Ethyl 4-Methylpiperidine-4-carboxylate Hydrochloride

4M Solution of hydrogen chloride in 1, 4-dioxane (3 mL) was added to a solution of 1- tert-butyl 4-ethyl 4-methylpiperidine-1, 4-dicarboxylate (0.34 g, 1.25 mmol) in ethanol (4 mL) and the resulting mixture was stirred for 6 hours at room temperature. The solvents were evaporated and the residue was treated with diethyl ether, filtered and washed with diethyl ether to yield the hydrochloride salt of the title compound (0.3 g, 99percent) as a white solid.LRMS (mlz): 172 (M+1)+.To a solution of Intermediate 25 ( 11.0 g, 40.5 mmol) dissolved in 1, 4-Dioxane (30.0 mL) at 0-5°C was added HC1 (15.2 mL, 4 M in 1, 4-dioxane) the mixture was allowed to warm to r.t. and stirred for 18h. The reaction mixture was concentrated in vacuo and residue washed with diethyl ether, yielding the title compound as an orange solid (5.02 g, 59.6percent). 1H NMR (DMSO-dTo a solution of Intermediate 37 (11.0 g, 40.5 mmol) dissolved in 1 , 4-dioxane (30.0 mL) at 0-5°C was added HC1 (15.2 mL, 4 M in 1, 4-dioxane). The mixture was allowed to warm to r.t. and stirred for 1 8h. The reaction mixture was concentrated in vacuo and residue washed with diethyl ether, yielding the title compound as an orange solid (5.02 g, 59.6percent). 1H NMR (DMSO-d6) ö: 9.00 (m, 1 H), 4.14 (q, J 6.8 Hz, 2 H), 3.16 (m, 2 H), 2.82 (m, 2 H), 2.08 (d, J 14.4 Hz, 2 H), 1.65 (m, 2 H), 1.22 (m, 6 H).Ethyl 4-methylpiperidine-4-carboxylate hydrochloride (ii) The compound 400 mg of [5-({[6- (trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H- indazol-2-yl]acetic acid were reacted with 296 mg of ethyl 4-methylpiperidine-4- carboxylate hydrochloride (1:1) in the presence of EDC, HOBt and triethylamine. This gave 544 mg of ethyl 4-methyl-1-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- 2H-indazol-2-yl]acetyl} piperidine-4-carboxylate as a crude product. Ethanol and THF and 348 mg of lithium hydroxide monohydrate in water were added, and the mixture was stirred overnight and acidified with citric acid solution. Extraction with ethyl acetate and purification by HPLC gave 89 mg of 4-methyl-1-{[5-({[6-(trifluoro-methyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperidine-4- carboxylic acid. 49 mg of thiswere reacted with 15 mg of 1-methylpiperazine in the presence of EDC, HOBt and triethylamine in THF. Purification by HPLC gave 29 mg of N-[2-(2-{4-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol- 5-yl]-6-(trifluoromethyl) pyridine-2-carboxamide. 1H-NMR (300 MHz, DMSO-d6, selected signals): delta = 1.25 (s, 3H), 1.36-1.57 (m, 2H), 1.98-2.22 (m, 5H), 2.27 (br. s., 4H), 3.13 (t), 3.54 (s), 3.60-3.80 (m, 2H), 5.35-5.50 (m, 2H), 7.51-7.63 (m, 2H), 8.17 (dd, 1H), 8.26-8.42 (m, 4H), 10.37 (s, 1H).A mixture of A mixture of Intermediate 37 (200 mg, 0.52 mmol) and ethyl 4-methylpiperidine- 4-carboxylate hydrochloride (216 mg, 1.04 mmol) in pyridine (0.5 mL) was heated at 180C under microwave irradiation for 4 h. The reaction mixture was concentrated and the residue was purified by FCC, eluting with 20-100%) EtOAc in heptanes, to afford the title compound (131 mg, 47%) as an off-white solid. deltaEta (500 MHz, CD3OD) 8.88 (d, J 1.4 Hz, IH), 8.57 (d, J2.3 Hz, IH), 8.37 (d, J 1.4 Hz, IH), 8.01 (dd, J9.0, 2.5 Hz, IH), 7.31 (ddd, J 8.6, 6.8, 2.3 Hz, IH), 7.26-7.11 (m, 3H), 7.08-6.71 (m, 2H), 4.43 (s, 2H), 4.19 (q, J7.1 Hz, 2H), 4.01 (dt, J 13.7, 4.2 Hz, 2H), 3.18 (ddd, J 13.6, 10.7, 2.9 Hz, 2H), 2.46 (s, 3H), 2.17 (d, J 13.6 Hz, 2H), 1.51 (ddd, J 14.1, 10.7, 4.0 Hz, 2H), 1.27 (t, J7.1 Hz, 3H), 1.23 (s, 3H). Method B HPLC-MS: MH+ mlz 536, RT 1.96 minutesA mixture of Intermediate 145 (97% pure, 50mg, 0.12 mmol) and ethyl 4- methylpiperidine-4-carboxylate hydrochloride (48 mg, 0.23 mmol) in pyridine (2 mL) was heated at 180C under microwave irradiation for a total of 4 h. The reaction mixturewas concentrated under vacuum. The residue was purified by FCC, using a KP-NHcartridge (Biotage) and eluting with 0-30% ethyl acetate in heptane followed by 100%EtOAc. The material was then triturated with MeCN/water, and purified by preparativeHPLC (Method C), to afford the title compound (56 mg, 32%) as an orange oil. OH (500MHz, DMSO-d6) 8.55-8.44 (m, 2H), 8.12 (d, J2.2 Hz, 1H), 7.54 (d, J1.1 Hz, 2H), 7.46-7.05 (m, 4H), 7.05-6.93 (m, 1H), 4.39 (s, 2H), 4.13 (q, J7.1 Hz, 2H), 3.59-3.46 (m, 2H), 3.09-2.90 (m, 2H), 2.30 (s, 3H), 2.11 (d, J14.0 Hz, 2H), 1.58 (ddd, J 13.4, 10.2, 3.5 Hz, 2H), 1.27-1.11 (m, 6H). Method A HPLC-MS: MH+ m/z 569, RT 4.15 minutes.A mixture of 2-chloropyrimidine-5-boronic acid (3.95 g, 24.2 mmol), Intermediate 26 (5.03 g, 24.2 mmol) and TEA (60.6 mmol, 8.50 mL) in EtOH (50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was separated and re-extracted with further ethyl acetate (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying over MgS04, filtering under reduced pressure and concentrating in vacuo, yieling the title compound as a brown foam (quantitive yield). LCMS (ES+) RT 1.228 min, 294.0 (M+H)+.A mixture of 2-chloropyrimidine-5-boronic acid (3.95 g, 24.2 mmol), Intermediate 38 (5.03 g, 24.2 mmol) and triethylamine (60.6 mmol, 8.50 mL) in EtOH(50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and EtOAc (100 mL). The aq. layer was separated and re-extracted with further EtOAc (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying (MgSO4), filtering under reduced pressure and concentrating in vacuo, yielding the title compound as a brown foam (quantitive yield).LCMS (ESj RT 1.23 mm 294.0 (M+H).To 2-chloropyrimidine-5-boronic acid (4.00 g, 25.3 mmol) were added A mixture of 2-chloropyrimidine-5-boronic acid (3.95 g, 24.2 mmol), Intermediate 26 (5.03 g, 24.2 mmol) and TEA (60.6 mmol, 8.50 mL) in EtOH (50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was separated and re-extracted with further ethyl acetate (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying over MgS04, filtering under reduced pressure and concentrating in vacuo, yieling the title compound as a brown foam (quantitive yield). LCMS (ES+) RT 1.228 min, 294.0 (M+H)+.A mixture of 2-chloropyrimidine-5-boronic acid (3.95 g, 24.2 mmol), Intermediate 38 (5.03 g, 24.2 mmol) and triethylamine (60.6 mmol, 8.50 mL) in EtOH(50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and EtOAc (100 mL). The aq. layer was separated and re-extracted with further EtOAc (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying (MgSO4), filtering under reduced pressure and concentrating in vacuo, yielding the title compound as a brown foam (quantitive yield).LCMS (ESj RT 1.23 mm 294.0 (M+H).To 2-chloropyrimidine-5-boronic acid (4.00 g, 25.3 mmol) were added [2?, 6?-Bis(propan-2-yloxy)biphenyl-2-yl] (dicyclohexyl)phosphane (12 mg, 0.026 mmol) and palladium diacetate (5 mg, 0.02 1 mmol) were charged to a sealed tube with anhydrous 1 , 4-dioxane (2 mL) and heated at 80C for 5 minutes, then cooled to room temperature. A solution of Intermediate 99 (190 mg, 0.43 mmol) in 1, 4-dioxane (3 mL)was added, together with Intermediate 94 (80% pure, 0.29 g, 0.498 mmol), ethyl 4-methylpiperidine-4- carboxylate hydrochloride (319 mg, 1.53 mmol), potassium carbonate (283 mg, 2.05 mmol) and 1 -methyl-2-pyrrolidinone (3 mL) were charged to a microwave tube and stirred under microwave irradiation at 180C for 2 h. The reaction mixture was dilutedwith EtOAc (5 mL) and separated, then the inorganic residue was washed with EtOAcx 5 mL). The combined organic layers were extracted with water (2 x 5 mL). LCMS of the aqueous and organic layers showed product evenly distributed between both. The aqueous and organic layers were combined and concentrated under vacuum. The residue5 was purified by preparative HPLC (Method D) to afford the title compound (54 mg, 20%) as a light brown solid. oH (250 MHz, DMSO-d6) 8.66-8.54 (m, 2H), 8.36 (d, J 1.2 Hz, 1H), 7.77 (dd, J9.4, 1.6 Hz, 1H), 7.63-7.01 (m, 5H), 6.98 (dd, J7.6, 1.4 Hz, 1H), 4.352H), 4.01 (d, J 13.7 Hz, 2H), 3.26-3.16 (m, 2H), 2.33 (s, 3H), 2.09-1.95 (m, 2H), 1.41 (t, 9.9 Hz, 2H), 1.17 (s, 3H). Method D HPLC-MS: MH+ m/z 508, RT 2.29 minutes.

Molecular Weight:207.70
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:207.1026065
Monoisotopic Mass:207.1026065
Topological Polar Surface Area:38.3
Heavy Atom Count:13
Complexity:162
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes