WO2021104506A1 - 环状砜类化合物及其制备方法、药物组合物和用途 - Google Patents

环状砜类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2021104506A1
WO2021104506A1 PCT/CN2020/132544 CN2020132544W WO2021104506A1 WO 2021104506 A1 WO2021104506 A1 WO 2021104506A1 CN 2020132544 W CN2020132544 W CN 2020132544W WO 2021104506 A1 WO2021104506 A1 WO 2021104506A1
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compound
amino
pharmaceutically acceptable
hydroxy
synthesis
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French (fr)
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许恒
陈晓光
董毅
季鸣
陈佳静
金晶
薛妮娜
王明晋
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中国医学科学院药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

Definitions

  • the invention belongs to the technical field of pharmacy, and relates to a CXCR2 antagonist cyclic sulfone compound and a preparation method, pharmaceutical composition and application thereof.
  • Chemokines are a type of low molecular weight (mostly 8-10kDa) protein that can chemotactic cell directional movement, composed of 70-100 amino acids. According to the number of highly conserved cysteine residues at the N-terminus of their peptide chains and their relative positions, chemokines are divided into four categories: CXC, CC, C, and CX3C. Studies have shown that chemokines can be released from many inflammatory and structural cells after stimulation, and act through chemokine receptors in the G protein coupled receptor (GPCR) superfamily.
  • GPCR G protein coupled receptor
  • the chemokine receptor CXCR2 can be expressed on neutrophils, macrophages, vascular endothelial cells, oligodendrocyte precursor cells, bone marrow-derived suppressor cells and tumor cells.
  • the glutamate-leucine-arginine motif (+ELR) CXC chemokines combine to play a role, such as interleukin-8 (IL-8 or CXCL8) or growth-related oncogenes (GRO ⁇ , ⁇ , ⁇ or CXCL1,2,3) etc. (see Zarbock et al. Front.Immunol., 3:1 (2012); Ley et al. Am.J Physiol-Reg I 283:R7–R28 (2002); Kurareva et al. Curr .Opin.Pharmacol.30:27(2016)).
  • CXCR2 receptor and its ligand can induce many different cellular responses, and it plays an important role in inflammation, tumors, and central nervous system and other diseases.
  • inflammatory disease models such as chronic obstructive pulmonary disease, acute lung injury, asthma, and atherosclerosis
  • blocking or eliminating CXCR2 can significantly reduce leukocyte recruitment, tissue damage and mortality.
  • some small molecule compounds such as Danirixin, AZD5069 and Navarixin, are used as CXCR2 antagonists, and relevant clinical trials have been carried out for diseases such as chronic obstructive pulmonary disease and asthma (see Neamati et al. Theranostics, 7:1543 (2017)).
  • CXCR2 ligands including growth-regulating oncogenes GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , and IL-8 are highly expressed It also binds and activates CXCR2 expressed on the surface of vascular endothelial cells and neutrophils in peripheral blood vessels to stimulate angiogenesis and promote tumor growth (see Damme et al. Cytokine Growth FR, 22: 345 (2011)).
  • bone marrow-derived suppressor cells In the tumor microenvironment, bone marrow-derived suppressor cells (MDSC) highly express CXCR2. A number of studies have proved that MDSC plays a vital role in protecting tumors from cytotoxic T cell-mediated anti-tumor effects and suppressing immune checkpoint blockade. The infiltration of T cell programmed death protein-1 (PD-1) and MDSCs is a key factor in tumor immune escape. A large number of studies have shown that blocking CXCR2 can prevent the migration of neutrophils and myeloid suppressor cells from the bone marrow to the tumor site. , Increase the infiltration of T cells in tumors and increase the effect of PD-1/PD-L1 inhibitors in mouse tumor models (see Mackall et al. Sci. Transl.
  • CXCR2 antagonists can also directly inhibit the proliferation of tumor cells. Studies have shown that the use of CXCR2 small molecule antagonists to treat human melanoma cells, compared with the control group, after 72 hours of treatment with CXCR2 antagonists, cell proliferation was significantly reduced, and showed a dose-dependent relationship (see Li et al. Med. Clin-barcelona ,152:425(2019)).
  • CXCR2 is highly expressed on oligodendrocytes (OPC) in the central nervous system (CNS), and affects the demyelination response mediated by neutrophils and the myelin repair response mediated by OPC. Function promotes demyelination and affects CNS mechanisms to damage myelin regeneration. Therefore, CXCR2 has also become a potential target for the treatment of multiple sclerosis, brain injury diseases, and Alzheimer’s disease and other central nervous system diseases in recent years (see Lane et al. J. Virol., 93: e00240-19 (2019); McLarno et al. J. Neuroinflamm., 12: 144 (2015)).
  • CXCR2 plays a key role in the pathogenesis of various diseases
  • a CXCR2 antagonist and a preparation method thereof are invented, which can be used to treat or prevent various diseases mediated by CXCR2.
  • the technical problem solved by the present invention is to provide a new type of CXCR2 antagonist, its preparation method, pharmaceutical composition and application have strong antagonistic activity to the chemokine receptor CXCR2, thereby preventing diseases mediated by CXCR2 receptor Has preventive and/or therapeutic effects.
  • the present invention provides the following technical solutions:
  • the first aspect of the technical solution of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • A is selected from
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-3 alkyl, methoxy, ethoxy, trifluoromethyl, and difluoromethyl.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, and trifluoromethyl
  • R 2 is selected from hydrogen, fluorine, and chlorine
  • R 3 is selected from hydrogen, chlorine, and bromine.
  • the preferred compounds according to the present invention are as follows:
  • the second aspect of the technical scheme of the present invention also provides a preparation method of the compound.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
  • the third aspect of the technical solution of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt , And optionally pharmaceutically acceptable carriers and/or excipients; preferably, the pharmaceutical composition further comprises in addition to the compound, its stereoisomers, geometric isomers, tautomers or One or more pharmaceutical active ingredients for preventing and/or treating inflammatory diseases, tumors, autoimmune diseases or neurological diseases other than pharmaceutically acceptable salts; preferably, the pharmaceutical composition is pharmaceutically acceptable Pharmaceutical preparations for the prevention and/or treatment of inflammatory diseases, tumors, autoimmune diseases or neurological diseases.
  • the present invention also provides a pharmaceutical preparation, which comprises at least one of the described compounds, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof, and optionally
  • the pharmaceutical preparation is selected from the following pharmaceutical dosage forms: preparations for parenteral administration, such as injection solutions or suspensions; preparations for enteral administration, such as Oral formulations, such as tablets or capsules; topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.
  • the present invention also provides the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition is prepared for prevention and/ Or use in medicines for the treatment of inflammatory diseases, tumors, autoimmune diseases or neurological diseases.
  • the present invention provides a method for preventing and/or treating inflammatory diseases, tumors, autoimmune diseases or neurological diseases, which method comprises administering to a subject in need thereof a preventive and/or therapeutically effective amount of the compound , Its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl optionally substituted by halogen means that halogen may but need not be present, and the description includes the case where the alkyl group is substituted by halogen and the case where the alkyl group is not substituted by halogen.
  • the compounds of the present invention may contain one or more chiral centers, which exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and their mixtures (such as racemic mixtures) are within the scope of the present invention .
  • the compounds described in the present invention include their geometric isomers.
  • the compound of the present invention may have geometric isomers, and their cis and trans forms and mixtures of cis and trans are all included in the scope of the present invention .
  • Tautomers refer to structural isomers of different energies that are transformed into each other via a low energy barrier.
  • the compound of the present invention also includes its isotope-labeled compound, in which one or more atoms are replaced by naturally found atoms having the same atomic number but different atomic mass or mass number.
  • Examples include, but are not limited to: hydrogen isotopes 2 H and 3 H; carbon isotopes 11 C, 13 C, and 14 C; chlorine isotopes 36 Cl; fluorine isotopes 18 F; iodine isotopes 123 I and 125 I; nitrogen isotopes 13 N and 15 N ; Oxygen isotope 15 O, 17 O and 18 O; Phosphorus isotope 32 P and Sulfur isotope 35 S.
  • Prodrugs of the compounds of the present invention are also included in the scope of the present invention. Certain derivatives of the compounds of the present invention have weak pharmacological activity or no pharmacological activity, but when these derivatives are administered to the body or administered to the body, they can be converted to have pharmacological activity by means such as hydrolysis and cleavage. Of the compounds described in the present invention, these derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed.EBRoche, Found in American Pharmaceutical Association).
  • the compounds of the present invention include their pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable and has the required pharmacological activity of the parent compound. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • the compound of the present invention may contain sufficient acidic groups, sufficient basic groups or both types of functional groups, and correspondingly react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceuticals.
  • the acceptable salt refers to a salt that is pharmaceutically acceptable and has the required pharmacological activity of the parent compound. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • the compound of the present invention may contain sufficient acidic groups, sufficient basic groups or both types of functional groups, and correspondingly react with some inorganic or organic bases, or inorganic and organic acids to
  • Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, Hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, Propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyl Alkyne-1,6-dioxate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , Phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • the pharmaceutical composition of the compound of the present invention When the compound of the present invention is used as a medicine, it is usually administered in the form of a pharmaceutical composition. Therefore, the pharmaceutical composition of the compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient is also included in the scope of the present invention.
  • the carriers, adjuvants, and excipients used herein include any and all solvents, diluents or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, suitable for the specific dosage form desired. Thickener or emulsifier, preservative, solid binder, lubricant, etc. In Remington: The Science and Practice of Pharmacy, 21 st edition, 2005, ed.
  • composition of the present invention can be administered by any route suitable for the condition to be treated.
  • it is administered in the following forms: parenteral, for example, in the form of injectable solutions or suspensions; enteral, for example, orally, for example, in the form of tablets or capsules; topically, for example, in the form of lotions, gels, ointments Or in the form of an emulsion or in the form of a nasal or suppository.
  • Topical application is, for example, application to the skin.
  • Another form of topical administration is administration to the eye.
  • the pharmaceutical composition may be administered in a solid, semi-solid, liquid or gaseous form, or may be in a dry powder, such as a lyophilized form.
  • the pharmaceutical composition can be packaged in a form for convenient delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, lozenges, and lozenges.
  • solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, lozenges, and lozenges.
  • the type of packaging will generally depend on the route of administration. It also covers implantable sustained-release formulations, as well as transdermal formulations.
  • materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphate), Glycine, sorbic acid or potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal dioxide Silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g.
  • lactose glucose and sucrose
  • starches e.g. corn starch and potato Starch
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate
  • tragacanth powder malt
  • gelatin gelatin
  • excipients such as cocoa butter and suppositories Waxes
  • oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil
  • glycols such as propylene glycol or polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • Agar buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, and other non-toxic compatible lubrication Agents such as sodium lauryl sulfate and magnesium stearate.
  • the compounds of the present invention can be used alone or in combination with other therapeutic agents for the treatment of the diseases or disorders (such as cancer) described in the present invention.
  • the compound of the present invention is combined with a second compound that has anti-hyperproliferative properties or is used to treat hyperproliferative diseases (such as cancer) in a pharmaceutical combination preparation, or is administered as a combination therapy. Joint in the program.
  • the second compound of the drug combination formulation or the dosing regimen preferably has complementary activities to the compound of the present invention, so that they do not adversely affect each other.
  • Such compounds are suitably present in the combination in an amount effective for the intended purpose.
  • the compound of the invention is combined with other anti-tumor drugs.
  • the anti-tumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, leuconin, carmustine; metal platinum, including but not limited to carboplatin, cisplatin, oxa Liplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to anisomycin, actinomycin D, daunorin Anti-microtubule or anti-mitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, doxorubicin; Antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine; antibodies, including but not limited to Herceptin and Bevacizumab; Hormones, including but not limited to letrazole, vor
  • the fourth aspect of the technical solution of the present invention also provides the compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the third aspect is prepared for the prevention and/or treatment of CXCR2 receptor mediators.
  • the use of drugs for mediated diseases, wherein the CXCR2 receptor-mediated diseases include chronic obstructive pulmonary disease, asthma, cystic fibrosis, cancer, arthritis, psoriasis, inflammatory bowel disease, pain, multiple sexual sclerosis, Alzheimer's disease, Parkinson's disease.
  • the compound of the present invention shows significant antagonistic activity to CXCR2 in an in vitro test.
  • the compounds of the present invention can be synthesized according to the synthetic schemes herein and/or techniques well known in the art.
  • the compounds provided by the present invention can be prepared according to the following general synthetic methods.
  • R 1 Cl or Me
  • R 2 Cl or F
  • the polysubstituted diarylurea derivatives of the present invention described in the present invention can be prepared by an 8-step reaction.
  • compound B is prepared by acylation reaction
  • compound B is prepared by cyclization and chlorosulfonylation reactions to prepare compound C
  • compound C is prepared by reduction reaction to prepare compound D
  • compound D is prepared by reacting with chloropropionic acid Compound E
  • Compound E undergoes intramolecular acylation to prepare compound F
  • Compound F undergoes oxidation reaction to produce compound G
  • Compound F undergoes ring-opening reaction to produce compound H
  • Compound H reacts with isocyanate to produce the polysubstituted diaryl described in the present invention Base urea derivatives.
  • R 1 F, Cl, Br, Me, CF 3 or H
  • R 2 F, Cl or H
  • R 3 Cl,Me or H
  • the polysubstituted diarylurea derivatives of the present invention described in the present invention can be prepared by a 10-step reaction.
  • compound G is prepared by a 6-step reaction; compound G is prepared by reduction reaction to prepare compound I; compound I is prepared by intramolecular dehydration reaction to prepare compound J; compound J is prepared by ring-opening reaction Compound K; Compound H reacts with isocyanate to prepare the polysubstituted diarylurea derivatives of the present invention.
  • R 1 Cl, Br or Me
  • R 2 F, Cl or H
  • the polysubstituted diaryl squaraamide derivatives of the present invention described in the present invention can be prepared through an 11-step reaction.
  • compound A is used as a starting material to prepare compound K through a 9-step reaction
  • compound L is used as another starting material to prepare compound M by reacting compound L with aniline
  • compound M and compound The K reaction prepares the polysubstituted diaryl squaraamide derivatives of the present invention.
  • R 1 F, Cl, Br, Me, CF 3 or H
  • R 2 F, Cl or H
  • R 3 Me or H
  • the polysubstituted diarylurea derivatives of the present invention described in the present invention can be prepared through an 11-step reaction.
  • compound K is prepared by 9-step reaction; compound K is reduced to prepare compound N; compound N is reacted with isocyanate to prepare the compound of the present invention.
  • the multi-substituted diarylurea derivatives can be prepared through an 11-step reaction.
  • R 1 Cl, Br or Me
  • R 2 H, F or Cl
  • the polysubstituted diaryl squaraamide organisms of the present invention described in the present invention can be prepared by a 12-step reaction.
  • compound A is used as a starting material to prepare compound K through a 10-step reaction
  • compound L is used as another starting material, through compound L and aniline
  • the compound M is prepared by reaction; the compound N is reacted with the compound M to prepare the polysubstituted diaryl squaraamide derivative of the present invention.
  • the compounds of the present invention can be synthesized according to one or more synthetic schemes and/or techniques well known in the art. Those skilled in the art should recognize that the synthesis methods of certain embodiments described in detail in the present invention can be easily adapted to synthesize other embodiments.
  • the compounds described herein can be prepared by an appropriate combination of synthetic methods well known in the art. Many starting materials and other reagents can be purchased from commercial suppliers, such as Alfa Aesar (China) Chemical Co., Ltd., or can be easily prepared using synthetic methods commonly used in the art.
  • the 1 H NMR spectrum was recorded on an instrument operating at 400 MHz or 500 MHz.
  • the 1 H NMR spectrum was obtained as a solution (reported in ppm), using CDCl 3 (7.26 ppm) or DMSO-d 6 (2.50 ppm) or internal standard tetramethylsilane (0.00 ppm) as the reference standard.
  • peak multiplicity the following abbreviations are used: s (single peak), d (double peak), t (triplet), q (quartet), m (multiple peak), br (broad peak), dd( Double doublet), dt (double triplet).
  • the coupling of Changshu is given in Hertz (Hz).
  • Me refers to methyl
  • Et refers to ethyl
  • Boc refers to tert-butoxycarbonyl
  • PE refers to petroleum ether
  • EtOAc refers to ethyl acetate
  • MeOH refers to methanol
  • DMSO-d 6 refers to deuterated dimethyl sulfoxide
  • DCM deuterated dimethyl sulfoxide
  • rt refers to room temperature
  • mL refers to milliliters
  • mmol refers to Means millimoles
  • ⁇ M means micromoles
  • nM means nanomoles
  • °C means degrees Celsius.
  • Step 8 Synthesis of 1-(2,3-dichlorophenyl)-3-(8-hydroxy-1,1'-dioxo-4-oxothiochromen-7-yl)urea
  • the title compound was prepared by reacting 7-amino-8-hydroxythiochroman-4-one 1,1-dioxide and 2methyl-3-fluorophenyl isocyanate.
  • Step 1 Synthesis of 2-(tert-butyl)-6-hydroxy-7,8-dihydro-6hydro-thiochroman[7,8-d]oxazole 9,9-dioxide.
  • Step 2 Synthesis of 2-(tert-butyl)-8hydro-thiochromen[7,8-d]oxazole 9,9-dioxide.
  • Step 3 Synthesis of 2-(tert-butyl)-7,8-dihydro-6hydro-thiochroman[7,8-d]oxazole 9,9-dioxide.
  • Step 4 Synthesis of 7-amino-8-hydroxythiochroman 1,1-dioxide.
  • step 7 in Example 1 the title was synthesized from 2-(tert-butyl)-7,8-dihydro-6hydro-thiochroman[7,8-d]oxazole 9,9-dioxide Compound.
  • Step 5 Synthesis of 1-(2,3-dichlorophenyl)-3-(8-hydroxy-1,1-dioxothiochroman-7-yl)urea.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2,3-dichlorophenyl isocyanate.
  • Step 1 Synthesis of 7-amino-8-hydroxy-2 hydrogen-thiochromene 1,1-dioxide.
  • the title compound was synthesized from 2-(tert-butyl)-8hydro-thiochrome [7,8-d]oxazole 9,9-dioxide.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2,3-dichlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-methyl-3-fluorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2methyl-3-fluorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 4-bromophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-fluorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-bromophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-chlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-trifluoromethylphenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-methyl-3-chlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2,4-dichlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 4-methylphenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 2-chloro-3-fluorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-fluorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-bromophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-chlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-trifluoromethylphenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-methyl-3-chlorophenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 4-methylphenyl isocyanate.
  • step 8 in Example 1 the title compound was synthesized from 7-amino-8-hydroxythiochroman 1,1-dioxide and 2-chloro-3-fluorophenyl isocyanate.
  • Step 2 Synthesis of 3-((2,3-dichlorophenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione.
  • Step 3 3-((2,3-Dichlorophenyl)amino)-4-((8-hydroxy-1,1-dioxo-2hydro-thiochromen-7-yl)amino) Synthesis of cyclobut-3-ene-1,2-dione
  • Step 1 According to the method of step 2 in Example 21, 3-ethyl was synthesized from 3,4-diethoxycyclobut-3-ene-1,2-dione and 3-fluoro-2-methylaniline -4-((3-Fluoro-2methylphenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 2 According to the method of step 3 in Example 21, 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 3-ethyl-4-((3-fluoro -2-Methylphenyl)amino)cyclobut-3-ene-1,2-dione synthesis of the title compound.
  • Step 1 According to the method of step 2 in Example 21, 3,4-diethoxycyclobut-3-ene-1,2-dione and 2-chloroaniline were used to synthesize 3-ethyl-4-(( 2-Chlorophenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 2 According to the method of step 3 in Example 21, 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 3-ethyl-4-((2-chloro The title compound was synthesized by phenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 1 According to the method of step 2 in Example 21, 3,4-diethoxycyclobut-3-ene-1,2-dione and 2-chloro-3-fluoroaniline were used to synthesize 3-ethyl- 4-((2-Chloro-3-fluorophenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 2 According to the method of step 3 in Example 21, 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 3-ethyl-4-((2-chloro The title compound was synthesized from -3-fluorophenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 1 According to the method of step 2 in Example 21, 3,4-diethoxycyclobut-3-ene-1,2-dione and 2-bromoaniline were used to synthesize 3-ethyl-4-(( 2-Bromophenyl)amino)cyclobut-3-ene-1,2-dione.
  • Step 2 According to the method of step 3 in Example 21, 7-amino-8-hydroxy-2hydro-thiochromene 1,1-dioxide and 3-ethyl-4-((2-bromo The title compound was synthesized by phenyl)amino)cyclobut-3-ene-1,2-dione.
  • step 3 in Example 21 7-amino-8-hydroxy-thiochroman 1,1-dioxide and 3-ethyl-4-((2-chlorophenyl)amino)cyclobutane Synthesis of the title compound from -3-ene-1,2-dione.
  • step 3 in Example 21 7-amino-8-hydroxy-thiochroman 1,1-dioxide and 3-ethyl-4-((2-chloro-3-fluorophenyl) Amino)cyclobut-3-ene-1,2-dione synthesis of the title compound.
  • step 3 in Example 21 7-amino-8-hydroxy-thiochroman 1,1-dioxide and 3-ethyl-4-((2-methyl-3-fluorophenyl ) Amino) cyclobut-3-ene-1,2-dione to synthesize the title compound.
  • step 3 in Example 21 7-amino-8-hydroxy-thiochroman 1,1-dioxide and 3-ethyl-4-((2-bromophenyl)amino)cyclobutane Synthesis of the title compound from -3-ene-1,2-dione.
  • step 3 in Example 21 the combination of 7-amino-8-hydroxy-thiochroman 1,1-dioxide and 3-ethyl-4-((2,3-dichlorophenyl)amino ) Synthesis of the title compound by cyclobut-3-ene-1,2-dione.
  • PathHunter cell line is resuscitated, passaged and expanded. The cells were plated in a 384-well plate with a white background, 20 ⁇ l per well, and incubated at 37°C for detection.
  • Antagonist activity detection pre-incubate the cells with the antagonist, and then add the EC80 concentration of the agonist. Dilute the sample stock solution to 5 times the concentration of the sample to be tested with the detection buffer (5X sample). Add 5 ⁇ l of 5X sample to the cells and incubate at 37°C or room temperature for 30 minutes. The solvent concentration is 1%. Add 5 ⁇ l of 6X EC80 agonist in the buffer to be tested into the cells, and incubate at 37°C or room temperature for 90 to 180 minutes.
  • mice were numbered and divided into normal control group, model group, and administration group according to the principle of random grouping, with 6 animals in each group.
  • the back hair of the mice was removed.
  • 5 mL of purified air was injected into the back of each mouse in the ultra-clean table with a syringe.
  • 2.5 mL of pure air was injected in the ultra-clean table and the administration was started.
  • the 30mg/kg compound was administered by gavage twice a day.
  • the model and the control group were administered with CMC water solution.
  • the number of neutrophils is calculated according to the following formula:
  • Number of neutrophils concentration of neutrophils (x10 9 /L) x volume ( ⁇ L) x 10 -6
  • the compounds of the present invention all show antagonistic activity against CXCR2, among which compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 14, 15, 17, 18, 22, 23, 24, 25, 26, 27
  • the IC 50 value of 31 is less than 1 ⁇ M. 7, 8, 31 can significantly inhibit the neutrophils to carrageenan-induced C57BL mouse subcutaneous chronic inflammation model back air sacs and have obvious anti-inflammatory effects.

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Abstract

环状砜类化合物及其制备方法、药物组合物和用途。具体的，所述环状砜类化合物及其药学上可接受的盐由式(I)所示，其可用于在制备CXCR2拮抗剂，同时可应用于制备预防和/或治疗CXCR2受体介导的疾病的药物。

Description

环状砜类化合物及其制备方法、药物组合物和用途 技术领域
本发明属于制药技术领域，涉及一种CXCR2拮抗剂环状砜类化合物及其制备方法、、药物组合物和用途。
背景技术
趋化因子是一类能够趋化细胞定向移动的低分子量(多为8-10kDa)蛋白，由70-100个氨基酸构成。根据其肽链N端高度保守的半胱氨酸残基数量及其相对位置的不同，趋化因子分为CXC,CC,C,和CX3C四大类。研究表明，趋化因子可以在刺激后从许多炎症和结构细胞中释放出来，并通过G蛋白偶联受体(GPCR)超家族的趋化因子受体发挥作用。这其中，趋化因子受体CXCR2可在中性粒细胞、巨噬细胞、血管内皮细胞、少突胶质前体细胞、骨髓来源的抑制性细胞和肿瘤细胞等多种细胞上表达，与含有谷氨酸-亮氨酸-精氨酸基序(+ELR)的CXC趋化因子结合发挥作用，如白细胞介素-8(IL-8或CXCL8)或与生长相关的致癌基因(GROα，β，γ或CXCL1,2,3)等(参见Zarbock等人Front.Immunol.,3:1(2012)；Ley等人Am.J Physiol-Reg I 283:R7–R28(2002)；Kurareva等人Curr.Opin.Pharmacol.30:27(2016))。
CXCR2受体与其配体的结合可诱导许多不同的细胞反应，在炎症、肿瘤和中枢神经系统等多种疾病中均发挥着重要作用。在炎性疾病模型中,如慢性阻塞性肺病、急性肺损伤、哮喘以及动脉粥样硬化等,阻断或消除CXCR2可以显著降低白细胞的募集、组织损伤和死亡率。目前，一些小分子化合物，如Danirixin，AZD5069以及Navarixin等作为CXCR2的拮抗剂，针对慢性阻塞性肺病、哮喘等疾病开展了相关的临床试验(参见Neamati等人Theranostics,7:1543(2017))。
研究表明+ELR趋化因子具有血管生成特性，如在结直肠癌模型中，包括生长调节癌基因GRO-α，GRO-β，GRO-γ，和IL-8等在内的CXCR2配体高表达并与周围血管中的血管内皮细胞、中性粒细胞表面上表达的CXCR2结合和活化刺激血管生成，促进肿瘤生长(参见Damme等人Cytokine Growth F.R.,22：345(2011))。
在肿瘤微环境中，骨髓来源的抑制细胞(MDSC)高表达CXCR2。多项研究证明，MDSC在保护肿瘤免受细胞毒性T细胞介导的抗肿瘤作用和抑制免疫检查点阻滞的功效方面起着至关重要的作用。T细胞的程序性死亡蛋白-1(PD-1)和MDSCs的浸润是肿瘤免疫逃逸的关键因素，大量研究表明阻断CXCR2可以阻止中性粒细胞和髓性抑制细胞从骨髓向肿瘤部位的迁移，增加肿瘤中T细胞的浸润并增加PD-1/PD-L1抑制剂 在小鼠肿瘤模型中的效果(参见Mackall等人Sci.Transl.Med.,6：237(2014)；Sansom等人Cancer Cell,29:832(2016))。此外CXCR2拮抗剂还可以直接抑制肿瘤细胞的增殖。研究表明，使用CXCR2小分子拮抗剂处理人黑色素瘤细胞,和对照组相比，用CXCR2拮抗剂处理72小时后，细胞增殖显著降低，并且呈现剂量依赖关系(参见Li等人Med.Clin-barcelona,152:425(2019))。
此外，CXCR2在中枢神经系统(CNS)中的少突胶质细胞(OPC)上高表达，并且影响中性粒细胞介导的脱髓鞘反应以及OPC介导的髓鞘修复反应，同时发挥外周功能促进脱髓鞘并影响CNS机制损害髓鞘再生，因此CXCR2也成为了近年来治疗多发性硬化症、脑损伤疾病以及阿尔茨海默病等中枢神经系统疾病的潜在靶点(参见Lane等人J.Virol.,93:e00240-19(2019)；McLarno等人J.Neuroinflamm.,12：144(2015))。
鉴于CXCR2在多种疾病发病机制中起到关键的作用，发明一种CXCR2拮抗剂及其制备方法，可用于治疗或预防由CXCR2介导的多种疾病。
发明内容
本发明解决的技术问题是提供一种新型的CXCR2拮抗剂，其制备方法、药物组合物和用途，对趋化因子受体CXCR2具有较强的拮抗活性，从而对由CXCR2受体介导的疾病具有预防和/或治疗效果。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一种式(I)所示的化合物或其药学上可接受的盐：
Figure PCTCN2020132544-appb-000001
其中
A选自
Figure PCTCN2020132544-appb-000002
B选自
Figure PCTCN2020132544-appb-000003
R 1、R 2和R 3分别独立的选自氢、卤素、C 1-3烷基、甲氧基、乙氧基、 三氟甲基、二氟甲基。
优选地，本发明提供了一种式(I)所示的化合物或其药学上可接受的盐：
其中
A为
Figure PCTCN2020132544-appb-000004
B为
Figure PCTCN2020132544-appb-000005
R 1选自氢、氟、氯、溴、甲基、三氟甲基；
R 2选自氢、氟、氯；
R 3选自氢、氯、溴。
具体来说，根据本发明优选的化合物如下：
Figure PCTCN2020132544-appb-000006
本发明技术方案的第二方面还提供了所述化合物的制备方法。
利用方法-1制备式(1)所示化合物：
Figure PCTCN2020132544-appb-000007
R 1、R 2和R 3分别独立的选自氢、卤素、C1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基
(1)以化合物A为起始物料，经过酰化反应制备化合物B；
(2)化合物B经过环化、氯磺酰化反应制备化合物C；
(3)化合物C经过还原反应制备化合物D；
(4)化合物D与氯丙酸反应制备化合物E；
(5)化合物E经过分子内酰化反应制备化合物F；
(6)化合物F经过氧化反应制备化合物G；
(7)化合物F经过开环反应制备化合物H；
(8)化合物H与异氰酸酯反应制备所述化合物或其药学上可接受的盐。
利用方法-2制备式(1)所示化合物：
Figure PCTCN2020132544-appb-000008
R 1、R 2和R 3分别独立的选自氢、卤素、C1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基
(1)化合物G经过还原反应制备化合物I；
(2)化合物I经过分子内脱水反应制备化合物J；
(3)化合物J经过开环反应制备化合物K；
(4)化合物H与异氰酸酯反应制备所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐。
利用方法-3制备式(1)所示化合物：
Figure PCTCN2020132544-appb-000009
R 1、R 2和R 3分别独立的选自氢、卤素、C1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基
(1)化合物L与苯胺反应制备化合物M；
(2)化合物M与化合物K反应制备化合物所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐。
利用方法-4制备式(1)所示化合物：
Figure PCTCN2020132544-appb-000010
R 1、R 2和R 3分别独立的选自氢、卤素、C1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基
(1)化合物K经过还原反应制备化合物N；
(2)化合物N与异氰酸酯反应制备所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐。
利用方法-5制备式(1)所示化合物：
Figure PCTCN2020132544-appb-000011
R 1、R 2和R 3分别独立的选自氢、卤素、C1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基
(1)化合物N与化合物M反应制备所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐。
本发明技术方案的第三方面是提供了一种药物组合物，所述药物组合物包含所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐，以及任选的药学上可接受的载体和/或赋形剂；优选地，所述药物组合物还包含除所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐之外的一种或多种预防和/或治疗炎性疾病、肿瘤、自身免疫性疾病或神经疾病的药物活性成分；优选地，所述药物组合物为药学上可接受的用于预防和/或治疗炎性疾病、肿瘤、自身免疫性疾病或神经疾病的药物制剂。
又一方面，本发明还提供了一种药物制剂，其包含至少一种所述的化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐以及任选的药学上可接受的载体或/或赋形剂；优选地，所述药物制剂选自以下列药物剂型：胃肠道外给药制剂，例如注射溶液或混悬剂；经肠给药制剂，例如口服制剂，如片剂或胶囊剂；局部给药制剂，例如洗剂、凝胶、软膏、乳剂、经鼻给药制剂、栓剂、经皮给药制剂或眼用制剂。
又一方面，本发明还提供了所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐、或者所述药物组合物在制备用于预防和/或治疗炎性疾病、肿瘤、自身免疫性疾病或神经疾病的药物中的用途。换言之，本发明提供了一种预防和/或治疗炎性疾病、肿瘤、自身免疫性疾病或神经疾病的方法，该方法包括给予有需要的受试者预防和/或治疗有效量的所述化合物、其立体异构体、几何异构体、互变异构体或药学上可接受的盐，或者所述药物组合物。
以下就本发明所使用的部分术语定义如下，其它未定义的术语具有所属技术领域技术人员公知的含义。
卤素是指氟、氯、溴或碘。
“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选地被卤素取代的烷基”意味着卤素可以但不必须存在，该说明包括烷基被卤素取代的情形和烷基不被卤素取代的情形。
本发明所述的化合物可以含有一个或多个手性中心，其以不同立体异构形式存在。本发明化合物的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)均在本发明的范围内。
本发明所述的化合物包括其几何异构体。例如，若本发明的所述化合物含有双键或稠环，这些化合物可存在几何异构体，则它们的顺式、反式形式以及顺式和反式的混合物均包括在本发明的范围内。
本发明所述的化合物包括其互变异构体。互变异构体是指经由低能垒相互转化的不同能量的结构异构体。
本发明所述的化合物还包括其同位素标记化合物，其中一个或多个原子被天然发现的具有相同原子序数、但是不同原子质量或质量数的原子替代。实例包括但不限于：氢同位素 2H和 3H；碳同位素 11C、 13C和 14C；氯同位素 36Cl；氟同位素 18F；碘同位素 123I和 125I；氮同位素 13N和 15N；氧同位素 15O、 17O和 18O；磷同位素 32P和硫同位素 35S。
本发明所述的化合物或其盐的各种水合物和溶剂合物以及其多晶型(polymorphisms)也包括在本发明的范围内。
本发明所述的化合物的前药也包括在本发明的范围内。本发明所述的化合物的某些衍生物自身具有较弱药理活性或没有药理活性，但当这些衍生物给至体内或给至身体上时，它们可通过例如水解断裂等方式被转化成具有药理活性的本发明所述的化合物，这些衍生物称为“前药”。关于前药用途的进一步信息可以在Pro-drugs as Novel Delivery Systems,Vol.14,ACS Symposium Series(T.Higuchi and W.Stella)和Bioreversible Carriers in Drug Design,Pergamon Press,1987(ed.E.B.Roche,American Pharmaceutical Association)中找到。
本发明所述的化合物包括其药学上可以接受的盐。药学上可接受的盐是指为药学上可接受的并且具有母体化合物所需的药理活性的盐。Berge等人在J.Pharma.Sci.,1977,66,1-19中详细描述了医药学上可接受的盐，所述文献以引用的方式并入本文中。本发明所述的化合物可以含有足够的酸性基团、足够的碱性基团或兼具这两种类型的功能基团，并相应地与一些无机或有机碱、或无机和有机酸反应形成药学上可接受的盐。药学上可接受的盐的实例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、单氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、羟乙酸盐、酒石酸盐、甲烷磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
本发明所述的化合物在作为药物使用时，通常是以药物组合物的形式给药。因此，本发明所述的化合物和药学上可接受的载体、稀释剂或赋形剂的药物组合物也包括在本发明的范围。本文所用的载体、助剂、赋形剂包括适合于期望的特定剂型的任意的和所有的溶剂、稀释剂或其他液体赋形剂、分散剂或助悬剂、表面活性剂、等渗剂、增 稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。在Remington：The Science and Practice of Pharmacy，21 st edition，2005，ed.D.B.Troy，Lippincott Williams&Wilkins，Philadelphia，和Encyclopedia of Pharmaceutical Technology，eds.J.Swarbrick和J.C.Boylan，1988-1999，Marcel Dekker，New York中，公开了用于配制药学可接受的组合物的各种载体和用于其制备的已知技术，将它们的内容都通过参考引入本文。
本发明所述的组合物可通过适于待治疗的病症的任何途径给药。特别是经以下列形式给药：胃肠道外，例如以可注射溶液或混悬剂形式；经肠，例如口服，例如以片剂或胶囊剂形式；局部，例如以洗剂、凝胶、软膏或乳剂形式或以鼻或栓剂形式。局部施用是例如施用于皮肤。局部给药的另一种形式是给药于眼。
药物组合物可以以固体、半固体、液体或气态形式施用，或可呈干燥的散剂，诸如冻干形式。药物组合物可包装为便于传递的形式，包括例如固体剂型，诸如胶囊、药囊、扁囊剂、明胶、纸、片剂、栓剂、团粒、丸剂、含片及锭剂。包装的类型一般将取决于施用途径。也涵盖可植入的持续释放的制剂，以及经皮制剂。
能够作为药学可接受的载体的材料的一些实例包括但不限于：离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质(例如人血清白蛋白)、缓冲物质(例如磷酸盐)、甘氨酸、山梨酸或山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐)、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡类、聚乙烯-聚氧丙烯嵌段共聚物、羊毛脂、糖类(例如乳糖、葡萄糖和蔗糖)、淀粉(例如玉米淀粉和马铃薯淀粉)、纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；西黄蓍胶粉；麦芽；明胶；滑石粉；赋形剂，例如可可脂和栓剂用蜡；油类，例如花生油、棉籽油；红花油；芝麻油；橄榄油；玉米油和大豆油；二醇，例如丙二醇或聚乙二醇；酯类，例如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，例如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐水；林格液；乙醇；和磷酸盐缓冲液，以及其他无毒的可相容的润滑剂，例如月桂基硫酸钠和硬脂酸镁。根据制剂人员的判断，在组合物中也可以存在着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂。
本发明所述的化合物可以单独使用或与其它治疗本发明所述的疾病或病症(例如癌症)的治疗剂联合使用。在某些实施方案中，本发明所述的化合物与具有抗高度增殖性质或用于治疗高度增殖性疾病(例如癌症)的第二种化合物在药物组合制剂中联合，或作为联合治疗在给药方案中联合。药物联合制剂或者定量给药方案的第二化合物 优选具有与本发明所述化合物互补的活性，以使它们不会相互产生不利影响。这样的化合物适当地以对计划目的有效的量存在于组合中。在一个实施方案中，本发明的化合物与其他抗肿瘤药物联合。所述抗肿瘤药物包括：烷化剂类，包括但不仅限于环磷酰胺、氮芥、马法兰、瘤可宁、卡莫司汀；金属铂类，包括但不仅限于卡铂、顺铂、奥沙利铂；拓扑异构酶抑制剂，包括但不仅限于拓扑特肯、喜树碱、拓扑替康、依立替康；抗生素类，包括但不仅限于茴环霉素、放线菌素D、柔红霉素、阿霉素、米托蒽醌、博来霉素、普卡霉素；抗微管或抗有丝分裂剂，包括但不仅限于紫杉醇、长春瑞滨、多西他赛、多柔比星；抗代谢物类，包括但不仅限于氟尿嘧啶，甲氨蝶呤，阿糖胞苷，巯嘌呤(mecaptopurine)，硫鸟嘌呤，及吉西他滨；抗体类，包括但不仅限于赫赛汀、贝伐单抗；激素类，包括但不仅限于来曲唑(Letrazole)、伏罗唑(vorazole)、他莫西芬、托瑞米芬，氟维司群、氟他胺、尼鲁米特，曲普瑞林；激酶抑制剂类，EGFR激酶抑制剂，包括但不仅限于吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)、阿法替尼(afatinib)；VEGFR抑制剂，包括但不仅限于索拉非尼(Sorafenib)、瑞格菲尼(Regorafenib)、舒尼替尼(Sunitinib)、卡博替尼(Cabozantinib)、帕唑帕尼(Pazopanib)、凡德他尼(vandetanib)、阿昔替尼(axitinib)；ALK抑制剂，包括但不仅限于克唑替尼(Crizotinib)、色瑞替尼(ceritinib)、Alectinib；Bcr-Abl抑制剂，包括但不仅限于伊马替尼(Imatinib)、帕纳替尼(Ponatinib)、尼洛替尼(Nilotinib)、达沙替尼(Dasatinib)；BTK抑制剂，包括但不仅限于依鲁替尼(Ibrutinib)；B-RAF抑制剂，包括但不仅限于维罗非尼(Vemurafenib)；细胞周期蛋白依赖性激酶CDK4/6抑制剂，帕博西尼(Palbociclib)；mTOR抑制剂，包括但不仅限于雷帕霉素(rapamycin)、依维莫司(everolimus)；去乙酰化酶抑制剂，包括但不仅限于伏立诺他(vorinostat)；PD1/PDL1抗体，Keytruda(Pembrolizumab)、Opdivo(Nivolumab)。
本发明技术方案的第四方面还提供了本发明第一方面所述化合物或其药学上可接受的盐、或者第三方面所述药物组合物在制备用于预防和/或治疗CXCR2受体介导的疾病的药物中的用途，其中所述的CXCR2受体介导的疾病包括慢性阻塞性肺病、哮喘、囊肿性纤维化、癌症、关节炎、银屑病、炎症性肠病、疼痛、多发性硬化症、阿尔茨海默病、帕金森病。
有益技术效果：本发明化合物在体外测试中显示出对CXCR2显著的拮抗活性。
附图说明
图1.化合物对小鼠炎症气囊中性粒细胞驱化的抑制作用n＝6，显著性差异分析使用student t检验进行分析： #表示模型组与对照组比较结果， ###表示p<0.001. *表示p<0.05, **表示p<0.01, ***表示p<0.001。
具体实施方式
以下是本发明的具体实施例，其对本发明的技术方案做进一步的描述，但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或是等同替代均包括在本发明的保护范围内。
制备方法
本发明所述的化合物可以根据本文中的合成方案和/或本领域熟知的技术来合成。例如，本发明提供的化合物可以根据以下通用合成方法制备。
在一种通用合成方法中，根据方法-1制备式(I)所示的化合物。
方法-1
Figure PCTCN2020132544-appb-000012
R 1＝Cl或Me
R 2＝Cl或F
具体地，在方法-1中，本发明所述的本发明所述的多取代的二芳基脲类衍生物。可以通过8步反应制备。例如，以化合物A为起始物料，经过酰化反应制备化合物B；化合物B经过环化、氯磺酰化反应制备化合物C；化合物C经过还原反应制备化合物D；化合物D与氯丙酸 反应制备化合物E；化合物E经过分子内酰化反应制备化合物F；化合物F经过氧化反应制备化合物G；化合物F经过开环反应制备化合物H；化合物H与异氰酸酯反应制备本发明所述的多取代的二芳基脲类衍生物。
在另一种通用合成方法中，根据方法-2制备式(I)所示的化合物。
方法-2
Figure PCTCN2020132544-appb-000013
R 1＝F,Cl,Br,Me,CF 3或H
R 2＝F,Cl或H
R 3＝Cl,Me或H
具体地，在合成方法-2中，本发明所述的本发明所述的多取代的二芳基脲类衍生物，可以通过10步反应制备。例如，利用方法-1，以化合物A为起始物料，通过6步反应制备化合物G；化合物G经过还原反应制备化合物I；化合物I经过分子内脱水反应制备化合物J；化合物J经过开环反应制备化合物K；化合物H与异氰酸酯反应制备本发明所述的多取代的二芳基脲类衍生物。
在另一种通用合成方法中，根据方法-3制备式(I)所示的化合物。
方法-3
Figure PCTCN2020132544-appb-000014
R 1＝Cl,Br或Me
R 2＝F,Cl或H
具体地，在合成方法-3中，本发明所述的本发明所述的多取代的二芳基方酰胺类衍生物，可以通过11步反应制备。例如，利用方法-1 和方法-2，以化合物A为起始物料，通过9步反应制备化合物K；以化合物L为另一起始物料，通过化合物L与苯胺反应制备化合物M；化合物M与化合物K反应制备本发明所述的本发明所述的多取代的二芳基方酰胺类衍生物。
在另一种通用合成方法中，根据方法-4制备式(I)所示的化合物。
方法-4
Figure PCTCN2020132544-appb-000015
R 1＝F,Cl,Br,Me,CF 3或H
R 2＝F,Cl或H
R 3＝Me或H
具体地，在合成方法-4中，本发明所述的本发明所述的多取代的二芳基脲类衍生物，可以通过11步反应制备。例如，利用方法-1和方法-2，以化合物A为起始物料，通过9步反应制备化合物K；化合物K经过还原反应制备化合物N；化合物N与异氰酸酯反应制备本发明所述的本发明所述的多取代的二芳基脲类衍生物。
在另一种通用合成方法中，根据方法-5制备式(I)所示的化合物。
方法-5
Figure PCTCN2020132544-appb-000016
R 1＝Cl,Br或Me
R 2＝H,F或Cl
具体地，在合成方法-5中，本发明所述的本发明所述的多取代的二芳基方酰胺类生物，可以通过12步反应制备。例如，利用方法-1、方法-2和方法-4，以化合物A为起始物料，通过10步反应制备化合物K；利用方法-3，以化合物L为另一起始物料，通过化合物L与苯胺反应制备化合物M；化合物N与化合物M反应制备本发明所述的本发明所述的多取代的二芳基方酰胺类衍生物。
本发明所述的化合物可以根据本文中一个或多个合成方案和/或本领域熟知的技术来合成。本领域技术人员应认识到，本发明中详细描述的某些实施方式的合成方法，可容易适用于合成其他实施方式。在一些实施方式中，本文所述的化合物可以通过本领域熟知的合成方法的适当组合来制备。许多起始物料和其他试剂可购自商业供应商，例如阿法埃莎(中国)化学有限公司，或使用本领域常用的合成方法容易地制备。
1H NMR谱在400MHz或500MHz下操作的仪器上记录。 1H NMR谱以溶液形式获得(以ppm报道)，使用CDCl 3(7.26ppm)或DMSO-d 6(2.50ppm)或内标四甲基硅烷(0.00ppm)作为参考标准。当报导峰多重性时，使用以下缩写：s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，br(宽峰)，dd(双二重峰)，dt(双三重峰)。给出的偶合常熟以赫兹(Hz)计。
在以下制备方法及实例中，“Me”是指甲基，“Et”是指乙基，“Boc”是指叔丁氧羰基，“PE”是指石油醚，“EtOAc”是指乙酸乙酯，“MeOH”是指甲醇，“DMSO-d 6”是指氘代二甲亚砜，“DCM”是指二氯甲烷，“rt”是指室温，“mL”是指毫升，“mmol”是指毫摩尔，“μM”是指微摩尔，“nM”是指纳摩尔，“℃”是指摄氏度。
实施例1：1-(2,3-二氯苯基)-3-(8-羟基-1,1-二氧-4-硫代色满酮-7-基)脲(化合物1)的合成
Figure PCTCN2020132544-appb-000017
步骤1：N-(3-氯苯基)特戊酰胺的合成
Figure PCTCN2020132544-appb-000018
将58.8g的3-氯苯胺置于1L茄形瓶中，加入300mLDCM，剧烈搅拌下，加入96.5mL的Et 3N，反应液降温至0℃后，缓慢滴加68.4mL的PivCl，滴加完后逐渐升温至室温，反应1小时。加水淬灭反应，用二氯甲烷萃取两遍，有机相合并，饱和食盐水洗一遍，干燥、蒸干后得淡黄色固体，用EA/PE＝1:10的混合液超声，过滤后，得到白色固体93.7g，产率96％)。
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.84(t,J＝2.0Hz,1H),7.59(ddd,J＝8.2,1.9,0.8Hz,1H),7.31(t,J＝8.1Hz,1H),7.08(ddd,J＝8.0,2.1,0.9Hz,1H),1.22(s,9H).
MS(ESI+)m/z 212.1[M+H] +。
步骤2：2-(叔丁基)苯并[d]恶唑-7-砜基氯化物的合成
Figure PCTCN2020132544-appb-000019
将30g的N-(3-氯苯基)特戊酰胺置于2L茄形瓶中，加入300mLTHF，反应液置换氩气后降温至-78℃，缓慢滴加150mL(2.5M)正丁基锂，滴加完45分钟内升温至-20℃反应2小时，再次降温至-78℃，滴加75mL的SO 2Cl 2，在-78度下反应2小时，升温至室温过夜。加水淬灭反应，水洗，EA萃取两遍，有机相合并，饱和食盐水干燥，无水硫酸钠干燥后浓缩，湿法上样，进行柱层析分离(PE:EA＝1:30)，得到粗品22.1g,直接用于下一步反应。
步骤3：2-(叔丁基)苯并[d]恶唑-7-硫酚的合成
Figure PCTCN2020132544-appb-000020
将22.1g的2-(叔丁基)苯并[d]恶唑-7-砜基氯化物置于1L茄形瓶中，加入400mL甲苯和65g三苯基膦，回流5小时。停止反应，蒸干甲苯，向混合物中加入EA超声，析出白色固体，过滤，滤液蒸干得到的2-(叔丁基)苯并[d]恶唑-7-硫酚粗品18.0克，直接用于下一步反应。
步骤4：3-((2-(叔丁基)苯并[d]恶唑-7-基)硫代)丙酸的合成
Figure PCTCN2020132544-appb-000021
将18.0克2-(叔丁基)苯并[d]恶唑-7-硫酚粗品置于500mL茄形瓶中，加入180mL乙醇和16mL10％的KOH水溶液，室温搅拌10分钟后加入3.56克氯丙酸及4.56克K 2CO 3，回流过夜。反应结束后蒸干溶剂，向混合物中加入200mL水，EA萃取水相(300mL×2)，两次萃取的有机相舍弃，水相调pH为1，EA萃取(300mL×2)，有机相用饱和食盐水干燥，无水硫酸钠干燥后进行柱层析纯化(PE:EA＝3:1)，得到淡黄色固体8.3g(步骤2-4总产率：21％)。
1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),7.57(dd,J＝7.2,1.7Hz,1H),7.35–7.27(m,2H),3.27(t,J＝7.0Hz,2H),2.57(t,J＝7.0Hz,2H),1.43(s,9H).
MS(ESI+)m/z 280.1[M+H] +.
步骤5：2-(叔丁基)-7,8-二氢-6氢-硫代吡喃[7,8-d]恶唑-6-酮的合成
Figure PCTCN2020132544-appb-000022
将2.0克3-((2-(叔丁基)苯并[d]恶唑-7-基)硫代)丙酸置于100mL茄形瓶中，在0度下分批多次加入到20mL的浓硫酸中,使之尽可能的溶解，室温下静置过夜。将反应液缓慢倒入冰水中，充分搅拌后，EA萃取水相(150mL×2),水相舍弃。有机相中加入NaOH水溶液调pH＝10,用EA萃取两遍，合并有机相饱和氯化钠水洗，无水硫酸钠干燥，蒸干后得目标产物，1.85g淡黄色固体，直接用于下一步反应，产率为99％。
1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝8.5Hz,1H),7.50(d,J＝8.4Hz,1H),3.45(dd,J＝7.2,5.6Hz,2H),2.98–2.93(m,2H),1.44(s,9H).
MS(ESI+)m/z 262.1[M+H] +.
步骤6：2-(叔丁基)-7,8-二氢-6氢-硫代吡喃[7,8-d]恶唑-6-酮-9,9-二氧化物的合成
Figure PCTCN2020132544-appb-000023
将1.3g的2-(叔丁基)-7,8-二氢-6氢-硫代吡喃[7,8-d]恶唑-6-酮置于250mL茄形瓶中,加入70mL二氯甲烷，降温至0度后，分批多次加入1.72g的m-CPBA,常温反应2小时。停止反应后将反应液直接浓缩、进行柱层析分离纯化得白色固体1.2g，产率为82％。
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝8.4Hz,1H),8.02(d,J＝8.4Hz,1H),4.19–4.14(m,2H),3.33–3.28(m,2H),1.48(s,9H).
MS(ESI+)m/z 294.1[M+H] +.
步骤7：4-胺基-8-羟基硫色满-4-酮-1,1’-二氧化物的合成
Figure PCTCN2020132544-appb-000024
将1.2g的2-(叔丁基)-7,8-二氢-6H-硫代色烯[7,8-d]恶唑-6-酮9,9-二氧化物置于500mL茄形瓶中，加入108mL1,4-二氧六环和20mL水，剧烈搅拌下缓慢滴加2.9mL浓硫酸，回流反应48小时。停止反应，将反应液直接浓缩蒸干，加入100mL水，用4N的氢氧化钠水溶液调pH＝6，二氯甲烷萃取水相(200mL×2),合并有机相，饱和氯化钠水洗，无水硫酸钠干燥，蒸干后得目标产物粗品为褐色油状物，直接用于下一步反应。
步骤8：1-(2,3-二氯苯基)-3-(8-羟基-1,1’-二氧-4-氧代硫代色烯-7-基)脲的合成
Figure PCTCN2020132544-appb-000025
将100mg的7-氨基-8-羟基硫色满-4-酮1,1-二氧化物置于100mL茄形瓶中，加入20mL二氯甲烷，室温搅拌下加入82.8mg的2,3-二氯苯基异氰酸酯，室温反应3小时，反应液析出固体变浑浊，过滤，用二氯甲烷洗两次滤饼(10mL×2)，得目标产物120mg,产率为67％。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.42(s,1H),8.31(d,J＝8.7Hz,1H),8.06(t,J＝4.9Hz,1H),7.47(d,J＝7.5Hz,1H),7.34(d,J＝0.8Hz,1H),7.33(d,J＝0.5Hz,1H),3.91–3.85(m,2H),3.15–3.09(m,2H).
MS(ESI+)m/z 415.1[M+H] +.
实施例2：1-(3-氟-2-甲基苯基)-3-(8-羟基-1,1-二氧-4-氧代硫代色烯-7-基)脲(化合物2)的合成
Figure PCTCN2020132544-appb-000026
根据实施例1中步骤8的方法，由7-氨基-8-羟基硫色满-4-酮1,1-二氧化物和2甲基-3-氟苯基异氰酸酯反应制备标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.32(s,1H),9.01(s,1H),8.43–8.33(m,1H),7.64(d,J＝8.2Hz,1H),7.60(d,J＝8.7Hz,1H),7.19(dd,J＝15.1,8.1Hz,1H),6.90(t,J＝8.8Hz,1H),4.03–3.92(m,2H),3.20–3.12(m,2H),2.17(d,J＝1.9Hz,3H).
MS(ESI+)m/z 379.1[M+H] +.
实施例3：1-(2，3-二氯苯基)-3-(8-羟基-1,1-二氧硫色满-7-基)脲(化合物3)的合成
Figure PCTCN2020132544-appb-000027
步骤1：2-(叔丁基)-6-羟基-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物的合成。
Figure PCTCN2020132544-appb-000028
将1.18克2-(叔丁基)-7,8-二氢-6氢-硫代吡喃[7,8-d]恶唑-6-酮-9,9-二氧化物溶于20mL甲醇中，降温至0度，加入304mg硼氢化钠，搅拌5分钟后，加水淬灭反应，有机相用乙酸乙酯萃取，饱和食盐水干燥后得2-(叔丁基)-6-羟基-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物，直接用于下一步反应。
MS(ESI+)m/z 296.1[M+H] +.
步骤2：2-(叔丁基)-8氢-硫代色烯[7,8-d]恶唑9,9-二氧化物的合成。
Figure PCTCN2020132544-appb-000029
将885mg的2-(叔丁基)-6-羟基-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物溶于30mL甲苯中，加入30mg对甲苯磺酸，130度回流24小时，柱层析纯化得到690mg的2-(叔丁基)-8氢-硫代色烯[7,8-d]恶唑9,9-二氧化物。
MS(ESI+)m/z 278.1[M+H] +.
步骤3：2-(叔丁基)-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物的合成。
Figure PCTCN2020132544-appb-000030
将500mg的2-(叔丁基)-8氢-硫代色烯[7,8-d]恶唑9,9-二氧化物溶于20mL的甲醇中，加入500mg钯碳，在氢气条件下，室温搅拌过夜。过滤钯碳后，将溶剂蒸干得到498mg2-(叔丁基)-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物，直接用于下一步反应。
MS(ESI+)m/z 280.1[M+H] +.
步骤4：7-胺基-8-羟基硫色满1,1-二氧化物的合成。
Figure PCTCN2020132544-appb-000031
根据实施例1中步骤7的方法，由2-(叔丁基)-7,8-二氢-6氢-硫色满[7,8-d]恶唑9,9-二氧化物合成标题化合物。
MS(ESI+)m/z 214.1[M+H] +.
步骤5：1-(2,3-二氯苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲的合成。
Figure PCTCN2020132544-appb-000032
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2,3-二氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.26(d,J＝8.0Hz,1H),8.96(s,1H),8.09(dd,J＝7.5,2.4Hz,1H),7.73(d,J＝8.3Hz,1H),7.35–7.30(m,3H),6.82(d,J＝8.4Hz,1H),3.44–3.39(m,2H),2.90(t,J＝6.1Hz,2H),2.24–2.15(m,2H).
MS(ESI+)m/z 401.1[M+H] +.
实施例4：1-(2，3-二氯苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物4)的合成
Figure PCTCN2020132544-appb-000033
步骤1：7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物的合成。
Figure PCTCN2020132544-appb-000034
根据实施例1中步骤7的方法，由2-(叔丁基)-8氢-硫代色烯[7,8-d]恶唑9,9-二氧化物合成标题化合物。
MS(ESI+)m/z 212.1[M+H] +.
步骤2：1-(2，3-二氯苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲
Figure PCTCN2020132544-appb-000035
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2,3-二氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.38(s,1H),9.24(s,1H),8.19(d,J＝8.4Hz,1H),8.09(dd,J＝6.8,3.0Hz,1H),7.36–7.29(m,2H),6.99(d,J＝8.4Hz,1H),6.72(d,J＝10.4Hz,1H),6.09(dt,J＝10.0,4.9Hz,1H),4.26(dd,J＝4.8,1.6Hz,2H).
MS(ESI+)m/z 399.1[M+H] +.
实施例5：1-(3-氟-2-甲基苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物5)的合成
Figure PCTCN2020132544-appb-000036
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-甲基-3-氟苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.90(s,1H),8.65(s,1H),7.72(d,J＝8.4Hz,1H),7.62(d,J＝8.2Hz,1H),7.17(dd,J＝15.1,8.1Hz,1H),6.87(t,J＝8.9Hz,1H),6.81(d,J＝8.4Hz,1H),3.45–3.38(m,2H),2.90(t,J＝6.0Hz,2H),2.24–2.14(m,5H).
MS(ESI+)m/z 365.1[M+H] +.
实施例6：1-(3-氟-2-甲基苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物6)的合成
Figure PCTCN2020132544-appb-000037
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2甲基-3-氟苯基异氰酸酯合成标题化合物。
1H NMR(500MHz,DMSO-d6)δ9.65(s,1H),8.96(s,1H),8.80(s,1H),8.18(d,J＝8.4Hz,1H),7.62(d,J＝8.2Hz,1H),7.14(dd,J＝15.2,7.8Hz,1H),6.94(d,J＝8.4Hz,1H),6.84(t,J＝8.9Hz,1H),6.67(d,J＝10.3Hz,1H),6.03(dt,J＝9.9,4.8Hz,1H),4.21(d,J＝3.7Hz,2H),2.12(s,3H).
MS(ESI+)m/z 363.1[M+H] +.
实施例7：1-(4-溴苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物7)的合成
Figure PCTCN2020132544-appb-000038
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与4-溴苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.63(s,1H),8.55(s,1H),8.23(d,J＝8.4Hz,1H),7.60–7.40(m,4H),6.98(d,J＝8.4Hz,1H),6.71(d,J＝10.4Hz,1H),6.07(dt,J＝10.0,4.8Hz,1H),4.25(dd,J＝4.7,1.2Hz,2H).
MS(ESI+)m/z 409.1[M+H] +.
实施例8：1-(2-氟苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物8)的合成
Figure PCTCN2020132544-appb-000039
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-氟苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.38(s,1H),9.06(s,1H),8.24(d,J＝8.3Hz,1H),8.14(t,J＝8.1Hz,1H),7.27–7.20(m,1H),7.14(t,J＝7.5Hz,1H),7.07–6.95(m,2H),6.72(d,J＝10.1Hz,1H),6.13–6.03(m,1H),4.25(d,J＝3.8Hz,2H).
MS(ESI+)m/z 349.1[M+H] +.
实施例9：1-(2-溴苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物9)的合成
Figure PCTCN2020132544-appb-000040
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-溴苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.31(s,1H),8.94(s,1H),8.18(d,J＝8.4Hz,1H),7.95(dd,J＝8.2,1.4Hz,1H),7.62(dd,J＝8.0,1.3Hz,1H),7.39–7.32(m,1H),7.08–6.94(m,2H),6.71(d,J＝10.3Hz,1H),6.08(dt,J＝10.0,4.8Hz,1H),4.25(dd,J＝4.8,1.4Hz,2H).
MS(ESI+)m/z 409.1[M+H] +.
实施例10：1-(2-氯苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物10)的合成
Figure PCTCN2020132544-appb-000041
Figure PCTCN2020132544-appb-000042
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.32(s,1H),9.09(s,1H),8.19(d,J＝8.1Hz,1H),8.08(d,J＝8.0Hz,1H),7.46(d,J＝7.6Hz,1H),7.30(t,J＝7.3Hz,1H),7.06(t,J＝7.2Hz,1H),6.98(d,J＝8.1Hz,1H),6.71(d,J＝10.0Hz,1H),6.12–6.05(m,1H),4.25(s,2H).
MS(ESI+)m/z 365.1[M+H] +.
实施例11：1-(2-三氟甲基苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物11)的合成
Figure PCTCN2020132544-appb-000043
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-三氟甲基苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.24(s,1H),8.91(s,1H),8.20(d,J＝8.4Hz,1H),7.83(d,J＝8.2Hz,1H),7.69(d,J＝8.0Hz,1H),7.65(t,J＝7.8Hz,1H),7.32(t,J＝7.6Hz,1H),6.97(d,J＝8.5Hz,1H),6.71(dt,J＝10.2,1.5Hz,1H),6.08(dt,J＝10.0,4.9Hz,1H),4.25(dd,J＝4.8,1.7Hz,2H).
MS(ESI+)m/z 399.1[M+H] +.
实施例12：1-(2-甲基-3-氯苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物12)的合成
Figure PCTCN2020132544-appb-000044
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-甲基-3-氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.97(s,1H),8.89(s,1H),8.21(d,J＝8.4Hz,1H),7.74–7.68(m,1H),7.20 –7.16(m,2H),6.97(d,J＝8.4Hz,1H),6.71(d,J＝10.3Hz,1H),6.10–6.03(m,1H),4.25(dd,J＝4.8,1.4Hz,2H),2.31(s,3H).
MS(ESI+)m/z 379.1[M+H] +.
实施例13：1-(2，4-二氯苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物13)的合成
Figure PCTCN2020132544-appb-000045
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2，4-二氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.34(s,1H),9.17(s,1H),8.19(d,J＝8.4Hz,1H),8.13(d,J＝8.9Hz,1H),7.62(d,J＝2.4Hz,1H),7.38(dd,J＝9.0,2.4Hz,1H),6.98(d,J＝8.4Hz,1H),6.72(d,J＝10.4Hz,1H),6.08(dt,J＝10.0,4.8Hz,1H),4.25(dd,J＝4.8,1.3Hz,2H)
MS(ESI+)m/z 399.1[M+H] +.
实施例14：1-(4-甲基苯基)-3-(8-羟基-1,1-二氧-2氢-硫代色烯-7-基)脲(化合物14)的合成
Figure PCTCN2020132544-appb-000046
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与4-甲基苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.97(s,1H),8.68(s,1H),8.21(d,J＝8.4Hz,1H),7.77(d,J＝8.0Hz,1H),7.16(dd,J＝17.4,7.7Hz,2H),6.98(dd,J＝7.1,5.4Hz,2H),6.71(d,J＝10.3Hz,1H),6.06(dt,J＝10.0,4.9Hz,1H),4.25(dd,J＝4.7,1.2Hz,2H),2.26(s,3H)
MS(ESI+)m/z 345.1[M+H] +.
实施例15：1-(2-氯-3-氟苯基)-3-(8-羟基-1,1-二氧-2氢-硫代 色烯-7-基)脲(化合物15)的合成
Figure PCTCN2020132544-appb-000047
根据实施例1中步骤8的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与2-氯-3-氟苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6))δ9.65(s,1H),9.37(s,1H),9.24(s,1H),8.20(d,J＝8.4Hz,1H),7.98(dt,J＝8.5,1.3Hz,1H),7.34(td,J＝8.4,6.5Hz,1H),7.10–7.05(m,1H),6.98(d,J＝8.5Hz,1H),6.72(dt,J＝10.3,1.6Hz,1H),6.12–6.05(m,1H),4.25(dd,J＝4.9,1.7Hz,2H).
MS(ESI+)m/z 383.1[M+H] +.
实施例16：1-(2-氟苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物16)的合成
Figure PCTCN2020132544-appb-000048
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-氟苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.10(d,J＝1.9Hz,1H),8.81(s,1H),8.11(td,J＝8.3,1.6Hz,1H),7.79(d,J＝8.4Hz,1H),7.24(ddd,J＝11.6,8.2,1.4Hz,1H),7.14(t,J＝7.8Hz,1H),7.06–6.98(m,1H),6.82(d,J＝8.4Hz,1H),3.46–3.37(m,2H),2.90(t,J＝6.1Hz,2H),2.25–2.17(m,2H).
MS(ESI+)m/z 351.1[M+H] +.
实施例17：1-(2-溴苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物17)的合成
Figure PCTCN2020132544-appb-000049
Figure PCTCN2020132544-appb-000050
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-溴苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.14(s,1H),8.63(s,1H),7.98(dd,J＝8.3,1.5Hz,1H),7.70(d,J＝8.3Hz,1H),7.62(dd,J＝8.0,1.4Hz,1H),7.37–7.31(m,1H),7.02–6.97(m,1H),6.82(d,J＝8.4Hz,1H),3.44–3.39(m,2H),2.90(t,J＝6.0Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 411.1[M+H] +.
实施例18：1-(2-氯苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物18)的合成
Figure PCTCN2020132544-appb-000051
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.07(d,J＝31.9Hz,1H),8.79(s,1H),8.08(dd,J＝8.3,1.5Hz,1H),7.72(d,J＝8.3Hz,1H),7.46(dd,J＝8.0,1.4Hz,1H),7.33–7.26(m,1H),7.10–7.01(m,1H),6.82(d,J＝8.4Hz,1H),3.45–3.38(m,2H),2.90(t,J＝6.1Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 367.1[M+H] +.
实施例19：1-(2-氯苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物19)的合成
Figure PCTCN2020132544-appb-000052
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-三氟甲基苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.08(s,1H),8.63(s,1H),7.87(d,J＝8.2Hz,1H),7.74(d,J＝8.4Hz,1H),7.69(d,J＝7.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.31(t,J＝7.6 Hz,1H),6.82(d,J＝8.4Hz,1H),3.50–3.38(m,2H),2.90(t,J＝6.1Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 401.1[M+H] +.
实施例20：1-(2-甲基-3-氯苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物20)的合成
Figure PCTCN2020132544-appb-000053
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-甲基-3-氯苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.77(s,1H),8.66(s,1H),7.74–7.66(m,2H),7.19–7.16(m,2H),6.81(d,J＝8.4Hz,1H),3.46–3.36(m,2H),2.90(t,J＝6.1Hz,2H),2.30(s,3H),2.26–2.13(m,2H).
MS(ESI+)m/z 381.1[M+H] +.
实施例21：1-(4-甲基苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物21)的合成
Figure PCTCN2020132544-appb-000054
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与4-甲基苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.80(s,1H),8.45(s,1H),7.73(d,J＝7.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.19(d,J＝7.5Hz,1H),7.15(t,J＝7.8Hz,1H),6.98(td,J＝7.4,1.1Hz,1H),6.81(d,J＝8.4Hz,1H),3.47–3.38(m,2H),2.90(t,J＝6.1Hz,2H),2.25(s,3H),2.23–2.15(m,2H).
MS(ESI+)m/z 347.1[M+H] +.
实施例22：1-(2-氯-3-氟苯基)-3-(8-羟基-1,1-二氧代硫色满-7-基)脲(化合物22)的合成
Figure PCTCN2020132544-appb-000055
根据实施例1中步骤8的方法，由7-胺基-8-羟基硫色满1,1-二氧化物与2-氯-3-氟苯基异氰酸酯合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.15(s,1H),8.93(s,1H),7.99(dt,J＝8.5,1.2Hz,1H),7.75(d,J＝8.4Hz,1H),7.33(td,J＝8.4,6.5Hz,1H),7.09–7.03(m,1H),6.83(d,J＝8.4Hz,1H),3.45–3.40(m,2H),2.91(t,J＝6.1Hz,2H),2.21(dt,J＝12.0,6.1Hz,2H).
MS(ESI+)m/z 385.1[M+H] +.
实施例23：3-((2，3-二氯苯基)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮(化合物23)的合成
Figure PCTCN2020132544-appb-000056
步骤1：3，4-二乙氧环丁-3-烯-1，2-二酮的合成
Figure PCTCN2020132544-appb-000057
将3,4-二羟基-3-烯-1,2-二酮(140mmol)溶于二氯甲烷200mL中，加入16滴DMF后冰浴下逐滴加入草酰氯(2.2当量)，回流反应过夜，TLC监测反应完全，浓缩得粗品，直接用于下一步。
步骤2：3-((2，3-二氯苯基)胺基)-4-乙氧环丁-3-烯-1，2-二酮的合成。
Figure PCTCN2020132544-appb-000058
将3，4-二乙氧环丁-3-烯-1，2-二酮(13.3mmol)溶于二氯甲烷(50mL)中,降温至零度，逐滴加入溶于二氯甲烷(25mL)的2，3-二氯苯胺(13.3mmol)溶液，零度反应3小时,向反应液中加水(100mL)淬灭，二氯甲烷萃取反应液水相(75mL×3)后合并有机相，经饱和氯 化钠洗，无水硫酸钠干燥，柱色谱纯化得目标产物3-((2，3-二氯苯基)胺基)-4-乙氧环丁-3-烯-1，2-二酮。
步骤3：3-((2，3-二氯苯基)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮的合成
Figure PCTCN2020132544-appb-000059
将7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物溶于四氢呋喃(15mL)中，加入3-((2，3-二氯苯基)胺基)-4-乙氧环丁-3-烯-1，2-二酮(0.24mmol),回流反应48h,浓缩后加入二氯甲烷(10mL),超声下有固体析出，过滤得标题化合物。
1H NMR(500MHz,DMSO-d6)δ8.15(s,1H),7.69(s,1H),7.51(d,J＝7.5Hz,1H),7.43–7.34(m,2H),6.72(s,1H),6.63(d,J＝9.6Hz,1H),6.03(s,1H),4.12(s,2H).
MS(ESI+)m/z 451.1[M+H] +.
实施例24：3-((3-氟-2甲基苯基)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮(化合物24)的合成
Figure PCTCN2020132544-appb-000060
步骤1：根据实施例21中步骤2的方法，由3,4-二乙氧基环丁-3-烯-1,2-二酮与3-氟-2-甲基苯胺合成3-乙基-4-((3-氟-2甲基苯基)氨基)环丁-3-烯-1,2-二酮。
Figure PCTCN2020132544-appb-000061
步骤2：根据实施例21中步骤3的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与3-乙基-4-((3-氟-2甲基苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),9.87(s,2H),7.78(d,J＝8.3Hz,1H),7.24(dd,J＝14.6,7.7Hz,1H),7.18(d, J＝8.0Hz,1H),7.03(d,J＝8.3Hz,1H),6.99(t,J＝8.8Hz,1H),6.74(d,J＝10.3Hz,1H),6.13(dt,J＝9.9,4.8Hz,1H),4.27(d,J＝3.6Hz,2H),2.26(s,3H).
MS(ESI+)m/z 415.1[M+H] +.
实施例25：3-((2-氯)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮(化合物25)的合成
Figure PCTCN2020132544-appb-000062
步骤1：根据实施例21中步骤2的方法，由3,4-二乙氧基环丁-3-烯-1,2-二酮与2-氯苯胺合成3-乙基-4-((2-氯苯基)氨基)环丁-3-烯-1,2-二酮。
Figure PCTCN2020132544-appb-000063
步骤2：根据实施例21中步骤3的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与3-乙基-4-((2-氯苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),10.13(s,1H),9.96(s,1H),7.77(d,J＝8.3Hz,1H),7.54(ddd,J＝7.8,6.2,1.4Hz,2H),7.40–7.35(m,1H),7.21–7.16(m,1H),7.05(d,J＝8.4Hz,1H),6.75(d,J＝10.4Hz,1H),6.14(dt,J＝10.0,4.8Hz,1H),4.28(dd,J＝4.8,1.6Hz,2H).
MS(ESI+)m/z 417.1[M+H] +.
实施例26：3-((2-氯-3-氟)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮(化合物26)的合成
Figure PCTCN2020132544-appb-000064
步骤1：根据实施例21中步骤2的方法，由3,4-二乙氧基环丁-3-烯-1,2-二酮与2-氯-3-氟苯胺合成3-乙基-4-((2-氯-3-氟苯基)氨基)环丁-3-烯-1,2-二酮。
Figure PCTCN2020132544-appb-000065
步骤2：根据实施例21中步骤3的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与3-乙基-4-((2-氯-3-氟苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.19(d,J＝8.4Hz,2H),9.96(s,1H),7.75(d,J＝8.3Hz,1H),7.46–7.36(m,2H),7.24–7.17(m,1H),7.05(d,J＝8.3Hz,1H),6.75(d,J＝10.4Hz,1H),6.14(dt,J＝10.0,4.8Hz,1H),4.28(dd,J＝4.9,1.5Hz,2H).
MS(ESI+)m/z 435.1[M+H] +.
实施例27：3-((2-溴)胺基)-4-((8-羟基-1,1-二氧-2氢-硫代色烯-7-基)胺基)环丁-3-烯-1，2-二酮(化合物27)的合成
Figure PCTCN2020132544-appb-000066
步骤1：根据实施例21中步骤2的方法，由3,4-二乙氧基环丁-3-烯-1,2-二酮与2-溴苯胺合成3-乙基-4-((2-溴苯基)氨基)环丁-3-烯-1,2-二酮。
Figure PCTCN2020132544-appb-000067
步骤2：根据实施例21中步骤3的方法，由7-胺基-8-羟基-2氢-硫代色烯1,1-二氧化物与3-乙基-4-((2-溴苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),10.01(s,1H),9.93(s,1H),7.78(d,J＝8.3Hz,1H),7.69(dd,J＝8.0,1.3Hz,1H),7.47–7.37(m,2H),7.12(ddd,J＝8.0,7.3,1.8Hz,1H),7.05(d,J＝8.4Hz,1H),6.75(dd,J＝8.8,1.7Hz,1H),6.14(dt,J＝10.0,4.9Hz,1H),4.28(dd,J＝4.9,1.7Hz,2H).
MS(ESI+)m/z 461.1[M+H] +.
实施例28：3-((2-氯胺基)-4-((8-羟基-1,1-二氧-硫色满-7-基)胺基)环丁-3-烯-1，2-二酮(化合物28)的合成
Figure PCTCN2020132544-appb-000068
根据实施例21中步骤3的方法，由7-胺基-8-羟基-硫色满1,1-二氧化物与3-乙基-4-((2-氯苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(500MHz,DMSO-d6)δ10.09(s,1H),9.84(s,1H),7.59(d,J＝8.0Hz,1H),7.51(d,J＝7.9Hz,2H),7.36(t,J＝7.6Hz,1H),7.15(t,J＝7.5Hz,1H),6.77(s,1H),3.40(s,2H),2.91(s,2H),2.21(s,2H).
MS(ESI+)m/z 419.1[M+H] +.
实施例29：3-((2-氯-3-氟胺基)-4-((8-羟基-1,1-二氧-硫色满-7-基)胺基)环丁-3-烯-1，2-二酮(化合物29)的合成
Figure PCTCN2020132544-appb-000069
根据实施例21中步骤3的方法，由7-胺基-8-羟基-硫色满1,1-二氧化物与3-乙基-4-((2-氯-3-氟苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.91(s,1H),7.48(dd,J＝13.1,8.3Hz,2H),7.40(dd,J＝14.3,8.1Hz,1H),7.18(t,J＝8.5Hz,1H),6.87(d,J＝8.4Hz,1H),3.47–3.42(m,2H),2.95–2.90(m,2H),2.25–2.15(m,2H).
MS(ESI+)m/z 437.1[M+H] +.
实施例30：3-((2-甲基-3-氟胺基)-4-((8-羟基-1,1-二氧-硫色满-7-基)胺基)环丁-3-烯-1，2-二酮(化合物30)的合成
Figure PCTCN2020132544-appb-000070
根据实施例21中步骤3的方法，由7-胺基-8-羟基-硫色满1,1-二氧化物与3-乙基-4-((2-甲基-3-氟苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.71(s,1H),7.51(d,J＝8.3Hz,1H),7.27–7.17(m,2H),7.00–6.94(m,1H),6.85(d,J＝8.4Hz,1H),3.46–3.40(m,2H),2.97–2.89(m,2H),2.26(s,3H),2.24–2.14(m,2H).
MS(ESI+)m/z 417.1[M+H] +.
实施例31：3-((2-溴胺基)-4-((8-羟基-1,1-二氧-硫色满-7-基)胺基)环丁-3-烯-1，2-二酮(化合物31)的合成
Figure PCTCN2020132544-appb-000071
根据实施例21中步骤3的方法，由7-胺基-8-羟基-硫色满1,1-二氧化物与3-乙基-4-((2-溴苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.74(s,1H),7.67(dd,J＝8.0,1.3Hz,1H),7.52(d,J＝8.3Hz,1H),7.47(dd,J＝8.1,1.6Hz,1H),7.42–7.38(m,1H),7.13–7.08(m,1H),6.87(d,J＝8.4Hz,1H),3.47–3.42(m,2H),2.95–2.91(m,2H),2.24–2.16(m,2H).
MS(ESI+)m/z 463.1[M+H] +.
实施例32：3-((2，3-二氯胺基)-4-((8-羟基-1,1-二氧-硫色满-7-基)胺基)环丁-3-烯-1，2-二酮(化合物32)的合成
Figure PCTCN2020132544-appb-000072
Figure PCTCN2020132544-appb-000073
根据实施例21中步骤3的方法，由7-胺基-8-羟基-硫色满1,1-二氧化物与3-乙基-4-((2，3-二氯苯基)氨基)环丁-3-烯-1,2-二酮合成标题化合物。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),10.00(s,1H),9.91(s,1H),7.54(dd,J＝7.4,2.1Hz,1H),7.49(d,J＝8.4Hz,1H),7.43–7.34(m,2H),6.87(d,J＝8.4Hz,1H),3.46–3.41(m,4H),2.92(t,J＝6.0Hz,2H),2.26–2.16(d,J＝5.8Hz,2H).
MS(ESI+)m/z 453.1[M+H] +.
药理活性评价
实验例1：CXCR2拮抗活性测试
(1)细胞处理：PathHunter细胞系复苏、传代并扩增。将细胞铺到白底的384孔板中，每孔20μl，37℃孵育以待检测。
(2)拮抗活性检测：将细胞和拮抗剂预孵育，之后加入EC80浓度的激动剂。用检测缓冲液将样品储存液稀释到样品待测浓度的5倍浓度(5X样品)。将5μl的5X样品加入细胞中并在37℃或室温下孵育30分钟。溶剂浓度为1％。将5μl在待测缓冲液中的6X EC80激动剂加入细胞中，37℃或室温下孵育90到180分钟。
(3)信号检测：一次性加入12.5μl或15μl(50％v/v)PathHunter检测试剂，室温孵育1小时后进行检测。用PerkinElmer EnvisionTM产生信号后，读板检测化学发光信号。
(4)数据分析：使用CBIS数据分析软件(ChemInnovation,CA)分析化合物活性。使用以下公式计算化合物抑制百分比:％抑制＝100％X(1-(测试样品的平均RLU-溶剂对照的平均RLU)/(EC80对照的平均RLU-溶剂的平均RLU))。结果见表1：
表1：CXCR2拮抗活性测试结果
化合物 CXCR2拮抗活性_IC 50(μM)
1 0.404
2 0.415
3 0.214
4 0.129
5 0.095
6 0.034
7 1.481
8 0.315
9 0.049
10 0.066
11 1.603
12 1.638
13 5.918
14 0.189
15 0.028
16 1.015
17 0.136
18 0.213
19 4.513
20 2.434
21 1.321
22 0.043
23 2.499
24 0.370
25 0.196
26 0.702
27 0.078
28 1.051
29 3.449
30 1.630
31 0.514
32 9.994
实验例2：CXCR2抑制小鼠中性粒细胞向炎症气囊趋化作用的功效研究
将动物编号并按随机分组原则分为正常对照组、模型组、给药组，每组6只。使用100mL生理盐水溶解2g角叉菜胶配制成为2％角叉菜胶溶液。剔除小鼠背部毛发，第一天使用注射器于超净台中向每只小鼠背部注射纯净空气5mL，第四天于超净台补充注射2.5mL纯净空气并开始给药，给药组小鼠按30mg/kg化合物每天灌胃给药两次，模型及对照组使用CMC水溶液灌胃，第七天给药一次后1h补充注射2.5mL纯净空气后向气囊中注射1mL 2％角叉菜胶溶液并摇晃均匀完成造模。待角叉菜胶刺激4h后，使用5％戊巴比妥生理盐水麻醉小鼠，将4mL生理盐 水注射入气囊中冲洗气囊得到气囊灌洗液，1000rpm离心5min得到灌洗液中的全部细胞，使用PBS洗两次细胞，最终使用100μL PBS重悬细胞，将20μL细胞重悬液加入至2mL血细胞分析用稀释液中。混匀细胞稀释液，使用血细胞五分类分析仪进行检测，记录中性粒细胞的浓度。结果间图1和表2。
中性粒细胞数量按照以下公式计算：
中性粒细胞数量＝中性粒细胞浓度(x10 9/L)x体积(μL)x10 -6
Figure PCTCN2020132544-appb-000074
注：n＝6，显著性差异分析使用student t检验进行分析：#表示模型组与对照组比较结果， ###表示p<0.001， *表示p<0.05, **表示p<0.01, ***表示p<0.001。药理活性总结：
本发明化合物对CXCR2都显示出拮抗活性，其中化合物1、2、3、4、5、6、8、9、10、14、15、17、18、22、23、24、25、26、27、31的IC 50值小于1μM。7、8、31可显著抑制中性粒细胞向角叉菜胶诱导C57BL小鼠皮下慢性炎症模型背部气囊中的驱化作用，有明显的抗炎作用。

Claims (7)

  1. 一种式(I)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2020132544-appb-100001
    其中，
    A选自
    Figure PCTCN2020132544-appb-100002
    B选自
    Figure PCTCN2020132544-appb-100003
    R 1、R 2和R 3分别独立的选自氢、卤素、C 1-3烷基、甲氧基、乙氧基、三氟甲基或二氟甲基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中
    A选自
    Figure PCTCN2020132544-appb-100004
    B选自
    Figure PCTCN2020132544-appb-100005
    R 1选自氢、氟、氯、溴、甲基或三氟甲基；
    R 2选自氢、氟或氯；
    R 3选自氢、氯或溴。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2020132544-appb-100006
  4. 一种药物组合物，其特征在于，所述的药物组合物包含至少一种权利要求1至3中任一项所述的化合物或其药学上可接受的盐以 及任选的药学上可接受的载体和/或赋形剂。
  5. 根据权利要求4所述的药物组合物，其还包含除所述化合物或其药学上可接受的盐之外的药物活性成分。
  6. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐，或根据权利要求4或5任一项所述的药物组合物在制备用于预防和/或治疗CXCR2受体介导的疾病的药物中的应用。
  7. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐，或根据权利要求4或5任一项所述的药物组合物在制备用于预防和/或治疗慢性阻塞性肺病、哮喘、囊肿性纤维化、癌症、关节炎、银屑病、炎症性肠病、疼痛、多发性硬化症、阿尔茨海默病、帕金森病的药物中的应用。
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