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EGF 816 , Nazartinib

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EGF 816, Nazartinib

EGF-816; EGFRmut-TKI EGF816

Novartis Ag innovator

(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide

NCI-H1975 (L858R/T790M): 25 nM
H3255 (L858R): 9 nM
HCC827 (Del ex19): 11 nM

M.Wt 495.02
Formula C26H31ClN6O2
CAS No 1508250-71-2

EGF816 is a novel covalent inhibitor of mutant-selective EGFR; overcomes T790M-mediated resistance in NSCLC.

Epidermal growth factor receptor antagonists; Protein tyrosine kinase inhibitors

  • Phase IINon-small cell lung cancer
  • Phase I/IISolid tumours
    • 01 Feb 2015Phase-II clinical trials in Non-small cell lung cancer (Late-stage disease, Combination therapy) in Singapore (PO) (NCT02323126)
    • 24 Nov 2014Phase-I/II clinical trials in Non-small cell lung cancer (Combination therapy, Late-stage disease) in Spain (PO) after November 2014 (EudraCT2014-000726-37)
    • 24 Nov 2014Phase-I/II clinical trials in Non-small cell lung cancer (Combination therapy, Late-stage disease) in Germany (PO)
Determine MTD, or recommended phase II dose in patients with NSCLC harboring EGFR mutations, in combination with INC280 Recruiting
Phase I/II (NCT02335944)
Determine MTD, or recommended phase II dose in adult patients with EGFRm+ solid malignancies Recruiting
Phase I/II (NCT02108964)
Determine efficacy and safety in patients with previously treated NSCLC, in combination with nivolumab Recruiting
Phase II (NCT02323126)

In November 2015, FDA approved osimertinib (Tagrisso™) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR TKI therapy. Based on the clinical performance of the third generation EGFR drugs, more regulatory approvals can be expected.

Nazartinib, also known as EGF816, is an orally available, irreversible, third-generation, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. EGF816 covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors

PATENT

WO 2016016822

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016822

PATENT

WO 2015081463

http://www.google.co.in/patents/WO2015081463A1?cl=en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015085482&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Intermediate 26

1055 (R)-tert-butyl 3-(2-amino-7-chloro- 1 H-benzo[dlimidazol- 1 -yOazepane- 1 -carboxylate

Step A: (R)-tert-butyl 3 -((2-chloro-6-nitrophenyl)amino)azepane-l -carboxylate (I-26a) was prepared following procedures analogous to 1-15, Step A, using the appropriate starting materials. JH-NMR (400MHz, CDC13): d 8.00-7.91 (m, 1H), 7.58-7.49 (m, 1H), 7.02-6.51

1060 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for Ci7H25ClN304 (M+H+) 370.15, found 370.10.

Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH (22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na2C03 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined

1065 organic phase was washed with brine, dried with Na2S04 and concentrated in vacuo to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l -carboxylate (I-26b). MS calculated for Ci7H27ClN302 (M+H+) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following

1070 procedures analogous to 1-15, Step C. 1H-NMR (400MHz, CDC13): d Ί .34-126 (m, 1H),

7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10-4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82-1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for C18H26CIN4O2 (M+H+) 365.17,

1075 found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzo[dlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

Intermediate 27

Step A

1080 Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH2CI2 (120 ml) was treated at room temperature with NEt3 (4.1 mL, 29.4 mmol). The

reaction was stirred for 1 hour before it was slowly added into a CH2CI2 solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt3 (4.1 mL, 29.4 mmol) was added and 1085 the mixture stirred for 2 h. The mixture was then diluted with CH2CI2 (240 mL), washed with H20 (2 x 80 mL), saturated aqueous NaHC03 solution (70 mL), and brine (70 mL). The organic phase was dried with Na2SC>4, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford

(R)-tert-butyl

1090 3-(7-chloro-2-(2-methylisonicotinamido)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. 1H-NMR (400MHz, CDC13): d 12.81 (br s, 1H), 8.65-8.62 (m, 1H), 7.95-7.85 (m, 2H), 7.27-7.1 1 (m, 3H), 5.64 – 5.51 (m, 1H), 4.56-4.44 (m, 1H),

4.07-3.92 (m, 1H), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, 1H), 2.71-2.59 (m, 1H), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, 1H), 1.51-1.45 (m, 1H), 1.50 (s,

1095 3.5H), 1.41 (s, 5.5H); MS calculated for C25H3iClN503 (M+H+) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HC1 in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound (Intermediate 27). The product was used in the next step without further purification. A sample was treated

1 100 with 1M NaOH, extracted with EtOAc, dried with Na2SC>4 and concentrated under reduced pressure to afford 1-27 as a free base. 1H-NMR (400MHz, CD3CN): d 8.49 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.50 (br d, J=7.52 Hz, 1H), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, 1H), 3.77 (dd, J = 6.54, 14.3 Hz, 1H), 3.18 (dd, J = 5.3, 14.3 Hz, 1H), 3.05 – 2.98 (m, 1H), 2.76-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.47 (s, 3H), 2.10-2.03 (m, 1H),

1 105 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for

C2oH23ClN50 (M+H+) 384.15, found 384.20.

(i?.E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[dlimidazol-2

-yl)-2-methylisonicotinamide

1 1 10

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 1 1 15 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under

reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na2S04, and concentrated under reduced pressure. The crude was purified by

1 120 column chromatography (9: 1 :0.175N CH2Cl2/MeOH/NH3 in CH2C12, 0% to 100%) to afford the title compound. JH NM (400 MHz, DMSO-d6) δ 8.59 (d, J= 4.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30-7.22 (m, 2H), 6.71-6.65 (m, 1H), 6.57-6.54 (m, 1H), 5.54 (br. s, 1H), 4.54 (br. s, 1H), 4.20 (br s, 1H), 3.95 (br s, 1H), 3.48 (br s, 1H), 2.98 (br s, 2H), 2.72 (d, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, J =

1 125 6.7 Hz, 3H), 1.88 (br s, 1H), 1.46 (d, J=l 1.3 Hz, 1H); MS calculated for C26H32C1N602

(M+H+) 495.22, found 495.10. Melting point (1 14.6 °C).

 

WO 2015083059

https://www.google.com/patents/WO2015083059A1?cl=en

 

Intermediate 26

(RVtert-butyl 3-(2-amino-7-chloro-lH-benzo[dlimidazol-l-vf)azepane-l-carboxylate

Step A: (R)-tert- butyl 3-((2-chloro-6-nitrophenyl)amino)azepane-l-carboxylate (I-26a) was prepared following procedures analogous to 1-15, Step A, using the appropriate starting materials. 1H-NMR (400MHz, CDC13): d 8.00-7.91 (m, 1H), 7.58-7.49 (m, 1H), 7.02-6.51 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for Ci7H25ClN304 (M+H+) 370.15, found 370.10.

Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH

(22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na2CC>3 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined organic phase was washed with brine, dried with Na2S04 and concentrated in vacuum to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l-carboxylate (I-26b). MS calculated for C17H27CIN3O2 (M+H+) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following procedures analogous to 1-15, Step C. ‘H-NMR (400MHZ, CDCI3): d 7.34-7.26 (m, 1H), 7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10-4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82-1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for Ci8H26ClN402(M+H+) 365.17, found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzo[dlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

5-26 step A l~27a intermediate 27

Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH2C12 (120 ml) was treated at room temperature with NEt3 (4.1 mL, 29.4 mmol). The reaction was stirred for 1 hour before it was slowly added into a CH2C12solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt3 (4.1 mL, 29.4 mmol) was added and the mixture stirred for 2 h. The mixture was then diluted with CH2C12 (240 mL), washed with H20 (2 x 80 mL), saturated aqueous NaHCC solution (70 mL), and brine (70 mL). The organic phase was dried with Na2S04, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford

(R)-tert-butyl

3-(7-chloro-2-(2-methylisonicotinamido)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. 1H-NMR (400MHz, CDCI3): d 12.81 (br s, 1H), 8.65-8.62 (m, 1H), 7.95-7.85 (m, 2H), 7.27-7.11 (m, 3H), 5.64 – 5.51 (m, 1H), 4.56-4.44 (m, 1H),

4.07-3.92 (m, 1H), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, 1H), 2.71-2.59 (m, 1H), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, 1H), 1.51-1.45 (m, 1H), 1.50 (s, 3.5H), 1.41 (s, 5.5H); MS calculated for C25H3iClN503 (M+H+) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HCI in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound (Intermediate 27). The product was used in the next step without further purification. A sample was treated with 1M NaOH, extracted with EtOAc, dried with Na2S04 and concentrated under reduced pressure to afford 1-27 as a free base. ‘H-NMR (400MHZ, CD3CN): d 8.49 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.50 (br d, J=7.52 Hz, 1H), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, 1H), 3.77 (dd, J = 6.54, 14.3 Hz, 1H), 3.18 (dd, J = 5.3, 14.3 Hz, 1H), 3.05 -2.98 (m, 1H), 2.76-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.47 (s, 3H), 2.10-2.03 (m, 1H), 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for

C20H23CIN5O (M+H+) 384.15, found 384.20.

(i?,£,)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[dlimidazol-2

-νΠ-2-methylisonicotinamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na2S04, and concentrated under reduced pressure. The crude was purified by column chromatography (9: 1 :0.175N CH2Cl2/MeOH/NH3 in CH2C12, 0% to 100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30-7.22 (m, 2H), 6.71-6.65 (m, 1H), 6.57-6.54 (m, 1H), 5.54 (br. s, 1H), 4.54 (br. s, 1H), 4.20 (br s, 1H), 3.95 (br s, 1H), 3.48 (br s, 1H), 2.98 (br s, 2H), 2.72 (d, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, J = 6.7 Hz, 3H), 1.88 (br s, 1H), 1.46 (d, J=11.3 Hz, 1H); MS calculated for C26H32C1N602 (M+H+) 495.22, found 495.10. Melting point (114.6 °C).

 

PATENT

WO 2015112705

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015112705

 

PATENT

WO 2013184757

https://www.google.com/patents/WO2013184757A1?cl=en

Intermediate 26

(R)-tert-butyl 3 -(2-amino-7-chloro- 1 H-benzo Tdlimidazol- 1 – vDazepane- 1 – carboxylate

Figure imgf000092_0003

Intermediate 26

Step A: (R)-tert-butyl 3-((2-chloro-6-nitrophenyl)amino)azepane-l-carboxylate (I- 26a) was prepared following procedures analogous to 1-15, Step A, using the appropriate starting materials. 1 H-NMR (400MHz, CDC13): d 8.00-7.91 (m, 1H), 7.58-7.49 (m, 1H), 7.02-6.51 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for C17H25CIN3O4 (M+H+) 370.15, found 370.10. Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH (22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na2CC>3 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined organic phase was washed with brine, dried with Na2S04 and concentrated in vacuo to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l-carboxylate (I-26b). MS calculated for Ci7H27ClN302 (M+H+) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following procedures analogous to 1-15, Step C. ]H-NMR (400MHz, CDC13): d 7. ,34-7.26 (m, 1H), 7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10- 4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82- 1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for Ci8H26ClN402 (M+H+) 365.17, found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzordlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

Figure imgf000093_0001

l-27a Intermediate 27

Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza- 1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH2C12 (120 ml) was treated at room temperature with NEt3 (4.1 mL, 29.4 mmol). The reaction was stirred for 1 hour before it was slowly added into a CH2C12 solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt3 (4.1 mL, 29.4 mmol) was added and the mixture stirred for 2 h. The mixture was then diluted with CH2C12 (240 mL), washed with H20 (2 x 80 mL), saturated aqueous NaHC03 solution (70 mL), and brine (70 mL). The organic phase was dried with Na2S04, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford (R)-tert-butyl 3-(7-chloro-2-(2-methylisonicotinamido)- lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. ]H- NMR (400MHz, CDC13): d 12.81 (br s, IH), 8.65-8.62 (m, IH), 7.95-7.85 (m, 2H), 7.27- 7.11 (m, 3H), 5.64 – 5.51 (m, IH), 4.56-4.44 (m, IH), 4.07-3.92 (m, IH), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, IH), 2.71-2.59 (m, IH), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, IH), 1.51-1.45 (m, IH), 1.50 (s, 3.5H), 1.41 (s, 5.5H); MS calculated for C25H31CIN5O3 (M+H+) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HCl in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound

(Intermediate 27). The product was used in the next step without further purification. A sample was treated with 1M NaOH, extracted with EtOAc, dried with Na2S04 and concentrated under reduced pressure to afford 1-27 as a free base. ]H-NMR (400MHz, CD3CN): d 8.49 (d, J=5.0 Hz, IH), 7.81 (s, IH), 7.72 (d, J=4.8 Hz, IH), 7.50 (br d, J=7.52 Hz, IH), 7.16 – 7.09 (m, 2H), 5.66-5.59 (m, IH), 3.77 (dd, J = 6.54, 14.3 Hz, IH), 3.18 (dd, J = 5.3, 14.3 Hz, IH), 3.05 – 2.98 (m, IH), 2.76-2.69 (m, IH), 2.63-2.53 (m, IH), 2.47 (s, 3H), 2.10-2.03 (m, IH), 1.96-1.93 (m, 2H), 1.86 – 1.75 (m, 2H), 1.61 – 1.54 (m, 2H); MS calculated for C20H23CIN5O (M+H+) 384.15, found 384.20.

Example 5

(/?,£,)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)- lH- benzordlimidazol-2-yl)-2-methylisonicotinamide

Figure imgf000126_0001

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na2SC>4, and concentrated under reduced pressure. The crude was purified by column chromatography (9: 1 :0.175N CH2Cl2/MeOH/NH3 in CH2C12, 0% to 100%) to afford the title compound (Example 5). ]H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.8 Hz, IH), 7.89 (s, IH), 7.79 (d, J = 4.8 Hz, IH), 7.60 (d, / = 7.5 Hz, IH), 7.30-7.22 (m, 2H), 6.71-6.65 (m, IH), 6.57-6.54 (m, IH), 5.54 (br. s, IH), 4.54 (br. s, IH), 4.20 (br s, IH), 3.95 (br s, IH), 3.48 (br s, IH), 2.98 (br s, 2H), 2.72 (d, / = 12.0 Hz, IH), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, / = 6.7 Hz, 3H), 1.88 (br s, IH), 1.46 (d, 7=11.3 Hz, IH); MS calculated for C26H32CIN6O2 (M+H+) 495.22, found 495.10. Melting point (114.6 °C).

(/?,E)-N-(7-chloro- l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH- benzo[d]imidazol-2-yl)-2-methylisonicotinamide (1.0 g) was dissolved in acetone (30 mL) by heating to 55°C to form a solution. Methanesulfonic acid (325 μί) was added to acetone (50 mL), and the methanesulfonic acid/acetone (22.2 mL) was added to the solution at 0.05ml/min. Following precipitation, the resulting suspension was cooled to room temperature at 0.5 °C/min, and crystals were collected by filtration, and dried for 4 hours at 40°C under vacuum. The collected crystals (300 mg) were suspended in acetone/H20 (6 mL; v/v=95/5) by heating to 50°C. The suspension was kept slurrying for 16 hours, and cooled to room temperature at 0.5 °C/min. The crystal was collected by filtration and dried for 4 hours at 40°C under vacuum.

The structure of (7?,£)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)- lH-benzo[d]imidazol-2-yl)-2-methylisonicotinamide mesylate was confirmed by Differential Scanning Calorimetry, X-Ray Powder Diffraction, and Elemental Analyses. Melting point (170.1 °C). Theoretical calculated: C (54.8); H (5.9); N (14.2); 0 (13.5); %S (5.4); and C1 (6.0); C:N ratio: 3.86. Found: C (52.0); H (5.8); N (13.3); C1 (5.9); C:N ratio: 3.91. Stoichiometry: 1.01.

References

AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA.

nmr http://www.medchemexpress.com/product_pdf/HY-12872/EGF816-NMR-HY-12872-17795-2015.pdf

/////EGF 816, EGF816, EGFR, Covalent inhibitor, T790M, Oncogenic mutation, Lung cancer, NSCLC, SBDD, Drug resistance, EGF-816,  EGFRmut-TKI EGF816, Nazartinib

O=C(NC1=NC2=CC=CC(Cl)=C2N1[C@H]3CN(C(/C=C/CN(C)C)=O)CCCC3)C4=CC=NC(C)=C4


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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