5-AMINOMETHYL INDAZOLE

A solution of 1H-indazole-5-carbonitrile (100 mg, 0.699 mmol) in tetrahydrofuran (4 ml) was added to a solution of lithium aluminum hydride (53 mg, 1.40 mmol) in tetrahydrofuran (4 ml) at room temperature, and the resulting mixture was refluxed for 2 hours. Subsequently, water (0.053 ml), a 2N-aqueous lithium hydroxide solution (0.106 ml) and water (0.212 ml) were added in that order to the reaction solution and stirred, followed by filtration. The solvent was distilled off under reduced pressure and the residue was dried under reduced pressure to obtain 1-(1H-indazol-5-yl)methanamine (97 mg, 94percent).General procedure: Using a gas tight syringe, N-methylmorpholine (1.1equiv) was added dropwise to a stirring solution of 14a-c (40.0 mg, 1.0 equiv) in dry DMF (6 mL) at 10 C. The resulting solution wasstirred for 10 min before isobutylchloroformate (1.1 equiv) wasadded dropwise. After 10 min, a solution of corresponding headgroup amines A-E (1.5 equiv) and N-methylmorpholine (1.1 equiv)*in dry DMF (3 mL) were added dropwise. The reaction mixture wasstirred for another 30 min before it was warmed to room temperatureand stirred for an additional 12 h. After the reaction wascomplete, as indicated by TLC, the DMF was removed by rotaryevaporation at 30 torr and 70 C. The crude materialwas purified bymethods described in each individual entry.*Since head group amine C was received as a hydrochloride salt, one extra equivalent of DIPEA (in Method A) or N-methylmorpholine(in Method B) was added to free base the amine in situ.General procedure: Using a gas tight syringe, N-methylmorpholine (1.1equiv) was added dropwise to a stirring solution of 14a-c (40.0 mg, 1.0 equiv) in dry DMF (6 mL) at 10 C. The resulting solution wasstirred for 10 min before isobutylchloroformate (1.1 equiv) wasadded dropwise. After 10 min, a solution of corresponding headgroup amines A-E (1.5 equiv) and N-methylmorpholine (1.1 equiv)*in dry DMF (3 mL) were added dropwise. The reaction mixture wasstirred for another 30 min before it was warmed to room temperatureand stirred for an additional 12 h. After the reaction wascomplete, as indicated by TLC, the DMF was removed by rotaryevaporation at 30 torr and 70 C. The crude materialwas purified bymethods described in each individual entry.*Since head group amine C was received as a hydrochloride salt, one extra equivalent of DIPEA (in Method A) or N-methylmorpholine(in Method B) was added to free base the amine in situ.General procedure: Using a gas tight syringe, N-methylmorpholine (1.1equiv) was added dropwise to a stirring solution of 14a-c (40.0 mg, 1.0 equiv) in dry DMF (6 mL) at 10 C. The resulting solution wasstirred for 10 min before isobutylchloroformate (1.1 equiv) wasadded dropwise. After 10 min, a solution of corresponding headgroup amines A-E (1.5 equiv) and N-methylmorpholine (1.1 equiv)*in dry DMF (3 mL) were added dropwise. The reaction mixture wasstirred for another 30 min before it was warmed to room temperatureand stirred for an additional 12 h. After the reaction wascomplete, as indicated by TLC, the DMF was removed by rotaryevaporation at 30 torr and 70 C. The crude materialwas purified bymethods described in each individual entry.*Since head group amine C was received as a hydrochloride salt, one extra equivalent of DIPEA (in Method A) or N-methylmorpholine(in Method B) was added to free base the amine in situ.To tert-butyl 4-[(chlorocarbonyl)[(2, 4-difluorophenyl)methyl]amino]piperidine-l- carboxylate (50 mg, 129 mupiiotaomicron) and diisopropylethylamine (33.6 mu, 193 mupiiotaomicron) in dichloromethane 1 ml was added (lH-indazol-5-yl)methanamine. The mixture was sonicated for 2 hours and then the crude product collected by filtration. To the crude TFA 500 mu in 1 ml THF was added and the reaction was heated to 60 C for 1.5 hours. The mixture was concentrated and then suspended in methanol filtered and concentrated. This material, formaldehyde (11.5 mu, 155 mupiiotaomicron) and sodium triacetoxyborohydride (54.7 mg, 258 mupiiotaomicron) were stirred in tetrahydrofuran (1.0 ml) for 2 hours, more formaldehyde (17.3 mu, 233 mupiiotaomicron) and sodium triacetoxyborohydride (109 mg, 516 mupiiotaomicron) were added and the reaction stirred for 1 hour. Ammonia (27% aqueous, 1 ml) was added and the reaction was stirred overnight. The reaction was concentrated and the crude material purified by HPLC, eluting with 10-40 % acetonitrile in water (containing 0.1 % trifluoroacetic acid). Yield: 9 % from carbamoyl chloride. NMR (400 MHz, Methanol-^) delta 7.97 (s, 1H), 7.60 (s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 7.22 (q, 1H), 6.99 - 6.90 (m, 1H), 6.87 (t, 1H), 4.53 (s, 2H), 4.46 (s, 2H), 4.40 - 4.26 (m, 1H), 3.50 (d, 2H), 3.15 - 3.00 (m, 2H), 2.82 (s, 3H), 2.09 - 1.85 (m, 4H).; LCMS: 414.3 [M+H]+.General procedure: To an ice-cold solution of carboxylic acid (1 equiv.), amine (1 .2 equiv.) and propylphosphonic anhydride solution (T3P) (50 wt. % in ethyl acetate; 2 equiv.) in dry dichloromethane was added triethylamine (7 equiv.). The resulting reaction mixture was stirred at room temperature for 4 to 16 h (monitored by TLC). The reaction was diluted with ice water and extracted with dichloromethane (2-3 times). The combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography, to afford the desired product as a white solid.A solution of (5Z, 8Z, l lZ, 14Z)-icosa-5, 8, l l, 14-tetraenoic acid (200 mg, 0.58 mmol) in DCM (4 ml) and DMF (0.12 ml) was cooled to 0 C and oxalyl chloride (0.116 ml, 1.31 mmol) was added dropwise. The reaction mixture was stirred for an additional 1 h followed by the addition of a solution of 8 (200 mg, 1.37 mmol) in pyridine (0.493 ml, 0.493 mmol). The mixture was warmed to rt and stirred for an additional 30 minutes. The mixture was diluted with DCM (5mL) and washed with 10% aq. HC1 and water. The organic layer was dried (Na2S04), concentrated and purified by flash Si02 chromatography (Hexanes/EtOAc) to provide 12 (30 mg, 12.0% yield) as a pale yellow oil: 1H NMR (400 MHz, CDC13) delta 8.11 (s, 1H), 7.68 (s, 1H), 7.54-7.56 (d, 1H), 7.41-7.43 (d, 1H), 5.75 (s, 1H), 5.31-5.40 (m, 9H), 4.55-4.56 (d, 2H), 2.79-2.82 (m, 6H), 2.22-2.57 (t, 2H), 2.11-2.14 (m, 2H), 2.02-2.07 (m, 2H), 1.74-1.78 (m, 2H), 1.25-1.29 (m, 6H), 0.88 (t, J = 6.80 Hz, 3H); C28H39N30 Exact Mass: 433.31 EST m/z 456.2 [M+Na]+.8 mmol of Compound C was dissolved in 50 mL of absolute ethanol, Then, 9 mmol of compound D, Acetic acid 35mmol dissolved in 40mL anhydrous ethanol, A solution of Compound D and acetic acid in ethanol was added to the ethanol solution of Compound C over 10 minutes while stirring at 5 C, After stirring for 2 h, 20 mmol of NaBH (OAc) 3 was slowly added, After stirring overnight at room temperature, After completion of the reaction, Concentrated under reduced pressure, Using sodium carbonate adjusted system pHwei8.0, Washed with ethyl acetate 100 mL x 3, And then washed with 100 mL of a saturated aqueous sodium chloride solution 3, Dried over anhydrous sodium sulfate, Concentrated under reduced pressure, To give compound I, 2-Chloro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride (275 mg, 0.856 mmol) (prepared similarly to Example 3, step 6, or Example 27, step 6) was dissolved in DMA (18.6 mL). To the solution was added l-(lH-indazol-5-yi)methanamine (151 mg, 1.03 mmol) and triethylamine (0.597 mL, 4.28 mmol), and the mixture was stirred at rt for 16 h. To the mixture was added saturated aqueous NaHC03 and EtOAc. The layers were separated and the aqueous layer was extracted two more times with EtOAc. The combined organic layer was washed with water then brine and dried over anhydrous MgSO^ Purified by silica gel to give 2-chloro-3-(4-fluorophenyl)-N-(lH-indazol-5-ylmethyl)quinoxaline-6- carboxamide (184 mg, 50%) as a pale yellow solid. LCMS (ESI+): m/z = 432.1 (Mu+Eta). NMR (400 MHz, DMSO-i/fi) S 13.02 (s, 1 H), 9.50 (t, J= 5.9 Hz, 1 H), 8.73 (d, J= 1.5 Hz, 1 H), 8.38 (dd, J= 8.8, 1.9 Hz, 1 H), 8.19 (d, J= 8.7 Hz, 1 H), 8.05 (s, 1 H), 7.94 (dd, J= 8.8, 5.5 Hz, 2 H), 7.74 (s, 1 H), 7.53 (d, J= 8.6 Hz, 1 H), 7.42 (dd, J= 16.3, 7.5 Hz, 3 H), 4.66 (d, J= 5.8 Hz, 2 H).Example 2516-(2, 3-dimethylphenyl)-4-N-(1 H-indazol-5-ylmethyl)pyrimidine-2, 4-diamine.4-Chloro-6-(2, 3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0, 050 mmol), 1 Hindazol-5-ylmethanamine (15 mg, 0, 10 mmol), Et3N (0.040 mL, 0, 30 mmol) and 1- butanol (0, 20 mL) were stirred at 10000 for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product.LCMS [M+H] 345.Example 251 6-(2, 3-dimethylphenyl)-4-N-(1 H-indazol-5-ylmethyl)pyrimidine-2, 4-diamine. 4-Chloro-6-(2, 3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0, 050 mmol), 1 H- indazol-5-ylmethanamine (15 mg, 0, 10 mmol), Et3N (0.040 mL, 0, 30 mmol) and 1- butanol (0, 20 mL) were stirred at 100C for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]+ 345.

Molecular Weight:147.18
XLogP3:0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:147.079647300
Monoisotopic Mass:147.079647300
Topological Polar Surface Area:54.7
Heavy Atom Count:11
Complexity:137
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes