4-(Aminomethyl)-1-piperidineethanol

To the solution of compound 1-(2-hydroxyethyl)piperidine-4-carbonitrile (300 mg, 2 mmol) in dry THF (5 mL) at 0° C., BH17 g of 1- (2-hydroxyethyl) piperidine-4-carboxamide was added to 200 ml of tetrahydrofuran, Cooled to 0 ° C, slowly added 9g lithium aluminum hydride, stirred at room temperature for 2 hours, Add dilute aqueous sodium hydroxide solution, filter, collect the mother liquor, dry, concentrate, the residue separated by column to give 12g 2- (4- (Aminomethyl) piperidin-1-yl) ethanol12 g of 2- (4- (aminomethyl) piperidin-1-yl) ethanol was added to150 ml of N, N-dimethylformamide, Add 18g bromoethane, then add 15g of potassium carbonate, Heated to reflux for 2 hours, Water and ethyl acetate were added, the mixture was extracted and separated, and the organic phase was collected, dried and concentrated. The residue was separated on a silica gel column to obtain 9 g2- (4 - ((ethylamino) methyl) piperidin-1-yl) ethanol.17 g of 1- (2-hydroxyethyl) piperidine-4-carboxamide was added to 200 ml of tetrahydrofuran, Cooled to 0 C, slowly added 9g lithium aluminum hydride, stirred at room temperature for 2 hours, Add dilute aqueous sodium hydroxide solution, filter, collect the mother liquor, dry, concentrate, the residue separated by column to give 12g 2- (4- (Aminomethyl) piperidin-1-yl) ethanol(Z)-4-(((1 -Acetyl-6-(methoxycarbonyl)-5-methyl-2-oxoindolin-3-ylidene) (phenyl)methyl)ami no)benzoic acid, trifluoroacetate adduct (Intermediate E) (75 mg, 0.128 mmol), and HATU (73 mg, 0.192 mmol) in DMF (2 mL) were stirred at rt for 10 mm thenHunig's base (179 p1, 1.03 mmol) and General procedure: The general synthesis of compound D-9 is illustrated in Scheme 4. The carboxylic acid group of intermediate D-1 is converted to ethyl ester. The reactionsof tert-butyl acetate substitution with K2C03 and tert-butyl eater hydrolysis with TFA are followed to afford acetic acid intermediate D-4. The intermediate D-4 is chlorinated with oxalyl chloride and DMF and coupled with 3-aminoisonicotinamide to afford the amide intermediate D-6. Subsequent cyclization with NaOtBu and hydrolysis with NaOH lead to intermediate D-8. This is followed by amide coupling reaction with HATU, which leads to amide compound D-9.To the solution of compound 1-(2-hydroxyethyl)piperidine-4-carbonitrile (300 mg, 2 mmol) in dry THF (5 mL) at 0 C., BH3.SMe2 (220 mg, 2.4 mmol) was added dropwise. The mixture was stirred at 0 C. for 2 hrs. Water was added then K2CO3. The mixture was filtered and concentrated to give compound [00351 ] To the solution of compound 2-(4-(aminomethyl)piperidin-1 - yl)ethanol (150 mg, 0.95 mmol) and compound 6-chloro-3-(3- (trifluoromethoxy)phenyl)imidazo[1 , 2-b]pyridazine (200 mg, 0.64 mmol) in 3 ml_ DMSO was added DIEA (0.3 ml_, 1 .37 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120 C, Then the mixture was purified by HPLC to afford the compound 2-(4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1 , 2-b]pyridazin-6- yl)amino)methyl)cyclohexyl)ethanol (34 mg, 8.2 %) as a brown solid. [00352] 1 H-NMR (CDCI3/400 MHz): delta 8.61 (s, 1 H), 8.20 - 8.25 (m, 1 H), 7.95 - 8.05 (m, 2 H), 7.66 (t, J = 4.4 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 3.80 - 3.90 (m, 2 H), 3.62 - 3.75 (m, 2 H), 3.37 (d, J = 6.4 Hz, 2 H), 3.21 (t, J = 5.2 Hz, 2 H), 2.91 - 3.09 (m, 2 H), 2.10 (d, J = 14.0 Hz, 2 H), 1 .51 - 1 .69 (m, 2 H). MS (ES+, m/z): (M+H)+: 435.5.To the solution of compound

Molecular Weight:158.24
XLogP3:-0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:158.141913202
Monoisotopic Mass:158.141913202
Topological Polar Surface Area:49.5
Heavy Atom Count:11
Complexity:100
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes