Example 1
A solution of tert-butyl (R)-(1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate (Intermediate 2, 25.2 mg, 0.052 mmol) in 1,4-dioxane (0.7 mL) was treated with (2,6-difluorophenyl)boronic acid (16.3 mg, 0.103 mmol), XPhos Pd G2 (7.5 mg), potassium phosphate tribasic (21.8 mg, 0.103 mmol), and water (0.1 mL). The reaction mixture was then sparged with nitrogen, sealed, and stirred at 80° C. overnight. After cooling to r.t., the reaction mixture was concentrated and TFA (1 mL) was added and the resulting mixture was stirred at r.t. for 30 minutes. The reaction mixture was then diluted with acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C23H21F2N6OS (M+H)+: m/z=467.1; Found 467.2. 1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.34 (d, J=5.0 Hz, 1H), 8.55 (d, J=8.8 Hz, 1H), 8.31-8.15 (m, 4H), 7.95 (d, J=8.8 Hz, 1H), 7.71 (tt, J=8.4, 6.4 Hz, 1H), 7.39 (t, J=8.4 Hz, 2H), 3.81 (s, 1H), 3.69-3.59 (m, 2H), 3.53 (q, J=8.2 Hz, 1H), 3.34-3.24 (m, 1H), 2.85 (s, 3H), 2.24-2.14 (m, 1H), 2.08-1.98 (m, 1H).
Example 2
This compound was prepared according to the procedures described in Example 1, using (2-fluoro-6-methylphenyl)boronic acid instead of (2,6-difluorophenyl)boronic acid as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C24H24FN6OS (M+H)+: m/z=463.2; Found: 463.2. 1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.33 (d, J=5.0 Hz, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.19 (d, J=5.0 Hz, 1H), 8.16 (br s, 3H), 7.95 (d, J=8.8 Hz, 1H), 7.50 (td, J=8.0, 5.8 Hz, 1H), 7.28 (m, 2H), 3.70 (s, 1H), 3.65-3.58 (m, 2H), 3.52 (q, J=8.4 Hz, 1H), 3.25 (td, J=8.4, 3.8 Hz, 1H), 2.84 (s, 3H), 2.30 (s, 3H), 2.12-2.01 (m, 1H), 2.00-1.91 (m, 1H).
Example 3
This compound was prepared according to the procedures described in Example 1, using (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid instead of (2,6-difluorophenyl)boronic acid as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C24H21F4N6OS (M+H)+: m/z=517.1; Found: 517.1.
Example 4
This compound was prepared according to the procedures described in Example 1, using tert-butyl (3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (Intermediate 3) instead of (2,6-difluorophenyl)boronic acid as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C26H29FN7S (M+H)+: m/z=506.2; Found: 506.3. 1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.33 (d, J=5.0 Hz, 1H), 9.15 (br s, 2H), 8.49 (d, J=8.8 Hz, 1H), 8.32 (br s, 2H), 8.20 (d, J=5.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.42 (d, J=10.1 Hz, 1H), 7.38 (s, 1H), 4.24 (s, 2H), 3.73-3.66 (m, 1H), 3.65-3.59 (m, 2H), 3.53 (q, J=8.4 Hz, 1H), 3.26 (td, J=8.4, 3.8 Hz, 1H), 2.84 (s, 3H), 2.64 (s, 3H), 2.31 (s, 3H), 2.14-1.94 (m, 2H).
Example 11
Example 12
Example 13
This compound was prepared according to the procedures described in Example 12, using 4-chloro-2-isopropyl-5-nitrobenzo[d]thiazole (Intermediate 12) instead of 4-chloro-2-ethyl-5-nitrobenzo[d]thiazole (Intermediate 11) as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C27H30FN6O3S (M+H)+: m/z=537.2; Found: 537.1.
Example 16
HATU (15 mg, 0.040 mmol) was added to a solution of tert-butyl ((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (Intermediate 10, 15 mg, 0.040 mmol), 2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate 14, 10.6 mg, 0.040 mmol) and triethylamine (0.01 mL, 0.072 mmol) in DMF (1 mL). The reaction mixture was stirred at 50° C. for 30 minutes. After cooling to r.t., water was added and the precipitated product was collected via filtration, washed with water, and air dried. The solid residue was then dissolved in TFA and the resultant solution was stirred at r.t. for 30 minutes. The reaction mixture was then diluted with acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C25H25F2N6O3S (M+H)+: m/z=527.2; Found: 527.1. 1H NMR (500 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.32 (d, J=5.0 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.26 (br s, 3H), 8.20 (d, J=5.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.64 (q, J=9.4 Hz, 1H), 7.07 (ddd, J=9.4, 3.6, 1.7 Hz, 1H), 4.44 (t, J=5.0 Hz, 1H), 4.00 (qd, J=7.3, 5.0 Hz, 1H), 3.78 (s, 3H), 3.70-3.60 (m, 1H), 3.55 (dd, J=10.4, 5.8 Hz, 1H), 3.24-3.17 (m, 1H), 3.17-3.11 (m, 1H), 2.87 (s, 3H), 2.34-2.26 (m, 1H), 1.84-1.75 (m, 1H).
Example 17
This compound was prepared according to the procedures described in Example 16, using 2-(3-cyano-2-fluoro-6-(methoxy-d3)phenyl)pyrimidine-4-carboxylic acid (Intermediate 15) instead of 2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate 14) as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C26H22D3FN7O3S (M+H)+: m/z=537.2; Found: 537.2.
Example 18
A solution of N-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide (Example 11, 57 mg, 0.11 mmol) in 1,2-DCE (1 mL) was treated with acetone (0.02 mL, 0.27 mmol), acetic acid (0.02 mL, 0.35 mmol), and sodium triacetoxyborohydride (47.5 mg, 0.224 mmol). The reaction mixture was then stirred at r.t. overnight. Water was then added and the reaction mixture was concentrated under vacuum, diluted with acetonitrile, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C2H32FN6O3S (M+H)+: m/z=551.2; Found: 551.2. 1H NMR (600 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.29 (d, J=5.0 Hz, 1H), 8.97 (br d, J=79.1 Hz, 2H), 8.60 (d, J=8.8 Hz, 1H), 8.17 (d, J=5.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.57 (td, J=8.5, 6.9 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.02 (t, J=8.8 Hz, 1H), 4.49 (t, J=5.2 Hz, 1H), 4.12 (tt, J=8.0, 5.2 Hz, 1H), 3.78 (s, 3H), 3.55-3.46 (m, 2H), 3.46-3.39 (m, 1H), 3.21-3.11 (m, 3H), 2.84 (s, 3H), 2.33-2.25 (m, 1H), 1.99-1.91 (m, 1H), 1.13 (dd, J=22.8, 6.4 Hz, 6H).
Example 19
This compound was prepared according to the procedures described in Example 18, using tetrahydro-4H-pyran-4-one instead of acetone as starting material. Purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C3H34FN6O4S (M+H)+: m/z=593.2; Found: 593.2.
Example 20
A solution of N-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide (Example 11, 38 mg, 0.075 mmol) in DMF (1 mL) was treated with a 0.1 M stock solution of acetic acid (0.75 mL, 0.075 mmol) in THF, HATU (28.4 mg, 0.075 mmol), and triethylamine (0.04 mL, 0.287 mmol). The reaction mixture was stirred at 50° C. for 30 minutes. After cooling to r.t., the reaction mixture was concentrated slightly, water was added and the precipitated product was collected via filtration, washed with water, and air dried. The crude material was then dissolved in acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C27H28FN6O4S (M+H)+: m/z=551.2; Found: 551.2.
Example 21
A solution of N-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example 11, 38 mg, 0.075 mmol) and triethylamine (8 mg, 0.079 mmol) in anhydrous THF (2 mL) was treated with a 0.1 M solution of methanesulfonyl chloride (0.75 mL, 0.075 mmol) in anhydrous THF. The reaction mixture was stirred at r.t. for 15 minutes. The reaction was then treated with water, and the resulting mixture was diluted with acetonitrile and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C26H28FN6O5S2 (M+H)+: m/z=587.2; Found: 587.1. 1H NMR (600 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.28 (d, J=5.0 Hz, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.16 (d, J=5.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.57 (td, J=8.4, 6.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.02 (t, J=8.8 Hz, 1H), 4.31 (br s, 1H), 3.93-3.85 (m, 1H), 3.75-3.83 (m, 4H), 3.44 (dd, J=9.5, 5.8 Hz, 1H), 3.21 (dd, J=9.5, 5.8 Hz, 1H), 3.19-3.08 (m, 2H), 2.86 (s, 6H), 2.18-2.10 (m, 1H), 1.75-1.67 (m, 1H).
Example 22
This compound was prepared according to the procedures described in Example 11, using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C25H23FN5O3S (M+H)+: m/z=492.2; Found: 492.2.
Example 23
This compound was prepared according to the procedures described in Example 11, using tert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C25H26FN6O3S (M+H)+: m/z=509.2; Found: 509.2.
Example 24
This compound was prepared according to the procedures described in Example 11, using N-methyl-1-(1-methylpyrrolidin-3-yl)methanamine instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C27H30FN6O2S (M+H)+: m/z=521.2; Found: 521.3.
Example 26
This compound was prepared according to the procedures described in Example 11, using tert-butyl (S)-(morpholin-3-ylmethyl)carbamate instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C25H26FN6O3S (M+H)+: m/z=509.2; Found: 509.2.
Example 27
This compound was prepared according to the procedures described in Example 11, using tert-butyl (R)-3-(methylamino)piperidine-1-carboxylate instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C26H28FN6O2S (M+H)+: m/z=507.2; Found: 507.2.
Example 28
This compound was prepared according to the procedures described in Example 11, using tert-butyl octahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C27H28FN6O2S (M+H)+: m/z=519.2; Found: 519.2.
Example 29
This compound was prepared according to the procedures described in Example 11, using 2-(pyrrolidin-3-yl)pyridine instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C29H26FN6O2S (M+H)+: m/z=541.2; Found: 541.2.
Example 30
This compound was prepared according to the procedures described in Example 11, using (S)-(4,4-difluoropyrrolidin-2-yl)methanol instead of tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material. LCMS calculated for C25H23F3N5O3S (M+H)+: m/z=530.2; Found: 530.2.
Example 31
This compound was prepared according to the procedures described in Example 11, using tert-butyl (1S,4S)-5-(5-amino-2-methylbenzo[d]thiazol-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Intermediate 17) instead of tert-butyl ((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (Intermediate 10) and 2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid (Intermediate 16) instead of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate 4) as starting materials. LCMS calculated for C25H23F2N6OS (M+H)+: m/z=493.2; Found: 493.2.
