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CAS No. : | 58347-49-2 | MDL No. : | MFCD04035684 |
Formula : | C6H4ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YCZQHXPIKQHABJ-UHFFFAOYSA-N |
M.W : | 153.57 | Pubchem ID : | 12281647 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 38.0 |
TPSA : | 30.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.46 |
Log Po/w (XLOGP3) : | 1.29 |
Log Po/w (WLOGP) : | 1.38 |
Log Po/w (MLOGP) : | 1.18 |
Log Po/w (SILICOS-IT) : | 1.16 |
Consensus Log Po/w : | 1.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.27 |
Solubility : | 0.823 mg/ml ; 0.00536 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.52 |
Solubility : | 4.6 mg/ml ; 0.0299 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.31 |
Solubility : | 0.747 mg/ml ; 0.00486 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.8 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
71% | at 90℃; | PREPARATION 32 7-Chloropyrazolo[1,5-a]pyrimidine Pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88 mL, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 mL, 0.74 mmols) were mixed and stirred at 90ºC overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuo. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1) to afford the expected compound (83 mg, 71percent). LRMS (m/z): 154 (M+1)+ 1H NMR (400 MHz, DMSO-d6) d ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d, 1 H) 8.52 (d, 1 H) |
71% | at 90℃; | Pyrazolo[1 ,5-a]pyrimidin-7(4/-/)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88 mL, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 mL, 0.74 mmols) were mixed and stirred at 90°C overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1 ) to afford the expected compound (83 mg, 71 percent).LRMS (m/z): 154 (M+1 )+ 1H NMR (400 MHz, DMSO-d6) δ ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d, 1 H) 8.52 (d, 1 H) |
71% | at 90℃; | PREPARATION 897-Chloropyrazolo[1 ,5-a]pyrimidinePyrazolo[1 ,5-a]pyrimidin-7(4H)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88ml, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13ml, 0.74 mmols) were mixed and stirred at 90°C overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1 ) to afford the expected compound (83mg, 71 percent).LRMS (m/z): 154 (M+1 )+ 1 H N MR (400 MHz, DMSO-d6) d ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d , 1 H) 8.52 (d, 1 H) |
65% | at 90℃; for 2.5 h; | 7-Hydroxypyrazolo[1 ,5-a]pyrimidine (60 g, 444 mmol), phosphorus oxychloride (108 mL, 1.15 mol) and dimethylaniline (10.8 mL, 89 mmol) were added to a 250 mL round- bottomed flask and the contents heated to 90 0C. After 2.5 h, the reaction mixture was allowed to cool and was concentrated. The black residue was poured into a beaker containing crushed ice (600 mL) and the resulting solution kept cold using an ice bath. The aqueous solution was extracted with CH2CI2 (3 χ 150 mL) and the combined organic phase was washed with brine (100 mL). The organic phase was dried and concentrated to yield the desired crude product, 7-chloropyrazolo[1 ,5-a]pyrimidine, (44.2 g, 65percent) as a red solid. As the crude product was sufficiently pure to use in the subsequent step, a small sample was purified by column chromatography (33-66percent EtOAc/hexane) to yield an analytical sample as a white solid. HPLC 95percent; 1H NMR (250 MHz, CDCI3) δ 8.41 (d, J = 4.5 Hz, 1 H), 8.25 (d, J = 2.3 Hz, 1 H)1 6.99 (d, J ~ 4.5 Hz, 1 H), 6.84 (d, J = 2.3 Hz, 1 H); 13C NMR (62.9 MHz, CDCI3) δ 150.0, 148.2, 145.4, 139.0, 108.0, 98.7; MS (APCI) 154 [M+Hf. |
47% | for 72 h; | The compound prepared in preparative example 1 (2.4 g, 17.4 mmol) was stirred in POCl3 (54 mL) and N,N-dimethylaniline (6.7 mL) 3 days. The reaction mixture was concentrated, dissolved in saturated NaHCO3 (2000 mL) and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 2.5percent MeOH in CH2Cl2 solution as eluent (1.3 g, 47percent yield): M+H=154. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 16 h; | A solution of crude 7-chloropyrazolo[1,5-a]pyrimidine (44.2 g, 289 mmol) in dichloromethane (289 mL) was cooled to 0 0C using an ice bath. Λ/-bromosuccinimide(51.4 g, 289 mmol) was added slowly to the solution that was stirred for 16 h at room temperature. The dark orange solution was diluted with dichloromethane (200 mL) and was washed with 10percent potassium carbonate solution (3 x 150 mL) and brine (100 mL).The organic phase was dried and concentrated to give a dark orange solid, which was triturated using MeOH to yield the desired product, 3-bromo-7-chloropyrazolo[1,5- EPO <DP n="46"/>a]pyrimidine (50.9 g, 76percent) as a yellow solid. HPLC 96percent; lH NMR (250 MHz, CDCI3) δ 8.49 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.07 (d, J = 5.2 Hz, 1H); 13C NMR (62.9 MHz, DMSO) δ 150.4, 145.9, 144.7, 138.5, 109.5, 84.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 90℃; | PREPARATION 32 7-Chloropyrazolo[1,5-a]pyrimidine Pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88 mL, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 mL, 0.74 mmols) were mixed and stirred at 90ºC overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuo. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1) to afford the expected compound (83 mg, 71%). LRMS (m/z): 154 (M+1)+ 1H NMR (400 MHz, DMSO-d6) d ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d, 1 H) 8.52 (d, 1 H) |
71% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 90℃; | Pyrazolo[1 ,5-a]pyrimidin-7(4/-/)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88 mL, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 mL, 0.74 mmols) were mixed and stirred at 90C overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1 ) to afford the expected compound (83 mg, 71 %).LRMS (m/z): 154 (M+1 )+ 1H NMR (400 MHz, DMSO-d6) delta ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d, 1 H) 8.52 (d, 1 H) |
71% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 90℃; | PREPARATION 897-Chloropyrazolo[1 ,5-a]pyrimidinePyrazolo[1 ,5-a]pyrimidin-7(4H)-one (0.50g, 3.70 mmols), phosphorus oxychloride (0.88ml, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13ml, 0.74 mmols) were mixed and stirred at 90C overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1 ) to afford the expected compound (83mg, 71 %).LRMS (m/z): 154 (M+1 )+ 1 H N MR (400 MHz, DMSO-d6) d ppm 6.93 (d, 1 H) 7.43 (d, 1 H) 8.37 (d , 1 H) 8.52 (d, 1 H) |
65% | With trichlorophosphate;N,N-dimethyl-aniline; at 90℃; for 2.5h; | 7-Hydroxypyrazolo[1 ,5-a]pyrimidine (60 g, 444 mmol), phosphorus oxychloride (108 mL, 1.15 mol) and dimethylaniline (10.8 mL, 89 mmol) were added to a 250 mL round- bottomed flask and the contents heated to 90 0C. After 2.5 h, the reaction mixture was allowed to cool and was concentrated. The black residue was poured into a beaker containing crushed ice (600 mL) and the resulting solution kept cold using an ice bath. The aqueous solution was extracted with CH2CI2 (3 chi 150 mL) and the combined organic phase was washed with brine (100 mL). The organic phase was dried and concentrated to yield the desired crude product, 7-chloropyrazolo[1 ,5-a]pyrimidine, (44.2 g, 65%) as a red solid. As the crude product was sufficiently pure to use in the subsequent step, a small sample was purified by column chromatography (33-66% EtOAc/hexane) to yield an analytical sample as a white solid. HPLC 95%; 1H NMR (250 MHz, CDCI3) delta 8.41 (d, J = 4.5 Hz, 1 H), 8.25 (d, J = 2.3 Hz, 1 H)1 6.99 (d, J ~ 4.5 Hz, 1 H), 6.84 (d, J = 2.3 Hz, 1 H); 13C NMR (62.9 MHz, CDCI3) delta 150.0, 148.2, 145.4, 139.0, 108.0, 98.7; MS (APCI) 154 [M+Hf. |
47% | With N,N-dimethyl-aniline; trichlorophosphate; for 72h; | The compound prepared in preparative example 1 (2.4 g, 17.4 mmol) was stirred in POCl3 (54 mL) and N,N-dimethylaniline (6.7 mL) 3 days. The reaction mixture was concentrated, dissolved in saturated NaHCO3 (2000 mL) and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 2.5% MeOH in CH2Cl2 solution as eluent (1.3 g, 47% yield): M+H=154. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-diethylaniline; In toluene; | EXAMPLE 1 Preparation of 7-(3,5-di-t-butyl-4-hydroxyphenyl)-aminopyrazolo[1,5-a]pyrimidine: A suspension of <strong>[58347-49-2]7-chloropyrazolo[1,5-a]pyrimidine</strong> (1.0 g), 3,5-di-t-butyl-4-hydroxyaniline hydrochloride (1.8 g) and diethylaniline (2.3 ml) in toluene (50 ml) is heated at 120 C. for 30 minutes. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; CHCl3) to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)aminopyrazolo[1,5-a]pyrimidine (890 mg) as colorless crystal. M.p. 264-266 C. (decomposed) 1 H-NMR (CDCl3): delta 1.48 (s, 18H), 5.63 (s, 1H), 5.92 (s, 1H), 6.55 (d, J=2.3 Hz, 1H), 7.47 (s, 2H), 8.14 (d, J=2.3 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃; for 16.0h; | A solution of crude 7-chloropyrazolo[1,5-a]pyrimidine (44.2 g, 289 mmol) in dichloromethane (289 mL) was cooled to 0 0C using an ice bath. Lambda/-bromosuccinimide(51.4 g, 289 mmol) was added slowly to the solution that was stirred for 16 h at room temperature. The dark orange solution was diluted with dichloromethane (200 mL) and was washed with 10% potassium carbonate solution (3 x 150 mL) and brine (100 mL).The organic phase was dried and concentrated to give a dark orange solid, which was triturated using MeOH to yield the desired product, 3-bromo-7-chloropyrazolo[1,5- EPO <DP n="46"/>a]pyrimidine (50.9 g, 76%) as a yellow solid. HPLC 96%; lH NMR (250 MHz, CDCI3) delta 8.49 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.07 (d, J = 5.2 Hz, 1H); 13C NMR (62.9 MHz, DMSO) delta 150.4, 145.9, 144.7, 138.5, 109.5, 84.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.8% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h; | Intermediate 15 (324 mg, 1.0 mmol), l-(2-aminoethyl)imidazolidin-2-one (260 mg, 2.0 mmol), DIPEA (270 mg, 2.0 mmol) and n-butanol (5.0 mL) were combined in a sealed tube and heated to 12O0C for 72 h. After cooling, the mixture was dissolved in a 1 :1 mixture OfEt2O and EtOAc (200 mL) and washed with saturated brine (3 x 50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-5% MeOH in DCM) gave a yellow solid (76 mg, 17%). This was dissolved in DCM (5 mL) and treated with TFA (1 mL) and the mixture stirred for 4 h at r.t. before being quenched with 2M NaOH solution (30 mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale orange gum (55 mg, 94%). This was combined with 7-chloropyrazolo[l,5-alpha]- pyrimidine (38 mg, 0.22 mmol) and DIPEA (100 mg, 0.78 mmol) in n-butanol (2 mL) and the mixture heated at 1200C for 16 h. After cooling, the mixture was dissolved in a 1 :1 mixture OfEt2O and EtOAc (100 mL) and washed with saturated brine (3 x 10 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by preparative HPLC gave the title compound (6 mg, 7.8%) as a white solid. deltaH (MeOD-d0 8.16 (IH, d, J2.32 Hz), 8.10 (IH, d, J5.40 Hz), 7.95 (IH, s), 7.60 (IH, dd, J8.85, 6.33 Hz), 7.31 (IH, dd, J 11.11, 2.53 Hz), 6.97 (IH, td, J8.72, 2.56 Hz), 6.49 (IH, d, J2.33 Hz), 5.93 (IH, d, J5.43 Hz), 5.06 (IH, q, J6.73 Hz), 4.00- 3.90 (IH, m), 3.83-3.73 (IH, m), 3.72-3.52 (4H, m), 3.32-3.26 (2H, m), 1.78 (3H, d, J 6.74 Hz). LCMS (ES+) 435 (M+H)+, 8.93 minutes {Method 9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 18h; | A mixture of Intermediate 23 (1.0 g, 2.9 mmol), l-(2-aminoethyl)imidazolidin-2- one (0.5 g, 3.9 mmol) and DIPEA (0.8 mL, 5.8 mmol) in «-butanol (10 mL) was heated at 1200C for 72 h. After cooling, the reaction mixture was partitioned between Et2O (200 mL) and water (100 mL). The organic layer was washed with water (3 x 100 mL) and brine (100 mL), separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 5% MeOH in DCM) to give a pale yellow solid. This was dissolved in DCM (20 mL), treated with TFA (5 mL) and stirred for 4 h at r.t. After quenching with 2M NaOH solution (30 mL), the organic layer was washed with water (3 x 10 mL), separated, dried (MgSO4), filtered and concentrated in vacuo to give an orange oil (0.8 g, 82%). A portion of this oil (100 mg, 0.3 mmol), 7- chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.33 mmol) and DIPEA (100 mg, 0.78 mmol) in «-butanol (2 mL) was heated at 12O0C for 18 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (57 mg, 42%) as a clear glass. deltaH (CDCl3) 8.09 (IH, d, J5.17 Hz), 8.04 (IH, d, J2.33 Hz), 7.81 (IH, s), 7.63 (IH, dd, Jl.56, 1.36 Hz), 7.46 (IH, dd, J7.98, 1.36 Hz), 7.14-7.04 (IH, m), 6.92 (IH, d, J5.76 Hz), 6.53 (IH, d, J2.32 Hz), 6.37 (IH, s), 5.80 (IH, d, J5.21 Hz), 4.94- 4.84 (IH, m), 4.59 (IH, s), 3.98-3.89 (IH, m), 3.86-3.77 (IH, m), 3.68-3.52 (4H, m), 3.38-3.24 (2H, m), 1.80 (3H, d, J6.76 Hz). LCMS (ES+) 451 (M+H)+, 3.41 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | A mixture of Intermediate 16 (280 mg, 0.83 mmol), 3-methoxypropylamine (98 mg, 1.1 mmol) and DIPEA (0.4 mL, 2.19 mmol) in n-butanol (2 mL) was heated at 1200C for 5 days. The reaction mixture was cooled and partitioned between water (30 mL) and EtOAc (100 mL). The organic layer was washed with water (5 x 20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 75-100% EtOAc in isohexane) to give an off-white solid. This was dissolved in 1,4- dioxane (10 mL) and treated with HCl (2 mL; 4.0M in 1,4-dioxane) and the mixture was stirred at r.t. overnight. The reaction mixture was concentrated in vacuo to give an orange oil (200 mg, 81%). A portion of this oil (70 mg, 0.25 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (38 mg, 0.25 mmol) and DIPEA (100 mg, 0.78 mmol) in n-butanol (2 mL) was heated at HO0C overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to give the title compound (29 mg, 30%) as a white solid. deltaH (CDCl3) 8.11 (IH, d, J5.12 Hz), 8.05 (IH, d, J2.32 Hz), 7.76 (IH, s), 7.34 (IH, dd, J 8.81, 6.23 Hz), 6.94 (IH, t, J9.00 Hz), 6.66 (IH, d, J5.60 Hz), 6.55 (IH, d, J2.32 Hz), 5.74 (IH, d, J5.14 Hz), 5.69 (IH, t, J4.76 Hz), 4.80-4.70 (IH, m), 3.79 (2H, q, J 5.57 Hz), 3.59-3.53 (2H, m), 3.27 (3H, s), 2.56 (3H, d, J2.40 Hz), 2.06-1.93 (2H, m), 1.79 (3H, d, J6.70 Hz). LCMS (ES+) 409 (M+H)+, 3.41 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1h;Microwave Irradiation; | A solution of Intermediate 39 (75 mg, 0.248 mmol), 7-chloropyrazolo[l,5- alpha]pyrimidine (38 mg, 0.248 mmol) and DIPEA (1.0 mL, 5.46 mmol) in r°-butanol (5 mL) was heated at 14O0C under microwave irradiation for 1 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford the title compound (26.1 mg, 28%) as an off-white solid. deltaH (DMSO-d6) 8.41 (IH, s), 8.21 (IH, d, J2.29 Hz), 8.10 (IH, d, J5.20 Hz), 8.03 (IH, s), 7.65 (IH, d, J7.52 Hz), 7.58 (IH, d, J7.89 Hz), 7.20 (IH, d, J5.73 Hz), 7.12 (IH, t, 77.73 Hz), 6.51 (IH, d, J2.28 Hz), 5.87 (IH, d, J5.27 Hz), 5.19 (IH, d, J6.85 Hz), 3.82-3.62 (5H, m), 1.69 (3H, d, J6.57 Hz). LCMS (ES+) 383 (M+H)+, 13.2 minutes {Method 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 64h; | To a solution of Intermediate 14 (4.0 g, 12.2 mmol) in MeOH (20 mL) was added cone. HCl (1 mL) and the mixture stirred at r.t. for 2 h. The reaction mixture was partitioned between DCM (100 mL) and 2M NaOH solution (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. A portion of the resulting material (280 mg, 1.2 mmol), 7-chloropyrazolo[l,5-alpha]pyrimidine (310 mg, 1.9 mmol) and DIPEA (0.7 mL, 4 mmol) in n-butanol (3 mL) were combined and heated at 1000C for 64 h. The mixture was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was separated, extracted into EtOAc (20 mL) and the combined organics washed with water (15 mL), brine (15 mL), separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-60% EtOAc in hexanes) to give the title compound (300 mg, 72%) as a pale yellow solid. deltaH (CDCl3) 8.22 (IH, d, J7.6 Hz), 8.11 (IH, s), 7.82 (IH, d, J2.3 Hz), 7.57 (IH, dd, J8.8, 6.1 Hz), 7.28 (IH5 m), 6.06 (IH, d, J2.0 Hz), 6.03 (IH, d, J7.6 Hz), 5.51 (2H, m), 2.65 (3H, d, J 2.3 Hz), 1.69 (3H, d, J 6.8 Hz). LCMS (ES+) 356.2 (M+H)+. | |
In butan-1-ol; at 100℃; for 3h;Inert atmosphere; | INTERMEDIATE 42(S)-iV-ri-(2-Chloro-7-fluoro-8-methylquinolin-3-yl')ethyllpyrazolori,5-alpha1pyrimidin-7- amineIntermediate 15 (0.52 g, 1.54 mmol) and 4N HCl in 1,4-dioxane (10 niL) were stirred at r.t. for 40 minutes. The excess solvent was removed in vacuo and the residue obtained was partitioned between DCM (50 mL) and saturated NaHCO3 solution (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue (0.35 g, 1.47 mmol) was dissolved in H-BuOH (10 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (0.23 g, 1.49 mmol) was added. The mixture was heated at 1000C for 3 h. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 50% EtOAc in 40-60 petroleum ether) to afford the title compound (440 mg, 80%) as a pale yellow foam. deltaH (CDCl3) 8.10 (m, 3H), 7.56 (dd, J9.1, 6.1 Hz, IH), 7.29 (m, IH), 6.82 (d, J6.1 Hz, IH), 6.56 (d, J2.3 Hz, IH), 5.65 (d, J5.1 Hz, IH), 5.29 (m, IH), 2.67 (d, J 2.3 Hz, 3H), 1.82 (d, J 6.8 Hz, 3H). LCMS (ES+) 356 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
KOtBu (0.11 g, 1.04 eq.) was added to 5-hydroxyindole (0.13 g, 1.0 eq.) in DMF (1.7 mL) and the resulting solution stirred at room temperature for three hours. To the reaction mixture was then added the compound prepared in Preparative Example 2 (0.15 g, 0.98 mmol) and K2CO3 (0.068 g, 0.5 eq.) and the resulting solution was heated at 80 C. overnight. The reaction mixture was cooled to room temperature, diluted with saturated NaCl (6 mL) and extracted with EtOAc. The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography. M+H=251; mp=201-201 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 1h;Inert atmosphere; Microwave irradiation; | EXAMPLE 284-{8-Methyl-3-r(pyrazolori,5-alphalpyrimidin-7-ylamino)methyllquinolin-2-yl}piperazin-2- oneIntermediate 24 (60 mg, 0.22 mmol) in NMP (1.0 mL) was treated with 7-chloro- pyrazolo[l,5-alpha]pyrimidine (41 mg, 0.27 mmol) and DIPEA (0.20 mL, 1.11 mmol). The mixture was heated at 12O0C under microwave irradiation for 1 h. Purification by preparative HPLC gave the title compound (38.0 mg, 44%) as a beige solid. 6H (CDCl3) 8.19 (IH, d, J5.13 Hz), 8.13-8.06 (IH, m), 8.03 (IH, d, J2.31 Hz), 7.53 (2H, t, J8.30 Hz), 7.33 (IH, t, J7.56 Hz), 7.18 (IH, t, J5.93 Hz), 6.55 (IH, d, J2.31 Hz), 6.25 (IH, s), 5.88 (IH, d, J5.15 Hz), 4.79 (2H, d, J5.94 Hz), 4.11 (2H, s), 3.59 (4H, s), 2.72 (3H, s). LCMS (ES+) 388 (M+H)+, RT 2.04 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
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10% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 44(S)-A- { 7-Fluoro-8-methyl-3 -[I -(pyrazolo F 1 ,5 -a1pyrimidin-7-ylamino')ethyl1 quinolin-2- yl |piperazin-2-one TFA (1 mL) was added to a stirred solution of Intermediate 21 (1.50 g, 3.73 mmol) and the mixture was allowed to stand at r.t. for 16 h before being concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and purified by SCX column chromatography eluting with MeOH, then IM NH3 in MeOH, to afford a clear oil (1.10 g, 97%). To a solution of this oil (100 mg, 0.33 mmol) in «-BuOH (3 mL) were added 7- chloropyrazolo[l,5-alpha]pyrimidine (56 mg, 0.37 mmol) and DIPEA (100 mg, 0.78 mmol) and the mixture was heated at 12O0C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (13.9 mg, 10%) as a cream solid. deltaH (CDCl3) 8.16 (IH, s), 8.12 (IH, d, J5.2 Hz), 8.02 (IH, s), 7.52 (IH, dd, J 8.8 Hz), 7.19 (IH, t, J8.8 Hz), 6.89 (IH, d, J6.4 Hz), 6.52 (IH, s), 6.12 (IH, s), 5.89 (IH, d, J5.2 Hz), 5.14-5.23 (IH, m), 4.12 (2H, q, J 17.5 Hz), 3.50-3.59 (4H, m), 2.61 (3H, s), 1.85 (3H, d, J 6.8 Hz). LCMS (ES+) 420 (M+H)+, RT 2.16 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
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21% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; for 18h;Inert atmosphere; | EXAMPLE 41(^-N-d-ry-Fluoro-S-methyl^-fpyrrolidin-l-vDquinolin-S-yllethvUpyrazolofhS-alphai- pyriniidin-7-amine Intermediate 27 (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (10 mL) andHCl (4M in 1,4-dioxane, 4 mL) was added. The reaction mixture was stirred at r.t. for 2 h then basified with 15% NaOH solution and extracted with DCM (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil (70 mg, 90%). This material (70 mg, 0.21 mmol), 7-chloropyrazolo[l,5-alpha]pyrimidine (40 mg, 0.26 mmol) and DIPEA (100 mg, 0.78 mmol) in «-BuOH (2.0 mL) were stirred at HO0C for 18 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (20 mg, 21%) as a cream solid. deltaH (CDCl3) 8.14 (IH, d, J5.2 Hz), 8.05 (IH, s), 7.95 (IH, s), 7.39 (IH, dd, J8.8 Hz), 7.02 (IH, t, J8.8 Hz), 6.74 (IH, d, J6.4 Hz), 6.55 (IH, s), 5.84 (IH, d, J5.2 Hz), 5.22-5.30 (IH, m), 3.72-3.78 (4H, m), 2.59 (3H, s), 2.08-2.18 (4H, m), 1.75 (3H, d, J6.8 Hz). LCMS (ES+) 391 (M+H)+, RT 3.99 minutes (Method I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 1h;Microwave irradiation; Inert atmosphere; | EXAMPLE 56Methyl 4-{7-fluoro-8-methyl-3-|Yl»Sy 1 -(pyrazoloFl ,5-alpha]pyrimidin-7-ylamino')ethyl1- quinolin-2-vUpiperazine-l-carboxylateA mixture of Intermediate 15 (501 mg, 1.48 mmol), methyl piperazine-1- carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39 mmol) in NMP (3 mL) was heated under microwave irradiation at 1300C for 4.5 h. After cooling, the mixture was dissolved in a 1 :1 mixture of EtOAc and Et2O (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc in DCM) gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)+. To this oil (400 mg, 0.896 mmol) dissolved in DCM (23 mL) was added TFA (4.1 mL). The reaction mixture was stirred at r.t. for 1.5 h. The excess solvent was removed in vacuo. The oil obtained was basified with 0.2M NaOH (40 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 95:4:1 DCM/MeOH/NH3 solution in MeOH) gave a colourless gum (278 mg, 90%). LCMS (ES+) 347 (M+H)+. A portion of this material (55.6 mg, 0.161 mmol), 7-chloropyrazolo[l,5-«]pyrimidine (37 mg, 0.241 mmol), DIPEA (0.084 mL, 0.482 mmol) and n-BuOH (1 mL) were combined and heated under microwave irradiation at 1300C for 1 h. Purification by preparative HPLC gave the title compound (43.7 mg, 59%) as a yellow solid. deltaH (DMSO-d6) 8.64 (s, IH), 8.41 (d, J 7.84 Hz, IH), 8.11-8.14 (m, 2H), 7.74 (dd, J 8.95, 6.27 Hz, IH), 7.34 (t, J 9.12 Hz, IH), 6.44 (d, J2.27 Hz, IH), 6.27 (d, J5.30 Hz, IH), 5.16 (t, J7.20 Hz, IH), 3.75-3.83 (m, 2H), 3.70 (s, 3H), 3.65-3.70 (m, 2H), 3.30-3.35 (m, 2H), 3.22-3.30 (m, 2H), 2.11 (s, 3H), 1.88 (d, J6.71 Hz, 3H). LCMS (ES+) 464 (M+H)+, RT 3.71 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃;Inert atmosphere; | EXAMPLE 7(^-4-{8-Chloro-3-|"l-(pyrazolo[l,5-alphalpyrimidin-7-ylamino)ethyllquinolin-2-vU- piperazin-2-oneTo a solution of Intermediate 5 (1.0 g, 3.17 mmol) in 1,4-dioxane (15 mL) was added HCl (15.8 mL, 63.4 mmol; 4M in 1,4-dioxane). After 2 h, the solvent was removed in vacuo. The residue (100 mg, 0.33 mmol), NMP (2 mL), DIPEA (0.17 mL, 0.98 mmol) and 7-chloropyrazolo[l,5-alpha]pyrimidine (76 mg, 0.5 mmol) were combined in a sealed tube and heated to 14O0C overnight. The reaction mixture was cooled and the solvent removed in vacuo. The residue was redissolved in DCM (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was separated, dried (MgSO4) and filtered, and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound (16.7 mg, 12%) as a light orange solid. deltaH (DMSO-d6) 8.67 (IH, s), 8.12-8.07 (2H, m), 8.04 (IH, s), 7.85-7.79 (2H, m), 7.42-7.37 (IH, m), 6.43 (IH, d, J 2.28 Hz), 6.10 (IH, d, J5.28 Hz), 5.14-5.07 (IH, m), 4.12 (IH, d, J 17.14 Hz), 3.90 (IH, d, J 17.13 Hz), 3.63-3.45 (4H, m), 1.87 (3H, d, J6.67 Hz). NH not seen. LCMS (ES+) 422/424 (M+H)+, RT 2.13 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | EXAMPLE 14(4-{8-Chloro-3-f(15f)-l-(pyrazolo[l,5-alpha1pyrimidin-7-ylamino)ethyl1quinolin-2- vUpiperazin-l-yl)acetic acidIntermediate 22 (500 mg, 1.05 mmol), EtOH (5 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 4 days. The reaction mixture was then concentrated to give a yellow glass (526 mg, quantitative). A portion of this material (50 mg, 0.11 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 1400C for 1 h. 15% NaOH solution (0.2 mL) was added to the reaction mixture, which was stirred at r.t. for 18 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (33.8 mg, 66%) as a tan glass, delta? (DMSO- d6) 8.68 (IH, s), 8.46 (IH, t, J5.75 Hz), 8.12 (2H, m), 7.86-7.76 (2H, m), 7.40 (IH, t, J 7.81 Hz), 6.44 (IH, d, J 2.28 Hz), 6.26 (IH, d, J 5.27 Hz), 5.11 (IH, m), 3.48-3.40 (2H, m), 3.38-3.29 (2H, m), 3.30 (2H, s), 3.05-2.97 (2H, m), 2.94-2.86 (2H, m), 1.90 (3H, d, J 6.68 Hz). OH not seen. LCMS (ES+) 466/468 (M+H)+, RT 1.89 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1h;Inert atmosphere; Microwave irradiation; | EXAMPLE 15Ethyl (4- { 8 -chloro-3 - IY 1 S)- 1 -(pyrazolof 1 ,5 -a]pyrimidin-7-ylamino)ethyllquinolin-2- yl } piperazin- 1 - vDacetateIntermediate 22 (500 mg, 1.05 mmol), EtOH (5 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 4 days. The reaction mixture was then concentrated to give a yellow glass (526 mg, quantitative). A portion of this material (50 mg, 0.11 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 14O0C for 1 h. The reaction mixture was then concentrated and purified by preparative HPLC to give the title compound (39.3 mg, 72%) as a tan glass. deltaH (DMSOd6) 8.68 (IH, s), 8.47 (IH, d, J7.70 Hz), 8.14-8.09 (2H, m), 7.86-7.76 (2H, m), 7.40 (IH, t, J7.81 Hz), 6.44 (IH, d, J2.27 Hz), 6.26 (IH, d, J5.28 Hz), 5.14-5.05 (IH, m), 4.16 (2H, q, J7.10 Hz), 3.47-3.38 (2H, m), 3.42 (2H, s), 3.38-3.29 (2H, m), 3.00-2.93 (2H, m), 2.90-2.82 (2H, m), 1.90 (3H, d, J 6.69 Hz), 1.25 (3H, t, J 7.09 Hz). LCMS (ES+) 494/496 (M+H)+, RT 3.50 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1h;Inert atmosphere; Microwave irradiation; | EXAMPLE 132-(4-{8-Chloro-3-r(l^-l-(pyrazolori,5-alpha]pyrimidin-7-ylamino)ethyl1quinolin-2- yl } piperazin- 1 -yPethanolIntermediate 4 (700 mg, 2.05 mmol), l-(2-hydroxyethyl)piperazine (1 mL), n- BuOH (6 mL) and DIPEA (1 mL) were combined in a sealed tube and heated to 1200C for 4 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-100% EtOAc in isohexane) to give a clear gum (681 mg, 76%). This material (670 mg, 1.54 mmol), MeOH (5 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow solid (670 mg, quantitative). A portion of this material (65 mg, 0.159 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 14O0C for 1 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (34 mg, 47%) as an off-white solid. 6H (DMSO-d6) 8.68 (IH, s), 8.46 (IH, d, J7.72 Hz), 8.12 (2H, m), 7.84-7.78 (2H, m), 7.40 (IH, t, J7.81 Hz), 6.44 (IH, d, J2.27 Hz), 6.25 (IH, d, J5.29 Hz), 5.15-5.07 (IH, m), 4.49 (IH, t, J5.33 Hz), 3.62 (2H, q, J5.72 Hz), 3.45-3.25 (4H, m), 2.90-2.80 (2H, m), 2.78-2.70 (2H, m), 2.58-2.51 (2H, m), 1.90 (3H, d, J 6.71 Hz). LCMS (ES+) 452/454 (M+H)+, RT 2.92 minutes {Method I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Inert atmosphere; Microwave irradiation; | EXAMPLE 16N- ( (2>;R)- 1 - ( 8-Chloro-3 - IT 1 S)- 1 -( pyrazolo [ 1.5 -alpha1pyrimidin-7-ylamino)ethyllquinolin-2- yllpyrrolidin-3-yl]methyl|acetamideIntermediate 4 (700 mg, 2.05 mmol), (5)-l-[3-(aminomethyl)pyrrolidin-l-yl)]- ethanone (710 mg, 4.02 mmol), n-BuOH (6 mL) and DIPEA (1 mL) were combined in a sealed tube and heated to 1300C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-100% EtOAc in isohexane) to give tert-butyl (5)-l-{2-[(/?)-3-(acetamidomethyl)pyrrolidin-l-yl]-8-chloro- quinolin-3-yl}ethylcarbamate (258 mg) as a white solid (from rearrangement of amine in situ) and tert-butyl (5)-l-(2-[(5)-l-acetylpyrrolidin-3-ylmethyl]amino}-8-chloro- quinolin-3-yl)ethylcarbamate (189 mg) as a clear glass. tert-Butyl (S)-I -{2-[(i?)-3- (acetamidomethy^pyrrolidin-l-ylJ-delta-chloroquinolin-S-ylJethylcarbamate (240 mg), MeOH (5 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 1 day. The reaction mixture was then concentrated in vacuo to give a yellow solid (250 mg). A portion of this solid (50 mg, 0.15 mmol), n-BuOH (6 mL), DIPEA (1 mL) and 7-chloro- pyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (7.6 mg, 11%) as a tan solid. deltaH (DMSO-d6) 8.46 (IH, s), 8.37 (IH, s), 8.25-8.22 (IH, m), 8.18-8.11 (2H, m), 7.77 (IH, d), 7.71 (IH, d), 7.25 (IH, t, J7.77 Hz), 6.55 (IH, d, J2.28 Hz), 6.12-6.06 (IH, m), 5.34 (IH, m), 3.99-3.84 (3H, m), 3.78-3.65 (IH, m), 3.33-3.21(2H, m), 2.61-2.52 (IH, m), 2.24-2.14 (IH, m), 1.95-1.81 (7H, m). LCMS (ES+) 464/466 (M+H)+, RT 2.91 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Inert atmosphere; Microwave irradiation; | EXAMPLE 171 - { 7-Fluoro-8-methyl-3 - ( 1 S)- 1 -(pyrazolo [ 1 ,5 -alpha1pyrimidin-7-ylamino)ethyll quinolin-2- yl ) piperidine-4-carboxamide Intermediate 15 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid amide (0.5 g,3.9 mmol), n-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 13O0C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a clear gum. This material, MeOH (10 mL) and 2N HCl in Et2O (7 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow solid. A portion of this material (60 mg), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloro- pyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 1600C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (25.2 mg, 34%) as a beige solid. deltaH (DMSO-d6) 8.60 (IH, s), 8.40 (IH, d, J7.74 Hz), 8.13-8.08 (2H, m), 7.70 (IH, dd, J8.94, 6.31 Hz), 7.38 (IH, s), 7.30 (IH, t, J9.12 Hz), 6.87 (IH, s), 6.43 (IH, d, J2.28 Hz), 6.25 (IH, d, J5.29 Hz), 5.07 (IH, m), 3.69 (IH, d, J 12.66 Hz), 3.56 (IH, d, J 12.72 Hz), 3.18 (IH, t, J 12.09 Hz), 2.92 (IH, t, J 12.09 Hz), 2.56 (3H, s), 2.47-2.37 (IH, m), 2.10-1.97 (2H, m), 1.98-1.86 (5H, m). LCMS (ES+) 448 (M+H)+, RT 2.34 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Inert atmosphere; Microwave irradiation; | EXAMPLE 18N-r(35r)-l-{7-Fluoro-8-methyl-3-r(15r)-l-(pyrazolorL5-alphalpyrimidin-7-ylamino>;)ethyl1- quinolin-2-vUpyrrolidin-3-yl]cyclopropanecarboxamide(5)-(-)-3 -Amino- 1-pyrrolidinecarboxylic acid tert-butyl ester (500 mg, 2.68 mmol), DCM (30 mL), DIPEA (2 mL) and cyclopropanecarbonyl chloride (0.275 mL, 3 mmol) were combined at r.t. under a nitrogen atmosphere. The reaction mixture was stirred for 1 day, then diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give a brown oil. This oil, MeOH (10 mL) and 2N HCl in Et2O (5 mL) were stirred at r.t. for 3 days. The reaction mixture was then concentrated in vacuo. The resulting material, Intermediate 15 (500 mg, 1.48 mmol), H-BuOH (16 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 13O0C for 15 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-100% EtOAc in isohexane) to give a tan solid. This material, MeOH (10 mL) and 2N HCl in Et2O (7 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a brown glass. A portion of this material (50 mg, 0.127 mmol), n- BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (32.3 mg, 54%) as a brown glass. 6H (DMSO-d6) 8.44 (IH, d, J6.91 Hz), 8.38 (IH, d, J6.91 Hz), 8.25 (IH, s), 8.17 (IH, d, J 2.27 Hz), 8.10 (IH, d, J5.21 Hz), 7.57 (IH, dd, J8.84, 6.41 Hz), 7.10 (IH, t, J9.10 Hz), 6.49 (IH, d, J2.27 Hz), 6.06 (IH, d, J 5.28 Hz), 5.27 (IH, m), 4.50-4.42 (IH, m), 4.07- 3.94 (2H, m), 3.82-3.74 (IH, m), 3.60 (IH, dd, J 10.47, 5.21 Hz), 2.51 (3H, s), 2.32-2.23 (IH, m), 2.04-1.94 (IH, m), 1.77 (3H, d, J6.54 Hz), 1.66-1.58 (IH, m), 0.77-0.67 (4H, m). LCMS (ES+) 474 (M+H)+, RT 2.51 minutes {Method I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Inert atmosphere; Microwave irradiation; | EXAMPLE 19N- (3R)- 1 - { 8-Chloro-3- |Y 1 S)- 1 -(pyrazolo [1,5 -fl|pyrirrndin-7-ylarnino)ethyllquinolin-2- yUpyrrolidin-3-yl1-2-hydroxyacetamide(R)-(+)-3 -Amino- 1-pyrrolidinecarboxylic acid tert-butyl ester (400 mg, 2.15 mmol), DCM (30 mL), DIPEA (2 mL), and acetoxyacetyl chloride (0.247 mL, 2.3 mmol) were combined at r.t. under nitrogen atmosphere. The reaction mixture was stirred for 7 days, then diluted with DCM (50 mL) and washed with water (30 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give a tan oil. This material, MeOH (10 mL) and 2N HCl in Et2O (4 mL) were stirred at r.t. for 1 day. The reaction mixture was concentrated in vacuo. The resulting material, Intermediate 4 (400 mg, 1.17 mmol), «-BuOH (14 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 13O0C for 13 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-100% EtOAc in isohexane then 10% MeOH in EtOAc) to give an off-white foam. This material, MeOH (10 mL) and 2N HCl in Et2O (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.13 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (10.3 mg, 17%) as an off-white solid. deltaH (DMSOd6) 8.43 (IH, d, J7.03 Hz), 8.32 (IH, s), 8.20-8.06 (3H, m), 7.72 (IH, d, J7.48 Hz), 7.65 (IH, d, J8.00 Hz), 7.20 (IH, t, J7.77 Hz), 6.49 (IH, d, J2.32 Hz), 6.03 (IH, d, J5.23 Hz), 5.50 (IH, s), 5.27 (IH, m), 4.59-4.51 (IH, m), 4.00-3.84 (6H, m), 2.24 (IH, m), 2.11 (IH, m), 1.80 (3H, d, J 6.51 Hz). LCMS (ES+) 466/468 (M+H)+, RT 2.79 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 20(4- { 7-Fluoro-8-methyl-3 - |Y 1 S)- 1 -(pyrazolo[ 1.5 -alphalpyrimidin-7-ylamino)ethyl]quinolin-2- yllpiperazin-l-yl)acetic acidIntermediate 15 (700 mg, 2.06 mmol), ethyl 1-piperazineacetate (0.5 g), H-BuOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 13O0C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-100% EtOAc in isohexane). The resulting material, EtOH (7 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a pale yellow solid. A portion of this material (50 mg), tt-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. 15% NaOH solution (0.2 mL) was then added to the reaction mixture which was stirred at r.t. for 3 days. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (32.9 mg, 60%) as a beige solid. deltaH (DMSO-d6) 8.67 (IH, s), 8.47 (IH, d, J8.21 Hz), 8.19-8.14 (2H, m), 7.77 (IH, dd, J8.96, 6.25 Hz), 7.36 (IH, t, J9.11 Hz), 6.49 (IH, d, J2.27 Hz), 6.34 (IH, d, J 5.30 Hz), 5.16 (IH, m), 3.50-3.30 (6H, m), 3.08-2.91 (4H, m), 2.62 (3H, s), 1.94 (3H, d, J 6.71 Hz). OH not seen. LCMS (ES+) 464 (M+H)+, RT 2.37 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Inert atmosphere; Microwave irradiation; | EXAMPLE 21l-(4-{8-Chloro-3-[(l,S^-l-(pyrazolo[l,5-fl]pyriinidin-7-ylamino)ethyl]quinolin-2- yl Ipiperazin- 1 -ylV2-hydroxyethanone Intermediate 4 (700 mg, 2.05 mmol), 2-hydroxy-l-(piperazin-l-yl)ethanone hydrochloride, H-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 13O0C for 7 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a yellow gum. This material, MeOH (5 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow glass. A portion of this material (50 mg, 0.13 mmol), H-BuOH (6 mL), DIPEA (1 mL) and 7- chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (8.8 mg, 15%) as a yellow solid. deltaH (DMSO-de) 8.67 (IH, s), 8.40 (IH, d, J7.79 Hz), 8.09 (2H, t, J2.40 Hz), 7.82-7.75 (2H, m), 7.38 (IH, t, J7.82 Hz), 6.40 (IH, d, J2.27 Hz), 6.21 (IH, d, J5.29 Hz), 5.13 (IH, m), 4.64 (IH, t, J5.50 Hz), 4.21-4.14 (2H, m), 3.86- 3.56 (4H, m), 3.41-3.19 (4H, m), 1.85 (3H, d, J6.70 Hz). LCMS (ES+) 466/468 (M+H)+, RT 2.24 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃; for 2h;Microwave irradiation; Inert atmosphere; | EXAMPLE 22l-(4-{8-Chloro-3-[(l.Sr)-l-(pyrazolo|'L5-alphalpyrimidin-7-ylaminoN)ethyllquinolin-2- vUpiperazin-l-yl)-2-(dimethylamino')ethanone formic acid salt Intermediate 4 (700 mg, 2.05 mmol), 2-(dimethylamino)-l-(piperazin-l-yl)- ethanone (500 mg), «-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 13O0C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a cream solid. This material, MeOH (6 mL) and 2N HCl in Et2O (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), H-BuOH (6 mL), DIPEA (1 mL) and 7- chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (7 Lambda mg, 11%) as a clear glass. deltaH (DMSOd6) 8.71 (IH, s), 8.45 (IH, d, J7.71 Hz), 8.27 (IH, s), 8.13 (2H, m), 7.83 (2H, t, J8.63 Hz), 7.42 (IH, t, J7.81 Hz), 6.44 (IH, d, J2.29 Hz), 6.26 (IH, d, J5.27 Hz), 5.18 (IH, m), 4.04-3.74 (4H, m), 3.49-3.14 (6H, m), 2.26 (6H, s), 1.91 (3H, d, J 6.64 Hz). LCMS (ES+) 493/495 (M+H)+, RT 3.05 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 23l-{7-Fluoro-8-methyl-3-[(iy)-l-(pyrazolori,5-alphalpyrimidin-7-ylamino')ethyl1quinolin-2- yl}piperidine-4-carboxylic acidIntermediate 15 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid methyl ester hydrochloride (500 mg, 2.78 mmol), H-BuOH (10 mL) and DIPEA (4 niL) were combined in a sealed tube and heated to 13O0C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc). The resulting material, MeOH (10 mL) and 2N HCl in Et2O (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a tan foam. A portion of this material (50 mg), H-BuOH (6 mL), DIPEA (1 mL) and 7- chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 16O0C for 2 h. 15% NaOH solution (0.2 mL) was added to the reaction mixture, which was stirred at r.t. for 3 days. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (21.8 mg, 43%) as a tan solid. deltaH (DMSO-d6) 8.60 (IH, s), 8.40 (IH, m), 8.11 (2H, m), 7.70 (IH, dd, J8.93, 6.31 Hz), 7.30 (IH, t, J9.12 Hz), 6.43 (IH, d, J2.27 Hz), 6.25 (IH, d, J5.29 Hz), 5.07 (IH, m), 3.63 (IH, d, J 12.90 Hz), 3.53 (IH, d, J 13.17 Hz), 3.26-3.17 (IH, m), 2.99 (IH, dt, J 13.20, 6.76 Hz), 2.55 (3H, s), 2.14 (IH, d, J 13.29 Hz), 2.06 (2H, d, J5.12 Hz), 1.97-1.87 (4H, m). OH not seen. LCMS (ES+) 449 (M+H)+, RT 2.71 minutes {Method 1) |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 16h;Inert atmosphere; | EXAMPLE 242-rDimethylaminoVl-(4-{7-fluoro-8-methyl-3-r(lS)-l-rpyrazolori.5-alpha1pyrimidin-7- ylamino)ethyl1quinolin-2-vUpiperazin- 1 -vDethanone Intermediate 15 (700 mg, 2.06 mmol), 2-(dimethylamino)-l-(piperazin-l-yl)- ethanone (500 mg), «-BuOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 13O0C for 13 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a white solid. This material, MeOH (8 mL) and 2N HCl in Et2O (4 mL) were combined and stirred at r.t. for 2 days. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), n-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 13O0C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (28 mg, 48%) as a tan glass. deltaH (DMSO-Ci6) 8.64 (IH, s), 8.41 (IH, d, J7.80 Hz), 8.13 (2H, m), 7.74 (IH, dd, J8.95, 6.28 Hz), 7.33 (IH, t, J9.13 Hz), 6.44 (IH, d, J2.27 Hz), 6.28 (IH, d, J5.30 Hz), 5.21- 5.13 (IH, m), 4.16-3.73 (4H, m), 3.42-3.17 (6H, m), 2.56 (3H, s), 2.25 (6H, s), 1.89 (3H, d, J 6.71 Hz). LCMS (ES+) 491 (M+H)+, RT 3.23 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 16h;Inert atmosphere; | EXAMPLE 25l-{7-Fluoro-8-methyl-3-[(lS)-l-(pyrazolo[l,5-alphalpyrimidin-7-ylamino)ethyl]quinolin-2- yl } --/V-methylpiperidine-4-carboxamideIntermediate 15 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid methylamide (426 mg, 3 mmol), H-BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 13O0C for 20 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a white solid. This material, MeOH (10 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 4 days. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.12 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 13O0C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (36.9 mg, 67%) as a brown glass. deltaH (DMSO-(I6) 8.60 (IH, s), 8.41 (IH, m), 8.13-8.08 (2H, m), 7.85 (IH, m), 7.70 (IH, dd, J8.94, 6.31 Hz), 7.30 (IH, t, 79.12 Hz), 6.43 (IH, d, J2.27 Hz), 6.25 (IH, d, J 5.30 Hz), 5.07 (IH, m), 3.70 (IH, d, J 12.74 Hz), 3.57 (IH, d, J 12.76 Hz), 3.21-3.14 (IH, m), 2.96-2.88 (IH, t, J 12.16 Hz), 2.65 (3H, d, J4.53 Hz), 2.55 (3H, s), 2.47-2.37(1H, m), 2.16-1.87 (7H, m). LCMS (ES+) 462 (M+H)+; RT 3.72 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 16h;Inert atmosphere; | EXAMPLE 26l-{8-Chloro-3-[(liy)-l-(pyrazolo|"l,5-alpha1pyriniidin-7-ylamino)ethyl]quinolin-2-vU-N- methylpiperidine-4-carboxamideIntermediate 4 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid methylamide (426 mg, 3 mmol), «-BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 1300C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (SiO2, 0-10% MeOH in EtOAc) to give a white solid. This material, MeOH (10 mL) and 2N HCl in Et2O (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.12 mmol), H-BuOH (6 mL), DIPEA (1 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 1300C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (33 mg, 59%) as a tan solid. deltaH (DMSO-d6) 8.67 (IH, s), 8.44 (IH, d, J7.70 Hz), 8.14-8.09 (2H, m), 7.88-7.76 (3H, m), 7.39 (IH, t, J7.81 Hz), 6.44 (IH, d, J2.27 Hz), 6.23 (IH, d, J5.27 Hz), 5.12-5.04 (IH, m), 3.73 (IH, d, J 12.82 Hz), 3.61 (IH, d, J 12.75 Hz), 3.22-3.15 (2H, m), 2.96 (IH, t, J 12.22 Hz), 2.65 (3H, d, J4.50 Hz), 2.44 (IH, m), 2.18-1.95 (2H, m), 1.95-1.82 (4H, m). LCMS (ES+) 464/466 (M+H)+, RT 2.37 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃;Inert atmosphere; | EXAMPLE 27(5f)-MN-Dimethyl-2-(4-{7-fluoro-8-methyl-3-ri-(pyrazolori,5-alphalpyrimidin-7-ylamino')- ethyl1quinolin-2-yl)piperazin-l-yl)acetamideIntermediate 15 (822 mg, 2.04 mmol), N,N-dimethyl-2-(piperazin-l-yl)acetamide (1.75 g, 10.2 mmol), DIPEA (1.78 mL, 10.2 mmol) and H-BUOH (5.0 mL) were combined in a sealed tube and heated to 14O0C for 48 h. After cooling, the reaction mixture was dissolved in a 1 : 1 mixture of EtOAc and Et2O (400 mL) and washed with saturated brine (3 x 100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc in isohexane) gave an oil (800 mg, 83%). To this material (400 mg, 0.84 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was allowed to stand at r.t. for 3 h before being concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with 2M NaOH solution (2 x 30 mL) and water (30 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. To a portion of the resulting material (132 mg, 0.35 mmol) dissolved in n-BuOH (2.5 mL) and DIPEA (0.19 mL, 1.05 mmol) was added 7-chloropyrazolo[l,5-alpha]pyrimidine (71 mg, 0.46 mmol) and the mixture was heated to 13O0C overnight in a sealed tube. The reaction mixture was cooled and the solvent removed in vacuo. The residue was redissolved in DCM (50 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was separated, dried (MgSO4) and filtered, and the solvent was removed in vacuo. Purification by preparative HPLC afforded the title compound (104.1 mg, 58%) as a white solid. deltaH (CDCl3) 8.12 (IH, d, J5.22 Hz), 8.09 (IH, s), 8.00 (IH, d, J2.32 Hz), 7.49 (IH, dd, J8.93, 6.02 Hz), 7.19-7.09 (IH, m), 6.88 (IH, d, J6.73 Hz), 6.49 (IH, d, J2.32 Hz), 6.04 (IH, d, J5.25 Hz), 5.21-5.10 (IH, m), 3.43-3.38 (4H, m), 3.35 (2H, d, J5.15 Hz), 3.13 (3H, s), 2.98 (2H, s), 3.02-2.78 (3H, m), 2.75-2.65 (2H, m), 2.60 (3H, d, J2.40 Hz), 1.83 (3H, d, J6.73 Hz). LCMS (ES+) 491 (M+H)+, RT 1.89 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 1h;Inert atmosphere; Microwave irradiation; | EXAMPLE 32(S)-N-(I -{7-Fluoro-8-methyl-2-[4-(pyridin-2-yl')piperazin-l-yl1quinolin-3-vUethyl')- pyrazolo|T ,5-fl]pyrimidin-7-amineTo a solution of Intermediate 15 (500 mg, 1.48 mmol) in NMP (6 mL) were added l-(pyridin-2-yl)piperazine (500 mg, 3.00 mmol) and DIPEA (1.3 mL) and the resulting mixture was heated at 1400C for 16 h. The reaction mixture was taken up in EtOAc (150 mL) and water (50 mL) and the organic layer was washed with water (2 x 50 mL) and brine (50 mL). The organic layer was separated, dried (phase separation cartridge), and the solvent removed in vacuo. Purification by column chromatography (SiO2, 10-20% EtOAc in isohexane) gave a beige solid (530 mg, 77%). To a solution of this material (530 mg, 1.13 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution stirred at r.t. for 15 minutes. The solvents were removed in vacuo. The residue was dissolved in MeOH (5 mL) and placed on an SCX cartridge, washed (MeOH), eluted (7M ammonia in MeOH) and concentrated in vacuo. The solvent was concentrated in vacuo to afford a white solid (416 mg, 100%). To a portion of this material (60 mg, 0.16 mmol) in NMP (1.2 niL) were added DIPEA (0.14 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (30 mg, 0.194 mmol) and the resulting solution was heated under microwave irradiation at 15O0C for 1 h. Purification by preparative HPLC afforded the title compound (20 mg, 26%) as an off-white solid. deltaH (DMSO-(I6) 8.66 (IH, s), 8.43 (IH, d, J7.76 Hz), 8.21 (IH, dd, J4.94, 1.93 Hz), 8.14-8.11 (2H, m), 7.74 (IH, dd, J8.97, 6.26 Hz), 7.63 (IH, dd, J8.58, 7.09 Hz), 7.33 (IH, t, J9.12 Hz), 6.98 (IH, d, J8.63 Hz), 6.73 (IH, dd, J7.09, 4.91 Hz), 6.44 (IH, s), 6.33 (IH, d, J5.30 Hz), 5.21 (IH, m), 3.94-3.87 (2H, m), 3.84- 3.77 (2H, m), 3.52-3.43 (4H, m), 2.58 (3H, m), 1.92 (3H, d, J6.71 Hz). LCMS (ES+) 483 (M+H)+, RT 2.33 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 47(S)- 1 -(4- { 8-Chloro-3 -[ 1 -(pyrazolo [ 1 ,5 -fllpyrimidin-7-ylamino)ethyl]qumolin-2-yl } - piperazin- 1 - vDethanoneTo a solution of Intermediate 31 (86.5 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was added HCl (2.25 mL; 4M in 1,4-dioxane). The mixture was stirred at r.t. for 1 h, then the excess solvent was removed in vacuo. The resulting material was dissolved in n-BuOH (2.5 mL) and DIPEA (0.78 mg, 0.6 mmol) and 7-chloropyrazolo[l,5-alpha]pyrimidine (38 mg, 0.25 mmol) were added. The mixture was heated at 12O0C for 16 h and the solvent was removed in vacuo. The residue was purified by preparative HPLC to afford the title compound (22.8 mg, 17%) as an off-white solid. deltaH (CDCl3) 8.19 (IH, s), 8.13 (IH, d, J 5.2 Hz), 8.02 (IH, s), 7.73 (IH, d, J8.8 Hz), 7.62 (IH, d, J8.8 Hz), 7.32 (IH, t, J 8.8 Hz), 6.89 (IH, d, J6.8 Hz), 6.52 (IH, s), 5.92 (IH, d, J5.2 Hz), 5.12-5.20 (IH, m), 3.92-3.98 (IH, m), 3.84-3.92 (2H, m), 3.70-3.76 (IH, m), 3.48-3.54 (2H, m), 3.32-3.36 (2H, m), 2.21 (3H, s), 1.87 (3H, d, J6.8 Hz). LCMS (ES+) 450/452 (M+H)+, RT 2.35 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 1h;Microwave irradiation; Inert atmosphere; | EXAMPLE 574-{7-Fluoro-8-methyl-3-[(liotay)-l-(pyrazolo[l,5-alpha]pyrimidin-7-ylamino)ethyllquinolin-2- yl } -./V-methyrpiperazine- 1 -carboxamide A solution of Intermediate 15 (500 mg, 1.476 mmol), l-[(methylamino)carbonyl]- piperazine (677 mg, 4.73 mmol) and DIPEA (1.54 mL, 8.85 mmol) in NMP (3.5 mL) was heated under microwave irradiation at 15O0C for 3.5 h. After cooling, the mixture was dissolved in a 1 : 1 mixture of EtOAc and Et2O (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 2% EtOAc in DCM) gave a pale yellow solid (214 mg, 33%). LCMS (ES+) 446 (M+H)+. To this solid (214 mg, 0.48 mmol) dissolved in DCM (12 mL) was added TFA (2.2 mL). The reaction mixture was stirred at r.t. for 1.5 h and the excess solvent was removed in vacuo. The oil obtained was basified with 0.5M NaOH solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow glass (179 mg, 100%). LCMS (ES+) 346 (M+H)+. A portion of this material (44.7 mg, 0.129 mmol), 7-chloropyrazolo[l,5-alpha]pyrimidine (29.8 mg, 0.194 mmol), DIPEA (0.068 mL, 0.388 mmol) and H-BuOH (1 mL) were combined and heated under microwave irradiation at 13O0C for 1 h. Purification by preparative HPLC gave the title compound (5.5 mg, 9%) as a yellow solid. deltaH (DMSO-d6) 8.64 (s, IH), 8.41 (d, J 7.85 Hz, IH), 8.11-8.14 (m, 2H), 7.74 (dd, J8.96, 6.27 Hz, IH), 7.33 (t, J9.12 Hz, IH), 6.60 (d, J4.79 Hz, IH), 6.44 (d, J2.28 Hz, IH), 6.29 (d, J5.31 Hz, IH), 5.16 (t, J7.21 Hz, IH), 3.56-3.72 (m, 4H), 3.18-3.34 (m, 4H), 2.65 (d, J4.23 Hz, 3H), 2.56 (s, 3H), 1.87 (d, J 6.72 Hz, 3H). LCMS (ES+) 463 (M+H)+, RT 3.08 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃;Inert atmosphere; | EXAMPLE 59(/?)-4-{8-Chloro-3-|'l-(pyrazolori,5-alpha1pyrimidin-7-ylamino>;)ethyl1quinolin-2-vU- piperazin-2-oneTFA (2 mL) was added to a solution of Intermediate 41 (232 mg, 0.57 mmol) in DCM (5 mL) and the mixture was allowed to stand at r.t. overnight before being concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with 2M NaOH solution (2 x 20 mL) and water (20 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. To the resulting material dissolved in n- BuOH (2.0 mL) and DIPEA (0.30 mL, 1.7 mmol) was added 7-chloropyrazolo[l,5-alpha]- pyrimidine (115 mg, 0.75 mmol) and the mixture was heated to 1200C overnight in a sealed tube. The mixture was cooled and the solvent removed in vacuo. The residue was redissolved in DCM (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried (MgSO4) and filtered, and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound (132 mg, 54%) as a white solid. deltaH (CDCl3) 8.21 (IH, s), 8.12 (IH, d, J5.11 Hz), 8.02 (IH, d, J2.32 Hz), 7.75 (IH, dd, J7.52, 1.31 Hz), 7.62 (IH, dd, J8.16, 1.31 Hz), 7.33 (IH, t, J 7.83 Hz), 6.84 (IH, d, J6.41 Hz), 6.52 (IH, d, J2.32 Hz), 6.45-6.40 (IH, m), 5.85 (IH, d, J5.15 Hz), 5.20-5.10 (IH, m), 4.20 (IH, d, J 17.26 Hz), 4.11 (IH, d, J 17.26 Hz), 3.80-3.61 (4H, m), 1.87 (3H, d, J 6.71 Hz). LCMS (ES+) 422/424 (M+H)+, RT 2.22 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 1h;Inert atmosphere; Microwave irradiation; | EXAMPLE 29(S)-2,2-Dimethyl-l-(4-{7-fluoro-8-methyl-3-[l-(pyrazolori,5-alphalpyrimidin-7-ylamino)- ethvnquinolin-2-vUpiperazin- 1 -vDpropan- 1 -oneTo a solution of Intermediate 25 (60 mg, 0.16 mmol) in NMP (1.2 mL) were added DIPEA (0.14 mL) and 7-chloropyrazolo[l,5-alpha]pyrimidine (30 mg, 0.194 mmol) and the resulting solution was heated under microwave irradiation at 1500C for 1 h. Purification by preparative HPLC afforded the title compound (42 mg, 54%) as an off- white solid. deltaH (DMSOd6) 8.64 (IH, s), 8.43 (IH, d, J7.76 Hz), 8.13 (2H, m), 7.74 (IH, dd, J8.96, 6.23 Hz), 7.33 (IH, t, J9.12 Hz), 6.44 (IH, d, J2.27 Hz), 6.28 (IH, d, J5.30 Hz), 5.17 (IH, m), 4.01-3.93 (2H, m), 3.91-3.83 (2H, m), 3.20-3.40 (4H, m), 2.58 (3H, s), 1.89 (3H, d, J 6.70 Hz), 1.30 (9H, s). LCMS (ES+) 490 (M+H)+, RT 2.85 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 40(S)- 1 -(4- { 7-Fluoro-3 -[I -(pyrazoloF 1 ,5 -alpha1pyrimidin-7-ylamino)ethyllquinolin-2- y 1} - piperazin- 1 -vDethanoneA solution of Intermediate 26 (75 mg, 0.23 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (40 mg, 0.26 mmol) and DIPEA (100 mg, 0.77 mmol) in H-BuOH (3 mL) was heated at 12O0C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (11 mg, 11%) as a cream solid. deltaH (CDCl3) 8.16 (IH, s), 8.14 (IH, d, J5.2 Hz), 8.02 (IH, s), 7.69 (IH, dd, J8.8 Hz), 7.52 (IH, dd, J 7.6 Hz), 7.23 (IH, t, J 8.8 Hz), 6.94 (IH, d, J 6.4 Hz), 6.52 (IH, s), 5.94 (IH, d, J5.2 Hz), 5.10-5.18 (IH, m), 3.90-4.02 (IH, m), 3.80-3.85 (2H, m), 3.66-3.71 (IH, m), 3.32-3.38 (2H, m), 3.20-3.24 (2H, m), 2.20 (3H, s), 1.85 (3H, d, J6.8 Hz). LCMS (ES+) 434 (M+H)+, RT 2.20 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 42(S)- 1 -(4- { 7-Fluoro-8-methyl-3 - 1 -(pyrazolo [ 1 ,5 -fl}pyrimidin-7-ylamino)ethyl] quinolin-2- yl } piperazin- 1 -yl)ethanoneA solution of Intermediate 28 (70 mg, 0.25 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (43 mg, 0.27 mmol) and DIPEA (100 mg, 0.77 mmol) in w-BuOH (3 mL) was heated at 12O0C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (79.6 mg, 79.6%) as a cream solid, delta? (CDCl3) 8.15 (IH, s), 8.14 (IH, d, J5.2 Hz), 8.04 (IH, s), 7.55 (IH, dd, J8.8 Hz), 7.19 (IH, t, J8.8 Hz), 6.99 (IH, d, J6.4 Hz), 6.52 (IH, s), 6.00 (IH, d, J 5.2 Hz), 5.10-5.18 (IH, m), 3.90-4.02 (IH, m), 3.80-3.88 (2H, m), 3.66-3.71 (lH, m), 3.35-3.41 (2H, m), 3.20-3.24 (2H, m), 2.65 (3H, s), 2.25 (3H, s), 1.89 (3H, d, J6.8 Hz). LCMS (ES+) 448 (M+H)+, RT 2.49 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 45(^-4-(7-FIuOrO-S-[I-(PVrOZoIOn, 5-Qipyrimidin-7-ylamino)ethyllquinolin-2-yUpiperazni- 2-oneA solution of Intermediate 29 (55 mg, 0.19 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (33.8 mg, 0.22 mmol) and DIPEA (28.0 mg, 0.22 mmol) in n-BuOH (3 mL) was heated at 1200C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (54.8 mg, 71%) as a cream solid. 6H (CDCl3) 8.21 (IH, s), 8.13 (IH, d, J5.2 Hz), 8.02 (IH, s), 7.70 (IH, dd, J8.8 Hz), 7.55 (IH, dd, J8.8 Hz), 7.19 (IH, t, J8.8 Hz), 7.02 (IH, br s), 6.89 (IH, d, J6.4 Hz), 6.52 (IH, s), 5.89 (IH, d, J5.2 Hz), 5.14-5.20 (IH, m), 4.12 (2H, q, J 17.5 Hz), 3.53-3.68 (4H, m), 1.85 (3H, d, J 6.8 Hz). LCMS (ES+) 406 (M+H)+, RT 2.10 minutes (Method I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 46(S)-A- { 5,7-Difluoro-3 -[ 1 -(pyrazolof 1 ,5 -alpha]pyrimidin-7-ylamino)ethyllquinolin-2-yl} - piperazin-2-oneA solution of Intermediate 30 (61.2 mg, 0.20 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (33.8 mg, 0.2 mmol) and DIPEA (28.5 mg, 0.22 mmol) in M-BuOH (3 mL) was heated at 12O0C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (14.9 mg, 18%) as a cream solid. 6H (CDCl3) 8.45 (IH, s), 8.13 (IH, d, J5.2 Hz), 8.02 (IH, s), 7.35 (IH, dd, J 8.8 Hz), 6.90 (IH, t, J8.8 Hz), 6.88 (IH, d, J6.4 Hz), 6.55 (IH, br s), 6.48 (IH, s), 5.89 (IH, d, J5.2 Hz), 5.12-5.18 (IH, m), 4.09 (2H, q, J 17.5 Hz), 3.52-3.68 (4H, m), 1.88 (3H, d, J6.8 Hz). LCMS (ES+) 424 (M+H)+, RT 3.07 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 51(S)- 1 -(4- { 5 J-Difluoro-3 - [ 1 -(pyrazolof 1 ,5 -alpha1pyrimidin-7-ylamino')ethyllquinolin-2-vU - piperazin- 1 -vDethanoneA solution of Intermediate 32 (70 mg, 0.21 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (37 mg, 0.24 mmol) and DIPEA (50 mg, 0.4 mmol) in rc-BuOH (3 mL) was heated at 12O0C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (84.8 mg, 89%) as a cream solid. 6H (CDCl3) 8.42 (IH, s), 8.18 (IH, d, J5.2 Hz), 8.02 (IH, d, J2.4 Hz), 7.33 (IH, d, J8.8 Hz), 7.12 (IH, d, J8.8 Hz), 6.95 (IH, t, J8.8 Hz), 6.54 (IH, d, J2.4 Hz), 6.00 (IH, d, J 5.2 Hz), 5.14-5.20 (IH, m), 3.93-3.99 (IH, m), 3.80-3.88 (2H, m), 3.68-3.74 (IH, m), 3.39-3.43 (2H, m), 3.20-3.30 (2H, m), 2.20 (3H, s), 1.87 (3H, d, J6.8 Hz). LCMS (ES+) 452 (M+H)+, RT 2.96 minutes (Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 54l-(4-{7-Fluoro-8-methyl-3-r(pyrazolo[l,5-fllpyrimidin-7-ylamino)methyl1quinolin-2-vU- piperazin- 1 -vDethanoneA solution of Intermediate 34 (50 mg, 0.16 mmol), 7-chloropyrazolo[l,5-a]- pyrimidine (30 mg, 0.19 mmol) and DIPEA (40 mg, 0.31 mmol) in «-BuOH (3 mL) was heated at 1200C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (30 mg, 44%) as a cream solid. 5H (CDCl3) 8.20 (IH, d, J2.4 Hz), 8.02 (IH, d, J2.4 Hz), 8.00 (IH, s), 7.48-7.54 (IH, m), 7.44 (IH, br s), 7.18 (IH, t, J8.8 Hz), 6.54 (IH, d, J2.4 Hz), 5.90 (IH, d, J2.4 Hz), 4.78 (2H, d, J5.6 Hz), 3.88-3.92 (2H, m), 3.76-3.80 (2H, m), 3.44-3.48 (2H, m), 3.28-3.32 (2H, m), 2.61 (3H, s), 2.05 (3H, s). LCMS (ES+) 434 (M+H)+, RT 3.39 minutes (Method |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 16h;Inert atmosphere; | EXAMPLE 55(^-l-(4-(3-ri-(Pyrazolo[l,5-alpha1pyrimidin-7-ylaminoN)ethyl]quinolin-2-vUpiperazin-l-ylV ethanone A solution of Intermediate 35 (70 mg, 0.23 mmol), 7-chloropyrazolo[l,5-alpha]- pyrimidine (39 mg, 0.25 mmol) and DIPEA (60 mg, 0.46 mmol) in H-BUOH (3 mL) was heated at 1200C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (15.2 mg, 17%) as a cream solid. 5H (CDCl3) 8.18 (IH, s), 8.14 (IH, d, J 5.2 Hz), 8.02 (IH, d, J 2.4 Hz), 7.89 (IH, d, J 8.8 Hz), 7.72 (IH, d, J8.8 Hz), 7.66 (IH, t, J 8.8 Hz), 7.63 (IH, t, J8.8 Hz), 6.94 (IH, d, J 6.4 Hz), 6.51 (IH, d, J2.4 Hz), 5.94 (IH, d, J5.2 Hz), 5.17-5.23 (IH, m), 3.94-3.98 (IH, m), 3.80-3.88 (2H, m), 3.65-3.73 (IH, m), 3.30-3.41 (2H, m), 3.22-3.26 (2H, m), 2.20 (3H, s), 1.86 (3H, d, J6.8 Hz). LCMS (ES+) 416 (M+H)+, RT 2.60 minutes {Method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1h;Microwave irradiation; Inert atmosphere; | EXAMPLE 584-{7-Fluoro-8-methyl-3-r(l»S^-l-(pyrazolori,5-alpha1pyrimidin-7-ylamino')ethyl]quinolin-2- yl I piperazine- 1 -carboxamide Intermediate 36 (50 mg, 0.151 mmol), 7-chloropyrazolo[l,5-alpha]pyrimidine (34.7 mg, 0.226 mmol), DIPEA (0.079 mL, 0.453 mmol) and n-BuOH (1 mL) were combined and heated under microwave irradiation at 1400C for 1 h. After cooling, the mixture was dissolved in EtOAc (100 mL) and washed with saturated brine (3 x 20 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (7 mg, 10%) as a yellow solid. deltaH (DMSO-d6) 8.24 (d, J4.99 Hz, IH), 8.14 (s, IH), 8.10 (d, J2.33 Hz, IH), 7.70 (dd, J8.89, 6.22 Hz, IH), 7.25 (t, J9.13 Hz, IH), 6.58 (d, J7.55 Hz, IH), 6.51 (d, J2.33 Hz, IH), 6.40 (d, J 5.03 Hz, IH), 5.46 (s, 2H), 5.05 (t, J6.89 Hz, IH), 3.95-4.02 (m, 2H), 3.81-3.88 (m, 2H), 3.67-3.75 (m, 2H), 3.27-3.32 (m, 2H), 2.49 (d, J2.33 Hz, 3H), 1.29 (d, J6.59 Hz, 3H). LCMS (ES+) 449 (M+H)+, RT 2.59 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-dimethyl-aniline; trichlorophosphate; at 20℃;Reflux; | To a solution of pyrazolo[1,5-a]pyrimidin-7-ol (C-1) (19.0 g, 14.1 mmol, 1.0 eq) in phosphoroxychloride (100 mL, 1.06 mol, 76 eq) at RT, N,N-dimethylaniline (7.0 g, 58.0 mmol, 4.1 eq) is added dropwise and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo to remove the phosphoroxychloride. The residue is poured into ice water (200 mL), neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 8-9 while keeping the temperature below 5 C. The mixture is stirred at RT for 30 min and then extracted with ethyl acetate (4×200 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (1-3% ethyl acetate-petroleum ether) to afford the product, 7-chloropyrazolo[1,5-a]pyrimidine (C-2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 7h; | EXAMPLE 22 (S)-N-(1-(5-Methoxy-3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine 7-Chloropyrazolo[1,5-a]pyrimidine (40 mg, 0.26 mmols, Preparation 32) and DIEA (0.09 mL, 0.52 mmols) were added to a solution of (S)-1-(5-methoxy-3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethanamine (70 mg, 0.26 mmols, Preparation 14) in buthanol (10 mL). It was stirred at 120ºC for 7 h. It was concentrated in vacuo. Ethyl acetate was added and it was washed with water. The organic phase was dried, filtered and concentrated in vacuo. It was purified by chromatography (Silica gel, dichloromethane / methanol / ammonia 100:8:1). The expected compound was obtained (63 mg, 40%). LRMS (m/z): 386 (M+1)+ 1H NMR (400 MHz, DMSO-d6) d ppm 1.62 (d, 3 H) 3.72 (s, 3 H) 5.10 - 5.34 (m, 1 H) 5.97 (d, 1 H) 6.42 (d, 1 H) 6.78 (d, 1 H) 7.30 - 7.71 (m, 4 H) 7.85 - 8.23 (m, 3 H) |
40% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 7h; | 7-Chloropyrazolo[1 ,5-a]pyrimidine (40 mg, 0.26 mmols, Preparation 32) and DIEA (0.09 ml_, 0.52 mmols) were added to a solution of (SJ-l -iS-methoxy-S-phenyl-S/-/- imidazo[4,5-b]pyridin-2-yl)ethanamine (70 mg, 0.26 mmols, Preparation 14) in buthanol (10 ml_). It was stirred at 120C for 7 h. It was concentrated in vacuum. Ethyl acetate was added and it was washed with water. The organic phase was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, dichloromethane/methanol/ammonia 100:8:1 ). The expected compound was obtained (63 mg, 40%).LRMS (m/z): 386 (M+1 )+ 1 H NMR (400 MHz, DMSO-d6) d ppm 1 .62 (d, 3 H) 3.72 (s, 3 H) 5.10 - 5.34 (m, 1 H) 5.97 (d, 1 H) 6.42 (d, 1 H) 6.78 (d, 1 H) 7.30 - 7.71 (m, 4 H) 7.85 - 8.23 (m, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h; | To a solution of <strong>[58347-49-2]7-chloropyrazolo[1,5-a]pyrimidine</strong> (3.0 g, 19.5mmol) in DMF (30 mL) was added N-iodobutanimide (5.3 g, 23 mmol), and then the reaction mixture was stirred at rt for 12.0 hours. To the reaction mixture was added water (25 mL), and a lot of solid precipitated out. The resulting mixture was stirred for 15 minutes, and then filtered. The filter cake was dried under vacuum to give the title compound as a white solid (4.8 g, 88%). The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 280.0 [M+1]+. |
88% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h; | [00371] To a solution of <strong>[58347-49-2]7-chloropyrazolo[1,5-a]pyrimidine</strong> (3.0 g, 19.5 mmol) in DMF (30 mL) was added NIS (5.3 g, 23 mmol). The reaction mixture was stirred at rt for 12 hours. To the mixture was added water (25 mL), and a lot of solid precipitated out. The resulting mixture was further stirred for 15 minutes, and then filtered. The filter cake was dried to give the title compound as an off-white solid (4.8 g, 88%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 279.9 [M+1]. |
88% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h; | <strong>[58347-49-2]7-chloropyrazolo[1,5-a]pyrimidine</strong> (3.0 g, 19.5 mmol) was dissolved in 30 mL of DMF, NIS (5.3 g, 23 mmol) was added and reacted at room temperature for 12 h. To the system was added 25mL of water, a large number of solid precipitation, stirring was continued for 15min, suction filtered and dried to give a white-like solid 4.8g, a yield of 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.28 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | Step c. A solution of 7-chloropyrazolo[l,5-a]pyrimidine (0.18g, 1.17 mmol), tert-butyl (S)-3- ((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)pyrrolidine-l- carboxylate (2.43g, 5.86 mmol) and K2C03 (0.48g, 3.52 mmol) in DMF (10 ml) was prepared in a glass vial. The reaction mixture was degassed for 20 min. Pd(dppf)Cl2 (0.06g, 0 093 mmol) was added and the reaction mixture was heated at 80C for 2 h . The resulting reaction mixture was cooled to rt and poured into water (50 ml). The obtained mixture was extracted with EtOAc (2 x 50 ml). The combined organic phase was washed with water (100 ml), dried over a2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (60% EtOAc in hexane) yielding tert-butyl (S)-3-((4- (pyrazolo[l,5-a]pyrimidin-7-yl)pyridin-2-yl)carbamoyl)pyrrolidine-l-carboxylate (0.28 g, 0.68 mmol). LCMS: Method A, 2.14 min, MS: ES+ 409.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; | A mixture of 7-chloropyrazolo[i,5-a]pyrimidine (0.193 g, 1.260 mmol), Intermediate 143E (0.400 g, 1.298 mmol), Na2CO3 (0.534 g, 5.04 mmol), and Pd(Ph3P)4(0.073 g, 0.063 mmol) in dioxane (11.67 ml) and water (3.89 ml) was heated at 100C overnight. The reaction was quenched with water and diluted with EtOAc. Layers were separated. The aqueous phase was extracted with EtOAc (3X). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. Purification of the crude material by silica gel chromatography using an ISCO machine(40 g column, 40 mL/min, 0-70% EtOAc in hexanes over 16 mi t = 10.5 mm) gave197F (0.224 g, 0.748 mmol, 59.4% yield) as a yellow residue. ESI MS (M+H) = 300.2. HPLC Peak t = 0.95 minutes. HPLC conditions: method A. |
59.4% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; | A mixture of 7-chloropyrazolo[ 1 ,5-a]pyrimidine (0.193 g, 1.260 mmol), Intermediate 143E (0.400 g, 1.298 mmol), Na2C03 (0.534 g, 5.04 mmol), and Pd(Ph3P)4 (0.073 g, 0.063 mmol) in dioxane (11.67 ml) and water (3.89 ml) was heated at 100 C overnight. The reaction was quenched with water and diluted with EtOAc. Layers were separated. The aqueous phase was extracted with EtOAc (3X). The organics were combined, dried over Na2S04, filtered, and concentrated to afford a brown residue. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-70% EtOAc in hexanes over 16 min, tr = 10.5 min) gave 143F (0.224 g, 0.748 mmol, 59.4% yield) as a yellow residue. ESI MS (M+H)+ = 300.2. HPLC Peak tr = 0.95 minutes. HPLC conditions: method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium bromide; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (0.04 g, 0.260 mmol), (8)- tert-butyl (1 -(2-cyano-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenoxy)-2,4- dimethylpentan-2-yl)carbamate (prepared as in Example 254, Part B-G) (0.119 g, 0.260 mmol), KBr (0.03 1 g, 0.260 mmol), and potassium phosphate, tribasic (0.045g, 0.260 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen gas for 30 mm. PdC12(dppf)-CH2C12 adduct (0.021 g, 0.026 mmol) was added to the reaction mixture and the solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated at 100 C for 12 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (30 mL) and water (30 mL). Thebiphasic mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (25 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (5)-tert-butyl (1- (2-cyano-4-(pyrazolo [1,5-al pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2- yl)carbamate (cmde yield) (62 mg, 0.138 mmol, 53% yield) as a brown solid whichwas carried forward without further purification. LCMS (ESI) m/e 451.2 [(M+H) , calcd for C25H32N503 450.21; LC/MS retention time (method B): tR = 1.09 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 150℃; for 1.5h;Inert atmosphere; | A solution of 7-chloropyrazolo[l,5-ajpyrimidine (0.1 g, 0.651 mmol), 6-bromo-2-(difluoromethyl)-3 -fluoropyridine (0.162 g, 0.716 mmol) and 1,1,1,2,2,2-hexamethyldistannane (0.235 g, 0.7 16 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen gas for 10 mi Pd(Ph3P)4 (0.075 g, 0.065 mmol) was added to the reaction mixture and the solution was purged with nitrogen gas for another 10 mm. The reaction mixture was heated at 150 C for 1.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue waspurified by silica-gel chromatography (pet ether/ethyl acetate (0-40%)) to afford 7- (6-(difluoromethyl)-5-fluoropyridin-2-yl) pyrazolo [1,5-al pyrimidine (40 mg, 0.151 mmol, 23% yield) as a yellow solid .LCMS (ESI) m/e 265.0 [(M+H), calcd for C12H8F3N4 265.11; LC/MS retention time (Method Al): tR = 2.08 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium bromide; In 1,4-dioxane; at 88℃; for 12h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (0.04 g, 0.260 mmol), (5)- tert-butyl (1 -(2-fluoro-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as in Example 253, Part B) (0.118 g, 0.260 mmol), KBr (0.031 g, 0.260 mmol), and potassium phosphate, tribasic (0.045 g, 0.260 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen gas for 10 mm. PdC12 (dppf)-CH2C12 adduct (0.021 g, 0.026 mmol) was added to the reaction mixture and the solution was purged with nitrogen gas again for 10 mm. The reaction mixturewas heated at 88 C for 12 h. The reaction mixture was concentrated then dissolved in ethyl acetate (30 mL) and water (30 mL). The biphasic mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product (5)-tert-butyl (i-(2-fluoro-4-(pyrazolo [1 ,5-ajpyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (62 mg, 0.098 mmol, 38% yield) as an off-white solid which wascarried forward without further purification. LCMS (ESI) m/e 443.2 [(M+H), calcd for C24H32FN403 443.21; LC/MS retention time (Method Al): tR = 2.33 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; potassium bromide; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (0.15 g, 0.977 mmol), (8)-tert-butyl (2,4-dimethyl- 1 -(4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (prepared as described in Example255, Parts A and B) (0.588 g, 1.172 mmol), C52CO3 (0.955 g, 2.93 mmol), and KBr(0.116 g, 0.977 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen gas for 30mi PdC12(dppf)-CH2C12 adduct (0.080 g, 0.098 mmol) was added to the reactionmixture and the solution was purged with nitrogen gas again for 10 mm. Thereaction mixture was heated at 80C for 12 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (50 mL) and water (40 mL). The biphasic mixture was filtered through diatomaceous earth and the diatomaceous earth was washed with ethyl acetate (50 mL). The ethyl acetate layer was separated,dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown solid which was purified by silica gel column chromatography (0-30% ethyl acetate in pet ether) to afford (5)-tert-butyl (2,4-dimethyl-1-(4-(pyrazolo[1,5- aj pyrimidin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (0.13 g, 0.264 mmol, 27% yield) as a off-white semi-solid. LCMS (ESI) m/e 493.2 [(M+H) , calcdfor C25H32F3N403 493.21; LC/MS retention time (method B): tR = 1.27 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 150℃; for 2h;Inert atmosphere; Microwave irradiation; | A solution of 7-chloropyrazolo[l,5-ajpynmidine (0.05 g, 0.326 mmol), 2- bromo-5-fluoroisonicotinonitrile (0.065 g, 0.326 mmol) and 1,1,1,2,2,2- hexamethyldistannane (0.107 g, 0.326 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen gas for 10 mi Pd(Ph3P)4 (0.03 8 g, 0.033 mmol) was added and the solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated in a microwave at 150 C for 2 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (20 mL) and water (20 mL). Thebiphasic mixture was filtered through diatomaceous earth (Diatomaceous earth) and the bed was washed with ethyl acetate (25 mL). The ethyl acetate layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown colored solid. The solid was purified by silica gel chromatography (0-40% EtOAc in pet ether) to afford 5-fluoro-2-(pyrazolo[1,5-ajpyrimidin-7-yl)isonicotinonitrile (30 mg, 0.125 mmol, 39% yield) as a light yellow solid. LCMS (ESI) m/e 240.0 [(M+H) , calcd for C12H7FN5 240.11; LC/MS retention time (Method Al): tR = 1.97 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 2.0h;Inert atmosphere; | A stirred solution of 7-chloropyrazolo[1,5-ajpyrimidine (50 mg, 0.326mmol), <strong>[904326-92-7](6-fluoro-5-methylpyridin-3-yl)boronic acid</strong> (50.4 mg, 0.326 mmol), andcesium carbonate (212 mg, 0.65 1 mmol) in a mixture of 1,4-dioxane (5 mL) andwater (0.5 mL) was purged with nitrogen. XPhos generation precatalyst (38.4mg, 0.049 mmol) was added in one portion and the reaction mixture was heated to 85C and stirred for 2 h. The solution was concentrated under reduced pressure. Water(50 mL) was added and the solution was extracted with EtOAc (2 x 50 mL). Thecombined organic extracts were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc in hexanes) to afford 7-(6-fluoro- 5-methylpyridin-3-yl)pyrazolo[ 1 ,5-ajpyrimidine (38 mg, 0.165 mmol, 51% yield).LCMS (ESI) m/e 229.2 [(M+H), calcd for C12H10FN4, 229.11; LC/MS retentiontime (method D) tR = 1.86 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 2h;Inert atmosphere; | A stirred solution of 7-chloropyrazolo[1,5-ajpyrimidine (100 mg, 0.651 mmol), (5-chloro-6-fluoropyridin-3-yl)boronic acid (114 mg, 0.65 1 mmol), and cesium carbonate (424 mg, 1.302 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was purged with nitrogen. PdC12(dppf)-CH2C12 adduct (80 mg, 0.098mmol) was added in one portion and the reaction mixture was heated to 85 C and stirred for 2 h. The solution cooled to room temperature and was concentrated under reduced pressure. Water (50 mL) was added and the solution was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc in hexanes) to afford 7-(5-chloro-6-fluoropyridin-3-yl)pyrazolo[ 1,5 -alpyrimidine (56 mg, 0.122 mmol, 19 % yield). LCMS (ESI) m/e 249.0 [(M+H), calcd for C11H7C1FN4, 249.01; LC/MS retention time (method B) tR = 0.95 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; potassium bromide; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (0.05 g, 0.326 mmol), (8)-tert-butyl (2,4-dimethyl- 1 -(2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)pentan-2-yl)carbamate (prepared as described in Example 259, Part A and B) (0.146 g, 0.326 mmol), C52CO3 (0.212 g, 0.651 mmol), and KBr (0.039 g, 0.326 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen gas for 30 mi PdC12 (dppf)-CH2C12 adduct (0.027 g, 0.033 mmol) was added to the reaction mixture andthe solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated at 80C for 12 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (30 mL) and water (30 mL). The biphasic mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (50 mL). The ethyl acetate layer was separated, dried overNa2SO4, filtered, and concentrated under reduced pressure to afford a brown solid which was purified by silica-gel column chromatography (0-40% EtOAc in pet ether) to afford (5)-tert-butyl (2,4-dimethyl- 1 -(2-methyl-4-(pyrazolo [1,5-al pyrimidin-7- yl)phenoxy)pentan-2-yl)carbamate (40 mg, 0.09 1 mmol, 28% yield) as a light yellow semi-solid. LCMS (ESI) m/e 439.4 [(M+H), calcd for C25H35N403 439.31; LC/MSretention time (Method Al): tR = 2.60 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 150℃; for 2h;Inert atmosphere; Microwave irradiation; | A solution of 7-chloropyrazolo[i,5-ajpyrimidine (0.1 g, 0.651 mmol), 6- bromo-3-fluoro-2-methylpyridine (0.124 g, 0.651 mmol) and 1,1,1,2,2,2- hexamethyldistannane (0.213 g, 0.651 mmol) in 1,4-dioxane (2 mL) was purged withnitrogen gas for 10 mm. Pd(Ph3P)4 (0.075 g, 0.065 mmol) was added to the reaction mixture and the solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated in a microwave at 150C for 2 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (20 mL) and water (20 mL). The biphasic mixture was filtered through diatomaceous earth (Diatomaceous earth) and the bed was washed with ethyl acetate (25 mL). The ethyl acetate layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown colored solid. The solid was purified by silica gelchromatography (0-40% EtOAc in pet ether) to afford 7-(5-fluoro-6-methylpyridin-3- yl)pyrazolo[1,5-ajpyrimidine (0.06 g, 0.263 mmol, 40% yield) as a light yellow solid. LCMS (ESI) m/e 228.22 [(M+H), calcd for C12H9FN4 229.2j; LC/MS retention time (Method Al): tR = 2.20 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium phosphate; palladium diacetate; triphenylphosphine; In 1,4-dioxane; water; at 100℃; for 0.75h;Inert atmosphere; | A mixture of 7-chloropyrazolo[1,5-ajpyrimidine (0.02 g, 0.130 mmol), (8)- tert-butyl (2,4-dimethyl- 1 -((7- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzo[djthiazol-4-yl)oxy)pentan-2-yl)carbamate (prepared as described inExample 267) (0.077 g, 0.156 mmol), triphenylphosphine (6.83 mg, 0.026 mmol), and tripotassium phosphate (0.055 g, 0.260 mmol) in 1,4-dioxane (2 mL) and water (4.69 1iL, 0.260 mmol) was purged with nitrogen for 15 mi Palladium(II) acetate (2.92 mg, 0.013 mmol) was added and the mixture was purged for a further 5 mm, then the reaction mixture was heated to 100 C for 45 mm. The reaction mixture wascooled to room temperature and diluted with 1,4-dioxane (10 mL) and filtered through diatomaceous earth. The diatomaceous earth bed was washed with 15 mL of ethyl acetate. The filtrate was concentrated under reduced pressure. The cmde was purified via reverse phase HPLC. The desired fractions were concentrated under reduced pressure to afford (5)-tert-butyl (2,4-dimethyl- 1 -((7-(pyrazolo [1,5-ajpyrimidin-7-yl)benzo[dlthiazol-4-yl)oxy)pentan-2-yl)carbamate (0.025 g, 0.051 mmol, 31% yield) as a yellow semi-solid. LCMS (ESI) m/e 482.2 [(M+H), calcd for C25H32N503S, 482.21; LC/MS retention time (Method Al); tR = 2.81 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; potassium bromide; In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (0.05 g, 0.326 mmol), (8)-tert-butyl (1 -(2-chloro-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as described in Example 260, Part A and B) (0.152 g, 0.326 mmol), C52CO3 (0.212 g, 0.65 1 mmol), and KBr (0.039 g, 0.326 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was purged with nitrogen gas for 30 mi PdC12 (dppf)-CH2C12 adduct (0.027 g, 0.033 mmol) was added to the reactionmixture and the solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated at 80 C for 12 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (30 mL) and water (30 mL). The biphasic mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (50 mL). The organic layer wasseparated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford cmde product as a brown solid which was purified by silica-gel column chromatography (pet ether/ethyl acetate) to afford (5)-tert-butyl (1 -(2-chloro-4- (pyrazolo [1,5 -aj pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.08 g, 0.174 mmol, 54% yield) as an off-white solid. LCMS (ESI) m/e 459.2 [(M+H) ,calcd for C24H32C1N403 459.21; LC/MS retention time (Method Al): tR = 3.28 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 150℃; for 2h;Inert atmosphere; Microwave irradiation; | A solution of 7-chloropyrazolo[l,5-ajpyrimidine (0.1 g, 0.651 mmol), 5- bromo-2-fluoronicotinonitrile (prepared as described in Example 487) (0.131 g, 0.651 mmol) and 1,1,1,2,2,2-hexamethyldistannane (0.213 g, 0.651 mmol) in 1,4- dioxane (2 mL) was purged with nitrogen gas forlO mm. Pd (Ph3P)4 (0.075 g, 0.065mmol) was added to the reaction mixture and the solution was purged with nitrogen gas again for 10 mm. The reaction mixture was heated in a microwave at 150 C forh. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (20 mL) and water (20 mL). The biphasic mixture was filtered through diatomaceous earth (Diatomaceous earth) and the bed was washed withethyl acetate (25 mL). The ethyl acetate layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown colored solid. The solid was purified by silica gel chromatography (0-40% EtOAc in pet ether) to afford 2-fluoro-5 -(pyrazolo [1,5 -aj pyrimidin-7-yl)nicotinonitrile (0.032 g, 0.134 mmol, 21% yield) as a light-yellow color solid. LCMS (ESI) m/e 239.0 [(M), calcdfor C12H6FN5 239.11; LC/MS retention time (Method Al): tR = 2.33 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; potassium bromide; In 1,4-dioxane; at 88℃; for 2h;Inert atmosphere; | A solution of 7-chloropyrazolo[1,5-ajpyrimidine (25 mg, 0.163 mmol), (8)-tert-butyl (1 -(2,5 -difluoro-4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as described in Example 285) (76 mg,0.163 mmol), C52CO3 (106 mg, 0.326 mmol), and KBr (19.37 mg, 0.163 mmol) in1,4-dioxane (10 mL) was purged with nitrogen gas for 30 mi PdC12 (dppf)-CH2C12 adduct (13.29 mg, 0.016 mmol) was added to the reaction mixture and the solutionwas purged with nitrogen gas again for 10 mm. The reaction mixture was heated in a microwave at 88 C for 2 h. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate (30 mL) and water (30 mL). The biphasic mixture was filtered through diatomaceous earth (Diatomaceous earth) and the bed was washed with ethyl acetate (50 mL). The ethyl acetate layer was separated, driedover Na2SO4, filtered, and concentrated under reduced pressure to afford (8)-tert- butyl (1 -(2,5 -difluoro-4-(pyrazolo [1,5 -ajpyrimidin-7-yl)phenoxy)-2,4- dimethylpentan-2-yl)carbamate (40 mg, 0.087 mmol, 53% yield) as a brown solid which was carried forward without further purification. LCMS (ESI) m/e 461.2 [(M+H), calcd for C24H31F2N403 461.21; LC/MS retention time (Method Al): tR =2.73 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 130℃; for 1.5h;Inert atmosphere; Microwave irradiation; | A solution 7-chloropyrazolo[1,5-ajpyrimidine (75 mg, 0.488 mmol), 6- bromo-3 -fluoro-2-(fluoromethyl)pyridine (102 mg, 0.488 mmol), tetrakis(triphenylphosphine)palladium (0) (28.2 mg, 0.024 mmol) and hexamethylditin (0.101 mL, 0.488 mmol) in 1,4-dioxane (2 mL) was purged withnitrogen gas for 2 mm and irradiated at 130 C in a microwave for 90 mm. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added and the solution was extracted with ethyl acetate (2x10 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate in hexanes) to afford 7-(5-fluoro-6-(fluoromethyl)pyridin-2-yl)pyrazolo [1,5 -aj pyrimidine (72 mg, 0.120 mmol, 25% yield) as a yellow solid. LCMS (ESI) m/e 247.0 [(M+H) , calcd for C12H9F2N4 247.11; LC/MS retention time (Method C): tR = 0.79 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Selectfluor; In acetonitrile; at 20℃; for 16h;Inert atmosphere; | 7-Chloro-3-fluoro-pyrazolo[l,5-a]pyrimidine and 3,7-dichloropyrazolo[l,5- ajpyrimidine: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere; | Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 7- chloropyrazolo[1 ,5-a]pyrimidine (2) (307mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10ml_) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (34mg, 8%). |
Tags: 58347-49-2 synthesis path| 58347-49-2 SDS| 58347-49-2 COA| 58347-49-2 purity| 58347-49-2 application| 58347-49-2 NMR| 58347-49-2 COA| 58347-49-2 structure
[ 57489-77-7 ]
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H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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