Momelotinib

Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50 of 11 nM/18 nM, ~10-fold selectivity versus JAK3. Phase 3.

Momelotinib is a benzamide obtained by formal condensation of the carboxy group of 4-{2-[4-(morpholin-4-yl)anilino]pyrimidin-4-yl}benzoic acid with the primary amino group of aminoacetonitrile. It is an ATP-competitive JAK1/JAK2 inhibitor with IC50 of 11 nM and 18 nM, respectively. Used for the treatment of patients with intermediate- or high-risk myelofibrosis. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an antineoplastic agent, an anti-anaemic agent and an apoptosis inducer. It is an aminopyrimidine, a member of morpholines, a secondary amino compound, a tertiary amino compound, a member of benzamides and a nitrile.|Momelotinib has been used in trials studying the treatment of Polycythemia Vera, Primary Myelofibrosis, Post-Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis (PMF), among others.|Momelotinib is an orally bioavailable small-molecule inhibitor of Janus kinases 1 and 2 (JAK1/2) with potential antineoplastic activity. JAK1/2 inhibitor CYT387 competes with JAK1/2 for ATP binding, which may result in inhibition of JAK1/2 activation, inhibition of the JAK-STAT signaling pathway, and so the induction of apoptosis and a reduction of tumor cell proliferation in JAK1/2-expressing tumor cells. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity and is often dysregulated in a variety of tumor cell types.

Et3N (4.1 mL, 30 mmol) was added to a mixture of compound 6(1.88 g, 5.0 mmol) in DMF (20 mL). Then aminoacetonitrile hydrochloride (0.93 g, 10 mmol) was added followed by N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol). The mixture was stirred overnight at room temperature. After removing the solvents under reduced pressure, the residue was dissolved in CH2Cl2 (100 mL) and washed with NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on 200–300 mesh silica with EtOAc to afford momelotinib as: Yellow solid; yield 1.86 g (90percent); m.p. 232–234 °C (lit.14 238–243 °C); IR: 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232 cm–1. Anal. calcd for C23H22N6O2: C, 66.65; H, 5.35; N, 20.28; found: C, 66.78; H, 5.49; N, 20.39percent. ESI-MS: 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M – H]–; 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74–3.77 (m, 4H), 3.04–3.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6): δ 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.To 2g (5.3mmol) C4 was added 4.42 ml (32mmol) triethylamine, 0.98g (10.6mmol) aminoacetonitrile hydrochloride, 1.22g (6.6mmol) EDCI, and 860 ml (6.6mmol) HOBT. It was dissolved in 20mL DMF. After reacting at room temperature overnight, concentrate to dry, by adding dichloromethane, with saturated sodium bicarbonate solution, salt water after washing, concentrating, methanol used for recrystallization to obtain the yellow solid, yield 90percent.To a suspension of 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid (theoretically 32.59 g, 86.6 mmol) in DMF (400 mL) was added triethylamine (72.4 mL, 519.6 mmol, 6 eq.) The mixture was sonicated to ensure dissolution. Aminoacetonitrile hydrochloride (16.02 g, 173.2 mmol) was added followed by iV-hydroxybenzotriazole (anhydrous, 14.04 g, 103.8 mmol) and l-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (19.92 g, 103.8 mmol). The suspension was stirred vigorously overnight. The solvent was evaporated under reduced pressure, the residue was diluted with 5percent sodium bicarbonate (400 mL) and water (300 mL), giving a yellow solid, which was broken up and filtered. The solids were washed several times with 100 mL portions of water, triturated with hot methanol/dichloromethane (500 mL, 1:1), concentrated to a volume of approximately 300 mL), cooled and filtered. The solids were washed with cold methanol (3 x 100 mL), ether (200 mL) and hexane (200 mL) prior to drying to afford Compound 3 (31.69 g, 88percent). M.p. 238-243°C. Microanalysis: Found C, 66.52; H, 5.41 ; N, 20.21. C4-(2-(4-(morpholino)phenylamino) pyrimidin-4-yl) benzoic acid (0.500 g, 1.328 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.305 g, 1.594 mmol), 1-hydroxy-phenylpropyl triazole (0.215 g, 1.594 mmol), triethylamine (0.805 g, 7.968 mmol) and N, N-dimethylformamide (5 mL) were added to a flask under nitrogen protection. 2-amino-acetonitrile hydrochloride (0.368 g, 3.985 mmol) was added under stirring, and reacted for 20h under room temperature. Purified water (5mL) and saturated bicarbonate solution (5mL) were added to the reaction mixture, and there was yellow solid precipitated. After stirred for 30 mins, it was filtered and washed by clear water. The crude product was obtained after drying, and was separated and purified by preparative chromatography to obtain yellow solid desired product (0.130 g, PLC purity: 98.3percent, yield: 24percent); MS Calcd.: 414; MS Found: 415 (M+H)A stirred mixture of 1-(4-morpholinophenyl)guanidine (12) (6.8 g, 0.031 mol) andN-(cyanomethyl)-4-(3-(dimethylamino)acryloyl)benzamide (18) (8.0 g, 0.031 mol) in MeCN (50 mL)was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and the resultingsolid was collected by suction filtration, dried at 45 C for 4 h to give the crude product 1 (11.7 g, 91percent), which was stirred and heated with 1:2 (v/v) EtOH/EtOAc (30 mL) to reflux for 1 h then cooled to roomtemperature overnight, the resulting solid was filtered and washed with 1:2 (v/v) EtOH/EtOAc (10 mL ×2), dried at 45 °C for 5 h to afford 1 (9.9 g, 77percent) as an off-white solid; mp 240.5 °C. A stirred mixture of 1-(4-morpholinophenyl)guanidine (12) (6.8 g, 0.031 mol) andN-(cyanomethyl)-4-(3-(dimethylamino)acryloyl)benzamide (18) (8.0 g, 0.031 mol) in MeCN (50 mL)was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and the resultingsolid was collected by suction filtration, dried at 45 C for 4 h to give the crude product 1 (11.7 g, 91%), which was stirred and heated with 1:2 (v/v) EtOH/EtOAc (30 mL) to reflux for 1 h then cooled to roomtemperature overnight, the resulting solid was filtered and washed with 1:2 (v/v) EtOH/EtOAc (10 mL ×2), dried at 45 C for 5 h to afford 1 (9.9 g, 77%) as an off-white solid; mp 240.5 C. 1H NMR (400 MHz, DMSO-d6): delta 3.06 (t, 4H), 3.75 (t, 4H), 4.36 (d, J = 5.3 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 5.1Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 8.27 (d, J = 8.3 Hz, 2H), 8.54 (d, J = 5.1 Hz, 1H), 9.34 (t, J = 5.6 Hz, 1H), 9.48 (s, 1H).N-(cyanomethyl)-4-(3-(dimethylamino)acryloyl)benzamide (0.14 g, 0.5 mmol) and 1-(4-morpholinophenyl)guanidine (0.12 g, 0.5 mmol) was placed in a 50 mL eggplant-shaped flask. At room temperature, 10 mL of acetonitrile was added and heated to 100 C. After refluxing, the reaction was followed by thin layer chromatography (TLC). After 2 days, TLC showed the end of the reaction. After cooling the reaction mixture to room temperature, a large amount of solid was formed, which was filtered, dried and recrystallized. Momelotinib (0.16 g) was obtained in a yield of 76.7%.37% Hydrochloric acid (3.3 mL, 0.04 mol) was added to asuspension of 1 (8.28 g, 0.02 mol) in methyl t-butyl ether (MTBE) (60 mL) and the mixture was stirred atroom temperature for 1 h. The resulting solid was collected by suction filtration, washed with MTBE (20mL × 2), and dried at 45 C for 4 h to give 19 (8.8 g, 91%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 3.49 (s, 4H), 4.03 (s, 4H), 4.36 (d, J = 5.4 Hz, 2H), 7.55 (d, J = 5.2 Hz, 1H), 7.65 (s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 8.30 (d, J = 8.5 Hz, 2H), 8.64 (d, J = 5.2 Hz, 1H), 9.46(t, J = 5.4 Hz, 1H), 10.00 (s, 1H). 13C NMR (100 MHz, DMSO-d6): delta 28.3, 49.8, 66.7, 108.1, 116.1, 118.0, 120.9, 127.4, 128.4, 133.3, 135.0, 140.5, 146.8, 159.7, 160.9, 163.0, 166.7. MS (ESI): m/z = 415.2 [M +H]+.HPLC Conditions: Column: Acclaim C18 (150 mm × 2.1 mm × 5 mum); Detection: 220 nm; Flow rate: 0.8mL/min; Temperature: 30 C; Injection load: 1 muL; Solvent: MeOH; Concentration: 0.2 mg/mL; Run time:15 min; Mobile phase: MeOH/H2O = 80/20, tR: 3.787 min, purity: 99.16%.

Molecular Weight:414.5
XLogP3:2.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:414.18042397
Monoisotopic Mass:414.18042397
Topological Polar Surface Area:103
Heavy Atom Count:31
Complexity:615
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes