WO2018161831A1 - Gpr84受体拮抗剂及其应用 - Google Patents

Gpr84受体拮抗剂及其应用 Download PDF

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WO2018161831A1
WO2018161831A1 PCT/CN2018/077584 CN2018077584W WO2018161831A1 WO 2018161831 A1 WO2018161831 A1 WO 2018161831A1 CN 2018077584 W CN2018077584 W CN 2018077584W WO 2018161831 A1 WO2018161831 A1 WO 2018161831A1
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independently
ring
compound
alkyl
group
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PCT/CN2018/077584
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English (en)
French (fr)
Inventor
南发俊
谢欣
陈林海
张庆
肖瑜峰
杨慧
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中国科学院上海药物研究所
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Priority to US16/490,837 priority Critical patent/US11098071B2/en
Priority to JP2019548461A priority patent/JP6918957B2/ja
Priority to EP18763472.0A priority patent/EP3594221B1/en
Priority to KR1020197028924A priority patent/KR102305710B1/ko
Publication of WO2018161831A1 publication Critical patent/WO2018161831A1/zh

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    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
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    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • 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]
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    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
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    • C07F9/06—Phosphorus compounds without P—C bonds
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    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
    • C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655381—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a seven-(or more) membered ring
    • C07F9/65539—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to a ligand molecule of G protein-coupled receptor 84 (GPR84).
  • GPR84 G protein-coupled receptor 84
  • the ligand molecule of the present invention has an antagonistic activity of GPR84, can competitively inhibit the activation of the receptor by an agonist of GPR84, and can be used for the treatment of a related disease caused by high expression or excitability of GPR84.
  • a related disease caused by high expression or excitability of GPR84.
  • a related disease caused by high expression or excitability of GPR84.
  • a related disease caused by high expression or excitability of GPR84.
  • GPR84 G protein-coupled receptor 84
  • C9-C14 medium-chain fatty acid receptor discovered by Wittenberger et al. in 2001 (J. Mol. Biol. 2001, 307, 799-813)
  • GPR84 Mainly expressed in bone marrow, peripheral blood leukocytes (including neutrophils, eosinophils, basophils) and fat cells.
  • LPS lipopolysaccharide
  • GPR84 expression is up-regulated in monocytes/macrophages, and medium-chain fatty acids can up-regulate the expression of IL-12p40 subunit in macrophage cell line RAW264.7 by GPR84, and regulate Th1.
  • the cellular immune response promotes inflammation and plays an important role in the development of inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel disease, and arthritis.
  • MS multiple sclerosis
  • metabolic diseases such as obesity and diabetes is closely related to chronic inflammation.
  • macrophages invade adipose tissue, inflammatory factors can be promoted by secreting cytokines, and GPR84 expression in adipocytes will increase, indicating that GPR84 is also involved.
  • GPR84 can promote inflammation, it plays an important role in the development of inflammation-related diseases. Therefore, by inhibiting the activity of GPR84 by a GPR84 antagonist, it is possible to treat an inflammation-related disease such as multiple sclerosis, inflammatory bowel disease, arthritis and the like.
  • GPR84 antagonists of GPR84 are only reported in two patents by the Belgian Galapagos Company (WO 2013/092791; WO 2014/095798). Both of these patents show that such antagonists all have a structural nucleus of dihydropyrimidine isoquinolinone.
  • the company reported that the GPR84 antagonist GLPG1205 (unpublished in structure) was induced by dextran sulphate sodium (DSS) in a mouse model of inflammatory bowel disease (IBD). At 3mg/kg/d, it can relieve the symptoms of enteritis. The effect is similar to the clinically positive drug cyclosporin (20mg/kg/d) and sulfazalazine (25mg/kg/d).
  • GLPG1205 may be a defect in the activity or drug-like nature of the compound itself, and GPR84 remains an effective target for targeted therapy of inflammatory diseases.
  • GPR84 remains an effective target for targeted therapy of inflammatory diseases.
  • the current research on GPR84 is still relatively preliminary, its detailed pathological function and its role in immune regulation remain to be further elucidated, but the discovery of GPR84 antagonist with high activity and high selectivity will continue to promote the receptor. Functional studies, target validation studies, and research and development of drugs targeting this receptor.
  • Y is O or S
  • Z is H, or an ion of the following metal: Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn, or a conjugated acid of the following base: NH 3 , Arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine Azine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.;
  • L 3 and L 6 are each independently O, S, NH or CH 2 ;
  • Rings A, B, C, and D are each independently a C 6 -C 10 aromatic ring, a C 3 -C 10 cycloalkane ring, a C 3 -C 10 heterocycloalkane ring, a C 3 -C 10 heteroaryl ring;
  • R 1 , R 2 , R 3 and R 4 are each independently represented by 1 to 4 substituents on the ring A, B, C and D, and each substituent is independently a non-hydroxy group, a thiol group, an amino group, an F, a Cl group.
  • L 2 and L 5 are each independently none, CH, N;
  • the rings A, B, C, and D are each independently a benzene ring, a C 3 -C 6 cycloalkane ring, a C 3 -C 6 heterocycloalkane ring, or a C 3 -C 6 heteroaryl ring.
  • the rings A, B, C, and D are each independently a benzene ring, a thiophene ring, a furan ring, a pyridine ring, a pyrimidine ring, an oxazole ring, a thiazole ring, a pyrazole ring, a pyrrole ring, a furan ring. a cyclohexane ring, a cyclopentane ring or a cycloheptane ring.
  • R 1 , R 2 , R 3 , R 4 are each independently represented by 1 or 2 or 3 substituents on Ring A, B, C, D, each independently being none, substituted or not Substituted C 1 -C 4 alkyl, -C r H 2r -L 7 -C s H 2s+1 , -C r H 2r -N(C t H 2t+1 )-C s H 2s+1 , hydroxyl , fluorenyl, amino, F, Cl, Br; the above substitution means having one or more substituents selected from the group consisting of halogen, hydroxy, amino, -COOC 1 -C 6 alkyl, -COOH, and L 7 are each independently
  • the ground is O, S, and NH, and each r is independently an integer of 0-4, and each s is independently an integer of 0-4, and each t is independently an integer of 1-4.
  • the C 3 -C 6 oxacycloalkyl group is -C(dioxolane)-.
  • L 2 and/or L 5 is CH or N
  • R 1 represents 1-2 substituents on Ring A, and each substituent is independently, —O(C 1 -C 4 )alkyl, hydroxy, F, Cl, Br, I. C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -C 2 H 4 COOH, -C 2 H 4 COOC 2 H 5 .
  • R 2 represents 1-2 substituents on Ring B, and each substituent is independently No, -O(C 1 -C 4 )alkyl, hydroxy, F, Cl, Br, I C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -C 2 H 4 COOH, -C 2 H 4 COOC 2 H 5 .
  • R 3 represents 1-2 substituents on Ring C, and each substituent is independently, independently -O(C 1 -C 4 )alkyl, hydroxy, F, Cl, Br, I C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -C 2 H 4 COOH, -C 2 H 4 COOC 2 H 5 .
  • R 4 represents 1-2 substituents on Ring D, and each substituent is independently, independently -O(C 1 -C 4 )alkyl, hydroxy, F, Cl, Br, I C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -C 2 H 4 COOH, -C 2 H 4 COOC 2 H 5 .
  • the compound is:
  • each of the rings and substituents described in Formula I are each independently a corresponding group of each specific compound described in the specification.
  • the compound of the formula S1, the compound of the formula S2 and the compound of the formula S3 are used as a raw material to obtain a compound having the structure of the formula I,
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , Y, Z, ring A, B, C, D are as defined above.
  • X is F, Cl, Br or I.
  • a third aspect of the invention provides a process for the preparation of the compound of the first aspect, the method comprising the steps of:
  • the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , Y, Z, ring A, B, C, D are as defined above.
  • X is F, Cl, Br or I.
  • a pharmaceutical composition comprising the compound of the first aspect or a pharmaceutically acceptable salt
  • a pharmaceutically acceptable carrier is selected from:
  • a fifth aspect of the invention provides the use of a compound of the first aspect or a pharmaceutically acceptable salt or a pharmaceutical composition according to the fourth aspect, wherein the use is:
  • the disease is multiple sclerosis, inflammatory bowel disease, or arthritis.
  • a method for treating a related disease caused by high expression or excitability of a GPR84 receptor is provided, and a compound of the present invention or a pharmaceutically acceptable salt is administered to a patient in need thereof.
  • the inventors of the present application have extensively and intensively studied to develop a novel structure of an antagonist of GPR84, which can competitively inhibit the activation of the receptor by an agonist of GPR84, and can be used for the preparation of a therapeutic GPR84 receptor.
  • a drug of a related disease caused by high expression or hyperexcitability which includes multiple sclerosis, inflammatory bowel disease, arthritis, and the like. On the basis of this, the present invention has been completed.
  • C 6 - C 10 means having 6 to 10 carbon atoms
  • C 3 - C 6 means having 3 to 6 carbon atoms, and so on.
  • An integer of 0-4 means 0, 1, 2, 3, 4; 6-10 carbon atoms means 6, 7, 8, 9, 10 carbon atoms, and so on.
  • alkyl refers to a saturated linear or branched hydrocarbon group; for example, -CH 3 or -CH(CH 3 ) 2 ; an alkylene group refers to a portion of a saturated hydrocarbon group that formally eliminates two remaining monovalent hydrogens, including but not It is limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the like.
  • Alkoxy refers to -O- (alkyl), including but not limited to -OCH 3, -OCH 2 CH 3 and the like.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group such as a cyclohexyl group.
  • Heterocycloalkyl refers to a saturated cyclic hydrocarbon group containing at least one hetero atom (e.g., N, O or S).
  • a heteroaryl ring refers to an aromatic ring containing at least one hetero atom.
  • the aromatic ring, heteroaryl ring, cycloalkane ring, alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, and the like described herein include both substituted and unsubstituted, possible Substituents include, but are not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, hydroxy, halogen , mercapto, cyano, nitro, carboxyl and carboxylate groups, and the like.
  • the GPR84 antagonist provided by the present invention is a compound having the structure of formula I:
  • the compounds of formula I according to the invention are compounds prepared in the examples.
  • the invention also provides a pharmaceutically acceptable salt thereof, comprising a salt of a compound of formula I which is reacted with an inorganic or organic base compound.
  • Salts derived from inorganic bases include, but are not limited to, aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, Zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • salts of pharmaceutically acceptable organic non-toxic bases including, but not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ions Exchange resin such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol , ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, Porphyrin, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • the compound of formula I can be achieved by any of the following routes 1 through 6:
  • the reaction is carried out in pyridine; the reaction temperature is from 60 ° C to 100 ° C; the reaction time is about 1 to 24 hours; after the reaction is completed, it is extracted with a solvent such as AcOEt, Et 2 O, CH 2 Cl 2 or CHCl 3 , and washed with saturated brine. After drying, the solvent was removed under reduced pressure at a low temperature, and the concentrate was subjected to column chromatography to give the desired product, and the obtained product was confirmed by NMR or the like.
  • a solvent such as AcOEt, Et 2 O, CH 2 Cl 2 or CHCl 3
  • the reaction requires two equivalents of the raw material S1, and the obtained product P1 has a symmetrical structure.
  • the reaction is formed as a mixture of three products of P1 to P3, and each product is separated by column chromatography.
  • the reaction is carried out in toluene; the base used is hexamethyldisilazane, the reaction temperature is 80 ° C to 120 ° C; the reaction time is about 1 to 24 hours; after the reaction is completed, AcOEt, Et 2 O, CH 2 Cl 2 ,
  • the solvent is extracted by a solvent such as CHCl 3 and washed with a saturated aqueous sodium chloride solution. After drying, the solvent is removed under reduced pressure at a low temperature, and the concentrate is subjected to column chromatography to give the desired product.
  • the reaction requires two equivalents of the raw material S1, and the obtained product P1 has a symmetrical structure.
  • the reaction is formed into a mixture of three products of P1 to P3, and each product is separated by column chromatography.
  • the raw material P2 is dissolved in EA, and the aqueous solution of the base (the conjugate base of M, the hydroxide of M or the carbonic acid compound of M) is added twice, the aqueous layer is back-extracted with EA, the EA layer is concentrated, and the crude product is subjected to silica gel column chromatography.
  • the product P4 was obtained.
  • M is a cation of the following metals: Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn;
  • a conjugated acid of the following base NH 3 , arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- Dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine Acid, methyl glucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.; other Each substituent is as defined above.
  • R1' is a C1-C4 alkyl group, and the other substituents are as defined above.
  • R 5 is a C1-C4 alkyl group
  • L 7 is a C1-C4 alkylene group, and the other substituents are as defined above.
  • the starting material P9 was dissolved in MeOH, and a solution of Oxone in H 2 O was added dropwise with stirring at room temperature, and allowed to react at room temperature overnight.
  • the reaction solution was diluted with water, extracted with EA, washed with brine, concentrated with organic layer, and purified by silica gel column chromatography.
  • the compound of the formula I as an antagonist of GPR84, is capable of competitively inhibiting the activation of the receptor by an agonist of GPR84, and can be used for the preparation of a medicament for treating a disease caused by high expression or excitability of the GPR84 receptor.
  • the diseases include multiple sclerosis, inflammatory bowel disease, arthritis and the like.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier”, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which Must have sufficient purity and low enough toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermixing with the active ingredient of the present invention (a compound of formula I or a pharmaceutically acceptable salt thereof) and the like, without significantly reducing the active ingredient. The efficacy of the drug.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, Magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • solid lubricants such as stearic acid, Magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannito
  • the compounds and pharmaceutical compositions of the present invention may be in various forms, and may be administered orally or in the form of an injection, such as a capsule, a tablet, a granule, a solution, a powder, a powder or a syrup, or the present invention.
  • the compounds and pharmaceutical compositions may be presented in a suitable solid or liquid vehicle and in a suitable sterilizing device for injection or drip.
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • the compounds and pharmaceutical compositions of this invention are useful for clinical use in mammals, including humans and animals, and can be administered by the oral, nasal or gastrointestinal routes.
  • the most preferred route of administration is oral.
  • NMR was measured using a Mercury-VX 300M or Mercury-VX400M instrument manufactured by Varian, NMR calibration: ⁇ H 7.26 ppm (CDCl 3 ), 2.50 ppm (DMSO-d 6 ), 3.15 ppm (CD 3 OD).
  • the reagents are mainly supplied by Shanghai Chemical Reagent Company; the TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silicone Development Co., Ltd., model HSGF 254; the normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao Marine Chemical Plant Branch. , model zcx-11, 200-300 mesh.
  • G1 synthetic reference J. Med. Chem. 2010, 53, 7021 - 7034; PCT Int. Appl., 2009016085, 05 Feb 2009.
  • Analogs of G1, some of which can be purchased from reagent companies, are prepared using the same or similar routes as for the synthesis of G1.
  • the raw material G2 was purchased from a reagent company, and the synthesis of the raw material G3 was carried out in the same synthetic route as G1.
  • the starting material G2 (62.7 mg, 0.192 mmol), G3 (49.2 mg, 0.192 mmol) was dissolved in dry pyridine (0.5 mL), and the re-evaporated POCl 3 (21 uL, 0.230 mmol) was added dropwise under N 2 and reacted at 130 ° C for 2 h. .
  • the GPR84 antagonistic activity test of the compounds of the invention was carried out.
  • the human GPR84 cell line was obtained by transfecting a plasmid encoding GPR84 and G ⁇ 16 proteins in a HEK293 cell line.
  • Fluorescent dye Fluo-4AM was purchased from Invitrogen.
  • Intracellular Ca 2+ ion is a very important second messenger of the G protein-coupled receptor signaling pathway. When combined with G ⁇ 16 protein-coupled GPR84 and agonist, the intracellular Ca 2+ ion concentration can be significantly increased. .
  • Fluo-4 is a Ca 2+ ion-specific fluorescent probe that binds quantitatively to Ca 2+ ions and fluoresces. Therefore, the agonistic or antagonistic activity of the compound is detected in a 96-well or 384-well flat-bottomed microplate using a fluorescence assay.
  • Detection of receptor inhibitory effect by GPR84 antagonist After incubation with fluorescent dye Fluo-4, GPR84 cells were incubated with different concentrations of antagonistic compounds for a period of time to occupy the binding site of agonist to GPR84 (antagonistic binding site). Add a certain concentration of agonist (6-OAU), compete with the antagonist compound for binding sites, and simultaneously use a light source with a wavelength of 485 nm to excite and detect changes in the fluorescence intensity of the dye caused by changes in intracellular calcium concentration at the 525 nm band. PRISM software calculated half-maximum inhibition concentration (IC 50).
  • HBSS 0.4 g/L KCl (5.4 mM), 0.12 g/L Na 2 HPO 4 ⁇ 12H 2 O (0.3 mM), 0.06 g/L KH 2 PO 4 (0.4 mM), 0.35 g/L NaHCO 3 ( 4.2 mM), 0.14 g/L CaCl 2 (1.3 mM), 0.10 g/L MgCl 2 ⁇ 6H 2 O (0.5 mM), 0.05 g/L MgSO 4 (0.6 mM), 8.0 g/L NaCl (137 mM), The above ingredients were weighed and dissolved in ultrapure water, adjusted to pH 7.4 with hydrochloric acid or NaOH solution, filtered, and stored at 4 ° C for one month.
  • Preparation of calcium buffer first prepare 560 mM D-glucose (100X) aqueous solution, 250 mM 1,2-diphenyl-4-(2-phenylsulfinyl)ethyl-3,5-pyrazolidinedione ( 1000X) stock solution. Then add BSA (0.5g), 560mM D-glucose stock solution (1mL) and 250mM 1,2-diphenyl-4-(2-phenylsulfinyl)ethyl-3,5-pyrene in 100mL HBSS.
  • the cells were seeded at a density of 40,000/well on a 96-well cell culture plate, and culture was continued for 24 hours or more to make the cell density to 80 to 90% for experimental detection. Aspirate the culture medium in the well to be tested, add 40 ⁇ L/well of freshly prepared dye, and incubate in a 37-degree incubator for 40 min to 50 min.
  • Formulation of the compound during cell incubation (this step can also be prepared in advance): Dilute the compound used as the antagonist to 1.5 times the final working concentration with freshly prepared calcium buffer before the experiment, and dilute the compound used as the agonist to the final work. Three times the concentration (if the DMSO dissolved compound should ensure that the DMSO concentration does not exceed 1% at the end of the work).
  • the dye is discarded, washed with calcium buffer and then replaced with 50 ⁇ L of calcium buffer containing different concentrations of antagonist for another 10 min.

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Abstract

本发明涉及一种GPR84受体拮抗剂及其应用。本发明的GPR84受体拮抗剂，结构如式（I）所示，其中R1、R2、R3、R4、L1、L2、L3、L4、L5、L6、Y、Z、环A、B、C、D的定义如说明书和权利要求书所述。本发明的GPR84受体拮抗剂，可以竞争性的抑制GPR84的激动剂引起的该受体的激活，可用于制备治疗因GPR84受体高表达或兴奋性过高所导致的相关疾病的药物，所述疾病包括多发性硬化症、炎症性肠病、关节炎等。

Description

GPR84受体拮抗剂及其应用 技术领域
本发明涉及一类G蛋白偶联受体84(G protein-coupled receptor 84，简称GPR84)的配体分子。本发明所涉及的配体分子具有GPR84的拮抗活性，可以竞争性的抑制GPR84的激动剂引起的该受体的激活，可用于因GPR84高表达或兴奋性过高所导致的相关疾病的治疗，如多发性硬化症、炎症性肠病、关节炎等。
背景技术
GPR84(G protein-coupled receptor 84，G蛋白偶联受体84)是2001年Wittenberger等首次发现的中链脂肪酸(C9-C14)受体(J.Mol.Biol.2001,307,799-813)，GPR84主要表达在骨髓、外周血白细胞(包括中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞)和脂肪细胞中。在脂多糖(Lipopolysaccharide,LPS)存在下，单核/巨噬细胞中的GPR84表达上调，中链脂肪酸可以通过GPR84显著上调巨噬细胞系RAW264.7细胞中IL-12p40亚基的表达，调节Th1细胞免疫应答，促进炎症发生，在多发性硬化症(multiple sclerosis,MS)、炎症性肠病、关节炎等炎症性疾病的发生过程中起重要作用。此外，肥胖、糖尿病等代谢性疾病的发生与慢性炎症密切相关，当巨噬细胞侵润脂肪组织时可通过分泌细胞因子促进炎症反应的发生，同时脂肪细胞中GPR84表达会增加，显示GPR84也参与了脂肪酸代谢和免疫系统间的交叉调节。
由于GPR84可以促进炎症发生，在炎症相关疾病的发生过程中起重要作用。因此通过GPR84拮抗剂来抑制该GPR84的活性，则可以治疗炎症相关疾病，如多发性硬化症、炎症性肠病、关节炎等。
至今为止，GPR84的拮抗剂只有比利时Galapagos公司的两篇专利报道(WO 2013/092791；WO 2014/095798)。这两篇专利显示该类拮抗剂均具有二氢嘧啶异喹啉酮的结构母核。同年12月份，该公司报道GPR84拮抗剂GLPG1205(结构未公布)在葡聚糖硫酸钠(dextran sulphate sodium,DSS)诱导的小鼠炎症性肠病(inflammatory bowel disease,IBD)模型中，口服剂量为3mg/kg/d时，即可明显缓解肠炎症状，效果与临床阳性用药环孢素(cyclosporin,20mg/kg/d)与柳氮磺胺吡啶(sulfazalazine,25mg/kg/d)相当(J Crohns Colitis 2015,9 Suppl 1,S387；J  Crohns Colitis 2015,9 Suppl 1,S92-3)。GLPG1205的I期临床试验已于一年前完成，但该公司在2016年1月底报道，在IIa期临床试验中，GLPG1205对炎症性肠病的治疗效果与安慰剂无明显差异，此次临床试验宣布失败，具体结果将于今年下半年公布。GLPG1205将可能作为其它适应症的治疗药物继续开发。
GLPG1205的临床试验受挫可能是该化合物本身的活性或类药性存在缺陷，GPR84依然是炎症性疾病靶向治疗的有效靶点。尽管目前GPR84的研究仍较为初步，其详细的病理学功能及其在免疫调节中的作用仍有待进一步阐明，但是具有高活性和高选择性的GPR84拮抗剂的发现，必将继续推动该受体的功能研究、靶点验证研究以及靶向该受体药物的研发。
发明内容
本发明的目的在于提供一种新型的GPR84的拮抗剂及其制备方法和用途。
本发明的第一方面，提供一种具有式I所示结构的化合物或药学上可接受的盐，
Figure PCTCN2018077584-appb-000001
式中，Y为O或S；Z为H，或以下金属的离子：Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn，或以下碱的共轭酸：NH 3、精氨酸、甜菜碱、咖啡因、胆碱、N，N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等；
L 3、L 6各自独立地为O、S、NH或CH 2；
环A、B、C、D各自独立地为C 6-C 10芳环、C 3-C 10环烷烃环、C 3-C 10杂环烷烃环、C 3-C 10杂芳环；
R 1、R 2、R 3、R 4各自独立地表示为环A、B、C、D上1-4个取代基，各取代 基各自独立地为无、羟基、巯基、氨基、F、Cl、Br、I、-C rH 2r-L 7-C sH 2s+1、-C rH 2r-N(C tH 2t+1)-C sH 2s+1、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 6～C 10芳基、取代或未取代的C 3～C 10杂芳基，上述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基、氨基、-COOC 1～C 6烷基、-COOH；L 7各自独立地为O、S、NH，各r独立为0-6的整数，各s独立为0-6的整数，各t独立为1-6的整数；
L 2、L 5各自独立地为无、CH、N；
L 1、L 4各自独立地为无、CH、O、S、SO、SO 2、-CH＝CH-、CO、-C(＝CH 2)-、取代或未取代的C 1～C 6亚烷基、-NH-、-N(C 1～C 4烷基)-、C 3～C 6环烷基或C 3～C 6杂环烷基，所述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基；
Figure PCTCN2018077584-appb-000002
表示单键或双键。
在另一优选例中，环A、B、C、D各自独立地为苯环、C 3-C 6环烷烃环、C 3-C 6杂环烷烃环、C 3-C 6杂芳环。
在另一优选例中，环A、B、C、D各自独立地为苯环、噻吩环、呋喃环、吡啶环、嘧啶环、噁唑环、噻唑环、吡唑环、吡咯环、呋喃环、环己烷环、环戊烷环或环庚烷环。
在另一优选例中，R 1、R 2、R 3、R 4各自独立地表示为环A、B、C、D上1或2或3个取代基，各自独立地为无、取代或未取代的C 1～C 4烷基、-C rH 2r-L 7-C sH 2s+1、-C rH 2r-N(C tH 2t+1)-C sH 2s+1、羟基、巯基、氨基、F、Cl、Br；上述取代是指具有选自下组的一个或多个取代基：卤素、羟基、氨基、-COOC 1～C 6烷基、-COOH，L 7各自独立地为O、S、NH，各r独立为0-4的整数，各s独立为0-4的整数，各t独立为1-4的整数。
在另一优选例中，L 1、L 4各自独立地为无、CH、O、S、SO、SO 2、-CH＝CH-、CO、-C(＝CH 2)-、取代或未取代的C 1～C 4亚烷基、-NH-、-N(C 1～C 3烷基)-、C 3～C 6环烷基或C 3～C 6氧杂环烷基，所述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基。
在另一优选例中，C 3～C 6氧杂环烷基为-C(二氧戊环)-。
在另一优选例中，L 2和/或L 5为无时，与L 3和/或L 6相连的碳与环B和/或环D的碳形成-CH＝CH-。
在另一优选例中，L 2和/或L 5为CH或N时，与L 3和/或L 6相连的碳与L 2和/或L 5形成-CH＝CH-或-CH＝N-。
在另一优选例中，R 1表示环A上1-2个取代基，各取代基各自独立地为无、-O(C 1-C 4)烷基、羟基、F、Cl、Br、I、C 1-C 4烷基、C 1-C 4卤代烷基、-C 2H 4COOH、-C 2H 4COOC 2H 5。
在另一优选例中，R 2表示环B上1-2个取代基，各取代基各自独立地为无、-O(C 1-C 4)烷基、羟基、F、Cl、Br、I、C 1-C 4烷基、C 1-C 4卤代烷基、-C 2H 4COOH、-C 2H 4COOC 2H 5。
在另一优选例中，R 3表示环C上1-2个取代基，各取代基各自独立地为无、-O(C 1-C 4)烷基、羟基、F、Cl、Br、I、C 1-C 4烷基、C 1-C 4卤代烷基、-C 2H 4COOH、-C 2H 4COOC 2H 5。
在另一优选例中，R 4表示环D上1-2个取代基，各取代基各自独立地为无、-O(C 1-C 4)烷基、羟基、F、Cl、Br、I、C 1-C 4烷基、C 1-C 4卤代烷基、-C 2H 4COOH、-C 2H 4COOC 2H 5。
在另一优选例中，L 1为无、CH、CH 2、O、-N(C 1～C 2烷基)-、S、-CH＝CH-、-C(＝CH 2)-、-C(＝O)-、-CH(CH 3)-、-CH 2CH 2-、-C(CH 2CH 2)-、-S(＝O)-、-SO 2-或-C(-OCH 2CH 2O-)-。
在另一优选例中，L 4为无、CH、CH 2、O、-N(C 1～C 2烷基)-、S、-CH＝CH-、-C(＝CH 2)-、-C(＝O)-、-CH(CH 3)-、-CH 2CH 2-、-C(CH 2CH 2)-、-S(＝O)-、-SO 2-或-C(-OCH 2CH 2O-)-。
在另一优选例中，L 2为无时，与L 3相连的碳与环B的碳形成-CH＝CH-。
在另一优选例中，L 5为无时，与L 6相连的碳与环D的碳形成-CH＝CH-。
在另一优选例中，L 2为CH或N时，与L 3相连的碳与L 2形成-CH＝CH-或-CH＝N-。
在另一优选例中，L 5为CH或N时，与L 6相连的碳与L 5形成-CH＝CH-或-CH＝N-。
在另一优选例中，所述化合物为：
Figure PCTCN2018077584-appb-000003
Figure PCTCN2018077584-appb-000004
Figure PCTCN2018077584-appb-000005
Figure PCTCN2018077584-appb-000006
或在另一优选例中，式I中所述的各环和取代基各自独立为说明书中记载的各具体化合物中相应的基团。
本发明的第二方面，提供第一方面所述的化合物的制备方法，所述方法包括以下步骤：
Figure PCTCN2018077584-appb-000007
以式S1化合物、式S2化合物和式S3化合物为原料，反应获得具有式I所示结构的化合物，
其中，R 1、R 2、R 3、R 4、L 1、L 2、L 3、L 4、L 5、L 6、Y、Z、环A、B、C、D的定义如前所示，
Figure PCTCN2018077584-appb-000008
表示单键或双键；
X为F、Cl、Br或I。
本发明的第三方面，提供第一方面所述的化合物的制备方法，所述方法包括以下步骤：
所述方法包括以下步骤：
Figure PCTCN2018077584-appb-000009
其中，R 1、R 2、R 3、R 4、L 1、L 2、L 3、L 4、L 5、L 6、Y、Z、环A、B、C、D的定义如前所示，
Figure PCTCN2018077584-appb-000010
表示单键或双键；
X为F、Cl、Br或I。
本发明的第四方面，提供一种药物组合物，所述药物组合物包含第一方面所述的化合物或药学上可接受的盐；以及
药学上可接受的载体。
本发明的第五方面，提供第一方面的化合物或药学上可接受的盐或第四方面所述的药物组合物的用途，所述用途为：
(i)用于制备GPR84拮抗剂；
(ii)用作GPR84拮抗剂；
(iii)用于制备治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的药物。
在另一优选例中，所述疾病为多发性硬化症、炎症性肠病、或关节炎。
本发明的第五方面，提供一种用于治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的方法，向有需要的患者给予本发明的化合物或药学上可接受的盐。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种新型结构的GPR84的拮抗剂，能够竞争性的抑制GPR84的激动剂引起的该受体的激活，可用于制备治疗因GPR84受体高表达或兴奋性过高所导致的相关疾病的药物，所述疾病包括多发性硬化症、炎症性肠病、关节炎等。在此基础上，完成了本发明。
定义
本发明中，C 6-C 10是指具有6-10个碳原子，C 3-C 6是指具有3-6个碳原子，依此类推。
0-4的整数是指0、1、2、3、4；6-10个碳原子是指6、7、8、9、10个碳原子，依此类推。
本发明中，除非另有说明，芳环、环烷烃环、烷基等术语与本领域熟练人员所熟悉的意义相同。例如，烷基是指饱和的线性或支链烃基；例如-CH 3或-CH(CH 3) 2；亚烷基是指饱和烃基从形式上消去两个一价氢剩余的部分，包括但不限于亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)等。烷氧基是指-O-(烷基)，包括但不限 于-OCH 3、-OCH 2CH 3等。环烷基是指饱和的环状烃基，例如环己基。杂环烷基是指包含至少一个杂原子(例如N,O或S)的饱和的环状烃基。杂芳环是指包含至少一个杂原子的芳环。
除非另外说明，本文所述的芳环、杂芳环、环烷烃环、烷基、亚烷基、烷氧基、环烷基、杂环烷基等同时包括取代的和未取代的，可能的取代基包括，但不限于：C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 20环烷基、C 3-C 20环烯基、C 1-C 20杂环烷基、C 1-C 20杂环烯基、C 1-C 10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、羟基、卤素、巯基、氰基、硝基、羧基和羧酸酯基等。
GPR84拮抗剂
本发明提供的GPR84拮抗剂，为具有式I结构的化合物：
Figure PCTCN2018077584-appb-000011
各取代基的定义同前。
最优选地，本发明所述的式I化合物为实施例制备的化合物。
本发明还提供其药学上可接受的盐，包括式I化合物与无机碱或有机碱类化合物反应而得到的盐。
得自无机碱的盐包括但不局限于：铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。
得自药学上可接受的有机无毒碱的盐，所述碱包括但不局限于伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N，N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
制备方法
式I化合物可通过下述路线一至路线六中的任何一种来实现：
路线一：
反应在吡啶中进行；反应温度为60℃～100℃；反应时间约需1～24小时；反应完成后用AcOEt、Et 2O、CH 2Cl 2、CHCl 3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
当原料S1＝S3时，该反应需要两当量的原料S1，所得产物P1为对称结构。当原料S1≠S3时，反应生成为P1～P3三个产物的混合物，各产物通过柱层析分离。
Figure PCTCN2018077584-appb-000012
各取代基定义如前所述。
路线二：
反应在甲苯中进行；所用碱为六甲基二硅氮烷，反应温度为80℃～120℃；反应时间约需1～24小时；反应完成后用AcOEt、Et 2O、CH 2Cl 2、CHCl 3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
Figure PCTCN2018077584-appb-000013
当原料S4＝S6时，该反应需要两当量的原料S1，所得产物P1为对称结构。当原料S4≠S6时，反应生成为P1～P3三个产物的混合物，各产物通过柱层析分离。
各取代基定义如前所述。
路线三：成盐
Figure PCTCN2018077584-appb-000014
原料P2溶于EA中，加入碱(M的共轭碱、M的氢氧化物或M的碳酸化合物)的水溶液洗涤两次，水层用EA反萃，EA层浓缩，粗品用硅胶柱层析得产物P4。
M为以下金属的阳离子：Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn；
或以下碱的共轭酸：NH 3、精氨酸、甜菜碱、咖啡因、胆碱、N，N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、 嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等；其它各取代基定义如前所述。
路线四：脱烷基
Figure PCTCN2018077584-appb-000015
将原料P5溶于干燥的DCM，N 2保护，干冰-丙酮冷却下滴加BBr 3的DCM溶液，然后渐升至室温，搅拌过夜。反应液加水稀释，EA萃取，EA层用brine洗涤，有机相浓缩，硅胶柱层析的产物P6。
R1’为C1～C4烷基，其它各取代基定义如前所述。
路线五：水解
Figure PCTCN2018077584-appb-000016
将原料P7溶于DCM/MeOH的混合溶液，室温搅拌下加入NaOH水溶液，室温反应。反应完毕后将反应液减压浓缩除去MeOH，再加水稀释，用1N HCl调pH＝2，然后EA萃取，brine洗涤，有机相用无水Na 2SO 4干燥，过滤，浓缩，所得粗品用PE/DCM重结晶，得水解产物P8。
R 5为C1～C4烷基，L 7为C1～C4亚烷基，其它各取代基定义如前所述。
路线六：氧化
Figure PCTCN2018077584-appb-000017
将原料P9溶于MeOH，室温搅拌下滴加Oxone的H 2O溶液，室温反应过夜。反应液加水稀释，EA萃取，brine洗涤，有机相浓缩，硅胶柱层析得产物P10和 P11。
用途
式I化合物作为GPR84的拮抗剂，能够竞争性的抑制GPR84的激动剂引起的该受体的激活，可用于制备治疗因GPR84受体高表达或兴奋性过高所导致的相关疾病的药物，所述疾病包括多发性硬化症、炎症性肠病、关节炎等。
药物组合物
本发明的药物组合物含有治疗有效量的式I化合物或其药学上可接受的盐，以及含有一种或多种可药用的载体。
“可药用的载体”、“药学上可接受的载体”或“药学上可用的载体”是指一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分(式I化合物或其药学上可接受的盐)以及它们之间相互掺和，而不明显降低活性成分的药效。可药用的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2018077584-appb-000018
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的化合物和药物组合物可以是多种形式，可以通过如胶囊、片剂、颗粒剂、溶液状、粉剂、散剂或糖浆等形式口服给药或以注射剂的形式非口服给药，本发明的化合物和药物组合物可以存在于适宜的固体或液体载体中和适宜的用于注射或滴注的消毒器具中。上述制剂可通过常规制药方法制备。
本发明的化合物和药物组合物可用于哺乳动物临床使用，包括人和动物，可以通过口、鼻或胃肠道等途径给药。最优选的给药途径为口服。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
下述实施例中，NMR用Varian生产的Mercury-VX 300M或Mercury-VX400M仪器测定，NMR定标：δH 7.26ppm(CDCl 3)，2.50ppm(DMSO-d 6)，3.15ppm(CD 3OD)；试剂主要由上海化学试剂公司提供；TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产，型号HSGF 254；化合物纯化使用的正相柱层析硅胶为山东青岛海洋化工厂分厂生产，型号zcx-11，200-300目。
实施例1
化合物CLH514的制备
Figure PCTCN2018077584-appb-000019
G1合成参考文献：J.Med.Chem.2010,53,7021–7034；PCT Int.Appl.,2009016085,05Feb 2009。G1的类似物，部分可从试剂公司购买，其余采用与合成G1相同或相似的路线进行制备。
原料G1(510mg,2.25mmol。)溶于干燥的吡啶(2.5mL)，N 2保护下滴加重蒸的POCl 3(207uL,2.25mmol)，130℃下反应3h。反应液冷却至室温，加水稀释，6N HCl调pH＝2，EA萃取，水层反萃三次，无水Na 2SO 4干燥。过滤，浓缩，硅胶柱层析(DCM/MeOH＝20/1～10/1)，得目标化合物CLH514(230mg，40％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ7.63(d,J＝7.2Hz,2H),7.41-7.50(m,4H),7.20-7.40(m,12H),3.56(br,1H).
用同样方法合成以下化合物：
Figure PCTCN2018077584-appb-000020
Figure PCTCN2018077584-appb-000021
实施例2
化合物CLH536的制备
Figure PCTCN2018077584-appb-000022
原料G1(2.635g,11.64mmol)溶于干燥的吡啶(10mL)，N 2保护下滴加重蒸的POCl 3(0.610mL,6.64mmol)，130℃下反应3h。反应液冷却至室温，加水稀释，6N HCl调pH＝2，EA萃取，EA层用饱和Na 2CO 3洗涤，水层反萃三次，无水Na 2SO 4干燥。过滤，浓缩，硅胶柱层析(DCM/MeOH＝10/1)，得目标化合物CLH536(2.247g，72％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ7.72(dd,J＝5.4Hz,1.8Hz,2H),7.40-7.44(m,4H),7.15-7.35(m,12H)。
用同样方法合成以下化合物
Figure PCTCN2018077584-appb-000023
Figure PCTCN2018077584-appb-000024
Figure PCTCN2018077584-appb-000025
Figure PCTCN2018077584-appb-000026
Figure PCTCN2018077584-appb-000027
Figure PCTCN2018077584-appb-000028
Figure PCTCN2018077584-appb-000029
实施例3
化合物CLH666的制备
Figure PCTCN2018077584-appb-000030
原料G2从试剂公司购买得到，原料G3的合成采用与G1相同的合成路线。
原料G2(62.7mg，0.192mmol)、G3(49.2mg，0.192mmol)溶于干燥的吡啶(0.5mL)，N 2保护下滴加重蒸的POCl 3(21uL，0.230mmol)，130℃下反应2h。反应液加入EA稀释，然后加水稀释，用6N HCl调pH＝1，EA萃取三次，EA层分别用饱和食盐水、饱和Na 2CO 3洗涤，有机相浓缩，硅胶柱层析(DCM/MeOH＝20/1～6/1)，得目标化合物CLH666(23mg，18％，白色固体)。 1H NMR(CDCl 3,300MHz):δ7.53(d,J＝6.9Hz,1H),7.42(d,J＝7.8Hz,1H),7.16-7.37(m,5H),6.83-7.16(m,8H),6.61(d,J＝8.4Hz,1H),3.75-4.00(m,2H),3.69(s,3H),3.43(q,J＝6.9Hz,1H),1.22(d,J＝6.9Hz,3H),1.01(t,J＝6.9Hz,3H).
实施例4
化合物CLH568、CLH582的制备
Figure PCTCN2018077584-appb-000031
原料CLH596a(45.2mg，0.076mmol)溶于干燥的DCM(1mL)，N2保护，干冰-丙酮冷却下滴加2N BBr3的DCM溶液(190uL，0.3mmol)，然后渐恢复至室温，搅拌过夜。反应液加水稀释，EA萃取三次，EA层分别用brine、饱和Na2CO3洗涤，有机相浓缩，硅胶制备板纯化(DCM/MeOH＝7/1展开两次)，得产物
CLH568(18.3mg，42.3％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ9.50-9.70(br,2H),7.47(d,J＝6.3Hz,2H),7.10-7.35(m,10H),7.04(t,J＝7.8Hz,2H),6.89(J＝7.8Hz,2H).
CLH582(11.2mg，25.3％，白色固体)。 1H NMR(CDCl 3,300MHz):δ7.30-7.40(m,3H),7.15-7.26(m,3H),7.12(d,J＝7.2Hz,1H),6.70-7.05(m,8H),6.38(d,J＝8.1Hz,1H),3.61(s,3H).
实施例5
化合物CLH680的制备
Figure PCTCN2018077584-appb-000032
原料CLH736(13mg，0.018mmol)溶于4mL甲醇，室温搅拌下加入1N NaOH水溶液(1mL)，室温反应2h。反应液减压浓缩除去MeOH，然后加水稀释，用1N HCl调pH＝2，然后EA萃取，brine洗涤水层反萃一次，有机相无水Na2SO4干燥，过滤，浓缩，所得粗品用PE/DCM重结晶，得产物CLH680(8.8mg，72％， 白色固体)。 1H NMR(CDCl 3,300MHz):δ7.57(d,J＝7.5Hz,2H),7.20-7.40(m,6H),6.90-7.15(m,8H),3.44(q,J＝7.2Hz,2H),1.24(d,J＝7.2Hz,6H).
用同样方法合成以下化合物：
Figure PCTCN2018077584-appb-000033
实施例6
化合物CLH600、CLH584、CLH568a的制备
Figure PCTCN2018077584-appb-000034
原料CLH536(100mg，0.186mmol)溶于MeOH(20mL)，室温搅拌下滴加Oxone(过一硫酸氢钾复合盐，500mg，1.627mmol)的H 2O(20mL)溶液，室温反应过夜。反应液加水稀释，EA萃取，brine洗涤，硅胶柱层析(DCM/MeOH＝25/1～6/1)，得产物：
CLH600(20mg，18％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ8.16(s,2H),8.06(d,J＝7.2Hz,4H),7.65-7.80(m,8H),7.50-7.65(m,4H).
CLH584(12mg，11％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ8.00-8.12 (m,3H),7.46-7.80(m,11H),7.30-7.46(m,4H).
CLH568a(10mg，9％，白色固体)。 1H NMR(d 6-DMSO,300MHz):δ6.60-7.90(m,8H),7.56(t,J＝7.2Hz,2H),7.32-7.50(m,7H),7.25(d,J＝7.2Hz,1H).
实施例7
化合物XYF532的制备
将原料G1(226mg，1mmol)溶于THF(4mL)中，冰浴下滴加甲基溴化镁的乙醚溶液(3mol/L，0.5mL)，升至室温反应3小时，加入饱和氯化铵淬灭反应。用EA萃取，饱和食盐水洗，无水硫酸钠干燥，旋干后加入盐酸/乙酸乙酯溶液(4mol/L，2mL)，室温反应过夜，反应液浓缩，粗品经柱层析分离(PE/EA＝20/1～10/1)，得产物G4(135mg，产率60％)。
Figure PCTCN2018077584-appb-000035
将原料G4(135mg，0.60mmol)溶于四氯化碳(5mL)，依次加入NBS(139mg，0.78mmol)和AIBN(10mg)，加热回流反应5小时后，冷却到室温，过滤除去固体，滤液浓缩后柱层析分离，得产物G5(82mg，产率45％)。
将原料G5(100mg，0.33mmol)和次亚磷酸胺盐(11mg，0.13mmol)溶于无水甲苯(1.5mL)，氩气保护下加入六甲基二硅氮烷(HMDS，110μL，0.53mmol)，加热回流过夜。冷却到室温，旋干甲苯，加入二氯甲烷：甲醇(1:1)溶解，旋干后硅胶柱层析(DCM/MeOH＝25/1～6/1)，得产物XYF532(30mg，产率43％)。 1H NMR(CDCl 3,300MHz):δ7.10-7.40(m,18H),2.96-3.27(br,4H).
实施例8
1.实验目的
进行本发明化合物的GPR84拮抗活性测试。
2.材料来源
人源GPR84细胞系，通过在HEK293细胞系中转染编码GPR84和Gα16蛋白的质粒得到。荧光染料Fluo-4AM购自Invitrogen公司。
3.测试原理
细胞内Ca 2+离子是一种非常重要的G蛋白偶联受体信号通路第二信使，当与Gα 16蛋白偶联的GPR84和激动剂结合后，细胞内的Ca 2+离子浓度能够显著增加。Fluo-4是一种Ca 2+离子特异性荧光探针，能够和Ca 2+离子定量结合并发出荧光。因此采用荧光检测法，在96孔或384孔平底微孔板中检测化合物的激动活性或拮抗活性。
GPR84拮抗剂对受体抑制效应的检测：GPR84细胞经荧光染料Fluo-4孵育后，加入不同浓度的拮抗化合物孵育一段时间，使其占据激动剂与GPR84的结合位点(拮抗结合位点)，再加入一定浓度的激动剂(6-OAU)，与拮抗化合物竞争结合位点，同时用波长为485nm的光源激发并于525nm波段检测细胞内钙离子浓度变化引起的染料荧光强度的改变，用GraphPad PRISM软件进行计算得到化合物的半数抑制浓度(IC 50)。
4.实验过程
配制HBSS：0.4g/L KCl(5.4mM)，0.12g/L Na 2HPO 4·12H 2O(0.3mM)，0.06g/L KH 2PO 4(0.4mM)，0.35g/L NaHCO 3(4.2mM)，0.14g/L CaCl 2(1.3mM)，0.10g/L MgCl 2·6H 2O(0.5mM)，0.05g/L MgSO 4(0.6mM)，8.0g/L NaCl(137mM)，称取上述各成分并用超纯水溶解，用盐酸或NaOH溶液调节pH至7.4，过滤，4℃保存一个月。
配制钙缓冲液：首先配制560mM D-葡萄糖(100X)水溶储存液，250mM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮(1000X)储存液。然后在100mL HBSS中加BSA(0.5g)，560mM的D-葡萄糖储存液(1mL)和250mM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮储存液(100μL)，使终浓度分别为0.5％BSA，5.6mM D-葡萄糖，250μM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮，混匀，现配现用。
配制染料：首先配制3％的Cremophor EL(100X)PBS溶解的储存液和2mM Fluo-4(1000X)DMSO溶解的储存液，然后每毫升染料的配制为先将1μL的2mM Fluo-4AM和10μL的3％的Cremophor EL混匀，再用1mL钙缓冲液稀释并混匀。
以4万个/孔的密度将细胞接种到96孔细胞培养板上，继续培养24小时以上使细胞密度至80～90％用于实验检测。吸去待检测细胞孔内培养液，加入新鲜配制的染料40μL/孔，置于37度培养箱内恒温孵育40min至50min。
在细胞孵育过程中配制化合物(此步骤也可以提前准备)：用实验前新鲜配制钙缓冲液将作拮抗剂使用的化合物稀释至最终工作浓度1.5倍，将作激动剂使用的化合物稀释至最终工作浓度的3倍(如果是DMSO溶解的化合物应保证最终工作时DMSO浓度不超过1％)。
在孵育步骤完成后将染料吸尽弃去，用钙缓冲液洗一遍后换50μL的含不同浓度拮抗剂的钙缓冲液再孵育10min。
用FlexStation III微孔板检测仪加入25μL/孔含一定浓度(一般选取激动剂EC 80左右的有效浓度)激动剂的钙缓冲液进行刺激，同时用波长为485nm的光源激发并于525nm波段检测细胞内钙离子浓度变化引起的染料荧光强度的改变。
5.实验结果
表1、GPR84钙流模型检测化合物的IC 50
Figure PCTCN2018077584-appb-000036
Figure PCTCN2018077584-appb-000037
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种具有式I所示结构的化合物或药学上可接受的盐，
    Figure PCTCN2018077584-appb-100001
    式中，
    Y为O或S；
    Z为H，或以下金属的离子：Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn，或以下碱的共轭酸：NH 3、精氨酸、甜菜碱、咖啡因、胆碱、N，N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇；
    L 3、L 6各自独立地为O、S、NH或CH 2；
    环A、B、C、D各自独立地为C 6-C 10芳环、C 3-C 10环烷烃环、C 3-C 10杂环烷烃环、C 3-C 10杂芳环；
    R 1、R 2、R 3、R 4各自独立地表示为环A、B、C、D上1-4个取代基，各取代基各自独立地为无、羟基、巯基、氨基、F、Cl、Br、I、-C rH 2r-L 7-C sH 2s+1、-C rH 2r-N(C tH 2t+1)-C sH 2s+1、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 6～C 10芳基、取代或未取代的C 3～C 10杂芳基，上述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基、氨基、-COOC 1～C 6烷基、-COOH；L 7各自独立地为O、S、NH，各r独立为0-6的整数，各s独立为0-6的整数，各t独立为1-6的整数；
    L 2、L 5各自独立地为无、CH、N；
    L 1、L 4各自独立地为无、CH、O、S、SO、SO 2、-CH＝CH-、CO、-C(＝CH 2)-、取代或未取代的C 1～C 6亚烷基、-NH-、-N(C 1～C 4烷基)-、C 3～C 6环烷基或C 3～C 6杂环烷基，所述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基；
    Figure PCTCN2018077584-appb-100002
    表示单键或双键。
  2. 如权利要求1所述的化合物，其特征在于，环A、B、C、D各自独立地为苯环、C 3-C 6环烷烃环、C 3-C 6杂环烷烃环、C 3-C 6杂芳环。
  3. 如权利要求1所述的化合物，其特征在于，R 1、R 2、R 3、R 4各自独立地表示为环A、B、C、D上1或2或3个取代基，各自独立地为无、取代或未取代的C 1～C 4烷基、-C rH 2r-L 7-C sH 2s+1、-C rH 2r-N(C tH 2t+1)-C sH 2s+1、羟基、巯基、氨基、F、Cl、Br、I；上述取代是指具有选自下组的一个或多个取代基：卤素、羟基、氨基、-COOC 1～C 6烷基、-COOH，L 7各自独立地为O、S、NH，各r独立为0-4的整数，各s独立为0-4的整数，各t独立为1-4的整数。
  4. 如权利要求1所述的化合物，其特征在于，L 1、L 4各自独立地为无、CH、O、S、SO、SO 2、-CH＝CH-、CO、-C(＝CH 2)-、取代或未取代的C 1～C 4亚烷基、-NH-、-N(C 1～C 3烷基)-、C 3～C 6环烷基或C 3～C 6氧杂环烷基，所述取代是指具有选自下组的一个或多个取代基：C 1～C 6烷基、C 1～C 6烷氧基、卤素、羟基。
  5. 如权利要求1所述的化合物，其特征在于，L 2和/或L 5为无时，与L 3和/或L 6相连的碳与环B和/或环D的碳形成-CH＝CH-；或
    L 2和/或L 5为CH或N时，与L 3和/或L 6相连的碳与L 2和/或L 5形成-CH＝CH-或-CH＝N-。
  6. 如权利要求1所述的化合物，其特征在于，所述化合物为：
    Figure PCTCN2018077584-appb-100003
    Figure PCTCN2018077584-appb-100004
    Figure PCTCN2018077584-appb-100005
    Figure PCTCN2018077584-appb-100006
  7. 如权利要求1所述的化合物的制备方法，其特征在于，所述方法包括以下步骤：
    Figure PCTCN2018077584-appb-100007
    以式S1化合物、式S2化合物和式S3化合物为原料，反应获得具有式I所示结构的化合物，
    其中，R 1、R 2、R 3、R 4、L 1、L 2、L 3、L 4、L 5、L 6、Y、Z、环A、B、C、D的定义如权利要求1所示，
    Figure PCTCN2018077584-appb-100008
    表示单键或双键；
    X为F、Cl、Br或I。
  8. 如权利要求1所述的化合物的制备方法，其特征在于，所述方法包括以下步骤：
    Figure PCTCN2018077584-appb-100009
    其中，R 1、R 2、R 3、R 4、L 1、L 2、L 3、L 4、L 5、L 6、Y、Z、环A、B、C、D的定义如权利要求1所示，
    Figure PCTCN2018077584-appb-100010
    表示单键或双键；
    X为F、Cl、Br或I。
  9. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-6任一项所述的化合物或药学上可接受的盐；以及
    药学上可接受的载体。
  10. 根据权利要求1所述的化合物或药学上可接受的盐，或权利要求9所述的的药物组合物的用途，其特征在于，所述用途为：
    (i)用于制备GPR84拮抗剂；
    (ii)用作GPR84拮抗剂；
    (iii)用于制备治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的药物。
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