WO2019218957A1 - Composé en tant qu'inhibiteur du récepteur 4 activé par la protéase (par4) pour le traitement de l'agrégation plaquettaire - Google Patents

Composé en tant qu'inhibiteur du récepteur 4 activé par la protéase (par4) pour le traitement de l'agrégation plaquettaire Download PDF

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WO2019218957A1
WO2019218957A1 PCT/CN2019/086558 CN2019086558W WO2019218957A1 WO 2019218957 A1 WO2019218957 A1 WO 2019218957A1 CN 2019086558 W CN2019086558 W CN 2019086558W WO 2019218957 A1 WO2019218957 A1 WO 2019218957A1
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mmol
acid
group
methoxy
pyridin
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PCT/CN2019/086558
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Chinese (zh)
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吴俊军
李硕
温晓明
阳华
魏国平
胡允金
钱苏
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深圳信立泰药业股份有限公司
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Priority to CN201980030133.4A priority Critical patent/CN112074522B/zh
Publication of WO2019218957A1 publication Critical patent/WO2019218957A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention is in the field of chemical pharmaceutical technology, and particularly provides a series of compounds as protease inhibitory receptor 4 (PAR4) inhibitors for treating platelet aggregation and their medical uses.
  • PAR4 protease inhibitory receptor 4
  • a compound or a pharmaceutically acceptable salt thereof, which is a protease activated receptor 4 (PAR4) inhibitor for treating platelet aggregation, has the following structure:
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • the C 1-4 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • P is selected from CH, N;
  • R 2 is selected from the group consisting of hydrogen, methoxy, butoxy, methoxyethoxy,
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, amber Acids, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, cit
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as deuterium (2 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • Step E Synthesis of 2-bromo-5-[imidazo[1,2-a]pyridin-2-yl]imidazo[2,1-b][1,3,4]thiadiazole
  • 3,5-Dimethoxypyridine (10.00 g, 71.9 mmol) was dissolved in dichloromethane (250.0 mL). Subsequently, diphenylphosphonylhydroxylamine (20.00 g, 85.8 mmol) was added in portions to the above solution. Stir at room temperature for 18 hours.
  • Step C Synthesis of 4-methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid
  • N,4-Dimethoxy-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide (1.00 g, 4.25 mmol) was dissolved in tetrahydrofuran (30 mL).
  • a saturated aqueous ammonium chloride solution 50 ml was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (200 mL EtOAc).
  • Step A Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylthio)imidazo[2,1-b][1,3 , 4] thiadiazole
  • Step G 6-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1,3 , 4] thiadiazole
  • Step I Synthesis of 2-bromo-1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one
  • Step B See Example 1 for details, Step C: 2-bromo-1-(pyridazin-2-yl)ethan-1-one (85 mg, 0.36 mmol), 5-bromo-1,3,4- Thiadiazole-2-amine (128 mg, 0.72 mmol), isopropanol (3.0 mL). 2-Bromo-6-(pyridazin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (50 mg, 43.5%) was obtained as a brown solid. MS (ESI) M / Z: 319 [M+H + ].
  • Step D Synthesis of 6-(6-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-2 -yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
  • Step F Synthesis of 1-(4-(benzyloxy)-6-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanol
  • Step H Synthesis of 1-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoethyl ketone
  • the reaction was quenched by the addition of methanol (10 mL). The reaction solution was warmed to room temperature and concentrated.
  • the crude product was purified by reverse phase column [reverse phase column: C18; mobile phase A: water (containing 0.05% formic acid), mobile phase B: acetonitrile; gradient: 30% acetonitrile to 90% acetonitrile in 8 min; detection wavelength: 254 nm
  • reverse phase column reverse phase column: C18; mobile phase A: water (containing 0.05% formic acid), mobile phase B: acetonitrile; gradient: 30% acetonitrile to 90% acetonitrile in 8 min; detection wavelength: 254 nm
  • the fractions were collected and directly lyophilized.
  • Step L Synthesis of 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridyl) Zoxao[1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)morpholine
  • Step D Synthesis of 6-(6-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)ethoxy)pyrazolo[1,5-a]pyridine- 2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
  • the separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% in 7 minutes 100%; detection wavelength: 254 nm. Lyophilized under reduced pressure, purified, and lyophilized to give a white solid (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N,N-dimethylimidazo[ 2,1-b][1,3,4]thiadiazol-2-amine (16.1 mg, 22.2%). MS (ESI) M / Z: 345 [M+H + ].
  • Step A Synthesis of 4-(3-(6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)propyl)morpholine
  • Step A Ethyl 2-bromothiazole-4-carboxylate (2.00 g, 8.50 mmol) was dissolved in 1,4-dioxane (40.0 mL). Subsequently, triethylamine (3.90 g, 38.6 mmol) and 4-fluoropiperidine hydrochloride (3.60 g, 25.7 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 4 hours.
  • Step B Ethyl 2-(4-fluorocyclohexyl)thiazole-4-carboxylate (1.00 g, 3.90 mmol) was dissolved in tetrahydrofurane (20.0 mL). Subsequently, lithium borohydride (340 mg, 15.5 mmol) and methanol (500 mg, 15.5 mmol) were added in portions to the above solution. The reaction solution was stirred at room temperature for 5 hours.
  • Step A Methyl-2-bromo-5-methyl-thiazole-4-carboxylic acid (1.00 g, 4.24 mmol) was dissolved in dimethyl sulfoxide (20.0 mL). Subsequently, anhydrous potassium carbonate (2.35 g, 17.0 mmol) and 2-oxa-6-azaspiro[3.3] heptane (851 mg, 8.60 mmol) were sequentially added to the above solution. The reaction solution was stirred at 120 ° C for 24 hours.
  • Step C Azodiyldipiperidine (383 mg, 1.52 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (478 mg, 2.36 mmol) was added to the above solution. After the reaction solution was stirred at room temperature for 20 minutes, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- was further added thereto.
  • Step A Ethyl 2-bromothiazole-4-carboxylate (910 mg, 3.86 mmol) was dissolved in 1,4-dioxane (20.0 mL). Subsequently, triethylamine (1.75 g, 17.3 mmol) was added to the above solution.
  • Step B Ethyl 2-(3-fluoroazetidin-1-yl)thiazole-4-carboxylate (400 mg, 1.74 mmol) was dissolved in THF (20.0 mL). The reaction liquid was cooled to 0 ° C, and lithium borohydride (152 mg, 7.00 mmol) was added portionwise to the above solution. Subsequently, methanol (227 mg, 7.00 mmol) was slowly added dropwise thereto. The reaction solution was slowly warmed to room temperature and stirred for 2 hours.
  • Step A Ethyl 2-bromothiazole-4-carboxylate (2.00 g, 8.51 mmol) was dissolved in 1,4-dioxane (50.0 mL). Subsequently, triethylamine (1.30 g, 12.8 mmol) and morpholine (2.22 g, 25.5 mmol) were successively added to the above solution. The reaction solution was heated to 120 ° C and stirred for 6 hours.
  • Step C Azodiyldipiperidine (1.15 g, 4.56 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (1.44 g, 7.12 mmol) was added dropwise to the above solution. After the reaction solution was stirred at room temperature for 30 minutes, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- was further added thereto.
  • Step A 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (100 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (2.0 mL). Subsequently, 3-(bromomethyl)tetrahydrofuran (78 mg, 0.47 mmol) and anhydrous potassium carbonate (131 mg, 0.95 mmol) were added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step A 2-Bromo-4-((tert-butyldimethylsilyloxy)methyl)-5-methylthiazole (510 mg, 1.58 mmol) was dissolved in tetrahydrofuran (20.0). In milliliters). After cooling the above solution to -78 ° C, n-hexane solution of n-butyllithium (0.85 ml, 2.05 mmol, 2.5 mol / liter) was slowly added dropwise thereto. The reaction solution was stirred at -78 ° C for 30 minutes. Subsequently, tetrahydropyranone (237 mg, 2.37 mmol) in tetrahydrofuran (5.0 ml) was added dropwise thereto. The reaction solution was stirred at -78 ° C for 1 hour.
  • Step B 4-(4-((tert-Butyldimethylsilyloxy)methyl)-5-methylthiazol-2-yl)-tetrahydro-2H-pyran-4-ol (430 mg, 1.25 mmol) was dissolved in tetrahydrofuran (50.0 mL). The reaction solution was stirred at room temperature for 1 hour.
  • Step C Azodiyldipiperidine (496 mg, 1.97 mmol) and tributylphosphine (621 mg, 3.08 mmol) were dissolved in tetrahydrofuran (13.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution.
  • Step A 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (200 mg, 0.62 mmol), mp. 3-(methylamino)propionitrile (79 mg, 0.94 mmol), cesium carbonate (243 mg, 0.75 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime ( 43 mg, 0.07 mmol) was dissolved in 1,4-dioxane (5.0 mL). Subsequently, palladium acetate (14 mg, 0.06 mmol) was added to the above solution. The reaction solution was heated to 100 ° C and stirred for 12 hours.
  • Step B 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)propanenitrile (90.0 mg) , 0.28 mmol) was dissolved in tetrahydrofuran (1.0 mL). Subsequently, a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.50 ml, 1.0 mol/liter) was added to the above solution. The reaction solution was stirred at room temperature for 30 minutes.
  • Step C Azodiyldipiperidine (242 mg, 0.96 mmol) was dissolved in tetrahydrofurane (2.0 mL). Subsequently, a solution of tributylphosphine (311 mg, 1.44 mmol) in tetrahydrofuran (1.0 ml) was added to the above solution. After the reaction solution was stirred at room temperature for 30 minutes, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- was further added thereto.
  • Step A 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridine-4-hydroxyl (100 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, anhydrous potassium carbonate (87 mg, 0.63 mmol) and 3-bromo-2-(bromomethyl)pyridine (158 mg, 0.64 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step A 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (100 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, 3-(bromomethyl)pyridine hydrobromide (160 mg, 0.63 mmol) and anhydrous potassium carbonate (174 mg, 1.26 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step A Methyl 2-(2-bromo-5-methylthiazol-4-yl)acetate (776 mg, 3.29 mmol) was dissolved in THF (30.0 mL). After the reaction liquid was cooled to 0 ° C, lithium borohydride (276 mg, 13.1 mmol) was added portionwise. Subsequently, methanol (421 mg, 13.1 mmol) was slowly added dropwise thereto. The reaction solution was stirred at 0 ° C for 2 hours.
  • Step B (2-Bromo-5-methylthiazol-4-yl)methanol (660 mg, 3.17 mmol) was dissolved in dichloromethane (45.0 mL). Subsequently, imidazole (431 mg, 6.35 mmol) and trimethyl-tert-butylchlorosilane (950 mg, 6.35 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 1 hour.
  • Step C 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (380 mg, 1.18 mmol), mp. 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.38 mmol), Pd(dppf)Cl 2 (263 mg, 0.36 mmol), cesium carbonate (1.20 g, 3.59 mmol) dissolved in 1,4-dioxane (10.0 mL) and water (1.80 mL) Mixed solution. The reaction system was heated to 100 ° C and stirred overnight.
  • Step D 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methylthiazole (326 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, a solution of tetrabutylammonium fluoride in tetrahydrofuran (2.0 ml, 1.0 mol/liter) was added to the above solution.
  • Step E Azodiyl dipiperidine (572 mg, 2.27 mmol) and tributylphosphine (717 mg, 3.55 mmol) were dissolved in tetrahydrofuran (10.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution.
  • Step A (2-Bromo-5-methylthiazol-4-yl)methanol (200 mg, 0.96 mmol) was dissolved in 1,4-dioxane (10.0 mL). . Subsequently, azetidine-3-carbonitrile hydrochloride (171 mg, 1.44 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.048 mmol), 4,5 was added to the above solution. Bis-diphenylphosphino-9,9-dimethyloxaxan (55.6 mg, 0.096 mmol) and anhydrous cesium carbonate (939 mg, 2.88 mmol). The reaction solution was heated to 120 ° C and stirred for 2 hours.
  • Step A (2-Bromo-5-methylthiazol-4-yl)methanol (2.00 g, 9.61 mmol) and (E)-3-(4,4,5,5).
  • - tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (4.35 g, 19.2 mmol) dissolved in 1,4-dioxane (40.0 mL) and Water (8.0 ml) in a mixed solution.
  • anhydrous potassium carbonate (2.66 g, 19.2 mmol
  • tetrakistriphenylphosphine palladium 560 mg, 0.48 mmol
  • Step B Ethyl (E)-3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)acrylate (900 mg, 3.96 mmol) was dissolved in methanol (20.0 mL). Subsequently, palladium on water (900 mg, 10%) was added to the above solution. Subsequently, the reaction system was replaced with hydrogen three times. The reaction solution was stirred at room temperature for 2 hours.
  • Step C Ethyl 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoate (400 mg, 1.75 mmol) was dissolved in ethanol (2.0 mL) and water (2.0 mL) In a mixed solution. Subsequently, lithium hydroxide monohydrate (366 mg, 8.73 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step D Dissolving 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (200 mg, 0.99 mmol) in N,N-dimethylformamide (2.0 mL) in. Subsequently, methylaminoacetonitrile hydrochloride (130 mg, 1.19 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N' was sequentially added to the above solution. Tetramethylurea hexafluorophosphate (570 mg, 1.49 mmol) and N,N-diisopropylethylamine (390 mg, 2.98 mmol). The reaction solution was stirred at room temperature for 1 hour.
  • the crude product was purified by high pressure liquid chromatography, and the separation conditions were as follows: column; XBridge Shield RP18 OBD Column, 5 um, 19*150 mm mobile phase: A: water (containing 0.1% ammonium hydrogencarbonate), B: acetonitrile. Flow rate: 25 ml/min, gradient: 5 minutes from 25% acetonitrile to 55% acetonitrile.
  • the product was collected and lyophilized to give N-(cyanomethyl)-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b]) as a white solid.
  • Step A 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (1.00 g, 3.12 mmol), mp. 3-(ethylamino)propionitrile (610 mg, 6.22 mmol), tris(dibenzylideneacetone)dipalladium (143 mg, 9.35 mmol), 4,5-bisdiphenylphosphine-9,9 -Methyloxaxime (180 mg, 0.31 mmol), anhydrous cesium carbonate (3.05 g, 9.35 mmol) dissolved in toluene (10.0 mL). The reaction solution was heated to 120 ° C and stirred for 2 hours.
  • Step B 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)(ethyl)amino)propanenitrile (240 mg) , 0.71 mmol, dissolved in tetrahydrofuran (10 mL). Subsequently, tetrabutylammonium fluoride (1.42 ml, 1.42 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 1 hour.
  • Step C Azodiyldipiperidine (1.12 g, 4.44 mmol) was dissolved in tetrahydrofuran (7.0 mL). Subsequently, tributylphosphine (1.20 g, 5.56 mmol) was added to the above solution. After the reaction mixture was stirred at room temperature for 30 minutes, 3-(ethyl(4-(hydroxymethyl)-5-methylthiazol-2-yl)amino)propanenitrile (125 mg, 0.56 mmol) was added thereto.
  • Step A (2-Bromo-5-methylthiazol-4-yl)methanol (150 mg, 0.72 mmol), 2-(azetidin-3-yl)acetonitrile at room temperature under nitrogen. (143 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol), anhydrous cesium carbonate (704 mg, 2.16 mmol) and 4,5-bisdiphenylphosphine -9,9-Dimethyloxanthene (42 mg, 0.07 mmol) was dissolved in 1,4-dioxane (10.0 mL). The reaction was heated to 120 ° C and stirred overnight.
  • Step B Azodiyldipiperidine (478 mg, 2.36 mmol) and tributylphosphine (378 mg, 1.51 mmol) were dissolved in tetrahydrofuran (2.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution.
  • the preparation conditions were as follows: Column: XBridge Prep OBD C18 19mm *250mm, 5um; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 41% to 50% in 25 minutes; detection wavelength: 254 nm.
  • Step A 3-(4-(Hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (120 mg, 0.59 mmol) was dissolved in dichloromethane (15.0 mL). Subsequently, methyl ethylamine hydrochloride (143 mg, 1.49 mol), triethylamine (362 mg, 3.58 mmol) and 1-propylphosphoric acid tricyclic anhydride (1.00 ml, 1.34 mmol, 50) were sequentially added to the above solution. % wt of ethyl acetate solution). The reaction solution was stirred at room temperature for 2 hours.
  • Step B Azodiyldipiperidine (342 mg, 1.36 mmol) and tributylphosphine (428 mg, 2.12 mmol) were dissolved in tetrahydrofurane (12.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution.
  • Step A Dissolving 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (400 mg, 1.99 mmol) in N,N-dimethylformamide (50.0 mL) in. Subsequently, N,N-diisopropylethylamine (1.54 g, 11.9 mmol), 3-(methylamino)propionitrile (501 mg, 5.97 mmol) and O-(7-) were sequentially added to the above solution. Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.51 g, 3.98 mmol). The reaction solution was stirred at room temperature for 1 hour.
  • Step B Azodiyldipiperidine (764 mg, 3.03 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (957 mg, 4.73 mmol) was added to the above solution. After the reaction solution was stirred at room temperature for 30 minutes, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- was further added thereto.

Abstract

L'invention concerne un composé en tant qu'inhibiteur du récepteur 4 activé par protéase (PAR4) pour le traitement de l'agrégation plaquettaire et son application médicale, appartenant au domaine technique des médicaments chimiques.
PCT/CN2019/086558 2018-05-16 2019-05-13 Composé en tant qu'inhibiteur du récepteur 4 activé par la protéase (par4) pour le traitement de l'agrégation plaquettaire WO2019218957A1 (fr)

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