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CAS No. : | 862723-42-0 | MDL No. : | MFCD07367523 |
Formula : | C13H17BN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SAGPUUKLGWNGOS-UHFFFAOYSA-N |
M.W : | 244.10 | Pubchem ID : | 17750469 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.46 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 72.57 |
TPSA : | 47.14 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.99 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.54 |
Log Po/w (WLOGP) : | 1.86 |
Log Po/w (MLOGP) : | 1.19 |
Log Po/w (SILICOS-IT) : | 1.88 |
Consensus Log Po/w : | 1.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.26 |
Solubility : | 0.135 mg/ml ; 0.000553 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.18 |
Solubility : | 0.162 mg/ml ; 0.000665 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.52 |
Solubility : | 0.00744 mg/ml ; 0.0000305 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.85 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium acetate In N,N-dimethyl-formamide at 90℃; for 24 h; | Example 9; 545-r(iiS.5iS)-6-methyl-3.6-diazabi(^clor3.2.01heptan-3-yl1pyridin-3-vU-liy-indazole bistrifluoroacetateExample 9A 5-("4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ylVlH-indazole5-bromo-lH-indazole (US2003199511, 9.45 g, 48 mmol,) was coupled with bis(pinacolato)diboron (Combi-Blocks, 15.5g, 61 mmol) under the catalysis of Pd(dppf)2Cl2*Cη2Cl2 (Aldrich, 985 mg, 1.2 mmol) in the presence of KOAc (Aldrich, 16.7 g, 170 mmol) in dry DMF (160 ml) at 900C for 24 hours. After the reaction was completed, it was cooled to ambient temperature, diluted with EtOAc (250 mL) and washed with water (2 x 50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified with chromatography (SiO2, Hexane:EtOAc (v. 10:1), Rf=O.6) to give the title compound (9.8 g, yield, 84percent). 1H NMR (300 MHz, CD3OD) δ ppm 1.36 (s, 12 H) 7.51 (dt, J=8.5, 1.0 Hz, 1 H) 7.73 (dd, J=8.5, 1.0 Hz, 1 H) 8.08 (d, J=1.0 Hz, 1 H) 8.23 (t, J=1.0 Hz, 1 H); MS (DCI/NH3) m/z 245 (M+ 1)+. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; for 24 h; Inert atmosphere | The A13-1 (300mg, 1.52mmol) was dissolved in DMSO (10mL), was added bis (pinacolato) borate (570mg, 2.24mmol), KOAc(440mg, 4.49mmol), Pd (dppf) 2Cl2 (60mg, 0.073mmol), purged with nitrogen, 90 stirred for 24 hours, cooled to room temperature, siliconDiatomaceous earth filtration, the filtrate was diluted with ethyl acetate (20 mL), saturated brine (20mL × 3), dried over anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent,The residue was purified by column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to give a brown oil (300mg, 81percent). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 130℃; for 12 h; Inert atmosphere | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4 ',4',5,5,5 ',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (48.58 g, 0.191 mol), Pd(dppf)Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and the mixture at 130°C, It was stirred for 12 hours. After the reaction was terminated by the removal of water and then extracted with ethyl acetate and MgSO4, purified by column chromatography (Hexane: EA = 10: 1 (v / v)) purified 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, a yield of 72percent). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 130℃; for 12 h; Inert atmosphere | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3 ,2-dioxaborolane) (48.58 g, 0.191 mol), Pd (dppf) Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and then, the mixture at 130 °C was stirred for 12 hours. After completion of the reaction, the reaction extracted with ethyl acetate, and purified by the removal of water with MgSO4 and column chromatography (Hexane: EA = 10: 1 (v / v)) to give 5- (4,4,5 a, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, yield: to obtain a 72percent). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 130℃; for 12 h; Inert atmosphere | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4 ', 4', 5,5, 5 ', 5'-octamethyl-2,2'-bi (1,3 ,2-dioxaborolane) (48.58 g, 0.191 mol), Pd (dppf) Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and the mixture 130? in It was stirred for 12 hours.After the reaction was terminated by the removal of water and then extracted with ethyl acetate and MgSO4, purified by column chromatography (Hexane: EA = 10: 1 (v / v)) purified 5- (4,4,5,5-tetramethyl- by a 1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, a yield of 72percent). |
1 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere | To a solution of 5-bromoindazole (1.97 g, 10 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (2.67 g, 10.5 mmol), l,l-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.82 g, 1 mmol), and potassium acetate (2.0 g, 20 mmol). The resulting mixture was degassed and then stirred overnight at 80 °C under an Ar atmosphere. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (200 mL) and then extracted with EtOAc. The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by column chromatography (EtOAc / Pet = 1 : 1) to give indazole-5-boronic acid pinacol ester (1.0 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; CyJohnPhos; In 1,4-dioxane; ethanol; water; at 150℃; for 0.25h;Microwave, 300W; | EXAMPLE 5B 5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indazole A mixture of Example 1A (158 mg, 0.62 mmol) and the product of Example 5A (308 mg, 1.26 mol) were treated with bis(triphenylphosphine)palladium(II) chloride (Aldrich, 7.02 mg, 0.01 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (Strem Chemicals, 10.5 mg, 0.03 mmol) in dioxane/EtOH/Na2CO3 (aq., 1 M) (v. 1/1/1, 3 mL) were heated and microwaved to 150 C. and 300 watts for 15 minutes in an Emry Creator microwave reactor. The mixture was cooled to ambient temperature, solid was filtered off with a syringe filter and the organic solution was directly purified by chromatography (40 g SiO2, EtOAc:MeOH:NH3.H2O, 90:10:1, Rf=0.10) to provide the title compound. 1H NMR (300 MHz, CD3OD) delta 2.02-2.33 (m, 8H), 2.36 (s, 3H), 3.25 [s (br.), 2H], 5.47 (t, J=4.92 Hz, 1H), 7.23 (d, J=9.16 Hz, 1H), 7.67 (dt, J=8.82, 0.85 Hz, 1H), 8.07 (dd, J=8.82, 1.70 Hz, 1H), 8.10-8.19 (m, 2H), 8.36 (dd, J=1.53, 0.85 Hz, 1H) ppm; MS (DCI/NH3): m/z 336 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; at 150℃; for 0.5h;Microwave; | A solution of the compound of Example 107 (c) (1.30 g, 2. 61mmol), 5- (4, 4,5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-indazole (0. 7 g, 2.87 mmol), Pd (PPh3) 4 catalytic amount and 2M aqueous Na2CO3 (3.2 ml, 6.5 mmol) was heated at 150 C for 30min in microwave. The reaction mixture was filtered by celite, concentrated and purified by flash column chromatography (20%-60% EtOAclHexane) to give 1.09 g product (yield 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.277778h; | Example 13, Step 1 : [2-fluoro-5-(1H-indazol-5-yl)phenyl](phenyl)methanone. The following reagents were mixed in no particular order and heated to 15O0C in a microwave for 1000 seconds: (5-bromo-2-fluorophenyl)(phenyl)methanone (from example 9, step 1) (278mg, 1.0 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1H-indazole (486mg, 2.0mmol), dichlorobis(triphenyl-phosphine)palladium(ll) (70 mg, O.IOmmol), dimethoxyethane (2mL), ethanol (1 mL) and a 2M aqueous solution of sodium carbonate (1mL, 2.0mmol). The reaction mixture was then filtered through a plug of celite, rinsed with methanol and concentrated to dryness. Purification from silica gel eluting with a 50% solution of ethyl acetate and hexanes affords [2-fluoro-5- (1H-indazol-5-yl)phenyl](phenyl)methanone (187mg, 0.6mmol) 1 H NMR (400 MHz, DMSO-D6) delta ppm 13.1 (s, 1 H) 8.1 (s, 1 H) 8.1 (s, 1 H) 8.0 (m, J=5.9 Hz, 1 H) 7.8 (m, J=7.5 Hz, 3 H) 7.7 (m, 2 H) 7.6 (m, 3 H) 7.5 (dd, .7=9.1 , 9.1 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | In a pressure tube, 5-bromo-1 H-indazole (400 mg, 2 mmol), bis(pinacolato)diboron (773 mg, 3 mmol) and KOAc (598 mg, 6 mmol) were dissolved in 40 mL of dry DMF and sparged with argon for 10 mi Pd(dppf)012 (149 mg, 0.2 mmol) was added in one portion, and the reactionmixture was sparged with argon for additional 3 mm. The pressure tube was capped and the reaction mixture was heated at 10000 overnight. After full conversion (monitored by LOMS), the reaction mixture was filtered throught Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and co-evaporated with silica. Product was purified by column chromatography, eluting with hexane:EtOAc (0-50%) to afford the title product asa white solid (0.5 g, 2 mmol, quant.). ESI-MS: 245.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) 613.15 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.61 (dd, J = 8.4, 1.1 Hz, 1H), 7.52 (dt, J = 8.4, 1.0 Hz,1H), 1.31 (s, 12H). |
84% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 90℃; for 24h; | Example 9; 545-r(iiS.5iS)-6-methyl-3.6-diazabi(^clor3.2.01heptan-3-yl1pyridin-3-vU-liy-indazole bistrifluoroacetateExample 9A 5-("4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ylVlH-indazole5-bromo-lH-indazole (US2003199511, 9.45 g, 48 mmol,) was coupled with bis(pinacolato)diboron (Combi-Blocks, 15.5g, 61 mmol) under the catalysis of Pd(dppf)2Cl2*Ceta2Cl2 (Aldrich, 985 mg, 1.2 mmol) in the presence of KOAc (Aldrich, 16.7 g, 170 mmol) in dry DMF (160 ml) at 900C for 24 hours. After the reaction was completed, it was cooled to ambient temperature, diluted with EtOAc (250 mL) and washed with water (2 x 50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified with chromatography (SiO2, Hexane:EtOAc (v. 10:1), Rf=O.6) to give the title compound (9.8 g, yield, 84%). 1H NMR (300 MHz, CD3OD) delta ppm 1.36 (s, 12 H) 7.51 (dt, J=8.5, 1.0 Hz, 1 H) 7.73 (dd, J=8.5, 1.0 Hz, 1 H) 8.08 (d, J=1.0 Hz, 1 H) 8.23 (t, J=1.0 Hz, 1 H); MS (DCI/NH3) m/z 245 (M+ 1)+. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 24h;Inert atmosphere; | The A13-1 (300mg, 1.52mmol) was dissolved in DMSO (10mL), was added bis (pinacolato) borate (570mg, 2.24mmol), KOAc(440mg, 4.49mmol), Pd (dppf) 2Cl2 (60mg, 0.073mmol), purged with nitrogen, 90 stirred for 24 hours, cooled to room temperature, siliconDiatomaceous earth filtration, the filtrate was diluted with ethyl acetate (20 mL), saturated brine (20mL × 3), dried over anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent,The residue was purified by column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to give a brown oil (300mg, 81%). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 130℃; for 12h;Inert atmosphere; | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4 ',4',5,5,5 ',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (48.58 g, 0.191 mol), Pd(dppf)Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and the mixture at 130C, It was stirred for 12 hours. After the reaction was terminated by the removal of water and then extracted with ethyl acetate and MgSO4, purified by column chromatography (Hexane: EA = 10: 1 (v / v)) purified 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, a yield of 72%). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 130℃; for 12h;Inert atmosphere; | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3 ,2-dioxaborolane) (48.58 g, 0.191 mol), Pd (dppf) Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and then, the mixture at 130 C was stirred for 12 hours. After completion of the reaction, the reaction extracted with ethyl acetate, and purified by the removal of water with MgSO4 and column chromatography (Hexane: EA = 10: 1 (v / v)) to give 5- (4,4,5 a, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, yield: to obtain a 72%). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 130℃; for 12h;Inert atmosphere; | Under a nitrogen flow 5-bromo-1H-indazole (25.22 g, 0.128 mol), 4,4,4 ', 4', 5,5, 5 ', 5'-octamethyl-2,2'-bi (1,3 ,2-dioxaborolane) (48.58 g, 0.191 mol), Pd (dppf) Cl2 (5.2 g, 5 mol), KOAc (37.55 g, 0.383 mol) and 1,4-dioxane (500 ml) and the mixture 130? in It was stirred for 12 hours.After the reaction was terminated by the removal of water and then extracted with ethyl acetate and MgSO4, purified by column chromatography (Hexane: EA = 10: 1 (v / v)) purified 5- (4,4,5,5-tetramethyl- by a 1,3,2-dioxaborolan-2-yl) -1H-indazole (22.49 g, a yield of 72%). |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 90℃; for 24h; | EXAMPLE 5A 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole A flask containing 5-bromo-1H-indazole (Ref. US 2003199511, 9.45 g, 48 mmol) and bis(pinacolato)diboron (Aldrich, 15.5 g, 61 mmol) in dry DMF (160 mL) was added KOAc (16.7 g, 170 mmol). The mixture was degassed and purged with N2 three times followed by the addition of PdCl2(dppf).CH2Cl2 (Aldrich, 985 mg, 1.21 mmol). The mixture was heated to 90 C. and stirred for 24 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (250 mL), washed with water (2*50 mL). The organic phase was concentrated under reduced pressure and the residue was purified by chromatography (400 g SiO2, hexane:EtOAc 90:10, Rf-0.6) to provide the title compound. 1H NMR (300 MHz, CD3OD) delta 1.36 (s, 12H), 7.51 (dt, J=8.48, 1.02 Hz, 1H), 7.73 (dd, J=8.48, 1.02 Hz, 1H), 8.08 (d, J=1.02 Hz, 1H), 8.23 (t, J=1.02 Hz, 1H) ppm. MS (DCI/NH3): m/z 245 (M+H)+. | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 150℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 5 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f-indazole 11[00201] Potassium acetate (0.44 g, 4.5 mmol) was added to a solution of 5-bromo-lH- indazole 10 (0.1 g, 0.5 mmol) and bis (pinacolato)diboron (0.38 g, 1.52 mmol) in DMSO. Nitrogen gas was bubbled through followed by the addition of 3 mole % of dichloro 1,1 '- bis(diphenyl phosphino)ferrocene palladium II (Pd(dppf)Cl2) and the reaction mixture was heated at 150 0C in a microwave for 30 minutes. The solvent was removed, and the residue was taken up into ethyl acetate and filtered through celite. The organic portions were washed with water and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude material obtained was then purified using silica gel chromatography using hexane and ethyl acetate as eluent to give 11. | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃; for 16h; | A solution of 5-bromo-1H-indazole (1.00 g, 5.08 mmol), bis(pinacolato)diboron (3.87 g, 15.24 mmol), potassium acetate (KOAC, 2.49 g, 25.40 mmol), and PdCl2(dppf) (112 mg, 0.152 mmol) in 20 mL of DMF was stirred at 100 C. for 16 h. EtOAc was added and the organic layer washed with brine (×4), dried over MgSO4. After evaporation to dryness, the residue was purified by silica gel column, eluting with 10% EtOAc in hexane to yield 1.2 g. MS: DCI(+) m/e 245.0 (M+H)+; m/e 262.1 (M+NH4)+ | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | 5-Bromo-1H-indazole (1.00 g) was dissolved in N,N-dimethylformamide (20 ml), and bis(pinacolato)diboron (3.87 g), potassium acetate (2.49 g) and a [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (0.12 g) were added. The mixture was stirred with heating under nitrogen atmosphere at 100 C. overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (1.99 g).MS (ESI) m/z: 245 (M+H)+. | |
1 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; | To a solution of 5-bromoindazole (1.97 g, 10 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (2.67 g, 10.5 mmol), l,l-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.82 g, 1 mmol), and potassium acetate (2.0 g, 20 mmol). The resulting mixture was degassed and then stirred overnight at 80 C under an Ar atmosphere. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (200 mL) and then extracted with EtOAc. The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by column chromatography (EtOAc / Pet = 1 : 1) to give indazole-5-boronic acid pinacol ester (1.0 g) |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 90℃; for 15h;Inert atmosphere; | A mixture of 5-bromo-1 H-indazole (500 mg; 2.54 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1 .29 g; 5.08 mmol), Pd(dppf)CI2- DCM (200 mg; 0.24 mmol) and KOAc (1 .24 g; 12.6 mmol) in DMF (10 mL) was stirred at 90 C for 15 hours under nitrogen. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with H2O (50 mLx2), brine (50 mL), dried over anhydrous Na2SO4, filtered through Celite, and concentrated to afford 1 .18 g (quant.) of the title compound as a yellow oil, which was used directly without further purification. LC-MS for Ci3Hi7BN2O2+H+ [M+H]+: calcd. 245.1 ; found: 245.2. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 100℃; for 10h; | To a solution of 5-bromo-1H-indazole (3.0 g, 15.2 mmol), Bis(pinacolato)diboron (7.7 g, 30.4 mmol) and Cs2CO3 (9.9 g, 30.4 mmol) in dioxane (30 mL), was added Pd(dppf)Cl2 (1.24 g, 1.52 mmol) in one portion. The mixture was stirred at 100 for 10 h, then washed with brine and extracted with EA. The combined organic layer was dried over Na2SO4, filtered and concentrated to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indazole as a white solid (quantitative yield). The crude was used as such in the next step. LC-MS (ESI): m/z (M+H) = 245.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 60℃; for 72h; | EXAMPLE 121A (122 mg, 0.5 mmol) and potassium carbonate (415 mg. 3 mmol) were added to 10 mL of acetone. 2-Chlorobenzyl bromide (130 L, 1 mmol) was added, and the mixture was stirred at 60 C. for 3 days. After filtration, the filtrate was concentrated in vacuo and the residue was dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; | Example 10 4-(1H-indazol-5-yl)-N-(3-methoxybenzyl)benzamide Prepared in a similar manner as described for Example 3b from 4-bromo-N-(3-methoxybenzyl)benzamide (150 mg, 0.468 mmol), <strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> (0.171 g, 0.702 mmol), 2M aq. sodium carbonate (0.351 mL, 0.702 mmol), dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.023 mmol), DME (2.0 mL) and EtOH (1.0 mL) to give 4-(1H-indazol-5-yl)-N-(3-methoxybenzyl)benzamide (4.8 mg) as a solid. 1H NMR (300 MHz, DMSO-d6) delta ppm 3.71 (s, 3H), 4.45 (d, J=5.9 Hz, 2H), 6.78-6.89 (m, 3H), 7.22 (t, J=8.2 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 8.10 (d, J=10.4 Hz, 2H), 9.03 (t, J=6.0 Hz, 1H), 13.13 (br s, 1H); MS m/z 358 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 140℃; for 0.333333h;Microwave irradiation; | 0.23 mmol 4-(2-bromo-6-methoxy-4-methyl-3H-inden-l-yl)-thiophene-3-carbonitrile were dissolved in 2 ml EtOH(95%)/toluene (8:2) and 0.023 mmol of tetrakis- triphenylphosphine-palladium(O), 0.46 mmol potassium carbonate and 0.46 mmol 5-(4,4,5,5- Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole were added. The mixture was heated to 1400C in the microwave for 20 min. IM HCl and dichloromethane were added and the phases were separated. After flash chromatographic separation 0.078 mmol of 4-[2-(lH~mdazol-5-yl)-6- methoxy-4-methyl-3H-inden- 1 -yl]-thiophene-3 -carbonitrile were obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; acetonitrile; at 125℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 6 4-chloro-6-(lH-indazol-5-yl)-l-methyl-lH-pyrazolo[3,4- b]pyridine 12[00203] 4,6-Dichloro-l-methyl-lH-pyrazolo[3,4-6]pyridine 5 (0.180 g, 0.89 mmol) was dissolved in 2 mL dioxane and 2 mL acetonitriile in a microwave tube, and nitrogen was bubbled through the solution. 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (0.217 g, 0.89 mmol) and a IM solution of potassium acetate (2 mL, 2 mmol) were added. Nitrogen gas was bubbled through the mixture followed by the addition of 5 mole % of tetrakis(triphenylphosphine) palladium (0). The resultant mixture was microwaved at 125 0C for 30 minutes. Purification via Biotage reverse phase system (4: 1 ethyl acetate / hexanes) gave 12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; dichloromethane; water; toluene; at 110 - 145℃; for 1.75h;microwave irradiation; | Into a microwave vial, propane- 1 -sulfonic acid {3-[5-bromo-l -(2,6-dichloro-benzoyl)- 1 H- pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (11, 0.100 g, 0.158 mmol), 5-(4,4,5,5- tetramethyl-[l ,3,2]dioxaborolan-2-yl)- 1 H-indazole (12, 0.080 g, 0.33 mmol) and 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(Il) (0.07 g, 0.086 mmol, 1 : 1 complex with dichloromethane) are combined with 2.0 mL of toluene and 2.0 mL of ethanol. The mixture is stirred for 5 minutes, then potassium carbonate (0.475 mL, 1.0 M aqueous) is added and the reaction heated at 1 10 C for 60 minutes in a microwave, followed by 140 C for 45 minutes. The reaction is added to silica and the solvents are removed under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate (with 2% acetic acid):hexanes. Appropriate fractions are combined and concentrated under vacuum, then washed with acetonitrile to provide the desired compound (P-0001). MS (ESI) [M+H+]+ = 496.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 140℃; for 0.833333h;microwave irradiation; | Into a microwave vial, 5-(4,4,5,5-tetramethyl-[ l ,3,2]dioxaborolan-2-yl)- 1 H-indazole (12, 28 mg, 0.1 1 mmol) is combined with N-[3'-(5-bromo- 1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]-2,5-difluoro-benzenesulfonamide (26, 50 mg, 0.09 mmol),tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.0019 mmol), and potassium carbonate ( 1.0 mL, 1.0 in water) in 3 mL of acetonitrile. The reaction is heated at 140 C for 50 minutes in a microwave, the solvents removed under vacuum, and the residue purified by silica gel column chromatography, eluting with dichloromethane and methanol. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a white solid (P-0002, 28 mg, 50%). MS (ESI) [M+H+]+ = 565.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 90℃; for 240h; | To a stirred solution of 5,7-difluoro-N-(5-iodo-2-morpholinopyridin-4-yl)-3- methyl-2-(pyridin-2-yl)quinolin-4-amine (0.10 g, 0.18 mmol) in 1,4-dioxane (3.6 mL) was added lH-<strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (0.092 g, 0.38 mmol), tricyclohexylphosphine (8.52 mg, 0.030 mmol), and tris(dibenzylideneacetone)- dipalladium (0) (0.015 g, 0.016 mmol) followed by aq. 1.3M potassium phosphate tribasic (0.220 mL, 0.29 mmol). The resulting reaction was heated to 90 C.Stirring continued for 10 days. The reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-75% of a premixed solution of 89:9: 1 DCM: MeOH: ammonium hydroxide in DCM) to afford a film that was further purified by reverse phase HPLC to give the pure product N-(5- (lH-indazol-5-yl)-2-morpholinopyridin-4-yl)-5,7-difluoro-3-methyl-2-(pyridin-2- yl)quinolin-4-amine, isolated as the free base after washing with a saturated solution of sodium bicarbonate. 1H NMR (500 MHz, CD2C12) delta ppm 8.69 (1 H, d, J=4.6 Hz), 8.13 (1 H, s), 8.01 (1 H, s), 7.87 - 7.95 (3 H, m), 7.68 (1 H, d, J=8.6 Hz), 7.50 - 7.63 (2 H, m), 7.37 - 7.43 (1 H, m), 7.00 (1 H, m), 6.88 (1 H, br s), 4.73 - 4.76 (2 H, d, J =3.0 Hz), 3.77 (4 H, m), 3.46 - 3.64 (4 H, m), 3.36 (3 H, s); Mass Spectrum (ESI) m/e = 550.3 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | c) 5-[4-(4- [ 1 -(cyclopropylcarbonyl)-3-azetidinyl]methyl} -4H- 1 ,2,4-triazol-3-yl)phenyl]- lH-indazoleA mixture of 5-[4-(4-[l-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-4H-l,2,4- triazol-3-yl)phenyl]-lH-indazole (100 mg, 0.277 mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole (70 mg, 0.287 mmol), and PdCl2(dppf) (20 mg, 0.024 mmol) in 1,4-dioxane (2 mL) and 2 M aq. K2C03 (1 mL) was purged with nitrogen and stirred at 100 C for 1 h. The reaction mixture was cooled to room temperature and the 1,4-dioxane layer was filtered through a plug of Celite and Na2S04, rinsing with 1,4- dioxane (4 mL). The combined 1,4-dioxane layers were concentrated in vacuo and the residue was purified by reverse phase HPLC (10-70% CH3CN/water with 0.1% NH4OH) to afford the title compound (25 mg, 22%) as a solid. MS(ES)+ m/e 399.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; at 100℃;Sealed tube; Inert atmosphere; | Example 87 5-[(3S)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(lH-indazol-5- yl)phenyl]-2,4-dihydro-3H-l,2, -triazol-3-onea) A solution of 4-(4-bromo-2-fluorophenyl)-5-[(3S)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.244 mmol) in dioxane (1.5 mL) was treated with 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (0.269 mmol), dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.733 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100 C overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH ~4 using IN aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (10-50% acetonitrile/water + 0.1%> NH4OH) to afford the title compound as a beige solid (32%). MS(ES)+ m/e 447.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 150℃; for 0.25h;Inert atmosphere; microwave irradiation; | Methyl 8-chloro-1 -cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), cesium carbonate (335 mg, 1 .03 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-indazole (92 mg, 0.38 mmol) were added to a mixture of 1 ,2-dimethoxyethane (3 mL) and water (1 mL). The mixture was degassed with argon. 1 ,1 '-Bis-(diphenylphosphino)-ferrocene) palladium dichloride (28 mg, 0.03 mmol) was added. The reaction mixture was heated at 150 C in a microwave oven under argon atmosphere for 0.25 h. The reaction mixture was cooled. The mixture was diluted with DCM (3 mL) and water was added (3 mL). The layers were separated using a phase separator and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were concentrated in vacuum. The crude product was purified by flash silica column chromatography (DCM:MeOH) (1 :0 to 9:1 ) and dried in vacuum to afford the title compound as a yellow solid (93 mg, 72%).ESI-MS m/z: 374 (M+H)+. |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 150℃; for 0.25h;Inert atmosphere; | Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), cesium carbonate (335 mg, 1.03 mmol) and <strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> (92 mg, 0.38 mmol) were added to a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The mixture was degassed with argon. 1,1'-Bis-(diphenylphosphino)-ferrocene) palladium dichloride (28 mg, 0.03 mmol) was added. The reaction mixture was heated at 150 C under argon atmosphere for 0.25 h. The reaction mixture was cooled. The mixture was diluted with CH2Cl2 (3 mL) and water was added (3 mL). The layers were separated using a phase separator and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were concentrated in vacuo. The crude product was purified by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) and dried in vacuo to afford the title compound as a yellow solid (93 mg, 72%). ESI-MS m/z: 374 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 90℃;Inert atmosphere; | (f) 5-[4-(l-[(3S)-l-(Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-6-fluoro-lH- benzimidazol-2-yl)phenyl] -lH-indazole2-(4-Bromophenyl)- 1 - { [(3 S)- 1 -(cyclopropylcarbonyl)-3 -pyrrolidinyljmethyl} -6-f uoro- lH-benzimidazole (45 mg, 0.102 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazole (37.2 mg, 0.153 mmol), cesium carbonate (99 mg, 0.305 mmol) and bis(tri-t- butylphosphine)palladium(O) (5.20 mg, 10.17 muiotaetaomicron) were added to a microwave vial and purged with nitrogen. Dioxane (800 mu) was added followed by water (250 mu), and the reaction mixture heated overnight at 90 C. The reaction mixture was filtered and purified by preparative reverse phase HPLC. The appropriate fractions were combined, the pH neutralized with aqueous NaHC03 and extracted with EtOAc. The EtOAc extract was dried over sodium sulfate, filtered and evaporated to dryness. The product was further purified by silica gel column chromatography using a gradient of 10-100% EtOAc/hexanes to afford 19.3 mg of the titled compound as a white solid. (LCMS m/z 480.1, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube; | A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.1 g, 0.304 mmol), <strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> (0.082 g, 0.33 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.058 g, 0.122 mmol) and Na2CO3 (0.097 g, 0.912 mmol) in dioxane (20 mL) and water (10 mL) was heated to 100 C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200?300 mesh, methanol:dichloromethane=1:30) to afford 6-(1H-indazol-5-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (48 mg, 38%) as a yellow solid. 1H NMR (300 MHz, DMSO): delta 13.25 (s, 1H), 9.59 (s, 1H), 8.87 (s, 1H), 8.29-8.17 (m, 3H), 7.96 (dd, 1H, J1=8.7 Hz, J2=1.8 Hz), 7.67-7.62 (m, 2H), 7.43 (t, 1H, J=7.8 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.06 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.63-3.58 (m, 1H), 3.44-3.39 (m, 1H), 2.10-2.05 (m, 3H), 1.70 (s, 1H), 1.12 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 411, tR=1.619 min, HPLC: 98.4% at 214 nm, 97.91% at 254 nm, tR=5.848 min. |
38% | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube; | A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-l-yl)pyridin-2-yl)imidazo [l,2-b]pyridazin-8- amine (O. lg, 0.304 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-lH-indazole (0.082 g, 0.33 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.058 g, 0.122 mmol) and Na2C03 (0.097 g, 0.912 mmol) in dioxane (20 mL) and water (10 mL) was heated to 100 C for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200 ~ 300 mesh, methanol: dichloro methane = 1 : 30) to afford 6-(lH-indazol-5-yl)-N-(6-(2-methylpyrrolidin-l-yl) pyridin-2-yl)imidazo[l ,2-b]pyridazin-8- amine (48 mg, 38 %) as a yellow solid. 1H NMR (300 MHz, DMSO): delta 13.25 (s, 1H), 9.59 (s, 1H), 8.87 (s, 1H), 8.29 - 8.17 (m, 3H), 7.96 (dd, 1H, Jl= 8.7 Hz, J2= 1.8 Hz), 7.67 - 7.62 (m, 2H), 7.43 (t, 1H, J= 7.8 Hz), 6.73 (d, 1H, J= 7.5 Hz), 6.06 (d, 1H, J= 8.1 Hz), 4.25 - 4.21 (m, 1H), 3.63 - 3.58 (m, 1H), 3.44- 3.39 (m, 1H), 2.10 - 2.05 (m, 3H), 1.70 (s, 1H), 1.12 (d, 3H, J= 6.0 Hz).. LC-MS : [M+H]+, 41 1 , tR = 1.619 min, HPLC: 98.4 % at 214nm, 97.91 % at 254nm, tR = 5.848 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In dimethyl sulfoxide; at 140℃;Inert atmosphere; Microwave irradiation; Sealed tube; | Example 74V-[(4,6-Dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-6-(lH-indazol-5-yl)-l-(l- methylethyl)-lH-pyrazolo[3,4-6]pyridine-4-carboxamideTo a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3- pyridinyl)methyl]-l-(l-methylethyl)-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (59.4 mg, 0.243 mmol), DMSO(1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The contents were sealed and irradiated (microwave) at 140 C overnight. The mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHC03, filtered, washed with water and dried under high vacuum to give 41 mg (48%) of product. LCMS E-S (M+H) = 456.0 1H NMR (400 MHz, DMSO- 6) delta ppm 1.56 (d, J= 6.8 Hz , 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.38 - 4.53 (m, 2 H), 5.27 - 5.49 (m, 1 H), 5.91 (s, 1 H), 7.59 - 7.75 (m, 1 H), 8.24 (s, 2 H), 8.37 (s, 2 H), 8.69 (s, 1 H), 8.95 - 9.09 (m, 1 H), 11.49 - 11.67 (m, 1 H), 13.21 - 13.35 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100 - 120℃;Sealed tube; Inert atmosphere; | Compound-43: Synthesis of 6-(lH-indazol-5-yl)-N-(2-morpholinobenzo[d]oxazol-6- yl)picolinamide. (i) 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l /-indazole, Cs2C03, Pd(dppf)Cl2, 1,4-Dioxane, H20, 100-120C, 8-14h. 6-(l H-indazol-5-yl)-N-(2-mophiholinobenzo[d]oxazol-6-yl)picolinamide (0.015g,30%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step- 1 of compound-34 by following the same process in step 4 of compound- 1. ? NMR (400MHz, DMSO- /6) delta 13.29 (bs, 1H), 10.65 (bs, 1H), 8.50 (s, 1H), 8.32 (d, J=6.9Hz, 1H), 8.17-8.09 (m, 5H), 7.91 (d, J=8.6Hz, 1H), 7.33 (d, J=8.5Hz, 1H), 3.75-3.73 (m, 4H), 3.61 -3.59 (m, 4H). MS (ES) m/e 441 (M+l, 60%).Step4;N-("2-morpholino-5-(piperidin-l -vl)benzordloxazol-6-vl)-6-(lH-pvrazol-5-vl) picolinamide. 20-30C, 2h. 1,4-dioxane (5 ml) was added to a mixture of 6-bromo-N-(2-morphoIino-5- (piperidin-l-yl)benzo[d]oxazol-6-yl)picolinamide (0.07 g, 0.14 mmol ,step-3) , 1 - (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.12 g,0.43 mmol), Pd(dppf)Cl2 (0.005 g, 0.007 mmol), Cs2C03 (0.093 g, 0.28 mmol) and H20 (0. 1 ml) in a sealed tube. The above mixture was degassed with Argon and heated to 100-120C. The mixture was stirred at the same temperature for 3h. The reaction mass was cooled to 20-30C; water (10 ml) was added and the extracted the aqueous layer with ethyl acetate (2 x 30 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was which was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in DCM as eluent to get the pure product. It was further treated with diethylether- HCl (3 ml) for 2h. The progress of the reaction was monitored by TLC. The reaction mass was neutralized with aqueousNaHCC solution. DCM layer was separated and concentrated under reduced pressure to get yellow solid as a pure product (0.015mg,21 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 110℃; for 2h;Microwave irradiation; | [00410] Step 1 : 2-Chloro-5-iodo-N-isopropylpyridin-4-amine (.15 g, 0.506 mmol) in Acetonitrile (2 mL) was added a2C03 (0.161 g, 1.518 mmol) followed by lH-indazole- 5-boronic acid pinacol ester (0.124 g, 0.508 mmol) and tetrakistriphenyl phosphine Pd(0) (0.026 g, 0.023 mmol). The reaction was thoroughly degassed and subjected to microwave radiation at 1 10 C for 2 hours. The reaction mixture was concentrated to remove acetonitrile, added water (10 mL) and extracted with ethyl acetate ( 3 times x 10 mL). The combined extracts were dried purified via column chromatography. The reaction was performed 3 times to provide of 30 mg which was used directly in the next step. |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 110℃; for 2h;Microwave irradiation; | [00411] Step 1 : 2-Chloro-5-iodo-N-isopropylpyridin-4-amine (.15 g, 0.506 mmol) in Acetonitrile (2 mL) was added a2C03 (0.161 g, 1.518 mmol) followed by lH-indazole- 5-boronic acid pinacol ester (0.124 g, 0.508 mmol) and tetrakistriphenyl phosphine Pd(0) (0.026 g, 0.023 mmol). The reaction was thoroughly degassed and subjected to microwave radiation at 1 10 C for 2 hours. The reaction mixture was concentrated to remove acetonitrile, added water (10 mL) and extracted with ethyl acetate ( 3 times x 10 mL). The combined extracts were dried purified via column chromatography. The reaction was performed 3 times to provide of 30 mg which was used directly in the next step. [00412] Step 2: 2-Chloro-5-(lH-indazol-5-yl)-N-isopropylpyridin-4-amine (30 mg, 0.105 mmol) in Dioxane (1 ml) in a microwave vial was added Xantphos (48.4 mg, 0.084 mmol), cesium carbonate (102 mg, 0.314 mmol), 6- aminobenzothiazole (18.8 mg, 0.126 mmol) and Pd2(dba)3 (38.3 mg, 0.042 mmol) and purged with 2 thoroughly for 10 minutes. The reaction mass was subjected to microwave radiation for 3 hours at 150 C. The crude mass was passed through a celite bed and the filtrate was concentrated to remove dioxane then added 10 mL of water and extracted with DCM (3 times x 8 mL). The combined organic layers were dried and concentrated. The crude mass was purified by prep TLC first and then preparative HPLC to give Example 177. 1H NMR: 400 MHz, CD3OD: delta 1.20 (d, J= 6.40 Hz, 6H), 3.70-3.73 (m, 1H), 6.20 (s, 1H), 7.41 (dd, J= 1.60, 8.80 Hz, 1H), 7.52 (dd, J= 2.40, 8.80 Hz, 1H), 7.67-7.69 (m, 2H), 7.79 (dd, J= 0.80, 1.20 Hz, 1H), 7.98 (d, J= 9.20 Hz, 1H), 8.13 (s, 1H), 8.33 (d, J= 2.00 Hz, 1H), 9.07 (s, 1H). LC/MS: ZORBAX SB C18, 4.6 x 50mm, 5muiotaeta; Solvent A = 10% MeOH: 90% H20: 0.1% TFA; Solvent B = 90% MeOH: 10% H20: 0.1% TFA; gradient 0-100% B over 2min (3min run time); retention time: 1.482min; LCMS (ES-API), m/z 401.2 (M+H). HPLC: Sunfire C18 (150 x 4.6mm), 3.5micron; Solvent A = 5% ACN: 95% H20: 0.05% TFA pH= 2.5; Solvent B = 95% ACN: 5% H20: 0.05% TFA pH= 2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: Iota.OmicronmuIota/min; Retention time: 6.21 1 min; Purity: 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h; | Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate: To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (51 mg, 0.095 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (28 mg, 0.123 mmol) in degassed 1,4-dioxane (250 muL) and water (25 muL) was added aqueous K2CO3 (95 muL of a 2.0 M solution) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The reaction mixture was heated at 100 C. for 6 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was used without any further purification. LCMS-ESI+: calc'd for C31H34ClN4O3S: 577.2 (M+H+). Found: 577.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of (S)-methyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate: A microwave tube was charged with (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (25.0 mg, 48.5 mumol), 5-(4?,4?,5?,5?-tetramethyl-1?,3?,2?-dioxaborolan-2?-yl)-1H-indazole (14.2 mg, 58.2 mumol), Pd(PPh3)4 (5.6 mg, 4.86 mumol), K2CO3 (27 mg, 0.19 mmol), H2O (400 muL), and dioxane (1.6 mL). The reaction was sealed and heated to 110 C. The reaction failed to reach completion during the next 2 h (boronate ester was fully consumed (LCMS analysis), yet (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate remained.). The reaction was cooled to 23 C. and charged with more 5-(4?,4?,5?,5?-tetramethyl-1?,3?,2?-dioxaborolan-2?-yl)-1H-indazole (10 mg, 41 mumol). Heating to 110 C. was continued. Reaction progressed further, but was still incomplete after 1 h. Again, the reaction was cooled to 23 C. and this time charged with 1H-indazole-5-boronic acid (20 mg, 120 mumol) and K2CO3 (15 mg, 0.11 mmol); heating to 110 C. was resumed. Reaction reached completion in 1 h. The crude product (S)-methyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate was detected in solution. The solution was used crude in the next reaction. LCMS-ESI+: calc'd for C33H29ClN4O3S: 597.2 and 599.2 (M+H+). Found: 597.3 and 599.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; acetonitrile; at 160℃; for 0.277778h;Sealed tube; Microwave irradiation; | A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (140 mg, 0.50 mmol), (1H-25 <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (150 mg, 0.60 mmol), dichloro-bis(triphenylphosphino)palladium (II) (20 mg, 0.025 mmol), potassium carbonate (110 mg, 0.75 mmol), acetonitrile (1.5 ml)and H20 (0.5 ml) was heated in a sealed conical vessel at 160C for 1000 s by microwaveirradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate(2 ml). The combined organic layers were concentrated under reduced pressure to afford an oil that30 was purified by reverse phase HPLC to afford butyi-[3-(1H-indazol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]amine(100 mg, 65%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) 8 ppm 8.62-8.68 (m, 1 H),8.13-8.20 (m, 2 H), 8.02 (dd, J=8.8, 1.5 Hz, 1 H), 7.94 (d, J=9.9 Hz, 1 H), 7.72 (d, J=8.8 Hz, 1 H), 7.21 (d, J=9.9 Hz, 1 H), 3.43 (t, J=7.2 Hz, 2 H), 1.66-1.79 (m, 2 H), 1.49 (dq, J=15.1, 7.4 Hz, 2 H),0.99 (t, J=7.5 Hz, 3 H); LCMS (ESI) mje 307.2 [(M+H)+, calcd for C11H19N6 307.2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h; | A mixture of 2-(6-dichloropyrazine) tert-butyl 1,4-diazepane-1-carboxylate (218 mg, 0.7 mmol) and <strong>[862723-42-0]1H-<strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong></strong> (854 mg, 3.5 mmol, 3 eq), K2CO3 (483 mg, 3.50 mol, 5 eq) and Pd(dppf)Cl2 (512 mg, 0.7mmol, 0.1 eq) in DMSO was degassed. The mixture was heated at 100C until the chloride starting material was consumed 2 h. After cooling the mixture was poured into water and stirred for 10 minutes. The mixture was extracted with ethyl acetate and the organic extracts dried over sodium sulfate and concentrated. The residue was purified by column chromatography (12 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 25% hexanes) provided the coupled product (109 mg, 39%) as a yellow foamy solid; 1H NMR (300 MHz, CDCl3) 8.40-8.60 (m, 3H), 8.18 (s, 1H), 8.00-7.97 (d, J = 8.7 Hz, 1H), 7.68-7.66 (d, J = 8.9 Hz, 1H), 3.59-3.53 (m, 4H), 3.46-3.33 (m, 2H), 2.64 (s, 2H), 1.99-1.94 (m, 2H), 1.46-1.44 (d, J = 5.3 Hz, 9H). ESMS (M+H) = 394. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6 mg; 6 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 95℃; for 10h;Inert atmosphere; | To a solution of 2-(5-bromo-pyridin-3-ylamino)-2-phenyl-acetamide (306 mg, 1.0 mmol) in DME/H20 (5 : 1, 12 mL) was added Pd(PPh3)4 (230 mg, 0.2 mmol), K2C03 (276 mg, 2.0 mmol) and <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (244 mg, 1.0 mmol). The resulting mixture was degassed and then stirred for 10 hours at 95 C under an Ar atmosphere. After cooling, the mixture was diluted with water (50 mL) and then extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by Prep-HPLC to give 2-[5-(lH-indazol-5-yl)-pyridin- 3-ylamino]-2-phenyl-acetamide (50 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation; | 5-Bromo-1H-indazole (60 mg, 0.3 mmol), bis(pinacolato)diboron (78 mg, 0.306 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol), butyldi-l-adamantylphosphine (9.7 mg, 0.027 mmol), potassium acetate (88 mg, 0.9 mmol) were added into a 10 mL microwave vial containing a magnetic stirrer bar, followed by DME (0.75 mL). The vessel was sealed with a cap under an argon atmosphere, and then the resulting mixture was heated to 83 C for 1 hour. N-[(i?)-2-(5-bromo-pyridin-3-ylamino)-2-phenyl-ethyl]-acetamide (80 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 1,4-dioxane (0.75 mL) and H20 (0.3 mL) were added into the above mixture successively. The vessel was sealed with a cap under an argon atmosphere, and then the reaction mixture was heated to 100 C for 2 hours under microwave. The mixture was cooled to room temperature and diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), and then the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give crude title compound. The crude title compound was purified by C-18 reversed phase HPLC column to give N-{(R)-2-[5- (lH-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethyl}-acetamide (40 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | With potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation; | 5-Bromo-1H-indazole (60 mg, 0.3 mmol), bis(pinacolato)diboron (78 mg, 0.306 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol), butyldi-1 adamantylphosphine (9.7 mg, 0.027 mmol), potassium acetate (88 mg, 0.9 mmol) were added into a 10 mL microwave vial containing a magnetic stirrer bar, followed by DME (0.75 mL). The vessel was sealed with a cap under an argon atmosphere, and then the resulting mixture was heated to 83 C for 1 hour. The crude N-[(i?)-2-(5-bromo-pyridin-3-ylamino)-2-phenyl-ethyl]-methanesulfonamide (89 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 1,4-dioxane (0.75 mL) and H20 (0.3 mL) were added into the reaction mixture successively. The vessel was sealed with a cap under an argon atmosphere, then the reaction mixture was heated to 100 C for 2 hours under microwave. The mixture was cooled to room temperature and diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), and then the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give crude title compound. The crude title compound was purified by C-18 reversed phase HPLC column to give N-{(R)-2-[5- (lH-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethyl}-methanesulfonamide (12 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Synthesis of compound 16-d[0127] To a solution of compound 16-e (400 mg, 1.628 mmol) in dichloromethane (5 mL) were added dihydropyran(DHP) (413 mg, 4.92 mmol) and p-toluenesulfonic acid (pTSA) (31 mg, 0.164 mmol). The mixture was stirred overnightat room temperature. In the next day, the reaction mixture was diluted with dichloromethane (10 mL), the organic layerwas washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residuewas purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound 16-d (404 mg, yield76%) as a colorless oil. LC-MS (ESI): m/e 329.2 (M+H)+.Synthesis of compound 16-c[0128] To a flask containing dioxane (18 mL) were added compound 1-g (256 mg, 0.902 mmol), compound 16-d (404mg, 0.902 mmol), PdCl2(dppf).CH2Cl2 (74 mg, 0.092 mmol) and 2 N sodium carbonate solution (1.5 mL). Under nitrogen,the reaction mixture was stirred overnight at 80C. Water (100 mL) was added, and the solution was extracted with ethylacetate (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by Prep-TLC (methylene chloride: petroleum ether = 2: 1) to give compound 16-c (170 mg, yield 42%) asa yellow solid. LC-MS (ESI): m/e 449.0 (M+H)+.Synthesis of compound 16-b[0129] Compound 16-c (150 mg, 0.335 mmol) and morpholine (73 mg, 0.837 mmol) were dissolved in DMAC (4 mL).Under nitrogen, the mixture was heated to 94C and stirred overnight. The mixture was diluted with water (50 mL), andthe solution was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-TLC (ethyl acetate: petroleumether = 1:4) to give compound 16-b (150 mg, yield 90%) as a yellow solid. LC-MS (ESI): m/e 500.1 (M+H)+.Synthesis of compound 16-a[0130] To a reaction tube containing THF (3 mL) and water (0.3 mL) were added compound 16-b (150 mg, 0.300mmol), compound 2-a (148 mg, 0.600 mmol), palladium acetate (14.6 mg, 0.06 mmol), X-phos (14.5 mg, 0.03 mmol)and cesium carbonate (0.293 g , 0.900 mmol). Under nitrogen, the mixture was stirred overnight in an 80Coil bath. Aftercooling, the reaction mixture was filtered through celite, washed with tetrahydrofuran. The filtrate and washings werecombined and concentrated. The residue was purified by Prep-TLC (methylene chloride: methanol = 50:1) to givecompound 16-a (55 mg, 31% yield) as a yellow solid. LC-MS (ESI): m/e 598.3 (M+H)+.Synthesis of compound 16[0131] To a round bottom flask containing methanol (3 mL) and water (1 mL) were added compound 16-a (55 mg,0.092 mmol), methanesulfonic acid (44 mg, 0.460 mmol) was added under nitrogen. The mixture was stirred at roomtemperature for 1 hour, and then warmed to 65C, stirred for another 16 hours. The reaction solution was washed withsaturated sodium bicarbonate solution to pH 7 ~ 8. Water (20 mL) was added, and the solution was extracted with ethylacetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by Prep-TLC (methylene chloride: methanol = 20:1) to give compound 16 (38 mg, 80% yield). LC-MS (ESI):m/e 514.2 (M+H)+. 1HNMR (500 MHz, CDCl3): delta 10.83 (s, 1H), 8.59 (s, 1H), 8.24-8.21 (m, 2H), 7.76 (s, 1H), 7.61 (d,1H), 3.98-3.96 (m, 4H), 3.49 (s, 2H), 3.30-3.28 (m, 4H), 2.78 (s, 3H), 2.74-2.72 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In Dimethyl ether; water; at 150℃; for 0.5h;Inert atmosphere; Microwave irradiation; | To a mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 ; 200 mg; 0.50 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indazole (Intermediate 1 1 ; 345 mg crude; 0.74 mmol) and Cs2CO3 (488 mg; 1 .50 mmol) in DME (6 imL) and water (2 imL) was added Pd(dppf)CI2- DCM (40 mg; 0.05 mmol) under nitrogen. The mixture was heated at 150C for 30 minutes in a microwave reactor. The mixture was filtered through Celite and diluted with EtOAc (100 imL) and water (100 imL). The aqueous layer was extracted with EtOAc (50 imL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg (quant.) of the title compound as a yellow oil, which was used directly without further purification. LC-MS for C2i H14FN3O2S+H+ [M+H]+: calcd. 392.1 ; found: 392.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54%; 26% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Microwave irradiation; | To a mixture of <strong>[862723-42-0]1H-<strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong></strong> (109 mg, 0.45 mmol) and K2CO3 (95 mg, 0.69 mmol) in DMF (1 mL) was added 2,2-dimethyloxirane (0.10 mL, 1.13 mmol) and the mixture heated at 100 C. for 2 h under microwave irradiation. The solution was concentrated in vacuo and the crude material was purified by Biotage (SNAP 25 g column, cyclohexane/EtOAc 100/0->70/30, then CH2Cl2/EtOH 70/30->50/50) to give 2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)propan-2-ol (76 mg, 54%) as a colourless resin and 2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)propan-2-ol (36 mg, 26%) as a colourless resin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; | General procedure: General Procedure for Boronate Ester Preparation: [000170j To a mixture of an intermediate of formula R2Br (1 eq), potassium acetate (3 eq) and bis(pinacolato)diboron (1.1 eq) in 1 ,4-dioxane, argon was bubbled through the solution for 15 mm. 1,1 ?-Bis(diphenylphosphino) ferrocene palladium(II)dichloride dichloromethane adduct (PdC12(dppf)?CH2C12) (0.1 eq) was added and the reaction mixture was stirred at 90 C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite, evaporated to dryness to afford the desired0R2_Bboronate ester, 0 , as crude product and used as such for the next step without furtherpurification.:_[000184j The title compound has been synthesized by following the General Procedure for Boronate Ester Preparation described above using bromo compound 9 in Scheme 4 and Bis (pinacolato) diboron. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | The A1-4 (66mg, 0.20mmol), A13-2 (146mg, 0.60mmol) dissolved in dioxane / water (5mL / 1mL), was added potassium carbonate (110mg,0.80mmol), tetrakistriphenylphosphine palladium phosphate (23mg, 0.02mmol), purged with nitrogen, stirred overnight at 100 deg.] C, cooled to room temperature, suction filtered through Celite, and the filtrateDiluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent, the residue was purified by column chromatography (dichloromethane: methanol= 100: 1-25: 1) to give a white solid (40mg, 49%). After parsing NMR spectrum (map data in Table 1), the resulting solid was compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In tetrahydrofuran; water; at 40 - 80℃; for 12h;Inert atmosphere; | Under a nitrogen flow 1-bromo-2-nitrobenzene (15.23 g, 75.41 mmol), <strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> obtained in the above (22.09 g, 90.49 mmol), NaOH (9.05 g, 226.24 mmol) and THF/H2O (ml/200 400 ml) and then a mixture, in 40C Pd(PPh3)4 (4.36 g, 5 mol put%) was stirred at 80C for 12 hours. After completion of the reaction and extracted with methylene chloride, filtered, put MgSO4. After removal of the solvent from the obtained organic layer was purified by column chromatography (Hexane: EA = 3: 1 (v / v)) to give 5- (2-nitrophenyl) -1H-indazole (13.64 g, yield 63%) was obtained. |
63% | With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In tetrahydrofuran; water; at 40 - 80℃; for 12h;Inert atmosphere; | A stream of nitrogen under 1-bromo-2-nitrobenzene (15.23 g, 75.41 mmol) and the preparation of Example 1 In the obtained 5 - (4,4,5,5-tetramethyl-1-dioxaborolan-,3,2 2-yl)-1H-indazole (22.09 g, 90.49 mmol), NaOH (9.05 g, 226.24mmol) and THF/H2O (ml/200 400 ml) and then a mixture, in 40 Pd (PPh3) 4 (4.36 g, into a 5 mol%) was stirred at 80 for 12 hours. After completion of the reaction, extracted with methylene chloride, and then filtered into a MgSO4. After removal of the solvent from the obtained organic layer was purified by column chromatography (Hexane: EA = 3: 1 (v / v)) to give 5- (2-nitrophenyl) -1H-indazole (13.64 g, yield: 63%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In tetrahydrofuran; water; at 40 - 80℃; for 12h;Inert atmosphere; | In a nitrogen stream <strong>[160938-18-1]4-chloro-2-iodo-1-nitrobenzene</strong> (21.37 g, 75.41 mmol) 5- obtained in the above (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-indazole (22.09 g, 90.49 mmol), NaOH (9.05 g, 226.24mmol) and THF/H2O (ml/200 400 ml) the mixture, and then 40? from Pd (PPh3) 4 (4.36 g, into a 5 mol%) was stirred at 80? for 12 hours.After completion of the reaction and extracted with methylene chloride, filtered, put MgSO4. After removing the solvent from the obtained organic layer was purified by column chromatography (Hexane: EA = 3:1 (v / v)) to obtain the 5 - (5-chloro-2-nitrophenyl)-1H-indazole (15.60 g, yield 63%) It was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Microwave irradiation; | General procedure: Step 3: A degassed solution of 5-bromo-4-(4-fluoro-3-methylphenyl)-1-methyl-1H-imidazole (50 mg, 0.2 mmol), <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (60 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and aqueous Na2CO3 (2 M, 0.3 mL) in a mixture of DME/EtOH/H2O (7:3:2, 1.0 mL) was irradiated in the microwave at 150 C. for 50 min. The reaction mixture was then dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by HPLC to provide 5-(4-(4-fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole. MS m/e: 307 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Microwave irradiation; | Step 3: A degassed solution of 5-bromo-4-(4-fluoro-3-methylphenyl)-2-methyl-1H-imidazole (50 mg, 0.2 mmol), <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (60 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and aqueous Na2CO3 (2 M, 0.3 mL) in a mixture of DME/EtOH/H2O (7:3:2, 1.0 mL) was irradiated in the microwave at 150 C. for 50 min. The reaction mixture was then dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by HPLC to provide 5-(4-(4-fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole. MS m/e: 307 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Microwave irradiation; | General procedure: Step 3: A degassed solution of 5-bromo-4-(4-fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazole (50 mg, 0.2 mmol), <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (60 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and aqueous Na2CO3 (2 M, 0.3 mL) in a mixture of DME/EtOH/H2O (7:3:2, 1.0 mL) was irradiated in the microwave at 150 C. for 50 min. The reaction mixture was then dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by HPLC to provide 5-(4-(4-fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazol-5-yl)-1H-indazole. MS m/e: 321 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Microwave irradiation; | General procedure: Step 3: A degassed solution of 5-bromo-4-(4-fluoro-3-methylphenyl)-2-ethyl-1H-imidazole (50 mg, 0.2 mmol), <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (60 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and aqueous Na2CO3 (2 M, 0.3 mL) in a mixture of DME/EtOH/H2O (7:3:2, 1.0 mL) was irradiated in the microwave at 150 C. for 50 min. The reaction mixture was then dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by HPLC to provide 5-(2-ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole. MS m/e: 321 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Microwave irradiation; | General procedure: Step 3: A degassed solution of 5-bromo-4-(4-fluoro-3-methylphenyl)-1H-imidazole (50 mg, 0.2 mmol), <strong>[862723-42-0]indazole-5-boronic acid pinacol ester</strong> (60 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and aqueous Na2CO3 (2 M, 0.3 mL) in a mixture of DME/EtOH/H2O (7:3:2, 1.0 mL) was irradiated in the microwave at 150 C. for 50 min. The reaction mixture was then dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by HPLC to provide 5-(4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole. MS m/e: 293 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 72℃; for 4h; | To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (306.6 mg, 665.97 mumol), in dioxane (4 mL) and water (0.5 ml), was added <strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> (201 mg, 823.43 mumol), Cs2CO3 (557 mg, 1.71 mmol), and Pd(dppf)Cl2 (70 mg, 85.72 mumol). The reaction mixture was heated at 72 C. for 4 hours and partitioned between water and DCM. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 26 mg (8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Compound 1d (100 mg, 0.398 mmol) was added sequentially under an argon atmosphere.<strong>[862723-42-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> 2a (97 mg, 0.397 mmol,Prepared by the well-known method "Journal of Medicinal Chemistry, 2014, 57 (9), 3856-3873"), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride(58 mg, 0.079 mmol) and potassium carbonate (165 mg, 1.19 mmol) were dissolved in 12 mL of a mixed solution of 1,4-dioxane and water (V/V = 6:1), heated to 80 C, stirred for 2 hours. . The reaction was quenched, cooled to room temperature, and the residue was evaporated.The obtained crude product was purified by high-purpur chromatography to give the title compound 2 (30 mg, yield: 20.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Conditions A: A pressure tube was charged with 5-chloro-6-phenylimidazo[1 ,2-a]pyrazin-8- amine (0.060 g, 0.25 mmol), 5-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole (0.072 g, 0.29 mmol), sodium carbonate (0.052 g, 0.49 mmol) and mixture of 1,4-dioxane and water 4:1 (2.5 mL). This mixture was then sparged with argon under sonication for a few minutes, subsequently Pd(dppf)012*DCM was added (0.020 g, 0.02 mmol), the reaction mixture was spargedwith argon shortly and the vessel was capped. The reaction mixture was heated at 150 00 for 2 h. LC-MS indicated completion of the reaction. The reaction mixture was filtered through Celite, and the filtrate was concentrated. Crude product was purified by flash chromatography on silica eluting with DCMIMeOH 0-5%. Additional purification by RP-H PLC (formic acid) was performed to afford the title product as freebase. Obtained product was then suspended in asmall volume of methanol and 2M HCI solution in diethyl ether (0.1 mL) was added. The resulting solution was stirred for 1 h at r.t. then concentrated under reduced pressure and finally lyophilized to afford the title product as hydrochloride salt (18 mg, 20%) as a yellow solid. ESIMS: 327.05 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) 6 9.35 - 8.6 (br s, 1 H), 8.20 (s, 1 H), 7.89 -7.82 (m, 2H), 7.65 - 7.55 (m, 2H), 7.38 - 7.33 (m, 3H), 7.32 - 7.26 (m, 3H), 5.05 -4.15 (br s,2H). |
Tags: 862723-42-0 synthesis path| 862723-42-0 SDS| 862723-42-0 COA| 862723-42-0 purity| 862723-42-0 application| 862723-42-0 NMR| 862723-42-0 COA| 862723-42-0 structure
[ 885618-33-7 ]
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole
Similarity: 0.92
[ 953411-16-0 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine
Similarity: 0.90
[ 1256359-09-7 ]
1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
Similarity: 0.90
[ 885068-10-0 ]
1H-Indazol-6-yl-6-boronic acid
Similarity: 0.76
[ 1245816-09-4 ]
(4-Methyl-1H-indazol-5-yl)boronic acid
Similarity: 0.76
[ 885618-33-7 ]
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole
Similarity: 0.92
[ 953411-16-0 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine
Similarity: 0.90
[ 1256359-09-7 ]
1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
Similarity: 0.90
[ 885068-10-0 ]
1H-Indazol-6-yl-6-boronic acid
Similarity: 0.76
[ 1245816-09-4 ]
(4-Methyl-1H-indazol-5-yl)boronic acid
Similarity: 0.76
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