2-AMINOISOPHTHALIC ACID

Preparation of a dry reaction vial under nitrogen was added (S)-2-(2-((3bS.4aR)-3- (1633) (difluoromethyl)-5, 5-difluoro-3b, 4, 4a, 5-tetrahydro-lH-cyclopropa[3, 4]cyclopenta[l, 2- c]pyrazol-l-yl)acetamido)-3-(3, 5-difluorophenyl)propanoic acid (68.7 mg, 0.154 mmol) (Int MS301b), 2-aiTiinoisophthalic acid (28.7 mg, 0.158 mmol) and anhydrous Pyridine (1 mL). The reaction was flushed with argon, treated with diphenyl phosphite (105 mu, 0.543 mmol) and heated at 75-80 C for 140 min. The reaction was treated with N-(7-amino-4- chloro-1 -methyl- lH-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (Int 17d, 62 mg, 0.157 mmol), heated at 70-75 C for 18 h, and the solvent was removed under a gentle stream of nitrogen. The residue was dissolved in dichloromethane and one half of the solution (75 mg, 0.077 mmol) was evaporated to dryness. The residue was dissolved in distilled THF (2 mL), treated with l-hydroxy-7-azabenzotriazole (15 mg, 0.110 mmol), EDC (40 mg, 0.209 mmol) ammonia, 2 M in i-PrOH (30 mu, 0.06 mmol) and the reaction was allowed to stir at room temp for 18 h. The reaction was treated with additional ammonia, 2 M in i-PrOH (100 mu, 0.2 mmol) and allowed to stir at room temp for 18h. The solvent was removed under a gentle stream of nitrogen while warming at 60 C, the residue was dissolved in dichloromethane (1.5 mL) and treated with TFA (3 mL), followed by triflic acid (160 mu, 1.802 mmol) and the reaction was allowed to stand at room temp for 90 min. The volatiles were removed under a gentle stream of nitrogen and the residue was partitioned with ethyl acetate vs aqueous NaHC03. The organic layer was washed with brine, dried sodium sulfate, evaporated and the crude residue was dissolved in DMF (1 mL) and the crude material was purified via preparative LC/MS to afford two elutes. (1634) Example 105: First eluting peak, 5.0 mg. LC/MS mlz = 848.1 (M+H)+. Column: (1635) Waters XBridge CI 8, 2.1 mm x 50 mm, 1.7 muetaiota particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 (1636) acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Retention Time: 1.82 min. (1637) Example 106: Second eluting peak, 6.2 mg. LC/MS m/z = 848.0 (M+H)+. (1638) Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 muetaiota particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 (1639) acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Retention Time: 1.87 min.

Molecular Weight:181.15
XLogP3:0.8
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:181.03750770
Monoisotopic Mass:181.03750770
Topological Polar Surface Area:101
Heavy Atom Count:13
Complexity:206
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes