5,6,7,8-TETRAHYDROIMIDAZO[1,2-A]PYRAZINE

Imidazo[1, 2-a]pyrazine (7.2 g, 60.44 mmol) was dissolved in 2-methoxyethanol (100 ml). Platinum(IV) oxide (1.2 g, 5.13 mmol) was added, and the mixture was stirred overnight at room temperature, under a hydrogen atmosphere of 4 bar, in an autoclave. The reaction mixture was flooded with nitrogen, filtered over Celite, concentrated and coevaporated with toluene. Purification was carried out by column chromatography dichloromethane/7 N ammonia in methanol 95:5). Yield: 5.7 g (76percent)Step 1 The indole obtained [1, 2-A] pyrazine (10g, 0.08mmol) was dissolved in 100mL of ethylene glycol monomethyl ether, was added 5percent palladium on carbon (2G), quickly replaced with hydrogen three times, at room temperature (20-25 ) The reaction was stirred, TLC detection reaction process, the reaction is complete after 30 hours, suction filtered through celite pad, and the filtrate was concentrated by rotary evaporation and purified by column chromatography by chromatography to give 5, 6, 7, 8- hydrogen-imidazo [1, 2-A] pyrazine 7g, the the yield of about 68percentImidazo[1, 2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. Step 2 The title compound was prepared from imidazo[1, 2-a]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration gave the title compound (512 mg) as a viscous oil. To (3R)-tert-butyl 3-(2-(N, N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)phenylsulfonamido)pyrrolidine-1-carboxylate (REFERENCE EXAMPLE 5) (120 mg, 0.125 mmol) and C-1 a (50 mg; 0.16 mmol) is dissolved in dioxane. 5, 6, 7, 8-tetrahydro-imidazo[1 , 2- a]pyrazine E-1a (19 mg; 0.16 mmol), sodium ie f-butoxide (40 mg; 0.42 mmol) and chloro(2-dicyclohexylphosphino-2', 4', 6'-tri-isopropyl-1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-i-butyl ether adduct (9 mg; 0.01 mmol) are added and the reaction mixture is stirred at 75 C for 2 h. The solvents are evaporated under reduced pressure and the crude material is purified using reversed phase chromatography (method: prep. HPLC1 ) to afford I-029. Yield: 48 % (27 mg; 0.08 mmol) HPLC-MS: (M+H)+ = 362; tRet = 0.96 min; method LCMSBAS1To a solution of 2-bromo-N-[1-(1 H-indol-3-ylmethyl)pentyl]thiazole-5- carboxamide (0.25 g, 0.61 mmol) and 5, 6, 7, 8-tetrahydroimidazo[1 , 2-a]pyrazine (0.09 g, 0.74 mmol) in dioxane (5 ml_), NaOtBu (0.09 g, 0.92 mmol) and RuPhos (0.06 g, 0.12 mmol) were added. The reaction mixture was purged with argon for 20 min followed by addition of Pd2(dba)3 (0.06 g, 0.06 mmol). The reaction mixture was heated at 1 10C for 6h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with H20 (70 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was separated, washed with brine (75 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude residue obtained was purified by column chromatography (silica, 230-400 mesh, 0 to 6% MeOH in DCM) and preparative HPLC to afford 2-(6, 8-dihydro-5H-imidazo[1 , 2-a]pyrazin-7-yl)-N-[1- (1 H-indol-3-ylmethyl)pentyl]thiazole-5-carboxamide (0.06 g, 19%) as an off- white solid. HPLC Purity: 98.7% MS (ESI) m/e [M+H]+/Rt %: 449.00/2.24/99.2% 1H NMR (400 MHz, DMSO-d6) delta 0.81 (t, J=6.85 Hz, 3H) 1.16 - 1.30 (m, 4H) 1.47 - 1.62 (m, 2H) 2.78-2.94 (m, 2H) 3.92-3.98 (m, 2H) 4.04-4.14 (m, 3H) 4.66 (s, 2H) 6.91 (s, 1 H) 6.95 (d, J=7.34 Hz, 1 H) 7.03 (t, J=7.58 Hz, 1 H) 7.09 (brs, 1 H) 7.14 (s, 1 H) 7.30 (d, J=7.83 Hz, 1 H) 7.56 (d, J=7.83 Hz, 1 H) 7.86 (s, 1 H) 8.01 (d, J=8.31 Hz, 1 H) 10.74 (brs, 1 H).(1855) [00533] To a solution of 2-(4-bromophenethyl)isoindoline-l, 3-dione (prepared according to the procedure described in Francis et al : Journal of Medicinal Chemistry (1991), 34(8), 2570- 2579; 0.2 M in anhydrous 1, 4-dioxane; 150 muEpsilon, 30 mumol), was added 5, 6, 7, 8- tetrah droimidazo[ 1 , 2- Jpyrazine (0, 2 M in anhydrous 1 , 4-dioxane; 180 muTau, 36 muetaiotaomicron), RuPhos solution (0.02 M in anhydrous 1, 4-dioxane/EtOAc; 75 uL, 1.5 mumo), RuPhos-Pd 2nd generation catalyst (0, 02 M in anhydrous 1, 4-dioxane, 75 mu., 1 , 5 muetaiotaomicron) and sodium fert-butoxide (2 M in THF; 150 mu^, 300 muthetaIota). The resulting mixture was heated at 100 C overnight. The reaction mixture was cooled to RT and used directly in Step 2 without further workup or i solation.

Molecular Weight:123.16
XLogP3:-0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:123.079647300
Monoisotopic Mass:123.079647300
Topological Polar Surface Area:29.8
Heavy Atom Count:9
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes