3-(2-Amino-5-benzoxazolyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Sapanisertib (INK-128) is a ATP-dependent mTOR1/2 inhibitor with an IC50 of 1 nM for mTOR kinase.

5-(4-amino-1-propan-2-yl-3-pyrazolo[3,4-d]pyrimidinyl)-1,3-benzoxazol-2-amine is a benzoxazole.|Sapanisertib has been used in trials studying the treatment of HCC, Solid Tumor, Gliosarcoma, Liver Cancer, and Glioblastoma, among others.|Sapanisertib is an orally bioavailable inhibitor of raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2) with potential antineoplastic activity. Sapanisertib binds to and inhibits both TORC1 and TORC2 complexes of mTOR, which may result in tumor cell apoptosis and a decrease in tumor cell proliferation. TORC1 and 2 are upregulated in some tumors and play an important role in the PI3K/Akt/mTOR signaling pathway, which is frequently dysregulated in human cancers.

3-Bromo-1-isopropyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (2) (20 g, 78.1 mmol) and 5-( 4, 4, 5, 5-15 tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo [d]oxazol-2-amine (5) (26.4 g, 102 mmol, l.3 eq) were dissolved in amixture of 1, 4-dioxane and water (300 mL/100 mL). To this mixture Pd(PPh3) 4 (7.21 g, 6.25 mmol, 0.08 eq) andsodium carbonate (41.4 g, 391 mmol, 5 eq) were added sequentially. The resulting mixture was degassed andback-filled with argon three times and then refluxed at 110°C for 3 h with stirring. The mixture was allowed tocool to room temperature, filtered and the cake was washed with ethyl acetate (50 mL x 2). The combined20 filtrate was concentrated in vacuo. The residue was suspended in a mixture of water and ethyl acetate (500mL/100 mL) and stirred for 30 min. The solid was collected by filtration, rinsed with water (50 mL) and ethylacetate (100 mL). The crude product thus obtained was suspended in ethyl acetate (100 mL) and stirred for 30min. The solid was collected by filtration, rinsed with ethyl acetate (50 mL), and dried in vacuo to afford thecrude product of Formula I(20 g, 83percent yield). The above obtained product (20 g) was dissolved in refluxing25 methanol (1600 mL), and activated charcoal (6 g, 30percent W/W) was added. The mixture was refluxed for 30 min, and then the hot mixture was filtered through a Buchner funnel. The cake was washed with hot methanol (1 00mL x 3). The combined filtrates were concentrated. The solid was slurried in ethyl acetate (300 mL), and thesuspension was stirred at room temperature for 30 min. The solid was collected by filtration, washed with ethylacetate (50 mL x 2), and dried in vacuo to afford the desired product of Formula I as polymorph Form A30 (16.27g, 67.3percent yield). m.p.: 273.67 oc (Onset Temperature); 1H NMR (400 MHz, DMSO-d6): i5 8.26 (s, 1H, pyrimidine), 7.56 (s, 2H, oxazol-2-amine), 7.48 (d, J = 8.1 Hz, 1H, Ph), 7.45 (d, J = 1.4 Hz, 1H, Ph), 7.27 (del, J= 8.1, 1.6 Hz, 1H, Ph), 5.08 (m, 1H, iPr) and 1.52 (d, J = 6.7 Hz, 6H, iPr); 13C NMR (100 MHz, DMSO-d6): i5163.4, 158.1, 155.4, 153.2, 148.3, 144.4, 143.7, 128.8, 120.5, 115.0, 108.8, 97.5, 48.0 and 21.8; analysis(percentcalcd, percent found for C15H15N70): C (58.24, 58.04), H (4.87, 4.83), N (31.70, 31.49); greater than 99percent purity35 based on LC-MS analysis.

3-(2-Amino-5-benzoxazolyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. TORC1/2 inhibitors are mechanistically distinct from rapamycinand offer a compelling approach to the treatment of cancer by targeting translational control, cell metabolism, growth andangiogenesis.

Molecular Weight:309.33
XLogP3:1.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:2
Exact Mass:309.13380813
Monoisotopic Mass:309.13380813
Topological Polar Surface Area:122
Heavy Atom Count:23
Complexity:436
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes