WO2019218957A1 - Compound as protease activated receptor 4 (par4) inhibitor for treating platelet aggregation - Google Patents

Compound as protease activated receptor 4 (par4) inhibitor for treating platelet aggregation 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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French (fr)
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/en
Publication of WO2019218957A1 publication Critical patent/WO2019218957A1/en

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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

A compound as a protease activated receptor 4 (PAR4) inhibitor for treating platelet aggregation and a medical application thereof, belonging to the technical field of chemical drugs.

Description

作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物a compound that acts as a protease activated receptor 4 (PAR4) inhibitor for the treatment of platelet aggregation 技术领域Technical field
本发明属于化学药物技术领域，特别提供了一系列作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物及其医药用途。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.
背景技术Background technique
血栓栓塞性疾病仍是目前死亡的主要原因之一，尽管有可利用的抗凝血剂如华法林，肝素，和抗血小板剂如阿司匹林和氯吡格雷，替格瑞洛，利伐沙班等等。Thromboembolic disease remains one of the leading causes of death, although available anticoagulants such as warfarin, heparin, and antiplatelet agents such as aspirin and clopidogrel, ticagrelor, rivaroxaban and many more.
血小板的主要生理功能是参与血栓与止血，任何凝血过程都涉及血小板的活化，这是一个复杂的信号级连过程，凝血酶在其中占有核心地位。凝血酶活化血小板主要通过一族G蛋白偶连的蛋白酶活化受体PARs(protease-activated receptors)介导。人类血小板表面表达PAR1与PAR4两种受体，凝血酶能连接并切割PAR1或PAR4，暴露新的N-末端，后者作为一个固定配基与受体进行分子内结合，从而激发跨膜信号传导，引起血小板聚集、释放以及膜糖蛋白的一系列改变。The main physiological function of platelets is to participate in thrombosis and hemostasis. Any blood coagulation process involves the activation of platelets, which is a complex signal cascade process in which thrombin plays a central role. Thrombin-activated platelets are mediated primarily by a family of G-protein-coupled protease-activated receptors (PARs). Human platelets express both PAR1 and PAR4 receptors. Thrombin can bind and cleave PAR1 or PAR4, exposing a new N-terminus, which acts as a binding ligand for intramolecular binding to the receptor, thereby stimulating transmembrane signaling. , causing platelet aggregation, release, and a series of changes in membrane glycoproteins.
PAR1抑制剂已得到广泛研究，包括vorapaxar(沃拉帕沙)和atopaxar(阿托帕沙)的数种化合物已进入后期临床试验。近来，在ACS患者的示踪III期试验中，vorapaxar没有显著减少心血管事件，而是显著增加严重出血的风险(Tricoci,P.等人，N.Eng.J.Med.,366(1)：20-33(2012)。因此，仍然需要发现新的具有增加功效和减少出血副作用的抗血小板药。PAR1 inhibitors have been extensively studied, and several compounds including vorapaxar (wolapasa) and atopaxar (attopasa) have entered late clinical trials. Recently, in the Phase III trial of ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of severe bleeding (Tricoci, P. et al., N. Eng. J. Med., 366(1) :20-33 (2012). Therefore, there is still a need to discover new antiplatelet drugs with increased efficacy and reduced bleeding side effects.
另外，有一些PAR4抑制剂专利申请公开，如CN104640869A和CN104583218A分别公开了下式I和II的一系列作为蛋白酶活化受体4(PAR4)抑制剂，用于抑制或防止血小板聚集的药物中的用途。In addition, some PAR4 inhibitor patent applications disclose, such as CN104640869A and CN104583218A, respectively, disclose a series of uses of the following formulas I and II as protease activated receptor 4 (PAR4) inhibitors for inhibiting or preventing platelet aggregation. .
Figure PCTCN2019086558-appb-000001
Figure PCTCN2019086558-appb-000001
所述化合物的研究还处于前期研究阶段，据专利申请公开资料显示，其五元母核中应当含有氧原子才有相应的PAR4活性。The study of the compound is still in the preliminary research stage. According to the patent application disclosure data, the nucleus of the quintuple should contain oxygen atoms to have the corresponding PAR4 activity.
发明内容Summary of the invention
为了寻找具有增加功效和减少出血副作用的抗血小板药，并且本发明提供了一系列作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物，本发明的化合物结构母核不同于已公开的PAR4抑制剂。In order to find anti-platelet drugs with increased efficacy and reduced bleeding side effects, and the present invention provides a series of compounds as protease activated receptor 4 (PAR4) inhibitors for the treatment of platelet aggregation, the structural nucleus of the compound of the present invention is different from A PAR4 inhibitor has been disclosed.
作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物或其药学上可接受的盐，所述化合物具有如下结构：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:
Figure PCTCN2019086558-appb-000002
Figure PCTCN2019086558-appb-000002
其中，R 0选自氢，卤素，C 1-4烷基，C 1-4的烷氧基，C 1-4的烷硫基，C 1-4的亚砜基，C 1-4的砜基，C 1-4的氨基； Wherein R 0 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 sulfoxide, C 1-4 sulfone a group, an amino group of C 1-4 ;
X，Y选自CH或者N；X, Y is selected from CH or N;
R 1选自氢，卤素、羟基、巯基、C 1-4的烷氧基； R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, decyl, C 1-4 alkoxy;
R 2选自氢，卤素、羟基、巯基、C 1-4的烷氧基、C 2-4的烯氧基、C 3-6的环烷氧基、C 5-8芳(杂)环-C 1-4的烷氧基、-O-(CH 2)n-NR 8R 9-CO-O-C 1-4烷基、甲氧基取代的C 1-4烷氧基、C 5-12脂杂环-W-C 1-4烷氧基，其中W为(CH 2)n-O、(CH 2)n-S或(CH 2)n-噻唑，其中烷氧基、烯氧基、环烷氧基、C 5-12脂杂环、C 5-8芳(杂)环、噻唑可进一步被卤素、C 1-4烷基、羟基、C 2-4氰基、-NR 4R 5、-(CH 2)n-CO-NR 6R 7取代，其中R 4、R 5分别独立选自C 1-4的烷基，C 2-4氰基；R 6、R 7分别独立的选自C 1-4的烷基，C 3-6的环烷基，C 2-4氰基，或者R 6、R 7成环；R 8R 9分别独立的选自氢，C 1-4烷基，n＝0、1、2或3。 R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, decyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 3-6 cycloalkoxy, C 5-8 aryl (hetero) ring - C 1-4 alkoxy, -O-(CH 2 )n-NR 8 R 9 -CO-OC 1-4 alkyl, methoxy-substituted C 1-4 alkoxy, C 5-12 lipid Heterocyclic-WC 1-4 alkoxy, wherein W is (CH 2 ) nO, (CH 2 ) nS or (CH 2 ) n-thiazole, wherein alkoxy, alkenyloxy, cycloalkoxy, C 5 -12 alicyclic, C 5-8 aryl (hetero) ring, thiazole may be further halogen, C 1-4 alkyl, hydroxy, C 2-4 cyano, -NR 4 R 5 , -(CH 2 )n -CO-NR 6 R 7 substituted, wherein R 4 and R 5 are each independently selected from C 1-4 alkyl, C 2-4 cyano; and R 6 and R 7 are each independently selected from C 1-4 alkane. a C 3-6 cycloalkyl group, a C 2-4 cyano group, or a R 6 and R 7 ring; R 8 R 9 are independently selected from hydrogen, C 1-4 alkyl, n=0, 1 , 2 or 3.
作为本发明的一种优选方案，所述卤素选自氟、氯、溴、碘。As a preferred embodiment of the present invention, the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
作为本发明的一种优选方案，所述C 1-4的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。 As a preferred embodiment of the present invention, the C 1-4 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
作为本发明的一种优选方案，所述C 1-4的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基；C 2-4氰基选自乙氰基、丙氰基、丁氰基；C 2-4的烯氧基选自乙烯氧基、丙烯氧基、丁烯氧基。 As a preferred embodiment of the present invention, the C 1-4 alkoxy group is selected from the group consisting of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a sec-butyl group. group, tert-butoxy; C 2-4 cyano group b is selected from cyano, cyano propoxy, butoxy cyano; C 2-4 alkylene group selected from ethylene group, propylene group, butylene group .
作为本发明的一种优选方案，所述C 1-4的亚砜基选自CH 3SO-,CH 3CH 2SO-,CH 3CH 2CH 2SO-,CH 3CH 2CH 2CH 2SO-。 As a preferred embodiment of the present invention, the C 1-4 sulfoxide group is selected from the group consisting of CH 3 SO-, CH 3 CH 2 SO-, CH 3 CH 2 CH 2 SO-, CH 3 CH 2 CH 2 CH 2 SO-.
作为本发明的一种优选方案，所述C 1-4的砜基选自CH 3SO 2-,CH 3CH 2SO 2-,CH 3CH 2CH 2SO 2-,CH 3CH 2CH 2CH 2SO 2-。 As a preferred embodiment of the present invention, the C 1-4 sulfone group is selected from the group consisting of CH 3 SO 2 -, CH 3 CH 2 SO 2 -, CH 3 CH 2 CH 2 SO 2 -, CH 3 CH 2 CH 2 CH 2 SO 2 -.
作为本发明的一种优选方案，所述C 1-4的氨基选自甲氨基、乙氨基、二甲氨基、丙氨基、异丙胺基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。 As a preferred embodiment of the present invention, the amino group of C 1-4 is selected from the group consisting of methylamino, ethylamino, dimethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino and tert-butyl. Amino group.
作为本发明的一种优选方案，所述C 1-4的烷硫基选自甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基。 As a preferred embodiment of the present invention, the C 1-4 alkylthio group is selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, and sec Sulfur-based, tert-butylthio.
作为本发明的一种优选方案，C 3-6的环烷选自环丙基、环丁基、环戊基、环己基；C 5-12脂杂环选自
Figure PCTCN2019086558-appb-000003
C 5-8芳(杂)环选自苯环、
Figure PCTCN2019086558-appb-000004
As a preferred embodiment of the present invention, the cycloalkane of C 3-6 is selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; and the C 5-12 aliphatic heterocyclic ring is selected from the group consisting of
Figure PCTCN2019086558-appb-000003
The C 5-8 aryl (hetero) ring is selected from the group consisting of benzene rings,
Figure PCTCN2019086558-appb-000004
作为本发明的一种优选方案，所述化合物通式结构为下式(II)，As a preferred embodiment of the present invention, the compound has a general structure of the following formula (II).
Figure PCTCN2019086558-appb-000005
Figure PCTCN2019086558-appb-000005
其中，R 0，R 1、R 2，X，Y如上定义。 Wherein R 0 , R 1 , R 2 , X, and Y are as defined above.
作为本发明的一种优选方案，所述化合物通式结构为下式(III)，As a preferred embodiment of the present invention, the compound has a general formula of the following formula (III).
Figure PCTCN2019086558-appb-000006
Figure PCTCN2019086558-appb-000006
其中，R 0，R 1、X，Y如上定义； Wherein R 0 , R 1 , X, Y are as defined above;
Z选自氧原子、亚甲基、C1-4烷基、取代或非取代的噻唑环；Z is selected from the group consisting of an oxygen atom, a methylene group, a C1-4 alkyl group, a substituted or unsubstituted thiazole ring;
m等于1，2，3或4；m is equal to 1, 2, 3 or 4;
n等于0，1，2或3；n is equal to 0, 1, 2 or 3;
P选自CH、N；P is selected from CH, N;
Q选自氧原子或者碳原子；Q is selected from an oxygen atom or a carbon atom;
R 3选自氢，卤素。 R 3 is selected from the group consisting of hydrogen and halogen.
作为本发明的一种优选方案，R 0选自甲氧基、溴、甲硫基、CH 3SO 2-、CH 3SO-、甲氨基、二甲氨基； As a preferred embodiment of the present invention, R 0 is selected from the group consisting of methoxy, bromo, methylthio, CH 3 SO 2 -, CH 3 SO-, methylamino, dimethylamino;
R 1选自氯、甲氧基； R 1 is selected from the group consisting of chlorine and methoxy;
R 2选自氢、甲氧基、丁氧基、甲氧乙氧基、
Figure PCTCN2019086558-appb-000007
Figure PCTCN2019086558-appb-000008
R 2 is selected from the group consisting of hydrogen, methoxy, butoxy, methoxyethoxy,
Figure PCTCN2019086558-appb-000007
Figure PCTCN2019086558-appb-000008
Figure PCTCN2019086558-appb-000009
Figure PCTCN2019086558-appb-000010
其中
Figure PCTCN2019086558-appb-000011
为连接键；
Figure PCTCN2019086558-appb-000009
Figure PCTCN2019086558-appb-000010
among them
Figure PCTCN2019086558-appb-000011
For the connection key;
X，Y如上定义。X, Y are as defined above.
作为本发明的一种优选方案，所述药学上可接受的盐选自无机酸或有机酸成盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、 扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、三氟乙酸、单宁酸、酒石酸和对甲苯磺酸。As a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from the group consisting of inorganic acids or organic acid salts selected from the group consisting of 2-acetoxybenzoic acid and 2-hydroxyethanesulfonic acid. Acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid , glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionethane, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzene Sulfonic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid and p-toluenesulfonic acid.
本发明优选自以下化合物：The invention is preferably derived from the following compounds:
Figure PCTCN2019086558-appb-000012
Figure PCTCN2019086558-appb-000012
Figure PCTCN2019086558-appb-000013
Figure PCTCN2019086558-appb-000013
Figure PCTCN2019086558-appb-000014
Figure PCTCN2019086558-appb-000014
Figure PCTCN2019086558-appb-000015
Figure PCTCN2019086558-appb-000015
本发明另一目的提供了一种药物组合物，其特征在于，包括前述的化合物或其药学上可接受的盐和一种以上药学上可接受的载体。Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
本发明另一目的在于提供所述的化合物或其药学上可接受的盐在制备用于制备治疗血栓相关疾病的药物用途。Another object of the present invention is to provide a pharmaceutical use of the compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a thrombosis.
进一步地，所述血栓相关疾病选自动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、脑血管血栓栓塞性病症、和心脏腔室或外周循环中的血栓栓塞性病症。Further, the thrombosis-related disease is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a thromboembolic disorder in the heart chamber or peripheral circulation.
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如甲酸、乙酸、三氟乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, 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. Examples of 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, citric acid, tartaric acid and methanesulfonic acid, etc.; also include amino acids (such as fine Salts of amino acids and the like, and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
优选以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is isolated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、三氟乙酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁酸、酒石酸和对甲苯磺酸。As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, Ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, ethanol Acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid , pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, trifluoroacetic acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid , sulfuric acid, tannic acid, tartaric acid and p-toluenesulfonic acid.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 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. For example, 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.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation carrier or vehicle that is capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient. Representative carriers include water, oil. , vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.
实施例1Example 1
合成6-(咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 6-(imidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000016
Figure PCTCN2019086558-appb-000016
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成咪唑并[1,2-A]吡啶-2-羧酸Step A: Synthesis of imidazo[1,2-A]pyridine-2-carboxylic acid
Figure PCTCN2019086558-appb-000017
Figure PCTCN2019086558-appb-000017
将咪唑并[1,2-A]吡啶-2-羧酸乙酯(5.00克，26.3毫摩尔)溶于乙醇(100.0毫升)与水(100.0毫升)的混合溶液中。随后，向上述溶液中加入氢氧化钠(3.20克，80.0毫摩尔)。在室温下搅拌8小时。Ethyl imidazo[1,2-A]pyridine-2-carboxylate (5.00 g, 26.3 mmol) was dissolved in a mixture of ethanol (100.0 mL) and water (100.0 mL). Subsequently, sodium hydroxide (3.20 g, 80.0 mmol) was added to the above solution. Stir at room temperature for 8 hours.
向反应液中缓慢滴加稀盐酸溶液(1.0摩尔/升)调节PH值至3-4。有白色固体析出。过滤，收集滤饼，滤饼烘干得到4.26克黄色固体咪唑并[1,2-A]吡啶-2-羧酸，无需纯化，直接用于下步反应。MS(ESI)M/Z：163[M+H +]。 A dilute hydrochloric acid solution (1.0 mol/liter) was slowly added dropwise to the reaction solution to adjust the pH to 3-4. A white solid precipitated. Filtration, collection of the filter cake, and drying of the filter cake gave 4.26 g of a yellow solid imidazo[1,2-A]pyridine-2-carboxylic acid, which was used in the next step without purification. MS (ESI) M / Z: 163 [M+H + ].
步骤B：合成N-甲氧基-N-甲基咪唑并[1,2-a]吡啶-2-甲酰胺Step B: Synthesis of N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide
Figure PCTCN2019086558-appb-000018
Figure PCTCN2019086558-appb-000018
将咪唑并[1,2-A]吡啶-2-羧酸(4.26克，26.3毫摩尔)和N,O-二甲基羟胺盐酸盐(12.80克，130.6毫摩尔)溶于二氯甲烷(300.0毫升)中。随后，向上述溶液中加入N,N-二异丙基乙基胺(23.8克，184.5毫摩尔)和1-羟基苯并***(5.30克，39.3毫摩尔)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(7.60克，39.6毫摩尔)。在室温下搅拌16小时。Imidazo[1,2-A]pyridine-2-carboxylic acid (4.26 g, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (12.80 g, 130.6 mmol) were dissolved in dichloromethane. 300.0 ml). Subsequently, N,N-diisopropylethylamine (23.8 g, 184.5 mmol) and 1-hydroxybenzotriazole (5.30 g, 39.3 mmol) and 1-ethyl-(3) were added to the above solution. -Dimethylaminopropyl)carbodiimide hydrochloride (7.60 g, 39.6 mmol). Stir at room temperature for 16 hours.
向反应液中加入饱和碳酸氢钠溶液(100毫升)淬灭反应。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相。有机相先用饱和食盐水(100毫升×3次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝4/6)。得到1.40克黄色固体N-甲氧基-N-甲基咪唑并[1,2-a]吡啶-2-甲酰胺(收率：26.0％)。MS(ESI)M/Z：206[M+H +]。 The reaction was quenched by the addition of saturated sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (200 mL×3×). Combine the organic phases. The organic phase was dried with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 6). 1.40 g of a yellow solid N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide (yield: 26.0%) was obtained. MS (ESI) M / Z: 206 [M+H + ].
步骤C：合成1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮Step C: Synthesis of 1-[imidazo[1,2-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000019
Figure PCTCN2019086558-appb-000019
在室温和氮气保护下，将N-甲氧基-N-甲基咪唑并[1,2-a]吡啶-2-甲酰胺(1.40克，6.83毫摩尔)溶于四氢呋喃(80.0毫升)中。随后，向上述溶液中缓慢滴加甲基溴化镁的四氢呋喃溶液(5.0毫升，15.0毫摩尔，3.0摩尔/升)。在室温下搅拌2小时。N-Methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide (1.40 g, 6.83 mmol) was dissolved in tetrahydrofuran (80.0 mL). Subsequently, a solution of methylmagnesium bromide in tetrahydrofuran (5.0 ml, 15.0 mmol, 3.0 mol/liter) was slowly added dropwise to the above solution. Stir at room temperature for 2 hours.
向反应液中缓慢滴加饱和氯化铵溶液淬灭反应。混合液用乙酸乙酯(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升×3次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝3/7)。得到720毫克白色固体1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮(收率：66.0％)。MS(ESI)M/Z：161[M+H +]。 The reaction was quenched by slowly dropwise adding a saturated ammonium chloride solution to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic layers were dried with brine (100 mL×3×) The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3/7). There was obtained 720 mg of white solid 1-[imidazo[1,2-a]pyridin-2-yl]ethan-1-one (yield: 66.0%). MS (ESI) M / Z: 161 [M+H + ].
步骤D：合成2-溴-1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮Step D: Synthesis of 2-bromo-1-[imidazo[1,2-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000020
Figure PCTCN2019086558-appb-000020
将1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮(720毫克，4.50毫摩尔)溶于氢溴酸溶液(15.0毫升，48％wt)中。随后，向上述溶液中加入溴素(718毫克，4.49毫摩尔)的氢溴酸溶液(10.0毫升)。将反应液加热至70摄氏度，并搅拌1小时。1-[Imidazo[1,2-a]pyridin-2-yl]ethan-1-one (720 mg, 4.50 mmol) was dissolved in hydrobronic acid (15.0 mL, 48% wt). Subsequently, a solution of bromine (718 mg, 4.49 mmol) in hydrobromic acid (10.0 ml) was added to the above solution. The reaction solution was heated to 70 ° C and stirred for 1 hour.
将反应液冷却到室温，并减压浓缩。将所得残余物加入丙酮与甲醇的混合溶液(15/1)中。有白色固体析出，过滤，收集滤饼，滤饼烘干得到450毫克黄色固体2-溴-1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮。无需纯化，直接用于下步反应。MS(ESI)M/Z：239,241[M+H +]。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was added to a mixed solution of acetone and methanol (15/1). A white solid was precipitated, filtered, and the filter cake was collected. The filter cake was dried to give <RTI ID=0.0>> It is used directly in the next step without purification. MS (ESI) M / Z: 239, 241 [M+H + ].
步骤E：合成2-溴-5-[咪唑并[1,2-a]吡啶-2-基]咪唑并[2,1-b][1,3,4]噻二唑Step E: Synthesis of 2-bromo-5-[imidazo[1,2-a]pyridin-2-yl]imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000021
Figure PCTCN2019086558-appb-000021
将2-溴-1-[咪唑并[1,2-a]吡啶-2-基]乙-1-酮(450毫克，1.88毫摩尔)和2-氨基-5-溴-1,3,4-噻二唑(392毫克，2.16毫摩尔)加入异丙醇(15.0毫升)中。在150摄氏度下微波反应器中加热搅拌30分钟。2-Bromo-1-[imidazo[1,2-a]pyridin-2-yl]ethan-1-one (450 mg, 1.88 mmol) and 2-amino-5-bromo-1,3,4 - Thiadiazole (392 mg, 2.16 mmol) was added to isopropanol (15.0 mL). The mixture was heated and stirred for 30 minutes at 150 ° C in a microwave reactor.
将反应液冷却到室温，并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝98/2)。得到330毫克黄色固体2-溴-5-[咪唑并[1,2-a]吡啶-2-基]咪唑并[2,1-b][1,3,4]噻二唑(收率：54.9％)。MS(ESI)M/Z：320,322[M+H +]。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting Obtained 330 mg of a yellow solid 2-bromo-5-[imidazo[1,2-a]pyridin-2-yl]imidazo[2,1-b][1,3,4]thiadiazole (yield: 54.9%). MS (ESI) M/Z: 320, 322 [M+H + ].
步骤F：合成6-(咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step F: Synthesis of 6-(imidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000022
Figure PCTCN2019086558-appb-000022
将2-溴-5-[咪唑并[1,2-a]吡啶-2-基]咪唑并[2,1-b][1,3,4]噻二唑(330毫克，1.03毫摩尔)溶于二氯甲烷(40.0毫升)与甲醇(16.0毫升)的混合溶液中。随后，向上述溶液中加入叔丁醇钾(116毫克，1.04毫摩尔)。在室温下搅拌1小时。2-Bromo-5-[imidazo[1,2-a]pyridin-2-yl]imidazo[2,1-b][1,3,4]thiadiazole (330 mg, 1.03 mmol) Dissolved in a mixed solution of dichloromethane (40.0 ml) and methanol (16.0 ml). Subsequently, potassium t-butoxide (116 mg, 1.04 mmol) was added to the above solution. Stir at room temperature for 1 hour.
向反应液中加入水淬灭反应。混合液用二氯甲烷(50毫升×3次)，合并有机相，有机相先用饱和食盐水(50毫升×3次)洗涤，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从5％升到100％；检测波长：254nm。纯化后，低温冻干得25.2毫克白色固体6-(咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：9.0％)。MS(ESI)M/Z：272[M+H +]。 1H NMR(300MHz,DMSO-d 6,ppm)δ8.86(d,J＝6.6Hz,1H),8.47(s,1H),8.21-8.15(m,2H),7.94(t,J＝7.5Hz,1H),7.50(t,J＝6.6Hz,1H),4.20(s,3H)。 Water was added to the reaction solution to quench the reaction. The mixture was combined with methylene chloride (50 mL×3×). The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% in 7 minutes 100%; detection wavelength: 254 nm. After purification, lyophilization at low temperature gave 25.2 mg of a white solid 6-(imidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4 Thiadiazole (yield: 9.0%). MS (ESI) M / Z: 272 [M+H + ]. 1 H NMR (300MHz, DMSO- d 6, ppm) δ8.86 (d, J = 6.6Hz, 1H), 8.47 (s, 1H), 8.21-8.15 (m, 2H), 7.94 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 6.6 Hz, 1H), 4.20 (s, 3H).
实施例2Example 2
合成(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000023
Figure PCTCN2019086558-appb-000023
步骤A：合成4,6-二甲氧基吡啶-2-胺Step A: Synthesis of 4,6-dimethoxypyridin-2-amine
Figure PCTCN2019086558-appb-000024
Figure PCTCN2019086558-appb-000024
在100毫升高压反应器中，将4,6-二氯吡啶-2-胺(2.00克，12.3毫摩尔)溶于甲醇钠的甲醇溶液(40毫升，40毫摩尔，1.0摩尔/升)中。在140摄氏度下搅拌过夜。TLC监测显示原料消失后。将体系冷却到室温并真空浓缩。将所得残余物溶于水(50毫升)中。混合液用乙酸乙酯(100毫升X2)萃取。合并后的有机相先用饱和盐水(50毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚40％)浓缩得棕色固体4,6-二甲氧基吡啶-2- 胺(800毫克，42.3％)。MS(ESI)M/Z:155[M+H +]。 4,6-Dichloropyridin-2-amine (2.00 g, 12.3 mmol) was dissolved in a solution of sodium methoxide in methanol (40 mL, 40 mmol, 1.0 mol/L). Stir at 140 degrees Celsius overnight. TLC monitoring showed disappearance of the raw materials. The system was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in water (50 mL). The mixture was extracted with ethyl acetate (100 mL EtOAc). The combined organic phases were back-washed with saturated brine (50 mL) then dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography chromatography eluting elut elut elut elut MS (ESI) M / Z: 155 [M+H + ].
步骤B：合成1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮Step B: Synthesis of 1-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000025
Figure PCTCN2019086558-appb-000025
将4,6-二甲氧基吡啶-2-胺(500毫克，3.25毫摩尔)溶于乙醇(25毫升)中。向体系中加入1-溴丁烷-2,3-二酮(1.32克，8.00毫摩尔)。在80摄氏度下搅拌30分钟。TLC监测显示原料消失后，将体系冷却到室温并真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚70％)浓缩得白色固体1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮(280毫克，39.2％)。MS(ESI)M/Z:221[M+H +]。 4,6-Dimethoxypyridin-2-amine (500 mg, 3.25 mmol) was dissolved in ethanol (25 mL). To the system was added 1-bromobutane-2,3-dione (1.32 g, 8.00 mmol). Stir at 80 degrees Celsius for 30 minutes. After TLC monitoring showed disappearance of the starting material, the system was cooled to room temperature and concentrated in vacuo. The crude product was purified with EtOAc EtOAc elut elut elut elut elut Ethyl ketone (280 mg, 39.2%). MS (ESI) M / Z: 221 [M+H + ].
步骤C：合成2-溴-1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮Step C: Synthesis of 2-bromo-1-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000026
Figure PCTCN2019086558-appb-000026
将1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮(230毫克，1.05毫摩尔)溶于氢溴酸(10毫升，47％wt)中。在80摄氏度下逐滴加入溴素(168毫克，1.05毫摩尔)。在80摄氏度下搅拌30分钟。TLC监测显示原料消失后，将反应液倒入饱和的碳酸氢钠水溶液(50毫升)淬灭反应。混合液用乙酸乙酯(100毫升X2)萃取。合并后的有机相先用饱和盐水(50毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用反相柱纯化[反相柱:C18；流动相A：水(含有0.05％的甲酸)，流动相B：乙腈；梯度:30％乙腈到90％乙腈在8分钟内；检测波长：254nm]浓缩得黄色固体2-溴-1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮(100毫克，31.8％)。MS(ESI)M/Z:299[M+H +]。 1-(5,7-Dimethoxyimidazo[1,2-a]pyridin-2-yl)ethanone (230 mg, 1.05 mmol) was dissolved in hydrobromic acid (10 mL, 47% wt) in. Bromine (168 mg, 1.05 mmol) was added dropwise at 80 °C. Stir at 80 degrees Celsius for 30 minutes. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (50 ml) to quench the reaction. The mixture was extracted with ethyl acetate (100 mL EtOAc). The combined organic phases were back-washed with saturated brine (50 mL) then dried over anhydrous sodium sulfate. 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: Concentration of 254 nm] yellow solid 2-bromo-1-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)ethanone (100 mg, 31.8%). MS (ESI) M / Z: 299 [M+H + ].
步骤D：合成2-溴-6-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑Step D: Synthesis of 2-bromo-6-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)imidazo[2,1-b][1,3,4] Thiadiazole
Figure PCTCN2019086558-appb-000027
Figure PCTCN2019086558-appb-000027
将2-溴-1-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)乙酮(200毫克，0.669毫摩尔)和5-溴-1,3,4-噻二唑-2-胺(180毫克，1.00毫摩尔)溶于1,2-二氯乙烷(5毫升)中。向体系中加入三氟甲磺酸银(257毫克，1.00毫摩尔)。在80摄氏度下搅拌过夜。TLC监测显示原料消失后，向体系中加入水(5毫升)淬灭反应。混合液用二氯甲烷(20毫升X2)萃取。合并后的有机相先用饱和盐水(20毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚60％)浓缩得黄色固体2-溴-6-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(60毫克，23.6％)。MS(ESI)M/Z:380[M+H +]。 2-Bromo-1-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)ethanone (200 mg, 0.669 mmol) and 5-bromo-1,3, 4-thiadiazol-2-amine (180 mg, 1.00 mmol) was dissolved in 1,2-dichloroethane (5 mL). Silver triflate (257 mg, 1.00 mmol) was added to the system. Stir at 80 degrees Celsius overnight. After TLC monitoring showed disappearance of the starting material, water (5 mL) was added to the system to quench the reaction. The mixture was extracted with dichloromethane (20 mL EtOAc). The combined organic phases were washed with saturated brine (20 mL) then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography eluting eluting eluting eluting Pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (60 mg, 23.6%). MS (ESI) M/Z: 380 [M+H + ].
步骤E：合成(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step E: Synthesis of (5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4] Thiadiazole
Figure PCTCN2019086558-appb-000028
Figure PCTCN2019086558-appb-000028
将2-溴-6-(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(57毫克，0.150毫摩尔)溶于二氯甲烷/甲醇(2毫升/1毫升)中。向体系中加入叔丁醇钾(19毫克，0.170毫摩尔)。在室温下搅拌4小时。TLC监测显示原料消失后，向体系中加入水(5毫升)淬灭反应。混合液用二氯甲烷(10毫升X2)萃取。合并后的有机相先用饱和盐水(10毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用制备型高效液相色谱纯化。制备条件如下。色谱柱：Xselect C18 19 mm*150mm；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。纯化后，低温冻干得棕色固体(5,7-二甲氧基咪唑并[1,2-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(8.0毫克，16.1％)。MS(ESI)M/Z:332[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.18(s,1H),7.87(s,1H),6.72(s,1H),5.85(s,1H),4.22(s,3H),4.08(s,3H),3.90(s,3H)。 2-Bromo-6-(5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (57 mg, 0.150 mmol) was dissolved in dichloromethane / methanol (2 mL / 1 mL). Potassium tert-butoxide (19 mg, 0.170 mmol) was added to the system. Stir at room temperature for 4 hours. After TLC monitoring showed disappearance of the starting material, water (5 mL) was added to the system to quench the reaction. The mixture was extracted with dichloromethane (10 mL EtOAc). The combined organic phases were back-washed with saturated brine (10 mL) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The preparation conditions are as follows. Column: Xselect C18 19 mm*150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile from 10% to 80% in 7 minutes; Wavelength: 254 nm. After purification, freeze-drying to give a brown solid (5,7-dimethoxyimidazo[1,2-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1 , 3,4] thiadiazole (8.0 mg, 16.1%). MS (ESI) M / Z: 332 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.18 (s, 1H), 7.87 (s, 1H), 6.72 (s, 1H), 5.85 (s, 1H), 4.22 (s, 3H), 4.08 (s, 3H), 3.90 (s, 3H).
实施例3Example 3
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadi Azole
Figure PCTCN2019086558-appb-000029
Figure PCTCN2019086558-appb-000029
步骤A：合成1-氨基-3,5-二甲氧基吡啶-1-鎓二苯基次膦酸盐Step A: Synthesis of 1-amino-3,5-dimethoxypyridin-1-indolediphenylphosphinate
Figure PCTCN2019086558-appb-000030
Figure PCTCN2019086558-appb-000030
将3,5-二甲氧基吡啶(10.00克，71.9毫摩尔)溶于二氯甲烷溶液(250.0毫升)中。随后，向上述溶液中分批次加入二苯基膦酰羟胺(20.00克，85.8毫摩尔)。在室温下搅拌18小时。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.
将反应液在减压下浓缩。得到26.8克白色固体1-氨基-3,5-二甲氧基吡啶-1-鎓二苯基次膦酸盐。无需纯化，直接用于下步反应。MS(ESI)M/Z:155[M +]。 The reaction solution was concentrated under reduced pressure. 26.8 g of a white solid 1-amino-3,5-dimethoxypyridin-1-indolediphenylphosphinate were obtained. It is used directly in the next step without purification. MS (ESI) M / Z: 155 [M + ].
步骤B：合成4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯Step B: Synthesis of dimethyl 4,6-dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylate
Figure PCTCN2019086558-appb-000031
Figure PCTCN2019086558-appb-000031
将1-氨基-3,5-二甲氧基吡啶-1-鎓二苯基次膦酸盐(26.89克，72.2毫摩尔)溶于N,N-二甲基甲酰胺溶液(120.0毫升)中。随后，向上述溶液中依次加入丁炔二酸二甲酯(15.30克，107.8毫摩尔)和无水碳酸钾(13.90克，100.7毫摩尔)。在室温下搅拌18小时。1-Amino-3,5-dimethoxypyridin-1-indolediphenylphosphinate (26.89 g, 72.2 mmol) was dissolved in N,N-dimethylformamide (120.0 mL) . Subsequently, dimethyl acetylenedicarboxylate (15.30 g, 107.8 mmol) and anhydrous potassium carbonate (13.90 g, 100.7 mmol) were successively added to the above solution. Stir at room temperature for 18 hours.
将反应液在减压下浓缩。所得的残余物用硅胶柱层析纯化(洗脱剂：石油醚/二氯甲烷＝1/1)。得到5.90克棕色固体4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯(收率：27.8％)。MS(ESI)M/Z:295[M+H +]。 The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (EtOAc:EtOAc 5.90 g of dimethyl 4,6-dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylate as a brown solid was obtained (yield: 27.8%). MS (ESI) M / Z: 295 [M+H + ].
步骤C：合成4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸Step C: Synthesis of 4,6-dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid
Figure PCTCN2019086558-appb-000032
Figure PCTCN2019086558-appb-000032
将4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯(5.90克，20.0毫摩尔)溶于四氢呋喃(20.0毫升)与水(20.0毫升)的混合溶液中。在室温下搅拌16小时。Dimethyl 4,6-dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylate (5.90 g, 20.0 mmol) was dissolved in tetrahydrofuran (20.0 mL) and water (20.0) ML) in a mixed solution. Stir at room temperature for 16 hours.
向反应液中缓慢滴加稀盐酸(1.0摩尔/升)调节PH值至中性。混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到3.10克棕色固体4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸(收率：58.0％)。MS(ESI)M/Z：267[M+H +]。 Dilute hydrochloric acid (1.0 mol/liter) was slowly added dropwise to the reaction solution to adjust the pH to neutral. The mixture was extracted with dichloromethane (50 mL×3×). The combined organic layers were washed with brine (50 mL×3×) and dried over anhydrous sodium sulfate. There was obtained 3.10 g of a brown solid 4,6-dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid (yield: 58.0%). MS (ESI) M/Z: 266 [M+H + ].
步骤D：合成4,6-二甲氧基吡唑并[1,5-a]吡啶-2-羧酸Step D: Synthesis of 4,6-dimethoxypyrazolo[1,5-a]pyridine-2-carboxylic acid
Figure PCTCN2019086558-appb-000033
Figure PCTCN2019086558-appb-000033
将4,6-二甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸(3.10克，11.6毫摩尔)加入到多聚磷酸(100.0毫升)中。将反应液加热至80摄氏度，并搅拌16小时。4,6-Dimethoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid (3.10 g, 11.6 mmol) was added to polyphosphoric acid (100.0 mL). The reaction solution was heated to 80 ° C and stirred for 16 hours.
将反应液冷却到室温，缓慢倒入冰水中。有白色固体析出。过滤，收集滤饼。滤饼烘干得到2.50克白色固体4,6-二甲氧基吡唑并[1,5-a]吡啶-2-羧酸(收率:96.9％)。MS(ESI)M/Z:223[M+H +]。 The reaction solution was cooled to room temperature and slowly poured into ice water. A white solid precipitated. Filter and collect the filter cake. The filter cake was dried to give 2.50 g of white solid 4,6-dimethoxypyrazolo[1,5-a]pyridine-2-carboxylic acid (yield: 96.9%). MS (ESI) M / Z: 223 [M+H + ].
步骤E：合成N,4,6-三甲基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺Step E: Synthesis of N,4,6-trimethyl-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide
Figure PCTCN2019086558-appb-000034
Figure PCTCN2019086558-appb-000034
详见实施例1，步骤B。4,6-二甲氧基吡唑并[1,5-a]吡啶-2-羧酸(3.10克，13.9毫摩尔)，N,O-二甲基羟胺盐酸盐(6.80克，69.3毫摩尔)，N,N-二异丙基乙基胺(12.7克，98.4毫升)，1-羟基苯并***(2.80克，20.7毫摩尔)，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(4.00克，20.8毫摩尔)。得到1.60克黄色固体N,4,6--三甲基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(收率：43.4％)。MS(ESI)M/Z：266[M+H +]。 See Example 1, Step B for details. 4,6-Dimethoxypyrazolo[1,5-a]pyridine-2-carboxylic acid (3.10 g, 13.9 mmol), N,O-dimethylhydroxylamine hydrochloride (6.80 g, 69.3 m Mole), N,N-diisopropylethylamine (12.7 g, 98.4 ml), 1-hydroxybenzotriazole (2.80 g, 20.7 mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (4.00 g, 20.8 mmol). 1.60 g of a yellow solid N,4,6-trimethyl-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide (yield: 43.4%) was obtained. MS (ESI) M / Z: 266 [M+H + ].
步骤F：合成1-[4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮Step F: Synthesis of 1-[4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000035
Figure PCTCN2019086558-appb-000035
详见实施例1，步骤C。N,4,6--三甲基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(1.60克，6.03毫摩尔)，甲基溴化镁的***溶液(12.0毫升，12.0毫摩尔，1.0摩尔/升)。得到1.00克白色固体1-[4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(收率：75.7％)。MS(ESI)M/Z:221[M+H +]。 See Example 1, Step C for details. N,4,6--trimethyl-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide (1.60 g, 6.03 mmol), methyl magnesium bromide in diethyl ether (12.0) ML, 12.0 mmol, 1.0 mol/L). There was obtained 1.00 g of white solid 1-[4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (yield: 75.7%). MS (ESI) M / Z: 221 [M+H + ].
步骤G:合成2-溴-1-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮Step G: Synthesis of 2-bromo-1-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000036
Figure PCTCN2019086558-appb-000036
将1-[4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(3.00克，13.6毫摩尔)溶于二氯甲烷(300.0毫升)中。冰水浴下，向上述溶液中依次加入N,N-二异丙基乙基胺(7.02克，54.4毫摩尔)和三氟甲磺酸三甲基硅酯(9.06克，40.8毫摩尔)。在0摄氏度下搅拌30分钟。向反应液中加入饱和碳酸氢钠淬灭反应。混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，并减压浓缩。将所得的残余物溶于四氢呋喃(50.0毫升)中。冰水浴下，向反应液中加入N-溴代丁二酰亚胺(2.43克，13.6毫摩尔)。在室温下搅拌1小时。1-[4,6-Dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (3.00 g, 13.6 mmol) was dissolved in dichloromethane (300.0 mL) in. Under ice-water bath, N,N-diisopropylethylamine (7.02 g, 54.4 mmol) and trimethylsilyl trifluoromethanesulfonate (9.06 g, 40.8 mmol) were sequentially added to the above solution. Stir at 0 degrees Celsius for 30 minutes. The reaction was quenched by the addition of saturated sodium hydrogencarbonate. The mixture was extracted with ethyl acetate (50 mL×3×). The organic phases were combined and concentrated under reduced pressure. The residue obtained was dissolved in tetrahydrofuran (50.0 mL). Under ice water bath, N-bromosuccinimide (2.43 g, 13.6 mmol) was added to the reaction mixture. Stir at room temperature for 1 hour.
将反应液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/9)。得到3.20克黄色固体2-溴-1-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮(收率：78.8％)。MS(ESI)M/Z:299,301[M+H +]。 The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 9). There was obtained 3.20 g of a yellow solid 2-bromo-1-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethanone (yield: 78.8%). MS (ESI) M/Z: 299, 301 [M+H + ].
步骤H：合成2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4,6-二甲氧基吡唑并[1,5-a]吡啶Step H: Synthesis of 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-4,6-dimethoxypyrazolo[1,5 -a]pyridine
Figure PCTCN2019086558-appb-000037
Figure PCTCN2019086558-appb-000037
详见实施例1，步骤E。2-溴-1-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮(1.60克,5.3毫摩尔)，2-氨基-5-溴-1,3,4-噻二唑(1.3克,7.2毫摩尔)，异丙醇(5.0毫升)。得到640毫克白色固体2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4,6-二甲氧基吡唑并[1,5-a]吡啶(收率：31.7％)。MS(ESI)M/Z：380,382[M+H +]。 See Example 1, Step E for details. 2-bromo-1-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethanone (1.60 g, 5.3 mmol), 2-amino-5-bromo- 1,3,4-thiadiazole (1.3 g, 7.2 mmol), isopropanol (5.0 mL). 640 mg of white solid 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-4,6-dimethoxypyrazolo[1, 5-a]pyridine (yield: 31.7%). MS (ESI) M/Z: 380, 382 [M+H + ].
步骤I：合成4,6-二甲氧基-2-[2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-5-基]吡唑并[1,5-a]吡啶Step I: Synthesis of 4,6-dimethoxy-2-[2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrazolo[1 ,5-a]pyridine
Figure PCTCN2019086558-appb-000038
Figure PCTCN2019086558-appb-000038
详见实施例1，步骤F。叔丁醇钾(9毫克，0.08毫摩尔)，2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4,6-二甲氧基吡唑并[1,5-a]吡啶(30毫克,0.08毫摩尔)，二氯甲烷(4.0毫升)，甲醇(1.0毫升)。得到5.1毫克白色固体4,6-二甲氧基-2-[2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-5-基]吡唑并[1,5-a]吡啶(收率：19.2％)。MS(ESI)M/Z：332[M+H +]； 1H NMR(300MHz,MeOD,ppm)δ8.12(s,1H),7.82(s,1H),6.87(s,1H),6.44(s,1H),4.27(s,3H),4.02(s,3H),3.87(s,3H)。 See Example 1, Step F for details. Potassium tert-butoxide (9 mg, 0.08 mmol), 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-4,6-dimethyl Oxypyrazolo[1,5-a]pyridine (30 mg, 0.08 mmol), dichloromethane (4.0 mL), MeOH (EtOAc) Obtained 5.1 mg of white solid 4,6-dimethoxy-2-[2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrazolo[ 1,5-a]pyridine (yield: 19.2%). MS (ESI) M / Z: 332 [M+H + ]; 1 H NMR (300 MHz, MeOD, ppm) δ 8.12 (s, 1H), 7.82 (s, 1H), 6.87 (s, 1H), 6.44 (s, 1H), 4.27 (s, 3H), 4.02 (s, 3H), 3.87 (s, 3H).
实施例4Example 4
合成2-甲氧基-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑Synthesis of 2-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000039
Figure PCTCN2019086558-appb-000039
步骤A：合成N-甲氧基-N-甲基吡唑[1,5-a]吡啶-2-甲酰胺Step A: Synthesis of N-methoxy-N-methylpyrazole [1,5-a]pyridine-2-carboxamide
Figure PCTCN2019086558-appb-000040
Figure PCTCN2019086558-appb-000040
将吡唑[1,5-a]吡啶-2-羧酸(1.00克，6.17毫摩尔)溶于N,N-二甲基甲酰胺(15毫升)中。向体系中依次加入N,O-二甲基羟胺盐酸盐(1.20克，12.4毫摩尔)，N,N-二异丙基乙胺(2.39克，18.5毫摩尔)和O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(2.81克，7.40毫摩尔)。在室温下搅拌过夜。TLC监测显示原料消失后，向体系中加入水(20毫升)淬灭反应。混合液用乙酸乙酯(50毫升X2)萃取。合并后的有机相先用饱和盐水(50毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚50％)浓缩得浅棕色油状物N-甲氧基-N-甲基吡唑[1,5-a]吡啶-2-甲酰胺(1.21克，95.3％)。MS(ESI)M/Z：206[M+H] + Pyrazole [1,5-a]pyridine-2-carboxylic acid (1.00 g, 6.17 mmol) was dissolved in N,N-dimethylformamide (15 mL). N,O-dimethylhydroxylamine hydrochloride (1.20 g, 12.4 mmol), N,N-diisopropylethylamine (2.39 g, 18.5 mmol) and O-(7-nitrogen) were sequentially added to the system. Heterobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.81 g, 7.40 mmol). Stir at room temperature overnight. After TLC monitoring showed disappearance of the starting material, water (20 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (50 mL EtOAc). The combined organic phases were back-washed with saturated brine (50 mL) then dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut 2-formamide (1.21 g, 95.3%). MS (ESI) M/Z: 206 [M+H] +
步骤B：合成1-(吡唑[1,5-a]吡啶-2-基)乙酮Step B: Synthesis of 1-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000041
Figure PCTCN2019086558-appb-000041
在室温和氮气保护下，将N-甲氧基-N-甲基吡唑[1,5-a]吡啶-2-甲酰胺(1.21克，5.87毫摩尔)溶于四氢呋喃(14毫升)中。在0摄氏度下向体系内缓慢滴加甲基溴化镁的四氢呋喃溶液(11.8毫升，1.0摩尔/升)。在室温下搅拌2小时。TLC监测显示原料消失后，向体系内缓慢加入饱和氯化铵水溶液(20毫升)淬灭反应。混合液用乙酸乙酯(100毫升X2)萃取。合并后的有机相先用饱和盐水(100毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。所得残余物用硅胶柱层析纯化(洗脱剂；乙酸乙酯/石油醚10％)浓缩得到浅黄色固体1-(吡唑[1,5-a]吡啶-2-基)乙酮(660毫克，69.8％)。MS(ESI)M/Z：161[M+H] + N-Methoxy-N-methylpyrazole [1,5-a]pyridine-2-carboxamide (1.21 g, 5.87 mmol) was dissolved in tetrahydrofuran (14 mL). A solution of methylmagnesium bromide in tetrahydrofuran (11.8 ml, 1.0 mol/liter) was slowly added dropwise to the system at 0 °C. Stir at room temperature for 2 hours. After TLC monitoring showed the disappearance of the starting material, the reaction was quenched by slowly adding a saturated aqueous solution of ammonium chloride (20 ml) to the system. The mixture was extracted with ethyl acetate (100 mL EtOAc). The combined organic phases were back-washed with saturated brine (100 mL) then dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAc elut elut elut elut elut Mg, 69.8%). MS (ESI) M/Z: 161 [M+H] +
步骤C：合成2-氯-1-(吡唑[1,5-a]吡啶-2-基)乙酮Step C: Synthesis of 2-chloro-1-(pyrazole[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000042
Figure PCTCN2019086558-appb-000042
将1-(吡唑[1,5-a]吡啶-2-基)乙酮(300毫克，1.88毫摩尔)溶于四氢呋喃(10毫升)中。向体系中加入苄基三甲基二氯碘酸铵(1.30克，3.75毫摩尔)。在室温下搅拌过夜。TLC监测显示原料消失后，向体系内加入饱和碳酸氢钠水溶液(20毫升)淬灭反应。混合液用乙酸乙酯(50毫升X2)萃取。合并后的有机相先用饱和盐水(50毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩得到浅黄色固体2-氯-1-(吡唑[1,5-a]吡啶-2-基)乙酮(360毫克)，无需纯化直接用于下一步。MS(ESI)M/Z：195[M+H] +。 1-(Pyrazol[1,5-a]pyridin-2-yl)ethanone (300 mg, 1.88 mmol) was dissolved in tetrahydrofuran (10 mL). To the system was added ammonium benzyltrimethyldichloroiodate (1.30 g, 3.75 mmol). Stir at room temperature overnight. After TLC monitoring showed the disappearance of the starting material, a saturated aqueous sodium hydrogen carbonate aqueous solution (20 ml) was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate (50 mL EtOAc). The combined organics were washed with saturated brine (50 mL) then dried over anhydrous sodium sulfate Ethyl ketone (360 mg) was used in the next step without purification. MS (ESI) M / Z: 195 [M+H] + .
步骤D：合成2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑Step D: Synthesis of 2-bromo-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000043
Figure PCTCN2019086558-appb-000043
将2-氯-1-(吡唑[1,5-a]吡啶-2-基)乙酮(200毫克，1.03毫摩尔)和5-溴-1,3,4-噻二唑-2-胺(185毫克，1.03毫摩尔)加入异丙醇(4毫升)中。在120摄氏度下微波反应器搅拌2小时。TLC监测显示原料消失后，将体系冷却到室温并真空浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚50％)浓缩得浅黄色固体2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑(60毫克，18.2％)。MS(ESI)M/Z 320[M+H] + 2-Chloro-1-(pyrazolo[1,5-a]pyridin-2-yl)ethanone (200 mg, 1.03 mmol) and 5-bromo-1,3,4-thiadiazole-2- The amine (185 mg, 1.03 mmol) was added to isopropyl alcohol (4 mL). The microwave reactor was stirred at 120 ° C for 2 hours. After TLC monitoring showed disappearance of the starting material, the system was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Imidazole [2,1-b][1,3,4]thiadiazole (60 mg, 18.2%). MS (ESI) M/Z 320 [M+H] +
步骤F：合成2-甲氧基-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑)Step F: Synthesis of 2-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole)
Figure PCTCN2019086558-appb-000044
Figure PCTCN2019086558-appb-000044
将2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑(60毫克，0.190毫摩尔)溶于二氯甲烷/甲醇(3.0毫升/1.5毫升)中。向体系中加入叔丁醇钾(25毫克，0.230毫摩尔)。在室温下搅拌2小时。TLC监测显示原料消失后，向体系内加入水(5毫升)淬灭反应。混合液用二氯甲烷(10毫升X2)萃取。合并后的有机相先用饱和盐水(10毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用制备型高效液相色谱纯化。制备条件如下。色谱柱：Xselect C18 19mm*150mm；流动相：水(0.05％NH 4HCO 3)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。纯化后，低温冻干得白色固体2-甲氧基-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑(19.0毫克，36.7％)。MS(ESI)M/Z：272[M+H] +； 1H NMR(300MHz,CDCl 3,ppm)δ8.47(d,J＝6.9Hz,1H),8.06(s,1H),7.53(d,J＝9.0Hz,1H),7.11(t,J＝9.0Hz,1H),6.87(s,1H),6.74(t,J＝6.9Hz,1H),4.23(s,3H). Dissolve 2-bromo-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (60 mg, 0.190 mmol) In dichloromethane / methanol (3.0 ml / 1.5 ml). Potassium tert-butoxide (25 mg, 0.230 mmol) was added to the system. Stir at room temperature for 2 hours. After TLC monitoring showed disappearance of the starting material, water (5 mL) was added to the system to quench the reaction. The mixture was extracted with dichloromethane (10 mL EtOAc). The combined organic phases were back-washed with saturated brine (10 mL) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The preparation conditions are as follows. Column: Xselect C18 19mm*150mm; mobile phase: water (0.05% NH 4 HCO 3 ) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; detection wavelength: 254 nm. After purification, freeze-drying to give a white solid 2-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazole [2,1-b][1,3,4]thiadipine Azole (19.0 mg, 36.7%). MS (ESI) M / Z: 272 [M+H] + ; 1 H NMR (300 MHz, CDCl 3 , ppm) δ 8.47 (d, J = 6.9 Hz, 1H), 8.06 (s, 1H), 7.53 ( d, J = 9.0 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.87 (s, 1H), 6.74 (t, J = 6.9 Hz, 1H), 4.23 (s, 3H).
实施例5Example 5
合成2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑Synthesis of 2-bromo-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000045
Figure PCTCN2019086558-appb-000045
步骤A：合成2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑Step A: Synthesis of 2-bromo-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000046
Figure PCTCN2019086558-appb-000046
将2-氯-1-(吡唑[1,5-a]吡啶-2-基)乙酮(240毫克，1.23毫摩尔)和5-溴-1,3,4-噻二唑-2-胺(221毫克，1.23毫摩尔)加入异丙醇(4毫升)中。在120摄氏度下微波反应器加热搅拌2小时。TLC监 测显示原料消失后，将体系冷却到室温并真空浓缩。粗产品用制备型高效液相色谱纯化。制备条件如下。色谱柱：Xselect C18 19mm*150mm；流动相：水(0.05％甲酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。纯化后，低温冻干得白色固体2-溴-6-(吡唑[1,5-a]吡啶-2-基)咪唑[2,1-b][1,3,4]噻二唑(6.6毫克，1.7％)。MS(ESI)M/Z：320,322[M+H] +； 1H NMR(300MHz,CDCl 3,ppm)δ8.48(d,J＝7.2Hz,1H),8.28(s,1H),7.56(d,J＝9.0Hz,1H),7.14(t,J＝7.8Hz,1H),6.91(s,1H),6.78(t,J＝7.8Hz,1H)。 2-Chloro-1-(pyrazolo[1,5-a]pyridin-2-yl)ethanone (240 mg, 1.23 mmol) and 5-bromo-1,3,4-thiadiazole-2- The amine (221 mg, 1.23 mmol) was added to isopropyl alcohol (4 mL). The microwave reactor was heated and stirred at 120 ° C for 2 hours. After TLC monitoring showed disappearance of the starting material, the system was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography. The preparation conditions are as follows. Column: Xselect C18 19mm*150mm; mobile phase: water (0.05% formic acid) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 80% in 7 minutes; detection wavelength: 254 nm. After purification, freeze-drying to give a white solid 2-bromo-6-(pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole ( 6.6 mg, 1.7%). MS (ESI) M / Z: 320, 322 [M+H] + ; 1 H NMR (300 MHz, CDCl 3 , ppm) δ 8.48 (d, J = 7.2 Hz, 1H), 8.28 (s, 1H), 7.56 ( d, J = 9.0 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.91 (s, 1H), 6.78 (t, J = 7.8 Hz, 1H).
实施例6Example 6
合成2-甲氧基-6-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 2-methoxy-6-(4-methoxypyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000047
Figure PCTCN2019086558-appb-000047
步骤A：合成1-氨基-3-甲氧基吡啶-1-鎓二苯基次膦酸盐Step A: Synthesis of 1-amino-3-methoxypyridine-1-indenyldiphenylphosphinate
Figure PCTCN2019086558-appb-000048
Figure PCTCN2019086558-appb-000048
将3-甲氧基吡啶(5.00克，46.0毫摩尔)溶于二氯甲烷(50毫升)中。向体系中加入二苯基膦酰羟胺(16.0克，69.0毫摩尔)。在40摄氏度下搅拌3小时。TLC监测显示原料消失后，将反应体系冷却到室温并真空浓缩得1-氨基-3-甲氧基吡啶-1-鎓二苯基次膦酸盐(19.7克)为浅黄色固体，直接用于下一步，无需纯化。MS(ESI)M/Z:125[M] +。 3-Methoxypyridine (5.00 g, 46.0 mmol) was dissolved in dichloromethane (50 mL). Diphenylphosphonylhydroxylamine (16.0 g, 69.0 mmol) was added to the system. Stir at 40 degrees Celsius for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction system was cooled to room temperature and concentrated in vacuo to give 1-amino-3-methoxypyridin-1-indolediphenylphosphinate (19.7 g) as a pale yellow solid. Next, no purification is required. MS (ESI) M/Z: 125 [M] + .
步骤B：合成2,3-二甲基-4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二乙酯Step B: Synthesis of diethyl 2,3-dimethyl-4-methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylate
Figure PCTCN2019086558-appb-000049
Figure PCTCN2019086558-appb-000049
将1-氨基-3-甲氧基吡啶-1-鎓二苯基次膦酸盐(15.7克,46.0毫摩尔)溶于N,N-二甲基甲酰胺(200毫升)中。向体系中依次加入丁-2-炔二酸二甲酯(33.6克，236毫摩尔)和无水碳酸钾(30.5克，220毫摩尔)。在60摄氏度下搅拌16小时。TLC监测显示原料消失后，向体系中加入水(100毫升)淬灭反应。混合液用乙酸乙酯(200毫升X2)萃取。合并后的有机相先用饱和盐水(200毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚30％-50％)浓缩得2,3-二甲基-4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二乙酯(4.50克，37.2％)为黄色固体。MS(ESI)M/Z:265[M+H] +。 1-Amino-3-methoxypyridine-1-indenyldiphenylphosphinate (15.7 g, 46.0 mmol) was dissolved in N,N-dimethylformamide (200 mL). To the system were sequentially added dimethyl 2-butynedicarboxylate (33.6 g, 236 mmol) and anhydrous potassium carbonate (30.5 g, 220 mmol). Stir at 60 degrees Celsius for 16 hours. After TLC monitoring showed disappearance of the starting material, water (100 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (200 mL EtOAc). The combined organic phases were back-washed with saturated brine (200 mL) then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 30%-50%) to give 2,3-dimethyl-4-methoxypyrazolo[1,5-a] Diethyl pyridine-2,3-dicarboxylate (4.50 g, 37.2%) was obtained as a yellow solid. MS (ESI) M / Z: 265 [M+H] + .
步骤C：合成4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸Step C: Synthesis of 4-methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid
Figure PCTCN2019086558-appb-000050
Figure PCTCN2019086558-appb-000050
将2,3-二甲基-4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸二乙酯(3.55克，13.4毫摩尔)溶于四氢呋喃/水(30毫升/30毫升)中。向体系中加入氢氧化锂(645毫克，26.9毫摩尔)。在室温下搅拌16小 时。TLC监测显示原料消失后，向体系中缓慢加入稀盐酸溶液(3.0摩尔/升)调节体系的PH值至酸性后有白色固体析出。过滤，收集滤饼，滤饼烘干得4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸(2.51克，79.4％)为白色固体。MS(ESI)M/Z:237[M+H] +。 Diethyl 2,3-dimethyl-4-methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylate (3.55 g, 13.4 mmol) was dissolved in tetrahydrofuran/water ( 30 ml / 30 ml). Lithium hydroxide (645 mg, 26.9 mmol) was added to the system. Stir at room temperature for 16 hours. After the TLC monitoring showed that the starting material disappeared, a dilute hydrochloric acid solution (3.0 mol/liter) was slowly added to the system to adjust the pH of the system to be acidic, and a white solid precipitated. Filtration, collection of the filter cake, and drying of the filter cake gave 4-methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid (2.51 g, 79.4%) as a white solid. MS (ESI) M / Z: 437 [M+H] + .
步骤D：合成4-甲氧基吡唑并[1,5-a]吡啶-2-羧酸Step D: Synthesis of 4-methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid
Figure PCTCN2019086558-appb-000051
Figure PCTCN2019086558-appb-000051
将4-甲氧基吡唑并[1,5-a]吡啶-2,3-二羧酸(2.51克,10.6毫摩尔)溶于多聚磷酸(80毫升)中。在80摄氏度下搅拌6小时。TLC监测显示原料消失后，将体系冷却到室温。将混合液缓慢倒入冰水中后有白色固体析出。过滤，收集滤饼，滤饼烘干得4-甲氧基吡唑并[1,5-a]吡啶-2-羧酸(1.05克，51.6％)。MS(ESI)M/Z:193(M+H) +。 4-Methoxypyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid (2.51 g, 10.6 mmol) was dissolved in polyphosphoric acid (80 mL). Stir at 80 degrees Celsius for 6 hours. After TLC monitoring showed disappearance of the starting material, the system was cooled to room temperature. The mixture was slowly poured into ice water and a white solid precipitated. Filtration, collection of the filter cake, and drying of the filter cake gave 4-methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid (1.05 g, 51.6%). MS (ESI) M / Z: 193 (M+H) + .
步骤E：合成N，4-二甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺Step E: Synthesis of N,4-dimethoxy-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide
Figure PCTCN2019086558-appb-000052
Figure PCTCN2019086558-appb-000052
将4-甲氧基吡唑并[1,5-a]吡啶-2-羧酸(1.05克，5.46毫摩尔)溶于N,N-二甲基甲酰胺(10毫升)中。向体系中依次加入N,O-二甲基羟胺盐酸盐(639毫克,6.56毫摩尔)，N,N-二异丙基乙胺(2.11克，16.4毫摩尔)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(3.11克，8.19毫摩尔)。在室温下搅拌2小时。TLC监测显示原料消失后，向体系中加入水(10毫升)淬灭反应。混合液用乙酸乙酯(100毫升X2)萃取。合并后的有机相先用饱和盐水(100毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚25％)浓缩得N，4-二甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(1.00克，78.1％)为白色固体。MS(ESI)M/Z:236(M+H) +。 4-Methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid (1.05 g, 5.46 mmol) was dissolved in N,N-dimethylformamide (10 mL). N,O-dimethylhydroxylamine hydrochloride (639 mg, 6.56 mmol), N,N-diisopropylethylamine (2.11 g, 16.4 mmol) and 2-(7-even) were sequentially added to the system. Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.11 g, 8.19 mmol). Stir at room temperature for 2 hours. After TLC monitoring showed the disappearance of the starting material, water (10 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (100 mL EtOAc). The combined organic phases were back-washed with saturated brine (100 mL) then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc:EtOAcEtOAc 2-Carboxamide (1.00 g, 78.1%) was a white solid. MS (ESI) M / Z: 236 (M+H) + .
步骤F：合成1-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮Step F: Synthesis of 1-(4-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000053
Figure PCTCN2019086558-appb-000053
将N，4-二甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(1.00克,4.25毫摩尔)溶于四氢呋喃(30毫升)中。在0摄氏度下向体系中加入甲基溴化镁的四氢呋喃溶液(4.25毫升，2.0摩尔/升)。在室温下搅拌1小时。TLC监测显示原料消失后，向体系中加入饱和氯化铵水溶液(50毫升)淬灭反应。混合液用乙酸乙酯(200毫升X2)萃取。合并后的有机相先用饱和盐水(100毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚5％)浓缩得1-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮(550毫克，68.1％)为白色固体。MS(ESI)M/Z:191[M+H] +。 N,4-Dimethoxy-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide (1.00 g, 4.25 mmol) was dissolved in tetrahydrofuran (30 mL). A solution of methylmagnesium bromide in tetrahydrofuran (4.25 mL, 2.0 mol/L) was added to the system at 0 °C. Stir at room temperature for 1 hour. After TLC monitoring showed the disappearance of the starting material, 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). The combined organic phases were back-washed with saturated brine (100 mL) then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 5%) to give 1-(4-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanone (550 mg, 68.1%) was obtained as a white solid. MS (ESI) M / Z: 191 [M+H] + .
步骤G：合成2-溴-1-[4-甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮Step G: Synthesis of 2-bromo-1-[4-methoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000054
Figure PCTCN2019086558-appb-000054
将1-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酮(550毫克，2.89毫摩尔)溶于二氯甲烷(20毫升)中。在0摄氏度下向体系中依次加入N,N-二异丙基乙胺(14.9克，11.6毫摩尔)和三氟甲磺酸三甲基硅酯(1.93克，8.67毫摩尔)。在室温下搅拌2小时。TLC监测显示原料消失后，向体系中加入饱和碳酸氢钠水溶液(10毫升)淬灭反应。混合液用乙酸乙酯(20毫升X2)萃取，合并后的有机相在真空下浓缩。将所得残余物溶于四氢呋喃(10毫升)中。在0摄氏度下向体系中加入N-溴代丁二酰亚胺(514毫克，2.89毫摩尔)。在室温下搅拌1小时。TLC监测显示原料消失后，向体系中加入水(10毫升)淬灭反应。混合液用乙酸乙酯(20毫升X2)萃取。合并后的有机相先用饱和盐水(20毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚5％)浓缩得2-溴-1-[4-甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(600毫克，77.4％)为白色固体。MS(ESI)M/Z:269,271[M+H] +。 1-(4-Methoxypyrazolo[1,5-a]pyridin-2-yl)ethanone (550 mg, 2.89 mmol) was dissolved in dichloromethane (20 mL). N,N-Diisopropylethylamine (14.9 g, 11.6 mmol) and trimethylsilyl trifluoromethanesulfonate (1.93 g, 8.67 mmol) were sequentially added to the system at 0 °C. Stir at room temperature for 2 hours. After TLC monitoring showed the disappearance of the starting material, a saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the mixture to quench the reaction. The mixture was extracted with EtOAc (20 mL EtOAc)EtOAc. The resulting residue was dissolved in tetrahydrofuran (10 mL). N-bromosuccinimide (514 mg, 2.89 mmol) was added to the system at 0 °C. Stir at room temperature for 1 hour. After TLC monitoring showed the disappearance of the starting material, water (10 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (20 mL EtOAc). The combined organic phases were washed with saturated brine (20 mL) then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 5%) to give 2-bromo-1-[4-methoxypyrazolo[1,5-a]pyridine-2- Ethyl ketone (600 mg, 77.4%) was obtained as a white solid. MS (ESI) M/Z: 269, 271 [M+H] + .
步骤H：合成2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4-甲氧基吡唑并[1,5-a]吡啶Step H: Synthesis of 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-4-methoxypyrazolo[1,5-a] Pyridine
Figure PCTCN2019086558-appb-000055
Figure PCTCN2019086558-appb-000055
将2-溴-1-[4-甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(130毫克，0.483毫摩尔)和2-氨基-5-溴-1,3,4-噻二唑(130毫克，0.725毫摩尔)加入异丙醇(2毫升)中。在150摄氏度下微波反应器中加热搅拌30分钟。TLC监测显示原料消失后，将反应体系冷却到室温并真空浓缩。粗产品用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷5％)浓缩得2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4-甲氧基吡唑并[1,5-a]吡啶(70毫克，41.4％)为黄色固体。MS(ESI)M/Z:350,352[M+H] +。 2-Bromo-1-[4-methoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (130 mg, 0.483 mmol) and 2-amino-5-bromo -1,3,4-thiadiazole (130 mg, 0.725 mmol) was added to isopropanol (2 mL). The mixture was heated and stirred for 30 minutes at 150 ° C in a microwave reactor. After TLC monitoring showed disappearance of the starting material, the reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: MeOH / hexanes 5%) to give 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazole-5 4-Methoxypyrazolo[1,5-a]pyridine (70 mg, 41.4%) was obtained as a yellow solid. MS (ESI) M/Z: 350, 352 [M+H] + .
步骤I：合成2-甲氧基-6-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑Step I: Synthesis of 2-methoxy-6-(4-methoxypyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4] Thiadiazole
Figure PCTCN2019086558-appb-000056
Figure PCTCN2019086558-appb-000056
将2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-5-基]-4-甲氧基吡唑并[1,5-a]吡啶(70毫克，0.200毫摩尔)溶于二氯甲烷/甲醇(4毫升/4毫升)中。向体系中加入叔丁醇钾(25.8毫克，0.230毫摩尔)。在室温下搅拌2小时。TLC监测显示原料消失后，向体系中加入水(10毫升)淬灭反应。混合液用二氯甲烷(10毫升X2)萃取。合并后的有机相用饱和盐水(10毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用硅胶柱层析(洗脱剂：乙酸乙酯/正己烷20％-50％)浓缩得2-甲氧基-6-(4-甲氧基吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(17.3毫克，28.7％)为白色固体。MS(ESI)M/Z:302[M+H] +。 1H NMR(300MHz,CDCl 3,ppm):δ8.14(d,J＝6.9Hz,1H),8.07(s,1H),7.00(s,1H),6.67(t,J＝7.2Hz,1H),6.40(d,J＝7.5Hz,1H),4.23(s,3H),3.99(s,3H)。 2-[2-Bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-4-methoxypyrazolo[1,5-a]pyridine (70 Mg, 0.200 mmol) was dissolved in dichloromethane/methanol (4 mL / 4 mL). Potassium tert-butoxide (25.8 mg, 0.230 mmol) was added to the system. Stir at room temperature for 2 hours. After TLC monitoring showed the disappearance of the starting material, water (10 mL) was added to the system to quench the reaction. The mixture was extracted with dichloromethane (10 mL EtOAc). The combined organic phases were back washed with saturated brine (10 mL)EtOAc The crude product was concentrated with silica gel column chromatography (eluent: ethyl acetate/hexanes 20% to 50%) to give 2-methoxy-6-(4-methoxypyrazolo[1,5-a] Pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (17.3 mg, 28.7%) was obtained as a white solid. MS (ESI) M / Z: 302 [M+H] + . 1 H NMR (300MHz, CDCl 3 , ppm): δ8.14 (d, J = 6.9Hz, 1H), 8.07 (s, 1H), 7.00 (s, 1H), 6.67 (t, J = 7.2Hz, 1H ), 6.40 (d, J = 7.5 Hz, 1H), 4.23 (s, 3H), 3.99 (s, 3H).
实施例7Example 7
合成4-甲氧基-2-[2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-5-基]吡唑并[1,5-a]吡啶Synthesis of 4-methoxy-2-[2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrazolo[1,5-a]pyridine
Figure PCTCN2019086558-appb-000057
Figure PCTCN2019086558-appb-000057
步骤A：合成4-甲氧基-2-[2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-5-基]吡唑并[1,5-a]吡啶Step A: Synthesis of 4-methoxy-2-[2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrazolo[1,5- a]pyridine
Figure PCTCN2019086558-appb-000058
Figure PCTCN2019086558-appb-000058
将2-溴-1-[4-甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(120毫克，0.450毫摩尔)和2-氨基-5-甲硫基-1,3,4-噻二唑(99毫克,0.67毫摩尔)加入异丙醇/乙腈(2毫升/2毫升)中。在80摄氏度下搅拌2小时，然后在150摄氏度下微波反应器中搅拌20分钟。TLC监测显示原料消失后。向体系中加入水(5毫升)淬灭反应。混合液用二氯甲烷(10毫升X2)萃取。合并后的有机相先用饱和盐水(10毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚50％)浓缩得白色固体4-甲氧基-2-[2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-5-基]吡唑并[1,5-a]吡啶(17.3毫克，12.1％)。MS(ESI)M/Z:318(M+H) +； 1H NMR(300MHz,CDCl 3，ppm)δ8.17-8.14(m,2H),7.02(s,1H),6.68(t,J＝7.2Hz,1H),6.40(d,J＝7.8Hz,1H),3.99(s,3H),2.79(s,3H)。 2-Bromo-1-[4-methoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (120 mg, 0.450 mmol) and 2-amino-5-A Thio-1,3,4-thiadiazole (99 mg, 0.67 mmol) was added to isopropanol / acetonitrile (2 mL / 2 mL). Stir at 80 degrees Celsius for 2 hours and then stir for 20 minutes at 150 degrees Celsius in a microwave reactor. TLC monitoring showed disappearance of the raw materials. Water (5 mL) was added to the system to quench the reaction. The mixture was extracted with dichloromethane (10 mL EtOAc). The combined organic phases were back-washed with saturated brine (10 mL) then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut [1,3,4]thiadiazol-5-yl]pyrazolo[1,5-a]pyridine (17.3 mg, 12.1%). MS (ESI) M / Z: 318 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 , ppm) δ 8.17-8.14 (m, 2H), 7.02 (s, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 3.99 (s, 3H), 2.79 (s, 3H).
实施例8Example 8
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲硫基)咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylthio)imidazo[2,1-b][1,3,4] Thiadiazole
Figure PCTCN2019086558-appb-000059
Figure PCTCN2019086558-appb-000059
步骤A：合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲硫基)咪唑并[2,1-b][1,3,4]噻二唑Step A: Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylthio)imidazo[2,1-b][1,3 , 4] thiadiazole
Figure PCTCN2019086558-appb-000060
Figure PCTCN2019086558-appb-000060
将2-溴-1-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙-1-酮(30毫克，0.100毫摩尔)和5-(甲硫基)-1,3,4-噻二唑-2-胺(15毫克，0.100毫摩尔)加入异丙醇(1毫升)中。在120摄氏度下微波反应器中加热搅拌45分钟。LCMS监测显示原料消失后。将体系冷却到室温并真空浓缩。所得的残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷1％)浓缩得白色固体(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲硫基)咪唑并[2,1-b][1,3,4]噻二唑(10.6毫克，30.5％)MS(ESI)M/Z：348[M+H +]； 1H NMR(300MHz,CDCl 3,ppm):δ8.16(s,1H),7.82(s,1H),6.98(s,1H),6.27(s 1H),3.97(s,3H),3.75(s,3H),2.80(s,3H)。 2-Bromo-1-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethan-1-one (30 mg, 0.100 mmol) and 5-(A) Thio)-1,3,4-thiadiazol-2-amine (15 mg, 0.100 mmol) was added to isopropanol (1 mL). The mixture was heated and stirred in a microwave reactor at 120 ° C for 45 minutes. LCMS monitoring showed disappearance of the starting material. The system was cooled to room temperature and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography eluting elut elut elut elut elut elut 2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole (10.6 mg, 30.5%) MS (ESI) M/Z: 348 [M+H + ]; 1 H NMR (300MHz, CDCl 3, ppm): δ8.16 (s, 1H), 7.82 (s, 1H), 6.98 (s, 1H), 6.27 (s 1H), 3.97 (s, 3H), 3.75 (s, 3H), 2.80 (s, 3H).
实施例9Example 9
合成6-(6-氯-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 6-(6-chloro-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b ][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000061
Figure PCTCN2019086558-appb-000061
步骤A：合成2-溴-5-氯吡啶-3-醇Step A: Synthesis of 2-bromo-5-chloropyridin-3-ol
Figure PCTCN2019086558-appb-000062
Figure PCTCN2019086558-appb-000062
将5-氯吡啶-3-醇(36.00克，277毫摩尔)溶于氢氧化钠溶液(250毫升，10％wt)中。随后，向上述溶液中缓慢滴加溴素(45.00克，281毫摩尔)的氢氧化钠溶液(250毫升，10％wt)。在室温下搅拌过夜。5-Chloropyridin-3-ol (36.00 g, 277 mmol) was dissolved in sodium hydroxide solution (250 mL, 10% wt). Subsequently, a solution of bromine (45.00 g, 281 mmol) in sodium hydroxide (250 ml, 10% by weight) was slowly added dropwise to the above solution. Stir at room temperature overnight.
向反应液中加入稀盐酸(1.0摩尔/升)调节PH值约为4-5。混合液用乙酸乙酯(500毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(500毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到20.00克黄色固体2-溴-5-氯吡啶-3-醇(收率：34.7％)MS(ESI)M/Z：208[M+H +]。 Dilute hydrochloric acid (1.0 mol/liter) was added to the reaction solution to adjust the pH to about 4-5. The mixture was extracted with ethyl acetate (500 mL×3×). The combined organic layers were washed with brine (500 mL×3×) and then dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAc EtOAc 20.00 g of a yellow solid 2-bromo-5-chloropyridin-3-ol (yield: 34.7%) MS (ESI) M/Z: 208 [M+H + ].
步骤B：合成3-(苄氧基)-2-溴-5-氯吡啶Step B: Synthesis of 3-(benzyloxy)-2-bromo-5-chloropyridine
Figure PCTCN2019086558-appb-000063
Figure PCTCN2019086558-appb-000063
将2-溴-5-氯吡啶-3-醇(6.90克，33.2毫摩尔)和无水碳酸钾(4.80克，34.8毫摩尔)加入N,N-二甲基甲酰胺(69.0毫升)中。冰水浴下，向上述溶液中缓慢滴加溴化苄(5.90克，34.5毫摩尔)。在室温下搅拌1小时。2-Bromo-5-chloropyridin-3-ol (6.90 g, 33.2 mmol) and anhydrous potassium carbonate (4.80 g, 34.8 mmol) were added to N,N-dimethylformamide (69.0 ml). Under ice-water bath, benzyl bromide (5.90 g, 34.5 mmol) was slowly added dropwise to the above solution. Stir at room temperature for 1 hour.
向反应液中加入水(200毫升)淬灭反应。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(200毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/20)。得到8.05克淡黄色油状品3-(苄氧基)-2-溴-5-氯吡啶(收率：81.1％)。MS(ESI)M/Z:298[M+H +]。 Water (200 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×3×). The combined organic layers were washed with brine (200 mL×3×) and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 20). 8.05 g of 3-(benzyloxy)-2-bromo-5-chloropyridine (yield: 81.1%) was obtained as pale yellow oil. MS (ESI) M / Z: 298 [M+H + ].
步骤C：合成4-(3-(苄氧基)-5-氯吡啶-2-基)丁-3-炔-2-醇Step C: Synthesis of 4-(3-(benzyloxy)-5-chloropyridin-2-yl)but-3-yn-2-ol
Figure PCTCN2019086558-appb-000064
Figure PCTCN2019086558-appb-000064
详见实施例17，步骤E。3-(苄氧基)-2-溴-5-氯吡啶(3.00克，10.0毫摩尔),二(三苯基磷)二氯化钯(70毫克，0.10毫摩尔)，丁-3-炔-2-醇(840毫克，12.0毫摩尔)，碘化亚铜(38毫克，0.20毫摩尔)，三乙胺(30毫升)。得到1.70克淡黄色固体4-(3-(苄氧基)-5-氯吡啶-2-基)丁-3-炔-2-醇(收率：59.0％)。MS(ESI)M/Z：288[M+H +]。 See Example 17, Step E for details. 3-(Benzyloxy)-2-bromo-5-chloropyridine (3.00 g, 10.0 mmol), bis(triphenylphosphine)palladium dichloride (70 mg, 0.10 mmol), but-3-yne 2-Alcohol (840 mg, 12.0 mmol), cuprous iodide (38 mg, 0.20 mmol), triethylamine (30 mL). 1.70 g of 4-(3-(benzyloxy)-5-chloropyridin-2-yl)but-3-yn-2-ol (yield: 59.0%) was obtained as pale yellow solid. MS (ESI) M / Z: 288 [M+H + ].
步骤D：合成1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙醇Step D: Synthesis of 1-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanol
Figure PCTCN2019086558-appb-000065
Figure PCTCN2019086558-appb-000065
详见实施例17，步骤F。4-(3-(苄氧基)-5-氯吡啶-2-基)丁-3-炔-2-醇(1.70g，5.90毫摩尔)，2,4,6-三甲基苯磺酰羟胺(4.76克，17.7毫摩尔，80％wt)，二氯甲烷(30毫升)，无水碳酸钾(1.63克，11.8毫摩尔)，N,N-二甲基甲酰胺(1.70升)。得到1.41克淡黄色固体1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙醇(收率：78.7％)。MS(ESI)M/Z：303[M+H +]。 See Example 17, Step F for details. 4-(3-(Benzyloxy)-5-chloropyridin-2-yl)but-3-yn-2-ol (1.70 g, 5.90 mmol), 2,4,6-trimethylbenzenesulfonyl Hydroxylamine (4.76 g, 17.7 mmol, 80% wt), dichloromethane (30 mL), anhydrous potassium carbonate (1.63 g, 11.8 mmol), N,N-dimethylformamide (1.70 L). 1.41 g of 1-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanol (yield: 78.7%) was obtained as pale yellow solid. MS (ESI) M / Z: 303 [M+H + ].
步骤E：合成1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙酮Step E: Synthesis of 1-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000066
Figure PCTCN2019086558-appb-000066
详见实施例17，步骤G。1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙醇(1.17克，3.86毫摩尔)，戴斯-马丁试剂(1.96克，4.62毫摩尔)，二氯甲烷(20.0毫升)。得到1.06克淡黄色固体1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙酮(收率：91.4％)。MS(ESI)M/Z：301[M+H +]。 See Example 17, Step G for details. 1-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanol (1.17 g, 3.86 mmol), Dess-Martin reagent (1.96 g, 4.62) Millimol), dichloromethane (20.0 mL). 1.06 g of a pale yellow solid of 1-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanone (yield: 91.4%) was obtained. MS (ESI) M / Z: 301 [M+H + ].
步骤F：1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴乙酮Step F: 1-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoethyl ketone
Figure PCTCN2019086558-appb-000067
Figure PCTCN2019086558-appb-000067
详见实施例3，步骤G。1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)乙酮(1.00克，3.32毫摩尔)，二氯甲烷(15.0毫升)，N,N-二异丙基乙胺(1.71克，13.3毫摩尔)，三氟甲磺酸三甲基硅酯(2.22克，10.0毫摩尔)，N-溴代丁二酰亚胺(593毫克，3.33毫摩尔)，四氢呋喃(10.0毫升)。得到810毫克白色固体1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴乙酮(收率：64.3％)。MS(ESI)M/Z:379,381[M+H +]。 See Example 3, Step G for details. 1-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)ethanone (1.00 g, 3.32 mmol), dichloromethane (15.0 mL), N , N-diisopropylethylamine (1.71 g, 13.3 mmol), trimethylsilyl trifluoromethanesulfonate (2.22 g, 10.0 mmol), N-bromosuccinimide (593 mg, 3.33 mmol), tetrahydrofuran (10.0 mL). There was obtained 810 mg of 1-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoethyl ketone as a white solid (yield: 64.3%). MS (ESI) M/Z: 379, 381 [M+H + ].
步骤G：6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑Step G: 6-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1,3 , 4] thiadiazole
Figure PCTCN2019086558-appb-000068
Figure PCTCN2019086558-appb-000068
详见实施例3，步骤H。1-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴乙酮(810毫克，2.14毫摩尔)，2-氨基-5-溴-1,3,4-噻二唑(689毫克，3.78毫摩尔)，异丙醇(26.0毫升)。得到296毫克褐色固体6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(收率：30.1％)。MS(ESI)M/Z:460,462[M+H +]。 See Example 3, Step H for details. 1-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoethyl ketone (810 mg, 2.14 mmol), 2-amino-5 Bromo-1,3,4-thiadiazole (689 mg, 3.78 mmol), isopropanol (26.0 mL). Yield 296 mg of brown solid 6-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1 , 3, 4] thiadiazole (yield: 30.1%). MS (ESI) M/Z: 460, 462 [M+H + ].
步骤H：6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step H: 6-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1 ,3,4]thiadiazole
Figure PCTCN2019086558-appb-000069
Figure PCTCN2019086558-appb-000069
详见实施例3，步骤I。6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(270毫克，0.59毫摩尔)，叔丁醇钾(66毫克，0.59毫摩尔)，二氯甲烷(20毫升)，甲醇(2毫升)。得到189毫克黄色固体6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：78.2％)。MS(ESI)M/Z:412[M+H +]。 See Example 3, Step I for details. 6-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1,3,4] Thiadiazole (270 mg, 0.59 mmol), potassium tert-butoxide (66 mg, 0.59 mmol), dichloromethane (20 mL) 189 mg of yellow solid 6-(4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b] [1,3,4]thiadiazole (yield: 78.2%). MS (ESI) M / Z: 422 [M+H + ].
步骤I：6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇Step I: 6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine -4-ol
Figure PCTCN2019086558-appb-000070
Figure PCTCN2019086558-appb-000070
详见实施例17，步骤K。6-(4-(苄氧基)-6-氯吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(180毫克，0.44毫摩尔)，五甲基苯(455毫克，3.07毫摩尔)，二氯甲烷(80毫升)，三氯化硼的二氯甲烷溶液(1.14毫升，1.14毫摩尔，1.0摩尔/升)。得到45毫克白色固体6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(收率：31.7％)。MS(ESI)M/Z：322[M+H +]。 See Example 17, Step K for details. 6-(4-(Benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3, 4] thiadiazole (180 mg, 0.44 mmol), pentamethylbenzene (455 mg, 3.07 mmol), dichloromethane (80 ml), boron trichloride in dichloromethane (1.14 ml, 1.14 m) Moore, 1.0 mol/L). Obtained 45 mg of white solid 6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridine-4-ol (yield: 31.7%). MS (ESI) M / Z: 322 [M+H + ].
步骤J：6-(6-氯-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step J: 6-(6-Chloro-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1 -b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000071
Figure PCTCN2019086558-appb-000071
详见实施例14,步骤A。6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(32毫克，0.10毫摩尔)，1-溴-2-甲氧基乙烷(28毫克，0.20毫摩尔)，无水碳酸钾(28毫克，0.20毫摩尔)，N,N-二甲基甲酰胺(1.0毫升)。得到5.1毫克白色固体6-(6-氯-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：13.4％)MS(ESI)M/Z：380[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.18(s,1H),8.04(s,1H),7.06(s,1H),6.42(s,1H),4.28(t,J＝4.5Hz,2H),4.24(s,3H),3.87(t,J＝4.5Hz,2H),3.51(s,3H)。 See Example 14, Step A for details. 6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4- Alcohol (32 mg, 0.10 mmol), 1-bromo-2-methoxyethane (28 mg, 0.20 mmol), anhydrous potassium carbonate (28 mg, 0.20 mmol), N,N-dimethyl Formamide (1.0 ml). Obtained 5.1 mg of white solid 6-(6-chloro-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2 , 1-b][1,3,4]thiadiazole (yield: 13.4%) MS (ESI) M/Z: 380 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.18 (s, 1H), 8.04 (s, 1H), 7.06 (s, 1H), 6.42 (s, 1H), 4.28 (t, J = 4.5Hz , 2H), 4.24 (s, 3H), 3.87 (t, J = 4.5 Hz, 2H), 3.51 (s, 3H).
实施例10Example 10
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基磺酰基)咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfonyl)imidazo[2,1-b][1,3,4 Thiadiazole
Figure PCTCN2019086558-appb-000072
Figure PCTCN2019086558-appb-000072
步骤A：合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基磺酰基)咪唑并[2,1-b][1,3,4]噻二唑Step A: Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfonyl)imidazo[2,1-b][1, 3,4]thiadiazole
Figure PCTCN2019086558-appb-000073
Figure PCTCN2019086558-appb-000073
将(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲硫基)咪唑并[2,1-b][1,3,4]噻二唑(100毫克，0.288毫摩尔)溶于醋酸(20毫升)。向体系中加入钨酸钠(120毫克，0.363毫摩尔)和双氧水(1.0毫升)。在室温下搅拌5小时。LCMS监测显示原料消失后，向体系中加入饱和碳酸氢钠溶液(50毫升)淬灭反应。混合液用乙酸乙酯(100毫升)萃取。合并后的有机相先用饱和盐水(50毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的甲酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。纯化后，低温冻干得到白色固体(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基磺酰基)咪唑并[2,1-b][1,3,4]噻二唑(9.3毫克，8.52％)。MS(ESI)M/Z：380[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.31(s,1H),7.79(s,1H),7.01(s,1H),6.27(s,1H),3.98(s,3H),3.86(s,3H),3.46(s,3H)。 (4,6-Dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylthio)imidazo[2,1-b][1,3,4] Thiadiazole (100 mg, 0.288 mmol) was dissolved in acetic acid (20 mL). Sodium tungstate (120 mg, 0.363 mmol) and hydrogen peroxide (1.0 mL) were added to the system. Stir at room temperature for 5 hours. After LCMS monitoring showed the disappearance of the starting material, a saturated sodium bicarbonate solution (50 ml) was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate (100 mL). The combined organic phases were back-washed with saturated brine (50 mL) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 50% to 60% in 7 minutes Detection wavelength: 254 nm. After purification, lyophilization at low temperature gave a white solid (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfonyl)imidazo[2,1- b] [1,3,4]thiadiazole (9.3 mg, 8.52%). MS (ESI) M/Z: 380 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.31 (s, 1H), 7.79 (s, 1H), 7.01 (s, 1H), 6.27 (s, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 3.46 (s, 3H).
实施例11Example 11
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N-甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N-methylimidazo[2,1-b][1,3,4]thiadiazole 2-amine
Figure PCTCN2019086558-appb-000074
Figure PCTCN2019086558-appb-000074
步骤A：合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N-甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺Step A: Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N-methylimidazo[2,1-b][1,3,4] Thiadiazole-2-amine
Figure PCTCN2019086558-appb-000075
Figure PCTCN2019086558-appb-000075
将2-溴-6-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(60毫克，0.160毫摩尔)溶于乙醇(10毫升)中。向体系中加入甲胺(4.9毫克，0.160毫摩尔)。在80摄氏度下搅拌2小时。LCMS监测显示原料消失后，将体系冷却到室温并真空浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的甲酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。纯化后,低温冻干得到白色固体(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N-甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺(18.1毫克，34.2％)。MS(ESI)M/Z：331[M+H +]。 2-Bromo-6-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadi The azole (60 mg, 0.160 mmol) was dissolved in ethanol (10 mL). Methylamine (4.9 mg, 0.160 mmol) was added to the system. Stir at 80 ° C for 2 hours. After LCMS monitoring indicated disappearance of the material, the system was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 50% to 60% in 7 minutes Detection wavelength: 254 nm. After purification, lyophilization at low temperature gave a white solid (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N-methylimidazo[2,1-b][1 , 3,4]thiadiazol-2-amine (18.1 mg, 34.2%). MS (ESI) M / Z: 331 [M+H + ].
实施例12Example 12
合成(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadi Azole
Figure PCTCN2019086558-appb-000076
Figure PCTCN2019086558-appb-000076
步骤A：合成2,6-二碘代吡啶-3-醇Step A: Synthesis of 2,6-diiodopyridin-3-ol
Figure PCTCN2019086558-appb-000077
Figure PCTCN2019086558-appb-000077
将吡啶-3-醇(92.50克，974毫摩尔)溶于水(1.23升)中。随后，向上述溶液中依次加入碘(900.0克，3.54摩尔)和无水碳酸钾(429.2克，3.11摩尔)。在室温下搅拌18小时。Pyridin-3-ol (92.50 g, 974 mmol) was dissolved in water (1.23 L). Subsequently, iodine (900.0 g, 3.54 mol) and anhydrous potassium carbonate (429.2 g, 3.11 mol) were sequentially added to the above solution. Stir at room temperature for 18 hours.
向反应液中加入饱和硫代硫酸钠水溶液(500毫升)淬灭反应。然后，向混合液中缓慢滴加稀盐酸(1.0摩尔/升)调节PH值约为6。混合液用乙酸乙酯(1.20升×3次)萃取。合并有机相，有机相先用饱和食盐水(500毫升×3次)洗涤，然后再用无水硫酸钠干燥，最后减压浓缩。所得残余物用氯仿重结晶。抽滤，收集滤饼，滤饼烘干得到160.0克黄色固体2,6-二碘代吡啶-3-醇(收率：47.3％)。MS(ESI)M/Z:348[M+H +]。 A saturated aqueous sodium thiosulfate solution (500 ml) was added to the reaction mixture to quench. Then, dilute hydrochloric acid (1.0 mol/liter) was slowly added dropwise to the mixture to adjust the pH to about 6. The mixture was extracted with ethyl acetate (1.20 L×3×). The combined organic phases were washed with brine (500 mL×3×) and then dried over anhydrous sodium sulfate. The resulting residue was recrystallized from chloroform. After suction filtration, the cake was collected, and the cake was dried to obtain 160.0 g of a yellow solid 2,6-diiodopyridin-3-ol (yield: 47.3%). MS (ESI) M/Z: 348[M+H + ].
步骤B：合成2,6-二碘-3-甲氧基吡啶Step B: Synthesis of 2,6-diiodo-3-methoxypyridine
Figure PCTCN2019086558-appb-000078
Figure PCTCN2019086558-appb-000078
将2,6-二碘代吡啶-3-醇(80.00克，230毫摩尔)和甲醇钠(15.06克，279毫摩尔)溶于N,N-二甲基甲酰胺(230.0毫升)中。随后，在冰水浴下，向上述溶液中缓慢滴加碘甲烷(39.56克，279毫摩尔)。在室温下搅拌18小时。2,6-Diiodopyridin-3-ol (80.00 g, 230 mmol) and sodium methoxide (15.06 g, 279 mmol) were dissolved in N,N-dimethylformamide (230.0 mL). Subsequently, methyl iodide (39.56 g, 279 mmol) was slowly added dropwise to the above solution under ice water bath. Stir at room temperature for 18 hours.
向反应液中加入饱和氯化铵溶液(50.0毫升)淬灭反应。混合液用乙酸乙酯(1.0升×3次)萃取。合并有机相，有机相用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10)。得到71.08克淡黄色固体2,6-二碘-3-甲氧基吡啶(收率：85.6％)。MS(ESI)M/Z:362[M+H +]。 A saturated ammonium chloride solution (50.0 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (1.0 L×3×). The combined organic phases were dried with anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/10). 71.08 g of pale yellow solid 2,6-diiodo-3-methoxypyridine were obtained (yield: 85.6%). MS (ESI) M/Z: 362 [M+H + ].
步骤C：合成2,6-二碘-3-甲氧基吡啶-4-醇Step C: Synthesis of 2,6-diiodo-3-methoxypyridin-4-ol
Figure PCTCN2019086558-appb-000079
Figure PCTCN2019086558-appb-000079
在氮气保护下，将二异丙胺(183克，181毫摩尔)溶于四氢呋喃(800毫升)中。将上述溶液冷却到-78摄氏度，向其中缓慢滴加正丁基锂的四氢呋喃溶液(72.4毫升，181毫摩尔，2.5摩尔/升)。在-78摄氏度下搅拌1小时。然后，向上述溶液中缓慢滴加2,6-二碘-3-甲氧基吡啶(59.57克，165毫摩尔)的四氢呋喃溶液(200.0毫升)。在-78摄氏度下继续搅拌1小时后。向其中加入硼酸三甲酯(19.45 克，187毫摩尔)，在-78摄氏度下继续搅拌两小时。将反应液缓慢升温至-60摄氏度，向上述溶液中加入双氧水(30.0毫升，30％wt)。Diisopropylamine (183 g, 181 mmol) was dissolved in tetrahydrofuran (800 mL) under nitrogen. The solution was cooled to -78 ° C, and a solution of n-butyllithium in tetrahydrofuran (72.4 ml, 181 mmol, 2.5 mol / liter) was slowly added dropwise. Stir at -78 degrees Celsius for 1 hour. Then, a solution of 2,6-diiodo-3-methoxypyridine (59.57 g, 165 mmol) in tetrahydrofuran (200.0 ml) was slowly added dropwise to the above solution. Stirring was continued for 1 hour at -78 degrees Celsius. Trimethyl borate (19.45 g, 187 mmol) was added thereto, and stirring was continued at -78 ° C for two hours. The reaction solution was slowly warmed to -60 ° C, and hydrogen peroxide (30.0 ml, 30% wt) was added to the above solution.
向反应液中加入饱和硫代硫酸钠溶液(100毫升)淬灭反应。混合液用乙酸乙酯(800毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(500毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到19.78克黄色固体2,6-二碘-3-甲氧基吡啶-4-醇(收率：31.8％)。MS(ESI)M/Z：378[M+H +]。 A saturated sodium thiosulfate solution (100 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (800 mL×3×). The combined organic layers were washed with brine (500 mL×3×) and then dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1). 19.78 g of a yellow solid 2,6-diiodo-3-methoxypyridin-4-ol was obtained (yield: 31.8%). MS (ESI) M / Z: 378 [M+H + ].
步骤D：合成2,6-二碘-3,4-二甲氧基吡啶Step D: Synthesis of 2,6-diiodo-3,4-dimethoxypyridine
Figure PCTCN2019086558-appb-000080
Figure PCTCN2019086558-appb-000080
将2,6-二碘-3-甲氧基吡啶-4-醇(14.40克，38.2毫摩尔)和无水碳酸银(12.00克，43.5毫摩尔)加入丙酮(230.0毫升)中。冰水浴下，向上述溶液中缓慢滴加碘甲烷(32.00克，225毫摩尔)。在常温避光下搅拌18小时。2,6-Diiodo-3-methoxypyridin-4-ol (14.40 g, 38.2 mmol) and anhydrous silver carbonate (12.00 g, 43.5 mmol) were added to acetone (230.0 mL). Methyl iodide (32.00 g, 225 mmol) was slowly added dropwise to the above solution under ice-water bath. Stir for 18 hours at room temperature in the dark.
向上述溶液中加入水(50毫升)淬灭反应。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(200毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到14.80克淡黄色固体2,6-二碘-3,4-二甲氧基吡啶。无需纯化，直接用于下步反应。MS(ESI)M/Z:392[M+H +]。 Water (50 ml) was added to the above solution to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×3×). The combined organic layers were washed with brine (200 mL×3×) and dried over anhydrous sodium sulfate. 14.80 g of pale yellow solid 2,6-diiodo-3,4-dimethoxypyridine were obtained. It is used directly in the next step without purification. MS (ESI) M / Z: 392 [M+H + ].
步骤E：合成2-碘-4,5-二甲氧基吡啶Step E: Synthesis of 2-iodo-4,5-dimethoxypyridine
Figure PCTCN2019086558-appb-000081
Figure PCTCN2019086558-appb-000081
将2,6-二碘-3,4-二甲氧基吡啶(14.80克，37.8毫摩尔)溶于四氢呋喃(200.0毫升)中。在-78摄氏度下，向上述溶液中缓慢滴加正丁基锂(15.1毫升，37.8毫摩尔，2.5摩尔/升)。在-78摄氏度下搅拌2小时。2,6-Diiodo-3,4-dimethoxypyridine (14.80 g, 37.8 mmol) was dissolved in tetrahydrofuran (200.0 mL). n-Butyllithium (15.1 ml, 37.8 mmol, 2.5 mol/L) was slowly added dropwise to the above solution at -78 °C. Stir at -78 degrees Celsius for 2 hours.
向反应液中加入水(100毫升)淬灭反应。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相。有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/3)。得到3.75克黄色固体2-碘-4,5-二甲氧基吡啶(收率：37.4％)。MS(ESI)M/Z:266[M+H +]。 Water (100 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×3×). Combine the organic phases. The organic phase was washed with saturated brine (100 ml × 3×), then dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc 3.75 g of a yellow solid 2-iodo-4,5-dimethoxypyridine was obtained (yield: 37.4%). MS (ESI) M / Z: 266 [M+H + ].
步骤F：合成4-(4,5-二甲氧基吡啶-2-基)丁-3-炔-2-醇Step F: Synthesis of 4-(4,5-dimethoxypyridin-2-yl)but-3-yn-2-ol
Figure PCTCN2019086558-appb-000082
Figure PCTCN2019086558-appb-000082
详见实施例1，步骤E。2-碘-4,5-二甲氧基吡啶(2.80克，10.6毫摩尔),二(三苯基磷)二氯化钯(842毫克，1.20毫摩尔)，but-3-yn-2-ol(1.12克，16.0毫摩尔),碘化亚铜(420毫克，2.21毫摩尔)，三乙胺(200.0毫升)。得到1.65克淡黄色固体4-(4,5-二甲氧基吡啶-2-基)丁-3-炔-2-醇(收率：75.3％)。MS(ESI)M/Z：208[M+H +]。 See Example 1, Step E for details. 2-iodo-4,5-dimethoxypyridine (2.80 g, 10.6 mmol), bis(triphenylphosphine)palladium dichloride (842 mg, 1.20 mmol), but-3-yn-2- Ol (1.12 g, 16.0 mmol), cuprous iodide (420 mg, 2.21 mmol), triethylamine (200.0 mL). There was obtained 1.65 g of pale yellow solid 4-(4,5-dimethoxypyridin-2-yl)but-3-yn-2-ol (yield: 75.3%). MS (ESI) M / Z: 208 [M+H + ].
步骤G：合成1-(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙-1-醇Step G: Synthesis of 1-(5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethan-1-ol
Figure PCTCN2019086558-appb-000083
Figure PCTCN2019086558-appb-000083
详见实施例17，步骤F。4-(4,5-二甲氧基吡啶-2-基)丁-3-炔-2-醇(1.00克，4.83毫摩尔)，2,4,6-三甲基苯磺酰羟胺(3.90克，14.5毫摩尔，80％wt)，二氯甲烷(100毫升)，无水碳酸钾(927毫克，6.72毫摩尔)，N,N-二甲基甲酰胺(5.0升)。得到330毫克白色油状物1-(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙-1-醇(收率：30.8％)。MS(ESI)M/Z：223[M+H +]。 See Example 17, Step F for details. 4-(4,5-Dimethoxypyridin-2-yl)but-3-yn-2-ol (1.00 g, 4.83 mmol), 2,4,6-trimethylbenzenesulfonyl hydroxylamine (3.90 Gram, 14.5 mmol, 80% wt), dichloromethane (100 mL), anhydrous potassium carbonate (927 mg, 6.72 mmol), N,N-dimethylformamide (5.0 L). There was obtained 330 mg of a white oil 1-(5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethan-1-ol (yield: 30.8%). MS (ESI) M / Z: 223 [M+H + ].
步骤H：合成1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮Step H: Synthesis of 1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000084
Figure PCTCN2019086558-appb-000084
详见实施例17，步骤G。1-(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)乙-1-醇(330毫克，1.49毫摩尔)，戴斯-马丁试剂(753毫克，1.77毫摩尔)，二氯甲烷(30.0毫升)。得到150毫克白色固体1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(收率：45.8％)。MS(ESI)M/Z:221[M+H +]。 See Example 17, Step G for details. 1-(5,6-Dimethoxypyrazolo[1,5-a]pyridin-2-yl)ethan-1-ol (330 mg, 1.49 mmol), Dess-Martin reagent (753 mg, 1.77 mmol), dichloromethane (30.0 mL). 150 mg of white 1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (yield: 45.8%) was obtained. MS (ESI) M / Z: 221 [M+H + ].
步骤I：合成2-溴-1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮Step I: Synthesis of 2-bromo-1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one
Figure PCTCN2019086558-appb-000085
Figure PCTCN2019086558-appb-000085
详见实施例17，步骤H。1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(150毫克，0.68毫摩尔)，N,N-二异丙基乙胺(352毫克，2.73毫摩尔)，三氟甲磺酸三甲基硅酯(455毫克，2.05毫摩尔)，N-溴代丁二酰亚胺(121毫克，0.68毫摩尔)，二氯甲烷(20.0毫升)，四氢呋喃(10.0毫升)。得到90毫克淡黄色固体2-溴-1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(收率：44.3％)。MS(ESI)M/Z:299,301[M+H +]。 See Example 17, Step H for details. 1-[5,6-Dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (150 mg, 0.68 mmol), N,N-diisopropyl Amine (352 mg, 2.73 mmol), trimethylsilyl trifluoromethanesulfonate (455 mg, 2.05 mmol), N-bromosuccinimide (121 mg, 0.68 mmol), methylene chloride (20.0 mL), tetrahydrofuran (10.0 mL). There was obtained 90 mg of pale yellow solid 2-bromo-1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (yield: 44.3%). MS (ESI) M/Z: 299, 301 [M+H + ].
步骤J：合成2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基]-5,6-二甲氧基吡唑并[1,5-a]吡啶Step J: Synthesis of 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl]-5,6-dimethoxypyrazolo[1,5 -a]pyridine
Figure PCTCN2019086558-appb-000086
Figure PCTCN2019086558-appb-000086
详见实施例3，步骤H。2-溴-1-[5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基]乙-1-酮(90毫克,0.30毫摩尔),2-氨基-5-溴-1,3,4-噻二唑(62毫克，0.34毫摩尔)，异丙醇(6.0毫升)。得到68毫克淡黄色固体2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基]-5,6-二甲氧基吡唑并[1,5-a]吡啶(收率：59.6％)。MS(ESI)M/Z:380,382[M+H +]。 See Example 3, Step H for details. 2-bromo-1-[5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl]ethan-1-one (90 mg, 0.30 mmol), 2-amino-5 Bromo-1,3,4-thiadiazole (62 mg, 0.34 mmol), isopropanol (6.0 mL). Obtained 68 mg of pale yellow solid 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl]-5,6-dimethoxypyrazolo[1 , 5-a]pyridine (yield: 59.6%). MS (ESI) M/Z: 380, 382 [M+H + ].
步骤K：合成(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step K: Synthesis of (5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4 Thiadiazole
Figure PCTCN2019086558-appb-000087
Figure PCTCN2019086558-appb-000087
详见实施例3，步骤I。2-[2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基]-5,6-二甲氧基吡唑并[1,5-a]吡啶(68毫克,0.18毫摩尔),叔丁醇钾(20毫克，0.18毫摩尔),二氯甲烷(8.0毫升)，甲醇(2.0毫升)。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在10分钟内，乙腈从60％升到80％；检测波长：254nm。减压冻干，得到9.6毫克类白色固体(5,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：16.2％)。MS(ESI)M/Z:332[M+H +]； 1H NMR(300MHz,CDCl 3,ppm):δ8.14–8.05(m,2H),6.80–6.76(m,2H),4.24(s,3H),3.98(s,3H),3.93(s,3H)。 See Example 3, Step I for details. 2-[2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl]-5,6-dimethoxypyrazolo[1,5-a]pyridine (68 mg, 0.18 mmol), potassium tert-butoxide (20 mg, 0.18 mmol), dichloromethane (EtOAc) The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile rose from 60% in 10 minutes 80%; detection wavelength: 254 nm. Lyophilized under reduced pressure to give 9.6 mg of white solid (5,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b ][1,3,4]thiadiazole (yield: 16.2%). MS (ESI) M / Z: 332 [M+H + ]; 1 H NMR (300 MHz, CDCl 3 , ppm): δ 8.14 - 8.05 (m, 2H), 6.80 - 6.76 (m, 2H), 4.24 ( s, 3H), 3.98 (s, 3H), 3.93 (s, 3H).
实施例13Example 13
合成6-(吲嗪-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 6-(pyridazin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000088
Figure PCTCN2019086558-appb-000088
具体实施步骤：Specific implementation steps:
Figure PCTCN2019086558-appb-000089
Figure PCTCN2019086558-appb-000089
步骤A：将1-(吲嗪-2-基)乙酮(150毫克，0.940毫摩尔)溶于氢溴酸的醋酸溶液(10.0毫升，33％wt)中。在冰水浴下，向上述溶液中缓慢加入溴素(181毫克，1.13毫摩尔)。在室温下搅拌1小时。Step A: 1-(Pyridazin-2-yl)ethanone (150 mg, 0.940 mmol) was dissolved in aqueous acetic acid (10.0 mL, 33% wt). Bromine (181 mg, 1.13 mmol) was slowly added to the above solution under ice-water bath. Stir at room temperature for 1 hour.
向反应液中加入饱和碳酸氢钠溶液(20毫升)淬灭反应。混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。粗产品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/6)，得到2-溴-1-(吲嗪-2-基)乙-1-酮(85毫克，37.9％)，为淡黄色固体。MS(ESI)M/Z：238,240[M+H +]。 The reaction was quenched by the addition of saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with brine (20 mL×3×) and then dried over anhydrous sodium sulfate. The crude product was purified with EtOAc EtOAc elut elut elut elut elut %) is a pale yellow solid. MS (ESI) M/Z: 238, 240 [M+H + ].
步骤B：详见实施例1，步骤C：2-溴-1-(吲嗪-2-基)乙-1-酮(85毫克，0.36毫摩尔)，5-溴-1,3,4-噻二唑-2-胺(128毫克，0.72毫摩尔)，异丙醇(3.0毫升)。得到2-溴-6-(吲嗪-2-基)咪唑并[2,1-b][1,3,4]噻二唑(50毫克，43.5％)，为棕色固体。MS(ESI)M/Z：319[M+H +]。 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 + ].
步骤C：详见实施例3，步骤I：2-溴-6-(吲嗪-2-基)咪唑并[2,1-b][1,3,4]噻二唑(50毫克，0.16毫摩尔)，二氯甲烷(3.0毫升)，甲醇(1.5毫升)，叔丁醇钾(14.4毫克，0.24毫摩尔)。得到6-(吲嗪-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(1.6毫克，3.7％)，为类白色固体。MS(ESI)M/Z：271[M+H +]。 1H NMR(300MHz,Methanol-d 4,ppm)δ8.07(d,J＝7.2Hz,1H),7.98(s,1H),7.73(s,1H),7.33(d,J＝9.0Hz,1H),6.69–6.63(m,2H),6.46(t,J＝6.6Hz,1H),4.25(s,3H)。 Step C: See Example 3 for details, Step I: 2-bromo-6-(pyridazin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (50 mg, 0.16) Millimol), dichloromethane (3.0 mL), methanol (1.5 mL), potassium tert-butoxide (14.4 mg, 0.24 mmol). 6-(Pyridazin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (1.6 mg, 3.7%) was obtained as an off white solid. MS (ESI) M / Z: 271 [M+H + ]. 1 H NMR (300 MHz, Methanol-d 4 , ppm) δ 8.07 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.69 - 6.63 (m, 2H), 6.46 (t, J = 6.6 Hz, 1H), 4.25 (s, 3H).
实施例14Example 14
合成2-甲氧基-6-(6-甲氧基-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 2-methoxy-6-(6-methoxy-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1 -b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000090
Figure PCTCN2019086558-appb-000090
步骤A：合成2-甲氧基-6-(6-甲氧基-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑Step A: Synthesis of 2-methoxy-6-(6-methoxy-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000091
Figure PCTCN2019086558-appb-000091
将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(30毫克,0.09毫摩尔)溶于N,N-二甲基甲酰胺(2.0毫升)中，加入1-溴-2-甲氧基乙烷(25毫克，0.18毫摩尔)和无水碳酸钾(25毫克，0.18毫摩尔)。在室温下搅拌4小时。LCMS监测显示原料消失后，过滤除去不溶物。滤液用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的甲酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。减压冻干。得到2.0毫克白色固体2-甲氧基-6-(6-甲氧基-4-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(收率：5.9％)。MS(ESI)M/Z：376[M+H +]。 1H NMR(300MHz,CDCl 3,ppm)8.00(s,1H),7.80(s,1H),6.96(s,1H),6.25(s,1H),4.27–4.23(m,5H),3.87-3.84(m,5H),3.51(s,3H)。 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridine 4-Alkyl alcohol (30 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and 1-bromo-2-methoxyethane (25 mg, 0.18 mmol). Anhydrous potassium carbonate (25 mg, 0.18 mmol). Stir at room temperature for 4 hours. LCMS monitoring showed disappearance of the starting material and filtration to remove insolubles. The filtrate was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 50% to 60% in 7 minutes Detection wavelength: 254 nm. Freeze dry under reduced pressure. Yield 2.0 mg of white solid 2-methoxy-6-(6-methoxy-4-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazole [2,1-b][1,3,4]thiadiazole (yield: 5.9%). MS (ESI) M/Z: 376 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm) 8.00 (s, 1H), 7.80 (s, 1H), 6.96 (s, 1H), 6.25 (s, 1H), 4.27-4.23 (m, 5H), 3.87- 3.84 (m, 5H), 3.51 (s, 3H).
实施例15Example 15
合成6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 6-(6-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridin-2-yl) 2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000092
Figure PCTCN2019086558-appb-000092
步骤A：合成2-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)四氢-2H-吡喃Step A: Synthesis of 2-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethoxy)tetrahydro-2H-pyran
Figure PCTCN2019086558-appb-000093
Figure PCTCN2019086558-appb-000093
详见实施例20，步骤A。四氢-2H-吡喃-4-醇(5.00克,49.02毫摩尔)，氢化钠(4.90克，122.5毫摩尔，60％wt)，N,N-二甲基甲酰胺溶液(150.0毫升)，2-(2-溴乙氧基)-四氢-2H-吡喃(11.2克,53.9毫摩尔)。得到4.68克无色油状物2-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)四氢-2H-吡喃(收率：41.5％)。MS(ESI)M/Z：231[M+H +]。 See Example 20, Step A for details. Tetrahydro-2H-pyran-4-ol (5.00 g, 49.02 mmol), sodium hydride (4.90 g, 122.5 mmol, 60% wt), N,N-dimethylformamide (150.0 mL), 2-(2-Bromoethoxy)-tetrahydro-2H-pyran (11.2 g, 53.9 mmol). There was obtained 4.68 g of 2-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethoxy)tetrahydro-2H-pyran as a colorless oil (yield: 41.5%). MS (ESI) M / Z: 231 [M+H + ].
步骤B：合成2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇Step B: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethan-1-ol
Figure PCTCN2019086558-appb-000094
Figure PCTCN2019086558-appb-000094
详见实施例20，步骤B。2-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)四氢-2H-吡喃(4.68克，20.35毫摩尔)，甲醇(100.0毫升)，盐酸的异丙醇溶液(15.0毫升，8.0摩尔/升)。得到2.10克无色油状物2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇(收率：70.8％)。MS(ESI)M/Z：147[M+H +]。 See Example 20, Step B for details. 2-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethoxy)tetrahydro-2H-pyran (4.68 g, 20.35 mmol), methanol (100.0 mL) Isopropyl alcohol solution (15.0 ml, 8.0 mol/l). 2.10 g of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethan-1-ol (yield: 70.8%) was obtained as a colorless oil. MS (ESI) M / Z: 147 [M+H + ].
步骤C：合成2-((四氢-2H-吡喃-4-基)氧基)乙基4-甲基苯磺酸酯Step C: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl 4-methylbenzenesulfonate
Figure PCTCN2019086558-appb-000095
Figure PCTCN2019086558-appb-000095
详见实施例20，步骤C。2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇(1.50克，10.3毫摩尔)，三乙胺(3.12克，30.9毫摩尔)，二氯甲烷(50.0毫升)，p-甲苯磺酰氯(2.93克，15.4毫摩尔)。得到650毫克黄色油状物2-((四氢-2H-吡喃-4-基)氧基)乙基4-甲基苯磺酸酯(收率：21.0％)。MS(ESI)M/Z：301[M+H +]。 See Example 20, Step C for details. 2-((Tetrahydro-2H-pyran-4-yl)oxy)ethan-1-ol (1.50 g, 10.3 mmol), triethylamine (3.12 g, 30.9 mmol), dichloromethane (50.0 ML), p-toluenesulfonyl chloride (2.93 g, 15.4 mmol). There was obtained 650 mg of a yellow oil as 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl 4-methylbenzenesulfonate (yield: 21.0%). MS (ESI) M / Z: 301 [M+H + ].
步骤D：合成6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑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
Figure PCTCN2019086558-appb-000096
Figure PCTCN2019086558-appb-000096
详见实施例20，步骤D。2-((四氢-2H-吡喃-4-基)氧基)乙基4-甲基苯磺酸酯(27毫克，0.084毫摩尔),2-((四氢-2H-吡喃-4-基)氧基)乙基4-甲基苯磺酸酯(34毫克，0.115毫摩尔)，无水碳酸钾(36毫克，0.261毫摩尔)，乙腈(2.5毫升)。得到4.4毫克白色固体6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：11.7％)。MS(ESI)M/Z:450[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.18(s,1H),8.04(s,1H),7.05(s,1H),6.46(s,1H),4.29(t,J＝4.8Hz，2H),4.25(s,3H),4.02–3.93(m,4H),3.69–3.62(m,1H),3.54-3.46(m,2H)，1.84–1.61(m,4H)。 See Example 20, Step D for details. 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl 4-methylbenzenesulfonate (27 mg, 0.084 mmol), 2-((tetrahydro-2H-pyran)- 4-yl)oxy)ethyl 4-methylbenzenesulfonate (34 mg, 0.115 mmol), anhydrous potassium carbonate (36 mg, 0.261 mmol), acetonitrile (2.5 mL). 4.4 mg of white solid 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 (yield: 11.7%). MS (ESI) M/Z: 450 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.18 (s, 1H), 8.04 (s, 1H), 7.05 (s, 1H), 6.46 (s, 1H), 4.29 (t, J = 4.8Hz , 2H), 4.25 (s, 3H), 4.02 - 3.93 (m, 4H), 3.69 - 3.62 (m, 1H), 3.54 - 3.46 (m, 2H), 1.84 - 1.61 (m, 4H).
实施例16Example 16
合成4-(2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)乙基)吗啉Synthesis of 4-(2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)ethyl)morpholine
Figure PCTCN2019086558-appb-000097
Figure PCTCN2019086558-appb-000097
步骤A：合成4-(2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)乙基)吗啉Step A: Synthesis of 4-(2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridyl) Oxazo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine
Figure PCTCN2019086558-appb-000098
Figure PCTCN2019086558-appb-000098
详见实施例14，步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(30毫克，0.09毫摩尔)，4-(2-bromoethyl)morpholine(35毫克，0.18毫摩尔)，无水碳酸钾(25毫克，0.18毫摩尔)，N，N-二甲基甲酰胺(2.0毫升)。得到1.7毫克白色固体4-(2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)乙基)吗啉(收率：4.39％)。MS(ESI)M/Z：431[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.00(s,1H),7.77(s, 1H)，6.92(s,1H),6.23(s,1H)，4.28–4.22(m,5H),3.84(s,3H),3.78–3.69(m,4H),2.95–2.92(m,2H),2.68(s,4H)。 See Example 14, Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (30 mg, 0.09 mmol), 4-(2-bromoethyl)morpholine (35 mg, 0.18 mmol), anhydrous potassium carbonate (25 mg, 0.18 mmol), N,N-dimethyl Amide (2.0 ml). 1.7 mg of white solid 4-(2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)) Pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine (yield: 4.39%). MS (ESI) M / Z: 431 [M+H + ]. 1 H NMR (300 MHz, CDCl 3 , ppm): δ 8.00 (s, 1H), 7.77 (s, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 4.28 - 4.22 (m, 5H) , 3.84 (s, 3H), 3.78 - 3.69 (m, 4H), 2.95 - 2.92 (m, 2H), 2.68 (s, 4H).
实施例17Example 17
合成4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)吗啉Synthesis of 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)morpholine
Figure PCTCN2019086558-appb-000099
Figure PCTCN2019086558-appb-000099
步骤A：合成5-甲氧基-2-硝基吡啶-3-醇Step A: Synthesis of 5-methoxy-2-nitropyridin-3-ol
Figure PCTCN2019086558-appb-000100
Figure PCTCN2019086558-appb-000100
冰水浴下，向5-甲氧基吡啶-3-醇(100.0克，800毫摩尔)的浓硫酸(436.0毫升)溶液中缓慢滴加发烟硝酸(37.8毫升)。在室温下搅拌3小时。To a solution of 5-methoxypyridin-3-ol (100.0 g, 800 mmol) in concentrated sulfuric acid (436.0 ml), EtOAc (3. Stir at room temperature for 3 hours.
将反应液倒入冰水中淬灭反应。混合液中有固体析出。过滤，所得滤饼用乙酸乙酯(100毫升×3次)。收集滤饼，滤饼烘干得到76.00克淡黄色固体5-甲氧基-2-硝基吡啶-3-醇。无需纯化，直接用于下步反应。MS(ESI)M/Z：171[M+H +]。 The reaction solution was poured into ice water to quench the reaction. A solid precipitated in the mixed solution. Filtration and the obtained cake were taken ethyl acetate (100 ml x 3 times). The filter cake was collected and the cake was dried to give 76.00 g of pale yellow solid 5-methoxy-2-nitropyridin-3-ol. It is used directly in the next step without purification. MS (ESI) M / Z: 171 [M+H + ].
步骤B：合成3-(苄氧基)-5-甲氧基-2-硝基吡啶Step B: Synthesis of 3-(benzyloxy)-5-methoxy-2-nitropyridine
Figure PCTCN2019086558-appb-000101
Figure PCTCN2019086558-appb-000101
将5-甲氧基-2-硝基吡啶-3-醇(76.00克，447.0毫摩尔)溶于乙腈(2.0升)中。随后，向上述溶液中依次加入无水碳酸钾(123.4克，894.0毫摩尔)和苄溴(91.70克，536.0毫摩尔)。将反应液加热至80摄氏度，并搅拌8小时。5-Methoxy-2-nitropyridin-3-ol (76.00 g, 447.0 mmol) was dissolved in acetonitrile (2.0 L). Subsequently, anhydrous potassium carbonate (123.4 g, 894.0 mmol) and benzyl bromide (91.70 g, 536.0 mmol) were sequentially added to the above solution. The reaction solution was heated to 80 ° C and stirred for 8 hours.
将反应液通过硅藻土过滤，所得滤液在真空下浓缩。所得残余物加入乙酸乙酯与石油醚的混合溶液(200毫升，1/10)中，搅拌30分钟。过滤，收集滤饼，滤饼烘干得到81.7克淡黄色固体3-(苄氧基)-5-甲氧基-2-硝基吡啶。无需纯化，直接用于下步反应。MS(ESI)M/Z：261[M+H +]。 The reaction solution was filtered through celite, and filtered. The obtained residue was added to a mixed solution of ethyl acetate and petroleum ether (200 ml, 1/10), and stirred for 30 minutes. Filtration, collection of the filter cake, and drying of the filter cake gave 81.7 g of pale yellow solid 3-(benzyloxy)-5-methoxy-2-nitropyridine. It is used directly in the next step without purification. MS (ESI) M / Z: 266 [M+H + ].
步骤C：合成3-(苄氧基)-5-甲氧基吡啶-2-胺Step C: Synthesis of 3-(benzyloxy)-5-methoxypyridin-2-amine
Figure PCTCN2019086558-appb-000102
Figure PCTCN2019086558-appb-000102
将3-(苄氧基)-5-甲氧基-2-硝基吡啶(61.70克，237.3毫摩尔)溶于乙酸(934.0毫升)与水(700.0毫升)的混合溶液中。随后，向上述溶液中分批次加入铁粉(53.10克，949.0毫摩尔)。将反应液加热至60摄氏度，并搅拌3小时。3-(Benzyloxy)-5-methoxy-2-nitropyridine (61.70 g, 237.3 mmol) was dissolved in a mixed solution of acetic acid (934.0 ml) and water (700.0 ml). Subsequently, iron powder (53.10 g, 949.0 mmol) was added in portions to the above solution. The reaction solution was heated to 60 ° C and stirred for 3 hours.
将反应液在减压下除去乙酸。所得的残余物溶于二氯甲烷(100毫升)中。向混合液中加入饱和碳酸氢钠溶液调节PH值至中性。混合液用二氯甲烷(500毫升×3次)萃取。合并有机相。有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到53.00克棕色固体3-(苄氧基)-5-甲氧基吡啶-2-胺。无需纯化，直接用于下步反应。MS(ESI)M/Z：231[M+H +]。 The reaction solution was subjected to removal of acetic acid under reduced pressure. The residue obtained was dissolved in dichloromethane (100 mL). Saturated sodium bicarbonate solution was added to the mixture to adjust the pH to neutral. The mixture was extracted with dichloromethane (500 mL×3×). Combine the organic phases. The organic phase was washed with saturated brine (100 ml × 3×), then dried over anhydrous sodium sulfate and evaporated. 53.00 g of a brown solid 3-(benzyloxy)-5-methoxypyridin-2-amine was obtained. It is used directly in the next step without purification. MS (ESI) M / Z: 231 [M+H + ].
步骤D：合成3-(苄氧基)-2-碘-5-甲氧基吡啶Step D: Synthesis of 3-(benzyloxy)-2-iodo-5-methoxypyridine
Figure PCTCN2019086558-appb-000103
Figure PCTCN2019086558-appb-000103
将3-(苄氧基)-5-甲氧基吡啶-2-胺(23.00克，100.0毫摩尔)，碘(25.4克，100.0毫摩尔)和碘化亚铜(19.0克，100.0毫摩尔)溶于二碘甲烷(500.0毫升)中。将反应液加热至85摄氏度，然后向反应液中加入亚硝酸异戊酯(35.1克，300毫摩尔)。在85摄氏度下搅拌10分钟。3-(Benzyloxy)-5-methoxypyridin-2-amine (23.00 g, 100.0 mmol), iodine (25.4 g, 100.0 mmol) and cuprous iodide (19.0 g, 100.0 mmol) Dissolved in diiodomethane (500.0 ml). The reaction solution was heated to 85 ° C, and then isoamyl nitrite (35.1 g, 300 mmol) was added to the reaction mixture. Stir at 85 degrees Celsius for 10 minutes.
将反应液冷却到室温，并在减压下浓缩除去二碘甲烷。所得残余物溶于二氯甲烷(1.0升)。过滤除去不溶物，所得滤液在减压下浓缩。所得残余物用硅胶柱层析纯化(乙酸乙酯/石油醚＝1/5)。得到16.1克棕色固体3-(苄氧基)-2-碘-5-甲氧基吡啶(收率：47.1％)。MS(ESI)M/Z：342[M+H +]。 The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove dichloromethane. The residue obtained was dissolved in dichloromethane (1.0 L). Insoluble materials were removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography (ethyl acetate 16.1 g of 3-(benzyloxy)-2-iodo-5-methoxypyridine as a brown solid was obtained (yield: 47.1%). MS (ESI) M / Z: 342 [M+H + ].
步骤E：合成4-(3-(苄氧基)-5-甲氧基吡啶-2-基)丁-3-炔-2-醇Step E: Synthesis of 4-(3-(benzyloxy)-5-methoxypyridin-2-yl)but-3-yn-2-ol
Figure PCTCN2019086558-appb-000104
Figure PCTCN2019086558-appb-000104
在氮气保护下，将3-(苄氧基)-2-碘-5-甲氧基吡啶(17.50克，51.0毫摩尔)溶于三乙胺(2.0升)中。随后，向上述溶液中依次加入丁基-3-炔-2-醇(4.28克，61.2毫摩尔)，Pd(dppf) 2Cl 2(1.07克，1.5毫摩尔)和碘化亚铜(570毫克，3.0毫摩尔)。将反应液加热至60摄氏度，并搅拌8小时。 3-(Benzyloxy)-2-iodo-5-methoxypyridine (17.50 g, 51.0 mmol) was dissolved in triethylamine (2.0 L). Subsequently, butyl-3-yn-2-ol (4.28 g, 61.2 mmol), Pd(dppf) 2 Cl 2 (1.07 g, 1.5 mmol) and cuprous iodide (570 mg) were sequentially added to the above solution. , 3.0 mmol). The reaction solution was heated to 60 ° C and stirred for 8 hours.
将反应液冷却到室温，并减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到14.00克棕色固体4-(3-(苄氧基)-5-甲氧基吡啶-2-基)丁-3-炔-2-醇(收率：96.7％)。MS(ESI)M/Z：284[M+H +]。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc 14.00 g of a brown solid 4-(3-(benzyloxy)-5-methoxypyridin-2-yl)but-3-yn-2-ol (yield: 96.7%) was obtained. MS (ESI) M / Z: 284 [M+H + ].
步骤F：合成1-(4-(苄氧基)-6-甲氧基吡唑并[1,5-a]吡啶-2-基)乙醇Step F: Synthesis of 1-(4-(benzyloxy)-6-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanol
Figure PCTCN2019086558-appb-000105
Figure PCTCN2019086558-appb-000105
将4-(3-(苄氧基)-5-甲氧基吡啶-2-基)丁-3-炔-2-醇(14.00克，49.2毫摩尔)溶于二氯甲烷(400.0毫升)中。冰水浴下，向上述溶液中缓慢滴加2,4,6-三甲基苯磺酰羟胺(39.7克，147.8毫摩尔，80％wt)的二氯甲烷(80.0毫升)溶液。将反应液升至室温，并搅拌过夜。4-(3-(Benzyloxy)-5-methoxypyridin-2-yl)but-3-yn-2-ol (14.00 g, 49.2 mmol) was dissolved in dichloromethane (400.0 mL) . A solution of 2,4,6-trimethylbenzenesulfonylhydroxylamine (39.7 g, 147.8 mmol, 80% by weight) in dichloromethane (80.0 ml) was slowly added dropwise to the above solution under ice-water bath. The reaction was allowed to warm to room temperature and stirred overnight.
将反应液在减压下浓缩。将所得残余物的N,N-二甲基甲酰胺(100毫升)溶液缓慢滴加到无水碳酸钾(13.60克，99.0毫摩尔)的N,N-二甲基甲酰胺(1.4升)溶液中。在室温下搅拌过夜。The reaction solution was concentrated under reduced pressure. A solution of the obtained residue in N,N-dimethylformamide (100 ml) was slowly added dropwise to a solution of anhydrous potassium carbonate (13.60 g, 99.0 mmol) of N,N-dimethylformamide (1.4 L) in. Stir at room temperature overnight.
将反应液在减压下浓缩除去N,N-二甲基甲酰胺。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)。得到10.00克黄色固体1-(4-(苄氧基)-6-甲氧基吡唑并[1,5-a]吡啶-2-基)乙醇(收率：68.2％)。MS(ESI)M/Z：299[M+H +]。 The reaction solution was concentrated under reduced pressure to remove N,N-dimethylformamide. The residue obtained was purified by silica gel column chromatography (EtOAc:EtOAc 10.00 g of 1-(4-(benzyloxy)-6-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanol as a yellow solid was obtained (yield: 68.2%). MS (ESI) M / Z: 299 [M+H + ].
步骤G：合成1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)乙酮Step G: Synthesis of 1-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)ethanone
Figure PCTCN2019086558-appb-000106
Figure PCTCN2019086558-appb-000106
将1-(4-(苄氧基)-6-甲氧基吡唑并[1,5-a]吡啶-2-基)乙醇(15.00克，50.0毫摩尔)溶于二氯甲烷(300.0毫升)中。冰水浴下，向上述溶液中加入戴斯-马丁氧化剂(42.4克，100.0毫摩尔)。在室温下搅拌2小时。1-(4-(Benzyloxy)-6-methoxypyrazolo[1,5-a]pyridin-2-yl)ethanol (15.00 g, 50.0 mmol) was dissolved in dichloromethane (300.0 mL) )in. Dess-Martin periodinane (42.4 g, 100.0 mmol) was added to the above solution under ice-water bath. Stir at room temperature for 2 hours.
向反应液中加入饱和碳酸氢钠溶液淬灭反应。混合液用二氯甲烷(300毫升×3次)萃取。合并有机相。有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到6.00克黄色固体1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)乙酮(收率：40％)。MS(ESI)M/Z：297[M+H +]。 The reaction was quenched by adding a saturated sodium hydrogencarbonate solution to the mixture. The mixture was extracted with dichloromethane (300 mL×3×). Combine the organic phases. The organic phase was washed with saturated brine (100 ml × 3×), then dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1). There was obtained 6.00 g of a yellow solid 1-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)ethanone (yield: 40%). MS (ESI) M / Z: 297 [M+H + ].
步骤H：合成1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴乙酮Step H: Synthesis of 1-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoethyl ketone
Figure PCTCN2019086558-appb-000107
Figure PCTCN2019086558-appb-000107
详见实施例3，步骤G。1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)乙酮(6.00克，20.3毫摩尔)，N,N-二异丙基乙胺(10.5克，81.2毫摩尔)，三氟甲磺酸三甲基硅酯(13.5克，60.9毫摩尔)，二氯甲烷(100.0毫升)，N-溴代丁二酰亚胺(3.61克，20.3毫摩尔)，四氢呋喃(200.0毫升)。得到4.00克黄色固体1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴乙酮(收率：52.6％)。MS(ESI)M/Z：375,377[M+H +]。 See Example 3, Step G for details. 1-(4-(Benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)ethanone (6.00 g, 20.3 mmol), N,N-diisopropylethylamine (10.5 g, 81.2 mmol), trimethylsilyl trifluoromethanesulfonate (13.5 g, 60.9 mmol), dichloromethane (100.0 mL), N-bromosuccinimide (3.61 g, 20.3) Millimol), tetrahydrofuran (200.0 ml). There was obtained 4.00 g of 1-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoethyl ketone as a yellow solid (yield: 52.6%). MS (ESI) M/Z: 375, 377 [M+H + ].
步骤I：合成6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑Step I: Synthesis of 6-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1,3 , 4] thiadiazole
Figure PCTCN2019086558-appb-000108
Figure PCTCN2019086558-appb-000108
详见实施例3，步骤H。1-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴乙酮(200毫克，0.53毫摩尔)，5-bromo-1,3,4-thiadiazol-2-amine(190毫克，1.06毫摩尔)，异丙醇(10.0毫升)。得到75毫克黄色固体6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(收率：31％)。MS(ESI)M/Z：456,458[M+H +]。 See Example 3, Step H for details. 1-(4-(Benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoethyl ketone (200 mg, 0.53 mmol), 5-bromo-1, 3,4-thiadiazol-2-amine (190 mg, 1.06 mmol), isopropanol (10.0 mL). Yield 75 mg of yellow solid 6-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1, 3,4]thiadiazole (yield: 31%). MS (ESI) M/Z: 456, 458 [M+H + ].
步骤J：合成6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Step J: Synthesis of 6-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1 ,3,4]thiadiazole
Figure PCTCN2019086558-appb-000109
Figure PCTCN2019086558-appb-000109
详见实施例5，步骤I。6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(1.5克，3.3毫摩尔)，叔丁醇钾(400毫克，3.6毫摩尔)，二氯甲烷(140毫升)，甲醇(70毫升)。得到1.20克黄色固体6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑。无需纯化，直接用于下步反应。MS(ESI)M/Z：408[M+H +]。 See Example 5, Step I for details. 6-(4-(Benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiophene Diazole (1.5 g, 3.3 mmol), potassium tert-butoxide (400 mg, 3.6 mmol), dichloromethane (140 mL) 1.20 g of a yellow solid 6-(4-(benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][ 1,3,4]thiadiazole. It is used directly in the next step without purification. MS (ESI) M/Z: 408 [M+H + ].
步骤K：合成6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇Step K: Synthesis of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] pyridin-4-ol
Figure PCTCN2019086558-appb-000110
Figure PCTCN2019086558-appb-000110
在氮气保护下，6-(4-(苄氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(608毫克，1.49毫摩尔)和五甲基苯(1.51克，10.4毫摩尔)溶于二氯甲烷(250.0毫升)中。在-78摄氏度下向上述溶液中缓慢滴加三氯化硼(3.87毫升，3.87毫摩尔，1.0摩尔/升)。在-78摄氏度下搅拌1小时。6-(4-(Benzyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][ under nitrogen protection 1,3,4]thiadiazole (608 mg, 1.49 mmol) and pentamethylbenzene (1.51 g, 10.4 mmol) were dissolved in dichloromethane (250.0 mL). Boron trichloride (3.87 ml, 3.87 mmol, 1.0 mol/l) was slowly added dropwise to the above solution at -78 °C. Stir at -78 degrees Celsius for 1 hour.
向反应体系中加入甲醇(10毫升)淬灭反应。将反应液升至室温，并减压浓缩。粗产品用反相柱纯化[反相柱:C18；流动相A：水(含有0.05％甲酸)，流动相B：乙腈；梯度:30％乙腈到90％乙腈在8分钟内；检测波长：254nm]收集馏分，直接低温冻干。得到300毫克黄色固体6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(收率：63.5％)；MS(ESI)M/Z：318[M+H +]。 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 The fractions were collected and directly lyophilized. Yield 300 mg of yellow solid 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 - a] pyridin-4-ol (yield: 63.5%); MS (ESI) M/Z: 318 [M+H + ].
步骤L：合成4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)吗啉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
Figure PCTCN2019086558-appb-000111
Figure PCTCN2019086558-appb-000111
在室温和氮气保护下，将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(24毫克，0.112毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中依次加入三丁基膦(240毫克，2.4毫摩尔)和偶氮二甲酰二哌啶(75毫克，0.285毫摩尔)。在室温下搅拌1小时。6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-ol (24 mg, 0.112 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (240 mg, 2.4 mmol) and azodiyldipiperidine (75 mg, 0.285 mmol) were successively added to the above solution. Stir at room temperature for 1 hour.
向反应液中加入水(1毫升)淬灭反应。混合液用乙酸乙酯(5毫升×3次)萃取。合并有机相。有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的TFA)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从5％升到100％；检测波长：254nm。纯化后，低温冻干得2.4毫克白色固体4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)吗啉(收率：)。MS(ESI)M/Z：514[M+H +]。 1H NMR(300MHz,CDCl 3，ppm)δ7.98(s,1H),7.78(s,1H),6.93(s,1H),6.46(s,1H),5.08(s,2H),4.22(s,3H),3.84-3.69(m,7H),3.51-3.36(m,4H),2.39(s,3H)。 Water (1 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (5 mL×3×). Combine the organic phases. The organic phase was washed with saturated brine (10 mL×3×) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes Detection wavelength: 254 nm. After purification, lyophilization at low temperature gave 2.4 mg of white solid 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thia) Zyrid-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)morpholine (yield:). MS (ESI) M / Z: 514 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm) δ7.98 (s, 1H), 7.78 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 5.08 (s, 2H), 4.22 ( s, 3H), 3.84 - 3.69 (m, 7H), 3.51-3.36 (m, 4H), 2.39 (s, 3H).
实施例18Example 18
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基亚磺酰基)咪唑并[2,1-b][1,3,4]噻二唑Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfinyl)imidazo[2,1-b][1,3, 4]thiadiazole
Figure PCTCN2019086558-appb-000112
Figure PCTCN2019086558-appb-000112
步骤A：合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基亚磺酰基)咪唑并[2,1-b][1,3,4]噻二唑Step A: Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfinyl)imidazo[2,1-b][1 ,3,4]thiadiazole
Figure PCTCN2019086558-appb-000113
Figure PCTCN2019086558-appb-000113
将(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲硫基)咪唑并[2,1-b][1,3,4]噻二唑(90毫克，0.259毫摩尔)溶于四氢呋喃(10毫升)中。向体系中加入间氯过氧苯甲酸(90毫克，0.518毫摩尔)。在室温下搅拌4小时。LCMS监测显示原料消失后，向体系中加入饱和碳酸氢钠溶液(10毫升)淬灭反应。混合液用乙酸乙酯(20毫升X2)萃取。合并后的有机相先用饱和盐水(20毫升)反洗，然后用无水硫酸钠干燥，最后真空浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的甲酸)和乙腈；流速：25毫升/分钟； 梯度：在7分钟内，乙腈从5％升到100％；检测波长：254nm。纯化后,低温冻干得到白色固体(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(甲基亚磺酰基)咪唑并[2,1-b][1,3,4]噻二唑(16.1毫克,17.1％)。MS(ESI)M/Z：364[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.44(s,1H),7.95(s,1H),7.06(s,1H),6.36(s,1H),4.00(s,3H),3.88(s,3H),3.17(s,3H)。 (4,6-Dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylthio)imidazo[2,1-b][1,3,4] Thiadiazole (90 mg, 0.259 mmol) was dissolved in tetrahydrofuran (10 mL). To the system was added m-chloroperoxybenzoic acid (90 mg, 0.518 mmol). Stir at room temperature for 4 hours. After LCMS monitoring showed the disappearance of the starting material, a saturated sodium bicarbonate solution (10 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (20 mL EtOAc). The combined organic phases were washed with saturated brine (20 mL) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes Detection wavelength: 254 nm. After purification, lyophilization at low temperature gave a white solid (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-2-(methylsulfinyl)imidazo[2,1 -b][1,3,4]thiadiazole (16.1 mg, 17.1%). MS (ESI) M / Z: 364 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.44 (s, 1H), 7.95 (s, 1H), 7.06 (s, 1H), 6.36 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.17 (s, 3H).
实施例19Example 19
合成4-(3-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)丙基)吗啉Synthesis of 4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)propyl)morpholine
Figure PCTCN2019086558-appb-000114
Figure PCTCN2019086558-appb-000114
步骤A：4-(3-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)丙基)吗啉Step A: 4-(3-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole And [1,5-a]pyridin-4-yl)oxy)propyl)morpholine
Figure PCTCN2019086558-appb-000115
Figure PCTCN2019086558-appb-000115
详见实施例17，步骤L。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(30毫克，0.09毫摩尔)，3-吗啉代丙-1-醇(26毫克，0.18毫摩尔)，三丁基膦(364毫克，1.8毫摩尔)，偶氮二甲酰二哌啶(113毫摩尔，0.45毫摩尔)，四氢呋喃(3毫升)。得到3.2毫克白色固体4-(3-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基基)氧基)丙基)吗啉(收率：8.0％)。MS(ESI)M/Z:445[M+H +]。 1H NMR(300MHz,CDCl 3，ppm):δ8.01(s,1H),7.77(s,1H),6.93(s,1H),6.24(s,1H),4.23(s,3H),4.18(t,J＝6.0Hz,2H)，3.97–3.84(m,7H),2.87–2.69(m,6H),2.19(br,2H)。 See Example 17, Step L for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-alcohol (30 mg, 0.09 mmol), 3-morpholinopropan-1-ol (26 mg, 0.18 mmol), tributylphosphine (364 mg, 1.8 mmol), azodicarboxylate Piperidine (113 mmol, 0.45 mmol), tetrahydrofuran (3 mL). Obtained 3.2 mg of white solid 4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)) Pyrazolo[1,5-a]pyridin-4-yl)oxy)propyl)morpholine (yield: 8.0%). MS (ESI) M/Z: 445 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.01 (s, 1H), 7.77 (s, 1H), 6.93 (s, 1H), 6.24 (s, 1H), 4.23 (s, 3H), 4.18 (t, J = 6.0 Hz, 2H), 3.97 - 3.84 (m, 7H), 2.87 - 2.69 (m, 6H), 2.19 (br, 2H).
实施例20Example 20
合成6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑Synthesis of 6-(6-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)ethoxy)pyrazolo[1,5-a]pyridin-2-yl )-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000116
Figure PCTCN2019086558-appb-000116
步骤A：合成2-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)-四氢-2H-吡喃Step A: Synthesis of 2-(2-((tetrahydro-2H-pyran-4-yl)methoxy)ethoxy)-tetrahydro-2H-pyran
Figure PCTCN2019086558-appb-000117
Figure PCTCN2019086558-appb-000117
在冰水浴下，将四氢-2H-吡喃-4-基)甲醇(5.00克，43.1毫摩尔)溶于N,N-二甲基甲酰胺溶液(150.0毫升)中。随后，向上述溶液中分批次加入氢化钠(4.31克，107.8毫摩尔)。在0摄氏度下搅拌15分钟。然后，向其中加入2-(2-溴乙氧基)-四氢-2H-吡喃(9.26克，45.3毫摩尔)的N,N-二甲基甲酰胺溶液(50.0毫升)。在0摄氏度下搅拌1小时。Tetrahydro-2H-pyran-4-yl)methanol (5.00 g, 43.1 mmol) was dissolved in N,N-dimethylformamide (150.0 mL). Subsequently, sodium hydride (4.31 g, 107.8 mmol) was added in portions to the above solution. Stir at 0 degrees Celsius for 15 minutes. Then, a solution of 2-(2-bromoethoxy)-tetrahydro-2H-pyran (9.26 g, 45.3 mmol) in N,N-dimethylformamide (50.0 ml) was added. Stir at 0 ° C for 1 hour.
向反应液中加入冰水(200.0毫升)淬灭反应。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/9)。得到3.89克无色油状物2-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)-四氢-2H-吡喃(收率：37.0％)。MS(ESI)M/Z：245[M+H +]。 The reaction solution was quenched by adding ice water (200.0 ml). The mixture was extracted with ethyl acetate (200 mL×3×). The combined organic layers were washed with brine (100 mL×3×) then dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAcEtOAc There was obtained 3.89 g of 2-(2-((tetrahydro-2H-pyran-4-yl)methoxy)ethoxy)-tetrahydro-2H-pyran as a colorless oil (yield: 37.0%). MS (ESI) M / Z: 245 [M+H + ].
步骤B：合成2-((四氢-2H-吡喃-4-基)甲氧基)乙醇Step B: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethanol
Figure PCTCN2019086558-appb-000118
Figure PCTCN2019086558-appb-000118
将2-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)-四氢-2H-吡喃(3.89克，15.9毫摩尔)溶于甲醇(100.0毫升)中。随后，向上述溶液中滴加盐酸的异丙醇溶液(90.0毫摩尔，15.0毫升，8.0摩尔/升)。在室温下搅拌30分钟。2-(2-((Tetrahydro-2H-pyran-4-yl)methoxy)ethoxy)-tetrahydro-2H-pyran (3.89 g, 15.9 mmol) was dissolved in methanol (100.0 mL) )in. Subsequently, a solution of hydrochloric acid in isopropanol (90.0 mmol, 15.0 ml, 8.0 mol/liter) was added dropwise to the above solution. Stir at room temperature for 30 minutes.
向反应液中加入饱和碳酸氢钠(30毫升)淬灭反应。混合液用乙酸乙酯(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到2.20克无色油状物2-((四氢-2H-吡喃-4-基)甲氧基)乙醇(收率：86.6％)。MS(ESI)M/Z：161[M+H +]。 The reaction was quenched by the addition of saturated sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic layers were washed with brine (100 mL×3×) then dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAc EtOAc There was obtained 2.20 g of 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethanol as a colorless oil (yield: 86.6%). MS (ESI) M / Z: 161 [M+H + ].
步骤C：合成2-((四氢-2H-吡喃-4-基)甲氧基)乙基4-甲基苯磺酸酯Step C: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethyl 4-methylbenzenesulfonate
Figure PCTCN2019086558-appb-000119
Figure PCTCN2019086558-appb-000119
在冰水浴下，将2-((四氢-2H-吡喃-4-基)甲氧基)乙醇(1.50克,9.38毫摩尔)和三乙胺(2.84克，28.1毫摩尔)溶于二氯甲烷(50.0毫升)中。随后，向上述溶液中加入p-对甲苯磺酰氯(2.67克，14.1毫摩尔)。在室温下搅拌2小时。In an ice water bath, 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethanol (1.50 g, 9.38 mmol) and triethylamine (2.84 g, 28.1 mmol) were dissolved in two In methyl chloride (50.0 ml). Subsequently, p-p-toluenesulfonyl chloride (2.67 g, 14.1 mmol) was added to the above solution. Stir at room temperature for 2 hours.
向反应液中加入饱和碳酸氢钠溶液(10毫升)淬灭反应。混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得到670毫克黄色油状物2-((四氢-2H-吡喃-4-基)甲氧基)乙基4-甲基苯磺酸酯(收率：22.7％)。The reaction mixture was quenched by the addition of saturated sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with brine (50 mL×3×) and dried over anhydrous sodium sulfate. The obtained residue was purified to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/4). There was obtained 670 mg of a yellow oil of 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (yield: 22.7%).
步骤D：合成6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑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
Figure PCTCN2019086558-appb-000120
Figure PCTCN2019086558-appb-000120
将6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(27毫克，0.084毫摩尔)溶于乙腈(2.5毫升)中。随后，向上述溶液中加入2-((四氢-2H-吡喃-4-基)甲氧基)乙基4-甲基苯磺酸酯(36毫克，0.115毫摩尔)和无水碳酸钾(36毫克，0.261毫摩尔)。将反应液加热至70摄氏度，并搅拌1小时。6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4 - Alcohol (27 mg, 0.084 mmol) was dissolved in acetonitrile (2.5 mL). Subsequently, 2-((tetrahydro-2H-pyran-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (36 mg, 0.115 mmol) and anhydrous potassium carbonate were added to the above solution. (36 mg, 0.261 mmol). The reaction solution was heated to 70 ° C and stirred for 1 hour.
将反应液冷却至室温，并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)。得到4.5毫克白色固体6-(6-氯-4-(2-((四氢-2H-吡喃-4-基)甲氧基)乙氧基)吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(收率：11.6％)MS(ESI)M/Z:464[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.18(s,1H),8.04(s,1H),7.02(s,1H),6.43(s,1H),4.28(t,J＝4.5Hz,2H),4.23(s,3H),4.02(d,J＝3.9Hz,2H),3.98(d,J＝3.9Hz,2H),3.89(t,J＝4.5Hz,2H),3.45-3.38(m,4H),1.78-1.67(m,2H),1.44-1.31(m,3H)。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1). Obtained 4.5 mg of white solid 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 (yield: 11.6%) MS (ESI) M/Z: 464 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.18 (s, 1H), 8.04 (s, 1H), 7.02 (s, 1H), 6.43 (s, 1H), 4.28 (t, J = 4.5Hz , 2H), 4.23 (s, 3H), 4.02 (d, J = 3.9 Hz, 2H), 3.98 (d, J = 3.9 Hz, 2H), 3.89 (t, J = 4.5 Hz, 2H), 3.45-3.38 (m, 4H), 1.78-1.67 (m, 2H), 1.44-1.31 (m, 3H).
实施例21Example 21
合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N，N-二甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N,N-dimethylimidazo[2,1-b][1,3,4] Thiadiazole-2-amine
Figure PCTCN2019086558-appb-000121
Figure PCTCN2019086558-appb-000121
步骤A：合成(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N，N-二甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺Step A: Synthesis of (4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)-N,N-dimethylimidazo[2,1-b][1,3 , 4] thiadiazol-2-amine
Figure PCTCN2019086558-appb-000122
Figure PCTCN2019086558-appb-000122
将2-溴-6-(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(80毫克，0.210毫摩尔)溶于乙醇(20毫升)中。向体系中加入二甲胺的四氢呋喃溶液(0.21毫升，0.42毫摩尔，2.0摩尔/升)。在80摄氏度下搅拌2小时。TLC监测显示原料消失后，将体系冷却到室温并真空浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从5％升到100％；检测波长：254nm。减压冻干，纯化后，低温冻干得到白色固体(4,6-二甲氧基吡唑并[1,5-a]吡啶-2-基)-N，N-二甲基咪唑并[2,1-b][1,3,4]噻二唑-2-胺(16.1毫克，22.2％)。MS(ESI)M/Z：345[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ7.92(s,1H),7.78(s,1H),7.03(s,1H),6.25(s,1H),3.96(s,3H),3.85(s,3H),3.18(s,6H)。 2-Bromo-6-(4,6-dimethoxypyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadi The azole (80 mg, 0.210 mmol) was dissolved in ethanol (20 mL). A solution of dimethylamine in tetrahydrofuran (0.21 mL, 0.42 mmol, 2.0 mol/L) was added to the system. Stir at 80 ° C for 2 hours. After TLC monitoring showed disappearance of the starting material, the system was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography. 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 + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ7.92 (s, 1H), 7.78 (s, 1H), 7.03 (s, 1H), 6.25 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.18 (s, 6H).
实施例22Example 22
合成4-(3-(6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)丙基)吗啉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
Figure PCTCN2019086558-appb-000123
Figure PCTCN2019086558-appb-000123
步骤A：合成4-(3-(6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)丙基)吗啉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
Figure PCTCN2019086558-appb-000124
Figure PCTCN2019086558-appb-000124
参见实施例9(从步骤A到步骤I)的合成。将6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(50毫克，0.16毫摩尔)，4-(3-溴丙基)吗啉(55毫克，0.27毫摩尔)和无水碳酸钾(83毫克，0.60毫摩尔)加入乙腈(4.0毫升)中。将反应液加热至70摄氏度，并搅拌1小时。See the synthesis of Example 9 (from step A to step I). 6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4 - Alcohol (50 mg, 0.16 mmol), 4-(3-bromopropyl)morpholine (55 mg, 0.27 mmol) and anhydrous potassium carbonate (83 mg, 0.60 mmol). . The reaction solution was heated to 70 ° C and stirred for 1 hour.
将反应液冷却到室温。过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/9)。得到5.5毫克白色固体4-(3-(6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)丙基)吗啉(收率：7.90％)。MS(ESI)M/Z:449[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.17(s,1H),8.03(s,1H),6.99(s,1H),6.43(s,1H),4.24(s,3H),4.22-4.18(m,2H),3.85-3.73(m,4H),2.70-2.43(m,6H)，2.19-2.04(m,2H)。 The reaction solution was cooled to room temperature. After filtration, the obtained filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc Obtained 5.5 mg of white solid 4-(3-(6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)propyl)morpholine (yield: 7.90%). MS (ESI) M / Z: 449 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.17 (s, 1H), 8.03 (s, 1H), 6.99 (s, 1H), 6.43 (s, 1H), 4.24 (s, 3H), 4.22 - 4.18 (m, 2H), 3.85-3.73 (m, 4H), 2.70-2.43 (m, 6H), 2.19-2.04 (m, 2H).
实施例23Example 23
合成6-(4-(2-(4,4-二氟哌啶-1-基)乙氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-B][1,3,4]噻二唑Synthesis of 6-(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-yl Oxyimidazo[2,1-B][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000125
Figure PCTCN2019086558-appb-000125
步骤A：2-(4,4-二氟哌啶-1-基)乙醇Step A: 2-(4,4-Difluoropiperidin-1-yl)ethanol
Figure PCTCN2019086558-appb-000126
Figure PCTCN2019086558-appb-000126
详见实施例14，步骤A。4,4-二氟哌啶(382毫克，3.16毫摩尔)，乙腈(20.0毫升)，无水碳酸钾(872毫克，6.32毫摩尔)，2-溴乙醇(790毫克，6.32毫摩尔)。得到300毫克黄色油状2-(4,4-二氟哌啶-1-基)乙醇(收率：57％)。MS(ESI)M/Z：166[M+H +]。 See Example 14, Step A for details. 4,4-Difluoropiperidine (382 mg, 3.16 mmol), acetonitrile (20.0 ml), anhydrous potassium carbonate (872 mg, 6.32 mmol), 2-bromoethanol (790 mg, 6.32 mmol). There was obtained 300 mg of 2-(4,4-difluoropiperidin-1-yl)ethanol as a yellow oil (yield: 57%). MS (ESI) M / Z: 166 [M+H + ].
步骤B：合成6-(4-(2-(4,4-二氟哌啶-1-基)乙氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-B][1,3,4]噻二唑Step B: Synthesis of 6-(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-6-methoxy[1,5-a]pyridin-2-yl)- 2-methoxyimidazo[2,1-B][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000127
Figure PCTCN2019086558-appb-000127
在室温和氮气保护下，向四氢呋喃(5.0毫升)中依次加入偶氮二甲酰二哌啶(496毫克，1.97毫摩尔)和三丁基膦(636毫克，3.15毫摩尔)。在室温下搅拌20分钟。随后，向上述溶液中缓慢滴加6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(66毫克，0.21毫摩尔)和2-(4,4-二氟哌啶-1-基)乙醇(102毫克，0.62毫摩尔)的四氢呋喃(10.0毫升)。在室温下搅拌3小时。Azodiyldipiperidine (496 mg, 1.97 mmol) and tributylphosphine (636 mg, 3.15 mmol) were added sequentially to tetrahydrofuran (5.0 mL) at room temperature under nitrogen. Stir at room temperature for 20 minutes. Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole was slowly added dropwise to the above solution. [1,5-a]pyridin-4-ol (66 mg, 0.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)ethanol (102 mg, 0.62 mmol) of tetrahydrofuran (10.0 ML). Stir at room temperature for 3 hours.
将反应液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝3/97)。收集产品用N,N-二甲基甲酰胺(4.0毫升)溶至澄清。粗产品用高效液相制备，制备条件：色谱柱：X select C1819mm*150mm；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从25％升到50％；检测波长：254nm。减压冻干，得到8.8毫克白色固体6-(4-(2-(4,4-二氟哌啶-1-基)乙氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-B][1,3,4]噻二唑(收率：9.03％)。MS(ESI)M/Z：465[M+H +]。 1H NMR(300MHz,CDCl 3,ppm):δ8.01(s,1H),7.78(s,1H),6.91(s,1H),6.23(s,1H),4.26-4.23(m,5H),3.84(s,3H),3.04–3.00(m,2H),2.84–2.77(m,4H),2.13–2.04(m,4H)。 The reaction solution was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcEtOAc The product was dissolved in clarified with N,N-dimethylformamide (4.0 mL). The crude product was prepared by high performance liquid phase. Preparation conditions: column: X select C1819mm*150mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: within 25 minutes, Acetonitrile was raised from 25% to 50%; detection wavelength: 254 nm. Lyophilized under reduced pressure to give 8.8 mg of white solid 6-(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-6-methoxy[1,5-a]pyridine. 2-yl)-2-methoxyimidazo[2,1-B][1,3,4]thiadiazole (yield: 9.03%). MS (ESI) M / Z: 465 [M+H + ]. 1 H NMR (300MHz, CDCl 3 , ppm): δ8.01 (s, 1H), 7.78 (s, 1H), 6.91 (s, 1H), 6.23 (s, 1H), 4.26-4.23 (m, 5H) , 3.84 (s, 3H), 3.04 - 3.00 (m, 2H), 2.84 - 2.77 (m, 4H), 2.13 - 2.04 (m, 4H).
实施例24：SAL02-142Example 24: SAL02-142
2-甲氧基-6-(6-甲氧基-4-((5-甲基-2-(4-甲基哌嗪-1-基)噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)methoxy)pyrazole And [1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000128
Figure PCTCN2019086558-appb-000128
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000129
Figure PCTCN2019086558-appb-000129
实施例24流程：Example 24 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(38毫克，0.15毫摩尔)和三丁基膦(48毫克，0.24毫摩尔)溶于四氢呋喃(1.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(5毫克，0.02毫摩尔)和(5-甲基-2-(4-甲基哌嗪-1-基)噻唑-4-基)甲醇(7毫克，0.03毫摩尔)的四氢呋喃溶液(1.0毫升)。反应液在室温下搅拌3小时。Step A: Azodiyldipiperidine (38 mg, 0.15 mmol) and tributylphosphine (48 mg, 0.24 mmol) were dissolved in tetrahydrofuran (1.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution. , 5-a]pyridin-4-ol (5 mg, 0.02 mmol) and (5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)methanol (7 mg, 0.03 mmol) in tetrahydrofuran (1.0 mL). The reaction solution was stirred at room temperature for 3 hours.
LCMS监测显示原料消失后，反应液在减压下浓缩。粗产品通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝97/3)，收集产品。粗产品进一步用制备型高效液相色谱纯化。制备条件如下：色谱柱：Xselect C18 19mm*150mm；流动相：水(含有0.05％碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。纯化后，低温冻干得白色固体2-甲氧基-6-(6-甲氧基-4-((5-甲基-2-(4-甲基哌嗪-1-基)噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(7.2毫克，收率86.8％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: methylene chloride/methanol=97/3). The crude product was further purified by preparative high performance liquid chromatography. The preparation conditions were as follows: column: Xselect C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 80% in 7 minutes Detection wavelength: 254 nm. After purification, freeze-drying to give a white solid 2-methoxy-6-(6-methoxy-4-((5-methyl-2-(4-methylpiperazin-1-yl)thiazole-4) -yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (7.2 mg, yield 86.8%) ).
MS(ESI)M/Z:527[M+H +]. MS (ESI) M/Z: 527 [M+H + ].
1H NMR(300MHz,DMSO-d 6):δ8.31(s,1H),8.04(s,1H),6.73(s,1H),6.66(s,1H),5.05(s,2H),4.20(s,3H),3.81(s,3H),3.33(m,4H),2.40(m,4H),2.33(s,3H),2.21(s,3H). 1 H NMR (300MHz, DMSO- d 6): δ8.31 (s, 1H), 8.04 (s, 1H), 6.73 (s, 1H), 6.66 (s, 1H), 5.05 (s, 2H), 4.20 (s, 3H), 3.81 (s, 3H), 3.33 (m, 4H), 2.40 (m, 4H), 2.33 (s, 3H), 2.21 (s, 3H).
实施例25：SAL02-287Example 25: SAL02-287
2-甲氧基-6-(6-甲氧基-4-(2,2,2-三氟乙氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2 , 1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000130
Figure PCTCN2019086558-appb-000130
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000131
Figure PCTCN2019086558-appb-000131
实施例25流程：Example 25 process:
步骤A：在室温下，将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(150毫克，0.47毫摩尔)溶于N,N-二甲基甲酰胺(20.0毫升)中。随后，向上述溶液中依次加入2,2,2-三氟乙基三氟甲磺酸(219毫克，0.94毫摩尔)和无水碳酸钾(130毫克，0.94毫摩尔)。反应液在室温下搅拌过夜。Step A: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-ol (150 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (20.0 mL). Subsequently, 2,2,2-trifluoroethyltrifluoromethanesulfonic acid (219 mg, 0.94 mmol) and anhydrous potassium carbonate (130 mg, 0.94 mmol) were sequentially added to the above solution. The reaction was stirred at room temperature overnight.
LCMS监测显示原料消失后，向上述溶液中加入水(20毫升)淬灭反应。混合液用乙酸乙酯(20 毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品用制备型高效液相色谱纯化。制备条件如下。色谱柱：Xselect C18 19mm*150mm；流动相：水(含有0.05％氨水)和乙腈；流速：25毫升/分钟；梯度：在11分钟内，乙腈从53％升到60％；检测波长：254nm。纯化后，低温冻干得白色固体2-甲氧基-6-(6-甲氧基-4-(2,2,2-三氟乙氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(59.0毫克，收率31.3％)。After LCMS monitoring showed disappearance of the starting material, water (20 mL) was added to the above solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The crude product was purified by preparative high performance liquid chromatography. The preparation conditions are as follows. Column: Xselect C18 19mm*150mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 53% to 60% in 11 minutes; detection wavelength: 254 nm. After purification, freeze-drying to give a white solid 2-methoxy-6-(6-methoxy-4-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine 2-yl)imidazo[2,1-b][1,3,4]thiadiazole (59.0 mg, yield 31.3%).
MS(ESI)M/Z:400[M+H +]。 MS (ESI) M/Z: 400 [M+H + ].
1H NMR(300MHz,DMSO-d 6):δ8.35(s,1H),8.15(s,1H),6.78(s,1H),6.74(s,1H),5.00-4.95(m,2H),4.21(s,3H),3.83(s,3H). 1 H NMR (300MHz, DMSO- d 6): δ8.35 (s, 1H), 8.15 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 5.00-4.95 (m, 2H) , 4.21 (s, 3H), 3.83 (s, 3H).
19F NMR(282MHz,DMSO-d 6)：72.48. 19 F NMR (282 MHz, DMSO-d 6 ): 72.48.
实施例26：SAL02-293Example 26: SAL02-293
6-(4-(环丙基甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-(cyclopropylmethoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1, 3,4]thiadiazole
Figure PCTCN2019086558-appb-000132
Figure PCTCN2019086558-appb-000132
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000133
Figure PCTCN2019086558-appb-000133
实施例26流程：Example 26 process:
步骤A：在室温下，将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(150毫克，0.47毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入(溴甲基)环丙烷(2.60克，19.3毫摩尔)和无水碳酸钾(196毫克，1.42毫摩尔)。反应液在室温下搅拌过夜。Step A: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-ol (150 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, (bromomethyl)cyclopropane (2.60 g, 19.3 mmol) and anhydrous potassium carbonate (196 mg, 1.42 mmol) were sequentially added to the above solution. The reaction was stirred at room temperature overnight.
LCMS监测显示原料消失后，向上述溶液中加入水(10毫升)淬灭。混合液用乙酸乙酯萃取(20毫升×3次)。有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用制备型高效液相色谱纯化。制备条件如下，色谱柱：Xselect C18 19mm*150mm；流动相：水(含有0.05％氨水)和乙腈；流速：25毫升/分钟；梯度：在11分钟内，乙腈从53％升到60％；检测波长：254nm。纯化后，低温冻干得6-白色固体(4-(环丙基甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(26.7毫克，收率15.2％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the above solution to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate The residue was purified by preparative high performance liquid chromatography. The preparation conditions were as follows, column: Xselect C18 19mm*150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 53% to 60% in 11 minutes; Wavelength: 254 nm. After purification, lyophilization at low temperature gave 6-white solid (4-(cyclopropylmethoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[ 2,1-b][1,3,4]thiadiazole (26.7 mg, yield 15.2%).
MS(ESI)M/Z：372[M+H +]。 MS (ESI) M / Z: 372 [M+H + ].
1H NMR(300MHz,DMSO-d 6)：δ8.33(s,1H),8.01(s,1H),6.77(s,1H),6.44(s,1H),4.20(s,3H),4.00(m,2H),3.80(s,3H),1.31(m,1H),0.63(m,2H),0.39(m,2H). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.33 (s, 1H), 8. s (s, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 4.20 (s, 3H), 4.00 (m, 2H), 3.80 (s, 3H), 1.31 (m, 1H), 0.63 (m, 2H), 0.39 (m, 2H).
实施例27：SAL02-294Example 27: SAL02-294
2-甲氧基-6-(6-甲氧基-4-(噻唑-5-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-(thiazol-5-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1- b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000134
Figure PCTCN2019086558-appb-000134
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000135
Figure PCTCN2019086558-appb-000135
实施例27流程：Example 27 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(710毫克，2.84毫摩尔)溶于四氢呋喃(12.0毫升)中。随后，向上述溶液中加入三丁基膦(367毫克，1.82毫摩尔)。反应液在室温下搅拌20分钟后，再向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(120毫克，0.38毫摩尔)和1,3-噻唑-5-基甲醇(65毫克，0.57毫摩尔)的四氢呋喃溶液(12.0毫升)。反应液在室温下搅拌1小时。Step A: Azodiyldipiperidine (710 mg, 2.84 mmol) was dissolved in tetrahydrofuran (12.0 mL). Subsequently, tributylphosphine (367 mg, 1.82 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-yl)pyrazolo[1,5-a]pyridin-4-ol (120 mg, 0.38 mmol) and 1,3-thiazol-5-ylmethanol (65 mg, 0.57 mmol) in tetrahydrofuran ( 12.0 ml). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向上述溶液中加入饱和碳酸氢钠溶液(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。残余物用制备型高效液相色谱纯化。制备条件如下，色谱柱：Xselect C18 19mm*150mm；流动相：水(含有0.05％氨水)和乙腈；流速：25毫升/分钟；梯度：在11分钟内，乙腈从50％升到60％；检测波长：254nm。纯化后，低温冻干得白色固体2-甲氧基-6-(6-甲氧基-4-(噻唑-5-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(22.0毫克，收率13.9％)。After LCMS monitoring showed the disappearance of the material, the mixture was applied to a saturated sodium hydrogen carbonate solution (20 mL). The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by preparative high performance liquid chromatography. The preparation conditions were as follows, column: Xselect C18 19mm*150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 50% to 60% in 11 minutes; Wavelength: 254 nm. After purification, freeze-drying to give a white solid 2-methoxy-6-(6-methoxy-4-(thiazol-5-ylmethoxy)pyrazolo[1,5-a]pyridine-2- Imidazo[2,1-b][1,3,4]thiadiazole (22.0 mg, yield 13.9%).
MS(ESI)M/Z:415[M+H +]。 MS (ESI) M / Z: 415 [M+H + ].
1H NMR(300MHz,CD 3OD):δ9.17(s,1H),8.31(s,1H),8.08(s,1H),8.07(s,1H),6.73(s,1H),6.71(s,1H),5.60(s,2H),4.20(s,3H),3.87(s,3H)。 1 H NMR (300MHz, CD 3 OD): δ9.17 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 6.73 (s, 1H), 6.71 ( s, 1H), 5.60 (s, 2H), 4.20 (s, 3H), 3.87 (s, 3H).
实施例28：SAL02-277Example 28: SAL02-277
6-(4-丁氧基-6-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-Butoxy-6-methoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole
Figure PCTCN2019086558-appb-000136
Figure PCTCN2019086558-appb-000136
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000137
Figure PCTCN2019086558-appb-000137
实施例28流程：Example 28 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(382毫克，1.56毫摩尔)溶于四氢呋喃 (10.0毫升)中。随后，向上述溶液中缓慢滴加三丁基膦(479毫克，2.34毫摩尔)。反应液在室温下搅拌20分钟后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基)(50毫克，0.16毫摩尔)的四氢呋喃溶液(5.0毫升)。反应液在室温下搅拌2小时。Step A: Azodiyldipiperidine (382 mg, 1.56 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (479 mg, 2.34 mmol) was slowly added dropwise 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 added to the above solution. A solution of pyrazolo[1,5-a]pyridin-4-hydroxy) (50 mg, 0.16 mmol) in tetrahydrofuran (5.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残留物用N,N-二甲基甲酰胺(3毫升)溶至澄清，经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％甲酸)和乙腈；流速:40毫升/分钟；梯度：在8分钟内，乙腈从41％升到43％；检测波长：254nm。纯化后，低温冻干得黄色固体6-(4-丁氧基-6-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(5.7毫克，收率9.7％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with EtOAc EtOAc EtOAc. The residue obtained was dissolved in EtOAc (3 mL) elute Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 40 ml / min; gradient: acetonitrile increased from 41% to 43% in 8 minutes; Detection wavelength: 254 nm. After purification, lyophilization at low temperature gave a yellow solid 6-(4-butoxy-6-methoxypyrazolo[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2, 1-b][1,3,4]thiadiazole (5.7 mg, yield 9.7%).
MS(ESI)M/Z:374[M+H +] MS (ESI) M/Z: 374 [M+H + ]
1H NMR(300MHz,CDCl 3):δ8.00(s,1H),7.76(s,1H),6.94(s,1H),6.22(s,1H),4.22(s,3H),4.09(t,J＝6.6Hz,2H),3.84(s,3H),1.94-1.79(m,2H),1.59-1.53(m,2H),1.02(t,J＝7.5Hz,3H). 1 H NMR (300MHz, CDCl 3 ): δ8.00 (s, 1H), 7.76 (s, 1H), 6.94 (s, 1H), 6.22 (s, 1H), 4.22 (s, 3H), 4.09 (t , J = 6.6 Hz, 2H), 3.84 (s, 3H), 1.94-1.79 (m, 2H), 1.59-1.53 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H).
实施例29：SAL02-292Example 29: SAL02-292
6-(4-(烯丙氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-(Allyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole
Figure PCTCN2019086558-appb-000138
Figure PCTCN2019086558-appb-000138
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000139
Figure PCTCN2019086558-appb-000139
实施例29流程：Example 29 process:
步骤A：在室温下，将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入无水碳酸钾(87毫克，0.63毫摩尔)和3-溴丙烯(761毫克，6.30毫摩尔)。反应液在室温下搅拌2小时。Step A: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridine-4-hydroxy (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-bromopropene (761 mg, 6.30 mmol) were successively added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向上述溶液中加入水(30毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残留物用N,N-二甲基甲酰胺(5毫升)溶至澄清，经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在8分钟内，乙腈从49％升到54％；检测波长：254nm。收集产品，减压冻干得白色固体6-(4-(烯丙氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(29.9毫克，收率26.3％)。After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the above solution and quenched. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue obtained was dissolved in EtOAc (5 mL). Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 49% to 54 in 8 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-(4-(allyloxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2] , 1-b][1,3,4]thiadiazole (29.9 mg, yield 26.3%).
MS(ESI)M/Z：358[M+H +]. MS (ESI) M/Z: 358 [M+H + ].
1H NMR(300MHz,CDCl 3)δ8.04(s,1H),7.81(s,1H),7.00(s,1H),6.27(s,1H),6.09-6.01(m,1H),5.52(m,1H),5.38(d,J＝9.0Hz,1H),4.72-4.64(m,2H),4.24(s,3H),3.85(s,3H). 1 H NMR (300MHz, CDCl 3 ) δ8.04 (s, 1H), 7.81 (s, 1H), 7.00 (s, 1H), 6.27 (s, 1H), 6.09-6.01 (m, 1H), 5.52 ( m, 1H), 5.38 (d, J = 9.0 Hz, 1H), 4.72-4.64 (m, 2H), 4.24 (s, 3H), 3.85 (s, 3H).
实施例30：SAL02-298Example 30: SAL02-298
6-(4-((2-(4-氟环己基)噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-((2-(4-Fluorocyclohexyl)thiazol-4-yl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxy Imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000140
Figure PCTCN2019086558-appb-000140
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000141
Figure PCTCN2019086558-appb-000141
实施例30流程：Example 30 process:
步骤A：在室温下，将2-溴噻唑-4-羧酸乙酯(2.00克，8.50毫摩尔)溶于1，4-二氧六环(40.0毫升)中。随后，向上述溶液中依次加入三乙胺(3.90克，38.6毫摩尔)和4-氟哌啶盐酸盐(3.60克，25.7毫摩尔)。反应液在室温下搅拌4小时。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.
LCMS监测显示原料消失后，过滤，所得滤液在减压下浓缩。所得残余物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)，收集产品，得到黄色固体2-(4-氟环己基)噻唑-4-羧酸乙酯(2.00克，收率91.3％)。After LCMS monitoring showed disappearance of the starting material, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 2.00 g, yield 91.3%).
MS(ESI)M/Z：259[M+H +]。 MS (ESI) M / Z: 259 [M+H + ].
步骤B:在室温和氮气保护下，将2-(4-氟环己基)噻唑-4-羧酸乙酯(1.00克，3.90毫摩尔)溶于四氢呋喃(20.0毫升)中。随后，向上述溶液中分批次加入硼氢化锂(340毫克，15.5毫摩尔)和甲醇(500毫克，15.5毫摩尔)。反应液在室温下搅拌5小时。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.
LCMS监测显示原料消失后。向反应液中加入甲醇(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，收集产品，得到(2-(4-氟环己基)噻唑-4-基)甲醇(700毫克，收率82.7％)。LCMS monitoring showed disappearance of the starting material. Methanol (10 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The residue obtained was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1), and the product was collected to give (2-(4-fluorocyclohexyl)thiazol-4-yl)methanol (700 mg) , yield 82.7%).
MS(ESI)M/Z：217[M+H +]。 MS (ESI) M / Z: 217 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(781毫克，3.10毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中加入三丁基膦(970毫克，4.80毫摩尔)。反应液在室温下搅拌20分钟。随后，向上述溶液中加入(2-(4-氟环己基)噻唑-4-基)甲醇(138毫克，0.64毫摩尔)和 6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)的四氢呋喃(3.0毫升)溶液。反应液在室温下搅拌2小时。Step C: Azodiyldipiperidine (781 mg, 3.10 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (970 mg, 4.80 mmol) was added to the above solution. The reaction was stirred at room temperature for 20 minutes. Subsequently, (2-(4-fluorocyclohexyl)thiazol-4-yl)methanol (138 mg, 0.64 mmol) and 6-methoxy-2-(2-methoxyimidazo[ 2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4-hydroxy (100 mg, 0.32 mmol) in tetrahydrofuran (3.0 mL) Solution. The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(5毫升)淬灭反应。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在8分钟内，乙腈从46％升到56％；检测波长：254nm。收集产品，低温冻干得白色固体6-(4-((2-(4-氟环己基)噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(29.3毫克，收率17.7％)After LCMS monitoring showed the disappearance of the starting material, a saturated sodium bicarbonate solution (5 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 46% to 56 in 8 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-(4-((2-(4-fluorocyclohexyl)thiazol-4-yl)methoxy)-6-methoxy[1,5-a]pyridine as a white solid. 2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (29.3 mg, yield 17.7%)
MS(ESI)M/Z：515[M+H +]. MS (ESI) M/Z: 515 [M+H + ].
1H NMR(400MHz,CDCl 3):δ8.02(s,1H),7.80(s,1H),7.02(s,1H),6.67(s,1H),6.42(s,1H),5.21(s,2H),5.02-4.98(m,1H),4.26(s,3H),3.84(s,3H),3.82-3.63(m,4H),2.17-2.02(m,4H). 1 H NMR (400MHz, CDCl 3 ): δ8.02 (s, 1H), 7.80 (s, 1H), 7.02 (s, 1H), 6.67 (s, 1H), 6.42 (s, 1H), 5.21 (s , 2H), 5.02-4.98 (m, 1H), 4.26 (s, 3H), 3.84 (s, 3H), 3.82-3.63 (m, 4H), 2.17-2.02 (m, 4H).
实施例31：SAL02-301Example 31: SAL02-301
6-(4-((2,2-二甲基环丙基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-((2,2-Dimethylcyclopropyl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[ 2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000142
Figure PCTCN2019086558-appb-000142
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000143
Figure PCTCN2019086558-appb-000143
实施例31流程：Example 31 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(603毫克，2.39毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基膦(329毫克，1.62毫摩尔)。反应液在室温下搅拌20分钟。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)和(2,2-二甲基环丙基)甲醇(47毫克，0.47毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌1小时。Step A: Azodiyldipiperidine (603 mg, 2.39 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (329 mg, 1.62 mmol) was added to the above solution. The reaction was stirred at room temperature for 20 minutes. Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution. , 5-a] Pyridine-4-hydroxyl (100 mg, 0.32 mmol) and (2,2-dimethylcyclopropyl)methanol (47 mg, 0.47 mmol) in tetrahydrofuran (10.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(20毫升)淬灭。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在8分钟内，乙腈从46％升到56％；检测波长：254nm。收集产品，减压冻干得6-(4-((2,2-二甲基环丙基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(21.4毫克，收率17.0％)。After LCMS monitoring showed the disappearance of the material, the mixture was evaporated to dryness with EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc. Purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 46% to 56 in 8 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-(4-((2,2-dimethylcyclopropyl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)- 2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (21.4 mg, yield 17.0%).
MS(ESI)M/Z：400[M+H +]。 MS (ESI) M/Z: 400 [M+H + ].
1H NMR(300MHz,CD 3OD)δ8.31(s,1H),8.01(s,1H),6.76(s,1H),6.48(s,1H),4.35-4.29(m,1H),4.21(s,3H),4.04-3.97(m,1H),3.87(s,3H),1.17-1.12(m,7H),0.62-0.59(m,1H),0.39-0.35(m,1H)。 1 H NMR (300 MHz, CD 3 OD) δ 8.31 (s, 1H), 8.1 (s, 1H), 6.76 (s, 1H), 6.48 (s, 1H), 4.35 - 4.29 (m, 1H), 4.21. (s, 3H), 4.04-3.97 (m, 1H), 3.87 (s, 3H), 1.17-1.12 (m, 7H), 0.62-0.59 (m, 1H), 0.39-0.35 (m, 1H).
实施例32：SAL02-296Example 32: SAL02-296
6-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-2-氧杂-6-氮杂螺[3.3]庚烷6-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane
Figure PCTCN2019086558-appb-000144
Figure PCTCN2019086558-appb-000144
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000145
Figure PCTCN2019086558-appb-000145
实施例32流程：Example 32 process:
步骤A：在室温下，将甲基-2-溴-5-甲基-噻唑-4-羧酸(1.00克，4.24毫摩尔)溶于二甲基亚砜(20.0毫升)中。随后，向上述溶液中依次加入无水碳酸钾(2.35克，17.0毫摩尔)和2-氧杂-6-氮杂螺[3.3]庚烷(851毫克，8.60毫摩尔)。反应液在120摄氏度下搅拌24小时。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.
LCMS监测显示原料消失后，将反应液冷却至室温后，向反应液中加入水(50毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/2)，得到黄色固体5-甲基-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)噻唑-4-羧酸甲酯(395毫克，收率36.9％)。After LCMS showed that the starting material had disappeared, the reaction mixture was cooled to room temperature, and then water (50 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj Methyl-6-yl)thiazole-4-carboxylate (395 mg, yield 36.9%).
MS(ESI)M/Z：255[M+H +]。 MS (ESI) M / Z: 495 [M+H + ].
步骤B：在冰水浴下，将5-甲基-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)噻唑-4-羧酸甲酯(560毫克，2.20毫摩尔)溶于四氢呋喃(20.0毫升)中。向上述溶液中分批次加入硼氢化锂(191毫克，8.80毫摩尔)。随后，向上述溶液中缓慢滴加甲醇(281毫克，8.80毫摩尔)。反应液缓慢升至室温并搅拌2小时。Step B: Methyl 5-methyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)thiazole-4-carboxylate (560 mg, 2.20 m). Mole) was dissolved in tetrahydrofuran (20.0 ml). To the above solution was added lithium borohydride (191 mg, 8.80 mmol) in portions. Subsequently, methanol (281 mg, 8.80 mmol) was slowly added dropwise to the above solution. The reaction solution was slowly warmed to room temperature and stirred for 2 hours.
LCMS监测显示原料消失后，向反应液中缓慢滴加甲醇(5毫升)和水(10毫升)淬灭反应。混合液用二氯甲烷(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)，得到白色固体(5-甲基-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)噻唑-4-基)甲醇(400毫克，收率80.5％)。After LCMS monitoring showed disappearance of the starting material, methanol (5 ml) and water (10 ml) were slowly added dropwise to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut ?hept-6-yl)thiazol-4-yl)methanol (400 mg, yield 80.5%).
MS(ESI)M/Z：227[M+H +]。 MS (ESI) M / Z: 227 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(383毫克，1.52毫摩尔)溶于四氢呋喃(10.0 毫升)中。随后，向上述溶液中加入三丁基膦(478毫克，2.36毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)和(5-甲基-2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)噻唑-4-基)甲醇(143毫克，0.63毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌2小时。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. Pyrazolo[1,5-a]pyridin-4-hydroxy (100 mg, 0.32 mmol) and (5-methyl-2-(2-oxa-6-azaspiro[3.3]heptane- A solution of 6-yl)thiazol-4-yl)methanol (143 mg, 0.63 mmol) in THF (10.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，过滤，所得滤饼用四氢呋喃(5毫升×3次)洗涤。收集滤饼，滤饼加入水(50毫升)中并搅拌30分钟。过滤，所得滤饼再用水(10毫升×3次)洗涤，收集滤饼。残余物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝40/1)，得到白色固体6-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-2-氧杂-6-氮杂螺[3.3]庚烷(19.8毫克，收率11.9％)。After LCMS monitoring showed the disappearance of the starting material, it was filtered, and the obtained cake was washed with tetrahydrofuran (5 ml × 3 times). The filter cake was collected and the filter cake was taken in water (50 mL) and stirred for 30 min. After filtration, the obtained cake was washed with water (10 ml × 3 times), and the filter cake was collected. The residue was purified by EtOAc EtOAcjjjjjjjjj And [2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methyl Thiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane (19.8 mg, yield 11.9%).
MS(ESI)M/Z：526[M+H +]。 MS (ESI) M/Z: 564 [M+H + ].
1H NMR(300MHz,CDCl 3)：δ7.98(s,1H),7.77(s,1H),6.92(s,1H),6.44(s,1H),5.09(s,2H),4.87(s,4H),4.28(s,4H),4.22(s,3H),3.84(s,3H),2.37(s,3H). 1 H NMR (300MHz, CDCl 3 ): δ7.98 (s, 1H), 7.77 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 5.09 (s, 2H), 4.87 (s , 4H), 4.28 (s, 4H), 4.22 (s, 3H), 3.84 (s, 3H), 2.37 (s, 3H).
实施例33：SAL02-299Example 33: SAL02-299
6-(4-((2-(3-氟氮杂环丁烷-1-基)噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,11-b][1,3,4]噻二唑6-(4-((2-(3-Fluoroazetidin-1-yl)thiazol-4-yl)methoxy)-6-methoxy[1,5-a]pyridine-2- 2-methoxyimidazo[2,11-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000146
Figure PCTCN2019086558-appb-000146
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000147
实施例10流程：
Figure PCTCN2019086558-appb-000147
Example 10 process:
步骤A：将2-溴噻唑-4-甲酸乙酯(910毫克，3.86毫摩尔)溶于1,4-二氧六环(20.0毫升)中。随后，向上述溶液中加入三乙胺(1.75克，17.3毫摩尔)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.
和3-氟丫丁啶盐酸盐(820毫克，7.38毫摩尔)。反应液在120摄氏度下搅拌24小时。And 3-fluoroazetidine hydrochloride (820 mg, 7.38 mmol). The reaction solution was stirred at 120 ° C for 24 hours.
LCMS监测显示原料消失后，将反应液冷却至室温。过滤，所得滤液在减压下浓缩。所得残余物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)，得到白色固体2-(3-氟氮杂环丁烷-1-基)噻唑-4-羧酸乙酯(760毫克，收率85.6％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature. After filtration, the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Ethyl acetate (760 mg, yield 85.6%).
MS(ESI)M/Z：231[M+H +]。 MS (ESI) M / Z: 231 [M+H + ].
步骤B：将2-(3-氟氮杂环丁烷-1-基)噻唑-4-羧酸乙酯(400毫克，1.74毫摩尔)溶于四氢呋喃(20.0毫升)中。将反应液冷却至0摄氏度，向上述溶液中分批次加入硼氢化锂(152毫克，7.00毫摩尔)。随后，再向其中缓慢滴加甲醇(227毫克，7.00毫摩尔)。将反应液缓慢升至室温并搅拌2小时。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.
LCMS监测显示原料消失后，向反应液缓慢加入甲醇(5毫升)淬灭。混合液用二氯甲烷(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到白色固体(2-(3-氮杂环丁烷-1-基)噻唑-4-基)甲醇(270毫克，收率82.6％)。After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was slowly quenched with methanol (5 mL). The mixture was extracted with EtOAc (EtOAc) (EtOAc) The obtained residue was purified to silicagel eluting elut elut elut elut elut elut elut elut Methanol (270 mg, yield 82.6%).
MS(ESI)M/Z：189[M+H +]。 MS (ESI) M / Z: 189 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(189毫克，0.76毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基膦(239毫克，1.18毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(50毫克，0.16毫摩尔)和(2-(3-氮杂环丁烷-1-基)噻唑-4-基)甲醇(59毫克，0.32毫摩尔)。反应液在室温下搅拌2小时。Step C: Azodiyldipiperidine (189 mg, 0.76 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (239 mg, 1.18 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. Pyrazolo[1,5-a]pyridine-4-hydroxy (50 mg, 0.16 mmol) and (2-(3-azetidin-1-yl)thiazol-4-yl)methanol ( 59 mg, 0.32 mmol). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，过滤除去不溶物。滤饼用四氢呋喃(5毫升×3次)洗涤，所得滤液在减压下浓缩。残余物用二甲基亚砜(3.0毫升)溶至澄清，经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在15分钟内，乙腈从42％升到46％；检测波长：220nm。收集产品，减压冻干得白色固体6-(4-((2-(3-氟吡咯烷-1-基)噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,11-b][1,3,4]噻二唑(27.7毫克，收率35.5％)。LCMS monitoring showed disappearance of the starting material and filtration to remove insolubles. The filter cake was washed with tetrahydrofuran (5 ml × 3 times), and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (3.0 mL) and purified and purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 42% in 15 minutes Increased to 46%; detection wavelength: 220nm. The product was collected and lyophilized to give 6-(4-((2-(3-fluoropyrrolidin-1-yl)thiazol-4-yl)methoxy)-6-methoxy[1,5 -a] Pyridin-2-yl)-2-methoxyimidazo[2,11-b][1,3,4]thiadiazole (27.7 mg, yield 35.5%).
MS(ESI)M/Z：488[M+H +]。 MS (ESI) M / Z: 488 [M+H + ].
1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.79(s,1H),7.00(s,1H),6.70(s,1H),6.35(s,1H),5.49(m,1H),5.15(s,2H),4.50-4.37(m,2H),4.35-4.24(m,2H),4.23(s,3H),3.84(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.01 (s, 1H), 7.79 (s, 1H), 7.00 (s, 1H), 6.70 (s, 1H), 6.35 (s, 1H), 5.49 (m, 1H), 5.15 (s, 2H), 4.50-4.37 (m, 2H), 4.35-4.24 (m, 2H), 4.23 (s, 3H), 3.84 (s, 3H).
19F NMR(282MHz,CDCl 3)：δ-179.4. 19 F NMR (282 MHz, CDCl 3 ): δ - 179.4.
实施例34：SAL02-302Example 34: SAL02-302
2-甲氧基-6-(6-甲氧基-4-(噻唑-4-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-(thiazol-4-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1- b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000148
Figure PCTCN2019086558-appb-000148
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000149
Figure PCTCN2019086558-appb-000149
实施例34流程：Example 34 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(363毫克，1.44毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中加入三丁基膦(436毫克，2.16毫摩尔)的四氢呋喃溶液(2.0 毫升)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(95毫克，0.30毫摩尔)和噻唑-4-基甲醇(60毫克，0.52毫摩尔)的四氢呋喃溶液(4.0毫升)。在室温下搅拌1小时。Step A: Azodiyldipiperidine (363 mg, 1.44 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, a solution of tributylphosphine (436 mg, 2.16 mmol) in tetrahydrofuran (2.0 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. A solution of pyrazolo[1,5-a]pyridin-4-ol (95 mg, 0.30 mmol) and thiazol-4-ylmethanol (60 mg, 0.52 mmol) in THF (4.0 mL). Stir at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/40)，得到淡黄色固体2-甲氧基-6-(6-甲氧基-4-(噻唑-4-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(21.9毫克，收率17.6％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified to silicagel eluting elut elut elut elut elut elut elut elut -ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (21.9 mg, yield 17.6%) .
MS(ESI)M/Z:415[M+H +]。 MS (ESI) M / Z: 415 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.88(s,1H),8.07(s,1H),7.86(s,1H),7.54(s,1H),7.08(s,1H),6.42(s,1H),5.48(s,2H),4.33(s,3H),3.85(s,3H)。 1 H NMR (300MHz, CDCl 3 ): δ8.88 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 7.08 (s, 1H), 6.42 (s , 1H), 5.48 (s, 2H), 4.33 (s, 3H), 3.85 (s, 3H).
实施例35：SAL02-305Example 35: SAL02-305
2-甲氧基-6-(6-甲氧基-4-((四氢-2H-吡喃-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl Imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000150
Figure PCTCN2019086558-appb-000150
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000151
Figure PCTCN2019086558-appb-000151
实施例35流程：Example 35 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(495毫克，1.97毫摩尔)溶于四氢呋喃(13.0毫升)中。随后，向上述溶液中加入三丁基膦(621毫克，3.08毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(130毫克，0.41毫摩尔)和4-羟甲基四氢吡喃(71毫克，0.62毫摩尔)的四氢呋喃溶液(13.0毫升)。反应液在室温下搅拌1小时。Step A: Azodiyldipiperidine (495 mg, 1.97 mmol) was dissolved in tetrahydrofuran (13.0 mL). Subsequently, tributylphosphine (621 mg, 3.08 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. a solution of pyrazolo[1,5-a]pyridin-4-ol (130 mg, 0.41 mmol) and 4-hydroxymethyltetrahydropyran (71 mg, 0.62 mmol) in tetrahydrofuran (13.0 mL) . The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用二氯甲烷(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在15分钟内，乙腈从42％升到46％；检测波长：220nm。收集产品，低温冻干得淡白色固体2-甲氧基-6-(6-甲氧基-4-((四氢-2H-吡喃-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(45.9毫克，收率26.4％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (10 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 42% in 15 minutes Increased to 46%; detection wavelength: 220nm. The product was collected and lyophilized to give a pale white solid of 2-methoxy-6-(6-methoxy-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1 , 5-a]pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (45.9 mg, yield 26.4%).
MS(ESI)M/Z：416[M+H] +. MS (ESI) M/Z: 416 [M+H] + .
1H NMR(300MHz,DMSO-d 6)δ8.31(s,1H),8.02(s,1H),6.77(s,1H),6.50(s,1H),4.21(s,3H),4.02(d,J＝6.3Hz,2H),3.96-3.86(m,2H),3.81(s,3H),3.41-3.37(m,2H),2.16-2.03(m,1H),1.76-1.69(m,2H), 1.47-1.32(m,2H). 1 H NMR (300MHz, DMSO- d 6) δ8.31 (s, 1H), 8.02 (s, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 4.21 (s, 3H), 4.02 ( d, J = 6.3 Hz, 2H), 3.96-3.86 (m, 2H), 3.81 (s, 3H), 3.41-3.37 (m, 2H), 2.16-2.03 (m, 1H), 1.76-1.69 (m, 2H), 1.47-1.32 (m, 2H).
实施例36：SAL02-311Example 36: SAL02-311
2-甲氧基-6-(6-甲氧基-4-((5-甲基噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1，3,4]噻二唑2-methoxy-6-(6-methoxy-4-((5-methylthiazol-4-yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazole And [2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000152
Figure PCTCN2019086558-appb-000152
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000153
Figure PCTCN2019086558-appb-000153
实施例36流程：Example 36 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(603毫克，2.37毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基膦(329毫克，1.52毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和(5-甲基噻唑-4-基)甲醇(61毫克，0.47毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌1小时。Step A: Azodiyldipiperidine (603 mg, 2.37 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (329 mg, 1.52 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. a solution of pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and (5-methylthiazol-4-yl)methanol (61 mg, 0.47 mmol) in tetrahydrofuran ( 10.0 ml). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠水溶液(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在15分钟内，乙腈从42％升到46％；检测波长：220nm。收集产品，低温冻干得白色固体2-甲氧基-6-(6-甲氧基-4-((5-甲基噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1，3,4]噻二唑(31.7毫克，收率23.2％)。After LCMS monitoring showed the disappearance of the material, aq. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The resulting residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 42% in 15 minutes Increased to 46%; detection wavelength: 220nm. The product was collected and lyophilized to give a white solid 2-methoxy-6-(6-methoxy-4-((5-methylthiazol-4-yl)methoxy)pyrazolo[1,5- a] Pyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (31.7 mg, yield 23.2%).
MS(ESI)M/Z：429[M+H +]. MS (ESI) M/Z: 429 [M+H + ].
1H NMR(300MHz,DMSO-d 6):δ8.89(s,1H),8.31(s,1H),8.04(s,1H),6.79(s,1H),6.72(s,1H),5.35(s,2H),4.20(s,3H),3.82(s,3H),2.54(s,3H). 1 H NMR (300MHz, DMSO- d 6): δ8.89 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 5.35 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H), 2.54 (s, 3H).
实施例37：SAL02-297Example 37: SAL02-297
4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基氨基)甲基)噻唑-2-基)吗啉4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxyamino)methyl)thiazol-2-yl)morpholine
Figure PCTCN2019086558-appb-000154
Figure PCTCN2019086558-appb-000154
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000155
Figure PCTCN2019086558-appb-000155
实施例37流程：Example 37 process:
步骤A：在室温下，将2-溴噻唑-4-羧酸乙酯(2.00克，8.51毫摩尔)溶于1,4-二氧六环(50.0毫升)中。随后，向上述溶液中依次加入三乙胺(1.30克，12.8毫摩尔)和***啉(2.22克，25.5毫摩尔)。将反应液加热至120摄氏度并搅拌6小时。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.
LCMS监测显示原料消失后，将反应液冷却至室温，向其中加入水(20毫升)淬灭。混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得到无色油状物2-吗啉代噻唑-4-羧酸乙酯(1.90克，收率92.3％)。After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature, and water (20 ml) was added and quenched. The mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with brine (50 ml) The residue was purified by EtOAcjjjjj elut elut elut elut elut elut elut elut ).
MS(ESI)M/Z：243[M+H +]。 MS (ESI) M / Z: 243 [M+H + ].
步骤B：将2-吗啉代噻唑-4-羧酸乙酯(1.00克，4.13毫摩尔)溶于四氢呋喃(20.0毫升)中。在冰水浴下，向上述溶液中分批次加入硼氢化锂(364毫克，16.5毫摩尔)。随后，再向其中缓慢滴加无水甲醇(529毫克，16.5毫摩尔)。将反应液缓慢升至室温并搅拌1小时。Step B: Ethyl 2-morpholinothiazole-4-carboxylate (1.00 g, 4.13 mmol) was dissolved in tetrahydrofurane (20.0 mL). Lithium borohydride (364 mg, 16.5 mmol) was added in portions to the above solution in an ice water bath. Subsequently, anhydrous methanol (529 mg, 16.5 mmol) was slowly added dropwise thereto. The reaction solution was slowly warmed to room temperature and stirred for 1 hour.
LCMS监测显示原料消失后，向反应液中缓慢滴加甲醇(10毫升)淬灭。混合液在减压下浓缩。粗产品通过硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10)，得到白色固体(2-吗啉代-4-基)甲醇(780毫克，收率94.5％)。After LCMS monitoring showed the disappearance of the starting material, methanol (10 mL) was slowly added dropwise to the reaction mixture to quench. The mixture was concentrated under reduced pressure. The crude product was purified by purified mjjjjjjjjjj
MS(ESI)M/Z：201[M+H +]。 MS (ESI) M / Z: 201 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(1.15克，4.56毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液滴加三丁基磷(1.44克，7.12毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(150毫克，0.47毫摩尔)和(2-吗啉代-4-基)甲醇(378毫克，1.89毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌2小时。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. a solution of pyrazolo[1,5-a]pyridin-4-ol (150 mg, 0.47 mmol) and (2-morpholino-4-yl)methanol (378 mg, 1.89 mmol) in tetrahydrofuran ( 10.0 ml). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升 ×3次)，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物通过经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在15分钟内，乙腈从40％升到43％；检测波长：220nm。收集产品，减压冻干得白色固体4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基氨基)甲基)噻唑-2-基)吗啉(30.8毫克，收率13.0％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was combined with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 40% in 15 minutes Increased to 43%; detection wavelength: 220nm. The product was collected and lyophilized to give 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4] thiadiazole) as a white solid. -6-yl)pyrazolo[1,5-a]pyridin-4-yloxyamino)methyl)thiazol-2-yl)morpholine (30.8 mg, yield 13.0%).
MS(ESI)M/Z：500[M+H +]。 MS (ESI) M/Z: 500 [M+H + ].
1H NMR(300MHz,CDCl 3)δ7.99(s,1H),7.78(s,1H),6.99(s,1H),6.68(s,1H),6.35(s,1H),5.13(s,2H),4.22(s,3H),3.86-3.83(m,7H),3.56-3.50(m,4H)。 1 H NMR (300MHz, CDCl 3 ) δ7.99 (s, 1H), 7.78 (s, 1H), 6.99 (s, 1H), 6.68 (s, 1H), 6.35 (s, 1H), 5.13 (s, 2H), 4.22 (s, 3H), 3.86-3.83 (m, 7H), 3.56-3.50 (m, 4H).
实施例38：SAL03-300Example 38: SAL03-300
6-(4-((2,2-二氟环丙基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-((2,2-Difluorocyclopropyl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2 , 1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000156
Figure PCTCN2019086558-appb-000156
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000157
Figure PCTCN2019086558-appb-000157
实施例38流程：Example 38 process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(1.50克，6.00毫摩尔)溶于四氢呋喃(15.0毫升)中。随后，向上述溶液中加入三丁基膦(1.90克，9.40毫摩尔)。反应液在室温下搅拌20分钟后，向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(200毫克，0.63毫摩尔)和2,2-二氟环丙基甲醇(59毫克，0.32毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌2小时。Step A: Azodiyldipiperidine (1.50 g, 6.00 mmol) was dissolved in tetrahydrofuran (15.0 mL). Subsequently, tributylphosphine (1.90 g, 9.40 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-yl group was added thereto. a solution of pyrazolo[1,5-a]pyridine-4-hydroxy (200 mg, 0.63 mmol) and 2,2-difluorocyclopropylmethanol (59 mg, 0.32 mmol) in tetrahydrofuran (10.0 mL) . The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后。向反应液中加入水(30毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在12分钟内，乙腈从48％升到64％；检测波长：220nm。收集产品，减压冻干。得到白色固体6-(4-((2,2-二氟环丙基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(25.8毫克，收率10.0％)。LCMS monitoring showed disappearance of the starting material. Water (30 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 48% in 12 minutes Increased to 64%; detection wavelength: 220nm. The product was collected and lyophilized under reduced pressure. Obtained 6-(4-((2,2-difluorocyclopropyl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazole as a white solid And [2,1-b][1,3,4]thiadiazole (25.8 mg, yield 10.0%).
MS(ESI)M/Z：408[M+H +]。 MS (ESI) M/Z: 408 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.01(s,1H),7.79(s,1H),6.97(s,1H),6.23(s,1H),4.29-4.19(m,4H),4.13(m,1H),3.84(s,3H),2.25-2.10(m,1H),1.74-1.58(m,1H),1.43-1.38(m,1H). 1 H NMR (300MHz, CDCl 3 ): δ8.01 (s, 1H), 7.79 (s, 1H), 6.97 (s, 1H), 6.23 (s, 1H), 4.29-4.19 (m, 4H), 4.13 (m, 1H), 3.84 (s, 3H), 2.25-2.10 (m, 1H), 1.74-1.58 (m, 1H), 1.43-1.38 (m, 1H).
19F NMR(282MHz,CDCl 3)：δ-129.0,-142.7. 19 F NMR (282 MHz, CDCl 3 ): δ - 129.0, -142.7.
实施例39：SAL03-303Example 39: SAL03-303
2-甲氧基-6-(6-甲氧基-4-((2-甲基噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-((2-methylthiazol-4-yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazole And [2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000158
Figure PCTCN2019086558-appb-000158
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000159
Figure PCTCN2019086558-appb-000159
实施例39流程：Example 39 Process:
步骤A：在室温和氮气保护下，将偶氮二甲酰二哌啶(781毫克，3.10毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中加入三丁基膦(970毫克，4.80毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)和(2-甲基噻唑-4-基)甲醇(83毫克，0.64毫摩尔)的四氢呋喃溶液(3.0毫升)。反应液在室温下搅拌2小时。Step A: Azodiyldipiperidine (781 mg, 3.10 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (970 mg, 4.80 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. a solution of pyrazolo[1,5-a]pyridine-4-hydroxy (100 mg, 0.32 mmol) and (2-methylthiazol-4-yl)methanol (83 mg, 0.64 mmol) in tetrahydrofuran ( 3.0 ml). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在12分钟内，乙腈从37％升到44％；检测波长：220nm。收集产品，减压冻干。得到白色固体6-(4-((2,2-二氟环丙基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(21毫克，收率15.3％)。After LCMS monitoring showed the disappearance of the material, a saturated aqueous sodium hydrogen carbonate solution (10 ml) was then evaporated. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 37% in 12 minutes Increased to 44%; detection wavelength: 220nm. The product was collected and lyophilized under reduced pressure. Obtained 6-(4-((2,2-difluorocyclopropyl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazole as a white solid And [2,1-b][1,3,4]thiadiazole (21 mg, yield 15.3%).
MS(ESI)M/Z：429[M+H +]。 MS (ESI) M / Z: 429 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.00(s,1H),7.80(s,1H),7.25(s,1H),6.99(s,1H),6.50(s,1H),5.30(s,2H),4.23(s,3H),3.84(s,3H),2.77(s,3H)。 1 H NMR (300MHz, CDCl 3 ): δ8.00 (s, 1H), 7.80 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.50 (s, 1H), 5.30 (s , 2H), 4.23 (s, 3H), 3.84 (s, 3H), 2.77 (s, 3H).
实施例40：SAL02-307Example 40: SAL02-307
2-甲氧基-6-(6-甲氧基-4-((四氢呋喃-3-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-((tetrahydrofuran-3-yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2, 1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000160
Figure PCTCN2019086558-appb-000160
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000161
Figure PCTCN2019086558-appb-000161
实施例40流程：Example 40 process:
步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)溶于N,N-二甲基甲酰胺(2.0毫升)中。随后，向上述溶液中加入3-(溴甲基)四氢呋喃(78毫克，0.47毫摩尔)和无水碳酸钾(131毫克，0.95毫摩尔)。反应液在室温下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(5.0毫升)淬灭。混合液用乙酸乙酯(5.0毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升的碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在12分钟内，乙腈从37％升到44％；检测波长：220nm。收集产品，减压冻干。得到白色固体2-甲氧基-6-(6-甲氧基-4-((四氢呋喃-3-基)甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(6.3毫克，收率4.94％)。After LCMS monitoring showed the disappearance of the starting material, water (5.0 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The resulting residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter of ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 37 in 12 minutes % rose to 44%; detection wavelength: 220 nm. The product was collected and lyophilized under reduced pressure. Obtained a white solid 2-methoxy-6-(6-methoxy-4-((tetrahydrofuran-3-yl)methoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazole [2,1-b][1,3,4]thiadiazole (6.3 mg, yield 4.94%).
MS(ESI)M/Z：402[M+H +]。 MS (ESI) M/Z: 402 [M+H + ].
1H NMR(300MHz,CD 3OD)δ8.31(s,1H),8.03(s,1H),6.76(s,1H),6.63(s,1H),4.21(s,3H),4.16-4.04(m,2H)，3.88-3.77(m,5H)，3.73-3.67(m,1H)，3.61-3.57(m,1H)，2.78-2.72(m,1H)，2.12-2.01(m,1H)，1.78-1.67(m,1H)。 1 H NMR (300 MHz, CD 3 OD) δ 8.31 (s, 1H), 8.03 (s, 1H), 6.76 (s, 1H), 6.63 (s, 1H), 4.21 (s, 3H), 4.16-4.04 (m, 2H), 3.88-3.77 (m, 5H), 3.73-3.67 (m, 1H), 3.61-3.57 (m, 1H), 2.78-2.72 (m, 1H), 2.12-2.01 (m, 1H) , 1.78-1.67 (m, 1H).
实施例41：SAL02-318Example 41: SAL02-318
4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)-tetrahydro-2H-pyran-4-ol
Figure PCTCN2019086558-appb-000162
Figure PCTCN2019086558-appb-000162
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000163
Figure PCTCN2019086558-appb-000163
实施例41流程：Example 41 process:
步骤A：在室温和氮气保护下，将2-溴-4-((叔丁基二甲硅氧基)甲基)-5-甲基噻唑(510毫克，1.58毫摩尔)溶于四氢呋喃(20.0毫升)中。将上述溶液冷却至-78℃后，向其中缓慢滴加正丁基锂的正己烷溶液(0.85毫升，2.05毫摩尔，2.5摩尔/升)。反应液在-78℃下搅拌30分钟。随后，再向其中滴加四氢吡喃酮(237毫克，2.37毫摩尔)的四氢呋喃溶液(5.0毫升)。反应液在-78℃下搅拌1小时。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.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭反应。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。得到油状残余物4-(4-((叔丁基二甲硅氧基)甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇(430毫克，粗品)，无需纯化直接用于下一步反应。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The oily residue was obtained 4-(4-((tert-butyldimethylsilyloxy)methyl)-5-methylthiazol-2-yl)-tetrahydro-2H-pyran-4-ol (430 mg, Crude), used directly in the next reaction without purification.
MS(ESI)M/Z：344[M+H] + MS (ESI) M/Z: 344 [M+H] +
步骤B：将4-(4-((叔丁基二甲硅氧基)甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇(430毫克，1.25毫摩尔)溶于四氢呋喃溶液(50.0毫升)中。反应液在室温下搅拌1小时。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.
LCMS监测显示原料消失后，向反应液中加入水(100毫升)淬灭。混合液用乙酸乙酯(100毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/3)，得到油状物4-(4-(羟甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇(160毫克，收率55.9％)。After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography elut elut elut elut elut -tetrahydro-2H-pyran-4-ol (160 mg, yield 55.9%).
MS(ESI)M/Z：230[M+H] + MS (ESI) M/Z: 230 [M+H] +
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(496毫克，1.97毫摩尔)和三丁基膦(621毫克，3.08毫摩尔)溶于四氢呋喃溶液(13.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(130毫克，0.41毫摩尔)和4-(4-(羟甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇(141毫克，0.62毫摩尔)的四氢呋喃溶液(13.0毫升)。反应液在室温下搅拌1小时。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. , 5-a]pyridin-4-ol (130 mg, 0.41 mmol) and 4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)-tetrahydro-2H-pyran-4 A solution of alcohol (141 mg, 0.62 mmol) in tetrahydrofuran (13.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用二氯甲烷(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。粗产品依次用纯水(100毫升)和石油醚/乙酸乙酯溶液(50毫升，40/1)洗涤，过滤，收集滤饼。粗产品用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到淡白色固体4-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)-四氢-2H-吡喃-4-醇(22.6毫克，收率10.4％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (100 mL×3×). The combined organic layers were washed with EtOAc EtOAc EtOAc. The crude product was washed successively with pure water (100 mL) and petroleum ether / ethyl acetate (50 ml, 40/1), filtered and collected. The crude product was purified by EtOAc EtOAcjjjjjjjj Imidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)methyl)-5-methyl Thiazol-2-yl)-tetrahydro-2H-pyran-4-ol (22.6 mg, yield 10.4%).
MS(ESI)M/Z：529[M+H] + MS (ESI) M/Z: 529 [M+H] +
1H NMR(300MHz,DMSO-d 6)：δ8.31(s,1H),8.05(s,1H),6.75(s,1H),6.72(s,1H),6.08(s,1H),5.25(s,2H),4.20(s,3H),3.82(s,3H),3.74-3.66(m,4H),2.48(s,3H),2.14-2.04(m,2H),1.68-1.64(m,2H). 1 H NMR (300MHz, DMSO- d 6): δ8.31 (s, 1H), 8.05 (s, 1H), 6.75 (s, 1H), 6.72 (s, 1H), 6.08 (s, 1H), 5.25 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H), 3.74 - 3.66 (m, 4H), 2.48 (s, 3H), 2.14 - 2.04 (m, 2H), 1.68-1.64 (m , 2H).
实施例42：SAL02-309Example 42: SAL02-309
3-((4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈3-((4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)propanenitrile
Figure PCTCN2019086558-appb-000164
Figure PCTCN2019086558-appb-000164
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000165
Figure PCTCN2019086558-appb-000165
实施例42流程：Example 42 process:
步骤A：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(200毫克，0.62毫摩尔)，3-(甲基氨基)丙腈(79毫克，0.94毫摩尔)、碳酸铯(243毫克，0.75毫摩尔)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(43毫克，0.07毫摩尔)溶于1,4-二氧六环(5.0毫升)中。随后，向上述溶液中加入醋酸钯(14毫克，0.06毫摩尔)。将反应液加热至100摄氏度并搅拌12小时。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.
LCMS监测显示原料消失后，将反应液在减压下浓缩。所得残余物用硅胶柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)，得到黄色油状产品3-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈(90毫克，收率44.7％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified to silica gel eluted elut elut elut elut elut elut elut elut elut (5-methylthiazol-2-yl)(methyl)amino)propanenitrile (90 mg, yield 44.7%).
MS(ESI)M/Z：326[M+H +]。 MS (ESI) M / Z: 326 [M+H + ].
步骤B：将3-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈(90.0毫克，0.28毫摩尔)溶于四氢呋喃(1.0毫升)中。随后，向上述溶液中加入四丁基氟化铵的四氢呋喃溶液(0.50毫升，1.0摩尔/升)。反应液在室温下搅拌30分钟。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.
LCMS监测显示原料消失后，向反应液中加入水(2毫升)淬灭反应。混合液用乙酸乙酯(5毫升×3次)萃取，合并有机相。用饱和食盐水(3毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩，所得残余物用硅胶柱纯化(洗脱剂：乙酸乙酯/二氯甲烷＝1/2)，得到白色固体3-((4-(羟甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈(50毫克，收率84.6％)。After LCMS monitoring showed the disappearance of the starting material, water (2 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (5 mL×3×) and the organic phases were combined. The extract was washed with aq. EtOAc (EtOAc) The white solid 3-((4-(hydroxymethyl)-5-methylthiazol-2-yl)(methyl)amino)propanenitrile (50 mg, yield 84.6%) was obtained.
MS(ESI)M/Z：212[M+H +]。 MS (ESI) M / Z: 212 [M+H + ].
步骤C:在室温和氮气保护下，将偶氮二甲酰二哌啶(242毫克，0.96毫摩尔)溶于四氢呋喃(2.0毫升)中。随后，向上述溶液中加入三丁基膦(311毫克，1.44毫摩尔)的四氢呋喃溶液(1.0毫升)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(63毫克，0.20毫摩尔)和3-((4-(羟甲基)-5-甲基噻唑-2-基)(甲基) 氨基)丙腈(46毫克，0.22毫摩尔)的四氢呋喃溶液(3.0毫升)。反应液在室温下搅拌1小时。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. Pyrazolo[1,5-a]pyridin-4-ol (63 mg, 0.20 mmol) and 3-((4-(hydroxymethyl)-5-methylthiazol-2-yl) (A) Amino)propanenitrile (46 mg, 0.22 mmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100)，得到白色固体3-((4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈(15.0毫克，收率14.4％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Imidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5- Methylthiazol-2-yl)(methyl)amino)propanenitrile (15.0 mg, yield 14.4%).
MS(ESI)M/Z:511[M+H +] MS (ESI) M/Z: 511 [M+H + ]
1H NMR(300MHz,DMSO-d 6):δ8.30(s,1H)，8.03(s,1H),6.73(s,1H),6.71(s,1H),5.07(s,2H),4.20(s,3H),3.82(s,3H),3.72(t,J＝6.6Hz,2H),3.05(s,3H),2.86(t,J＝6.6Hz,2H),2.34(s,3H)。 1 H NMR (300MHz, DMSO- d 6): δ8.30 (s, 1H), 8.03 (s, 1H), 6.73 (s, 1H), 6.71 (s, 1H), 5.07 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H), 3.72 (t, J = 6.6 Hz, 2H), 3.05 (s, 3H), 2.86 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H) .
实施例43：SAL02-323Example 43: SAL02-323
6-(4-((4-氟苄基)氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑三氟乙酸盐6-(4-((4-fluorobenzyl)oxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b] [1,3,4]thiadiazole trifluoroacetate
Figure PCTCN2019086558-appb-000166
Figure PCTCN2019086558-appb-000166
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000167
Figure PCTCN2019086558-appb-000167
实施例43流程：Example 43 Process:
步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)溶于N,N-二甲基甲酰胺(2.0毫升)中。随后，向上述溶液中加入4-氟溴苄(89毫克，0.47毫摩尔)和无水碳酸钾(131毫克，0.95毫摩尔)。反应液在室温下搅拌2小时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, 4-fluorobromobenzyl (89 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.
LCMS监测显示原料消失后，向反应液中加水(5毫升)淬灭。混合液用乙酸乙酯(5毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升的三氟乙酸)和乙腈；流速:25毫升/分钟；梯度：在12分钟内，乙腈从37％升到44％；检测波长：220nm。收集产品，减压冻干。得到6-(4-((4-氟苄基)氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑三氟乙酸盐(27.7毫克，收率16.1％)。After LCMS monitoring showed the disappearance of the starting material, water (5 mL) was then applied to the mixture. The mixture was extracted with EtOAc (EtOAc EtOAc. The resulting residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter of trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 37 in 12 minutes % rose to 44%; detection wavelength: 220 nm. The product was collected and lyophilized under reduced pressure. Yield 6-(4-((4-fluorobenzyl)oxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b ][1,3,4]thiadiazole trifluoroacetate (27.7 mg, yield 16.1%).
MS(ESI)M/Z：426[M+H +]。 MS (ESI) M / Z: 426 [M+H + ].
1H NMR(300MHz,DMSO-d 6):δ8.32(s,1H),8.03(s,1H),7.60-7.55,(m,2H),7.30-7.25,(m,2H),6.80(s,1H),6.60(s,1H),5.29(s,2H),4.21(s,3H),3.81(s,3H). 1 H NMR (300MHz, DMSO- d 6): δ8.32 (s, 1H), 8.03 (s, 1H), 7.60-7.55, (m, 2H), 7.30-7.25, (m, 2H), 6.80 ( s, 1H), 6.60 (s, 1H), 5.29 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H).
19F NMR(300MHz,DMSO-d 6)δ-74.8,-114.1 19 F NMR (300 MHz, DMSO-d 6 ) δ-74.8, -114.1
实施例44：SAL02-320Example 44: SAL02-320
6-(4-((3-溴吡啶-2-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3，4]噻二唑6-(4-((3-bromopyridin-2-yl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2, 1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000168
Figure PCTCN2019086558-appb-000168
反应流程:Reaction process:
Figure PCTCN2019086558-appb-000169
Figure PCTCN2019086558-appb-000169
实施例44流程：Example 44 process:
步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(100毫克，0.32毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入无水碳酸钾(87毫克，0.63毫摩尔)和3-溴-2-(溴甲基)吡啶(158毫克，0.64毫摩尔)。反应液在室温下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。所得残留物用N,N-二甲基甲酰胺(5毫升)溶至澄清，经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升的碳酸氢铵)和乙腈；流速:25毫升/分钟；梯度：在8分钟内，乙腈从55％升到61％；检测波长：254nm。收集产品，低温冻干得白色固体6-(4-((3-溴吡啶-2-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3，4]噻二唑(33.7毫克，收率21.9％)。After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue obtained was dissolved in EtOAc (5 mL). Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 10 mmol / liter of ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 55 in 8 minutes % rose to 61%; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-(4-((3-bromopyridin-2-yl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2 as a white solid. -Methoxy-imidazo[2,1-b][1,3,4]thiadiazole (33.7 mg, yield 21.9%).
MS(ESI)M/Z:487,489[M+H +]。 MS (ESI) M/Z: 487, 495 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.61(s,1H),7.99(s,1H),7.94(s,1H),7.79(s,1H),7.23(m,1H),6.97(s,1H),6.43(s,1H),5.43(s,2H),4.22(s,3H),3.83(s,3H). 1 H NMR (300MHz, CDCl 3 ): δ8.61 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.23 (m, 1H), 6.97 (s , 1H), 6.43 (s, 1H), 5.43 (s, 2H), 4.22 (s, 3H), 3.83 (s, 3H).
实施例45：SAL02-304Example 45: SAL02-304
2-甲氧基-6-(6-甲氧基-4-((5-甲基-2-(四氢-2H-吡喃-4-基)噻唑-4-基)甲氧基)吡唑并[1,5-α]吡啶吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-((5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)pyrene Zoxa[1,5-α]pyridinylpyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000170
Figure PCTCN2019086558-appb-000170
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000171
Figure PCTCN2019086558-appb-000171
实施例45流程：Example 45 process:
步骤A：将(2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲醇(300毫克，1.42毫摩尔)溶于甲醇溶液(80.0毫升)中。随后，向上述溶液中加入钯碳(10％，200毫克)。反应体系用氢气置换3次。反应液在室温下搅拌1小时Step A: Dissolving (2-(3,6-dihydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methanol (300 mg, 1.42 mmol) in methanol (80.0) In milliliters). Subsequently, palladium on carbon (10%, 200 mg) was added to the above solution. The reaction system was replaced with hydrogen three times. The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，过滤，所得滤液在减压下浓缩,得到白色固体(5-甲基-2-(四氢-2H-吡喃-4-基)噻唑-4-基)甲醇(200毫克，粗品)直接用于下一步反应，无需纯化。After LCMS monitoring showed the disappearance of the starting material, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to give a white solid (5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (200) Mg, crude) was used directly in the next step without purification.
MS(ESI)M/Z：214[M+H +]。 MS (ESI) M / Z: 214 [M+H + ].
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(684毫克，2.72毫摩尔)和三丁基膦(857毫克，4.25毫摩尔)溶于四氢呋喃(15.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-羟基(180毫克，0.57毫摩尔)和(5-甲基-2-(四氢-2H-吡喃-4-基)噻唑-4-基)甲醇(182毫克，0.85毫摩尔)的四氢呋喃溶液(15.0毫升)。反应液在30摄氏度下搅拌2小时。Step B: Azodiyldipiperidine (684 mg, 2.72 mmol) and tributylphosphine (857 mg, 4.25 mmol) were dissolved in tetrahydrofuran (15.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution. , 5-a]pyridine-4-hydroxy (180 mg, 0.57 mmol) and (5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (182 mg , 0.85 mmol) in tetrahydrofuran (15.0 mL). The reaction solution was stirred at 30 ° C for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(50毫升)淬灭，有白色固体析出。过滤，收集滤饼。滤饼用乙酸乙酯/石油醚(100毫升，40/1)洗涤得到粗产品。粗产品经高效液相色谱制备，制备条件：色谱柱：Gemini-NX C 18AXAI Packed 21.2*150mm 5um；流动相：水(含有0.1％三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从45％升到55％；检测波长：254nm。减压冻干得白色固体2-甲氧基-6-(6-甲氧基-4-((5-甲基-2-(四氢-2H-吡喃-4-基)噻唑-4-基)甲氧基)吡唑并[1,5-a]吡啶吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(46.6毫克，收率15.9％)。 After LCMS showed the disappearance of the starting material, water (50 ml) was added to the mixture and the mixture was evaporated. Filter and collect the filter cake. The filter cake was washed with ethyl acetate / petroleum ether (100 mL, 40/1). The crude product was prepared by high performance liquid chromatography, and the preparation conditions were as follows: column: Gemini-NX C 18 AXAI Packed 21.2*150 mm 5 um; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient : Acetonitrile was raised from 45% to 55% in 25 minutes; detection wavelength: 254 nm. Lyophilized to give a white solid 2-methoxy-6-(6-methoxy-4-((5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole-4-) Methoxy)pyrazolo[1,5-a]pyridinylpyridin-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (46.6 mg, yield 15.9%) ).
MS(ESI)M/Z：513[M+H] + MS (ESI) M/Z: 513 [M+H] +
1H NMR(300MHz,CDCl 3)：δ8.02(s,1H),7.81(s,1H),6.96(s,1H),6.49(s,1H),5.24(s,2H),4.23(s,3H),4.15-4.00(m,2H),3.84(s,3H),3.56(t,J＝11.6Hz,2H),3.29-3.16(m,1H),2.52(s,3H),2.11-2.01(m,2H),1.98-1.83(m,2H). 1 H NMR (300MHz, CDCl 3 ): δ8.02 (s, 1H), 7.81 (s, 1H), 6.96 (s, 1H), 6.49 (s, 1H), 5.24 (s, 2H), 4.23 (s , 3H), 4.15-4.00 (m, 2H), 3.84 (s, 3H), 3.56 (t, J = 11.6 Hz, 2H), 3.29-3.16 (m, 1H), 2.52 (s, 3H), 2.11 2.01 (m, 2H), 1.98-1.83 (m, 2H).
实施例46：SAL02-321Example 46: SAL02-321
2-甲氧基-6-(6-甲氧基-4-(吡啶-3-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1- b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000172
Figure PCTCN2019086558-appb-000172
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000173
Figure PCTCN2019086558-appb-000173
实施例46流程：Example 46 process:
步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入3-(溴甲基)吡啶氢溴酸盐(160毫克，0.63毫摩尔)和无水碳酸钾(174毫克，1.26毫摩尔)。反应液在室温下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品通过高压液相色谱纯化，色谱柱；X select C18 19mm*150mm,5um,19*150mm,流动相：A：水(含有10毫摩尔/升碳酸氢铵)，B：乙腈。流速：25毫升/分，梯度：5分钟从46％乙腈升至46％乙腈。收集产品，冻干得白色固体2-甲氧基-6-(6-甲氧基-4-(吡啶-3-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(17.2毫克，收率13.4％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The crude product was purified by high pressure liquid chromatography, chromatography column; X select C18 19 mm * 150 mm, 5 um, 19 * 150 mm, mobile phase: A: water (containing 10 mmol / liter ammonium bicarbonate), B: acetonitrile. Flow rate: 25 ml/min, gradient: from 46% acetonitrile to 46% acetonitrile in 5 minutes. The product was collected and lyophilized to give 2-methoxy-6-(6-methoxy-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl as a white solid. Imidazo[2,1-b][1,3,4]thiadiazole (17.2 mg, yield 13.4%).
MS(ESI)M/Z：409[M+H +]。 MS (ESI) M / Z: 409 [M+H + ].
1H NMR(300MHz,CDCl 3)δ8.74(s,1H),8.65(d,J＝4.6Hz,1H),7.99(s,1H),7.87(d,J＝7.9Hz,1H),7.80(d,J＝1.5Hz,1H),7.39(dd,J＝7.8,4.8Hz,1H),6.97(s,1H),6.33(s,1H),5.23(s,2H),4.22(s,3H),3.84(s,3H)。 1 H NMR (300MHz, CDCl 3 ) δ8.74 (s, 1H), 8.65 (d, J = 4.6Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 7.9Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 6.97 (s, 1H), 6.33 (s, 1H), 5.23 (s, 2H), 4.22 (s, 3H), 3.84 (s, 3H).
实施例47：SAL02-327Example 47: SAL02-327
6-(4-((2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-((2-(3,6-Dihydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methoxy)-6-methoxy[1, 5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000174
Figure PCTCN2019086558-appb-000174
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000175
Figure PCTCN2019086558-appb-000175
实施例47流程：Example 47 process:
步骤A：将2-(2-溴-5-甲基噻唑-4-基)乙酸甲酯(776毫克，3.29毫摩尔)溶于四氢呋喃(30.0毫升)中。将反应液冷却至0摄氏度后，向其中分批次加入硼氢化锂(276毫克，13.1毫摩尔)。随后，再向其中缓慢滴加甲醇(421毫克，13.1毫摩尔)。反应液在0摄氏度下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入甲醇(300毫升)淬灭。混合液在减压下直接浓缩。粗产品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10)，得到白色固体(2-溴-5-甲基噻唑-4-基)甲醇(660毫克，收率96.5％)。After LCMS showed the disappearance of the starting material, methanol (300 mL) was added to the reaction mixture to quench. The mixture was concentrated directly under reduced pressure. The crude product was purified by EtOAc EtOAcjjjjjjjj %).
MS(ESI)M/Z：208[M+H +]。 MS (ESI) M / Z: 208 [M+H + ].
步骤B：将(2-溴-5-甲基噻唑-4-基)甲醇(660毫克，3.17毫摩尔)溶于二氯甲烷(45.0毫升)中。随后，向上述溶液中依次加入咪唑(431毫克，6.35毫摩尔)和三甲基叔丁基氯硅烷(950毫克，6.35毫摩尔)。反应液在室温下搅拌1小时。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.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(50毫升)淬灭。混合液用乙酸乙酯(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝12/1)得无色油状物2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(918毫克，收率89.6％)。After LCMS monitoring showed the disappearance of the material, the mixture was then evaporated and evaporated. The mixture was extracted with ethyl acetate (30 mL×3×). The combined organic layers were washed with brine (30 ml) The residue was purified by EtOAc EtOAcjjjjjjjj Methyl)-5-methylthiazole (918 mg, yield 89.6%).
MS(ESI)M/Z：322[M+H +]。 MS (ESI) M / Z: 322 [M+H + ].
步骤C：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(380毫克，1.18毫摩尔)，2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(500毫克，2.38毫摩尔)，Pd(dppf)Cl 2(263毫克，0.36毫摩尔),碳酸铯(1.20克，3.59毫摩尔)溶于1,4-二氧六环(10.0毫升)和水(1.80毫升)的混合溶液。将反应体系加热至100摄氏度并搅拌过夜。 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.
LCMS监测显示原料消失后，混合液直接在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/8)，收集产品，得无色油状物4-(((叔丁基二甲基硅烷基)氧基)甲基)-2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑(326毫克，收率85.1％)。After LCMS monitoring showed disappearance of the starting material, the mixture was concentrated directly under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj Methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methylthiazole (326 mg, yield 85.1%).
MS(ESI)M/Z：326[M+H +]。 MS (ESI) M / Z: 326 [M+H + ].
步骤D：将4-(((叔丁基二甲基硅烷基)氧基)甲基)-2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑(326毫克，1.00毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入四丁基氟 化铵的四氢呋喃溶液(2.0毫升，1.0摩尔/升)。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.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)得到白色固体(2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲醇(160毫克，收率75.5％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (3 mL, EtOAc). The residue was purified with EtOAc EtOAcjjjjjjjjj Methylthiazol-4-yl)methanol (160 mg, yield 75.5%).
MS(ESI)M/Z：212[M+H +]。 MS (ESI) M / Z: 212 [M+H + ].
步骤E：在室温和氮气保护下，将偶氮二甲酰二哌啶(572毫克，2.27毫摩尔)和三丁基膦(717毫克，3.55毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(150毫克，0.47毫摩尔)和(2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲醇(150毫克，0.71毫摩尔)的四氢呋喃(10.0毫升)溶液。反应液在30摄氏度下搅拌2小时。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. , 5-a]pyridin-4-ol (150 mg, 0.47 mmol) and (2-(3,6-dihydro-2H-pyran-4-yl)-5-methylthiazol-4-yl) A solution of methanol (150 mg, 0.71 mmol) in tetrahydrofuran (10.0 mL). The reaction solution was stirred at 30 ° C for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(50毫升)淬灭反应。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得残余物硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)，收集产品，得到类白色固体6-(4-((2-(3,6-二氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(23.4毫克，收率9.7％)。After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. (eluent: ethyl acetate/petroleum ether = 1/4), product was collected to give an off-white solid 6-(4-(3,6-dihydro-2H-pyran-4-yl) -5-methylthiazol-4-yl)methoxy)-6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][ 1,3,4]thiadiazole (23.4 mg, yield 9.7%).
MS(ESI)M/Z：511[M+H] + MS (ESI) M/Z: 511 [M+H] +
1H NMR(300MHz,CDCl 3)：δ8.06(s,1H),7.83(s,1H),7.00(s,1H),6.55(s,2H),5.27(s,2H),4.36(s,2H),4.25(s,3H),3.94(m,2H),3.85(s,3H),2.68(s,2H),2.54(s,3H). 1 H NMR (300MHz, CDCl 3 ): δ8.06 (s, 1H), 7.83 (s, 1H), 7.00 (s, 1H), 6.55 (s, 2H), 5.27 (s, 2H), 4.36 (s , 2H), 4.25 (s, 3H), 3.94 (m, 2H), 3.85 (s, 3H), 2.68 (s, 2H), 2.54 (s, 3H).
实施例48：SAL02-322Example 48: SAL02-322
2-甲氧基-6-(6-甲氧基-4-(吡啶-2-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑2-methoxy-6-(6-methoxy-4-(pyridin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazo[2,1- b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000176
Figure PCTCN2019086558-appb-000176
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000177
Figure PCTCN2019086558-appb-000177
实施例48流程：Example 48 Process:
步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)的N,N-二甲基甲酰胺(5.0毫升)中。随后，向上述溶液中依次加入2-(溴甲基)吡啶(110毫克，0.64毫摩尔)和无水碳酸钾(88毫克，0.64毫摩尔)。反应液在室温下搅拌2小时。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) in N,N-dimethylformamide (5.0 mL). Subsequently, 2-(bromomethyl)pyridine (110 mg, 0.64 mmol) and anhydrous potassium carbonate (88 mg, 0.64 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱纯化。分离条件如下，色谱柱；X select C18 19mm *150mm,5um,19*150mm,流动相：A：水(含有0.1％三氟乙酸)，B：乙腈。流速：25毫升/分，梯度：5分钟从46％乙腈升至46％乙腈。收集产品，冻干得2-甲氧基-6-(6-甲氧基-4-(吡啶-2-基甲氧基)吡唑并[1,5-a]吡啶-2-基)咪唑并[2,1-b][1,3,4]噻二唑(16.7毫克，收率12.8％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by high pressure liquid chromatography. The separation conditions were as follows, column; X select C18 19 mm * 150 mm, 5 um, 19 * 150 mm, mobile phase: A: water (containing 0.1% trifluoroacetic acid), B: acetonitrile. Flow rate: 25 ml/min, gradient: from 46% acetonitrile to 46% acetonitrile in 5 minutes. The product was collected and lyophilized to give 2-methoxy-6-(6-methoxy-4-(pyridin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-2-yl)imidazole And [2,1-b][1,3,4]thiadiazole (16.7 mg, yield 12.8%).
MS(ESI)M/Z：409[M+H +]。 MS (ESI) M / Z: 409 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.64(d,J＝4.5Hz,1H),8.02(s,1H),7.82-7.68(m,2H)，7.64-7.63(m,1H)，7.28(s,1H),7.05(s,1H),6.34(s,1H)，5.35(s,2H)，4.23(s,3H),3.83(s,3H)。 1 H NMR (300MHz, CDCl 3 ): δ8.64 (d, J = 4.5Hz, 1H), 8.02 (s, 1H), 7.82-7.68 (m, 2H), 7.64-7.63 (m, 1H), 7.28 (s, 1H), 7.05 (s, 1H), 6.34 (s, 1H), 5.35 (s, 2H), 4.23 (s, 3H), 3.83 (s, 3H).
实施例49：SAL02-310Example 49: SAL02-310
2-((4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈2-((4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)acetonitrile
Figure PCTCN2019086558-appb-000178
Figure PCTCN2019086558-appb-000178
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000179
Figure PCTCN2019086558-appb-000179
实施例49流程：Example 49 process:
步骤A：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(500毫克，1.55毫摩尔)溶于甲苯(10.0毫升)中。随后，向上述溶液中依次加入甲氨基乙腈盐酸盐(248毫克，2.33毫摩尔)，无水碳酸铯(1.52克，4.65毫摩尔)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(90毫克，0.16毫摩尔)和三(二亚苄基丙酮)二钯(71毫克，0.08毫摩尔)。将反应液加热至120摄氏度并搅拌2小时。Step A: Dissolve 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (500 mg, 1.55 mmol) at room temperature under nitrogen. Intoluene (10.0 mL). Subsequently, methylaminoacetonitrile hydrochloride (248 mg, 2.33 mmol), anhydrous cesium carbonate (1.52 g, 4.65 mmol), 4,5-bisdiphenylphosphine-9,9- were sequentially added to the above solution. Dimethyl xanthene (90 mg, 0.16 mmol) and tris(dibenzylideneacetone) dipalladium (71 mg, 0.08 mmol). The reaction solution was heated to 120 ° C and stirred for 2 hours.
LCMS监测显示原料消失后，将反应液在减压下直接浓缩。残余物经硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝3:1)，得到无色油状物2-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈(230毫克，收率47.5％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was directly concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj )methyl)-5-methylthiazol-2-yl)(methyl)amino)acetonitrile (230 mg, yield 47.5%).
MS(ESI)M/Z：312[M+H +]。 MS (ESI) M / Z: 312 [M+H + ].
步骤B：将2-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈(220毫克，0.71毫摩尔)溶于在四丁基氟化铵的四氢呋喃溶液(2.1毫升，1.0摩尔/升)中。反应液在室温下搅拌1小时。Step B: 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)acetonitrile (220 mg, 0.71 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (2.1 mL, 1.0 mol/L). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(3.0毫升)淬灭。混合液用乙酸乙酯(3毫升 ×3次)萃取。合并有机相，有机相先用饱和食盐水(3毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到白色固体2-((4-(羟甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈(130毫克，收率92.1％)。After LCMS monitoring showed the disappearance of the starting material, water (3.0 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (3 mL×3×). The combined organic layers were washed with brine (3 mL) The residue was purified by silica gel column chromatography eluting elut elut elut elut elut (Methyl)amino)acetonitrile (130 mg, yield 92.1%).
MS(ESI)M/Z：198[M+H +]。 MS (ESI) M / Z: 198 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(724毫克，2.84毫摩尔)溶于四氢呋喃(10毫升)中。随后，向上述溶液中加入三丁基膦(367毫克，1.82毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(120毫克，0.38毫摩尔)和2-((4-(羟甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈(112毫克，0.57毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌1小时。Step C: Azodiyldipiperidine (724 mg, 2.84 mmol) was dissolved in tetrahydrofuran (10 mL). Subsequently, tributylphosphine (367 mg, 1.82 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. Pyrazolo[1,5-a]pyridin-4-ol (120 mg, 0.38 mmol) and 2-((4-(hydroxymethyl)-5-methylthiazol-2-yl) (A) A solution of acetonitrile (112 mg, 0.57 mmol) in tetrahydrofuran (10.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得溶液在减压下浓缩。残余物经高压液相色谱纯化。分离条件如下，色谱柱；XBridge Shield RP18 OBD Column,5um,19*150mm,流动相：A：水(含有0.1％的三氟乙酸)，B：乙腈。流速：25毫升/分，梯度：5分钟从46％乙腈升至46％乙腈。收集产品，冻干得白色固体2-((4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)乙腈(20.0毫克，收率10.7％)。After LCMS monitoring showed the disappearance of the material, the mixture was evaporated to dryness with EtOAc. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by high pressure liquid chromatography. The separation conditions were as follows, column; XBridge Shield RP18 OBD Column, 5 um, 19*150 mm, mobile phase: A: water (containing 0.1% trifluoroacetic acid), B: acetonitrile. Flow rate: 25 ml/min, gradient: from 46% acetonitrile to 46% acetonitrile in 5 minutes. The product was collected and lyophilized to give a white solid 2-((4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole) -6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)acetonitrile (20.0 mg, The rate is 10.7%).
MS(ESI)M/Z：497[M+H +]。 MS (ESI) M/Z: 495 [M+H + ].
1H NMR(300MHz,DMSO-d 6)δ8.42(s,1H),8.05(s,1H),6.75(s,1H),6.67(s,1H),5.10(s,2H),4.66(s,2H),4.20(s,3H),3.82(s,3H),3.04(s,3H),2.38(s,3H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.42 (s, 1H), 8.05 (s, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 5.10 (s, 2H), 4.66 ( s, 2H), 4.20 (s, 3H), 3.82 (s, 3H), 3.04 (s, 3H), 2.38 (s, 3H).
实施例50：SAL02-333Example 50: SAL02-333
6-(4-((2-(4-氟四氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(4-((2-(4-Fluorotetrahydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methoxy)-6-methoxy[1,5 -a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole
Figure PCTCN2019086558-appb-000180
Figure PCTCN2019086558-appb-000180
反应流程Reaction process
Figure PCTCN2019086558-appb-000181
Figure PCTCN2019086558-appb-000181
实施例50流程：Example 50 process:
步骤A：将4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)四氢-2H-吡喃-4-醇(70毫克，0.13毫摩尔)溶于三氯甲烷(15.0毫升)中。将上述溶液冷却至0摄氏度后，向其中加入二乙胺基三氟化硫(160毫克，0.99毫摩尔)。反应液在室温下搅拌1小时。Step A: 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)) Pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol (70 mg, 0.13 m Mole) was dissolved in chloroform (15.0 ml). After cooling the above solution to 0 ° C, diethylaminosulfur trifluoride (160 mg, 0.99 mmol) was added thereto. The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(50毫升)淬灭。混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱纯化。分离条件如下，色谱柱；XBridge Shield RP18 OBD Column,5um,19*150mm流动相：A：水(含有0.1％的碳酸氢铵)，B：乙腈。流速：25毫升/分，梯度：5分钟从40％乙腈升至60％乙腈。收集产品，冻干得淡白色固体6-(4-((2-(4-氟四氢-2H-吡喃-4-基)-5-甲基噻唑-4-基)甲氧基)-6-甲氧基[1,5-a]吡啶-2-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(23.9毫克，收率34.7％)。After LCMS monitoring showed the disappearance of the material, the mixture was then evaporated and evaporated. The mixture was extracted with dichloromethane (50 mL×3×). The combined organic layers were washed with brine (50 ml) The residue was purified by high pressure liquid chromatography. 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: from 40% acetonitrile to 60% acetonitrile in 5 minutes. The product was collected and lyophilized to give 6-(4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methoxy) as a pale white solid. 6-methoxy[1,5-a]pyridin-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (23.9 mg, yield 34.7 %).
MS(ESI)M/Z：531[M+H] + MS (ESI) M/Z: 531 [M+H] +
1H NMR(400MHz,CDCl 3):δ8.18(s,1H),7.95(s,1H),7.14(s,1H),6.66(s,1H),5.29(s,2H),4.30(s,3H),4.02-3.93(m,2H),3.92-3.84(m,5H),2.59(s,3H),2.52-2.30(m,2H),2.14-2.05(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ8.18 (s, 1H), 7.95 (s, 1H), 7.14 (s, 1H), 6.66 (s, 1H), 5.29 (s, 2H), 4.30 (s , 3H), 4.02-3.93 (m, 2H), 3.92-3.84 (m, 5H), 2.59 (s, 3H), 2.52-2.30 (m, 2H), 2.14 - 2.05 (m, 2H).
实施例51：SAL02-329Example 51: SAL02-329
3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N，N-二甲基丙酰胺3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N,N-dimethylpropanamide
Figure PCTCN2019086558-appb-000182
Figure PCTCN2019086558-appb-000182
反应流程Reaction process
Figure PCTCN2019086558-appb-000183
Figure PCTCN2019086558-appb-000183
实施例51流程：Example 51 process:
步骤A：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(90毫克，0.45毫摩尔)溶于三氯甲烷(12.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐(1.0毫升，1.34毫摩尔，50％wt的乙酸乙酯溶液)。反应液在室温下搅拌30分钟后，再向其中加入三乙胺(0.38毫升，2.70毫摩尔)和二甲胺盐酸盐(91毫克，1.10毫摩尔)。反应液在室温下搅拌2小时。Step A: 3-(4-(Hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (90 mg, 0.45 mmol) was dissolved in chloroform (12.0 mL). Subsequently, 1-propylphosphoric acid tricyclic anhydride (1.0 ml, 1.34 mmol, 50% by weight of an ethyl acetate solution) was added to the above solution. After the reaction mixture was stirred at room temperature for 30 minutes, triethylamine (0.38 ml, 2.70 mmol) and dimethylamine hydrochloride (91 mg, 1.10 mmol). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用二氯甲烷(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10)，收集产品。粗产品进一步用高效液相色谱纯化，制备条件如下：C18柱；流动相(A相：水(含有10毫摩尔/ 升的甲酸)，B相：乙腈)收集产品浓缩得白色固体3-(4-(羟甲基)-5-甲基噻唑-2-基)-N，N-二甲基丙酰胺(48毫克，47.3％)。After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (30 mL×3×). The combined organic layers were washed with brine (30 ml) The residue was purified by silica gel column chromatography eluting The crude product was further purified by high performance liquid chromatography under the following conditions: C18 column; mobile phase (phase A: water (containing 10 mmol/L formic acid), phase B: acetonitrile). The product was concentrated to give a white solid 3-(4 -(Hydroxymethyl)-5-methylthiazol-2-yl)-N,N-dimethylpropanamide (48 mg, 47.3%).
MS(ESI)M/Z：229[M+H] + MS (ESI) M/Z: 229 [M+H] +
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(435毫克，1.73毫摩尔)和三丁基膦(545毫克，2.70毫摩尔)溶于四氢呋喃(12.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(115毫克，0.36毫摩尔)和3-(4-(羟甲基)-5-甲基噻唑-2-基)-N,N-二甲基丙酰胺(108毫克，0.47毫摩尔)的四氢呋喃(12.0毫升)溶液。反应液在室温下搅拌1小时。Step B: Azodiyldipiperidine (435 mg, 1.73 mmol) and tributylphosphine (545 mg, 2.70 mmol) were dissolved in tetrahydrofuran (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. , 5-a]pyridin-4-ol (115 mg, 0.36 mmol) and 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)-N,N-dimethylpropanamide (108 mg, 0.47 mmol) in tetrahydrofuran (12.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(100毫升)淬灭。混合液用二氯甲烷(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，收集产品，得白色固体3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N，N-二甲基丙酰胺(23.2毫克，收率12.2％)After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (100 mL×3×). The combined organic layers were washed with brine (100 ml) The residue was purified by EtOAc EtOAcjjjjjjjj Oxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5 -methylthiazol-2-yl)-N,N-dimethylpropanamide (23.2 mg, yield 12.2%)
MS(ESI)M/Z：528[M+H] + MS (ESI) M/Z: 528 [M+H] +
1H NMR(300MHz,DMSO-d 6)δ8.31(s,1H),8.05(s,1H),6.72(s,1H),6.70(s,1H),5.23(s,2H),4.20(s,3H),3.82(s,3H),3.13(t,J＝6.9Hz,2H),2.97(s,3H),2.82(s,3H),2.77(t,J＝7.2Hz,2H),2.46(s,3H). 1 H NMR (300MHz, DMSO- d 6) δ8.31 (s, 1H), 8.05 (s, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 5.23 (s, 2H), 4.20 ( s, 3H), 3.82 (s, 3H), 3.13 (t, J = 6.9 Hz, 2H), 2.97 (s, 3H), 2.82 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 2.46(s,3H).
实施例52：SAL02-338Example 52: SAL02-338
1-(4-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-腈1-(4-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1, 5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)azetidin-3-carbonitrile
Figure PCTCN2019086558-appb-000184
Figure PCTCN2019086558-appb-000184
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000185
Figure PCTCN2019086558-appb-000185
实施例52流程：Example 52 process:
步骤A：在室温和氮气保护下，将(2-溴-5-甲基噻唑-4-基)甲醇(200毫克，0.96毫摩尔)溶于1，4-二氧六环(10.0毫升)中。随后，向上述溶液中加入氮杂环丁烷-3-腈盐酸盐(171毫克，1.44毫摩尔)，三(二亚苄基丙酮)二钯(44毫克，0.048毫摩尔)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(55.6毫克，0.096毫摩尔)和无水碳酸铯(939毫克，2.88毫摩尔)。将反应液加热至120摄氏度并搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭反应。混合液用乙酸乙酯(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)，得到黄色固体1-(4-(羟甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-腈(100毫克，收率49.7％)。After LCMS monitoring showed disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with brine (10 ml) The crude product was purified by silica gel column chromatography eluting Cyclobutane-3-nitrile (100 mg, yield 49.7%).
MS(ESI)M/Z：210[M+H +]。 MS (ESI) M / Z: 210 [M+H + ].
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(781毫克，3.1毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中加入三丁基膦(970毫克，4.8毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和1-(4-(羟甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-腈(99毫克，0.47毫摩尔)的四氢呋喃(3.0毫升)。反应液在室温下搅拌3小时。Step B: Azodiyldipiperidine (781 mg, 3.1 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (970 mg, 4.8 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. Pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and 1-(4-(hydroxymethyl)-5-methylthiazol-2-yl)azacyclo Butane-3-carbonitrile (99 mg, 0.47 mmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at room temperature for 3 hours.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠溶液(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经高压制备分离。分离条件如下，色谱柱；XBridge Shield RP18 OBD Column,5um,19*150mm流动相：A：水(含有0.1％的碳酸氢铵)，B：乙腈。流速：25毫升/分，梯度：5分钟从25％乙腈升至55％乙腈。收集产品，冻干得1-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-腈(11.5毫克，收率：7.1％)After LCMS monitoring showed the disappearance of the material, a saturated aqueous sodium hydrogen carbonate solution (10 ml) was then evaporated. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The crude product was separated by high pressure preparation. 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 1-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)azetidin-3-nitrile (11.5 mg, yield: 7.1) %)
MS(ESI)M/Z：509[M+H +]。 MS (ESI) M/Z: 495 [M+H + ].
1H NMR(300MHz,CDCl 3):δ8.01(s,1H),7.80(s,1H),6.97(s,1H),6.46(s,1H),5.09(s,2H),4.48-4.31(m,4H),4.24(s,3H),3.85(s,3H),3.75-3.65(m,1H),2.40(s,3H) 1 H NMR (300MHz, CDCl 3 ): δ8.01 (s, 1H), 7.80 (s, 1H), 6.97 (s, 1H), 6.46 (s, 1H), 5.09 (s, 2H), 4.48-4.31 (m, 4H), 4.24 (s, 3H), 3.85 (s, 3H), 3.75-3.65 (m, 1H), 2.40 (s, 3H)
实施例53：SAL02-335Example 53: SAL02-335
N-(氰基甲基)-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a] 吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺N-(cyanomethyl)-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole) -6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide
Figure PCTCN2019086558-appb-000186
Figure PCTCN2019086558-appb-000186
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000187
Figure PCTCN2019086558-appb-000187
实施例53流程：Example 53 process:
步骤A：在室温和氮气保护下，将(2-溴-5-甲基噻唑-4-基)甲醇(2.00克，9.61毫摩尔)和(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)丙烯酸乙酯(4.35克，19.2毫摩尔)溶于1,4-二氧六环(40.0毫升)和水(8.0毫升)的混合溶液中。随后，向上述溶液中依次加入无水碳酸钾(2.66克，19.2毫摩尔)，四三苯基膦钯(560毫克，0.48毫摩尔)。将反应液加热至80摄氏度并搅拌6小时。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. Subsequently, anhydrous potassium carbonate (2.66 g, 19.2 mmol), tetrakistriphenylphosphine palladium (560 mg, 0.48 mmol) was sequentially added to the above solution. The reaction solution was heated to 80 ° C and stirred for 6 hours.
LCMS监测显示原料消失后，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，得到(E)-3-(4-(羟甲基)-5-甲基噻唑-2-基)丙烯酸乙酯(2.10克，收率95.7％)。After LCMS showed the disappearance of the starting material, the mixture was extracted with ethyl acetate (20 mL×3×), and the organic phase was combined. The organic phase was washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate and filtered. Concentrate under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Ethyl acrylate (2.10 g, yield 95.7%).
MS(ESI)M/Z：228[M+H +]。 MS (ESI) M / Z: 228 [M+H + ].
步骤B：将(E)-3-(4-(羟甲基)-5-甲基噻唑-2-基)丙烯酸乙酯(900毫克，3.96毫摩尔)溶于甲醇(20.0毫升)中。随后，向上述溶液中加入有水钯碳(900毫克，10％)。随后，反应体系用氢气置换三次。反应液在室温下搅拌2小时。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.
LCMS监测显示原料消失后，过滤，所得滤液在减压下浓缩。得到无色油状物3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸乙酯(900毫克，粗品)，无需纯化，直接用于下一步反应。After LCMS monitoring showed disappearance of the starting material, it was filtered and the filtrate was concentrated under reduced pressure. Ethyl 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoate (900 mg, crude) was obtained as a colourless oil.
MS(ESI)M/Z：230[M+H +]。 MS (ESI) M/Z: 230 [M+H + ].
步骤C：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸乙酯(400毫克，1.75毫摩尔)溶于乙醇(2.0毫升)和水(2.0毫升)的混合溶液中。随后，向上述溶液中加入一水合氢氧化锂(366毫克，8.73毫摩尔)。反应液在室温下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入盐酸(3.0毫升，2.0摩尔/升)淬灭。混合液在减压下直接浓缩。粗产品经液相色谱制备纯化，制备条件如下，C18，(流动相：A：水(含有0.05％三氟乙酸)，B：乙腈。流速：50毫升/分，梯度：20分钟从0％乙腈升至35％乙腈。收集产品，得到浅黄色固体3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(330毫克，收率94.0％)。After LCMS monitoring showed the disappearance of the starting material, hydrochloric acid (3.0 mL, 2.0 mol/L) was added to the reaction mixture to quench. The mixture was concentrated directly under reduced pressure. The crude product was purified by liquid chromatography to give C18, (mobile phase: A: water (containing 0.05% trifluoroacetic acid), B: acetonitrile. Flow rate: 50 ml/min, gradient: 20 minutes from 0% acetonitrile The product was taken up to 35% acetonitrile, and the product was collected to give 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (330 mg, yield: 94.0%).
MS(ESI)M/Z：202[M+H +]。 MS (ESI) M / Z: 202 [M + H +].
步骤D：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(200毫克，0.99毫摩尔)溶于N,N-二甲基甲酰胺(2.0毫升)中。随后，向上述溶液中依次加入甲氨基乙腈盐酸盐(130毫克，1.19毫摩尔)，O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(570毫克，1.49毫摩尔)和N,N-二异丙基乙胺(390毫克，2.98毫摩尔)。反应液在室温下搅拌1小时。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.
LCMS监测显示原料消失后，向反应液中加入水(3毫升)淬灭。混合液用二氯甲烷/甲醇混合溶液萃取(5毫升×3次，5/1)。合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到无色晶状固体N-(氰基甲基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(150毫克，收率59.6％)。After LCMS monitoring showed the disappearance of the starting material, water (3 mL) was added to the reaction mixture to quench. The mixture was extracted with a dichloromethane/methanol mixed solution (5 ml × 3 times, 5/1). The combined organic layers were washed with brine (5 ml) The crude product was purified by EtOAc EtOAcjjjjjjj 5-5-methylthiazol-2-yl)-N-methylpropanamide (150 mg, yield 59.6%).
MS(ESI)M/Z：254[M+H +]。 MS (ESI) M / Z: 254 [M+H + ].
步骤E：在室温和氮气保护下，将偶氮二甲酰二哌啶(386毫克，1.51毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基膦(478毫克，2.37毫摩尔)。反应液在室温下搅拌20分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和N-(氰基甲基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(86毫克，0.38毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌1小时。Step E: Azodiyldipiperidine (386 mg, 1.51 mmol) was dissolved in tetrahydrofuran (10.0 mL). Subsequently, tributylphosphine (478 mg, 2.37 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. Pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and N-(cyanomethyl)-3-(4-(hydroxymethyl)-5-methyl A solution of thiazol-2-yl)-N-methylpropanamide (86 mg, 0.38 mmol) in THF (10.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠水溶液(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。After LCMS monitoring showed the disappearance of the material, aq. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
粗产品经高压液相色谱制备纯化，分离条件如下，色谱柱；XBridge Shield RP18 OBD Column,5um,19*150mm流动相：A：水(含有0.1％的碳酸氢铵)，B：乙腈。流速：25毫升/分，梯度：5分钟从25％乙腈升至55％乙腈。收集产品，冻干得，得到白色固体N-(氰基甲基)-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(16.8毫克，收率9.48％)。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. [1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N -methylpropanamide (16.8 mg, yield 9.48%).
MS(ESI)M/Z：553[M+H +]。 MS (ESI) M / Z: 553 [M+H + ].
1H NMR(300MHz,DMSO-d 6)：δ8.08(s,1H),7.84(s,1H),7.06(s,1H),6.53(s,1H),5.24(s,2H),4.40(s,2H),4.26(s,3H),3.86(s,3H),3.35-3.39(m,2H)，3.29(s,3H),3.00–2.95(m，2H)，2.52(s,3H)。 1 H NMR (300MHz, DMSO- d 6): δ8.08 (s, 1H), 7.84 (s, 1H), 7.06 (s, 1H), 6.53 (s, 1H), 5.24 (s, 2H), 4.40 (s, 2H), 4.26 (s, 3H), 3.86 (s, 3H), 3.35-3.39 (m, 2H), 3.29 (s, 3H), 3.00 - 2.95 (m, 2H), 2.52 (s, 3H) ).
实施例54：SAL02-337Example 54: SAL02-337
3-(乙基(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶哌啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氨基)丙腈3-(ethyl(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyridyl) Zoxa[1,5-a]pyridinylpiperidin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)amino)propanenitrile
Figure PCTCN2019086558-appb-000188
Figure PCTCN2019086558-appb-000188
反应流程:Reaction process:
Figure PCTCN2019086558-appb-000189
Figure PCTCN2019086558-appb-000189
实施例54流程：Example 54 process:
步骤A：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(1.00克，3.12毫摩尔)，3-(乙基氨基)丙腈(610毫克，6.22毫摩尔)，三(二亚苄基丙酮)二钯(143毫克，9.35毫摩尔)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(180毫克，0.31毫摩尔)，无水碳酸铯(3.05克，9.35毫摩尔)溶于甲苯(10.0毫升)中。将反应液加热至120摄氏度并搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(80毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝4/1)，收集产品，得到类白色固体3-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(乙基)氨基)丙腈(635毫克，收率60.3％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (80 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Oxy)methyl)-5-methylthiazol-2-yl)(ethyl)amino)propanenitrile (635 mg, yield 60.3%).
MS(ESI)M/Z：340[M+H +]。 MS (ESI) M/Z: 340 [M+H + ].
步骤B：将3-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(乙基)氨基)丙腈(240毫克，0.71毫摩尔)溶于四氢呋喃(10毫升)中。随后，向上述溶液中加入四丁基氟化胺(1.42毫升，1.42毫摩尔)。反应液在室温下搅拌1小时。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.
LCMS监测显示原料消失后，将反应液在减压下浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，收集产品，得到淡黄色固体3-(乙基(4-(羟甲基)-5-甲基噻唑-2-基)氨基)丙腈(150毫克，收率93.7％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Thiazole-2-yl)amino)propanenitrile (150 mg, yield 93.7%).
MS(ESI)M/Z：226[M+H +]。 MS (ESI) M/Z: 226 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(1.12克，4.44毫摩尔)溶于四氢呋喃(7.0毫升)中。随后，向上述溶液中加入三丁基磷(1.20克，5.56毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入3-(乙基(4-(羟甲基)-5-甲基噻唑-2-基)氨基)丙腈(125毫克，0.56毫摩尔)和6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(176毫克，0.56毫摩尔)的四氢呋喃溶液(5.0毫升)。反应液在室温下搅拌2小时。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. And 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine A solution of -4-ol (176 mg, 0.56 mmol) in tetrahydrofuran (5.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(20毫升 ×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸干燥，过滤，所得滤液在减压下浓缩。所得残余物经制备纯化，色谱柱；XBridge Shield RP18 OBD Column,5um,19*150mm流动相：A：水(含有0.1％的甲酸)，B：乙腈。流速：25毫升/分，梯度：5分钟从25％乙腈升至55％乙腈。收集产品，冻干得到类白色固体3-(乙基(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶哌啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氨基)丙腈(39.2毫克，收率13.5％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 mL) then dried over anhydrous The residue obtained was purified by preparative chromatography; XBridge Shield RP18 OBD Column, 5 um, 19*150 mm mobile phase: A: water (containing 0.1% formic acid), B: acetonitrile. Flow rate: 25 ml/min, gradient: 5 minutes from 25% acetonitrile to 55% acetonitrile. The product was collected and lyophilized to give an off-white solid 3-(ethyl(4-((6-methoxy-2-(2-methoxy)im[2,1-b][1,3,4]] Thiazol-6-yl)pyrazolo[1,5-a]pyridinylpiperidin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)amino)propanenitrile (39.2 mg , yield 13.5%).
MS(ESI)M/Z：525[M+H +]。 MS (ESI) M/Z: 525 [M+H + ].
1H NMR(300MHz,CDCl 3)：δ8.00(s,1H),7.80(s,1H),6.94(s,1H),6.59(s,1H),5.11(s,2H),4.23(s,3H),3.87-3.84(m,5H),3.53-3.48(m,2H),2.87-2.83(m,2H),2.39(s,3H),1.30(t,J＝7.2Hz,3H). 1H NMR (300MHz, CDCl 3) : δ8.00 (s, 1H), 7.80 (s, 1H), 6.94 (s, 1H), 6.59 (s, 1H), 5.11 (s, 2H), 4.23 (s, 3H), 3.87-3.84 (m, 5H), 3.53-3.48 (m, 2H), 2.87-2.83 (m, 2H), 2.39 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).
实施例55：SAL02-339Example 55: SAL02-339
2-(1-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-基)乙腈2-(1-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridyl) Zoxao[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)azetidin-3-yl)acetonitrile
Figure PCTCN2019086558-appb-000190
Figure PCTCN2019086558-appb-000190
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000191
Figure PCTCN2019086558-appb-000191
实施例55流程：Example 55 process:
步骤A：在室温和氮气保护下，将(2-溴-5-甲基噻唑-4-基)甲醇(150毫克，0.72毫摩尔)，2-(氮杂环丁烷-3-基)乙腈(143毫克，1.08毫摩尔)，三(二亚苄基丙酮)二钯(33毫克，0.04毫摩尔)，无水碳酸铯(704毫克，2.16毫摩尔)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(42毫克，0.07毫摩尔)溶于1,4-二氧六环(10.0毫升)。将反应液加热至120摄氏度并搅拌过夜。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.
LCMS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得滤液经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/6)得到黄色固 体2-(1-(4-(羟甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-基)乙腈(127毫克，收率78.8％)。After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The obtained filtrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 6) to afford 2-(1-(4-(hydroxymethyl)-5-methylthiazol-2-yl) Azetidine-3-yl)acetonitrile (127 mg, yield 78.8%).
MS(ESI)M/Z：224[M+H +]。 MS (ESI) M / Z: 224 [M+H + ].
步骤B:在室温和氮气保护下，将偶氮二甲酰二哌啶(478毫克，2.36毫摩尔)和三丁基膦(378毫克，1.51毫摩尔)溶于四氢呋喃(2.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和2-(1-(4-(羟甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-基)乙腈(106毫克，0.47毫摩尔)的四氢呋喃溶液(3.0毫升)。反应液在35摄氏度下搅拌2小时。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. , 5-a]pyridin-4-ol (100 mg, 0.32 mmol) and 2-(1-(4-(hydroxymethyl)-5-methylthiazol-2-yl)azetidin-3 A solution of acetonitrile (106 mg, 0.47 mmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at 35 ° C for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，收集产品，粗产品再经高压液相色谱纯化，制备条件如下：色谱柱：XBridge Prep OBD C18 19mm*250mm,5um；流动相：水(含有10毫摩尔/升的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从41％升到50％；检测波长：254nm。减压冻干得类白色固体2-(1-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氮杂环丁烷-3-基)乙腈(16.4毫克，收率9.8％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 ml) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/1). The product was collected and the crude product was purified by high-pressure liquid chromatography. 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. Lyophilized to give a white solid 2-(1-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4] thiophene) Diazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)azetidin-3-yl) Acetonitrile (16.4 mg, yield 9.8%).
MS(ESI)M/Z：523[M+H] + MS (ESI) M/Z: 523 [M+H] +
1H NMR(300MHz,CDCl 3)：δ8.00(s,1H),7.79(s,1H),6.94(s,1H),6.48(s,1H),5.14(s,2H),4.40(t,J＝8.3Hz,2H),4.23(s,3H),4.00(d,J＝6.3Hz,2H),3.84(s,3H),3.22-3.17(m,1H),2.79(d,J＝7.2Hz,2H),2.39(s,3H). 1 H NMR (300MHz, CDCl 3 ): δ8.00 (s, 1H), 7.79 (s, 1H), 6.94 (s, 1H), 6.48 (s, 1H), 5.14 (s, 2H), 4.40 (t , J = 8.3 Hz, 2H), 4.23 (s, 3H), 4.00 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.22-3.17 (m, 1H), 2.79 (d, J = 7.2 Hz, 2H), 2.39 (s, 3H).
实施例56：SAL02-344Example 56: SAL02-344
N-乙基-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺N-ethyl-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide
Figure PCTCN2019086558-appb-000192
Figure PCTCN2019086558-appb-000192
反应流程:Reaction process:
Figure PCTCN2019086558-appb-000193
Figure PCTCN2019086558-appb-000193
实施例56流程：Example 56 process:
步骤A：在室温下，将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(120毫克，0.59毫摩尔)溶于二氯甲烷(15.0毫升)中。随后，向上述溶液中依次加入甲乙胺盐酸盐(143毫克，1.49摩尔)，三 乙胺(362毫克，3.58毫摩尔)和1-丙基磷酸三环酸酐(1.00毫升，1.34毫摩尔，50％wt的乙酸乙酯溶液)。反应液在室温条件下搅拌2小时。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.
LCMS监测显示原料消失后，向反应液中加入水(40毫升)淬灭。混合液用二氯甲烷溶液(40毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(40毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，收集产品，得到N-乙基-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(79毫克，收率55.3％)。After LCMS monitoring showed the disappearance of the starting material, water (40 mL) was added to the reaction mixture to quench. The mixture was extracted with a methylene chloride solution (40 ml × 3×), and the organic layer was evaporated. . The crude product was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1 / 30), and product was collected to give N-ethyl-3-(4-(hydroxymethyl)-5-methylthiazole- 2-Based)-N-methylpropanamide (79 mg, yield 55.3%).
MS(ESI)M/Z：243[M+H +]。 MS (ESI) M / Z: 243 [M+H + ].
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(342毫克，1.36毫摩尔)和三丁基膦(428毫克，2.12毫摩尔)溶于四氢呋喃(12.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(90毫克，0.28毫摩尔)和N-乙基-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(89毫克，0.37毫摩尔)的四氢呋喃溶液(12.0毫升)。反应液在室温下搅拌1小时。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. , 5-a]pyridin-4-ol (90 mg, 0.28 mmol) and N-ethyl-3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)-N-methyl A solution of propionamide (89 mg, 0.37 mmol) in tetrahydrofuran (12.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(40毫升)淬灭。混合液用二氯甲烷(40毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(40毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩，所得滤液减压下浓缩。粗产品经高压液相色谱制备纯化，制备条件下：X Bridge Prep OBD C18 Column；19×250um；流动相：水(含有10毫摩尔/升的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在10分钟内，乙腈从35％升到42％，检测波长：254nm。减压冻干得淡白色固体N-乙基-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(33.4毫克，收率22.0％)。After LCMS monitoring showed the disappearance of the starting material, water (40 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (40 mL×3×), and then evaporated. The resulting filtrate was concentrated under reduced pressure. The crude product was purified by high pressure liquid chromatography under the conditions of preparation: X Bridge Prep OBD C18 Column; 19×250 um; mobile phase: water (containing 10 mmol/L of ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml/min Gradient: acetonitrile rose from 35% to 42% in 10 minutes, detection wavelength: 254 nm. Lyophilized to give a pale white solid N-ethyl-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4) Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide 33.4 mg, yield 22.0%).
MS(ESI)M/Z：542[M+H] + MS (ESI) M/Z: 542 [M+H] +
1H NMR(400MHz,CDCl 3)：δ8.03(s,1H),7.82(s,1H),6.97(s,1H),6.52(s,1H),5.27(s,2H),4.24(s,3H),3.85(s,3H),3.46(m,1H),3.38(m,3H),2.98(d,J＝21.4Hz,3H),2.89(m,2H),2.51(s,3H),1.16(dt,J＝28.2,7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.03 (s, 1H), 7.82 (s, 1H), 6.97 (s, 1H), 6.52 (s, 1H), 5.27 (s, 2H), 4.24 (s , 3H), 3.85 (s, 3H), 3.46 (m, 1H), 3.38 (m, 3H), 2.98 (d, J = 21.4 Hz, 3H), 2.89 (m, 2H), 2.51 (s, 3H) , 1.16 (dt, J = 28.2, 7.2 Hz, 3H).
实施例57：SAL02-348Example 57: SAL02-348
N-(2-氰基乙基)-3-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺N-(2-cyanoethyl)-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thia) Zh-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide
Figure PCTCN2019086558-appb-000194
Figure PCTCN2019086558-appb-000194
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000195
Figure PCTCN2019086558-appb-000195
实施例57流程：Example 57 process:
步骤A：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(400毫克，1.99毫摩尔)溶于N,N-二甲基甲酰胺(50.0毫升)中。随后，向上述溶液中依次加入N,N-二异丙基乙胺(1.54克，11.9毫摩尔)，3-(甲基氨基)丙腈(501毫克，5.97毫摩尔)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(1.51克，3.98毫摩尔)。反应液在室温下搅拌1小时。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.
LCMS监测显示原料消失后，向反应液里加入水(50毫升)淬灭。混合液用乙酸乙酯(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)，收集产品，得到黄色油状物N-(2-氰基乙基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(330毫克，收率61.9％)。After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (30 mL×3×). The combined organic layers were washed with brine (20 ml) The crude product was purified by EtOAc EtOAcjjjjjjjj Methyl)-5-methylthiazol-2-yl)-N-methylpropanamide (330 mg, yield 61.9%).
MS(ESI)M/Z：268[M+H] + MS (ESI) M/Z: 268 [M+H] +
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(764毫克，3.03毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基磷(957毫克，4.73毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和N-(2-氰基乙基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(169毫克，0.64毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌2小时。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. Pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and N-(2-cyanoethyl)-3-(4-(hydroxymethyl)-5- Methylthiazol-2-yl)-N-methylpropanamide (169 mg, 0.64 mmol) in tetrahydrofuran (10.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱制备，制备条件下：X Bridge Prep OBD C18 Column；19x250um；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在10分钟内，乙腈从35％升到42％，检测波长：254nm。减压冻干得N-(2-氰基乙基)-3-(4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(73.1毫克，收率40.3％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (30 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was prepared by high pressure liquid chromatography under the conditions of preparation: X Bridge Prep OBD C18 Column; 19×250 um; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: Within 10 minutes, acetonitrile rose from 35% to 42% with a detection wavelength of 254 nm. Lyophilization under reduced pressure gave N-(2-cyanoethyl)-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3 ,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide (73.1 mg, yield 40.3%).
MS(ESI)M/Z：567[M+H +]。 MS (ESI) M/Z: 564 [M+H + ].
1H NMR(300MHz,DMSO-d 6)δ8.32(s,1H),8.05(s,1H),6.72(s,1H),6.70(s,1H),5.23(s,2H),4.20(s,3H),3.82(s,3H),3.66-3.52(m,2H),3.18-3.10(m,2H),3.04(s,2H),2.86-2.78(m,3H),2.69(t,J＝6.7Hz,2H),2.46(s,3H)。 1 H NMR (300MHz, DMSO- d 6) δ8.32 (s, 1H), 8.05 (s, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 5.23 (s, 2H), 4.20 ( s, 3H), 3.82 (s, 3H), 3.66-3.52 (m, 2H), 3.18-3.10 (m, 2H), 3.04 (s, 2H), 2.86-2.78 (m, 3H), 2.69 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H).
实施例58：SAL02-351Example 58: SAL02-351
2-(乙基(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶哌啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氨基)乙腈2-(ethyl(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridyl) Zoxa[1,5-a]pyridinylpiperidin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)amino)acetonitrile
Figure PCTCN2019086558-appb-000196
Figure PCTCN2019086558-appb-000196
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000197
Figure PCTCN2019086558-appb-000197
实施例58流程：Example 58 Process:
步骤A：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(500毫克，1.56毫摩尔)和2-(乙基氨基)乙腈(250毫克，2.98毫摩尔)溶于甲苯(10.0毫升)中。随后，向上述溶液中依次加入无水碳酸铯(1.52克，4.68毫摩尔)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(70毫克，0.08毫摩尔)和三(二亚苄基丙酮)二钯(70毫克，0.08毫摩尔)。将反应液加热至120摄氏度并搅拌2小时。Step A: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (500 mg, 1.56 mmol) and mp. 2-(Ethylamino)acetonitrile (250 mg, 2.98 mmol) was dissolved in toluene (10.0 mL). Subsequently, anhydrous cesium carbonate (1.52 g, 4.68 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime (70 mg, 0.08 mmol) and then were added to the above solution. Tris(dibenzylideneacetone)dipalladium (70 mg, 0.08 mmol). The reaction solution was heated to 120 ° C and stirred for 2 hours.
LCMS监测显示原料消失后，将反应液在减压下直接浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)，得到黄色油状产品2-((4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(乙基)氨基)乙腈(323毫克，收率63.8％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut )methyl)-5-methylthiazol-2-yl)(ethyl)amino)acetonitrile (323 mg, yield 63.8%).
MS(ESI)M/Z：326[M+H +]。 MS (ESI) M / Z: 326 [M+H + ].
步骤B：将3-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-5-甲基噻唑-2-基)(甲基)氨基)丙腈(120毫克，0.37毫摩尔)溶于四氢呋喃(2.0毫升)中。随后，向上述溶液中加入四丁基氟化铵的四氢呋喃溶液(1.0毫升，1.0摩尔/升)。反应液在室温下搅拌30分钟。Step B: 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)(methyl)amino)propanenitrile (120) Mg, 0.37 mmol) was dissolved in tetrahydrofuran (2.0 mL). Subsequently, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 ml, 1.0 mol/liter) was added to the above solution. The reaction solution was stirred at room temperature for 30 minutes.
LCMS监测显示原料消失后，向反应液中加入水(5毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物用硅胶柱纯化(洗脱剂：乙酸乙酯/二氯甲烷＝1/2)，收集产品，得到白色固体2-(乙基(4-(羟甲基)-5-甲基噻唑-2-基)氨基)乙腈(70毫克，收率89.7％)。After LCMS monitoring showed the disappearance of the starting material, water (5 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified to silica gel elutd elut elut elut elut elut elut 2-yl)amino)acetonitrile (70 mg, yield 89.7%).
MS(ESI)M/Z：212[M+H +]。 MS (ESI) M / Z: 212 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(242毫克，0.96毫摩尔)溶于四氢呋喃(4.0毫升)中。随后，向上述溶液中加入三丁基膦(311毫克，1.44毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(87毫克，0.28毫摩尔)和2-(乙基(4-(羟甲基)-5-甲基噻唑-2-基)氨基)乙腈(64毫克，0.30毫摩尔)的四氢呋喃溶液(4.0毫升)。反应液在室温下搅拌1小时。Step C: Azodiyldipiperidine (242 mg, 0.96 mmol) was dissolved in tetrahydrofuran (4.0 mL). Subsequently, tributylphosphine (311 mg, 1.44 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. Pyrazolo[1,5-a]pyridin-4-ol (87 mg, 0.28 mmol) and 2-(ethyl(4-(hydroxymethyl)-5-methylthiazol-2-yl) Amino)acetonitrile (64 mg, 0.30 mmol) in tetrahydrofuran (4.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100)，收集产品，粗产品用N,N-二甲基甲酰胺(2毫升)溶至澄清，再经制备型高效液相色谱纯化。纯化条件如下， 色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％甲酸)和乙腈；流速:20毫升/分钟；梯度：在7分钟内，乙腈从30％升到50％；检测波长：254nm。收集产品，低温冻干得到白色固体2-(乙基(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)氨基)乙腈(21.6毫克，收率15.1％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Preparative high performance liquid chromatography purification. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 20 ml / min; gradient: acetonitrile from 30% to 50% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give a white solid 2-(ethyl(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]] Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)amino)acetonitrile (21.6 mg, yield 15.1%).
MS(ESI)M/Z：511[M+H +]。 MS (ESI) M/Z: 511 [M+H + ].
1H NMR(300MHz,CDCl 3)：δ8.02(s,1H),7.80(s,1H),6.97(s,1H),6.51(s,1H),5.10(s,2H),4.48(s,2H),4.23(s,3H)，3.85(s,3H),3.49(q,J＝7.1Hz,2H),2.40(s,3H),1.36(t,J＝7.1Hz,3H)。 1 H NMR (300MHz, CDCl 3 ): δ8.02 (s, 1H), 7.80 (s, 1H), 6.97 (s, 1H), 6.51 (s, 1H), 5.10 (s, 2H), 4.48 (s , 2H), 4.23 (s, 3H), 3.85 (s, 3H), 3.49 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).
实施例59：SAL02-355Example 59: SAL02-355
N-环丁基-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺N-cyclobutyl-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-) Pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylpropanamide
Figure PCTCN2019086558-appb-000198
Figure PCTCN2019086558-appb-000198
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000199
Figure PCTCN2019086558-appb-000199
实施例59流程：Example 59 process:
步骤A：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(202毫克，1.00毫摩尔)，N-甲基环丁胺(255毫克，3.00毫摩尔)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(760毫克，2.00毫摩尔)，N,N-二异丙基乙基胺(744毫克，6.00毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。反应液在室温下搅拌2小时。Step A: 3-(4-(Hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (202 mg, 1.00 mmol), N-methylcyclobutylamine (255 mg, 3.00 mmol) , 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (760 mg, 2.00 mmol), N,N-diisopropyl The amine (744 mg, 6.00 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(50毫升)淬灭。混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/3)，收集产品，得到白色固体N-环丁基-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(127毫克，收率47.4％)。After LCMS monitoring showed the disappearance of the starting material, water (50 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with brine (50 ml) The residue was purified by EtOAc EtOAcjjjjjjjjj Methylthiazol-2-yl)-N-methylpropanamide (127 mg, yield 47.4%).
MS(ESI)M/Z:269[M+H +]。 MS (ESI) M / Z: 269 [M+H + ].
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(381毫克，1.51毫摩尔)溶于四氢呋喃(5.0毫升)中。随后，向上述溶液中加入三丁基膦(458毫克，2.27毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和N-环丁基-3-(4-(羟甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺 (127毫克，0.47毫摩尔)的四氢呋喃溶液(5.0毫升)中。反应液在室温下搅拌2小时。Step B: Azodiyldipiperidine (381 mg, 1.51 mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently, tributylphosphine (458 mg, 2.27 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. Pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and N-cyclobutyl-3-(4-(hydroxymethyl)-5-methylthiazole-2 -N-methylpropanamide (127 mg, 0.47 mmol) in tetrahydrofuran (5.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中水(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物通过硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)，得到白色固体N-环丁基-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-N-甲基丙酰胺(18.0毫克，收率9.89％)。After LCMS showed the disappearance of the starting material, the mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by EtOAc EtOAcjjjjjjjjj 2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl -5-Methylthiazol-2-yl)-N-methylpropanamide (18.0 mg, yield 9.89%).
MS(ESI)M/Z：568[M+H +]。 MS (ESI) M / Z: 568 [M+H + ].
1H NMR(300MHz,CDCl 3):δ7.98(s,1H),7.78(s,1H),6.92(s,1H),6.45(s,1H),5.22(s,2H),5.07-4.97(m,0.5H),4.42-4.33(m,0.5H),4.22(s,3H),3.84(s,3H),3.30(t,J＝7.4Hz,2H),2.96(s,3H),2.90-2.79(m,2H),2.48(s,3H),2.29-2.04(m,4H),1.76-1.63(m,2H)。 1 H NMR (300MHz, CDCl 3 ): δ7.98 (s, 1H), 7.78 (s, 1H), 6.92 (s, 1H), 6.45 (s, 1H), 5.22 (s, 2H), 5.07-4.97 (m, 0.5H), 4.42-4.33 (m, 0.5H), 4.22 (s, 3H), 3.84 (s, 3H), 3.30 (t, J = 7.4 Hz, 2H), 2.96 (s, 3H), 2.90-2.79 (m, 2H), 2.48 (s, 3H), 2.29-2.04 (m, 4H), 1.76-1.63 (m, 2H).
实施例60：SAL02-349Example 60: SAL02-349
4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)丁腈4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)butyronitrile
Figure PCTCN2019086558-appb-000200
Figure PCTCN2019086558-appb-000200
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000201
Figure PCTCN2019086558-appb-000201
实施例60流程：Example 60 process:
步骤A：在室温和氮气保护下，将锌粉(974毫克，14.9毫摩尔)和碘(189毫克，0.75毫摩尔)加入N,N-二甲基甲酰胺(20.0毫升)中。将反应液加热至50摄氏度并搅拌30分钟。随后，向上述溶液中加入4-溴丁腈(551毫克，3.72毫摩尔)。反应液在50摄氏度下搅拌90分钟。Step A: Zinc powder (974 mg, 14.9 mmol) and iodine (189 mg, 0.75 mmol) were added to N,N-dimethylformamide (20.0 mL). The reaction solution was heated to 50 ° C and stirred for 30 minutes. Subsequently, 4-bromobutyronitrile (551 mg, 3.72 mmol) was added to the above solution. The reaction solution was stirred at 50 ° C for 90 minutes.
在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-5-甲基-噻唑(1.20克，3.72毫摩尔)和二(三苯基膦)二氯化钯(522毫克，0.75毫摩尔)溶于N,N-二甲基甲酰胺(15.0毫升)中，反应液搅拌10分钟后。将该溶液加入到第一步的反应体系中。反应液在70摄氏度下搅拌过夜。2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-thiazole (1.20 g, 3.72 mmol) and two at room temperature under nitrogen. (Triphenylphosphine) palladium dichloride (522 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (15.0 ml), and the mixture was stirred for 10 min. This solution was added to the reaction system of the first step. The reaction was stirred at 70 ° C overnight.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭反应。混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝4/1)，得到黄色油状液体4-(4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)丁腈(472毫克，收 率40.6％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (50 mL×3×). The combined organic layers were washed with brine (50 ml) The residue was purified by EtOAc EtOAcjjjjjjjj 5-(methylthiazol-2-yl)butyronitrile (472 mg, yield 40.6%).
MS(ESI)M/Z：311[M+H +]。 MS (ESI) M / Z: 311 [M+H + ].
步骤B:在室温下，将4-(4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)丁腈(472毫克，1.52毫摩尔)溶于四氢呋喃(45毫升)中。随后，向上述溶液中加入四丁基氟化铵(794毫克，3.04毫摩尔)的四氢呋喃溶液(45毫升)。反应液在室温条件下搅拌1小时。Step B: 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)butanenitrile (472 mg, 1.52 m) at room temperature Mole) was dissolved in tetrahydrofuran (45 ml). Subsequently, tetrabutylammonium fluoride (794 mg, 3.04 mmol) in tetrahydrofuran (45 ml) was added to the above solution. The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用二氯甲烷(40毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(40毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/9)得到黄色固体4-(4-(羟甲基)-5-甲基噻唑-2-基)丁腈(174毫克，收率58.2％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with methylene chloride (40 mL, EtOAc). The crude product was purified by silica gel column chromatography eluting (174 mg, yield 58.2%).
MS(ESI)M/Z：197[M+H +]。 MS (ESI) M / Z: 197 [M+H + ].
步骤C:在室温和氮气保护下，将偶氮二甲酰二哌啶(877毫克，4.34毫摩尔)和三丁基膦(694毫克，2.77毫摩尔)溶于四氢呋喃(4.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(183毫克，0.58毫摩尔)和4-(4-(羟甲基)-5-甲基噻唑-2-基)丁腈(170毫克，0.87毫摩尔)的四氢呋喃溶液(6.0毫升)。反应液在室温下搅拌1小时。Step C: Azodiyldipiperidine (877 mg, 4.34 mmol) and tributylphosphine (694 mg, 2.77 mmol) were dissolved in tetrahydrofuran (4.0 mL). Subsequently, 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1] was added to the above solution. , 5-a]pyridin-4-ol (183 mg, 0.58 mmol) and 4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)butyronitrile (170 mg, 0.87 mmol) A solution of tetrahydrofuran (6.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水洗涤(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品用高效液相制备，制备条件如下：色谱柱：XBridge Prep OBD C18 19mm*250mm,5um；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从45％升到49％；检测波长：254nm/220nm。减压冻干得到类白色固体4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)丁腈(37.1毫克，收率12.8％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 mL)EtOAc. The crude product was prepared by high-performance liquid phase, and the preparation conditions were as follows: column: XBridge Prep OBD C18 19 mm*250 mm, 5 um; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; Gradient: acetonitrile was increased from 45% to 49% in 25 minutes; detection wavelength: 254 nm / 220 nm. Lyophilization under reduced pressure gave 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-) 6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)butyronitrile (37.1 mg, yield 12.8%).
MS(ESI)M/Z：496[M+H] +。 MS (ESI) M / Z: 495 [M+H] + .
1H NMR(300MHz,CDCl 3)δ8.02(s,1H),7.79(s,1H),6.96(s,1H),6.55(s,1H),5.24(s,2H),4.23(s,3H),3.84(s,3H),3.11(t,J＝7.1Hz,2H),2.57-2.46(m,5H),2.25-2.14(m,2H). 1 H NMR (300MHz, CDCl 3 ) δ8.02 (s, 1H), 7.79 (s, 1H), 6.96 (s, 1H), 6.55 (s, 1H), 5.24 (s, 2H), 4.23 (s, 3H), 3.84 (s, 3H), 3.11 (t, J = 7.1 Hz, 2H), 2.57-2.46 (m, 5H), 2.25-2.14 (m, 2H).
实施例61：SAL02-356Example 61: SAL02-356
1-(氮杂环丁烷-1-基)-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)丙-1-酮1-(azetidin-1-yl)-3-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)propan-1-one
Figure PCTCN2019086558-appb-000202
Figure PCTCN2019086558-appb-000202
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000203
Figure PCTCN2019086558-appb-000203
实施例61流程：Example 61 process:
步骤A：将3-(4-(羟甲基)-5-甲基噻唑-2-基)丙酸(202毫克，1.00毫摩尔)溶于N,N-二甲基甲酰胺(10毫升)中。随后，向上述溶液中依次加入杂氮环丁烷盐酸盐(279毫克，3.00毫摩尔),2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(760毫克，2.00毫摩尔)和N,N-二异丙基乙基胺(744毫克，6.00毫摩尔)。反应液在室温下搅拌2小时。Step A: Dissolving 3-(4-(hydroxymethyl)-5-methylthiazol-2-yl)propanoic acid (202 mg, 1.00 mmol) in N,N-dimethylformamide (10 mL) in. Subsequently, azacyclobutane hydrochloride (279 mg, 3.00 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyl was sequentially added to the above solution. Urea hexafluorophosphate (760 mg, 2.00 mmol) and N,N-diisopropylethylamine (744 mg, 6.00 mmol). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(80毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(80毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/3)，收集产品，减压浓缩得到白色固体1-(氮杂环丁烷-1-基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)丙-1-酮(114毫克，收率47.3％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (80 mL×3×). The combined organic layers were washed with EtOAc EtOAc EtOAc. The crude product was purified by EtOAc EtOAcjjjjjjjjjj (4-(Hydroxymethyl)-5-methylthiazol-2-yl)propan-1-one (114 mg, yield 47.3%).
MS(ESI)M/Z:241[M+H +]。 MS (ESI) M / Z: 241 [M+H + ].
步骤B:在室温和氮气保护下，将偶氮二甲酰二哌啶(190毫克，0.75毫摩尔)溶于四氢呋喃(3.0毫升)中。随后，向上述溶液中加入三丁基膦(229毫克，1.13毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(50毫克，0.16毫摩尔)和1-(氮杂环丁烷-1-基)-3-(4-(羟甲基)-5-甲基噻唑-2-基)丙-1-酮(57毫克，0.24毫摩尔)的四氢呋喃溶液(2.0毫升)。反应液在室温下搅拌2小时。Step B: Azodiyldipiperidine (190 mg, 0.75 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (229 mg, 1.13 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. Pyrazolo[1,5-a]pyridin-4-ol (50 mg, 0.16 mmol) and 1-(azetidin-1-yl)-3-(4-(hydroxymethyl) A solution of -5-methylthiazol-2-yl)propan-1-one (57 mg, 0.24 mmol) in THF (MeOH). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到白色固体1-(氮杂环丁烷-1-基)-3-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)丙-1-酮(17.7毫克，收率20.5％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The crude product was purified by silica gel column chromatography eluting eluting elut elut -Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4 -yl)oxy)methyl)-5-methylthiazol-2-yl)propan-1-one (17.7 mg, yield 20.5%).
MS(ESI)M/Z：540[M+H +]。 MS (ESI) M/Z: 540 [M+H + ].
1H NMR(300MHz,CDCl 3)：δ8.00(s,1H),7.79(s,1H),6.93(s,1H),6.46(s,1H),5.22(s,2H),4.23(s,3H),4.16(t,J＝7.6Hz,2H),4.05(t,J＝7.6Hz,2H),3.85(s,3H),3.29(t,J＝7.2Hz,2H),2.60(t,J＝7.2Hz,2H),2.49(s,3H),2.32-2.20(m,2H)。 1 H NMR (300MHz, CDCl 3 ): δ8.00 (s, 1H), 7.79 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 5.22 (s, 2H), 4.23 (s , 3H), 4.16 (t, J = 7.6 Hz, 2H), 4.05 (t, J = 7.6 Hz, 2H), 3.85 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 2.60 (t , J = 7.2 Hz, 2H), 2.49 (s, 3H), 2.32-2.20 (m, 2H).
实施例62：SAL02-366Example 62: SAL02-366
5-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷5-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane
Figure PCTCN2019086558-appb-000204
Figure PCTCN2019086558-appb-000204
反应流程Reaction process
Figure PCTCN2019086558-appb-000205
Figure PCTCN2019086558-appb-000205
实施例62流程：Example 62 process:
步骤A：在室温和氮气保护下，将2-溴-4-[[(叔丁基二甲基硅烷基)氧基]甲基]-5-甲基-1,3-噻唑(500毫克，1.55毫摩尔)溶于丁醇(20.0毫升)中。随后，向上述溶液依次加入2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(321毫克，2.37毫摩尔)，2-二环己基磷-2,4,6-三异丙基联苯(221毫克，0.46毫摩尔)，碳酸铯(1.50克，4.60毫摩尔)，三(二亚苄基丙酮)二钯(424毫克，0.46毫摩尔)。将反应液加热至80摄氏度并搅拌6小时。Step A: 2-Bromo-4-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-1,3-thiazole (500 mg, at room temperature under nitrogen) 1.55 mmol) was dissolved in butanol (20.0 mL). Subsequently, 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (321 mg, 2.37 mmol), 2-dicyclohexylphosphorus-2,4,6-three was sequentially added to the above solution. Isopropylbiphenyl (221 mg, 0.46 mmol), cesium carbonate (1.50 g, 4.60 mmol), tris(dibenzylideneacetone) dipalladium (424 mg, 0.46 mmol). The reaction solution was heated to 80 ° C and stirred for 6 hours.
LCMS监测显示原料消失后，向反应液加入水(50毫升)淬灭反应。混合液用二氯甲烷(40毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(40毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)，收集产品，得5-(4-[[(叔丁基二甲硅烷)氧基]甲基]-5-甲基-1,3-噻唑-2-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(200毫克,收率37.8％)。After LCMS monitoring showed disappearance of the starting material, water (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (40 mL×3×). The combined organic layers were washed with brine (40 ml) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/2), and the product was collected to give 5-(4-[[((tert-butyldimethylsilane)oxy]methyl] 5-5-Methyl-1,3-thiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (200 mg, yield 37.8%).
MS(ESI)M/Z：341[M+H +]。 MS (ESI) M / Z: 341 [M+H + ].
步骤B：在室温下，将5-(4-[[(叔丁基二甲硅烷)氧基]甲基]-5-甲基-1,3-噻唑-2-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(350毫克，1.03毫摩尔)溶于四氢呋喃(22.0毫升)中。随后，向上述溶液中加入四丁基氟化铵四氢呋喃溶液(2.0毫升，2.00毫摩尔，1.0摩尔/升)。反应液在室温条件下搅拌2小时。Step B: 5-(4-[[(tert-Butyldimethylsilane)oxy]methyl]-5-methyl-1,3-thiazol-2-yl)-2-oxa at room temperature -5-Azabicyclo[2.2.1]heptane (350 mg, 1.03 mmol) was dissolved in tetrahydrofurane (22.0 mL). Subsequently, a tetrabutylammonium fluoride tetrahydrofuran solution (2.0 ml, 2.00 mmol, 1.0 mol/liter) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液加入水(30毫升)淬灭，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10)，收集产品，得到白色固体(5-甲基-2-[2-氧杂-5-氮杂双环[2.2.1]庚-5-基]-1,3-噻唑-4-基)甲醇(190毫克，收率81.8％)。After LCMS showed the disappearance of the starting material, water (30 ml) was added to the reaction mixture and the mixture was evaporated to ethyl acetate (30 ml×3×), and the organic phase was combined and washed with saturated brine (30 ml) Then, it was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting eluting elut elut 2.2.1]hept-5-yl]-1,3-thiazol-4-yl)methanol (190 mg, yield 81.8%).
MS(ESI)M/Z：227[M+H +]。 MS (ESI) M / Z: 227 [M+H + ].
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(711毫克，2.82毫摩尔)和三丁基膦(890 毫克，4.41毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(186毫克，0.58毫摩尔)和(5-甲基-2-[2-氧杂-5-氮杂双环[2.2.1]庚-5-基]-1,3-噻唑-4-基)甲醇(160毫克，0.71毫摩尔)的四氢呋喃溶液(10毫升)。反应液在室温下搅拌2小时。Step C: Azodiyldipiperidine (711 mg, 2.82 mmol) and tributylphosphine (890 mg, 4.41 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. , 5-a]pyridin-4-ol (186 mg, 0.58 mmol) and (5-methyl-2-[2-oxa-5-azabicyclo[2.2.1]hept-5-yl]- A solution of 1,3-thiazol-4-yl)methanol (160 mg, 0.71 mmol) in THF (10 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(40毫升)淬灭反应。混合液用二氯甲烷(40毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝8/1)，收集产品，粗产品再经高压液相色谱制备，制备条件：色谱柱：XBridge Prep OBD C 18 19mm*250mm,5um；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从45％升到49％；检测波长：254nm/220nm。减压冻干得类白色固体5-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)-2-氧杂-5-氮杂双环[2.2.1]庚烷(30毫克，收率9.7％)。 After LCMS monitoring showed the disappearance of the starting material, water (40 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (40 mL×3×). The combined organic layers were washed with brine (50 ml) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 8/1), product was collected, and the crude product was prepared by high-pressure liquid chromatography. Preparation conditions: column: XBridge Prep OBD C 18 19mm *250mm, 5um; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 45% to 49% in 25 minutes; detection wavelength: 254 nm /220nm. Lyophilized to give a white solid 5-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-) 6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-2-oxa-5-azabicyclo[2.2 .1] heptane (30 mg, yield 9.7%).
MS(ESI)M/Z：526[M+H] + MS (ESI) M/Z: 526 [M+H] +
1H NMR(300MHz,DMSO-d 6)δ8.31(s,1H),8.04(s,1H),6.73(s,1H),6.67(s,1H),5.06(s,2H),4.66(s,1H),4.50(s,1H),4.20(s,3H),3.82(s,3H),3.76(s,2H),3.48(d,J＝9.6Hz,1H),3.17(d,J＝9.6Hz,1H),2.34(s,3H),1.99-1.83(m,2H). 1 H NMR (300MHz, DMSO- d 6) δ8.31 (s, 1H), 8.04 (s, 1H), 6.73 (s, 1H), 6.67 (s, 1H), 5.06 (s, 2H), 4.66 ( s, 1H), 4.50 (s, 1H), 4.20 (s, 3H), 3.82 (s, 3H), 3.76 (s, 2H), 3.48 (d, J = 9.6 Hz, 1H), 3.17 (d, J = 9.6 Hz, 1H), 2.34 (s, 3H), 1.99-1.83 (m, 2H).
通过拆分SAL02-366，分离得到SAL02-378和SAL02-379。SAL02-378 and SAL02-379 were separated by splitting SAL02-366.
实施例63：SAL02-359Example 63: SAL02-359
4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-(三氟甲基)噻唑-2-基)吗啉4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)morpholine
Figure PCTCN2019086558-appb-000206
Figure PCTCN2019086558-appb-000206
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000207
Figure PCTCN2019086558-appb-000207
实施例63流程：Example 63 process:
步骤A：在50毫升的单口瓶中，加入溴代丙酮酸乙酯(11.0克，56.7毫摩尔)和硫脲(4.30克，56.7毫摩尔)。将反应液加热至100摄氏度并搅拌30分钟。Step A: To a 50 ml single-mouth bottle, ethyl bromopyruvate (11.0 g, 56.7 mmol) and thiourea (4.30 g, 56.7 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 30 minutes.
TLC监测显示原料消失后，混合液在减压下浓缩，得到棕色固体2-氨基噻唑-4-甲酸乙酯(12.0克，粗品)，直接用于下一步反应，无需纯化。After TLC monitoring showed the disappearance of the material, the mixture was concentrated under reduced pressure to give ethyl 2-aminothiazole-4-carboxylic acid ethyl ester (12.0 g, crude).
步骤B：在室温下，将2-氨基噻唑-4-甲酸乙酯(12.0克，56.7毫摩尔)，溴化钠(23.1克，227毫摩尔)溶于硫酸水溶液(140毫升，9.0摩尔/升)。在冰水浴下，向上述溶液中加入亚硝酸钠(4.70克，68.0毫摩尔)的水溶液(95.0毫升).反应液在0摄氏度下搅拌1小时。Step B: Ethyl 2-aminothiazole-4-carboxylate (12.0 g, 56.7 mmol), sodium bromide (23.1 g, 227 mmol) dissolved in aqueous sulfuric acid (140 mL, 9.0 mol/L). ). An aqueous solution (95.0 ml) of sodium nitrite (4.70 g, 68.0 mmol) was added to the above solution under ice-water bath. The reaction mixture was stirred at 0 ° C for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(200毫升)淬灭。混合液用乙酸乙酯(200毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(200毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后在减压下浓缩。得到黄色固体2-溴噻唑-4-甲酸乙酯(7.50克，粗品)，直接用于下一步反应，无需纯化。After LCMS monitoring showed the disappearance of the starting material, water (200 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (200 mL×3×). The combined organic layers were washed with EtOAc EtOAc. Ethyl 2-bromothiazole-4-carboxylate (7.50 g, crude) was obtained as a yellow solid.
MS(ESI)M/Z：236,238[M+H] + MS (ESI) M/Z: 236, 238 [M+H] +
步骤C：在室温下，将2-溴噻唑-4-甲酸乙酯(7.50克，31.9毫摩尔)溶于甲醇(90.0毫升)和浓硫酸(0.6毫升)的混合溶液中。将反应液加热至60摄氏度并搅拌12小时。Step C: Ethyl 2-bromothiazole-4-carboxylate (7.50 g, 31.9 mmol) was dissolved in a mixture of methanol (90.0 ml) and concentrated sulfuric acid (0.6 ml). The reaction solution was heated to 60 ° C and stirred for 12 hours.
LCMS监测显示原料消失后，将反应液冷却至室温并在减压下浓缩。将残余物溶于水(100毫升)并用饱和碳酸氢钠溶液调节PH值至中性。混合液用二氯甲烷(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝15/1)，得到白色固体2-溴噻唑-4-羧酸甲酯(4.50克，收率63.6％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (100 mL) and the pH was adjusted to neutral with saturated sodium hydrogen carbonate. The mixture was extracted with dichloromethane (100 mL×3×). The combined organic layers were washed with brine (100 ml) The obtained residue was purified to silicagel elut elut elut elut elut elut elut
MS(ESI)M/Z：222[M+H] + MS (ESI) M/Z: 222 [M+H] +
步骤D：在室温下，将2-溴噻唑-4-羧酸甲酯(1.80克，8.15毫摩尔)溶于四氢呋喃(90.0毫升)中。随后，向上述溶液中加入吗啉(1.40克，16.3毫摩尔)。将反应液加热至60摄氏度并搅拌18小时。Step D: Methyl 2-bromothiazole-4-carboxylate (1.80 g, 8.15 mmol) was dissolved in tetrahydrofurane (90.0 mL). Subsequently, morpholine (1.40 g, 16.3 mmol) was added to the above solution. The reaction solution was heated to 60 ° C and stirred for 18 hours.
LCMS监测显示原料消失，向反应液加入饱和碳酸氢钠水溶液(100毫升)淬灭。混合液用乙酸乙酯(200毫升×3次)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅 胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)，得到黄色固体2-吗啉代噻唑-4-羧酸甲酯(1.10克，收率59.2％)。The LCMS showed the disappearance of the material and the mixture was evaporated and evaporated. The mixture was washed with ethyl acetate (200 mL×3×) and dried over anhydrous sodium sulfate. The crude product was purified by EtOAc EtOAcjjjjjjjj .
MS(ESI)M/Z：229[M+H] + MS (ESI) M/Z: 229 [M+H] +
步骤E：在室温和氮气保护下，将2-吗啉代噻唑-4-羧酸甲酯(600毫克，2.63毫摩尔)溶于乙腈(30.0毫升)中。随后，向上述溶液加入磷酸钾(6.70克，31.6毫摩尔)，二氯三(1,10-邻二氮杂菲)钌(Ⅱ)水合物(88毫克，0.12毫摩尔)。反应液在荧光灯(13W)照射下搅拌24小时。Step E: Methyl 2-morpholinothiazole-4-carboxylate (600 mg, 2.63 mmol) was dissolved in acetonitrile (30.0 mL). Subsequently, potassium phosphate (6.70 g, 31.6 mmol), dichlorotris(1,10-phenanthroline)ruthenium (II) hydrate (88 mg, 0.12 mmol) was added to the above solution. The reaction solution was stirred under a fluorescent lamp (13 W) for 24 hours.
LCMS监测显示原料消失后，向反应液中加入水(100毫升)淬灭。混合液用乙酸乙酯(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到黄色油状物2-吗啉代-5-(三氟甲基)噻唑-4-羧酸甲酯(430毫克，收率55.2％)。After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic layers were washed with brine (100 ml) The crude product was purified by EtOAc EtOAcjjjjjjj Ester (430 mg, yield 55.2%).
MS(ESI)M/Z：297[M+H] + MS (ESI) M/Z: 297 [M+H] +
步骤F：在冰水浴下，将2-吗啉代-5-(三氟甲基)噻唑-4-羧酸甲酯(430毫克，1.45毫摩尔)溶于四氢呋喃溶液(10.0毫升)中。随后，向上述溶液中依次加入硼氢化钠(64毫克，2.90毫摩尔)和甲醇(93毫，2.90毫摩尔)。反应液在0摄氏度下搅拌30分钟后升至室温，在室温下搅拌3小时。Step F: Methyl 2-morpholino-5-(trifluoromethyl)thiazole-4-carboxylate (430 mg, 1.45 mmol) was dissolved in tetrahydrofurane (10.0 mL). Subsequently, sodium borohydride (64 mg, 2.90 mmol) and methanol (93 mM, 2.90 mmol) were sequentially added to the above solution. The reaction solution was stirred at 0 ° C for 30 minutes, then warmed to room temperature and stirred at room temperature for 3 hours.
LCMS监测显示原料消失后，向反应液中加入甲醇(10毫升)和水(100毫升)淬灭。混合液用乙酸乙酯(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，得到白色固体(2-吗啉代-5-(三氟甲基)噻唑-4-基)甲醇(230毫克，收率59.0％)。After LCMS showed the disappearance of the starting material, methanol (10 mL) and water (100 mL) were then evaporated. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic layers were washed with brine (100 ml) The crude product was purified by EtOAcjjjjjjjjjjj (230 mg, yield 59.0%).
MS(ESI)M/Z：269[M+H] + MS (ESI) M/Z: 269 [M+H] +
步骤G：在室温和氮气保护下，将偶氮二甲酰二哌啶(689毫克，2.74毫摩尔)和三丁基膦(863毫克，4.28毫摩尔)溶于四氢呋喃(12.0毫升)中。随后，向上述溶液中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(182毫克，0.57毫摩尔)和(2-吗啉代-5-(三氟甲基)噻唑-4-基)甲醇(231毫克，0.86毫摩尔)的四氢呋喃溶液(12.0毫升)。反应液在室温下搅拌1小时。Step G: Azodiyldipiperidine (689 mg, 2.74 mmol) and tributylphosphine (863 mg, 4.28 mmol) were dissolved in tetrahydrofuran (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. , 5-a]pyridin-4-ol (182 mg, 0.57 mmol) and (2-morpholino-5-(trifluoromethyl)thiazol-4-yl)methanol (231 mg, 0.86 mmol) Tetrahydrofuran solution (12.0 ml). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(100毫升)淬灭，混合液用二氯甲烷(100毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经高效液相色谱制备，制备条件如下：X Bridge Prep OBD C18 Column；19x 250um；流动相：水(含有10毫摩尔/升碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在15分钟内，乙腈从40％升到55％，检测波长：254nm。减压冻干得淡白色固体4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-(三氟甲基)噻唑-2-基)吗啉(51.2毫克，收率15.8％)。After LCMS showed the disappearance of the starting material, water (100 ml) was added to the mixture and the mixture was evaporated, and the mixture was extracted with dichloromethane (100 ml × 3 times). The combined organic layers were washed with brine (100 ml) The crude product was prepared by high performance liquid chromatography under the following conditions: X Bridge Prep OBD C18 Column; 19 x 250 um; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: The acetonitrile was raised from 40% to 55% in 15 minutes, and the detection wavelength was 254 nm. Lyophilized to give a pale white solid 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-) 6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)morpholine (51.2 mg, yield 15.8) %).
MS(ESI)M/Z：568[M+H] + MS (ESI) M/Z: 568 [M+H] +
1H NMR(300MHz,CDCl 3)：δ8.13(s,1H),7.90(s,1H),7.07(s,1H),6.50(s,1H),5.14(s,2H),4.28(s,3H),3.87(s,3H),3.84-3.70(m,2H),3.55-3.50(m,3H). 1 H NMR (300MHz, CDCl 3 ): δ8.13 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.50 (s, 1H), 5.14 (s, 2H), 4.28 (s , 3H), 3.87 (s, 3H), 3.84-3.70 (m, 2H), 3.55-3.50 (m, 3H).
实施例64：SAL02-372Example 64: SAL02-372
2-二氟乙基(2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙基)(甲基)氨基甲酸2-difluoroethyl (2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridyl) Oxazo[1,5-a]pyridin-4-yl)oxy)ethyl)(methyl)carbamic acid
Figure PCTCN2019086558-appb-000208
Figure PCTCN2019086558-appb-000208
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000209
Figure PCTCN2019086558-appb-000209
实施例64流程：Example 64 process:
步骤A：将2,2-二氟乙基-1-醇(1.00克，12.20毫摩尔)和三乙胺(2.46克，24.39毫摩尔)溶于二氯甲烷(10.0毫升)中。在冰水浴中，向上述溶液加入4-硝基苯基氯甲酸酯(3.68克，18.3毫摩尔)的二氯甲烷溶液(5.0毫升)。将反应液升至室温并搅拌2小时。Step A: 2,2-Difluoroethyl-1-ol (1.00 g, 12.20 mmol) and triethylamine (2.46 g, 24.39 mmol) were dissolved in dichloromethane (10.0 mL). To the above solution was added a solution of 4-nitrophenyl chloroformate (3.68 g, 18.3 mmol) in dichloromethane (5.0 mL). The reaction solution was warmed to room temperature and stirred for 2 hours.
TLC监测显示原料消失后，反应液在减压下浓缩。粗产品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/5)，收集产品，得到无色油状物2,2-二氟乙基(4-硝基苯基)碳酸酯(530毫克，收率17.6％)。After TLC monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:EtOAcEtOAc Ester (530 mg, yield 17.6%).
步骤B：在室温下，将2,2-二氟乙基(4-硝基苯基)碳酸酯(500毫克，2.02毫摩尔)和三乙胺(409克，4.05毫摩尔)溶于二氯甲烷(5.0毫升)中。将反应液冷却至0摄氏度，向上述溶液中加入2-(甲基氨基)乙烷-1-醇(167毫克，2.23毫摩尔)的二氯甲烷溶液(5.0毫升)。反应液在室温下搅拌2小时。Step B: Dissolve 2,2-difluoroethyl(4-nitrophenyl)carbonate (500 mg, 2.02 mmol) and triethylamine (409 g, 4.05 mmol) in dichloromethane at room temperature Methane (5.0 ml). The reaction solution was cooled to 0 ° C, and a solution of 2-(methylamino)ethane-1-ol (167 mg, 2.23 mmol) in dichloromethane (5.0 ml) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
TLC监测显示原料消失后，将反应液在减压下浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，收集产品，得到无色油状物2,2-二氟乙基(2-羟乙基)(甲基)氨基甲酸酯(312毫克，收率84.3％)。After TLC monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj Methyl)carbamate (312 mg, yield 84.3%).
步骤C：在室温和氮气保护下，将偶氮二甲酰二哌啶(661毫克，2.62毫摩尔)溶于四氢呋喃(3.0毫升)。随后，向上述溶液中加入三丁基膦(828毫克，4.10毫摩尔)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(86.6毫克，0.27毫摩尔)和2,2-二氟乙基(2-羟乙基)(甲基)氨基甲酸酯(100毫克，0.55毫摩尔)的四氢呋喃溶液(5.0毫升)。反应液在室温下搅拌1.5小时。Step C: Azodiyldipiperidine (661 mg, 2.62 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, tributylphosphine (828 mg, 4.10 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. Pyrazolo[1,5-a]pyridin-4-ol (86.6 mg, 0.27 mmol) and 2,2-difluoroethyl(2-hydroxyethyl)(methyl)carbamate ( 100 mg, 0.55 mmol) in tetrahydrofuran (5.0 mL). The reaction solution was stirred at room temperature for 1.5 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用乙酸乙酯和石油醚混合溶液打浆(82毫升，乙酸乙酯/石油醚＝1/40)，过滤，收集滤饼。滤饼用水(80毫升)洗涤，过滤，收集滤饼。粗产品经高压液相色谱纯化，制备条件如下:SunFire Prep C18 OBD Column,19×150mm 5um 10nm流动相：水(含有0.1％三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在14分钟内，乙腈从40％升到40％，检测波长：254nm。减 压冻干得白色固体2-二氟乙基(2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙基)(甲基)氨基甲酸(13.8毫克，收率10.5％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by a mixture of ethyl acetate and petroleum ether (82 ml, ethyl acetate / petroleum ether = 1/40). The filter cake was washed with water (80 mL), filtered and filtered. The crude product was purified by high pressure liquid chromatography under the following conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 um 10 nm mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: at 14 Within a minute, acetonitrile rose from 40% to 40% with a detection wavelength of 254 nm. Lyophilized to give a white solid 2-difluoroethyl (2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thia) Zyrid-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)(methyl)carbamic acid (13.8 mg, yield 10.5%).
MS(ESI)M/Z：483[M+H +]。 MS (ESI) M/Z: 483 [M+H + ].
1H NMR(300MHz,CDCl 3)：δ8.06(s,1H),7.81(s,1H),6.97(s,1H),6.27(s,1H),6.17-5.79(m,1H),4.63-4.17(m,7H),3.85(s,3H),3.85-3.79(m,2H),3.18(s,3H),1.28(s,1H). 1H NMR (300MHz, CDCl 3) : δ8.06 (s, 1H), 7.81 (s, 1H), 6.97 (s, 1H), 6.27 (s, 1H), 6.17-5.79 (m, 1H), 4.63- 4.17 (m, 7H), 3.85 (s, 3H), 3.85-3.79 (m, 2H), 3.18 (s, 3H), 1.28 (s, 1H).
实施例65：SAL02-374Example 65: SAL02-374
2,2-二氟乙基2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-氧基)氨基甲酸乙酯2,2-difluoroethyl 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyridinium Ethylzo[1,5-a]pyridin-4-yloxy)carbamate
Figure PCTCN2019086558-appb-000210
Figure PCTCN2019086558-appb-000210
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000211
Figure PCTCN2019086558-appb-000211
实施例65流程：Example 65 process:
步骤A：在冰水浴下，将2,2-二氟乙基(4-硝基苯基)碳酸酯(500毫克，2.02毫摩尔)溶于二氯甲烷(10.0毫升)中。随后，向上述溶液中依次加入三乙胺(409毫克，4.04毫摩尔)和乙醇胺(124毫克，2.02毫摩尔)的二氯甲烷(10.0毫升)溶液。将反应液缓慢升至室温并搅拌2小时。Step A: 2,2-Difluoroethyl(4-nitrophenyl)carbonate (500 mg, 2.02 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, a solution of triethylamine (409 mg, 4.04 mmol) and ethanolamine (124 mg, 2.02 mmol) in dichloromethane (10.0 ml) was sequentially added to the above solution. The reaction solution was slowly warmed to room temperature and stirred for 2 hours.
TLC监测显示原料消失后，将反应液在减压下直接浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，收集产品，得到无色油状物2,2-二氟乙基2-羟乙基氨基甲酸酯(290毫克，收率85.0％)。After TLC monitoring showed disappearance of the starting material, the reaction mixture was directly concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Ester (290 mg, yield 85.0%).
步骤B：在室温和氮气保护下，将偶氮二甲酰二哌啶(764毫克，3.03毫摩尔)溶于四氢呋喃(10.0毫升)中。随后，向上述溶液中加入三丁基磷(957毫克，4.73毫摩尔)。反应液在室温下搅拌30分钟后，再向其中6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(100毫克，0.32毫摩尔)和2,2-二氟乙基2-羟乙基氨基甲酸酯(107毫克，0.64毫摩尔)的四氢呋喃溶液(10.0毫升)。反应液在室温下搅拌2小时。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-yl was further added thereto. Pyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.32 mmol) and 2,2-difluoroethyl 2-hydroxyethylcarbamate (107 mg, 0.64 mmol) A solution of tetrahydrofuran (10.0 mL). The reaction solution was stirred at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯萃取(20毫升×3次)。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱纯化，制备条件：Column,XSelect CSH Prep C18 OBD  Column,,5um,19*150mm,流动相：水(含有0.1％三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在8分钟内，乙腈从40％升到44％，检测波长：254nm。减压冻干得2,2-二氟乙基2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-氧基)氨基甲酸乙酯(8.1毫克，收率5.5％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by high pressure liquid chromatography, and the preparation conditions were: Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; Gradient: Acetonitrile was raised from 40% to 44% in 8 minutes, detection wavelength: 254 nm. Lyophilized under reduced pressure to give 2,2-difluoroethyl 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole- 6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)carbamate (8.1 mg, yield 5.5%).
MS(ESI)M/Z：469[M+H +]。 MS (ESI) M / Z: 469 [M+H + ].
1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.86(s,1H),7.18(s,1H),6.33(s,1H),6.13-5.80(m,1H),4.37-4.24(m,7H),3.87(s,3H),3.79-3.69(m,2H),3.18(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.86 (s, 1H), 7.18 (s, 1H), 6.33 (s, 1H), 6.13-5.80 (m, 1H), 4.37- 4.24 (m, 7H), 3.87 (s, 3H), 3.79-3.69 (m, 2H), 3.18 (s, 3H).
实施例66：SAL02-383Example 66: SAL02-383
4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)吗啉-3-酮4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholin-3-one
Figure PCTCN2019086558-appb-000212
Figure PCTCN2019086558-appb-000212
反应流程：Reaction process:
Figure PCTCN2019086558-appb-000213
Figure PCTCN2019086558-appb-000213
实施例66流程：Example 66 Process:
步骤A：在室温和氮气保护下，将2-溴-4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑(1.80克，5.61毫摩尔)，吗啉-3-酮(900毫克，8.91毫摩尔)，无水碳酸铯(2.30克，7.06毫摩尔)，三(二亚苄基丙酮)二钯(260毫克，0.28毫摩尔)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(324毫克，0.56毫摩尔)溶于1,4-二氧六环(20.0毫升)中。将反应液加热至120摄氏度并搅拌1小时。Step A: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (1.80 g, 5.61 mmol), mp. Morpholin-3-one (900 mg, 8.91 mmol), anhydrous cesium carbonate (2.30 g, 7.06 mmol), tris(dibenzylideneacetone) dipalladium (260 mg, 0.28 mmol) and 4,5 Bis-diphenylphosphino-9,9-dimethyloxaxan (324 mg, 0.56 mmol) was dissolved in 1,4-dioxane (20.0 mL). The reaction solution was heated to 120 ° C and stirred for 1 hour.
LCMS监测显示原料消失后，反应液在减压下直接浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10)，得到黄色油状物4-(4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)吗啉-3-酮(1.44克，收率75.1％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was directly concentrated under reduced pressure. The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut Methyl)-5-methylthiazol-2-yl)morpholin-3-one (1.44 g, yield 75.1%).
MS(ESI)M/Z：343[M+H +]。 MS (ESI) M / Z: 343 [M+H + ].
步骤B：在室温下，将4-(4-(((叔丁基二甲基硅烷基)氧基)甲基)-5-甲基噻唑-2-基)吗啉-3-酮(1.20克，3.51毫摩尔)溶于四氢呋喃(20.0毫升)中。随后，向上述溶液中加入四丁基氟化铵的四氢呋喃溶液(1.0毫升，1.0摩尔/升)。反应液在室温下搅拌30分钟。Step B: 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)morpholin-3-one (1.20) at room temperature G, 3.51 mmol) was dissolved in tetrahydrofuran (20.0 mL). Subsequently, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 ml, 1.0 mol/liter) was added to the above solution. The reaction solution was stirred at room temperature for 30 minutes.
TLC监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/二氯甲烷＝1/3)，收集产品，得到白色固体4-(4-(羟甲基)-5-甲基噻唑-2-基)吗啉-3-酮(610毫克，收率76.2％)After TLC monitoring showed the disappearance of the starting material, water (10 ml) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut 2-yl)morpholin-3-one (610 mg, yield 76.2%)
MS(ESI)M/Z：229[M+H +]。 MS (ESI) M / Z: 229 [M+H + ].
步骤C:在室温和氮气保护下，将偶氮二甲酰二哌啶(756毫克，3.00毫摩尔)溶于四氢呋喃(8.0毫升)中。随后，向上述溶液中加入三丁基膦(916毫克，4.50毫摩尔)的四氢呋喃溶液(4.0毫升)。反应液在室温下搅拌30分钟后，再向其中加入6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(200毫克，0.63毫摩尔)和4-(4-(羟甲基)-5-甲基噻唑-2-基)吗啉-3-酮(215毫克，0.95毫摩尔)的四氢呋喃溶液(8.0毫升)。反应液在室温下搅拌1小时。Step C: Azodiyldipiperidine (756 mg, 3.00 mmol) was dissolved in tetrahydrofuran (8.0 mL). Subsequently, a solution of tributylphosphine (916 mg, 4.50 mmol) in tetrahydrofuran (4.0 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. Pyrazolo[1,5-a]pyridin-4-ol (200 mg, 0.63 mmol) and 4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)morpholine- 3-ketone (215 mg, 0.95 mmol) in tetrahydrofuran (8.0 mL). The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭反应。混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100)，收集产品，得到的粗产品再经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.1％的甲酸)和乙腈；流速:20毫升/分钟；梯度：在7分钟内，乙腈从30％升到50％；检测波长：254nm。收集产品馏分，减压浓缩，低温冻干得到白色固体4-(4-(((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)甲基)-5-甲基噻唑-2-基)吗啉-3-酮(41.0毫克，收率12.3％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1 / 100). The product was collected and the crude product was purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 20 ml / min; gradient: acetonitrile increased from 30% to 50% in 7 minutes Detection wavelength: 254 nm. The product fractions were collected, concentrated under reduced pressure, and lyophilized to give 4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4] thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholin-3-one ( 41.0 mg, yield 12.3%).
MS(ESI)M/Z：528[M+H +]。 MS (ESI) M/Z: 528 [M+H + ].
1H NMR(400MHz,CDCl 3)：δ7.98(s,1H),7.80(s,1H),6.92(s,1H),6.46(s,1H),5.19(s,2H),4.44(s,2H),4.28-4.19(m,5H),4.12-4.05(m,2H)，3.84(s,3H),2.48(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.98 (s, 1H), 7.80 (s, 1H), 6.92 (s, 1H), 6.46 (s, 1H), 5.19 (s, 2H), 4.44 (s , 2H), 4.28-4.19 (m, 5H), 4.12-4.05 (m, 2H), 3.84 (s, 3H), 2.48 (s, 3H).
实施例67：SAL02-266Example 67: SAL02-266
6-(2,4-二甲氧基吡咯[1,2-b]哒嗪-6-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑6-(2,4-Dimethoxypyrrole[1,2-b]pyridazin-6-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadi Azole
Figure PCTCN2019086558-appb-000214
Figure PCTCN2019086558-appb-000214
反应流程Reaction process
Figure PCTCN2019086558-appb-000215
Figure PCTCN2019086558-appb-000215
实施例67流程：Example 67 process:
步骤A：将3,5-二氯哒嗪(30.0克，201毫摩尔)溶于甲醇(500毫升)中。随后，向上述溶液中加入氢氧化钾(13.5克，242毫摩尔)。反应液在室温下搅拌3小时。Step A: 3,5-Dichloropyridazine (30.0 g, 201 mmol) was dissolved in methanol (500 mL). Subsequently, potassium hydroxide (13.5 g, 242 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 3 hours.
LCMS监测显示原料消失后，向反应液中加入水(200毫升)淬灭。混合液用乙酸乙酯(500毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，得到白色固体5-氯-3-甲氧基哒嗪(23.0克，收率79.0％)。After LCMS monitoring showed the disappearance of the starting material, water (200 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (500 mL×3×). The combined organic layers were washed with brine (100 ml) The residue was purified to silicagel eluting elut elut elut elut elut elut
MS(ESI)M/Z：145[M+H +]。 MS (ESI) M/Z: 145 [M+H + ].
步骤B：在室温下，将苄醇(18.9克，175毫摩尔)溶于四氢呋喃(40.0毫升)中。随后，向上述溶液中缓慢加入氢化钠(7.00克，175毫摩尔)，并搅拌30分钟。在冰水浴下，向上述溶液中加入5-氯-3-甲氧基哒(23.0克，159毫摩尔)的四氢呋喃溶液(120.0毫升)。反应液缓慢升至室温并搅拌过夜。Step B: Benzyl alcohol (18.9 g, 175 mmol) was dissolved in tetrahydrofuran (40.0 mL). Subsequently, sodium hydride (7.00 g, 175 mmol) was slowly added to the above solution, and stirred for 30 minutes. To the above solution was added a solution of 5-chloro-3-methoxyindole (23.0 g, 159 mmol) in tetrahydrofuran (120.0 mL). The reaction was slowly warmed to room temperature and stirred overnight.
LCMS监测显示原料消失后，向反应液中加入水(50毫升)淬灭。混合液用乙酸乙酯(200毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)，得到淡黄色固体3-(苄氧基)-5-甲氧基哒嗪(18.4克，收率53.5％)。After LCMS monitoring showed the disappearance of the starting material, water (50 ml) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAcjjjjjjjjjjj The rate is 53.5%).
MS(ESI)M/Z：217[M+H +]。 MS (ESI) M / Z: 217 [M+H + ].
步骤C：将2-溴乙酸乙酯(15.6克，93.6毫摩尔)和3-(苄氧基)-5-甲氧基哒嗪(18.4克，85.1毫摩尔)溶于乙腈(300.0毫升)中。将反应液加热至65摄氏度搅拌2.5小时。Step C: Ethyl 2-bromoacetate (15.6 g, 93.6 mmol) and 3-(benzyloxy)-5-methoxypyridazine (18.4 g, 85.1 mmol) were dissolved in acetonitrile (300.0 mL) . The reaction solution was heated to 65 ° C and stirred for 2.5 hours.
LCMS监测显示原料消失后，将反应液冷却至室温。反应液在减压下浓缩。得到淡黄色固体3-(苄氧基)-1-(2-乙氧基-2-氧代乙基)-5-甲氧基哒嗪-1-鎓(34.0克，粗品)，直接用于下一步反应，无需纯化。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure. Obtained as a pale yellow solid 3-(benzyloxy)-1-(2-ethoxy-2-oxoethyl)-5-methoxypyridazine-1-indole (34.0 g, crude) The next reaction, no purification is required.
MS(ESI)M/Z：303[M+H +]。 MS (ESI) M / Z: 303 [M+H + ].
步骤D：在室温和氧气气氛下，将3-(苄氧基)-1-(2-乙氧基-2-氧代乙基)-5-甲氧基哒嗪-1-鎓(34.0克，粗品)溶于甲苯(300毫升)中。随后，向上述溶液中依次加入丁炔二酸二甲酯(13.6克，95.8毫摩尔)，二氧化锰(14.5克，167毫摩尔)和三乙胺(9.60克，95.1毫摩尔)。将反应液加热至80摄氏度并搅拌过夜。Step D: 3-(Benzyloxy)-1-(2-ethoxy-2-oxoethyl)-5-methoxypyridazine-1-indole (34.0 g) at room temperature under an atmosphere of oxygen , crude) dissolved in toluene (300 ml). Subsequently, dimethyl erynedioate (13.6 g, 95.8 mmol), manganese dioxide (14.5 g, 167 mmol) and triethylamine (9.60 g, 95.1 mmol) were successively added to the above solution. The reaction was heated to 80 ° C and stirred overnight.
LCMS监测显示原料消失后，将反应液冷却至室温，通过硅藻土过滤，所得滤液在真空下浓缩。残余物用乙酸乙酯(300毫升)溶解。有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/6)，得到红色油状物7-乙基5,6-二甲基2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-5,6,7-三羧酸(10.7克，两步收率28.3％)。After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with brine (100 ml) The residue was purified with EtOAc EtOAc EtOAc elut elut elut elut elut Methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylic acid (10.7 g, 28.3% yield in two steps).
MS(ESI)M/Z：443[M+H +]。 MS (ESI) M / Z: 443 [M+H + ].
步骤E：将7-乙基5,6-二甲基2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-5,6,7-三羧酸(10.7克，24.2毫摩尔)溶于四氢呋喃(200.0毫升)中。随后，向上述溶液中加入氢氧化钾(4.28克，61.2毫摩尔)的水溶液(200.0毫升)。将反应液加热至65摄氏度并搅拌2小时。Step E: 7-Ethyl 5,6-dimethyl 2-(benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylic acid ( 10.7 g, 24.2 mmol) was dissolved in tetrahydrofuran (200.0 mL). Subsequently, an aqueous solution (200.0 ml) of potassium hydroxide (4.28 g, 61.2 mmol) was added to the above solution. The reaction solution was heated to 65 ° C and stirred for 2 hours.
LCMS监测显示原料消失后，将反应液冷却到室温。向反应液中加入稀盐酸(2.0摩尔/升)调节体系的PH值到4左右。混合液在减压下浓缩，有灰色固体析出，过滤，收集滤饼，滤饼在真空下干燥得到2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-5,6,7-三羧酸(9.20克，粗品)，直接用于下一步反应，无需进一步纯化。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature. Dilute hydrochloric acid (2.0 mol/L) was added to the reaction solution to adjust the pH of the system to about 4. The mixture was concentrated under reduced pressure, and a gray solid was precipitated, filtered, and the filter cake was collected. The filter cake was dried under vacuum to give 2-(benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazine. -5,6,7-tricarboxylic acid (9.20 g, crude) was used directly in the next step without further purification.
MS(ESI)M/Z：387[M+H +]。 MS (ESI) M/Z: 387 [M+H + ].
步骤F：在500毫升的封管中，将2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-5,6,7-三羧酸(9.20克，23.8毫摩尔)溶于二苯醚(180毫升)中。将反应液加热至200摄氏度并搅拌3小时。Step F: 2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylic acid (9.20 g, in a 500 mL closed tube) 23.8 mmol) was dissolved in diphenyl ether (180 mL). The reaction solution was heated to 200 ° C and stirred for 3 hours.
LCMS监测显示原料消失后，将反应液冷却至室温。反应液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，收集产品，得到白色固体2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-羧酸(6.30克，收率88.8％)After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj -b]pyridazine-6-carboxylic acid (6.30 g, yield 88.8%)
MS(ESI)M/Z：299[M+H +]。 MS (ESI) M / Z: 299 [M+H + ].
步骤G：将2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-羧酸(6.30克，21.1毫摩尔)，N,O-二甲基羟胺(3.87克，63.4毫摩尔)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(8.84克，23.3毫摩尔)和N,N-二异丙基乙基胺(8.18克，63.4毫摩尔)溶于N,N-二甲基甲酰胺(100毫升)中。在室温下搅拌2小时。Step G: 2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (6.30 g, 21.1 mmol), N,O-dimethylhydroxylamine (3.87 g, 63.4 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (8.84 g, 23.3 mmol) and N, N-Diisopropylethylamine (8.18 g, 63.4 mmol) was dissolved in N,N-dimethylformamide (100 mL). Stir at room temperature for 2 hours.
LCMS监测显示原料消失后，向反应液中加入水(100毫升)淬灭。混合液用乙酸乙酯(600毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(500毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)，收集产品，得到淡黄色油状物2-(苄氧基)-N，4-二甲氧基-N-甲基吡咯并[1,2-b]哒嗪-6-甲酰胺(4.55克，收率63.1％)。After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (600 mL×3×). The combined organic layers were washed with EtOAc EtOAc. The residue was purified with EtOAc EtOAc EtOAc elut elut elut elut N-Methylpyrrolo[1,2-b]pyridazine-6-carboxamide (4.55 g, yield 63.1%).
MS(ESI)M/Z：342[M+H +]。 MS (ESI) M / Z: 342 [M+H + ].
步骤H：在室温和氮气保护下，将2-(苄氧基)-N，4-二甲氧基-N-甲基吡咯并[1,2-b]哒嗪-6-甲酰胺(1.25克，3.67毫摩尔)溶于四氢呋喃(20毫升)中。向上述溶液中缓慢滴加甲基溴化镁的四氢呋喃溶液(3.47毫升，10.4毫摩尔，3.0摩尔/升)。在室温下搅拌1小时。Step H: 2-(Benzyloxy)-N,4-dimethoxy-N-methylpyrrolo[1,2-b]pyridazine-6-carboxamide (1.25) at room temperature under nitrogen. Grams, 3.67 mmol) were dissolved in tetrahydrofuran (20 mL). A solution of methylmagnesium bromide in tetrahydrofuran (3.47 ml, 10.4 mmol, 3.0 mol/liter) was slowly added dropwise to the above solution. Stir at room temperature for 1 hour.
LCMS监测显示原料消失后，向反应体系中加入饱和氯化铵水溶液(10毫升)淬灭。混合液用乙酸乙酯萃取(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)，收集产品，得到黄绿色油状物1-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)乙-1-酮(1.00克，收率91.7％)。After LCMS showed the disappearance of the starting material, a saturated aqueous solution of ammonium chloride (10 ml) was then applied to the mixture. The mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with brine (20 ml) The residue was purified by EtOAc EtOAcjjjjjjjj And [1,2-b]pyridazine-6-yl)ethan-1-one (1.00 g, yield 91.7%).
MS(ESI)M/Z：297[M+H +]。 MS (ESI) M / Z: 297 [M+H + ].
步骤I：在冰水浴下，将1-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)乙-1-酮(1.00克， 3.38毫摩尔)溶于二氯甲烷(15.0毫升)中。随后，向反应液中依次加入N,N-二异丙基乙基胺(1.53克，13.3毫摩尔)和三氟甲磺酸三甲基硅酯(2.22克，10.0毫摩尔)。反应液在室温下搅拌30分钟。Step I: 1-(2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazin-6-yl)ethan-1-one (1.00 g, in an ice water bath) 3.38 mmol) was dissolved in dichloromethane (15.0 mL). Subsequently, N,N-diisopropylethylamine (1.53 g, 13.3 mmol) and trimethylsilyl trifluoromethanesulfonate (2.22 g, 10.0 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 30 minutes.
TLC监测显示原料消失后，向反应液中加入碳酸氢钠水溶液(15毫升)淬灭。混合液用二氯甲烷(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，最后在减压下浓缩。将残余物溶于四氢呋喃(10毫升)中。在0摄氏度下，向上述溶液中加入N-溴代丁二酰亚胺(434毫克，3.38毫摩尔)的四氢呋喃溶液(5.0毫升)。反应液在0摄氏度下搅拌1小时。After TLC monitoring showed the disappearance of the starting material, aqueous solution of sodium bicarbonate (15 ml) was then applied to the mixture. The mixture was extracted with dichloromethane (10 mL×3×). The combined organic layers were washed with brine (10 mL) then dried over anhydrous sodium sulfate. The residue was dissolved in tetrahydrofuran (10 mL). To the above solution was added a solution of N-bromosuccinimide (434 mg, 3.38 mmol) in tetrahydrofuran (5.0 mL). The reaction solution was stirred at 0 ° C for 1 hour.
TLC监测显示原料消失后，反应液在减压下浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10)，得到白色固体1-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-溴乙烷-1-酮(762毫克，收率60.3％)。After TLC monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut 2-b]pyridazine-6-yl)-2-bromoethane-1-one (762 mg, yield 60.3%).
MS(ESI)M/Z:375[M+H +]。 MS (ESI) M/Z: 375 [M+H + ].
步骤J：在高压反应釜中，将1-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-溴乙烷-1-酮(750毫克，2.01毫摩尔)和2-氨基-5-溴-1,3,4-噻二唑(689毫克，3.78毫摩尔)加入异丙醇(10.0毫升)和乙腈(15.0毫升)的混合溶液中。将反应液加热至105摄氏度并搅拌5小时。Step J: 1-(2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazin-6-yl)-2-bromoethane-1 in an autoclave - Ketone (750 mg, 2.01 mmol) and 2-amino-5-bromo-1,3,4-thiadiazole (689 mg, 3.78 mmol), isopropyl alcohol (10.0 mL) and acetonitrile (15.0 mL) In a mixed solution. The reaction solution was heated to 105 ° C and stirred for 5 hours.
LCMS监测显示原料消失后，将反应液冷却至室温。向反应液加入水(10毫升)淬灭。混合液用乙酸乙酯(30毫升×3次)萃取。合并有机相，先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯/石油醚＝3/1/3)，收集产品，得到淡黄色固体6-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(420毫克，收率45.8％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was cooled to room temperature. Water (10 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (30 mL×3×). The combined organic layers were washed with brine (5 mL) The residue was purified with EtOAc EtOAcjjjjjjjjj -methoxypyrrolo[1,2-b]pyridazin-6-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (420 mg, yield 45.8 %).
MS(ESI)M/Z:456,458[M+H +]。 MS (ESI) M/Z: 456, 458 [M+H + ].
步骤K：在室温下，将6-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-溴咪唑并[2,1-b][1,3,4]噻二唑(420毫克,0.92毫摩尔)溶于二氯甲烷(5.0毫升)和甲醇(1.0毫升)的混合溶液中。随后，向上述溶液中加入叔丁醇钾(103毫克，0.92毫摩尔)。反应液在室温下搅拌18小时。Step K: 6-(2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazin-6-yl)-2-bromoimidazo[2,1 at room temperature -b][1,3,4]thiadiazole (420 mg, 0.92 mmol) was dissolved in a mixed solution of dichloromethane (5.0 ml) and methanol (1.0 ml). Subsequently, potassium t-butoxide (103 mg, 0.92 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 18 hours.
TLC监测显示原料消失后，向反应液中加入水(2毫升)淬灭。混合液用二氯甲烷(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯/石油醚＝1/1/1)，收集产品，得到淡黄色固体6-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(220毫克，收率58.6％)。After TLC monitoring showed the disappearance of the starting material, water (2 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj -methoxypyrrolo[1,2-b]pyridazin-6-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (220 mg, The rate is 58.6%).
MS(ESI)M/Z:408[M+H +]。 MS (ESI) M/Z: 408 [M+H + ].
步骤L：在室温和氮气保护下，将6-(2-(苄氧基)-4-甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(220毫克，0.54毫摩尔)溶于二氯甲烷(80毫升)中。将反应液冷却至-70摄氏度后，向上述溶液中加入三氯化硼的二氯甲烷溶液(1.40毫升，1.40毫摩尔，1.0摩尔/升)。反应液在-78摄氏度下搅拌1小时。Step L: 6-(2-(Benzyloxy)-4-methoxypyrrolo[1,2-b]pyridazin-6-yl)-2-methoxyimidazole at room temperature under nitrogen. [2,1-b][1,3,4]thiadiazole (220 mg, 0.54 mmol) was dissolved in dichloromethane (80 mL). After cooling the reaction mixture to -70 ° C, a solution of boron trichloride in dichloromethane (1.40 ml, 1.40 mmol, 1.0 mol/L) was added to the above solution. The reaction was stirred at -78 ° C for 1 hour.
LCMS监测显示原料消失后，向反应液中加入甲醇(6毫升)淬灭。将混合液倒入甲醇(50毫升)中并搅拌30分钟，混合液在减压下浓缩。残余物加入水(20毫升)中并搅拌30分钟，过滤，收集滤饼，滤饼在真空下干燥得白色固体4-甲氧基-6-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,2-b]哒嗪-2-醇(120毫克，粗品)。After LCMS monitoring showed the disappearance of the starting material, methanol (6 mL) was added to the reaction mixture to quench. The mixture was poured into methanol (50 ml) and stirred for 30 min. The residue was taken up in water (20 ml) and stirred for 30 min, filtered, and the filter cake was collected, and the filter cake was dried under vacuum to give 4-methoxy-6-(2-methoxyimidazo[2,1- b] [1,3,4]thiadiazole-6-yl)pyrrolo[1,2-b]pyridazin-2-ol (120 mg, crude).
MS(ESI)M/Z:318[M+H +]。 MS (ESI) M / Z: 318 [M+H + ].
步骤M：在冰水浴下，将4-甲氧基-6-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,2-b]哒嗪-2-醇(50毫克，0.16毫摩尔)溶于N,N-二甲基甲酰胺(3毫升)。随后，向上述溶液中加入无水碳酸钾(65毫克，0.47毫摩尔)和碘甲烷(22毫克，0.16毫摩尔)。反应液在室温下搅拌1小时。Step M: 4-methoxy-6-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrrolo[in the ice water bath] 1,2-b]pyridazine-2-ol (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (3 mL). Subsequently, anhydrous potassium carbonate (65 mg, 0.47 mmol) and methyl iodide (22 mg, 0.16 mmol) were added to the above solution. The reaction solution was stirred at room temperature for 1 hour.
LCMS监测显示原料消失后，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱纯化。纯化条件如下：色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。收集产品， 低温冻干得白色固体6-(2,4-二甲氧基吡咯并[1,2-b]哒嗪-6-基)-2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑(8.5毫克，收率16.3％)。After LCMS monitoring showed disappearance of the starting material, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high pressure liquid chromatography. Purification conditions were as follows: column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile rose from 50% in 7 minutes 60%; detection wavelength: 254 nm. The product was collected and lyophilized to give a white solid 6-(2,4-dimethoxypyrrolo[1,2-b]pyridazin-6-yl)-2-methoxyimidazo[2,1-b ][1,3,4]thiadiazole (8.5 mg, yield 16.3%).
MS(ESI)M/Z:318[M+H +] MS (ESI) M/Z: 318 [M+H + ]
1H NMR(300MHz,CD 3OD)：δδ7.95(s,1H),7.78(s,1H),6.74(s,1H),5.80(s,1H),4.24(s,3H),4.00(s,3H),3.94(s,3H)。 1 H NMR (300 MHz, CD 3 OD): δ δ 7.95 (s, 1H), 7.78 (s, 1H), 6.74 (s, 1H), 5.80 (s, 1H), 4.24 (s, 3H), 4.00 ( s, 3H), 3.94 (s, 3H).
生物活性测试：Biological activity test:
实施例68：Example 68:
体外筛选实验-FLIPR方法检测化合物抑制PAR4活性测试In vitro screening test-FLIPR method for detecting compounds inhibiting PAR4 activity test
1、准备试剂：1. Prepare reagents:
实验材料Experimental Materials
1)PAR4的激动剂及抑制剂1) Agonists and inhibitors of PAR4
PAR4的选择性激动剂TFLLR-NH 2、2-Furoyl-LIGRLO-NH 2和AYPGKF-NH 2由Sangon Biotech合成并购买或从Sigma-Aldrich直接购买。在FLIPR钙离子外流试验中它们对PAR4的EC 50分别为2.0μM、0.2μM和1.3μM。SAL02-001-00和SAL02-002-00为高活性的PAR4选择性抑制剂，在FLIPR钙离子外流试验中其对PAR4的IC 50值为5-10nM。 Selective PAR4 agonist TFLLR-NH 2, 2-Furoyl -LIGRLO-NH 2 and AYPGKF-NH 2 and later synthesized by Sangon Biotech or purchased directly from Sigma-Aldrich. In the FLIPR calcium efflux assay of PAR4 on their EC 50 values of 2.0μM, 0.2μM and 1.3μM. SAL02-001-00 SAL02-002-00 highly active and selective PAR4 inhibitor, calcium ion efflux in the FLIPR assay with an IC 50 value of PAR4 5-10nM.
2)PAR4表达细胞系2) PAR4 expression cell line
利用常规转染的方法将包含人源PAR4cDNA的哺乳动物细胞表达载体分别导入Flp-In-TREx-293细胞，经相应的抗生素筛选获得稳定高表达的Flp-In-TREx-293-PAR4细胞系并利用PAR4FLIPR钙离子外流实验进行功能验证。据文献报道HEK293细胞本身内源性高表达PAR4，因此Flp-In-TREx-293-PAR4细胞系可以用来进行PAR4小分子抑制剂的筛选实验。The mammalian cell expression vector containing human PAR4 cDNA was introduced into Flp-In-TREx-293 cells by conventional transfection method, and the stably high-expression Flp-In-TREx-293-PAR4 cell line was obtained by corresponding antibiotic screening. Functional verification was performed using the PAR4FLIPR calcium ion outflow assay. According to the literature, HEK293 cells express endogenously high expression of PAR4, so Flp-In-TREx-293-PAR4 cell line can be used for screening experiments of PAR4 small molecule inhibitors.
实施例69Example 69
利用FLIPR钙离子外流实验检测化合物对人源PAR4的抑制活性Detection of the inhibitory activity of compounds on human PAR4 by FLIPR calcium ion outflow assay
Flp-In-TREx-293-PAR4细胞培养于DEME高糖(Gibco)、10％胎牛血清、2mM GlutaMAX、1％青霉素-链霉素、15μg/ml blasticidin和200μg/ml潮霉素的培养基中，置于37℃、5％CO2细胞培养箱中培养。细胞接种至经poly-d-lysine处理过的384孔细胞培养板(Corning,3845)中，接种密度为8,000个细胞/孔/25μl细胞接种基质(DMEM高糖、10％胎牛血清、2mM GlutaMAX)于细胞培养箱培养过夜。加入25μl等体积的2X(400ng/ml)四环素诱导基质继续培养24h。实验当天，将培养板中的诱导基质更换为实验缓冲液(HBSS+20mM HEPES)，随后加入20μl等体积的2X Calcium 6dye，于37℃孵育2小时后置于室温待用。利用实验缓冲液将待测化合物和PAR4激动剂稀释至6X浓度，加入10μl 6X待测化合物至384孔细胞培养板，于室温孵育30分钟后，利用FLIPR Tetra将10μl 6X PAR4激动剂加入384孔细胞培养板，进行数据的测定和分析。整个反应体系为60μl，PAR4激动剂的终浓度为1.3μM(EC50)，DMSO的终浓度为0.3％。Flp-In-TREx-293-PAR4 cells cultured in DEME high glucose (Gibco), 10% fetal bovine serum, 2 mM GlutaMAX, 1% penicillin-streptomycin, 15 μg/ml blasticidin and 200 μg/ml hygromycin The medium was cultured in a 37 ° C, 5% CO 2 cell incubator. The cells were seeded into poly-d-lysine-treated 384-well cell culture plates (Corning, 3845) at a seeding density of 8,000 cells/well/25 μl of cell seeding matrix (DMEM high glucose, 10% fetal bovine serum, 2 mM GlutaMAX). ) Incubate overnight in a cell culture incubator. A 25 μl volume of 2X (400 ng/ml) tetracycline was added to induce the substrate to continue to culture for 24 h. On the day of the experiment, the induction matrix in the culture plate was changed to the experimental buffer (HBSS + 20 mM HEPES), followed by the addition of 20 μl of an equal volume of 2X Calcium 6dye, incubated at 37 ° C for 2 hours and then left at room temperature for use. The test compound and the PAR4 agonist were diluted to a 6X concentration using the experimental buffer, 10 μl of the 6X test compound was added to the 384-well cell culture plate, and after incubation for 30 minutes at room temperature, 10 μl of the 6X PAR4 agonist was added to the 384-well cell using FLIPR Tetra. The plates were incubated and the data were measured and analyzed. The entire reaction system was 60 μl, the final concentration of the PAR4 agonist was 1.3 μM (EC50), and the final concentration of DMSO was 0.3%.
实验结果如下：The experimental results are as follows:
Figure PCTCN2019086558-appb-000216
Figure PCTCN2019086558-appb-000216
Figure PCTCN2019086558-appb-000217
Figure PCTCN2019086558-appb-000217
Figure PCTCN2019086558-appb-000218
Figure PCTCN2019086558-appb-000218
注：A:0.1-20nM；B:20-100nMNote: A: 0.1-20nM; B: 20-100nM
结果显示：本发明所述化合物具有高活性。The results show that the compounds of the invention have high activity.
实施例70Example 70
血浆蛋白结合率试验Plasma protein binding rate test
实验采用平衡透析法，在平衡透析装置的两侧腔室中分别加入缓冲溶液和含有待测化合物的血浆，透析6小时，计算血浆蛋白结合率。In the experiment, balanced dialysis method was used, and a buffer solution and plasma containing the test compound were separately added to the chambers on both sides of the equilibrium dialysis device, and dialysis was carried out for 6 hours to calculate the plasma protein binding rate.
1.试验材料Test material
人和SD大鼠血浆购自BioreclamationIVT；食蟹猴血浆由康龙化成(北京)新药技术股份有限公司自制。平衡透析装置和透析膜购自HTDialysis。Human and SD rat plasma were purchased from Bioreclamation IVT; cynomolgus monkey plasma was made by Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. The equilibrium dialysis device and dialysis membrane were purchased from HTDialysis.
2.试验步骤2. Test procedure
采用平衡透析法，在96孔平衡透析装置的两侧腔室中分别加入120μL磷酸盐缓冲液(100mM，pH 7.4)和含有1μM待测化合物的血浆，在37℃、5％CO 2、100rpm的条件下，透析6小时。从平衡透析装置的两侧腔室中各取50μL样品至96孔板中。向取出的缓冲溶液样品中加入50μL空白血浆，向取出的血浆样品中加入50μL磷酸盐缓冲溶液，混合均匀后加入300μL含有内标的乙腈沉淀蛋白，样品涡旋离心后。取上清液进行LC-MS/MS分析。测定血浆中游离化合物的含量并计算血浆蛋白结合率。 Using balanced dialysis, 120 μL of phosphate buffer (100 mM, pH 7.4) and plasma containing 1 μM of test compound were added to both chambers of a 96-well equilibrium dialysis apparatus at 37 ° C, 5% CO 2 , 100 rpm. Under the conditions, dialysis for 6 hours. 50 μL of sample was taken from each of the chambers on both sides of the equilibrium dialysis device into a 96-well plate. 50 μL of blank plasma was added to the sample of the buffer solution taken out, 50 μL of the phosphate buffer solution was added to the taken-out plasma sample, and after mixing, 300 μL of the acetonitrile precipitated protein containing the internal standard was added, and the sample was vortexed and centrifuged. The supernatant was taken for LC-MS/MS analysis. The content of free compounds in plasma was measured and the plasma protein binding rate was calculated.
体外相关结果统计如下：The in vitro correlation results are as follows:
Figure PCTCN2019086558-appb-000219
Figure PCTCN2019086558-appb-000219
结果显示：本发明所述化合物比参考化合物BMS-986120的蛋白结合率明显降低。The results showed that the protein binding rate of the compound of the present invention was significantly lower than that of the reference compound BMS-986120.
实施例71Example 71
本发明部分化合物的药代动力学测试Pharmacokinetic testing of some compounds of the invention
1、以大鼠为受试动物，应用LC/MS/MS法测定了大鼠静脉注射和灌胃给予SAL02-104化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。1. Rats were used as test animals. The concentration of drug in plasma was determined by LC/MS/MS method at different time after intravenous administration and intragastric administration of SAL02-104 compound. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
2、试验方案2, the test plan
2.1试验药品2.1 test drugs
SAL02-104SAL02-104
2.2试验动物2.2 Test animals
健康大鼠8只，雌雄各半。2.3药物配制There are 8 healthy rats, half male and half female. 2.3 drug preparation
称取适量药物，加入5％DMSO和5％吐温80使溶解，后加生理盐水至终体积，配成溶液。Weigh the appropriate amount of the drug, add 5% DMSO and 5% Tween 80 to dissolve, then add physiological saline to the final volume, and prepare a solution.
2.4给药2.4 administration
大鼠8只，雌雄各半，分成相同两组；禁食一夜后一组静脉注射、一组灌胃给药。Eight rats, male and female, were divided into the same two groups; one group was given intravenous injection after one night of fasting, and one group was administered by intragastric administration.
3、操作3, operation
静脉注射组及灌胃给药组于给药前及给药后0.5、1.0、2.0、4.0、6.0、8.0、12.0、24.0h采血0.1ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。用LC/MS/MS法测定不同化合物静脉注射及灌胃给药后大鼠血浆中的待测化合物含量。In the intravenous group and the intragastric administration group, 0.1 ml of blood was collected before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 h after administration, and placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes. Store at -20 °C. The content of the test compound in the plasma of rats after intravenous injection and intragastric administration was determined by LC/MS/MS.
4、药代动力学参数结果4, pharmacokinetic parameters results
本发明部分化合物及参考化合物BMS-986120药代动力学参数如下：The pharmacokinetic parameters of some of the compounds of the present invention and the reference compound BMS-986120 are as follows:
Figure PCTCN2019086558-appb-000220
Figure PCTCN2019086558-appb-000220
结果显示：本发明所述化合物在血浆最高浓度，口服和静脉给药产生的暴露量方面性质明显优于参考化合物BMS-986120。The results show that the compounds of the present invention are significantly superior in nature to the reference compound BMS-986120 in terms of the highest concentration of plasma, exposure by oral and intravenous administration.
实施例72Example 72
溶解性实验测试：Solubility test:
1.摘要：以化合物在磷酸盐缓冲溶液pH＝7.4的溶解度考察专利化合物溶解性是否有显著改善。1. Abstract: The solubility of the compound in the phosphate buffer solution at pH=7.4 was investigated to see if there was a significant improvement in the solubility of the patented compound.
2.实验方法：2. Experimental method:
1)配制pH＝7.4磷酸盐缓冲溶液1) Prepare pH=7.4 phosphate buffer solution
2)对照品溶液的配制：各化合物精密称定，置于5mL具塞玻璃试管中，用少量DMSO溶解，并用pH＝7.4磷酸盐缓冲溶液稀释到0.5mg/mL,作为各化合物的自身对照品溶液。2) Preparation of reference solution: Each compound was accurately weighed, placed in a 5 mL stoppered glass test tube, dissolved in a small amount of DMSO, and diluted to 0.5 mg/mL with a pH=7.4 phosphate buffer solution as a self-control for each compound. Solution.
3)化合物的溶解度的测定：各化合物精密称定，置于5mL具塞玻璃试管中，加入pH＝7.4磷酸盐缓冲溶液1mL,超声至药物不再溶解(若完全溶解，继续称定加入化合物)，放入恒温振荡器中温度保持在37±1℃，振摇24h,将饱和溶液用0.45μm微孔滤膜过滤，并取0.1mL用pH＝7.4磷酸盐缓冲溶液稀释到1mL，即为待测化合物的溶解度溶液。3) Determination of solubility of the compound: Each compound was accurately weighed, placed in a 5 mL stoppered glass test tube, and added with a pH=7.4 phosphate buffer solution 1 mL, sonicated until the drug no longer dissolved (if completely dissolved, continue to be added to the compound) Put in a constant temperature oscillator and keep the temperature at 37±1°C, shake for 24h, filter the saturated solution with 0.45μm microporous membrane, and take 0.1mL diluted to 1mL with pH=7.4 phosphate buffer solution. The solubility solution of the compound is measured.
4)取自身对照品溶液及该待测化合物的溶解度溶液进入液相色谱，以外表峰面积法计算化合物在pH＝7.4磷酸盐缓冲溶液的溶解度，相关测定结果见下表。4) Take the self-control solution and the solubility solution of the test compound into the liquid chromatography, and calculate the solubility of the compound in the phosphate buffer solution at pH=7.4 by the peak area method. The relevant measurement results are shown in the following table.
实验结果：Experimental results:
Figure PCTCN2019086558-appb-000221
Figure PCTCN2019086558-appb-000221
结果显示：本发明所述化合物比参比化合物BMS-986120的溶解性有明显改善。The results showed that the solubility of the compound of the present invention was significantly improved over that of the reference compound BMS-986120.

Claims (17)

  1. 作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物或其药学上可接受的盐，其特征在于，所述化合物具有如下结构：A compound or a pharmaceutically acceptable salt thereof, which is a protease activated receptor 4 (PAR4) inhibitor for treating platelet aggregation, characterized in that the compound has the following structure:
    Figure PCTCN2019086558-appb-100001
    Figure PCTCN2019086558-appb-100001
    其中，R 0选自氢，卤素，C 1-4烷基，C 1-4的烷氧基，C 1-4的烷硫基，C 1-4的亚砜基，C 1-4的砜基，C 1-4的氨基； Wherein R 0 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 sulfoxide, C 1-4 sulfone a group, an amino group of C 1-4 ;
    X，Y选自CH或者N；X, Y is selected from CH or N;
    R 1选自氢，卤素、羟基、巯基、C 1-4的烷氧基； R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, decyl, C 1-4 alkoxy;
    R 2选自氢，卤素、羟基、巯基、C 1-4的烷氧基、C 2-4的烯氧基、C 3-6的环烷氧基、C 5-8芳(杂)环-C 1-4的烷氧基、-O-(CH 2)n-NR 8R 9-CO-O-C 1-4烷基、甲氧基取代的C 1-4烷氧基、C 5-12脂杂环-W-C 1-4烷氧基其中W为键、(CH 2)n-O、(CH 2)n-S或(CH 2)n-噻唑，其中烷氧基、烯氧基、环烷氧基、C 5-12脂杂环、C 5-8芳(杂)环、噻唑可进一步被卤素、C 1-4烷基、羟基、C 2-4氰基、-NR 4R 5、-(CH 2)n-CO-NR 6R 7取代，其中R 4、R 5分别独立选自C 1-4的烷基，C 2-4氰基；R 6、R 7分别独立的选自C 1-4的烷基，C 3-6的环烷基，C 2-4氰基，或者R 6、R 7成环；R 8R 9分别独立的选自氢，C 1-4烷基，n＝0、1、2或3。 R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, decyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 3-6 cycloalkoxy, C 5-8 aryl (hetero) ring - C 1-4 alkoxy, -O-(CH 2 )n-NR 8 R 9 -CO-OC 1-4 alkyl, methoxy-substituted C 1-4 alkoxy, C 5-12 lipid Heterocyclic-WC 1-4 alkoxy wherein W is a bond, (CH 2 ) nO, (CH 2 ) nS or (CH 2 ) n-thiazole, wherein alkoxy, alkenyloxy, cycloalkoxy, C 5-12 alicyclic, C 5-8 aryl (hetero) ring, thiazole may be further halogen, C 1-4 alkyl, hydroxy, C 2-4 cyano, -NR 4 R 5 , -(CH 2 ) n-CO-NR 6 R 7 substituted, wherein R 4 and R 5 are each independently selected from C 1-4 alkyl, C 2-4 cyano; and R 6 and R 7 are each independently selected from C 1-4 . An alkyl group, a C 3-6 cycloalkyl group, a C 2-4 cyano group, or R 6 , R 7 is a ring; R 8 R 9 are independently selected from hydrogen, C 1-4 alkyl, n=0, 1, 2 or 3.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述卤素选自氟、氯、溴、碘。A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 1-4 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl.
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基；C 2-4氰基选自乙氰基、丙氰基、丁氰基；C 2-4的烯氧基选自乙烯氧基、丙烯氧基、丁烯氧基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 1-4 alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy and isopropoxy. , n-butoxy, isobutoxy, sec-butoxy, tert-butoxy; C 2-4 cyano group b is selected from cyano, cyano propoxy, butoxy cyano; C 2-4 alkylene group selected from From vinyloxy, propyleneoxy, butenyloxy.
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的亚砜基选自CH 3SO-,CH 3CH 2SO-,CH 3CH 2CH 2SO-,CH 3CH 2CH 2CH 2SO-。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 1-4 sulfoxide group is selected from the group consisting of CH 3 SO-, CH 3 CH 2 SO-, CH 3 CH 2 CH 2 SO-, CH 3 CH 2 CH 2 CH 2 SO-.
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的砜基选自CH 3SO 2-,CH 3CH 2SO 2-,CH 3CH 2CH 2SO 2-,CH 3CH 2CH 2CH 2SO 2-。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 1-4 sulfone group is selected from the group consisting of CH 3 SO 2 -, CH 3 CH 2 SO 2 -, CH 3 CH 2 CH 2 SO 2 -, CH 3 CH 2 CH 2 CH 2 SO 2 -.
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的氨基选自甲氨基、乙氨基、二甲氨基、丙氨基、异丙胺基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the amino group of C 1-4 is selected from the group consisting of methylamino, ethylamino, dimethylamino, propylamino, isopropylamino, and Butylamino, isobutylamino, sec-butylamino and tert-butylamino.
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中，所述C 1-4的烷硫基选自甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 1-4 alkylthio group is selected from the group consisting of methylthio, ethylthio, propylthio and isopropylthio. , n-butylthio, isobutylthio, sec-butylthio, tert-butylthio.
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，其中C 3-6的环烷选自环丙基、环丁基、环戊基、环己基；C 5-12脂杂环选自
    Figure PCTCN2019086558-appb-100002
    Figure PCTCN2019086558-appb-100003
    C 5-8芳(杂)环选自苯环、
    Figure PCTCN2019086558-appb-100004
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cycloalkane of C 3-6 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C 5-12 Heterocycle selected from
    Figure PCTCN2019086558-appb-100002
    Figure PCTCN2019086558-appb-100003
    The C 5-8 aryl (hetero) ring is selected from the group consisting of benzene rings,
    Figure PCTCN2019086558-appb-100004
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述化合物通式结构为下式(II)，The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a general formula of the following formula (II).
    Figure PCTCN2019086558-appb-100005
    Figure PCTCN2019086558-appb-100005
    其中，R 0，R 1、R 2，X，Y如上定义。 Wherein R 0 , R 1 , R 2 , X, and Y are as defined above.
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述化合物通式结构为下式(III)，The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a general formula of the following formula (III),
    Figure PCTCN2019086558-appb-100006
    Figure PCTCN2019086558-appb-100006
    其中，R 0，R 1、X，Y如上定义； Wherein R 0 , R 1 , X, Y are as defined above;
    Z选自氧原子、亚甲基、C 1-4烷基、取代或非取代的噻唑环； Z is selected from the group consisting of an oxygen atom, a methylene group, a C 1-4 alkyl group, a substituted or unsubstituted thiazole ring;
    m等于1，2，3或4；m is equal to 1, 2, 3 or 4;
    n等于0，1，2或3；n is equal to 0, 1, 2 or 3;
    P选自CH、N；P is selected from CH, N;
    Q选自氧原子或者碳原子；Q is selected from an oxygen atom or a carbon atom;
    R 3选自氢，卤素。 R 3 is selected from the group consisting of hydrogen and halogen.
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
    R 0选自甲氧基、溴、甲硫基、CH 3SO 2-、CH 3SO-、甲氨基、二甲氨基； R 0 is selected from the group consisting of methoxy, bromo, methylthio, CH 3 SO 2 -, CH 3 SO-, methylamino, dimethylamino;
    R 1选自氯、甲氧基； R 1 is selected from the group consisting of chlorine and methoxy;
    R 2选自氢、甲氧基、丁氧基、甲氧乙氧基、
    Figure PCTCN2019086558-appb-100007
    Figure PCTCN2019086558-appb-100008
    R 2 is selected from the group consisting of hydrogen, methoxy, butoxy, methoxyethoxy,
    Figure PCTCN2019086558-appb-100007
    Figure PCTCN2019086558-appb-100008
    Figure PCTCN2019086558-appb-100009
    Figure PCTCN2019086558-appb-100010
    Figure PCTCN2019086558-appb-100011
    其中
    Figure PCTCN2019086558-appb-100012
    为连接键；
    Figure PCTCN2019086558-appb-100009
    Figure PCTCN2019086558-appb-100010
    Figure PCTCN2019086558-appb-100011
    among them
    Figure PCTCN2019086558-appb-100012
    For the connection key;
    X，Y如上定义。X, Y are as defined above.
  13. 根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐选自无机酸或有机酸成盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、三氟乙酸、单宁酸、酒石酸和对甲苯磺酸。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic or organic acid salts, and the inorganic or organic acid is selected from the group consisting of 2- Acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, rich Horse acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, Maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid Succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid and p-toluenesulfonic acid.
  14. 根据权利要求1所述化合物，其特征在于，选自以下化合物：A compound according to claim 1 which is selected from the group consisting of:
    Figure PCTCN2019086558-appb-100013
    Figure PCTCN2019086558-appb-100013
    Figure PCTCN2019086558-appb-100014
    Figure PCTCN2019086558-appb-100014
    Figure PCTCN2019086558-appb-100015
    Figure PCTCN2019086558-appb-100015
    Figure PCTCN2019086558-appb-100016
    Figure PCTCN2019086558-appb-100016
    Figure PCTCN2019086558-appb-100017
    Figure PCTCN2019086558-appb-100017
  15. 一种药物组合物，其特征在于，包括如权利要求1-14任一项所述的化合物或其药学上可接受的盐和一种以上药学上可接受的载体。A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  16. 如权利要求1-14任一项所述的化合物或其药学上可接受的盐在制备用于制备治疗血栓相关疾病的药物用途。A pharmaceutical use according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a thrombosis-related disease.
  17. 根据权利要求16的用途，其特征在于，所述血栓相关疾病选自动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、脑血管血栓栓塞性病症、和心脏腔室或外周循环中的血栓栓塞性病症。The use according to claim 16, wherein said thrombotic-related disease is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a cardiac chamber or peripheral circulation. A thromboembolic disorder.
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