the cancers described are preferably breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer , bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor.
  • cancer myelodysplastic syndrome
  • Alzheimer's disease autoimmune disease
  • depression anxiety, cataract
  • the cancers described are preferably breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone
  • the present invention also provides a pharmaceutical composition which is a compound of the foregoing, or an optical isomer thereof, or a cis-trans isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or Prodrugs are active ingredients, plus pharmaceutically acceptable excipients.
  • substituted means that a hydrogen atom in a molecule is replaced by another different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix Ca-b alkyl group indicates any alkyl group having "a" to "b" carbon atoms, including a linear chain.
  • Alkyl and branched alkyl Thus, for example, C1-6 alkyl means a straight-chain alkyl group and a branched alkyl group containing from 1 to 6 carbon atoms.
  • halogen means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • cycloalkyl group in the present invention means a saturated ring or a non-aromatic unsaturated ring formed by all carbon atoms.
  • heterocycloalkyl group in the present invention means a saturated ring or a non-aromatic unsaturated ring containing at least one hetero atom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom.
  • the "aryl group” in the present invention means an aromatic unsaturated ring formed by an all carbon atom.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • the pharmaceutically acceptable excipient of the present invention means a substance which is contained in a dosage form in addition to the active ingredient.
  • IDO inhibitors are a class of drugs that can be used to treat cancer, myelodysplastic syndromes, Alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, mental disorders, and AIDS.
  • the compound of the present invention exhibits excellent IDO enzymatic inhibitory activity and cytostatic activity, can be formulated into an IDO inhibitor, and treats various diseases including tumors, and has good pharmacokinetic properties, which are related to IDO inhibition. There is great potential for application in the field of cancer treatment.
  • PG is a protecting group including, but not limited to, Boc, Fmoc, and the like.
  • the chlorosulfonic acid isocyanate (0.212 g, 1.5 mmol) was dissolved in 5 mL of dichloromethane, cooled to 0 ° C, tert-butanol (0.115 g, 1.55 mmol) was added, and the reaction mixture was reacted at 0 ° C for 1 hour.
  • Reaction liquid A The compound (7.3) (320 mg, 0.752 mmol) was dissolved in 5 mL of dichloromethane, and 1.0 mL of triethylamine was added to obtain a reaction liquid B.
  • the reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour.
  • the compound (7.5) (260 mg, 0.516 mmol) was dissolved in 2 mL of tetrahydrofuran, and 0.5 mL of a 2.0 N sodium hydroxide solution was added at 0 ° C, and the reaction was stirred for 1 hour. After the completion of the reaction, a saturated aqueous solution of ammonium chloride (5 mL) was added and the mixture was evaporated. The title compound (7 mg (yield: white solid).
  • Example 1 The following example compounds were prepared in a similar manner to the synthesis of Example 1 described above.
  • Example 2 was prepared by a synthesis method similar to that of Example 1 described above using Compound 1 and tert-butanol 3-(aminomethyl)azetidin-1-carboxylate as a starting material.
  • Example 3 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azetidin-1-carboxylate as starting materials, Example 3.
  • Example 4 Using the synthesis method of Example 1 similar to the above, using Compound 3 as a raw material, Example 4 was prepared.
  • Example 5 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 5.
  • Example 6 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 6.
  • Example 7 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 7.
  • Example 8 Using the synthesis method of Example 1 similar to the above, using Compound 1 and (S)-tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 8.
  • Example 9 Using the synthesis method of Example 1 similar to the above, using Compound 1 and (R)-tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 9.
  • Example 10 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azide-1-carboxylate as starting materials, Example 10.
  • Example 11 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((4-sulfamoylmorpholin-2-yl)methyl)amino)-1,2 , 5-oxadiazole-3-carboquinone (11)
  • Example 11 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminomethyl)morpholine-4-carboxylate as starting materials, Example 11.
  • Example 12 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminomethyl)azetidin-1-carboxylate as starting materials, Example 12.
  • Example 13 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((l-sulfamoylzacyclopentan-2-yl)methyl)amino)-1 ,2,5-oxadiazole-3-carboquinone (13)
  • Example 13 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminomethyl)azolane-1-carboxylate as starting materials, Example 13.
  • Example 14 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminomethyl)azide-1-carboxylate as starting materials, Example 14.
  • Example 15 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminoethyl)azetidin-1-carboxylate as starting materials, Example 15.
  • Example 16 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminoethyl)azolane-1-carboxylate as starting materials, Example 16.
  • Example 17 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 2-(aminoethyl)azide-1-carboxylate as starting materials, Example 17.
  • Example 18 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 4-(aminomethyl)azide-1-carboxylate as starting materials, Example 18.
  • Example 19 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 4-(aminoethyl)azide-1-carboxylate as starting materials, Example 19.
  • Example 20 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 20 was prepared.
  • Example 21 Using the synthesis method of Example 1 similar to the above, using Compound 1 and tert-butanol 3-(aminomethyl)azolane-1-carboxylate as starting materials, Example 21.
  • Example 28 (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(1-sulfamoylazetidin-3-yl)) Amino)-1,2,5-oxadiazole-3-carboxamidine (Compound 132)
  • Test Example 1 Determination of Protease Inhibitory Activity of Human IDO1 by the Compound of the Present Invention:
  • test compound and the reference compound were added to DMSO to form a high concentration storage solution.
  • the reference compound stock solution was diluted with DMSO to prepare a 100x solution.
  • 8 ⁇ L of the above test compound and 100 ⁇ reference compound were added to the highest concentration, and the concentration was diluted 3 times to prepare a 100 ⁇ solution.
  • 0.5 ⁇ L of 100X compound solution was added to each well. HPE and ZPE control wells were spiked with 0.5 [mu]L of 100% DMSO.
  • Compound number IC 50 (nM) Compound number IC 50 (nM) 2 182 twenty one 141 3 430 twenty three 183 4 55 twenty four 69 5 276 25 96 6 88 26 340 7 59 27 628 8 112 28 107 9 84 29 173 10 254 78 69 11 206 81 142 12 133 85 115 13 214 86 167 14 279 89 183 16 151 91 128 18 114 92 64 19 119 150 81
  • the compounds of the present invention have a significant inhibitory effect on the activity of human IDO1 protease.
  • Test Example 2 Determination of inhibition of IDO protease activity in Hela cells by the compound of the present invention:
  • HeLa cells ATCC, Cat. No. CCL-2
  • Fetal bovine serum FBS (Invitrogen, Cat. No. 10100-147)
  • Phosphate buffer PBS pH 7.4 (Invitrogen, Cat. No. 10010023)
  • Penicillin-Streptomycin (P/S) (Invitrogen, Cat. No. 15070063)
  • N'-Diformyl kynurenine (NFK) J&K, Cat. No. F700490
  • Multidrop TM small tube metal tip dispensing box (Thermo, Cat. No. 24073295)
  • Multidrop TM standard tube metal tip dispensing box (Thermo, Cat. No. 24072670)
  • the compound (Compound 4, 8, 9, 78, 91 of the present invention) was placed in a concentration of 3 mM in DMSO, and then 15 ⁇ l of the compound was added to a 96-well plate, and the compound was serially diluted 3 times in total by 10 points. Transfer 2 ⁇ l of compound or DMSO (for HPE/ZPE) to a new 96-well plate. HeLa cell suspension was seeded into cell culture plates at a density of 10,000 cells/well.
  • the cell culture medium used for the detection was: HPE control well was DMEM; 10% FBS; 1% P/S; 122 ⁇ M Trp; ZPE control well and compound well was DMEM; 10% FBS; 1% P/S; 122 ⁇ M Trp; 25 ng/ml IFN ⁇ .
  • HPE control well was DMEM; 10% FBS; 1% P/S; 122 ⁇ M Trp; 25 ng/ml IFN ⁇ .
  • 192 ⁇ l of the above-prepared assay medium was added to a 96-well plate.
  • 78 ⁇ l of DMEM medium was added to the compound plate and mixed well, and then 8 ⁇ l of the DMEM-diluted compound was transferred to a 96-well plate to which the assay medium had been added.
  • the cell culture plate was taken out and the cell culture medium was discarded, and then 100 ⁇ l of the above compound was transferred to a cell culture plate, and the cell culture plate was transferred to a cell culture incubator for further 48 hours.
  • the cell culture plate was taken out at the time of detection, and 50 ⁇ l of the supernatant was transferred to a new 96-well plate, 200 ⁇ l of acetonitrile was added to the above plate and thoroughly mixed, centrifuged at 4 ° C for 20 minutes (speed: 4000 rpm), and 40 ⁇ l of the supernatant was transferred to another In a 96-well plate, 360 ⁇ l of deionized water containing 2 ⁇ g/ml of internal reference (3-nitro-L-tyrosine) was added, and the mixture was thoroughly mixed and detected by a RapidFire/MS system.
  • the IDO protease inhibitory activity of the compound of the present invention in HeLa cells was determined by the above test, and the measured IC 50 values are shown in Table 2.
  • the compound of the present invention has a remarkable inhibitory activity against IDO protease in HeLa cells, and Compound 4 and Compound 91 have excellent inhibitory activity and can treat cervical cancer.
  • Test Example 3 Mouse pharmacokinetics of the compounds of the present invention
  • mice Chengdu Dashuo Experimental Animal Co., Ltd.
  • the compound (the compound of the present invention was compound 4, and the similar reference compound INCB-24360 which entered the clinical stage III was used as a control compound) was accurately weighed, and 5 mg was added thereto, and the corresponding solvent was added to a final volume of 10 ml, and the mixture was vortexed by ultrasonic wave. A solution having a concentration of 0.5 mg/ml was prepared. 0.2 ml of the final solution was prepared and stored at -20 ° C for concentration determination.
  • Compound 4 was compared to mouse PK by a similar inventive reference compound INCB-24360 that had entered clinical phase III.
  • the compounds of the present invention have a longer half-life compared to similar reference compounds of the invention, with significant improvements in pharmacokinetics, with significant differences.
  • the compounds of the present invention exhibit excellent IDO enzymatic inhibitory activity and cytostatic activity, as well as good pharmacokinetics, and have great potential for application in the field of cancer treatment related to IDO inhibition.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

提供了一种式(I)所示的化合物。还涉及含有式(I)化合物的药物组合物以及该化合物在制备吲哚胺-2,3-双加氧酶(IDO)抑制剂类药物中的用途。所述化合物或其药物组合物可以用于制备预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。

Description

一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 技术领域
本发明属于医药化学领域，涉及一种吲哚胺-2,3-双加氧酶抑制剂极其制备方法和用途。
背景技术
恶性肿瘤是目前威胁人类健康和生命的主要疾病之一，根据国家卫生和计划生育委员会统计数据显示，我国大陆肿瘤发生率约为235/10万，死亡率约为144.3/10万。
由于恶性肿瘤的无限制生长于浸润、转移，现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞，因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后肿瘤治疗的第四种模式，其通过调动宿主的天然防御机制或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。
吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是肝脏以外唯一可催化色氨酸代谢，使其沿犬尿氨酸途径分解生成包含喹啉酸在内的一系列代谢产物的限速酶。催化色氨酸代谢的另一类酶为色氨酸-2,3-双加氧酶，其与IDO有相似的血红素活性位点，但两者仅有约10％的氨基酸序列相同。人体内约有95％的游离L-色氨酸可按犬尿氨酸途径代谢，并产生多种就有生物活性的代谢产物，包括犬尿氨酸、犬尿酸、3-羟基犬尿氨酸、3-羟基邻氨苯甲酸、吡啶甲酸、喹啉酸以及氧化辅酶A等。IDO在正常状态下表达水平较低，在炎症或感染过程中表达显著增加，此外脂多糖及细胞因子等均可诱导IDO的表达。体外研究发现，除犬尿氨酸外，色氨酸的中间代谢产物3-羟基邻氨苯甲酸和喹啉酸也可在体外诱导小鼠胸腺细胞的T淋巴细胞凋亡。肿瘤细胞可通过消耗局部色氨酸，产生代谢产物诱导局部免疫，同时肿瘤局部浸润性T淋巴细胞水平明显下降。简而言之，IDO可通过以下几种途径抑制肿瘤的局部免疫：①色氨酸耗竭机制：通过使IDO过渡表达，导致T细胞增殖所必需的色氨酸缺乏，影响T细胞的有效增殖，导致T细胞易发生凋亡而被清楚；②色氨酸代谢产物毒性机制：IDO催化色氨酸降解产生的代谢产物可以抑制活化T细胞的功能，甚至诱导T细胞凋亡；③IDO还可以通过诱导调节性T细胞的增殖从而抑 制活化T细胞的免疫功能。因此，IDO是一个具有潜力的肿瘤免疫治疗的靶标。
公开的选择性抑制IDO的抑制剂专利申请包括WO2010005958、WO2013174947、WO2014066834、WO2016155545、CN201610059454.5、CN201710060610.4等。
1-甲基色氨酸是由Newlink Genetics公司开发的口服小分子IDO抑制剂，用于治疗转移性乳腺癌和实体瘤，目前长期处于临床二期试验阶段。另外，Incyte公司正在研发的一系列口服IDO小分子抑制剂中INCB-24360也在进行临床三期试验，主要用于治疗包括骨髓增生异常综合症在内的多种癌症，但是在临床试验中出现了一定的药物代谢稳定性的毒性的问题。
因此，为了达到更好的肿瘤治疗效果和目的，更好的满足市场需求，现在急需开发出新一代的高效低毒的选择性IDO抑制剂。
发明内容
为了解决上述技术问题，本发明提供了式(I)所示的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体：
Figure PCTCN2018122247-appb-000001
其中，X为氨基、氧、硫；
R 1为氢、-(CH 2) mCOR 5、-(CH 2) mSO 2R 6、-(CH 2) mCOOR 7、烷基、卤代烷基、烷氧基、环烷基、取代环烷基、杂环烷基、取代杂环烷基、不饱和杂环基、取代不饱和杂环烷基、芳基、取代芳基、芳香杂环基、取代杂芳基；m选自0～5整数；
R 5、R 6、R 7分别独立地选自烷基、氨基、羟基、环烷基、烷氧基、杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、芳香杂环基；
R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
R 2为氢、烷基、羟基、氨基、烷氧基、烷胺基、卤素；
R 3、R 4分别选自氢、卤素、氰基、烷基、环烷基、杂环烷基、烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基；
其中，氢是指氢元素(H)或同位素氘(D)；
a＝0～5的整数；b＝0～5的整数；c＝1～5的整数；a和b不同时为0。
进一步地，所述化合物具有如式(Ⅱ)所示的结构：
Figure PCTCN2018122247-appb-000002
其中，R 6选自烷基、氨基、羟基、环烷基、烷氧基、杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、芳香杂环基；
R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
进一步地，所述化合物具有如式(Ⅲ)所示的结构：
Figure PCTCN2018122247-appb-000003
其中，R 5选自烷基、氨基、羟基、环烷基、烷氧基、杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、芳香杂环基；
R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环。
进一步地，a为0时，所述化合物具有如式(Ⅳ)所示的结构；b为0时，所述化合物具有如式(Ⅴ)所示的结构：
Figure PCTCN2018122247-appb-000004
Figure PCTCN2018122247-appb-000005
R 1为氢、-COR 5、-SO 2R 6、C1-C8烷基、C1-C8卤代烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、C3-C8不饱和杂环基、芳基、取代芳基、芳香杂环基、取代杂芳基；
R 5、R 6分别独立地选自烷基、羟基、C3-C8环烷基、烷氧基、C3-C8杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、杂芳基；
R 8、R 9分别独立地选自氢、氨基、羟基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基；
R 2为氢、C1-C8烷基、羟基、氨基、C1-C8烷氧基、C1-C8烷胺基、卤素；
R 3、R 4分别选自氢、卤素、C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C1-C8烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基。
进一步地，a＝1,b＝1时，所述化合物具有如式(VI)所示的结构：
Figure PCTCN2018122247-appb-000006
R 1为氢、-COR 5、-SO 2R 6、C1-C8烷基、C1-C8卤代烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、C3-C8不饱和杂环基、芳基、取代芳基、芳香杂环基、取代杂芳基；
R 5、R 6分别独立地选自烷基、羟基、C3-C8环烷基、烷氧基、C3-C8杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、杂芳基；
R 8、R 9分别独立地选自氢、氨基、羟基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
R 2为氢、C1-C8烷基、羟基、氨基、C1-C8烷氧基、C1-C8烷胺基、卤素；
R 3、R 4分别选自氢、卤素、C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C1-C8烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基。
进一步地，所述化合物为如下化合物之一，但是不局限于下列化合物：
Figure PCTCN2018122247-appb-000007
Figure PCTCN2018122247-appb-000008
Figure PCTCN2018122247-appb-000009
Figure PCTCN2018122247-appb-000010
Figure PCTCN2018122247-appb-000011
本发明还提供了前述化合物、或其光学异构体、或其顺反异构体或其溶剂合物、或其药学上可接受的盐、或其前体药物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。
本发明还提供了前述化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体在制备IDO抑制剂类药物中的用途
进一步地，所述具有IDO介导的色氨酸代谢途径的病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病；其中所述的癌症优选乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤。
本发明还提供了一种药物组合物，它是以前述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明中，“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
本发明中，碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca-b烷基表明任何含“a”至“b”个碳原子的烷基，包括直链烷基和支链烷基。因此，例如，C1-6烷基是指包含1～6个碳原子的直链烷基和支链烷基。
本发明中，卤素指氟原子、氯原子、溴原子、碘原子。
本发明中“环烷基”指全碳原子形成的饱和环或非芳香性的不饱和环。
本发明中的“杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子。
本发明中“芳基”指全碳原子形成的具有芳香性的不饱和环。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的 盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。
IDO抑制剂是一类药物，可以用于治疗癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病等疾病。
本发明的化合物显示了优良的IDO酶学抑制活性和细胞抑制活性，可以制成IDO抑制剂，治疗包括肿瘤在内的多种疾病，同时具有良好的药代动力学特性，在IDO抑制相关的癌症治疗领域有很大的应用潜力。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明化合物的合成
通用合成路线：
Figure PCTCN2018122247-appb-000012
PG为保护基，包括但不局限于Boc,Fmoc等。
制备得到了以下化合物：
实施例1：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰吡咯烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物7):
合成路线：
Figure PCTCN2018122247-appb-000013
(1)化合物1的合成
将3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(26g，76.01mmol)加入380mL三氟乙酸中，加入230mL双氧水溶液(30％)，于55℃-60℃反应12小时。反应结束后，冷却，将反应液倒入1L冰水中，搅拌条件下析出固体。过滤，固体用100mL水洗两次，得到的固体为化合物1，固体干燥后重13.57g(棕黄色固体)，产率48％。 1H NMR(DMSO-d 6，400MHz)：δ8.05(dd,J＝2.4,6.0Hz,1H),7.67(m,J＝2.4,4.4Hz,1H),7.57(t,J＝8.8,17.6Hz,1H)
(2)化合物7.1的合成
将化合物(1)(312.53mg，0.84mmol)溶于22.5mL四氢呋喃中，加入1-叔丁氧羰基-3-(氨基甲基)吡咯烷(336.47mg，1.68mmol)，加入2.25mL 2.5M的氢氧化钠溶液，搅拌反应30分钟。反应结束后，向反应液中加入饱和的氯化铵水溶液50mL，用乙酸乙酯萃取(50mL)，得到的有机相用0.2N的盐酸水洗(50mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品产物7.1(382mg，黄色固体)，产物不经纯化直接进行下一步反应。MS(ESI)m/e 499.1(M+H) +
(3)化合物(7.2)的合成
将化合物(7.1)(379.49mg，0.76mmol)溶于20mL乙酸乙酯中，加入N,N-羰基二咪唑(184.85mg,1.14mol)，搅拌条件下回流反应0.5小时。反应结束后，待反应液冷却后，用0.2N的盐酸水洗(50mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品产物7.2(362mg，黄色固体)，产物不经纯化直接进行下一步反应。MS(ESI)m/e 525.1(M+H) +
(4)化合物(7.3)的合成
将化合物(7.2)(360mg，0.689mmol)溶于3mL二氯甲烷中，加入1.5mL三氟乙酸，搅拌反应1小时。反应结束后，将反应液减压浓缩，得到粗品标题产物7.3(320mg，黄色油状物)，产物不经纯化直接进行下一步反应。MS(ESI)m/e 425.2(M+H) +
(5)化合物(7.4)的合成
将氯磺酸异氰酸酯(0.212g,1.5mmol)溶于5mL二氯甲烷中，冷却至0℃，加入叔丁醇(0.115g,1.55mmol)，反应液在0℃条件下反应1小时，制得反应液A。将化合物(7.3)(320mg，0.752mmol)溶于5mL二氯甲烷中，加入1.0mL三乙胺，制得反应液B。在0℃条件下将反应液A加入反应液B中，并在0℃条件下反应1小时。反应结束后，加入饱和碳酸氢钠溶液将反应液淬灭，分液，有机相用0.2N的盐酸水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法展开剂体系二氯甲烷/甲醇＝10:1纯化，得到产物7.4(291mg,白色固体)。MS(ESI)m/e 604.06(M+H) +.
(6)化合物(7.5)的合成
将化合物(7.4)(290mg，0.480mmol)溶于3mL二氯甲烷中，加入1.5mL三氟乙酸，搅拌反应1小时。反应结束后，将反应液减压浓缩，得到粗品产物7.5(265mg，白色固体)，产物不经纯化直接进行下一步反应。MS(ESI)m/e 504.01(M+H) +.
(7)化合物(7)的合成
将化合物(7.5)(260mg，0.516mmol)溶于2mL四氢呋喃中，在0℃条件下加入0.5mL2.0N氢氧化钠溶液，搅拌反应1小时。反应结束后，向反应液中加入饱和的氯化铵水溶液(5mL)，用乙酸乙酯萃取，得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法展开剂体系二氯甲烷/甲醇＝10:1纯化，得到标题产物7(185mg,白色固体)。
1H NMR(DMSO-d 6,400MHz)：δ11.46(s,1H),8.92(s,1H),7.19(t,J＝8.4,17.6Hz,1H),7.12-7.10(m,1H),6.78-6.71(m,3H),6.39-6.37(m,1H),3.27-3.07(m,5H),2.90-2.85(m,1H),2.55-2.51(m,1H),1.94-1.89(m,1H)，1.59-1.54(m,1H).MS(ESI)m/e 478(M+H) +.
用类似于上述的实施例1的合成方法制备了下列的实施例化合物。
实施例2：4-((氮杂环丁烷基-3-基甲基)氨基)-N-(3-溴-4-氟苯基)-N'-羟基-1,2,5-噁二唑-3-甲脒(化合物2)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环丁烷-1-甲酸酯为原料制备得了实施例2。
Figure PCTCN2018122247-appb-000014
1H NMR(DMSO-d 6,400MHz)：δ8.93(s,1H),7.19(t,J＝8.8,17.2Hz,1H),7.11-7.09(m,J＝2.8,6Hz,1H),6.77-6.75(m,J＝3.2,4.8Hz,1H),6.48(m,1H),3.89(t,J＝8.8,17.6Hz,2H),3.65(t,J＝7.2,16.4Hz,2H),3.51-3.35(m,3H),3.02(m,1H).MS(ESI):m/e 385(M+H) +.
实施例3：叔丁基3-(((4-(N-(3-溴-4-氟苯基)-N'-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)甲基)氮杂环丁烷-1-甲酸酯(化合物3)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环丁烷-1-甲酸酯为原料制备得了实施例3.
Figure PCTCN2018122247-appb-000015
1H NMR(400MHz,DMSO-d 6)：δ11.42(s,1H),8.93(s,1H),7.18(t,J＝8.8,17.6Hz,1H),7.12-7.10(m,J＝2.4,6Hz,1H),6.77-6.73(m,1H),6.40(t,J＝6.0,12Hz,1H),3.86(t,J＝8.0,16Hz,2H),3.53(m,2H),3.54-3.37(m,2H),2.79-2.76(m,1H),1.37(m,9H).MS(ESI):m/z(M+H) +485.1
实施例4：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰氮杂环丁烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物4)
用类似于上述的实施例1的合成方法，使用化合物3为原料制备得了实施例4.
Figure PCTCN2018122247-appb-000016
1H NMR(DMSO-d 6,400MHz)：δ11.43(s,1H),8.93(m,1H),7.19-7.0(m,2H),6.91(m,2H),6.84-6.77(m,1H),6.40(m,1H),3.75-3.41(m,8H),2.74(m,1H)。MS(ESI):m/z 464.2(M+H) +.
实施例5：叔丁基3-(((4-(N-(3-溴-4-氟苯基)-N'-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)甲基)氮杂环戊烷-1-甲酸酯(化合物5)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例5.
Figure PCTCN2018122247-appb-000017
MS(ESI):m/z(M+H) +499.1
实施例6：N-(3-溴-4-氟苯基)-N'-羟基-4-((氮杂环戊烷-3-基甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物6)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例6.
Figure PCTCN2018122247-appb-000018
MS(ESI):m/z(M+H) +399
实施例7：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰吡咯烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例7.
Figure PCTCN2018122247-appb-000019
1H NMR(DMSO-d 6,400MHz)：δ11.46(s,1H),8.92(s,1H),7.19(t,J＝8.4,17.6Hz,1H),7.12-7.10(m,1H),6.78-6.71(m,3H),6.39-6.37(m,1H),3.27-3.07(m,5H),2.90-2.85(m,1H),2.55-2.51(m,1H),1.94-1.89(m,1H)，1.59-1.54(m,1H)。MS(ESI):m/e 478(M+H) +.
实施例8：(S)-N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰吡咯烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物8)
用类似于上述的实施例1的合成方法，使用化合物1和(S)-叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例8.
Figure PCTCN2018122247-appb-000020
MS(ESI):m/z(M+H) +478
实施例9：(R)-N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰吡咯烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物9)
用类似于上述的实施例1的合成方法，使用化合物1和(R)-叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例9.
Figure PCTCN2018122247-appb-000021
MS(ESI):m/z(M+H) +478
实施例10：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰哌啶-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(化合物10)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环己烷-1-甲酸酯为原料制备得了实施例10.
Figure PCTCN2018122247-appb-000022
1HNMR(400Hz,DMSO-d6):δ11.459(1H,s),8.902(1H,s),7.204-7.160(1H,t,J＝8.8Hz),7.133-7.111(1H,dd,J＝6.2Hz，2.6Hz),6.774-6.734(1H,m),6.705(2H,s),6.290-6.260(1H,t,J＝6.0Hz),3.426-3.389(1H,m),3.345-3.294(1H,m),3.154-3.122(2H,m),2.544-2.523(1H,m),2.324-2.271(1H,t,J＝10.6Hz),1.958-1.880(1H,m),1.754-1.702(1H,m),1.660-1.620(1H,m),1.482-1.433(1H,m),1.049-0.952(1H,m).MS(ESI):m/z 492(M+H) +。
实施例11；：N-(3-溴-4-氟苯基)-N'-羟基-4-(((4-氨磺酰吗啉-2-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(11)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基甲基)吗啉-4-甲酸酯为原料制备得了实施例11.
Figure PCTCN2018122247-appb-000023
MS(ESI):m/z(M+H) +494
实施例12：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰氮杂环丁烷-2-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(12)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基甲基)氮杂环丁烷-1-甲酸酯为原料制备得了实施例12.
Figure PCTCN2018122247-appb-000024
1H NMR(DMSO-d 6,400MHz)：δ11.54(s,1H),8.88(s,1H),7.21–7.16(t,J＝8.8Hz,1H),7.14–7.12(dd,J＝6.2,2.6Hz,1H),6.98(s,2H),6.81–6.77(m,1H),6.29–6.26(t,J＝5.8Hz,1H),4.30–4.22(m,1H),3.73–3.66(m,1H),3.53–3.48(m,1H),3.46–3.43(m,2H),2.11–2.02(m,2H).MS(ESI):m/z(M+H) +464
实施例13：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰氮杂环戊烷-2-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(13)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例13.
Figure PCTCN2018122247-appb-000025
1H NMR(DMSO-d6,400MHz)：δ11.51(s,1H),8.88(s,1H),7.18(t,J＝8.8,17.6Hz,1H), 7.13-7.11(m,1H),6.80-6.76(m,3H),6.20(t,J＝6.0,12.4Hz,1H),3.85-3.83(m,1H),3.37-3.34(m,1H),3.29-3.19(m,3H),1.86-1.82(m,3H)，1.71-1.68(m,1H)。MS(ESI):m/z 478.1(M+H) +。
实施例14：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰氮杂环己烷-2-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(14)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基甲基)氮杂环己烷-1-甲酸酯为原料制备得了实施例14.
Figure PCTCN2018122247-appb-000026
1HNMR(400Hz,DMSO-d 6):δ11.4(1H,s),8.87(1H,s),7.18-7.14(1H,t,J＝8.8Hz),7.13-7.11(1H,t,J＝3.4Hz),6.78-6.74(1H,m),6.66(2H,s),6.19-6.16(1H,m),4.07-4.02(1H,m),3.56-3.50(2H,m),3.44-3.37(1H,m),3.01-2.95(1H,m),1.57-1.49(6H,m).MS(ESI):m/z(M+H) +492。
实施例15：N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰氮杂环丁烷-2-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(15)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基乙基)氮杂环丁烷-1-甲酸酯为原料制备得了实施例15.
Figure PCTCN2018122247-appb-000027
MS(ESI):m/z(M+H) +478
实施例16：N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰氮杂环戊烷-2-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(16)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基乙基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例16.
Figure PCTCN2018122247-appb-000028
1H NMR(DMSO-d 6,400MHz)：δ11.44(s,1H),8.89(s,1H),7.19(t,J＝8.8,17.6Hz,1H),7.12-7.11(m,1H),6.78-6.73(m,3H),6.17-6.14(m,1H),3.65-3.64(m,1H),3.28-3.22(m,3H),3.17-3.13(m,1H),1.94-1.58(m,6H)。MS(ESI):m/z(M+H) +492
实施例17：N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰氮杂环己烷-2-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(17)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇2-(氨基乙基)氮杂环己烷-1-甲酸酯为原料制备得了实施例17.
Figure PCTCN2018122247-appb-000029
1H NMR(DMSO-d 6,400MHz)：δ11.45(s,1H),8.90(s,1H),7.18(t,J＝8.8,17.6Hz,1H),7.11-7.09(m,1H),6.78-6.67(m,3H),6.20-6.17(m,1H),3.30-3.20(m,2H),2.25-2.23(m,1H),1.72-1.69(m,1H),1.53-1.46(m,4H)，1.49-1.46(m,1H)。MS(ESI):m/z(M+H) +506.2
实施例18：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨磺酰氮杂环己烷-4-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(18)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇4-(氨基甲基)氮杂环己烷-1-甲酸酯为原料制备得了实施例18.
Figure PCTCN2018122247-appb-000030
1H NMR(DMSO-d 6,400MHz)：δ11.43(s,1H),8.92(s,1H),7.19(t,J＝8.8,17.6Hz,1H),7.13-7.11(m,1H),6.79-6.76(m,1H),6.70(s 2H),6.29(t,J＝6.0,11.6Hz,1H),3.47-3.44(m,2H),3.11-3.08(m,2H),2.49-2.42(m,2H),1.68-1.65(m,3H)，1.23-1.17(m,2H)。MS(ESI): m/z(M+H) +492。
实施例19：N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰氮杂环己烷-4-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(19)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇4-(氨基乙基)氮杂环己烷-1-甲酸酯为原料制备得了实施例19.
Figure PCTCN2018122247-appb-000031
1H NMR(DMSO-d 6,400MHz)：δ11.44(s,1H),8.91(s,1H),7.19(t,J＝8.4,16.8Hz,1H),7.11(m,1H),6.78-6.68(m,3H),6.17(m,1H),3.44-3.42(m,2H),3.24-3.23(m,2H),2.47-2.44(m,2H),1.77-1.74(m,2H)，1.50-1.49(m,2H),1.19-1.17(m,3H).MS(ESI):m/z(M+H) +506.2。
实施例20：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-甲磺酰氮杂环戊烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(20)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例20.
Figure PCTCN2018122247-appb-000032
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.92(s,1H),7.21–7.16(t,J＝8.8Hz,1H),7.12–7.10(m,1H),6.79–6.75(m,1H),6.41–6.38(t,J＝5.8Hz,1H),3.37–3.28(m,2H),3.25–3.22(m,2H),3.21–3.18(m,1H),2.99–2.94(dd,J＝10.0,6.8Hz,1H),2.89(s,3H),2.60–2.55(m,1H),1.99–1.94(m,1H),1.66–1.59(m,1H).MS(ESI):m/z(M+H) +477.
实施例21：N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-环丙磺酰氮杂环戊烷-3-基)甲基)氨基)-1,2,5-噁二唑-3-甲脒(21)
用类似于上述的实施例1的合成方法，使用化合物1和叔丁醇3-(氨基甲基)氮杂环戊烷-1-甲酸酯为原料制备得了实施例21.
Figure PCTCN2018122247-appb-000033
1H NMR(400MHz,DMSO-d 6)：δ11.45(s,1H),8.93(s,1H),7.19(t,J＝8.8,17.6Hz,1H),7.12-7.11(m,1H),6.78-6.76(m,1H),6.41(m,1H),3.34-3.23(m,4H),3.06-3.02(m,1H),2.70-2.57(m,3H),1.66-1.63(m,1H),1.19-1.16(m,1H),0.96-0.94(m,1H).MS(ESI):m/z(M+H) +503
实施例22:(Z)-N-(3-溴-4-氟苯)-4-(((1-(N,N-二甲磺酰基)吡咯烷基-3-基)甲基)氨基)-N'-羟基-1,2,5-恶二唑-3-羧肟酰胺(化合物23)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000034
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.92(s,1H),7.18(t,J＝8.7Hz,1H),7.11(d,J＝3.5Hz,1H),6.78(s,1H),6.39(s,1H),3.27–3.17(m,5H),3.00–2.91(m,1H),2.74(s,1H),2.73(s,6H),1.62(dd,J＝12.2,7.9Hz,1H),1.36(m,2H).LC/MS(ESI+)calcd for C16H21BrFN7O4S([M+H]+)m/z:506.1；found 506.0.
实施例23:(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((1-氨磺酰基吡咯烷-3-基)甲氧基)-1,2,5-恶二唑-3-甲脒(化合物27)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000035
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),9.07(s,1H),7.17(t,J＝8.7Hz,1H),7.11(dd,J＝6.0,2.7Hz,1H),6.78(s,2H),6.72–6.65(m,1H),4.17(t,J＝7.6Hz,2H),3.26–3.21(m,1H),3.16–3.08(m,2H),2.88(dd,J＝10.2,6.5Hz,1H),1.89(dd,J＝12.6,5.3Hz,1H),1.52(dq,J＝14.8,7.4Hz,1H),0.95(t,J＝7.1Hz,1H).LC/MS(ESI+)m/z,479(M+H +)。
实施例24:N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-磺酰胺基吡咯烷-3-基)甲基)硫醚)-1,2,5-噁二唑-3-脒(化合物28)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000036
1H NMR(400MHz,DMSO-d 6)δ11.75(s,1H),9.02(s,1H),7.19(t,J＝8.7Hz,1H),7.09(dd,J＝5.9,2.5Hz,1H),6.78(s,2H),6.74–6.65(m,1H),3.27(ddd,J＝25.3,15.6,10.7Hz,4H),3.13(dd,J＝17.1,7.7Hz,1H),2.93(dd,J＝9.8,7.3Hz,1H),2.65–2.56(m,1H),2.04(dd,J＝12.0,4.9Hz,1H),1.67(dd,J＝12.3,7.9Hz,1H).LC/MS(ESI+)calcd for C 23H 24ClN 3O 2(M+H +)m/z,496.0；found:496.0
实施例25:(Z)-N-(3-溴-4-氟苯基)-4-(((1-(环丙基磺酰基)叠氮基-3-基)甲基)氨基)-N'-羟基-1,2,5-恶二唑-3-羧肟酰胺(化合物86)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000037
1H NMR(400MHz,DMSO-d 6)：δ11.40(s,1H),8.94(s,1H),7.19(t,J＝8.4,17.2Hz,1H),7.12-7.10(m,1H),6.75-6.71(m,1H),6.47(t,J＝5.6,11.6Hz,1H),3.93-3.89(m,2H),3.66-3.63(m,2H),3.44-3.38(m,2H),2.86-2.83(m,1H),2.75-2.71(m,1H),1.03-0.99(m,1H),0.92-0.89(m,1H).LC/MS(ESI +)C 16H 18BrFN 6O 4S(M+H +)m/z,489。
实施例26:(Z)N-(3-溴-4-氟苯基)-4-(3-氟-1-磺胺嘧啶-3-基)甲基)氨基)-N′-羟基1,2,5-恶二唑-3-羧肟酰胺(化合物91)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000038
1H NMR(CD 3OD,400MHz)：δ7.17-7.15(m,1H),7.09-7.05(m,1H),6.89-6.85(m,1H),3.99-3.95(m,4H),3.85-3.80(m,2H).LC/MS(ESI +)m/z,482(M+H +)。
实施例27:(Z)N-(3-溴-4-氟苯基)-N′-羟基-4-(3-羟基-1-磺胺嘧啶-3-基)甲基)氨基)-1,2,5-恶二唑-3-羧肟酰胺(化合物127)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000039
1H NMR(DMSO-d 6,400MHz)：δ11.62(s,1H),8.90(s,1H),7.21-7.12(m,2H),6.98(s,2H),6.82-6.78(m,1H),6.14-6.12(m,2H),3.65-3.59(m,4H),3.52-3.51(m,2H).LC/MS(ESI +)m/z,480(M+H +)。
实施例28:(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰基氮杂环丁烷-3-基)乙基)氨基)-1,2,5-恶二唑-3-甲脒(化合物132)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000040
1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.93(s,1H),7.20(t,J＝8.8Hz,1H),7.12(dd,J＝6.0,2.7Hz,1H),6.78(s,1H),6.22(s,1H),3.75(t,J＝8.0Hz,2H),3.60(d,J＝6.6Hz,1H),3.42–3.38(m,2H),3.18(d,J＝6.4Hz,2H),1.82(d,J＝7.0Hz,2H),1.77(dd,J＝6.8,3.3Hz,2H).LC/MS(ESI+)m/z,478(M+H +).
实施例29:(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨基甲酰基氮杂环丁烷)-3-甲基)胺)-1,2,5-恶二唑-3-甲脒(化合物140)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000041
1H NMR(400MHz,DMSO-d 6)δ11.54(s,1H),9.00(s,1H),7.27(t,J＝8.8Hz,1H),7.19(dd,J＝6.1,2.7Hz,1H),6.84(m,1H),6.46(d,J＝5.9Hz,1H),5.90(s,2H),3.89(t,J＝8.1Hz,2H),3.57(dd,J＝8.1,5.2Hz,2H),3.47(dd,J＝12.3,5.8Hz,2H),2.84(m,1H).LC/MS(ESI+)calcd for C 14H 15BrFN 7O 3([M+H] +)m/z 428.0；found 428.0.
实施例30:(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-(((1-氨基磺酰基氮杂环丁烷)-3-甲基)巯)-1,2,5-恶二唑-3-甲脒(化合物148)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000042
1H NMR(400MHz,DMSO-d 6)δ11.76(s,1H),8.99(s,1H),7.17(t,J＝8.8Hz,1H),7.07(dd,J＝6.0,2.4Hz,1H),6.92(s,2H),6.71(m,1H),3.82(t,J＝8.0Hz,2H),3.52(m,2H),3.40(d,J＝7.2Hz,1H),2.87(m,1H).LC/MS(ESI+)calcd for C 13H 14BrFN 6O 4S 2([M+H] +)m/z 481.0；found 481.0.
实施例31:(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(1-氨磺酰基氮杂环丁烷-3-基)乙基)硫代)-1,2,5-恶二唑-3-甲脒(化合物149)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000043
1H NMR(400MHz,DMSO-d 6)δ11.72(s,1H),9.01(s,1H),7.19(t,J＝8.8Hz,1H),7.07 (dd,J＝6.0,2.7Hz,1H),6.88(s,2H),6.71–6.67(m,1H),6.52(s,1H),3.76(t,J＝8.0Hz,2H),3.45–3.40(m,2H),3.13(t,J＝7.2Hz,2H),1.98(d,J＝7.1Hz,2H).LC/MS(ESI+)Calcd for C 14H 16BrFN 6O 4S 2(M+H +)m/z,496.0；Found,497.0
实施例32:(Z)N-(3-溴-4-氟苯基)-N′-羟基-4-(((1–磺胺嘧啶-3-基)甲基-D2)氨基)-1,2,5-恶二唑-3-羧肟酰胺(化合物150)
用类似于上述的实施例1的合成方法制备得到。
Figure PCTCN2018122247-appb-000044
1H NMR(CD 3OD,400MHz)：δ7.03-7.01(m,1H),6.97-6.93(m,1H),6.76-6.72(m,1H),3.80-3.76(m,2H),3.51-3.48(m,2H),2.78-2.75(m,1H).LC/MS(ESI +)m/z,466(M+H +)。
以下通过试验例来具体说明本发明的有益效果：
以下生物学试验例来进一步说明本发明的用途，但并不意味着限制本发明的应用范围。
试验例1：本发明化合物对人源IDO1蛋白酶抑制活性的测定：
1)实验材料及仪器：
IDO1(His-tag)酶(BPS Bioscience)
L-色氨酸(Sigma)
亚甲基蓝(Sigma)
源自牛肝脏的过氧化氢酶(Sigma)
L-抗坏血酸(Sigma)
丙三醇(Sigma)
磷酸二氢钾溶液(Sigma)
吐温20(Tween 20，Sigma)
自动加样工作平台Liquid handler(Bravo&Echo)
酶标仪SpectraMax M5e(Molecular Devices)
2)化合物测试实验方法：用吸光度试验方法对待测化合物进行测试：
将待测化合物和参照化合物加DMSO配成高浓度储存溶液。用DMSO稀释参照化合物 储存液，配成100×溶液。在工作板中第一列加入8μL上述待测化合物和100×参照化合物为最高浓度，3倍稀释11个浓度，配成100×溶液。取以上板中溶液0.5μL到检测板。每孔加入0.5μL 100X化合物溶液。HPE和ZPE对照孔加入0.5μL100％DMSO。
向每孔加入25μL 2×IDO1(His-tag)酶溶液(包含L-抗坏血酸，亚甲基蓝和过氧化氢酶)。HPE对照孔加入25μL不含有IDO1(His-tag)酶的反应液。将检测板1000rpm离心1分钟混匀。然后将检测板放置室温下孵育30分钟。再向每孔加入25μL上述2×底物(L-色氨酸)溶液。将检测板1000rpm离心1分钟混匀。将检测板置于酶标仪(SpectraMax M5e)，设置温度为25℃，每隔10分钟在320nm处测吸光度(OD值)，测至60分钟。
计算吸光值增长率：从SpectralMax M5e中导出10分钟到60分钟吸光值增长曲线的斜率。计算化合物抑制系数：化合物抑制率＝(ZPE对照孔吸光值增长率-化合物孔吸光值增长率)/(ZPE对照孔吸光值增长率-HPE对照孔吸光值增长率)X 100。结果用Prism 5.0进行分析。
3)结果：本发明中化合物对人源IDO1蛋白酶活性抑制IC 50见表1.
表1化合物对人源IDO1蛋白酶活性抑制
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
2 182 21 141
3 430 23 183
4 55 24 69
5 276 25 96
6 88 26 340
7 59 27 628
8 112 28 107
9 84 29 173
10 254 78 69
11 206 81 142
12 133 85 115
13 214 86 167
14 279 89 183
16 151 91 128
18 114 92 64
19 119 150 81
20 79 151 101
结论：本发明化合物对人源IDO1蛋白酶活性具有明显的抑制作用。
试验例2：本发明化合物对Hela细胞内IDO蛋白酶活性抑制的测定：
1)实验材料及仪器：
HeLa细胞(ATCC,Cat.No.CCL-2)
γ干扰素IFNγ(R&D,Cat.No.285-IF-100)
DMEM High Glucose培养基(Invitrogen,Cat.No.11965-084)
胎牛血清FBS(Invitrogen,Cat.No.10100-147)
胰酶Trypsin-EDTA(0.05％)(Invitrogen,Cat.No.25300-054)
磷酸盐缓冲液PBS,pH 7.4(Invitrogen,Cat.No.10010023)
青-链霉素Penicillin-Streptomycin(P/S)(Invitrogen,Cat.No.15070063)
L-色氨酸(Trp)(Sigma,Cat.No.T8941)
L-犬尿氨酸(Kyn)(Sigma,Cat.No.K8625)
N'-二甲酰犬尿氨酸(NFK)(J&K,Cat.No.F700490)
3-硝基-L-酪氨酸(J&K,Cat.No.N0905)
乙腈(Sigma,Cat.No.34851)
二甲基亚砜DMSO(Sigma,Cat.No.D8418)
抑制剂INCB024360(Selleckchem,Cat.No.S7910)
抑制剂INCB024360-analog(MedKoo,Cat.No.205493)
抑制剂NLG919(Selleckchem,Cat.No.S7111)
96孔透明平底聚苯乙烯细胞培养板(Corning,Cat#3599)
96孔V型底聚丙烯板(PE,Cat#6008290)
96孔U型底聚丙烯板(PE,Cat.No.6008390)
Multidrop TM小管金属尖端的分配盒(Thermo,Cat.No.24073295)
Multidrop TM标准管金属尖端的分配盒(Thermo,Cat.No.24072670)
自动加液工作平台(Agilent)
Multidrop TMCombi自动分液器(Thermo)
离心机(Eppendorf)
细胞培养箱(Thermo)
细胞计数仪(Thermo)
RapidFire质谱***(Agilent)
2)化合物测试实验方法：
用DMSO将化合物(本发明化合物4、8、9、78、91)配置成浓度3mM，然后取15μl化合物加入到96孔板中，以3倍连续稀释化合物共10个点。转移2μl化合物或DMSO(用于HPE/ZPE)到一个新的96孔板中。HeLa细胞悬液以10000个细胞/孔的密度接种到细胞培养板。用于检测的细胞培养基为：HPE对照孔为DMEM；10％FBS；1％P/S；122μM Trp；ZPE对照孔及化合物孔为DMEM；10％FBS；1％P/S；122μM Trp；25ng/ml IFNγ。加入192μl上述准备的检测培养基到一个96孔板中。化合物板中加入78μl DMEM培养基并充分混匀，然后转移8μl DMEM培养基稀释过的化合物到已经加入检测培养基的96孔板。取出细胞培养板并弃去其中的细胞培养基，然后转移100μl上述化合物到细胞培养板中，将细胞培养板转入细胞培养箱中继续培养48小时。检测时取出细胞培养板，并转出50μl上清到一新的96孔板，加入200μl乙腈到上述板中并充分混匀，4℃离心20分钟(转速4000rpm)，转移40μl上清到另一96孔板中，再加入360μl含有2μg/ml内参(3-硝基-L-酪氨酸)的去离子水，充分混匀后用RapidFire/MS***对样品进行检测。将L-色氨酸(Trp)和L-犬尿氨酸(Kyn)的标准品溶解于水中配置浓度为10mM，并进行三倍稀释配制标准曲线。所得数据计算出抑制率用Graphpad Prism5软件进行处理得到其IC 50曲线。
3)结果：
本发明化合物对HeLa细胞内IDO蛋白酶抑制活性通过以上的试验进行测定，测得的IC 50值见表2.
表2.本发明中化合物对HeLa细胞内IDO蛋白酶抑制活性
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
4 5 132 10
8 17 140 75
9 15 148 14
78 13 149 18
91 74 150 9
结果显示，本发明中化合物对HeLa细胞内IDO蛋白酶有显著抑制活性，其中化合物4和化合物91的抑制活性优良，可以治疗***。
试验例3：本发明化合物的小鼠药代动力学
1)实验材料及仪器：
LC-20AD高效液相色谱***(日本SHIMADZU(岛津)公司)
API4000三重四极杆质谱仪，(美国Applied Biosystem公司)
PhenixWinnolin药动学软件(Version 6.3，美国Certara公司)
高速冷冻离心机(Thermo Fisher Scientific)
分析天平(赛多利斯，SECURA225D-1CN)
实验动物：ICR小鼠(成都达硕实验动物有限公司)
DMA(Sigma)
CMC-Na(成都科龙化工)
肝素(成都科龙化工)
2)实验方法及结果
精密称取化合物(本发明化合物为化合物4，以进入临床III期的类似发明参照化合物INCB-24360为对照化合物)5mg，加入相应的溶媒至终体积10ml，超声涡旋混匀。配置成浓度为0.5mg/ml的溶液。取配制的终溶液0.2ml，于-20℃保存，用于浓度测定。健康成年ICR小鼠9只(20-30g)，禁食过夜(自由饮水)后，灌胃给药，给药体积0.2ml/10g；于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml，4℃离心5min分离血浆，于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。
表3.本发明化合物的药代动力学参数
Figure PCTCN2018122247-appb-000045
化合物4和已经进入临床III期的类似发明参照化合物INCB-24360做了小鼠PK进行比较。本发明的化合物相比于类似发明参照化合物有更长的半衰期，在药代动力学上有明显改善，差异显著。
本发明的化合物显示了优良的IDO酶学抑制活性和细胞抑制活性，以及良好的药代动 力学，在IDO抑制相关的癌症治疗领域有很大的应用潜力。

Claims (10)

  1. 式(I)所示的化合物、或其光学异构体、或其顺反异构体，或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体：
    Figure PCTCN2018122247-appb-100001
    其中，X为氨基、氧、硫；
    R 1为氢、-(CH 2) mCOR 5、-(CH 2) mSO 2R 6、-(CH 2) mCOOR 7、烷基、卤代烷基、烷氧基、环烷基、取代环烷基、杂环烷基、取代杂环烷基、不饱和杂环基、取代不饱和杂环烷基、芳基、取代芳基、芳香杂环基、取代杂芳基；m选自0～5整数；
    R 5、R 6、R 7分别独立地选自烷基、氨基、-NR 8R 9、羟基、环烷基、烷氧基、杂环烷基、-CONR 8R 9、芳基、芳香杂环基；
    R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
    R 2为氢、烷基、羟基、氨基、烷氧基、烷胺基、卤素；
    R 3、R 4分别选自氢、卤素、氰基、烷基、环烷基、杂环烷基、烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基；
    其中，氢是指氢元素(H)或同位素氘(D)；
    a＝0～5的整数；b＝0～5的整数；c＝1～5的整数；a和b不同时为0。
  2. 根据权利要求1所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体，其特征在于：所述化合物具有如式(Ⅱ)所示的结构：
    Figure PCTCN2018122247-appb-100002
    其中，R 6选自烷基、氨基、羟基、环烷基、烷氧基、杂环烷基、-CONR 8R 9、-NR 8R 9芳基、芳香杂环基；
    R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环。
  3. 根据权利要求1所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体，其特征在于：所述化合物具有如式(Ⅲ)所示的结构：
    Figure PCTCN2018122247-appb-100003
    其中，R 5选自烷基、氨基、羟基、环烷基、烷氧基、杂环烷基、-CO NR 8R 9、-NR 8R 9、芳基、芳香杂环基；
    R 8、R 9分别独立地选自氢、氨基、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环。
  4. 根据权利要求1所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体，其特征在于：a为0时，所述化合物具有如式(Ⅳ)所示的结构；b为0时，所述化合物具有如式(Ⅴ)所示的结构：
    Figure PCTCN2018122247-appb-100004
    Figure PCTCN2018122247-appb-100005
    R 1为氢、-COR 5、-SO 2R 6、C1-C8烷基、C1-C8卤代烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、C3-C8不饱和杂环基、芳基、取代芳基、芳香杂环基、取代杂芳基；
    R 5、R 6分别独立地选自烷基、羟基、C3-C8环烷基、烷氧基、C3-C8杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、杂芳基；
    R 8、R 9分别独立地选自氢、氨基、羟基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
    R 2为氢、C1-C8烷基、羟基、氨基、C1-C8烷氧基、C1-C8烷胺基、卤素；
    R 3、R 4分别选自氢、卤素、C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C1-C8烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基。
  5. 根据权利要求1所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体，其特征在于：a＝1,b＝1时，所述化合物具有如式(VI)所示的结构：
    Figure PCTCN2018122247-appb-100006
    R 1为氢、-COR 5、-SO 2R 6、C1-C8烷基、C1-C8卤代烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、C3-C8不饱和杂环基、芳基、取代芳基、芳香杂环基、取代杂芳基；
    R 5、R 6分别独立地选自烷基、羟基、C3-C8环烷基、烷氧基、C3-C8杂环烷基、-CONR 8R 9、-NR 8R 9、芳基、杂芳基；
    R 8、R 9分别独立地选自氢、氨基、羟基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、芳基、取代芳基、杂芳基、取代杂芳基，或者R 8和R 9链接成环；
    R 2为氢、C1-C8烷基、羟基、氨基、C1-C8烷氧基、C1-C8烷胺基、卤素；
    R 3、R 4分别选自氢、卤素、C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C1-C8烷氧基、氨基、羧基、芳基、取代芳基、杂芳基、取代杂芳基。
  6. 根据权利要求1所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体，其特征在于：所述化合物为如下化合物之一，但是不局限于下列化合物：
    Figure PCTCN2018122247-appb-100007
    Figure PCTCN2018122247-appb-100008
    Figure PCTCN2018122247-appb-100009
    Figure PCTCN2018122247-appb-100010
    Figure PCTCN2018122247-appb-100011
  7. 权利要求1-6任一项所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。
  8. 权利要求1-6任一项所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体在制备IDO抑制剂类药物中的用途。
  9. 根据权利要求7或8述的用途，其特征在于：所述药物是治疗癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病；其中所述的癌症优选乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤。
  10. 一种药物组合物，其特征在于：它是以权利要求1-6任一项所述的化合物、或其光学异构体、或其顺反异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体为活性成分，加上药学上可接受的辅料制备而成的制剂。
PCT/CN2018/122247 2017-12-20 2018-12-20 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 WO2019120237A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP18890728.1A EP3730484B1 (en) 2017-12-20 2018-12-20 Indoleamine-2,3-dioxygenase inhibitor, preparation method therefor, and application thereof
JP2020533145A JP2021509399A (ja) 2017-12-20 2018-12-20 インドールアミン−２，３−ジオキシゲナーゼ阻害剤およびその調製方法と使用
US16/956,581 US11447477B2 (en) 2017-12-20 2018-12-20 Indoleamine-2,3-dioxygenase inhibitor, the preparative method and the use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711385641 2017-12-20
CN201711385641.3 2017-12-20

Publications (1)

Publication Number Publication Date
WO2019120237A1 true WO2019120237A1 (zh) 2019-06-27

Family

ID=66992425

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/122247 WO2019120237A1 (zh) 2017-12-20 2018-12-20 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途

Country Status (5)

Country Link
US (1) US11447477B2 (zh)
EP (1) EP3730484B1 (zh)
JP (1) JP2021509399A (zh)
CN (1) CN109942565B (zh)
WO (1) WO2019120237A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110343098B (zh) * 2018-04-04 2023-05-26 中国科学院上海药物研究所 一类噁二唑类化合物及其制备方法、药物组合物和用途
CN110204537B (zh) * 2019-07-10 2021-10-08 盛世泰科生物医药技术(苏州)有限公司 一种用作吲哚胺2，3-双加氧酶的抑制剂的1，2，5-噁二唑衍生物
CN116444454B (zh) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101212967A (zh) * 2005-05-10 2008-07-02 因塞特公司 吲哚胺2,3-双加氧酶调节剂及其用法
WO2010005958A2 (en) 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
WO2013174947A1 (en) 2012-05-23 2013-11-28 Stemergie Biotechnology Sa Inhibitors of the activity of complex (iii) of the mitochondrial electron transport chain and use thereof
WO2014066834A1 (en) 2012-10-26 2014-05-01 The University Of Chicago Synergistic combination of immunologic inhibitors for the treatment of cancer
CN105646389A (zh) * 2016-01-28 2016-06-08 中国科学院上海有机化学研究所 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途
WO2016155545A1 (zh) 2015-03-31 2016-10-06 江苏恒瑞医药股份有限公司 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用
CN106565696A (zh) * 2015-10-09 2017-04-19 江苏恒瑞医药股份有限公司 噁二唑类衍生物、其制备方法及其在医药上的应用
WO2017106062A1 (en) * 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Novel compounds as indoleamine 2,3-dioxygenase inhibitors
CN106967005A (zh) * 2017-04-07 2017-07-21 钟燕 一种能抑制ido的化合物、其制备方法及其用途
CN107033097A (zh) * 2016-02-04 2017-08-11 江苏恒瑞医药股份有限公司 噁二唑类衍生物、其制备方法及其在医药上的应用
CN107176933A (zh) * 2016-03-09 2017-09-19 中国科学院上海有机化学研究所 一种含氮烷基化和芳基化亚砜亚胺的吲哚胺-2,3-双加氧酶抑制剂
CN107304191A (zh) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 吲哚胺2,3‑双加氧酶抑制剂及其制备方法与应用
WO2018024208A1 (zh) * 2016-08-02 2018-02-08 南京明德新药研发股份有限公司 Ido1抑制剂及其制备方法和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106883194A (zh) * 2015-12-16 2017-06-23 江苏恒瑞医药股份有限公司 噁二唑类衍生物、其制备方法及其在医药上的应用
WO2018072697A1 (zh) * 2016-10-17 2018-04-26 上海医药集团股份有限公司 含噁二唑环化合物、制备方法、中间体、组合物及应用
CN106866571B (zh) * 2017-01-20 2018-06-29 中国药科大学 杂环脲类化合物及其药物组合物和应用
CN108727361A (zh) * 2017-04-24 2018-11-02 南京药捷安康生物科技有限公司 吲哚胺2,3-双加氧酶抑制剂与应用
CN108586378B (zh) * 2018-01-22 2020-06-19 南京华威医药科技集团有限公司 吲哚胺2,3-双加氧化酶抑制剂及其制备方法和用途

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101212967A (zh) * 2005-05-10 2008-07-02 因塞特公司 吲哚胺2,3-双加氧酶调节剂及其用法
WO2010005958A2 (en) 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
CN102164902A (zh) * 2008-07-08 2011-08-24 因塞特公司 作为吲哚胺2,3-双加氧酶的抑制剂的1,2,5-二唑
WO2013174947A1 (en) 2012-05-23 2013-11-28 Stemergie Biotechnology Sa Inhibitors of the activity of complex (iii) of the mitochondrial electron transport chain and use thereof
WO2014066834A1 (en) 2012-10-26 2014-05-01 The University Of Chicago Synergistic combination of immunologic inhibitors for the treatment of cancer
WO2016155545A1 (zh) 2015-03-31 2016-10-06 江苏恒瑞医药股份有限公司 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用
CN106565696A (zh) * 2015-10-09 2017-04-19 江苏恒瑞医药股份有限公司 噁二唑类衍生物、其制备方法及其在医药上的应用
WO2017106062A1 (en) * 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Novel compounds as indoleamine 2,3-dioxygenase inhibitors
CN105646389A (zh) * 2016-01-28 2016-06-08 中国科学院上海有机化学研究所 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途
CN107033097A (zh) * 2016-02-04 2017-08-11 江苏恒瑞医药股份有限公司 噁二唑类衍生物、其制备方法及其在医药上的应用
CN107176933A (zh) * 2016-03-09 2017-09-19 中国科学院上海有机化学研究所 一种含氮烷基化和芳基化亚砜亚胺的吲哚胺-2,3-双加氧酶抑制剂
CN107304191A (zh) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 吲哚胺2,3‑双加氧酶抑制剂及其制备方法与应用
WO2018024208A1 (zh) * 2016-08-02 2018-02-08 南京明德新药研发股份有限公司 Ido1抑制剂及其制备方法和应用
CN106967005A (zh) * 2017-04-07 2017-07-21 钟燕 一种能抑制ido的化合物、其制备方法及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3730484A4

Also Published As

Publication number Publication date
US20210198247A1 (en) 2021-07-01
JP2021509399A (ja) 2021-03-25
EP3730484C0 (en) 2024-02-28
EP3730484A1 (en) 2020-10-28
EP3730484A4 (en) 2021-08-04
EP3730484B1 (en) 2024-02-28
CN109942565A (zh) 2019-06-28
US11447477B2 (en) 2022-09-20
CN109942565B (zh) 2021-03-26

Similar Documents

Publication Publication Date Title
ES2888473T3 (es) Bencimidazoles sustituidos con isoxazolilo
CN105263915B (zh) 谷氨酰胺酶抑制剂及使用方法
CA2673299C (en) Pyridazinone compounds for the treatment of proliferative diseases
JP4405602B2 (ja) ヒストン脱アセチル化酵素阻害剤
WO2018133716A1 (zh) 杂环脲类化合物及其药物组合物和应用
EP3070089A1 (en) N-benzyl tryptanthrin derivative, and preparation method and application thereof
WO2018184585A1 (zh) 一种能抑制ido的化合物、其制备方法及其用途
BR112015017963A2 (pt) composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto
JP6918378B2 (ja) ＣａＭＫＩＩ阻害剤及びその使用
WO2019120237A1 (zh) 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途
BR112013000783A2 (pt) derivados arilamídicos tendo propriedades antiandrogênicas
BR112020023115A2 (pt) inibidores da via integrada de resposta a tensão
TW201625620A (zh) 作為蛋白去乙醯酶抑制劑及雙蛋白去乙醯酶蛋白激酶抑制劑之雜環氧肟酸及其使用方法
JP2022516685A (ja) ホスファターゼ結合化合物およびそれらを使用する方法
EP3398942A1 (en) Substituted oxadiazole chemical compound and composition containing said chemical compound and use thereof
JP6291066B2 (ja) ナフチル尿素誘導体およびその医療適用
JP7301856B2 (ja) インドールアミン－２，３－ジオキシゲナーゼ阻害剤およびその調製方法と使用
WO2015021894A1 (zh) 新型羟肟酸衍生物及其医疗应用
JP2005120102A (ja) 縮合ヘテロアリール誘導体
WO2019157959A1 (zh) 一种嘧啶类化合物、其制备方法及其医药用途
JP7110335B2 (ja) プロテインキナーゼ阻害剤として有用なピリドキナゾリン誘導体
CA2887420C (en) Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases
EP3447045B1 (en) 1-(1-hydroxy-2,3-dihydro-1h-inden-5-yl)-urea derivatives and related compounds kcnq 2-5 channel activators for treating dysuria
WO2010083649A1 (zh) 双芳基脲类衍生物及用途
CN110256416B (zh) 组蛋白去乙酰化酶抑制剂及其制备方法与用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18890728

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020533145

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018890728

Country of ref document: EP

Effective date: 20200720