Tricyclic heteroaromatic inhibitors of klk5

Abstract

Disclosed are tricyclic heteroaromatic compounds of formulae (I) and (II), and pharmaceutically acceptable salts thereof, which are inhibitors of kallikrein-related peptidase 5 (KLK5). Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant KLK5 activity activity, such as Netherton Syndrome. Formulae (I) and (II)

Description

Scheme 201 Preparation of 3-(9-((4-(aminomethyl)-2,6-diisopropylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (201e) Step-1: Preparation of tert-butyl (4-amino-3,5-diisopropylbenzyl)carbamate (201b) Compound 201b was prepared according to the procedure reported in step-1 of scheme-173, from 4- amino-3,5-diisopropylbenzonitrile (201a) (0.3 g, 1.483 mmol; CAS# 153625-24-2) in MeOH (10 mL), using nickel(II) chloride.6H2O (0.264 g, 1.112 mmol), sodium borohydride (0.505 g, 13.35 mmol), di-tert-butyl dicarbonate (0.344 mL, 1.483 mmol), and diethylenetriamine (0.965 mL, 8.90 mmol) to afford after work up and purification method-AG, tert-butyl (4-amino-3,5- diisopropylbenzyl)carbamate (201b) (299 mg, 66% yield); MS (ES+): 307.3 (M+1). Step-2: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- diisopropylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (201c) Compound 201c was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (200 mg, 0.506 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (104 mg, 1.264 mmol), methanesulfonyl chloride (145 mg, 1.264 mmol), tert-butyl (4-amino-3,5-diisopropylbenzyl)carbamate (201b) (155 mg, 0.506 mmol) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- diisopropylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (201c) (187 mg, 0.248 mmol, 49.0 % yield); as a white solid; MS (ES+): 777.2 (M+Na). Step-3: Preparation of methyl 3-(9- ylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepi linate (201d) Compound 201d was prepared acc in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbo pylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepi linate (201c) (187 mg, 0.248 mmol) in DCM (5 mL) using TFA, . r 16 h at RT to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-diisopropylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxe -yl)-6-(propylcarbamoyl)picolinate (201d) (145 mg, 89% yield), which was used as such without further purification; MS (ES+): 655.3 (M+1). Step-4 eparation of 3-(9-((4-(aminomethyl)-2,6-diisopropylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (201e) Compound 201e was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)-2,6-diisopropylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6 ylcarbamoyl)picolinate (201d) (145 mg, 0.221 mmol) in THF (5 mL) using lithium hydroxidnohydrate (27.9 mg, 0.664 mmol) in water (1 mL) to afford after work up and purif method-O, 3-(9-((4-(aminomethyl)-2,6-diisopropylphenyl)carbamoyl)-4,5- dihydro enzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (201e) ( 98.9 mg, 70% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H, D2O exchangeable), 9.92 (s, 1H, D2O exchangeable), 9.29 (t, J = 6.1 Hz, 1H), 8.30 (s, 3H, D2O exchangeable), 8.20 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.24 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.35 (t, J = 5.9 Hz, 2H), 4.02 – 3.92 (m, 2H), 3.32 – 3.22 (m, 4H), 2.96 – 2.81 (m, 2H), 1.65 – 1.50 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H), 0.96 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 641.3 (M+1); (ES-): 639.2 (M-1). Scheme 202Preparation of 3-(9-((5-(aminomethyl)-6-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (202d) Step-1: Preparation of methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-6-methylpyridin-2- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (202b) Compound 202b was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (250 mg, 0.536 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (110 mg, 1.340 mmol), methanesulfonyl chloride (153 mg, 1.340 mmol), tert-butyl ((6-amino-2-methylpyridin- 3-yl)methyl)carbamate (202a) (127 mg, 0.536 mmol; CAS # 1300008-36-9) to afford after work up and purification method-AG, methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-6-methylpyridin- 2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (202b) (174 mg, 47% yield) as a white solid; MS (ES+): 686.3 (M+1). Step-2: Preparation of methyl 3-(9-((5-(aminomethyl)-6-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (202c) Compound 202c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-6-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (202b) (174 mg, 0.254 mmol) in DCM (5 mL) using TFA (195 µl, 2.54 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((5-(aminomethyl)-6-methylpyridin-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcar ol, 84 % yield), which was used as such without furthe Step-3: Preparation of 3-(9- moyl)-4,5- dihydrobenzo[b]thieno[2,3- cid (202d) Compound 202d was prepa -6 of scheme-12, from methyl 3-(9-((5-(aminomet drobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarol) in THF (5 mL) using lithium hydroxide monohydrate (26.9 mg, 0.640 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((5-(aminomethyl)-6-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (202d) (72.4 mg, 59% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H, D2O exchangeable), 9.18 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.35 (s, 3H, D2O exchangeable), 8.18 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 – 7.69 (m, 2H), 7.60 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1 96 (s, 1H), 4.37 (t, J =4.8 Hz, 2H), 4.00 (q, J = 5.8 Hz, 2H), 3.36 – 3.23 (m, 4H), 2.51 (s, 3H), 1.66 – 1.51 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 572.2 (M+1); (ES-): 570.1 (M-1). Scheme 203Preparation of 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (203e) Step-1: Preparation of tert-butyl ((6-amino-5-methylpyridin-3-yl)methyl)carbamate (203b)Compound 203b was prepared according to the procedure reported in step-1 of 6-amino-5- methylnicotinonitrile (203a) (500 mg, 3.76 mmol; CAS# 183428-91-3) in MeOH (10 mL), using nickel(II) chloride.6H2O (669 mg, 2.82 mmol), sodium borohydride (1279 mg, 33.8 mmol), di-tert- butyl dicarbonate (872 µl, 3.76 mmol), and diethylenetriamine (2444 µl, 22.53 mmol) to afford after work up and purification method-AG, tert-butyl ((6-amino-5-methylpyridin-3-yl)methyl)carbamate (203b) (643 mg, 72% yield); MS (ES+): 238.2 (M+1). Step-2: Preparation of methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-2- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203c) Compound 203c was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) ((250 mg, 0.536 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (110 mg, 1.340 mmol), methanesulfonyl chloride (153 mg, 1.340 mmol), and tert-butyl ((6-amino-5- methylpyridin-3-yl)methyl)carbamate (203b) (127 mg, 0.536 mmol) to afford after work up and purification method-AG, methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-2- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203c) (210 mg, 57% yield); MS (ES+): 686.3 (M+1). Step-3: Preparation of methyl 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203d) Compound 203d was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203c) (210 mg, 0.306 mmol) in DCM (5 mL) using TFA (236 µl, 3.06 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203d) (171 mg, 95 % yield), which was used as such without further purification; MS (ES+): 586.2 (M+1). Step-4: Preparation of 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (203e) Compound 203e was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (203d) (171 mg, 0.292 mmol) in THF (5 mL) using lithium hydroxide monohydrate (36.8 mg, 0.876 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((5-(aminomethyl)-3-methylpyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (203e) (98.6 mg, 59% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H, D2O Exchangeable), 10.64 (s, 1H, D2O exchangeable), 9.22 (t, J = 6.0 Hz, 1H, D2O exchangeable), 8.44 (s, 3H, D2Oexchangeable), 8.34 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H),7.60 (d, J = 5.2 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.37 (t, J = 5.1 Hz, 2H), 4.07 – 3.98 (m, 2H), 3.34 – 3.24 (m, 4H), 2.05 (s, 3H), 1.65 – 1.49 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 572.2 (M+1); (ES-): 570.1 (M-1). Scheme 204 Preparation of 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (204e) Step-1: Preparation of tert-butyl ((6-amino-5-chloropyridin-3-yl)methyl)carbamate (204b) Compound 204b was prepared according to the procedure reported in step-1 of 6-amino-5- chloronicotinonitrile (204a) (0.5 g, 3.26 mmol; CAS# 156361-02-3) in MeOH (10 mL), using nickel(II) chloride.6H2O (0.580 g, 2.442 mmol), sodium borohydride (1.109 g, 29.3 mmol), di-tert- butyl dicarbonate (0.756 mL, 3.26 mmol), and diethylenetriamine (2.119 mL, 19.54 mmol) to afford after work up and purification method-AG, tert-butyl ((6-amino-5-chloropyridin-3- yl)methyl)carbamate (204b) (572 mg, 68% yield); MS (ES+): 258.1 (M+1). Step-2: Preparation of methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-chloropyridin-2- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204c) Compound 204c was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (72b) (250 mg, 0.536 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (110 mg, 1.340 mmol), methanesulfonyl chloride (153 mg, 1.340 mmol), and tert-butyl ((6-amino-5- chloropyridin-3-yl)methyl)carbamate (204b) (138 mg, 0.536 mmol) to afford after work up and purification method-AG, methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-chloropyridin-2- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204c) (72 mg, 19% yield) as a white solid; MS (ES+): 706.1 (M+1). Step-3: Preparation of methyl 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204d) Compound 204d was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((5-(((tert-butoxycarbonyl)amino)methyl)-3-chloropyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204c) (72 mg, 0.102 mmol) in DCM (5 mL) using TFA (79 µl, 1.020 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204d) (45 mg, 0.074 mmol, 72.8 % yield), which was used as such without further purification; MS (ES+): 606.2 (M+1). Step-4: Preparation of 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (204e) Compound 204e was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (204d) (45 mg, 0.074 mmol) in THF (5 mL) using lithium hydroxide monohydrate (9.35 mg, 0.223 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((5-(aminomethyl)-3-chloropyridin-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (204e) (6.1 mg, 14% yield) HCl salt as a yellow solid;1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H, D2O exchangeable), 10.82 (s, 1H, D2O exchangeable), 9.22 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.44 (d, J = 2.1 Hz, 2H), 8.43 – 8.35 (m, 2H, D2O exchangeable), 8.18 (d, J = 8.0 Hz, 1H), 8.12 – 8.07 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.05 (q, J = 5.7 Hz, 2H), 3.30 – 3.22 (m, 4H), 1.65 – 1.50 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 592.1 (M+1); (ES-): 590.0 (M-1). Scheme 205Preparation of 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (205d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (205b) Compound 205b was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (250 mg, 0.536 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (110 mg, 1.340 mmol), methanesulfonyl chloride (153 mg, 1.340 mmol), tert-butyl (4-amino-3-chloro-5- methylbenzyl)carbamate (205a) (145 mg, 0.536 mmol; CAS# 911143-63-0) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (205b) (210 mg, 55% yield); as a white solid; MS (ES+): 741.1 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (205c) Compound 205c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (205b) (210 mg, 0.292 mmol) in DCM (5 mL) using TFA (225 µl, 2.92 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (205c) (178 mg, 98 % yield), which was used as such without further purification; MS (ES+): 619.2 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (205d) Compound 205d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (205c)( 178 mg, 0.287 mmol) in THF (5 mL) using lithium hydroxide monohydrate (36.2 mg, 0.862 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (205d) (30 mg, 17% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H, D2O exchangeable), 10.29 (s, 1H, D2O exchangeable), 9.21 (s, 1H, D2O exchangeable), 8.22 (s, 3H, D2O exchangeable), 8.20 – 8.13 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.37 (t, J = 5.1 Hz, 2H), 3.97 (s, 2H), 3.32 – 3.23 (m, 4H), 2.11 (s, 3H), 1.65 – 1.47 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 605.2 (M+1); (ES-): 603.1 (M-1). Scheme 206 Preparation of 3-(9-(5-(aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (206d)Step-1: Preparation of methyl 3-( yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxe nate (206b) To a mixture of methyl 3-(9-form oxepin-8-yl)-6- (propylcarbamoyl)picolinate (72minobenzonitrile (206a) (89 mg, 0.666 mmol; CAS# 17626-40-3) in THF (3 mL) was added acetic acid (38.1 µl, 0.666 mmol) and the mixture was stirred for 1 h at RT. The mixture was taken up with EtOAc and water, extracted with EtOAc, washed with brine, dried, filtered, and concentrated. The residue obtained was purified using method-B, to give methyl 3-(9-(5-cyano-1H-benzo[d]imidazol-2-yl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (206b) (200 mg, 53% yield) as a white solid; MS (ES+): 564.1 (M+1); (ES-): 562.2 (M-1). Step-2: Preparation of methyl 3-(9-(5-(aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (206c) To a solution of methyl 3-(9-(5-cyano-1H-benzo[d]imidazol-2-yl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (206b) (200 mg, 0.355 mmol) in MeOH (3 mL) was added nickel (II) chloride, 6H2O (84 mg, 0.355 mmol) and the mixture was cooled to 0 °C followed by portion wise addition of NaBH4(40.3 mg, 1.065 mmol) and stirred for ~2 hours. Then to the reaction mixture was added diethylenetriamine (293 mg, 2.84 mmol) and the mixture was stirred for 15 min followed by evaporation. Reaction mixture was diluted with EtOAc, washed with water. Combined organics were concentrated and purified using method-B to give methyl 3-(9-(5- (aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (206c) (32mg, 16% yield) as an orange solid; MS (ES+): 568.1 (M+1); (ES-): 566.2 (M-1). Step-3: Preparation of 3-(9-(5-(aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (206d) Compound 206d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-(5-(aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(propylcarbamoyl)picolinate (206c) (32mg, 0.056 mmol) in MeOH / THF (3 mL) using lithium hydroxide (2 M aqueous solution; 282 µl, 0.564 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-(5-(aminomethyl)-1H-benzo[d]imidazol-2-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (206d) (3.7mg, 6.68 µmol, 11.86 % yield) HCl salt as a yellow solid;1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H, D2O exchangeable), 9.21 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.28 (s, 3H, D2O exchangeable), 8.21 – 8.14 (m, 2H), 7.98 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 5.2 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 7.14 – 7.06 (m, 2H), 4.40 (s, 2H), 4.15 – 4.04 (m, 2H), 3.32 – 3.26 (m, 4H), 1.64 – 1.52 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 554.1 (M+1); (ES-): 552.2 (M-1).Scheme 207 O O O O O OOOSiOHO BrNK2CO3Br PdCl2(dppf)-CH2Cl2BONOND BISPIN, KOAc OH CC, DMAPTMSOTMSO O O 12a207a207b 207cO O O O O O O 207 S O B c N O O O O O S S S Br TMS N N O NH O TBAF 23, PdCl2(dppf)-CH2Cl2HN O O H O Pd (dba) N O HN O XPhos, Pcy3, K3PO4O OH NHBoc BocHN 207f147aO O O O OH O OH S S S N N LiOH O TFA HN O HN O O HN O OH OH BocHN H2N H2N 207g 207h 207iPreparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)pyridine-2,6-dicarboxylic acid (207h) Step-1: Preparation of 5-bromo-6-(methoxycarbonyl)picolinic acid (207a) A solution of dimethyl 3-bromopyridine-2,6-dicarboxylate (12a) (200 g, 729.74 mmol) in MeOH (800.0 mL) was stirred at 75 °C for 0.5 h. To this, a solution of K2CO3(100.85 g, 729.74 mmol) in H2O (400 mL) was added drop wise at 75 °C. When half of the volume of K2CO3solution was added a solid was observed in the reaction mixture, then H2O (400 mL) was added followed by adding the remaining K2CO3solution dropwise (in 0.5 h). The resulting mixture was stirred at 75 °C for 0.5 h, cooled to 55 °C, and the solid was filtered and washed with MeOH (500 mL) as Lot-I. The filtrate was diluted with MeOH (1.0 L), and the solid was filtered as a Lot-II. Both Lot-I and Lot-II solid materials were diluted with H2O (400 mL) and heated to 75 °C. When the solution was clear, it was cooled to 50 °C, and the pH was adjusted to acidic (pH~2) by using 4N HCl. The solid was filtered and dried to give 5-bromo-6-(methoxycarbonyl)picolinic acid (207a) (55.0 g, 29% yield) as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.72 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H). Step-2: Preparation of 2-methyl 6-(2-(trimethylsilyl)ethyl) 3-bromopyridine-2,6-dicarboxylate (207b)Compound 207b was prepared according to the procedure reported in step-4 of scheme-89, from 5- bromo-6-(methoxycarbonyl)picolinic acid (207a) (100 g, 384.56 mmol) in DCM (1600 mL) using 2- (trimethylsilyl)ethan-1-ol (44.32 g, 384.55mmol), DCC (79.34 g, 384.55 mmol), and DMAP (9.3 g, 76.91 mmol) and stirring for 12 h at RT to afford after workup and purification method-EJ, 2-methyl 6-(2-(trimethylsilyl)ethyl) 3-bromopyridine-2,6-dicarboxylate (207b) (80 g, 58% yield) as an oily mass;1H NMR (300 MHz, DMSO-d6) δ 8.45 (d J = 8.4 Hz 1H) 8.06 (d, J = 8.4 Hz, 1H), 4.47 – 4.35 (m, 2H), 3.94 (s, 3H), 1.16 – 1.04 ( Step-3: Preparation of 2-methyl 6-( ,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine-2,6-dicarboxylate (20Compound 207c was prepared according to the procedure reported in step-2 of scheme-48, from 2- methyl 6-(2-(trimethylsilyl)ethyl) 3-bromopyridine-2,6-dicarboxylate (207b) (79.0 g, 219.27 mmol) in 1,4-dioxane (1422 mL) using BISPIN (111.36 g, 438.54 mmol), KOAc (53.79 g, 548.18 mmol), PdCl2(dppf)-CH2Cl2(17.9 g, 21.92 mmol) and stirring at 100 °C for 12 h to afford after work up and purification method-EK, 2-methyl 6-(2-(trimethylsilyl)ethyl) 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine-2,6-dicarboxylate (207c) (42.0 g, 47% yield) as an oily mass;1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 2H), 4.53 – 4.31 (m, 2H), 3.91 (s, 3H), 1.33 (s, 12H), 1.18 – 1.13 (m, 2H), 0.06 (s, 9H); MS (ES+): 408.5 (M+1). Step-4: Preparation of 2-methyl 6-(2-(trimethylsilyl)ethyl) 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)pyridine-2,6-dicarboxylate (207d) Compound 207d was prepared according to the procedure reported in step-3 of scheme-21, from 2- methyl 6-(2-(trimethylsilyl)ethyl) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,6- dicarboxylate (207c) (3 g, 5.67 mmol) in dioxane / 2-MeTHF (75 mL; ratio 1:1) using tert-butyl (4-(8- bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)benzyl)carbamate (147a) (4.62 g, 11.33 mmol), potassium phosphate (3M) (3.78 mL, 11.33 mmol), Pd2(dba)3(0.519 g, 0.567 mmol), PdCl2(dppf)-CH2Cl2(0.463 g, 0.567 mmol), and XPhos (0.270 g, 0.567 mmol) and stirring at 100 °C for 10 h to afford after work up and purification method-AG, 2-methyl 6-(2-(trimethylsilyl)ethyl) 3- (9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)pyridine-2,6-dicarboxylate (207d) (1.7 g, 41% yield) as a clear oil; MS (ES+): 730.3 (M+1); (ES-): 728.1 (M-1); and tert-butyl (4-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxamido)benzyl)carbamate (207e) (250 mg, 10% yield) as a yellow oil; MS (ES+): 473.1 (M+Na); (ES-) 449.2 (M-1). Step-5: Preparation of 5-(9-((4 henyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]o ic acid (207f)Compound 207f was prepared according to the procedure reported in step-2 of scheme-48, from 2- methyl 6-(2-(trimethylsilyl)ethyl) 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)pyridine-2,6-dicarboxylate (207d) (1.7 g, 2.329 mmol) in THF (50 mL) using TBAF (1 M in THF) (6.99 mL, 6.99 mmol) and stirring for 4 h at RT to afford after work up and purification method-AG, 5-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (methoxycarbonyl)picolinic acid (207f) (1.1 g, 75% yield) as a clear oil; MS (ES+): 630.1 (M+1); 652.1 (M+Na); (ES-): 628.2 (M-1). Step-6: Preparation of 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)pyridine-2,6-dicarboxylic acid (207g) Compound 207g was prepared according to the procedure reported in step-6 of scheme-12, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (1.1 g, 1.747 mmol) in MeOH / THF (5 mL; ratio 1:1) using lithium hydroxide (2 M aqueous solution; 3.49 mL, 6.99 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)pyridine-2,6-dicarboxylic acid (207g) (812mg, 57% yield) as a white solid; MS (ES+): 616.1 (M+1); 638.2 (M+Na); (ES-): 614.1 (M-1). Step-7: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)pyridine-2,6-dicarboxylic acid (207h) Compound 207h was prepared according to the procedure reported in step-2 of scheme-8, from 3-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)pyridine-2,6-dicarboxylic acid (207g) (812mg, 1.319 mmol) in DCM (20 mL) using TFA (1.794 mL, 23.29 mmol) and stirring at RT for 3 h to afford after workup and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)pyridine-2,6-dicarboxylic acid (207h) (558 mg, 47% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H, D2O exchangeable), 8.26 – 8.01 (m, 4H, 3H is D2O exchangeable), 7.97 – 7.85 (m, 2H), 7.60 (d, J = 5.2 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 4.9 Hz, 2H), 4.00 – 3.88 (m, 2H), 3.28 – 3.26 (m, 2H); MS (ES+): 516.2 (M+1); (ES-): 514.1 (M-1). Scheme 210Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(phenylcarbamoyl)picolinic acid (210d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinate (210b) Compound 210b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (55mg, 0.087 mmol) in DMF (1 mL) using aniline (210a) (8.95 mg, 0.096 mmol), DIPEA (30.5 µl, 0.175 mmol), and HATU (43.2 mg, 0.114 mmol) and stirring overnight at RT to afford after work up and purification method-AG, methyl 3-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinate (210b) (46 mg, 75% yield) as a yellow oil; MS (ES+): 727.2 (M+Na); (ES-): 703.0 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinate (210c) Compound 210c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinate (210b) (46mg, 0.065 mmol) in DCM (2 mL) using TFA (75 µl, 0.979 mmol) stirring for 3 h at RT to afford after workupand purification method-AG, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinate (210c) (30 mg, 76% yield) as a yellow oil; MS (ES+): 605.1(M+1); (ES-): 603.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinic acid (210d) Compound 210d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (phenylcarbamoyl)picolinate (210c) (30 mg, 0.050 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 496 µl, 0.992 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(phenylcarbamoyl)picolinic acid (210d) (15 mg, 51% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H, D2O exchangeable), 11.01 – 10.57 (m, 2H, D2O exchangeable), 8.31 (d, J = 8.0 Hz, 1H), 8.13 (s, 2H, D2O exchangeable), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.87 – 7.79 (m, 2H), 7.65 – 7.51 (m, 3H), 7.42 (t, J = 7.9 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 4.01 – 3.86 (m, 2H), 3.31 – 3.21 (m, 2H); MS (ES+) 591.1 (M+1), (ES-) 589.2 (M-1); RT 2.018 min, 99.84%. Scheme 211Preparation of 2-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-5-((propylamino)methyl)benzoic acid (211e) Step-1: Preparation of tert-butyl 5-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (211b) Compound 211b was prepared according to the procedure reported in step-1 of scheme-26, from tert- butyl 5-formyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (211a) (5.4 g, 15.24 mmol) in anhydrous dioxane (40 mL) using BISPIN (7.74 g, 30.5 mmol), KOAc (3.74 g, 38.1 mmol), and PdCl2(dppf)- CH2Cl2(0.622 g, 0.762 mmol) and stirring at 90 °C for 5 h to afford after work up and purification method-BM, tert-butyl 5-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (211b) (5 g, 99% yield) as a clear oil;1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.28 – 8.23 (m, 1H), 8.09 (dd, J = 7.6, 1.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 1.58 (s, 9H), 1.34 (s, 12H). Step-2: Preparation of tert-butyl 2-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5-formylbenzoate (211c) Compound 211c was prepared according to the procedure reported in step-3 of scheme-21, from tert- butyl 5-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (211b) (685 mg, 2.062 mmol) in THF (10 mL) using tert-butyl (4-(8-chloro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxamido)benzyl)carbamate (148b) (500 mg, 1.031 mmol), potassium phosphate (3 M) (1375 µl,4.12 mmol), and Sphos Pd G2 (149 mg, 0.206 mmol) and stirring at 90 °C for 2 h to afford after work up and purification method-M, tert-butyl 2-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5- formylbenzoate (211c) (650 mg, 96% yield) yellow oil; MS (ES+): 655.2 (M+1); 677.1 (M+Na). Step-3: Preparation of tert-butyl 2-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5-((propylamino)methyl)benzoate (211d) To a solution of tert-butyl 2-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5-formylbenzoate (211c) (250mg, 0.382 mmol) in DCE (4 mL) propan-1-amine (22.57 mg, 0.382 mmol) and acetic acid (4.37 µl, 0.076 mmol) was added and was stirred at 50 °C for 1 h. The mixture was cooled to RT and NaBH4(14.44 mg, 0.382 mmol) was added, and the mixture was stirred for 2 h at RT. Then NH4Cl (sat.) was added and extracted with EtOAc (3x). Combined organics were washed with brine, dried, filtered, and concentrated in vacuo. The residue obtained was purified using method-M to provide tert-butyl 2-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5- ((propylamino)methyl)benzoate (211d) (61 mg, 23% yield) as a yellow oil; MS (ES+): 698.2 (M+1); (ES-): 696.3 (M-1). Step-4: Preparation of 2-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-5-((propylamino)methyl)benzoic acid (211e) Compound 211e was prepared according to the procedure reported in step-2 of scheme-8, from tert- butyl 2-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5-((propylamino)methyl)benzoate (211d) (61mg, 0.087 mmol) in DCM (4 mL) using TFA (135 µl, 1.748 mmol) and stirring at RT for 4 h to afford after workup and purification method-O, 2-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-5-((propylamino)methyl)benzoic acid (211e) (25mg, 53% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H, D2O exchangeable), 10.30 (s, 1H, D2O exchangeable), 9.26 (s, 2H, D2O exchangeable), 8.36 (s, 3H, D2O exchangeable), 8.02 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J = 7.9, 1.9 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.55 – 7.48 (m, 2H), 7.41 – 7.28 (m, 3H), 7.07 (d, J = 5.2 Hz, 1H), 6.82 (s, 1H), 4.34 (t, J = 4.9 Hz, 2H), 4.18 (t, J = 5.9 Hz, 2H), 3.92 (q, J = 5.8 Hz, 2H), 3.25 (t, J = 5.0 Hz, 2H), 2.93 – 2.77 (m, 2H), 1.73 – 1.59 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 542.2 (M+1); (ES-): 540.2 (M-1). Scheme 212Preparation of 4-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (212f) Step-1: Preparation of tert-butyl (4-(8-(2-formyl-4-hydroxyphenyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxamido)benzyl)carbamate (212b) Compound 212b was prepared according to the procedure reported in step-3 of scheme-21, from tert- butyl (4-(8-chloro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)benzyl)carbamate (148b) (500 mg, 1.031 mmol) in THF (4 mL) using 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (212a) (512 mg, 2.062 mmol), potassium phosphate (3 M) (1375 µl, 4.12 mmol), and Sphos Pd G2 (74.3 mg, 0.103 mmol) and stirring at 90 °C for 2 h to afford after work up and purification method-M, tert-butyl (4-(8-(2-formyl-4-hydroxyphenyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxamido)benzyl)carbamate (212b) (588mg, >99% yield) as a white solid; MS (ES+): 571.2 (M+1); (ES-): 569.1 (M-1). Step-2: Preparation of 4-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-3-formylphenyl trifluoromethanesulfonate (212c) Compound 212c was prepared according to the procedure reported in step-4 of schme-3, tert-butyl (4- (8-(2-formyl-4-hydroxyphenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxamido)benzyl)carbamate (212b) (588mg, 1.030 mmol) in DMF (20 mL) using 1,1,1-trifluoro- N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (736 mg, 2.061 mmol) and triethylamine (261 mg, 2.58 mmol) to afford after workup and purification using method-I, 4-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-3-) as a yellow oil; MS (ES+): 703.0 iphenyl]-4-yl)-4,5- mate (212d) in step-3 of scheme-21, from 4-(9- hydrobenzo[b]thieno[2,3- 50mg, 0.356 mmol) in THF (2g yp y g, . , potassium phosphate (3 M) (474 µl, 1.423 mmol), and Sphos Pd G2 (25.6 mg, 0.036 mmol) and stirring at 90 °C for 2 h to afford after work up and purification method-M, tert-butyl (4-(8-(3-formyl-4'-methoxy-[1,1'-biphenyl]-4-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)benzyl)carbamate (212d) (211mg, 90% yield) as a white solid; MS (ES+): 661.2 (M+1). Step-4: Preparation of 4-(9-(( ert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]o epin-8-yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (212e) Compound 212e was prepared according to the procedure reported in step-5 of schme-1, from tert- butyl (4-(8-(3-formyl-4'-methoxy-[1,1'-biphenyl]-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxamido)benzyl)carbamate (212d) (250mg, 0.378 mmol) in acetonitrile (2 mL) using tBuOH (2 mL), water (1 mL), sodium dihydrogenphosphate hydrate (78 mg, 0.568 mmol), 2-methyl-2-butene (265 mg, 3.78 mmol), and a solution of sodium chlorite (137 mg, 1.513 mmol) in water (1 mL) to afford after workup 4-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phebamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (212e) (245 mg, 96% yield) yellow oil, which was used as such for the next step; MS (ES+): 677.3 (M+1); (ES-): 675.2 (M-1). Step-5: Preparation of 4-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (212f) Compound 212f was prepared according to the procedure reported in step-2 of scheme-8, from 4-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (212e) (245mg, 0.362 mmol) in DCM (4 mL) using TFA (418 µl, 5.43 mmol) and stirring at RT for 30 min to afford after workup and purification method-O, 4-(9-((4-(aminomethyl)phenyl)ca dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic mg, 44% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.26 – 12O exchangeable), 10.24 (s,1H, D2O exchangeable), 8.27 (s, 3H, D2O exchangeable), 8.02 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.78 (dd, J = 8.0, 2.1 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.57 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.39– 7.26 (m, 3H), 7.09 – 7.00 (m, 3H), 6.88 (s, 1H), 4.35 (t, J = 5.1 Hz, 2H), 3.91 (s, 2H), 3.80 (s, 3H), 3.25 (t, J = 5.1 Hz, 2H); MS (ES+): 577.1 (M+1); (ES-): 575.2 (M-1). Scheme 213 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((2-methoxyethyl)carbamoyl)picolinic acid (213d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2-methoxyethyl)carbamoyl)picolinate (213b) Compound 213b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (55mg, 0.087 mmol) in DMF (1 mL) using 2-Methoxyethylamine (213a) ( 0.175 mmol), and HATU (43.2 mg, 0.114 mmol) and stir up and purification method- AG, methyl 3-(9-((4-(((tert-but moyl)-4,5- dihydrobenzo[b]thieno[2,3-d]o yl)picolinate (213b) (48 mg, 80% yield) as a yellow oil; MS -): 685.2 (M-1). Step-2: Preparation of methyl )-4,5- dihydrobenzo[b]thieno[2,3-d]o yl)picolinate (213c)Compound 213c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- drobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2-methoxyethyl)carbamoyl)picolinate (213b) (48mg, 0.070 mmol) in DCM (2 mL) using TFA (81 µl, 1.048 mmol) stirring for 3 h at RT to afford after workup and purification method-AG, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2-methoxyethyl)carbamoyl)picolinate (213c) (35 mg, 85% yield) as a yellow oil; MS (ES+): 587.1 (M+1); (ES-): 585.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepi Compo methyl ((2-met using li after w dihydro mg, 64 D2O ex 7.97 – (d, J = 3H), 3.-A mixture of methyl 3-(9-formyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (72a) (200 mg, 0.444 mmol), tert-butyl (4-aminobenzyl)carbamate (8a) (296 mg, 1.332 mmol), and acetic acid (203 µl, 3.55 mmol) in MeOH (20 mL) was stirred at 60 °C for 4 h. To this, NaBH3CN (418 mg, 6.66 mmol) was added and the mixture was stirred at 60 °C for 10 min. The reaction mixture was treat CO3and the organic phase was separated. Combined organics were washed w d, and concentrated. The residue obtained was purified using method-A to giv ert- butoxycarbonyl)amino)methyl)phen -dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (214a) (240 mg, 82% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 8.73 (t, J = 6.1 Hz, 1H), 8.24 – 8.09 (m, 2H), 7.73 (s, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.13 (t, J = 6.1 Hz, 1H), 7.00 (d, J = 5.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 6.78 (s, 1H), 6.40 (d, J = 8.4 Hz, 2H), 6.09 (t, J = 5.6 Hz, 1H), 4.27 (s, 2H), 4.10 – 3.79 (m, 4H), 3.69 (s, 3H), 3.34 – 3.23 (m, 2H), 3.19 (t, J = 5.2 Hz, 2H), 1.68 – 1.49 (m, 2H), 1.36 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H); MS (ES+) 657.3 (M+1). Step-2: Preparation of methyl 3-(9-(((4-(aminomethyl)phenyl)amino)methyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (214b)3- ( ( p; ,3- yl)- g l k O .49 ( ,( ( ( ( ( 1. , p g, . g p o afford after work up and purification method-AL, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenoxy)methyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (215c) (300 mg, 77% yield) as a white solid;1H NMR (300 MHz, DMSO-d6) δ 8.69 (t, J = 6.2 Hz, 1H), 8.16 – 8.05 (m, 2H), 7.84 (s, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.27 (t, J = 6.2 Hz, 1H), 7.11 – 7.00 (m, 3H), 6.85 (s, 1H), 6.77 (d, J = 8.5 Hz, 2H), 4.79 (s, 2H), 4.31 (s, 2H), 4.03 – 3.96 (m, 2H), 3.64 (s, 3H), 3.29 – 3.19 (m, 4H), 1.63 – 1.46 (m, 2H), 1.37 (s 9H), 0.87 (t, J = 7.4 Hz, 3H).; MS (ES+) 558.2 (M+2-Boc), MS (ES-): 656.8 (M-1). Step-2: Preparation of methyl 3-(9- dihydrobenzo[b]thieno[2,3-d]oxepi Compound 215d was prepared accomethyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenoxy)methyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (215c) (80 mg, 0.122 mmol) in DCM (5 mL) using TFA in at RT to afford after workup, methyl 3-(9-((4-(aminome nzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinate (): 558.2 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenoxy)methyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (215e) Compound 215e was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenoxy)methyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (215d) (64 mg, 0.115 mmol) in THF (5.00 mL) and MeOH (5 mL) using lithium hydroxide hydrate (48.2 mg, 1.148 mmol) in water (2 mL) stirring for 2 h at 60 °C to afford after work up and purification method-BV, 3-(9-((4-(aminomethyl)phenoxy)methyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (215e) (40 mg, 64% yield) HCl salt as a pale yellow solid;1H NMR (300 MHz, DMSO-d6) δ 9.13 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.29 (s, 3H, D2O exchangeable), 8.14 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.32 (dd, J = 9.1, 2.4 Hz, 2H), 7.04 (d, J = 5.2 Hz, 1H), 6.91 – 6.80 (m, 3H), 4.81 (d, J = 28.7 Hz, 2H), 4.30 (s, 2H), 3.87 (s, 2H), 3.29 – 3.15 (m, 4H), 1.61 – 1.54 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); MS (ES+): 544.2 (M+1); MS (ES-): 542.1 (M-1). Scheme 216Preparation of 3-(9-((5-cyanothiophen-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinic acid (216c) Step-1: Preparation of methyl 3-(9-((5-cyanothiophen-2-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (216b) Compound 216b was prepared according to the procedure reported in step-1 of scheme-11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (180 mg, 0.386 mmol) in DCM (20 mL) using 1-methyl-1H-imidazole (79 mg, 0.965 mmol), methanesulfonyl chloride ( g, 0.965 mmol), and 5-aminothiophene-2-carbonitrile (216a) (144 mg, 1.158 mmol; CAS # 525- 3-5) (11a) to afford after work up and purification method-BU, methyl 3-(9-((5-cyanothiophen-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)pico 216b) (0.190g, 86 % yield) as white solid;1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.58 (m, 1H), 8.19 (s, 1H), 8.06 – 7.98 (m, 2H), 7.75 (d, J = 4.3 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.06 (s, 1H), 6.94 – 6.85 (m, 1H), 4.39 (t, J = 5.0 Hz, 2H), 3.57 (s, 3H), 3.27 (d, J = 5.8 Hz, 4H), 1.57 (q, J = 7.3 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H).MS (ES+): 573.1 (M+1); (ES-): 571.1 (M-1). Step-2: Preparation of Preparation of 3-(9-((5-cyanothiophen-2-yl)carbamoyl), dihydrobenzo[b]thieno[2,3-d]oxepin-8 -(propylcarbamoyl)picolinic acid (216c)Compound 216c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((5-cyanothiophen-2-yl)car )-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (216b) (180mg, 0.314 mmol) in THF (10 mL) and MeOH (10 mL) using lithium hydroxide hydrate (132 mg, 3.14 mmol) in water (1 m afford after work up and purification method-DC, 3-(9-((5-cyanothi dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl 6 ropylcarbamoyl)pico yield) as a white solid;1H NMR (300 MMSO-d6) δ 12.82 (s, 11H D2O exchan eable) 927 (t J = 61 Hz 1H D2O exchan eable) 824 (d J = 80 Hz 1H) 804 (sPreparation of 3-(9-((5-(aminomethyl)thiophen-2-yl)carbamoyl thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)pico id (217a)Compound 217a was prepared according to the procedure repore s ep- o sc eme-206, from 3- (9-((5-cyanothiophen-2-yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (216d) (120 mg, 0.215 mmol) in MeOH (30 mL) using nickel (II) chloride, 6H2O (27.8 mg, 0.118 mmol) and the mixture was cooled to 0 °C followed by portion wise addition of NaBH4(24.38 mg, 0.644 mmol) in MeOH (1mL) and stirred for 5 min. Then to the reaction mixture, diethylenetriamine (222 mg, 2.148 mmol) was added, and the mixture was stirred for 15 min followed by evaporation Reaction mixture was diluted with EtOAc and washed withimidazole (18.94 g, 278 mmol) and TBDPS-Cl (36.1 mL, 139 mmol). The mixture was stirred at RT for 12 h to afford after work up and purification method-EL, (2-(4-bromothiophen-3-yl)ethoxy)(tert- butyl)diphenylsilane (221b) (50 g, 97% yield) as a light yellow oil;1H NMR (300 MHz, DMSO-d6) δ, (M-1). Step-5: Preparation of methyl 8-chloro-4,5-dihydrobenzo[b]thieno[3,4-d]oxepine-9-carboxylate (221f) Compound 221f was prepared according to the procedure reported in step-3 of scheme-26, from methyl 2-chloro-4-hydroxy-5-(4-(2-hydroxyethyl)thiophen-3-yl)benzoate (221e) (3.14 g, 10.04 mmol)DMSO-d6) δ 9.77 (s, 1H), 8.69 (t, J = 6.2 Hz, 1H), 8.42 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 3.2 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.48 – 7.38 (m, 1H), 6.95 (s, 1H), 4.52 – 4.32 (m, 2H), 3.63 (s, 3H), 3.33 – 3.26 (m, 2H), 3.19 – 3.06 (m, 2H), 1.64 – 1.53 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 451.1 (M+1). Step-9: Preparation of 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5- dihydrobenzo[b]thieno[3,4-d]oxepine-9-carboxylic acid (221j)y - y y y p y y , dihydrobenzo[b]thieno[3,4-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (221k) (170 mg, 0.253 mmol) in DCM (4 mL) using TFA (0.293 mL, 3.80 mmol) and stirring at RT for 48 h. The yellow oil obtained upon removal of solvent was treated with MeOH (3 mL), THF (1.5 mL), and lithium hydroxide hydrate (1M aqueous solution; 3 mL, 3.00 mmol) and stirring for 48 h at RT to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[3,4-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (221l) (106 mg, 71%Hz, 3H); MS (ES+): 707.1 (M+Na); 585.1 (M-Boc+2). Step-2: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[3,4-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (222b)carboxylic acid (221j) (200 mg, 0.429 mmol) in DCM (4 mL) using 1-methyl-1H-imidazole (85 µl, 1.072 mmol), methanesulfonyl chloride (83 µl, 1.072 mmol), and tert-butyl (4-amino-3,5- dimethylbenzyl)carbamate (172a) (322 mg, 1.286 mmol) to afford after work up and purification method-BU, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[3,4-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (223a) (220 mg, 73% yield) as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.59 (t, J = 6.2 Hz, 1H), 8.21 –mxure o me y - romo- -c oropco nae ( a) ( . g, . mmo; - - ), 4-(trifluoromethyl)-1H-pyrazole (224b) (1.605 g, 11.80 mmol; CAS # 52222-73-8), and K2CO3(3.26 g, 23.60 mmol) in DMF (5 mL) was stirred at 110 °C for 16 h. The mixture was diluted with water and extracted with MTBE. The aqueous layer was acidified with 2M HCl to pH~2 and extracted with EtOAc. Combined organics were dried, filtered, and concentrated in vacuo to provide 3-bromo-6-(4-1.36 (m, 2H), 1.24 – 1.10 (m, 2H), -0.00 (s, 9H). Step-5: Preparation of methyl 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3-(9-((2- (trimethylsilyl)ethoxy)carbonyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (224i) Compound 224i was prepared according to the procedure reported in step-1 of scheme-33, from 2- (trimethylsilyl)ethyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (224h)3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-, , Step-2: Preparation of methyl 3-bromo-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)picolinate (225c) Compound 225c was prepared according to the procedure reported in step-2 of scheme-224, from 3- bromo-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)picolinic acid (225b) (334mg, 0.994 mmol) in toluene (20 mL) and methanol (8 mL), a solution of (2-diazoethyl)trimethylsilane in hexanes (224d) (2 M, 1044 µl, 2.087 mmol) was added and mixture stirred for 2 h to afford after work up and purificationStep-6: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)picolinate (225g)Scheme 231Scheme 232mL), and a solution of (2-diazoethyl)trimethylsilane in hexanes (224d) (2 M, 1594 µl, 3.19 mmol) with stirring for 16 h to afford after work up and purification method-CA, methyl 3-bromo-6- (piperidin-1-yl)picolinate (232b) (294 mg, 65% yield) as a yellow oil; MS (ES+): 299.0, 301.0 (M+1). Step-3: Preparation of methyl 6-(piperidin-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)picolinate (232c) Compound 232c was prepared according to the procedure reported in step-1 of scheme-26 from methyl 3-bromo-6-(piperidin-1-yl)picolinate (232b) (630mg, 2.106 mmol) in anhydrous dioxane (40Compound 236c was prepared according to the procedure reported in step-6 of scheme-12, from a mixture of methyl 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(piperidin-1-yl)picolinate (236b) and methyl 3-(9-(((3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)carbonyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (piperidin-1-yl)picolinate (236d) (59 mg, 0.099 mmol) in MeOH (3 mL) and THF (3 mL) using lithium hydroxide monohydrate (41.5 mg, 0.989 mmol) in water (2 mL) and stirring at RT for 16 h toPreparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclopropylcarbamoyl)picolinic acid (237g) Step-1: Preparation of 2-methyl 6-(2-(trimethylsilyl)ethyl) 3-(9-formyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)pyridine-2,6-dicarboxylate (237a)8-yl)pyridine-2,6-dicarboxylate (237c) (3.4 g, >99% yield) as a yellow oil; MS (ES-) 742.2 (M-1). Step-4: Preparation of 5-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) Compound 237d was prepared according to the procedure reported in step-2 of scheme-48, from 2- methyl 6-(2-(trimethylsilyl)ethyl) 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)pyridine-2,6-dicarboxylate (237c) (3.4g, 4.57 mmol) in THF (50 mL) using TBAF (1M in THF) (13.71 mL, 13.71 mmol) and stirring for 4 h at RT to afford after work up and purification method-AG, 5-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (1.9 g, 65% yield) as a white solid; MS (ES+): 644.1 (M+1); MS (ES-): 642.2 (M-1).a e wo up a pu ca o e o - , - e y - - e ys y e y - - - e - butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-(cycloheptylcarbamoyl)picolinic acid (239d) (30 mg, 63% yield) HCl salt as a white solid; H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H, D2O exchangeable), 8.96 (d, J = 8.4 Hz, 1H, D2O exchangeable), 8.24 - 8.14 (m, 3H, 2H D2O exchangeable), 8.12 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.38 (t, J = 5.0 Hz, 2H),to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-((1-(methylcarbamoyl)cyclohexyl)carbamoyl)picolinate (240b) (68 mg, 68% yield) as a yellow oil; MS (ES-): 780.3 (M-1).(241b) Compound 241b was prepared according to the procedure reported in step-2 of scheme-8, fromStep-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (244c) Compound 244c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (244b) (58 mg, 0.080 mmol) in DCM (2 mL) using TFA (136 mg, 1.197 mmol) to afford after workup methyl 3-(9-((4-(t, J = 5.0 Hz, 2H), 4.24 (d, J = 5.8 Hz, 2H), 3.35 – 3.30 (m, 2H), 3.24 (t, J = 5.0 Hz, 2H), 1.64 – 1.52619.2 (M-1). Scheme 248methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-((1-(methoxycarbonyl)cyclohexyl)carbamoyl)picolinate (249b) (46 mg, 0.067 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 421 µl, 0.843 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- carboxycyclohexyl)carbamoyl)picolinic acid (249c) (31 mg, 70% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 2H, D2O exchangeable), 10.06 (s, 1H, D2O exchangeable),, , mmol) in DCM (2 mL) using TFA (160 µl, 2.072 mmol) to afford after workup, methyl 3-(9-((4- (aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (75 mg, 0.114 mmol) in DMF (4 mL) using cyclooctanamine (250a) (14.51 mg, 0.114 mmol), DIPEA (80 µl, 0.456 mmol), and HATU (56.4 mg, 0.148 mmol) and stirring overnight at RT to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-]oxepn- -y)- -(cyco epycar amoy)pco nc ac ( c)= 8.4 Hz, 1H, D2O exchangeable), 8.32 – 8.14 (m, 4H, 3H D2O exchangeable), 8.05 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 1.2 Hz, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 5.8 Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.07 – 3.99 (m, 1H), 3.95 (q, J = 5.9 Hz, 2H),Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinic acid (254d)73% yield) HCl salt as a white solid; H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H, D2O exchangeable), 8.87 (d, J = 8.5 Hz, 1H, D2O exchangeable), 8.26 – 8.11 (m, 4H, partially D2O exchangeable), 8.04 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 7.22 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.37 (t, J = 4.8 Hz, 2H), 3.94 (d, J = 5.1 Hz, 2H), 3.88 – 3.74 (m, 1H), 3.27 (t, J = 5.1 Hz, 2H), 2.14 (s, 3H), 1.93 – 1.81 (m, 2H), 1.80 – 1.70 (m, 2H), 1.68- 1.59 (m, 1H), 1.43 – 1.27 (m, 4H), 1.22 – 1.08 (m, 1H); MS (ES+) 611.3 (M+1), (ES-) 609.2 (M-1).Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (255d)p y p y y , y , p yl)-3',4',5'-trimethoxy-[1,1'-biphenyl]-3-carboxylic acid (256d) Step-1: Preparation of tert-butyl (4-(8-(3-formyl-3',4',5'-trimethoxy-[1,1'-biphenyl]-4-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)benzyl)carbamate (256b) Compound 256b was prepared according to the procedure reported in step-3 of scheme-21, from 4-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-butyl 2-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (258a) (51 mg, 75% yield) as a yellow oil; MS (ES+): 733.2 (M+Na); (ES-) 709.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (258b) Compound 258b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (258a) (51mg, 0.072 mmol) in DCM (10 mL) using TFA (83 µl, 1.076 mmol) and stirring at RT for 2 h to afford after((3,4,5-trimethoxyphenyl)carbamoyl)picolinate (259b) (56 mg, 0.081 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 403 µl, 0.806 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,4,5-trimethoxyphenyl)carbamoyl)picolinic acid (259c) (39 mg, 71% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.08 (s, 1H, D2O exchangeable), 10.82 – 10.59 (m, 2H, D2O exchangeable), 8.30 (d, J = 8.0 Hz, 1H), 8.18 (s, 3H, D2O exchangeable), 8.03 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.63 – 7.57 (m, 2H), 7.57 - 7.53 (m, 1H), 7.39 – 7.32 (m, 2H), 7.29 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 7.03 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 3.994-methoxyaniline hydrochloride (17.74 mg, 0.111 mmol), DIPEA (38.8 µl, 0.222 mmol), and HATU (55.0 mg, 0.145 mmol) stirring at RT overnight to afford after work up methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((4-methoxyphenyl)carbamoyl)picolinate (260a) (71 mg, 87% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 757.2 (M+Na); (ES-): 733.1 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((4-methoxyphenyl)carbamoyl)picolinate (260b)((2-hydroxy-2-methylpropyl)carbamoyl)picolinate (261b) (72 mg, 92% yield) as a yellow oil; MS (ES+): 723.1 (M+Na); (ES-): 699.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2-hydroxy-2-methylpropyl)carbamoyl)picolinate (261c) Compound 261c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- carbamoyl)picolinate (261b) (72 mg, 0.103 mmol mol) and stirring at RT for 3 h to afford after workup me )-4,5- dihydrobenzo[b]thieno[2,3- carbamoyl)picolinate (261c) (54 mg, 88% yield); Step-3: Preparation of 3-(9- drobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2-hydro 61d)Compound 261d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((2-hydroxy-2-methylpropyl)carbamoyl)picolinate (261c) (54 mg, 0.090 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 44.9 µl, 0.090 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2-hydroxy-2-methylpropyl)carbamoyl)picolinic acid ( (45 mg, 85% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H, D2O exchangeable), 10.62 (s, 1H, D2O exchangeable), 8.90 (t, J = 6.3 Hz, 1H), 8.26 (s, 3H, D2O exch le), 8.19 (d, J = 8.0 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.63 – 7.50 (m, 3H), 7.40 – 7.30 (m, 2H),. , J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.70 (s, 1H, D2O exchangeable), 4.36 (t, J = 5.0 Hz, 2H), 4.01 - 3.85 (m, 2H), 3.33 – 3.30 (m, 2H), 3.29 – 3.24 (m, 2H), 1.12 (s, 6H); MS (ES+): 587.2 (M+1); (ES-): 585.1 (M-1).Scheme 262Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1-hydroxycyclopropyl)methyl)carbamoyl)picolinic acid (262d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-hydroxycyclopropyl)methyl)carbamoyl)picolinate (262b) Compound 262b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (70 mg, 0.111 mmol) in DMF (1 mL) using 1-(aminomethyl)cyclopropan-1-ol (262a) (10.90 mg, 0.122 mmol; CAS # 74592-33-9), DIPEA (38.8 µl, 0.222 mmol), and HATU (55.0 mg, 0.145 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1-hydroxycyclopropyl)methyl)carbamoyl)picolinate (262b) (56 mg, 72% yield) as a yellow oil; MS (ES+): 721.1 (M+1); (ES-): 697.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-hydroxycyclopropyl)methyl)carbamoyl)picolinate 262Compound 262d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3 -yl)-6- (((1-hyd eOH (2 mL; rati r 2 h at 50 °C to moyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1- hydroxycyclopropyl)methyl)carbamoyl)picolinic acid (262d) (18 mg, 54% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H, D2O exchangeable), 10.63 (s, 1H, D2OPreparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinic acid (263d) Step-1: Preparation of methyl 6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (263b)Compound 263b was prepared accordin procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d in-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (70 mg, 0.111 mmol) in DMF (1 mL) using[1.1.1]pentan-1-amine hydrochloride (263a) (10.90 mg, 0.122 mmol; CAS # 22287-35-0), DIPEA (38.8 µl, 0.222 mmol), and HATU (55.0 mg, 0.145 mmol) and stirring at RT overnight to afford after work up and purification method-AG, methyl 6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3- (9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (263b) (63 mg, 82% yield) as a yellow oil; MS (ES+): 717.3 (M+Na); (ES-): 693.1 (M-1).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carba dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan- (263c) Compound 263c was prepared according procedure reported i m methyl 6-(bicyclo[1.1.1]pentan-1-ylcarb)-3-(9-((4-(((tert-b bonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- ate (263b) (63 mg, 0.091 mmol) in DCM (2 mL) using TFA (6.99 µl, 0.091 mmol) and RT for 3 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- nzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinate (263c)(46 mg, 85% yield); MS (ES+): 595.1 (M+1); (ES-): 593.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoy b]thieno[2,3- d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan- bamoyl)picolinicCompound 263d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinate (263c) (46 mg, 0.077 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 580 µl, 1.160 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinic acid (263d) (30 mg, 67% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H, D2O exchan eable) 1060 (s 1H D2O exchan eable) 961 (s 1H D2O exchan eable) 823 (s 3H. . , solid;1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H, D2O exchangeable), 8.77 (d, J = 6.8 Hz, 1H), 8.24 (s, 3H, D2O exchangeable), 8.16 (d, J = 7.9 Hz, 1H), 7.98 – 7.87 (m, 2H), 7.64 – 7.50 (m, 3H), 7.36 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.21 – 4.07 (m, 1H), 4.00 – 3.84 (m, 2H), 3.29 – 3.25 (m, 2H), 2.27 – 2.17 (m, 1H), 2.06 – 1.91 (m, 1H), 1.60 – 1.43 (m, 4H), 1.43 – 1.27 (m, 3H), 1.22 – 1.09 (m, 1H); MS (ES+): 609.2 (M+1); (ES-): 607.2 (M-1).d]oxepin-8-yl)-6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)picolinic acid (265c) Compound 265c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-2.21 – 2.13 (m, 1H), 1.91 – 1.66 (m, 8H), 1.47 – 1.30 (m, 2H); MS (ES+) 609.2 (M+1), (ES-) 607.2 (M-1). Scheme 266 Preparation of 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (266d) Step-1: Preparation of methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (266b) Compound 266b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (60 mg, 0.095 mmol) in DMF (1 mL) using amantadine hydrochloride (266a) (19.67 mg, 0.105 mmol), DIPEA (49.9 µl, 0.286 mmol), and HATU (47.1 mg, 0.124 mmol) and stirring at RT overnight to afford after work up and purification method- AG, methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (266b) (56 mg, 77 % yield) as a yellow oil; MS (ES+): 785.1 (M+Na). Step-2: Preparation of methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4- (aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (266c) Compound 266c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (266b) (56 mg, 0.073 mmol) in DCM (2 mL) using TFA (85 µl, 1.101 mmol) and stirring at RT for 3 h to afford after workup methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4- (aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (266c) (42 mg, 86% yield); MS (ES+): 663.2 (M+1); (ES-): 661.2 (M-1). Step-3: Preparation of 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4- (aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (266d) Compound 266d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (266c) (42mg, 0.063 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 475 µl, 0.951 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 6-(((1s,3s)-adamantan-1-yl)carbamoyl)-3-(9- ((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (266d) (30 mg, 73% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.07 (s, 1H, D2O exchangeable), 10.68 (s, 1H, D2O exchangeable), 8.31 – 8.05 (m, 5H, 3H is D2O exchangeable), 7.98 – 7.84 (m, 2H), 7.64 – 7.51 (m, 3H), 7.41 – 7.29 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.00 – 3.85 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.16 – 2.03 (m, 9H), 1.72 – 1.62 (m, 6H); MS (ES+): 649.2 (M+1); (ES-): 647.1 (M-1). Scheme 267Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(cyclooctylcarbamoyl)picolinic acid (267c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinate (267a) Compound 267a was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (60 mg, 0.095 mmol) in DMF (1 mL) using cyclooctylamine (250a) (13.34 mg, 0.105 mmol), DIPEA (49.9 µl, 0.286 mmol), and HATU (47.1 mg, 0.124 mmol) and stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinate (267a) (57 mg, 81 % yield) as a yellow oil; MS (ES+): 761.1 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinate (267b) Compound 267b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinate (267a) (57mg, 0.077 mmol) in DCM (2 mL) using TFA (59.4 µl, 0.771 mmol) and stirring at RT for 3 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(cyclooctylcarbamoyl)picolinate (267b) (43 mg, 87% yield); MS (ES+): 639.2 (M+1); (ES-): 637.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinic acid (267c) Compound 267c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclooctylcarbamoyl)picolinate (267b) (43 mg, 0.067 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 24.18 mg, 1.010 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclooctylcarbamoyl)picolinic acid (267c) (34 mg, 81% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H, D2O exchangeable), 10.65 (s, 1H, D2O exchangeable), 8.88 (d, J = 8.3 Hz, 1H, D2O exchangeable), 8.17 (d, J = 7.7 Hz, 4H, 3H D2O exchangeable), 7.97 – 7.84 (m, 2H), 7.64 – 7.49 (m, 3H), 7.35 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 5.3 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.11 – 4.00 (m, 1H), 3.99 – 3.85 (m, 2H),3.30 – 3.22 (m, 2H), 1.83 – 1.66 (m, 6H), 1.62 – 1.47 (m, 8H); MS (ES+): 625.2 (M+1); (ES-): 623.3 (M-1). Scheme 268 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(cycloheptylcarbamoyl)picolinic acid (268c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinate (268a) Compound 268a was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (60 mg, 0.095 mmol) in DMF (1 mL) using cycloheptanamine (239a) (11.87 mg, 0.105 mmol), DIPEA (49.9 µl, 0.286 mmol), and HATU (47.1 mg, 0.124 mmol) and stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinate (268a) (55mg, 80 % yield) as a yellow oil; MS (ES+): 725.2 (M+1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinate (268b) Compound 268b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinate (268a) (55mg, 0.076 mmol) in DCM (2 mL) using TFA (88 µl, 1.138 mmol) and stirring at RT for 3 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(cycloheptylcarbamoyl)picolinate (268b) (42 mg, 89% yield); MS (ES+): 625.2 (M+1); (ES-): 623.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinic acid (268c) Compound 268c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cycloheptylcarbamoyl)picolinate (268b) (42 mg, 0.067 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 504 µl, 1.008 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cycloheptylcarbamoyl)picolinic acid (268c) (35 mg, 85% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H, D2O exchangeable), 10.67 (s, 1H, D2O exchangeable), 8.88 (d, J = 8.4 Hz, 1H, D2O exchangeable), 8.26 – 8.07 (m, 4H, 3H D2O exchangeable), 7.97 – 7.86 (m, 2H), 7.63 – 7.52 (m, 3H), 7.39 – 7.30 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.07 – 3.87 (m, 3H), 3.27 (t, J = 5.0 Hz, 2H), 1.94 – 1.81 (m, 2H), 1.72 – 1.43 (m, 10H); MS (ES+): 611.3 (M+1); (ES-): 609.2 (M-1). Scheme 269Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(cyclopentylcarbamoyl)picolinic acid (269c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinate (269a) Compound 269a was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (60 mg, 0.095 mmol) in DMF (1 mL) using cyclopentanamine (CAS# 1003-03-08) (8.92 mg, 0.105 mmol), DIPEA (49.9 µl, 0.286 mmol), and HATU (47.1 mg, 0.124 mmol) and stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinate (269a) (56 mg, 84 % yield) as a yellow oil; MS (ES+): 719.2 (M+Na); (ES-): 695.1 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinate (269b) Compound 269b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinate (269a) (56mg, 0.080 mmol) in DCM (2 mL) using TFA (93 µl, 1.205 mmol) and stirring at RT for 3 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(cyclopentylcarbamoyl)picolinate (269b) (41 mg, 85% yield); MS (ES+): 597.1 (M+1); (ES-): 595.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinic acid (269c) Compound 269c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclopentylcarbamoyl)picolinate (269b) (41mg, 0.069 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2 M aqueous solution; 515 µl, 1.031 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclopentylcarbamoyl)picolinic acid (269c) (14 mg, 35% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H, D2O exchangeable), 10.66 (s, 1H, D2O exchangeable), 8.91 (d, J = 7.8 Hz, 1H, D2O exchangeable), 8.25 – 8.05 (m, 4H, 3H D2O exchangeable), 7.97 – 7.86 (m, 2H), 7.63 – 7.51 (m, 3H), 7.39 – 7.29 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.32 – 4.22 (m, 1H), 4.02 – 3.88 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.02 – 1.88 (m, 2H), 1.79 – 1.65 (m, 2H), 1.65 – 1.51 (m, 4H); MS(ES+) 583.1 (M+1), (ES-) 581.2 (M-1); Analysis calculated for C32H30N4O5S. HCl .2.25H2O: C, 58.26; H, 5.42; N, 8.49; Found: C, 58.14; H, 5.57; N, 8.46. Scheme 270 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinic acid (270d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270b) Compound 270b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (60 mg, 0.095 mmol) in DMF (1 mL) using tetrahydro-2H-pyran-4-amine (270a) (10.60 mg, 0.105 mmol), DIPEA (49.9 µl, 0.286 mmol), and HATU (47.1 mg, 0.124 mmol) and stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270b) (58 mg, 85% yield) as a yellow oil; MS (ES+): 735.1 (M+Na); (ES-): 711.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270c)Compound 270c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270b) (58 mg, 0.081 mmol) in DCM (2 mL) using TFA (94 µl, 1.221 mmol) and stirring at RT for 3 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270c) (42 mg, 84% yield); MS (ES+): 613.2 (M+1); (ES-): 611.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinic acid (270d) Compound 270d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinate (270c) (42 mg, 0.069 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2 M aqueous solution; 24.62 mg, 1.028 mmol) stirring for 2 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydro-2H-pyran-4-yl)carbamoyl)picolinic acid (270d) (30 mg, 73% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H, D2O exchangeable), 10.62 (s, 1H, D2O exchangeable), 9.03 (d, J = 8.3 Hz, 1H, D2O exchangeable), 8.31 (s, 3H, D2O exchangeable), 8.20 (d, J = 8.0 Hz, 1H), 7.94 (t, J = 4.0 Hz, 2H), 7.63 – 7.52 (m, 3H), 7.42 – 7.31 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.13 – 4.00 (m, 1H), 3.99 – 3.84 (m, 4H), 3.46 – 3.41 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 1.84 – 1.74 (m, 2H), 1.73 – 1.59 (m, 2H); MS (ES+): 599.2 (M+1); (ES-): 597.2 (M-1). Scheme 271 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(neopentylcarbamoyl)picolinic acid (271c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (271a) Compound 271a was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using 2,2-dimethylpropan-1-amine (244a) (11.42 mg, 0.131 mmol), DIPEA (41.6 µl, 0.238 mmol), and HATU (58.9 mg, 0.155 mmol) and stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (271a) (80 mg, 96% yield) as a clear gel; MS (ES+): 721.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (271b) Compound 271b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (271a) (80 mg, 0.114 mmol) in DCM (1.6 mL) using TFA (176 µl, 2.290 mmol) and stirring at RT for 2 h to afford after workup and purification method-CC, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinate (271b) (67 mg, 98% yield) as a white solid; MS (ES+): 599.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(neopentylcarbamoyl)picolinic acid (271c) Compound 271c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (neopentylcarbamoyl)picolinate (271b) (67 mg, 0.112 mmol) in THF / MeOH (0.9 mL) using lithium hydroxide (2M) (448 µl, 0.448 mmol) stirring for 3 h at 30 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)- 6-(neopentylcarbamoyl)picolinic acid (271c) (47 mg, 72% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H, D2O exchangeable), 10.73 (s, 1H, D2O exchangeable), 9.07 – 8.90 (m, 1H, D2O exchangeable), 8.28 – 8.03 (m, 4H, 3H D2O exchangeable), 7.99 – 7.85 (m, 2H), 7.64 – 7.50 (m, 3H), 7.42 – 7.26 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 3.97 – 3.83 (m, 2H), 3.31 – 3.10 (m, 4H), 0.92 (s, 9H); MS (ES-): 585.2 (M+1); (ES-): 583.2 (M- 1). Scheme 272Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (272c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (272a) Compound 272a was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using 1-methylcyclohexan-1-amine hydrochloride (255a) (19.61 mg, 0.131 mmol), DIPEA (62.4 µl, 0.357 mmol), and HATU (58.9 mg, 0.155 mmol) and stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (272a) (72 mg, 83% yield); MS (ES+): 747.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (272b) Compound 272b was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (272a) (71 mg, 0.098 mmol) in DCM (1.5 mL) using TFA (151 µl, 1.959 mmol) and stirring at RT for 1 h to afford after workup and purification method-CC, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (272b) (59 mg, 96% yield) as a white solid; MS (ES+): 625.2 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (272c) Compound 272c was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((1-methylcyclohexyl)carbamoyl)picolinate (272b) (59 mg, 0.094 mmol) in THF (0.800 mL) and MeOH (0.8 mL) using lithium hydroxide (2M) (378 µl, 0.378 mmol) stirring for 5 h at 50 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (272c) (49 mg, 85% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, D2O exchangeable), 8.29 – 8.04 (m, 5H, 4H D2O exchangeable), 7.99 – 7.85 (m, 2H), 7.65 – 7.48 (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.02 – 3.88 (m, 2H), 3.27 (t, J = 4.9 Hz, 2H), 2.25 – 2.09 (m, 2H), 1.60 – 1.31 (m, 11H); MS (ES-): 611.1 (M+1); (ES-): 609.3 (M-1).Preparatio ]oxepin-8- yl)-6-(((1R Step-1: Pre oyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1- yl)carbamoyl)picolinate (273b) Compound 273b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using memantine hydrochloride (273a) (28.3 mg, 0.131 mmol), DIPEA (41.6 µl, 0.238 mmol), and HATU (58.9 mg, 0.155 mmol) and stirring at RT overnight to afford after work up and purification method- C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1- yl)carbamoyl)picolinate (273b) (80 mg, 85% yield) as a clear gel; Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1- yl)carbamoyl)picolinate (273c)Compound 273c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1- yl)carbamoyl)picolinate (273b) (80 mg, 0.101 mmol) in DCM (1.6 mL) using TFA (156 µl, 2.023 mmol) and stirring at RT for 1 h to afford after workup and purification method-CC, methyl 3-(9-((4- (aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5- dimethyladamantan-1-yl)carbamoyl)picolinate (273c) (69 mg, 99% yield) as a white solid; MS (ES+): 691.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1-yl)carbamoyl)picolinic acid (273d) Compound 273d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1R,3S)-3,5-dimethyladamantan-1-yl)carbamoyl)picolinate (273c) (69 mg, 0.100 mmol) in THF (0.8 mL) and MeOH (0.8 mL) using lithium hydroxide (2M) (400 µl, 0.400 mmol) stirring for 3 h at 30 °C to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1R,3S)-3,5-dimethyladamantan-1- yl)carbamoyl)picolinic acid (273d) (56 mg, 83% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H, D2O exchangeable), 8.32 – 8.05 (m, 5H, 4H D2O exchangeable), 8.00 – 7.83 (m, 2H), 7.64 – 7.51 (m, 3H), 7.40 – 7.29 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.01 – 3.88 (m, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.15 (s, 1H), 2.00 – 1.89 (m, 2H), 1.85 – 1.60 (m, 4H), 1.44 – 1.26 (m, 4H), 1.17 (s, 2H), 0.86 (s, 6H); MS (ES-): 677.2 (M+1); (ES-): 675.3 (M-1). Scheme 274O O O O NH O O S2S N N O 274a HN O ClHN OOTFA OH HATU, DIPEA NH BocHNBocHNCl207f 274b O O O O HO O S S N N HN OOLiOHHN OONH NH Cl H Cl 2N 274cH2N 274dPreparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((3-chlorophenyl)carbamoyl)picolinic acid (274d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chlorophenyl)carbamoyl)picolinate (274b) Compound 274b was prepared according to the procedure reported in step-1 of scheme-39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using 3-chloroaniline (274a) (13.86 µl, 0.131 mmol; CAS# 108-42-9), DIPEA (41.6 µl, 0.238 mmol), and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chlorophenyl)carbamoyl)picolinate (274b) (85 mg, 97% yield); MS (ES+):761.2 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chlorophenyl)carbamoyl)picolinate (274c) Compound 274c was prepared according to the procedure reported in step-2 of scheme-8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chlorophenyl)carbamoyl)picolinate (274b) (82 mg, 0.111 mmol) in DCM (1.7 mL) using TFA (171 µl, 2.218 mmol) and stirring at RT for 1 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chl yield) as a white solid; MS (ES+): 639.1 (M+1). Step-3: Preparation of 3- benzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3-chl Compound 274d was pre f scheme-12, from methyl 3-(9-((4-(aminom[2,3-d]oxepin-8-yl)-6- ((3-chlorophenyl)carbamoyl)picolinate (274c) (67 mg, 0.105 mmol) in THF (0.9 mL) and MeOH (0.9 mL) using lithium hydroxide (1M aqueous solution; 419 µl, 0.419 mmol) stirring overnight at RT to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-chlorophenyl)carbamoyl)picolinic acid (274d) (59 mg, 90% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H, D2O exchangeable), 10.74 (s, 1H, D2O exchangeable), 8.31 (d, J = 8.0 Hz, 1H), 8.16 (s, 3H, D2O exchangeable), 8.08 – 8.00 (m, 2H), 7.96 (s, 1H), 7.80 (m, 1H), 7.63 – 7.53 (m, 3H), 7.45 (t, J = 8.1 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.27 – 7.21 (m, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 4.38 (t, J = 5.1 Hz, 2H), 4.00 – 3.84 (m, 2H), 3.28 (t, J = 5.0 Hz, 2H); MS (ES+): 625.2 (M+1); (ES-): 623.0 (M- 1). Scheme 275 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((4-methylpentan-2-yl)carbamoyl)picolinic acid (275d)( a ( a (d]oxepin-8-yl)-6-((4-methylpentan-2-yl)carbamoyl)picolinic acid (275d) Compound 275d was prepared according to the procedure reported in step-6 of scheme-12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((4-methylpentan-2-yl)carbamoyl)picolinate (275c) (0.037 g, 0.06 mmol) in THF (0.5 mL) and MeOH (0.5 mL) using lithium hydroxide (0.240 mL, 0.240 mmol) and stirring overnight at RT to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((4-methylpentan-2-yl)carbamoyl)picolinic acid (275d) (19 mg, 53% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H, D2O exchangeable), 8.83 (d, J = 9.0 Hz, 1H, D2O exchangeable), 8.28 – 8.06 (m, 4H, 3H D2O exchangeable), 8.01 – 7.86 (m, 2H), 7.65 – 7.46 (m, 3H), 7.40 – 7.28 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.21 – 4.14 (m, 1H), 4.02 – 3.84 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 1.71 – 1.52 (m, 2H), 1.40 – 1.25 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H), 0.89 (dd, J = 6.4, 1.7 Hz, 6H); MS (ES-): 599.3 (M+1); (ES-): 597.2 (M-1). Scheme 276Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((dicyclopropylmethyl)carbamoyl)picolinic acid (276d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinate (276b) Compound 276b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using dicyclopropylmethanamine hydrochloride (276a) (19.34 mg, 0.131 mmol; CAS # 51043-72-2), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((dicyclopropylmethyl)carbamoyl)picolinate (276b) (53 mg, 62% yield) as a white solid; MS (ES+): 745.2 (M+Na); (ES-): 721.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinate (276c) Compound 276c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinate (276b) (50 mg, 0.069 mmol) in DCM (1 mL) using TFA (107 µL, 1.383 mmol) and stirring at RT for 2 h to afford after workup and purification method-CC, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinate (276c) (41 mg, 95% yield) as a white solid; MS (ES+): 623.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinic acid (276d) Compound 276d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((dicyclopropylmethyl)carbamoyl)picolinate (276c) (40 mg, 0.064 mmol) in THF (0.5 mL) and MeOH (0.5 mL) using lithium hydroxide (241 µL, 0.241 mmol) stirring overnight at RT to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((dicyclopropylmethyl)carbamoyl)picolinic acid (276d) (22 mg, 56% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H, D2O exchangeable), 9.09 (d, J = 9.1 Hz, 1H, D2O exchangeable), 8.33 – 8.09 (m, 4H, 3H D2O exchangeable), 7.99 – 7.85 (m, 2H), 7.66 – 7.49 (m, 3H), 7.36 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.06 – 3.86 (m, 2H), 3.32 – 3.21 (m, 2H), 3.02 – 2.84 (m, 1H), 1.32 – 1.10 (m, 3H), 0.59 – 0.20 (m, 7H); MS (ES-): 609.2 (M+1); (ES-): 607.2 (M-1). Scheme 277 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(cyclobutylcarbamoyl)picolinic acid (277d)Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (277b) Compound 277b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using cyclobutanamine (277a) (15.25 µL, 0.179 mmol; CAS # 2516-34-9), DIPEA (41.6 µL, 0.238 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[23-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (277b) (74 mg 91% yie Ste dih Co hyl 3-( d]o usi me d]o (E Ste d]o Co me (cy ) usi aff dih4% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H, D2O exchangeable), 9.25 (d, J = 8.1 Hz, 1H, D2O exchangeable), 8.25 – 8.01 (m, 4H, 3H D2O exchangeable), 7.98 - 7.86 (m, 2H), 7.67 – 7.50 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.55 – 4.29 (m, 3H), 3.99 – 3.88 (m, 2H), 3.34 – 3.21 (m, 2H), 2.39 – 2.05 (m, 4H), 1.82 – 1.60 (m, 2H). MS (ES-): 569.2 (M+1); (ES-): 567.1 (M-1); Analysis calculated for C31H28N4O5S.2.65H2O. HCl: C, 57.03; H, 5.30; N, 8.58; Cl, 5.43; Found: C, 56.81; H, 5.24; N, 8.97; Cl, 5.52. Scheme 278Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamoyl)picolinic acid (278d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1- yl)carbamoyl)picolinate (278b) Compound 278b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using (1s,3r,5R,7S)-3-aminoadamantan-1-ol (278a) (21.91 mg, 0.131 mmol; CAS # 702-82-9), DIPEA (41.6 µL, 0.238 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamoyl)picolinate (278b) (92 mg, 99% yield) as an off- white solid; MS (ES+): 801.3 (M+Na); (ES-): 777.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1- yl)carbamoyl)picolinate (278c) Compound 278c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamoyl)picolinate (278b) (92 mg, 0.118 mmol) in DCM (1.8 mL) using TFA (182 µL, 2.362 mmol) and stirring at RT for 2 h to afford after workup and purification method-BS, methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1- yl)carbamoyl)picolinate (278c) (75 mg, 94% yield) as a white solid; MS (ES+): 679.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamoyl)picolinic acid (278d) Compound 278d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamoyl)picolinate (278c) (38 mg, 0.056 mmol) in THF / MeOH (3 mL; ratio 1:1) using lithium hydroxide (1M aqueous solution; 280 µL, 0.28 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)carbamoyl)picolinic acid (278d) (20 mg, 54% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO) δ 12.95 (s, 1H, D2O exchangeable), 10.66 (s, 1H, D2O exchangeable), 8.32 (s, 1H, D2O exchangeable), 8.27 – 8.07 (m, 4H, 3H D2O exchangeable), 8.01 – 7.89 (m, 2H), 7.65 – 7.50 (m, 3H), 7.41 – 7.32 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.61 (s, 1H, D2O exchangeable), 4.36 (t, J = 5.0 Hz, 2H), 4.01 – 3.87 (m, 2H), 3.28 – 3.22 (m, 2H), 2.24 – 2.14 (m, 2H), 2.06 – 1.89 (m, 6H), 1.66 – 1.41 (m, 6H); MS (ES-): 665.2 (M+1); (ES-): 663.2 (M-1). Scheme 279Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((2,4- Step-1: Pre oyl)-4,5- dihydroben te (279b) Compound from 5-(9- ((4-(((tert- 3- d]oxepin-8 mL) using 2,4-dimeth -3), DIPEA (62 to afford after work butoxycarb -8-yl)-6- ((2,4-dimet solid; MS (ES+): 749Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,4-dimethylpentan-3-yl)carbamoyl)picolinate (279c) Compound 279c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,4-dimethylpentan-3-yl)carbamoyl)picolinate (279b) (73 mg, 0.100 mmol) in DCM (1.5 mL) using TFA (155 µL, 2.009 mmol) and stirring at RT for 2 h to afford after workupmethyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((2,4-dimethylpentan-3-yl)carbamoyl)picolinate (279c) (63 mg, 0.101 mmol, 100 % yield); MS (ES+): 627.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,4-dimethylpentan-3-yl)carbamoyl)picolinic acid (279d) Compound 279d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((2,4-dimethylpentan-3-yl)carbamoyl)picolinate (279c) (63 mg, 0.101 mmol) in THF / MeOH (3 mL; ratio 1:1) using lithium hydroxide (1M aqueous solution; 400 µL, 0.40 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,4-dimethylpentan-3-yl)carbamoyl)picolinic acid (279d) (29 mg, 47% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO) δ 10.73 (s, 1H, D2O exchangeable), 8.45 (d, J = 10.2 Hz, 1H, D2O exchangeable), 8.27 – 8.04 (m, 4H, 3H D2O exchangeable), 7.99 – 7.83 (m, 2H), 7.68 – 7.50 (m, 3H), 7.42 – 7.23 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.03 – 3.86 (m, 2H), 3.75 – 3.57 (m, 1H), 3.30 – 3.20 (m, 2H), 2.05 – 1.83 (m, 2H), 0.98 – 0.79 (m, 12H); MS (ES+): 613.2 (M+1); (ES-): 611.2 (M-1). Scheme 280Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1-methylcyclopropyl)methyl)carbamoyl)picolinic acid (280d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-methylcyclopropyl)methyl)carbamoyl)picolinate (280b) Compound 280b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using (1-methylcyclopropyl)methanamine hydrochloride (280a) (15.93 mg, 0.131 mmol; CAS # 1260779- 19-8), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1-methylcyclopropyl)methyl)carbamoyl)picolinate (280b) (38 mg, 46% yield) as an off-white solid; MS (ES+): 719.2 (M+Na); (ES-): 695.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-methylcyclopropyl)methyl)carbamoyl)picolinate (280c) Compound 280c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1-methylcyclopropyl)methyl)carbamoyl)picolinate (280b) ( 38 mg, 0.055 mmol) in DCM (1.5 mL) using TFA (84 µL, 1.091 mmol) and stirring at RT for 2 h to afford after workup and purificatio dihydrobenzo[ )picolinate (280c) (33mg, Step-3: Prepar ieno[2,3- d]oxepin-8-yl) Compound 28 12, from methyl 3-(9-(( pin-8-yl)-6- (((1-methylcyc F / MeOH (0.88 mL; rati stirring for overnight at ro (4- (aminomethyl) methylcyclopr t as a white solid;1H NMR Hz, 1H, D2Oexchangeable), 8.19 (d, J = 8.0 Hz, 1H), 8.10 (s, 3H, D2O exchangeable), 8.00 – 7.89 (m, 2H), 7.65 – 7.45 (m, 3H), 7.34 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.42 – 4.29 (m, 2H), 3.98 – 3.89 (m, 2H), 3.31 – 3.20 (m, 4H), 1.07 (s, 3H), 0.58 – 0.47 (m, 2H), 0.32 – 0.22 (m, 2H). MS (ES-): 583.2 (M+1); (ES-): 581.1 (M-1); Analysis calculated for C32H30N4O5S.2.5H2O.1.25HCl: C, 57.09; H, 5.43; N, 8.32; Found: C, 57.22; H, 5.17; N, 8.70. Scheme 281 Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((cyclobutylmethyl)carbamoyl)picolinic acid (281d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclobutylmethyl)carbamoyl)picolinate (281b) Compound 281b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using cyclobutylmethanamine hydrochloride (281a) (15.93 mg, 0.131 mmol; CAS# 5454-82-0), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((cyclobutylmethyl)carbamoyl)picolinate (281b) (80mg, 96% yield) as a clear gel; MS (ES+): 719.2 (M+Na); (ES-): 695.2 (M-1).Step-2: dihydro Compou methyl 3-(9-((4 2,3- d]oxepi M (1.7 mL) usi purifica dihydro (67 mg, 98% yie Step-3: ,3- d]oxepi Compou m methyl yl)-6- ((cyclob eOH(0.9 mL) using lithium hydroxide (1M) (449 µL, 0.449 mmol) stirring for 3 h at 30oC to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclobutylmethyl)carbamoyl)picolinic acid (281d) (43 mg, 66% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H, D2O exchangeable), 10.71 (s, 1H, D2O exchangeable), 9.12 (t, J = 6.3 Hz, 1H, D2O exchangeable), 8.36 – 8.03 (m, 4H, 3H D2O exchangeable), 7.98 – 7.86 (m, 2H), 7.64 – 7.48 (m, 3H), 7.41 – 7.27 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 4.9 Hz, 2H), 4.01 – 3.85 (m, 2H), 3.45 – 3.37 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.66 – 2.53 (m, 1H), 2.17 – 1.57 (m, 6H). MS (ES-): 583.2 (M+1); (ES- ): 581.3 (M-1); Analysis calculated for C32H30N4O5S.2.5H2O. HCl: C, 57.87; H, 5.46; N, 8.44; Cl, 5.34; Found: C, 57.90; H, 5.41; N, 8.63; Cl, 5.34 Scheme 282Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-((2,6-dimethylheptan-4-yl)carbamoyl)picolinic acid (282d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-dimethylheptan-4-yl)carbamoyl)picolinate (282b) Compound 282b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using 2,6-dimethylheptan-4-amine (282a) (17.06 mg, 0.119 mmol; CAS # 65530-92-9), DIPEA (41.6 µL, 0.238 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-dimethylheptan-4-yl)carbamoyl)picolinate (282b)( 84 mg, 0.111 mmol, 93 % yield) as an off-white solid; MS (ES+): 777.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-dimethylheptan-4-yl)carbamoyl)picolinate (282c) Compound 282c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,6-dimethylheptan-4-yl)carbamoyl)picolinate (282b) (0.084 g, 0.111 mmol) in DCM (1.5 mL) using TFA (0.171 mL, 2.225 mmol) and stirring at RT for 2 h to afford after workupand purification dihydrobenzo[b linate (282c) (73 mg, >99% Step-3: Prepara thieno[2,3- d]oxepin-8-yl)- Compound 282 12, from methyl 3-(9-((4 epin-8-yl)-6- ((2,6-dimethylh MeOH (1.76 mL; ratio 1:1) u rring for overnight at RT (aminomethyl) 6- dimethylheptan solid;1H NMR (300 MH D2O exchangeable), 7.52 (m, 3H),7.43 – 7.25 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.43 – 4.30 (m, 2H), 4.30 – 4.09 (m, 1H), 4.01 – 3.82 (m, 2H), 3.30 – 3.21 (m, 2H), 1.70 – 1.41 (m, 4H), 1.39 – 1.15 (m, 2H), 1.00 – 0.72 (m, 12H); MS (ES+): 641.3 (M+1); (ES-): 639.2 (M-1); Analysis calculated for C36H40N4O5S.2H2O.1.15 HCl: C, 60.16; H, 6.33; N, 7.80; Cl, 5.67; Found: C, 59.90; H, 6.26; N, 8.02; Cl, 5.50. Scheme 283Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1-methylcyclobutyl)methyl)carbamoyl)picolinic acid (283d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-methylcyclobutyl)methyl)carbamoyl)picolinate (283b) Compound 283b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using (1-methylcyclobutyl)methanamine hydrochloride (283a) (21.00 mg, 0.155 mmol; CAS # 1245647-53- 3), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT for 7 h to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1-methylcyclobutyl)methyl)carbamoyl)picolinate (283b) (80 mg, 94% yield) as an off-white solid; MS (ES+): 733.2 (M+Na); (ES-): 709.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-methylcyclobutyl)methyl)carbamoyl)picolinate (283c) Compoun m methyl 3-(9-((4-( o[2,3- d]oxepin- mmol) in DCM (1. orkup methyl 3- 8-yl)-6- (((1-meth lid; MS (ES+): 611.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1-methylcyclobutyl)methyl)carbamoyl)picolinic acid (283d) Compound 283d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1-methylcyclobutyl)methyl)carbamoyl)picolinate (283c) (77 mg, 0.126 mmol) in THF (1 mL) and MeOH (1 mL) using lithium hydroxide (1M aqueous solution; 504 µL, 0.504 mmol) stirring overnight at RT to afford after work up and purification method-E, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1-methylcyclobutyl)methyl)carbamoyl)picolinic acid (283d) (70 mg, 93% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H, D2O exchangeable), 10.64 (s, 1H, D2O exchangeable), 9.11 (t, J = 6.5 Hz, 1H, D2Oexchangeable), 8.25 – 8.09 (m, 4H, 3H D2O exchangeable), 8.02 – 7.87 (m, 2H), 7.64 – 7.51 (m, 3H), 7.41 – 7.24 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.03 – 3.84 (m, 2H), 3.43 – 3.36 (m, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.06 -1.91 (m, 2H), 1.87 – 1.70 (m, 2H), 1.70 – 1.52 (m, 2H), 1.13 (s, 3H); MS (ES-): 597.2 (M+1); (ES-): 595.2 (M-1). Scheme 284Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (284d) Step-1: Preparation of methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (284b) Compound 284b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (284a) (21.10 mg, 0.143 mmol; CAS # 39245-79-9), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 6-(((1S,2S,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (284b) (79 mg, 92% yield) as an off-white solid; MS (ES+): 745.2 (M+Na).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (284c) Compound 284c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolin ol) and stirring at oyl)-4,5- dihydrobe yl)carbam 1). Step-3: Pr o[2,3- d]oxepin- Compoun rom methyl 3-( -8-yl)-6- (((1S,2S,4 n THF (0.85 mL) 424 mmol) stir (aminome ,4R)- bicyclo[2. white solid;1H O exchangea exchangea .2 Hz, 1H), 6.99 J = 5.1 Hz, 2H), 2 , 3H); MS (ES+): 60Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (285d) Step-1: Preparation of methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinate (285b) Compound 285b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (207f) (75 mg, 0.119 mmol) in DMF (1 mL) using (1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (285a) (21.91 mg, 0.131 mmol; CAS # 65481-69-8), DIPEA (62.4 µL, 0.357 mmol) and HATU (58.9 mg, 0.155 mmol) stirring at RT for 7 h to afford after work up and purification method-C, methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (285b) (82 mg, 95% yield) as an off-white solid; MS (ES+): 745.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (285c) Compound 285c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (285b) (81 mg, 0.112 mmol) in DCM (2 mL) using TFA (173 µL, 2.241 mmol) and stirring at RT for 1.5 h to afford after workup methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (285c) (67 mg, 96% yield) as a white solid; MS (ES+): 623.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1S 2R4R)-bicyclo

[0221] heptan-2-yl)carbamoyl)picolinic acid (285d) C m (( ( m (a b s e e , 1 H S (Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinic acid (286c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclobutylcarbamoyl)picolinate (286a) Compound 286a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (75 mg, 0.117mmol) in DMF (1 mL) using cyclobutanamine (277a) (9.12 mg, 0.128 mmol), DIPEA (81 µL, 0.466 mmol) and HATU (57.6 mg, 0.151 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclobutylcarbamoyl)picolinate (286a) (72 mg, 89% yield) as a yellow oil; MS (ES+) 719.2 (M+Na); (ES-) 695.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (286b) Compound 286b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (286a) (72 mg, 0.103 mmol) in DCM (2 mL) using TFA (239 µL, 3.10 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (286b) (48mg, 78% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 597.2 (M+1); (ES-): 595.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinic acid (286c) Compound 286c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(cyclobutylcarbamoyl)picolinate (286b) (48 mg, 0.080 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 19.26 mg, 0.804 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinic acid (286c)(31mg, 66% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H, D2O exchangeable), 9.95 (s, 1H, D2O exchangeable), 9.26 (d, J = 8.1 Hz, 1H, D2O exchangeable), 8.25 – 8.09 (m, 4H, 3H D2O exchangeable), 8.04 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 2.7 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 7.00 (s, 1H), 4.56 – 4.43 (m, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.02 - 3.87 (m, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.32 – 2.20 (m, 2H), 2.20 – 2.09 (m, 5H), 1.77 – 1.64 (m, 2H); MS (ES+): 583.2 (M+1); (ES-): 581.1 (M-1). Scheme 287Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(butylcarbamoyl)picolinic acid (287c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (butylcarbamoyl)picolinate (287a) Compound 287a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (75 mg, 0.117 mmol) in DMF (2 mL) using butan-1-amine (9.37 mg, 0.128 mmol), DIPEA (81 µL, 0.466 mmol) and HATU (81 µL, 0.466 mmol) stirring at RT overnight to afford after work up and purification method- C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(butylcarbamoyl)picolinate (287a) (66 mg, 81% yield) as a yellow oil; MS (ES+) 699.1 (M+1); (ES-) 697.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(butylcarbamoyl)picolinate (287b) Compound 287b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(butylcarbamoyl)picolinate (287a) (66 mg, 0.094 mmol) in DCM (2 mL) using TFA (218 µL, 2.83 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(butylcarbamoyl)picolinate (287b) (49 mg, 87% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 599.1 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(butylcarbamoyl)picolinic acid (287c) Compound 287c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(butylcarbamoyl)picolinate (287b) (49 mg, 0.082 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 409 µL, 0.818 mmol) stirring for 2 h at 50oC to affordafter ,5- dihyd yield) le), 9.14 ( , 1H), 7.95 ( 5.2 Hz, 1 3H), 1.57 – ): 583.3Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinic acid (288c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclohexylcarbamoyl)picolinate (288a) Compound 288a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (70 mg, 0.106 mmol) in DMF (1 mL) using cyclohexanamine (254a) (11.61 mg, 0.117 mmol), DIPEA (74.4 µL, 0.426 mmol) and HATU (52.6 mg, 0.138 mmol) stirring at RT overnight to afford after work up andpurification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclohexylcarbamoyl)picolinate (288a) (63mg, 0.085 mmol, 80 % yield) as a yellow oil; MS (ES+) 761.2 (M+Na); (ES-) 737.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (288b) Compound 288b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (288a) (63 mg, 0.085 mmol) in DCM (2 mL) using TFA (197 µL, 2.56 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (288b) (46 mg, 84% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 639.2 (M+1); (ES-): 637.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinic acid (288c) Compound 288c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclohexylcarbamoyl)picolinate (288b) (46 mg, 0.072 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 360 µL, 0.720 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclohexylcarbamoyl)picolinic acid (288c) (34 mg, 76% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H, D2O exchangeable), 8.92 (d, J = 8.5 Hz, 1H, D2O exchangeable), 8.22 – 8.05 (m, 4H, 2H D2O exchangeable), 7.93 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.16 – 7.06 (m, 3H), 6.97 (s, 1H), 4.37 (t, J = 5.0 Hz, 2H), 3.96 – 3.86 (m, 2H), 3.86 – 3.77 (m, 1H), 3.27 (t, J = 5.1 Hz, 2H), 2.09 (s, 6H), 1.92 – 1.81 (m, 2H), 1.81 – 1.70 (m, 2H), 1.68 – 1.59 (m, 1H), 1.45 – 1.25 (m, 4H), 1.23 – 1.07 (m, 1H); MS (ES+): 625.3 (M+1); (ES-): 623.2 (M-1). Scheme 289Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (289c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclohexyl)carbamoyl)picolinate (289a) Compound 289a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihy 4 mm mm o affo buto d]ox w oil; Step dihy Com met dihy 2 mg, ord afte dihy 2 mg, (ES Stepdihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinic acid (289c) Compound 289c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclohexyl)carbamoyl)picolinate (289b) (42 mg, 0.064 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 322 µL, 0.643 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclohexyl)carbamoyl)picolinic acid (289c) (27 mg, 66% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H, D2O exchangeable), 8.30 – 8.13 (m, 4H, partially D2O exchangeable), 8.09 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.07 (s, 2H), 7.02 (d, J = 5.3 Hz, 1H), 6.92 (s, 1H), 4.31 (t, J = 5.2 Hz, 2H), 3.92 - 3.75 (m, 2H), 3.22 – 3.19 (m, 2H), 2.19 – 2.08 (m, 2H), 2.02 (s, 6H), 1.50 – 1.36 (m, 6H), 1.33 (s, 3H), 1.29 – 1.08 (m, 2H); MS (ES+): 639.3 (M+1); (ES-): 637.2 (M-1). Scheme 290 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinic acid (290c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclobutylcarbamoyl)picolinate (290a) Compound 290a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (75 mg, 0.114 mmol) in DMF (1 mL) using cyclobutanamine (277a) (8.92 mg, 0.125 mmol), DIPEA (80 µL, 0.456 mmol) and HATU (56.4 mg, 0.148 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclobutylcarbamoyl)picolinate (290a) (72 mg, 89% yield) as a yellow oil; MS (ES+): 733.3 (M+Na); (ES-): 709.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (290b) Compound 290b was prepared according to the procedure reported in step-2 of scheme 8, frommethyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (290a) (72mg, 0.101 mmol) in DCM (2 mL) using TFA (234 µL, 3.04 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (290b) (55 mg, 89% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 611.2 (M+1); (ES-): 609.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinic acid (290c) Compound 290c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(cyclobutylcarbamoyl)picolinate (290b) (55mg, 0.090 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 21.57 mg, 0.901 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (cyclobutylcarbamoyl)picolinic acid (290c) (40 mg, 74% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H, D2O exchangeable), 9.32 (d, J = 8.1 Hz, 1H, D2O exchangeable), 8.21 – 8.10 (m, 4H, 2H D2O exchangeable), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.52 – 4.43 (m, 1H), 4.37 (t, J = 5.1 Hz, 2H), 3.96 – 3.85 (m, 2H), 3.29 – 3.25 (m, 2H), 2.30 – 2.20 (m, 2H), 2.19 – 2.00 (m, 8H), 1.78 – 1.65 (m, 2H); MS (ES+): 597.2 (M+1); (ES-): 595.2 (M-1). Scheme 291 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(butylcarbamoyl)picolinic acid (291c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (butylcarbamoyl)picolinate (291a)Compound 291a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (75 mg, 0.114 mmol) in DMF (2 mL) using butan-1-amine (9.17 mg, 0.125 mmol), DIPEA (80 µL, 0.456 mmol) and HATU (56.4 mg, 0.148 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)- 4,5-di yield) Step-2 dihydr Comp methy dihydr mol) in DC up methy d]oxe as used a Step-3 dihydr Comp methy d]oxepn-8-y )-6-(buty carbamoy )p co nate ( 9 b) ( 8 mg, 0.078 mmo ) n THF / MeOH ( mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 18.76 mg, 0.783 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (butylcarbamoyl)picolinic acid (291c) (38 mg, 81% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H, D2O exchangeable), 9.21 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.26 – 8.13 (m, 3H, 2H D2O exchangeable), 8.11 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.13 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 3.91 (s, 2H), 3.33 – 3.21 (m, 4H), 2.09 (s, 6H), 1.59 – 1.49 (m, 2H), 1.42 – 1.27 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS (ES+): 599.2 (M+1); (ES-): 597.2 (M-1). Scheme 292Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)picolinic acid (292c) Step-1: Preparation of methyl 6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (292a) Compound 292a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (70 mg, 0.106 mmol) in DMF (1 mL) using norbornan-1-amine hydrochloride (253a) (17.28 mg, 0.117 mmol), DIPEA (74.4 µL, 0.426 mmol) and HATU (52.6 mg, 0.138 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)-3-(9-((4- (((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (292a) (65 mg, 81% yield) as a yellow oil; MS (ES+): 773.3 (M+Na); (ES-) 749.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)picolinate (292b) Compound 292b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (292a) (65 mg, 0.087 mmol) in DCM (2 mL) using TFA (200 µL, 2.60 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)picolinate (292b) (40 mg, 71% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 651.2 (M+1); (ES-): 649.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.1]heptan-1-ylcarbamoyl)picolinic acid (292c)Compound 2 , from methyl 3-(9- o[2,3- d]oxepin-8-y mol) in THF / MeOH .615 mmol) stirring for 2 omethyl)- 2,6-dimethyl (bicyclo[2.2. a white solid;1H NM exchangeabl 3 (d, J = 8.0 Hz, 1H), 7.6 (t, J = 5.1 Hz, 2H), 3.9 66 (m, 8H), 1.46 – 1.33 (Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinic acid (293d) Step-1: Preparation of methyl 6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (293b) Compound 293b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (1 mL) using bicyclo[2.2.2]octan-1-amine hydrochloride (293a) (17.28 mg, 0.117 mmol; CAS # 1193-43-7), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 6-(bicyclo[2.2.2]octan-1- ylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (293b) (62 mg, 67% yield) as a yellow oil; MS (ES+): 787.4 (M+Na).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinate (293c) Compound 293c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (293b) (62 mg, 0.081 mmol) in DCM (2 mL) using TFA (92.4 mg, 0.081 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinate (293c) (47 mg, 87% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 665.2 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinic acid (293d) Compound 293d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinate (293c) (47mg, 0.071 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 421 µL, 0.843 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinic acid (293d) (19mg, 0.029 mmol) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H, D2O exchangeable), 8.27 – 8.13 (m, 4H, D2O exchangeable), 8.11 (d, J = 6.8 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 4.37 (t, J = 5.1 Hz, 2H), 3.95 – 3.84 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.08 (s, 6H), 2.01 – 1.89 (m, 6H), 1.74 – 1.54 (m, 7H); MS (ES+): 651.3 (M+1); (ES-): 649.3 (M-1). Scheme 294 Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinic acid (294c)Step-1: Prepa butoxycarbon 2,3-d]oxepin- 8-yl)picolinat Compound 2 9, from 5-(9- ((4-(((tert-but dihydrobenzo mg, 0.123 mmol) in DM g, 0.135 mmol), DIPE vernight to afford after w moyl)-3-(9- ((4-(((tert-but dihydrobenzo w solid; MS (ES+): 773.3 Step-2: Prepa dihydrobenzo ate (294b) Compound 2 , frommethyl 6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (294a) (62mg, 0.083 mmol) in DCM (2 mL) using TFA (188 mg, 1.651 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinate (294b) (46mg, 86% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 651.2 (M+1); (ES-): 649.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinic acid (294c) Compound 294c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(bicyclo[2.2.2]octan-1-ylcarbamoyl)picolinate (294b) (46 mg, 0.071 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 421 µL, 0.843 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[2.2.2]octan-1- ylcarbamoyl)picolinic acid (294c) (31 mg, 69% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.99 (s, 1H, D2O exchangeable), 8.25 – 8.09 (m, 5H, partially D2O exchangeable), 8.03 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.25 – 7.20 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.01 – 3.87 (m, 2H), 3.29 – 3.24 (m,2H), 2.14 (s, 3H), 2.02 – 1.81 (m, 6H), 1.71 – 1.54 (m, 7H); MS (ES+): 637.2 (M+1); (ES-): 635.2 (M-1). Scheme 295 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((3-methylcyclobutyl)methyl)carbamoyl)picolinic acid (295d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((3- methylcyclobutyl)methyl)carbamoyl)picolinate (295b) Compound 295b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- di m 0. l) st bu d] a ye St di (2 C yl 3- di (2 2 hdihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((3-methylcyclobutyl)methyl)carbamoyl)picolinate(295c) (45 mg, 80% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 639.2 (M+1); (ES-): 637.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((3-methylcyclobutyl)methyl)carbamoyl)picolinic acid (295d) Compound 295d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((3-methylcyclobutyl)methyl)carbamoyl)picolinate (295c) (45mg, 0.070 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 421 µL, 0.843 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((3- methylcyclobutyl)methyl)carbamoyl)picolinic acid (295d) (27 mg, 36% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.28 - 9.13 (m, 1H), 8.24 – 8.05 (m, 5H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 0.8 Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.00 - 3.83 (m, 2H), 3.43 (t, J = 6.7 Hz, 2H), 3.27 (d, J = 5.1 Hz, 2H), 2.45 - 2.32 (m, 1H), 2.21 – 2.13 (m, 1H), 2.09 (s, 6H), 1.96 – 1.84 (m, 1H), 1.70 – 1.59 (m, 1H), 1.44 - 1.19 (m, 2H), 1.08 (d, J = 6.9 Hz, 2H), 1.01 (d, J = 5.8 Hz, 1H); MS (ES+): 625.2 (M+1); (ES-): 623.3 (M-1). Scheme 296 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3-difluorocyclobutyl)carbamoyl)picolinic acid (296d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3- difluorocyclobutyl)carbamoyl)picolinate (296b) Compound 296b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (75 mg, 0.114mmol) in DMF (4 mL) using 3,3-difluorocyclobutan-1-amine hydrochloride (296a) (19.64 mg, 0.137 mmol; CAS # 637031-93-7), DIPEA (80 µL, 0.456 mmol) and HATU (56.4 mg, 0.148 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3,3-difluorocyclobutyl)carbamoyl)picolinate (296b) (78 mg, 92% yield) as a yellow oil; MS (ES-): 745.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3-difluorocyclobutyl)carbamoyl)picolinate (296c) Compound 296c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3-difluorocyclobutyl)carbamoyl)picolinate (296b) (78 mg, 0.104 mmol) in DCM (2 mL) using TFA (119 mg, 1.044 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihyd c) (63 m (M+1 Step- dihyd (296d Com meth d]oxe THF / ol) stirri l)- 2,6-d diflu ;1H NMR ), 9.50 , J = 8.0 H 4.29 (m, 3 R (282 calcuae o33 30 2 4 5.. ..2: , . ; , . ; , . ; ou : , . ; , 5.43; N, 7.82 Scheme 297Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinic acid (297d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3- trifluoropropyl)carbamoyl)picolinate (297b) Compound 297b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 3,3,3-trifluoropropan-1-amine (297a) (16.51 mg, 0.146 mmol; CAS# 460-39-9), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinate (297b) (82 mg, 90 % yield) as a yellow oil; MS (ES+): 775.7 (M+Na); (ES-): 751.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinate (297c) Compound 297c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinate (297b) (82 mg, 0.109 mmol) in DCM (2 mL) using TFA (124 mg, 1.089 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinate (297c) (48 mg, 68% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 653.2 (M+1); (ES-): 651.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinic acid (297d) Compound 297d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3-trifluoropropyl)carbamoyl)picolinate (297c) (48 mg, 0.074 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 421 µL, 0.843 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3,3,3- trifluoropropyl)carbamoyl)picolinic acid (297d) (34 mg, 44% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H, D2O exchangeable), 10.02 (s, 1H, D2O exchangeable), 9.36 (t, J = 6.0 Hz, 1H, D2O exchangeable), 8.18 (d, J = 8.0 Hz, 1H), 8.16 – 8.08 (m, 3H, 2H D2O exchangeable), 7.95 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.11 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.37 (t, J = 4.8 Hz, 2H), 3.99 – 3.85 (m, 2H), 3.66 – 3.54 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.66 – 2.56 (m, 2H), 2.07 (s, 6H);19F NMR (282 MHz, DMSO) δ -63.86; MS (ES+): 639.2 (M+1); (ES-): 637.1 (M-1). Scheme 298 Preparation of 6-((((3r,5r,7r)-adamantan-1-yl)methyl)carbamoyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (298d) Step-1: Preparation of methyl 6-((((3r,5r,7r)-adamantan-1-yl)methyl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (298b) Compound 298b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 1-Adamantanemethylamine (298a) (24.12 mg, 0.146 mmol; CAS# 17768-41-1), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 6-((((3r,5r,7r)-adamantan-1- yl)methyl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (298b) (85 mg, 87% yield) as a yellow oil; MS (ES+): 705.4 (M-Boc+2).( l ( - ,((((3r,5r,7r)-adamantan-1-yl)methyl)carbamoyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (298d) (39 mg, 81% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H, D2O exchangeable), 9.96 (s, 1H, D2O exchangeable), 9.00 (s, 1H, D2O exchangeable), 8.17 (d, J = 7.9 Hz, 1H), 8.09 (s, 3H, 2H D2O exchangeable), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.14 – 7.06 (m, 3H), 6.96 (s, 1H), 4.37 (t, J = 5.0 Hz, 2H), 3.96 – 3.85 (m, 2H), 3.30 – 3.21 (m, 2H), 3.07 (d, J = 6.5 Hz, 2H), 2.07 (s, 6H), 1.98 – 1.89 (m, 3H), 1.70 – 1.55 (m, 6H), 1.55 – 1.47 (m, 6H); MS (ES+): 691.3 (M+1); (ES-): 689.2 (M-1). Scheme 299Preparation of (R)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinic acid (299d) Step-1: Preparation of methyl (R)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3- yl)carbamoyl)picolinate (299b) Compound 299b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using (R)-Tetrahydrofuran-3-amine (299a) (12.72 mg, 0.146 mmol; CAS# 111769-26-7), DIPEA (0.085 mL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl (R)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinate (299b) (81 mg, 92% yield) as a yellow oil; MS (ES+): 749.2 (M+Na); (ES-): 725.2 (M-1). Step-2: Preparation of methyl (R)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinate (299c) Compound 299c was prepared according to the procedure reported in step-2 of scheme 8, from methyl (R)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinate (299b) (81mg, 0.111 mmol) in DCM (10 mL) using TFA (1 mL) and stirring at RT for 2 h to afford after workup methyl (R)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinate (299c) (59 mg, 77% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 627.2 (M+1); (ES-): 625.2 (M-1). Step-3: Preparation of (R)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinic acid (299d) Compound 299d was prepared according to the procedure reported in step-6 of scheme 12, from methyl (R)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((tetrahydrofuran-3-yl)carbamoyl)picolinate (299c) (59 mg, 0.094 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 0.5 mL) stirring for 2 h at 50oC to afford after work up and purification method-O, (R)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((tetrahydrofuran-3- yl)carbamoyl)picolinic acid (299d) (53 mg, 71.1 % yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H, D2O exchangeable), 10.00 (s, 1H, D2O exchangeable), 9.23 (d, J =7.3 Hz, 1H, D2O exchangeable), 8.27 – 8.13 (m, 4H, 3H D2O exchangeable), 8.12 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.63 – 4.50 (m, 1H), 4.38 (t, J = 5.0 Hz, 2H), 3.98 – 3.82 (m, 4H), 3.79 – 3.72 (m, 1H), 3.72 – 3.63 (m, 1H), 3.28 (t, J = 5.0 Hz, 2H), 2.31 – 2.17 (m, 1H), 2.09 (s, 6H), 1.99 – 1.87 (m, 1H); MS (ES+): 613.2 (M+1); (ES-): 611.1 (M-1). Scheme 300 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinic acid (300c) Step-1: Preparation of methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (300a) Compound 300a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (89 mg, 0.135 mmol) in DMF (1 mL) using (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (284a) (21.98 mg, 0.149 mmol), DIPEA (95 µL, 0.541 mmol) and HATU (66.9 mg, 0.176 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 6-(((1S,2S,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (300a) (81 mg, 92% yield) as a yellow oil; MS (ES+): 773.3 (M+Na); (ES-): 749.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (300b) Compound 300b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (300a) (98 mg, 0.131 mmol) in DCM (1 mL) using TFA (302 µL, 0.392mmol) and stirr -2,6- dimethylphenyl 4R)- bicyclo[2.2.1]h oil, which was used as such fo Step-3: Prepara dihydrobenzo[b yl)carbamoyl)p Compound 300 12, from methyl 3-(9-((4y , y p y y , y ieno[2,3- d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinate (300b) (80 mg, 0.123 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 615 µL, 1.229 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (300c) (55 mg, 70% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H, D2O exchangeable), 8.74 (d, J = 7.2 Hz, 1H, D2O exchangeable), 8.27 – 8.15 (m, 4H, 3H is D2O exchangeable), 8.12 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.13 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 3.98 – 3.86 (m, 2H), 3.86 – 3.74 (m, 1H), 3.28 (t, J = 5.0 Hz, 2H), 2.34 – 2.27 (m, 1H), 2.27 – 2.20 (m, 1H), 2.09 (s, 6H), 1.79 – 1.65 (m, 1H), 1.61 – 1.46 (m, 4H), 1.30 – 1.09 (m, 3H); MS (ES+): 637.3 (M+1); (ES-): 635.3 (M-1); Analysis calculated for C36H36N4O5S.(HCl).3(H2O): C, 59.45; H, 5.96; Cl, 4.87; N, 7.70; Found: C, 59.21; H, 5.91; Cl, 5.17; N, 8.01. Scheme 301 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinic acid (301d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- cyanocyclohexyl)carbamoyl)picolinate (301b)Compound 301b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-26-dimethylphenyl)carbamoyl)-45- di m (2 t R bu d] oil St di Co yl 3- di m d aft di m (E St di Co m d] T sti 2, cyNMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H, D2O exchangeable), 9.98 (s, 1H, D2O exchangeable), 9.13 (s, 1H, D2O exchangeable), 8.27 – 8.16 (m, 4H, 3H is D2O exchangeable), 8.12 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 3.96 – 3.85 (m, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.45 – 2.34 (m, 2H), 2.10 (s, 6H), 1.91 – 1.70 (m, 4H), 1.67 – 1.55 (m, 2H), 1.41 – 1.24 (m, 1H); MS (ES+): 650.2 (M+1); (ES-): 648.2 (M-1). Scheme 302Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinic acid (302c) Step-1: Preparation of methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (302a) Compound 302a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (89 mg, 0.135 mmol) in DMF (1 mL) using (1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (CAS#: 65481-69-8) (285a) (21.98 mg, 0.149 mmol), DIPEA (95 µL, 0.541 mmol) and HATU (66.9 mg, 0.176 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 6- (((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (302a) (97 mg, 95% yield) as a yellow oil; MS (ES+): 773.2 (M+Na); (ES-): 749.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (302b) Compound 302b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (302a) (97 mg, 0.129 mmol) in DCM (1 mL) using TFA (299 µL, 3.88 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinate (302b) (81 mg, 96% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 651.2 (M+1); (ES-): 649.3 (M-1).Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinic acid (302c) Compound 302c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinate (302b) (81 mg, 0.124 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 29.8 mg, 1.245 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (302c) 44 mg, 56% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.90 (s, 1H, D2O exchangeable), 9.94 (s, 1H, D2O exchangeable), 8.78 (d, J = 7.2 Hz, 1H, D2O exchangeable), 8.37 (s, 3H, D2O exchangeable), 8.19 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.15 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.38 (t, J = 5.0 Hz, 2H), 3.95 – 3.85 (m, 2H), 3.84 – 3.73 (m, 1H), 3.28 (t, J = 5.0 Hz, 2H), 2.33 – 2.27 (m, 1H), 2.27 – 2.20 (m, 1H), 2.10 (s, 6H), 1.79 – 1.66 (m, 1H), 1.63 – 1.45 (m, 4H), 1.27 – 1.10 (m, 3H); MS (ES+): 637.2 (M+1); (ES-): 635.3 (M-1). Scheme 303 Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinic acid (303d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclopentyl)carbamoyl)picolinate (303b) Compound 303b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (80 mg, 0.124 mmol) in DMF (1 mL) using 1-methylcyclopentan-1-amine hydrochloride (303a) (16.86 mg, 0.124 mmol; CAS# 102014-58-4), DIPEA (87 µL, 0.497 mmol) and HATU (61.4 mg, 0.162 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (303b) (80 mg, 89% yield) as a yellow oil; MS (ES+): 725.2 (M+Na); (ES-): 723.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (303c) Compound 303c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (303b) (80 mg, 0.110 mmol) in DCM (1 mL) using TFA (255 µL, 3.31 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (303c) (55 mg, 80 % yield) as a yellow oil, which was used as such for the next step; MS (ES+): 625.2 (M+1); (ES-): 623.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinic acid (303d) Compound 303d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (303c) (55 mg, 0.088 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 440 µL, 0.880 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclopentyl)carbamoyl)picolinic acid (303d) (45 mg, 84 % yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H, D2O exchangeable) 10.01 (s, 1H, D2O exchangeable), 8.53 (s, 1H, D2O exchangeable), 8.29 (s, 3H, D2O exchangeable), 8.18 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 1.2 Hz, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.38 (t, J = 4.9 Hz, 2H), 3.94 (s, 2H), 3.28 (t, J = 5.0 Hz, 2H), 2.15 (s, 5H), 1.74 – 1.61 (m, 6H), 1.46 (s, 3H); MS (ES+): 611.2 (M+1); (ES-): 609.2 (M-1). Scheme 304Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[23-d]oxepin-8-yl)-6-(((1r 3s)-3-ethyladamantan-1-yl)carbamoyl)picolinic a S d et C - (( d m m at b d s a S d ( C yl 3 d ( 2 h d ( 4 ( S d a C md]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (304c) (52 mg, 0.072 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 362 µL, 0.723 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3- ethyladamantan-1-yl)carbamoyl)picolinic acid (304d) (36 mg, 71% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H, D2O exchangeable), 8.33 (s, 1H, D2O exchangeable), 8.25 (s, 3H, D2O exchangeable), 8.18 – 8.07 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.13 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.37 (t, J = 4.8 Hz, 2H), 3.95 – 3.83 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.18 – 2.11 (m, 3H), 2.09 (s, 6H), 2.02 – 1.94 (m, 2H), 1.80 (s, 2H), 1.67 – 1.55 (m, 2H), 1.55 – 1.50 (m, 1H), 1.41 (d, J = 2.7 Hz, 4H), 1.16 (q, J = 7.5 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H); MS (ES+): 705.3 (M+1); (ES-): 703.3 (M-1). Scheme 305 Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (305c) Step-1: Preparation of methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)picolinate (305a) Compound 305a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (76 mg, 0.118 mmol) in DMF (1 mL) using (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (CAS#: 39245- 79-9) (284a) (19.18 mg, 0.130 mmol), DIPEA (82 µL, 0.472 mmol) and HATU (58.4 mg, 0.153mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 6- (((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (305a) (75 mg, 86% yield) as a yellow oil; (ES-): 735.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (305b) Compound 305b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)picolinate (305a) (75mg, 0.102 mmol) in DCM (1 mL) using TFA (235 µL, 3.05 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinate (305b) (48 mg, 74% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 637.2 (M+1); (ES-): 635.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinic acid (305c) Compound 305c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinate (305b) (48 mg, 0.075 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 377 µL, 0.754 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2S,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (305c) (25 mg, 53% yield) HCl salt as a yellow solid;1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H, D2O exchangeable), 8.69 (d, J = 7.2 Hz, 1H, D2O exchangeable), 8.27 – 8.09 (m, 4H, 3H is D2O exchangeable), 8.04 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 7.24 - 7.19 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.37 (t, J = 4.9 Hz, 2H), 3.99 – 3.88 (m, 2H), 3.83 – 3.72 (m, 1H), 3.30 – 3.25 (m, 2H), 2.34 – 2.26 (m, 1H), 2.26 – 2.19 (m, 1H), 2.14 (s, 3H), 1.77 – 1.67 (m, 1H), 1.57 – 1.47 (m, 4H), 1.27 – 1.13 (m, 3H); MS (ES+): 623.2 (M+1); (ES-): 621.2 (M-1). Scheme 306Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)picolinic acid (306c) Step-1: Preparation of methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)picolinate (306a) Compound 306a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (80 mg, 0.124 mmol) in DMF (1 mL) using (1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (285a) (20.18 mg, 0.137 mmol), DIPEA (87 µL, 0.497 mmol) and HATU (61.4 mg, 0.162 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 6-(((1S,2R,4R)- bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (306a) (72 mg, 79% yield) as a yellow oil; MS (ES+): 737.3 (M+1); (ES-): 735.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2- yl)carbamoyl)picolinate (306b) Compound 306b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)carbamoyl)-3-(9-((4-(((tert-bu in- 8- sti m bi as us St di yl C m in- 8- in T sti 2- m bi so D 1H H), 4. .25 (m , 3HPreparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinic acid (307c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3- ethyladamantan-1-yl)carbamoyl)picolinate (307a) Compound 307a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (76 mg, 0.118 mmol) in DMF (1 mL) using (3-Ethyl-1-adamantyl)amine hydrochloride (304a) (28.0 mg, 0.130 mmol; CAS# 80121-67-1), DIPEA (82 µL, 0.472 mmol) 58.4 mg, 0.153 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (307a) (66 mg, 69% yield) as a yellow oil. Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (307b) Compound 307b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (307a) (66 mg, 0.082 mmol) in DCM (1 mL) using TFA (189 µL, 2.460 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (307b) (45 mg, 78 % yield) as a yellow oil, which was used as such for the next step; MS (ES+): 705.3 (M+1); (ES-): 703.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinic acid (307c) Compound 307c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinate (307b) (45 mg, 0.064 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 319 µL, 0.638 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((1r,3s)-3-ethyladamantan-1-yl)carbamoyl)picolinic acid (307c) (18 mg, 41% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H, D2O exchangeable), 8.29 (s, 1H, D2O exchangeable), 8.24 (s, 2H, D2O exchangeable), 8.16 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.26 – 7.22 (m, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.01 – 3.87 (m, 2H), 3.28 (t, J = 5.1 Hz, 2H), 2.18 – 2.12 (m, 5H), 2.11 – 2.07 (m, 1H), 2.05 – 1.95 (m, 2H), 1.84 – 1.78 (m, 2H), 1.67 – 1.56 (m, 2H), 1.53 (d, J = 7.0 Hz, 1H), 1.47 – 1.36 (m, 4H), 1.17 (q, J = 7.5 Hz, 2H), 0.80 (t, J = 7.5 Hz, 3H); MS (ES+): 691.3 (M+1); (ES-): 689.2 (M-1). Scheme 308 Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinic acid (308c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- cyanocyclohexyl)carbamoyl)picolinate (308a) Compound 308a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (80 mg, 0.124 mmol) in DMF (1 mL) using 1-cyanocyclohexylamine hydrochloride (301a) (21.96 mg, 0.137 mmol), DIPEA (87 µL, 0.497 mmol), HATU (61.4 mg, 0.162 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- cyanocyclohexyl)carbamoyl)picolinate (308a) (59 mg, 63% yield) as a yellow oil. Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinate (308b) Compound 308b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinate (308a) (59 mg, 0.079 mmol) in DCM (1 mL) using TFA (182 µL, 2.360 mmol) and stirring at RT for 2 h toafford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinate (308b) (41 mg, 80% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 650.3 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinic acid (308c) Compound 308c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-((1-cyanocyclohexyl)carbamoyl)picolinate (308b) (41 mg, 0.063 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 315 µL, 0.631 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- cyanocyclohexyl)carbamoyl)picolinic acid (308c) (11 mg, 27% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H, D2O exchangeable), 9.09 (s, 1H, D2O exchangeable), 8.24 (d, J = 8.0 Hz, 1H), 8.19 (s, 3H, D2O exchangeable), 8.06 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.65 – 7.59 (m, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.09 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 4.38 (t, J = 5.1 Hz, 2H), 4.02 – 3.90 (m, 2H), 3.30 – 3.27 (m, 2H), 2.43 (d, J = 12.5 Hz, 2H), 2.16 (s, 3H), 1.89 – 1.71 (m, 4H), 1.66 – 1.57 (m, 2H), 1.52 (d, J = 7.0 Hz, 2H); MS (ES+): 636.2 (M+1); (ES-): 634.2 (M-1). Scheme 309Pr di St ) Co m 50 32- 0) 0.4mmol) in DCM (20 mL) to afford after workup and purification method-G, methyl 2-bromo-5-iodo-4- (2-(5-methylthiophen-3-yl)ethoxy)benzoate (309b) (15.5 g, 77% yield) as a white solid;1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.31 (s, 1H), 7.06 (d, J = 1.4 Hz, 1H), 6.87 (t, J = 1.3 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 3.00 (t, J = 6.5 Hz, 2H), 2.41 (d, J = 1.1 Hz, 3H). Step-2: Preparation of methyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylate (309c)Compound 309c was prepared according to the procedure reported in step-3 of scheme 1, from methyl 2-bromo-5-iodo-4-(2-(5-methylthiophen-3-yl)ethoxy)benzoate (309b) (7.8 g, 16.21 mmol) in DMSO (150 mL) using K2CO3(4.48 g, 32.4 mmol), Pd(OAc)2(0.364 g, 1.621 mmol) and triphenylphosphine (0.850 g, 3.24 mmol) and stirring for 30 min at 100 °C to afford after workup and purification method-AA, methyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (309c) (5.5 g, 15.57 mmol, 96 % yield) as an off-white solid;1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.35 (s, 1H), 6.74 (d, J = 1.2 Hz, 1H), 4.36 – 4.26 (m, 2H), 3.86 (s, 3H), 3.12 (t, J = 5.0 Hz, 2H), 2.42 (d, J = 1.1 Hz, 3H). Step-3: Preparation of 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (309d) Compound 309d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (309c) (5.5 g, 15.57 mmol) in THF / MeOH (50 mL; ratio 1:1) using lithium hydroxide hydrate (2.61 g, 62.3 mmol) in water (10 mL) and stirring for 3h at 50 °C to afford after workup 8-bromo-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (309d) (5.1 g, 97% yield) as a white solid; MS (ES-) 337.0 and 339.0 (M-1). Step-4: Preparation of 2-(trimethylsilyl)ethyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylate (309e) Compound 309e was prepared according to the procedure reported in step-1 of scheme 26, from 8- bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (309d) (4 g, 11.79 mmol) in DCM (100 mL) using 2-(trimethylsilyl)ethan-1-ol (1.394 g, 11.79 mmol), DCC (2.433 g, 11.79 mmol) and DMAP (0.288 g, 2.358 mmol) stirring for 10 h at RT to afford after work up 2- (trimethylsilyl)ethyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (309e) (4.2 g, 81% yield) as a white solid;1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.34 (s, 1H), 6.74 (d, J = 1.2 Hz, 1H), 4.43 – 4.35 (m, 2H), 4.35 – 4.26 (m, 2H), 3.11 (t, J = 5.0 Hz, 2H), 2.42 (d, J = 1.1 Hz, 3H), 1.17 – 1.06 (m, 2H), 0.07 (s, 9H). Step-5: Preparation of methyl 3-(2-methyl-9-((2-(trimethylsilyl)ethoxy)carbonyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (309f) Compound 309f was prepared according to the procedure reported in step-3 of scheme 21, from 2- (trimethylsilyl)ethyl 8-bromo-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (309e) (900 mg, 2.048 mmol) in THF (3 mL) using methyl 6-(propylcarbamoyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (13b) (1070 mg, 3.07 mmol), K3PO4(3M) (1707 µL, 5.12 mmol), Pd2(dba)3(188 mg, 0.205 mmol) and XPhos (195 mg, 0.410 mmol) to afford after work up and purification method-A, methyl 3-(2-methyl-9-((2-(trimethylsilyl)ethoxy)carbonyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (309f) (1.1 g, 92% yield) as a yellow oil; MS (ES+): 581.2 (M+1). Step-6: Preparation of 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (309g) Compound 309g was prepared according to the procedure reported in step-2 of scheme 48, from methyl 3-(2-methyl-9-((2-(trimethylsilyl)ethoxy)carbonyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(propylcarbamoyl)picolinate (309f) (1.1 g, 1.894 mmol) in THF (50 mL) using TBAF (1M in THF) (9.47 mL, 9.47 mmol) and stirring for 30 min at RT to afford after work up and purification method-O, 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (309g) (820 mg, 90% yield) as a white solid; MS (ES+): 481.1 (M+Na); (ES-): 479.1 (M-1). Step-7: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (309h) Compound 309h was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (309g) (120 mg, 0.250 mmol) in DCM (3 mL) using 1-methyl-1H- imidazole (51.3 mg, 0.624 mmol), methanesulfonyl chloride (71.5 mg, 0.624 mmol), tert-butyl (4- amino-3,5-dimethylbenzyl)carbamate (172a) (188 mg, 0.749 mmol) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (309h) (152 mg, 85% yield) as a yellow oil; MS (ES+): 735.2 (M+Na): MS (ES-): 711.2 (M+1). Step 8: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (309i) Compound 309i was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (309h) (152mg, 0.213 mmol) in DCM (10 mL) using TFA (1 mL) and stirring at RT for 2 h to afford after workup methyl 3- (9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (309i) (118 mg, 90% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 613.2 (M+1); MS (ES-): 611.3 (M-1). Step-9: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (309j)Comp methy dihydr mmol) 1.000 mmol) (amino pin-8- yl)-6-( MR (300 M 3 (t, J = 6.1 98 (s, 1H), 7 .89 (s, 2H), 3 ), 0.90 (tPreparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinic acid (310d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3- (hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310b) Compound 310b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using (3-aminocyclobutyl)methanol hydrochloride (310a) (25.1 mg, 0.182 mmol; CAS# 130369-06-1), DIPEA (106 µL, 0.608 mmol), HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310b) (67 mg, 74% yield) as a yellow oil; MS (ES+): 741.3 (M+1), (ES-): 739.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310c) Compound 310c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310b) (67 mg, 0.090 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310c) (50 mg, 64% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 641.3 (M+1); (ES-): 639.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinic acid (310d) Compound 310d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3-(hydroxymethyl)cyclobutyl)carbamoyl)picolinate (310c) (50 mg, 0.078 mmol) in THF / MeOH (5 mL; ratio 1:1) using lithium hydroxide monohydrate (608 µL, 1.216 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3- (hydroxymethyl)cyclobutyl)carbamoyl)picolinic acid (310d) (29 mg, 38% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H, D2O exchangeable), 9.87 (s, 1H, D2O exchangeable), 9.16 (d, J = 7.9 Hz, 1H, D2O exchangeable), 8.19 – 8.01 (m, 5H, 3H is D2O exchangeable), 7.88 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.09 – 6.97 (m, 3H), 6.92 (s, 1H), 4.63 – 4.38 (m, 1H, D2O exchangeable), 4.36 – 4.23 (m, 3H), 3.84 (q, J = 5.7 Hz, 2H), 3.35 – 3.32 (m, 2H), 3.21 (t, J = 5.1 Hz, 2H), 2.29 – 2.15 (m, 2H), 2.13 – 1.89 (m, 7H), 1.88 – 1.72 (m, 2H); MS (ES+): 627.3 (M+1); (ES-): 625.2 (M-1). Scheme 311Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((trans-3-hydroxycyclobutyl)carbamoyl)picolinic acid (311d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((trans)-3- hydroxycyclobutyl)carbamoyl)picolinate (311b) Compound 311b was prepared according to the procedure reported in step-1 of scheme 39, from 5- (9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using trans-3-aminocyclobutan-1-ol hydrochloride (311a) (22.55 mg, 0.182 mmol; CAS# 1205037-95-1), DIPEA (106 µL, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(((trans)-3-hydroxycyclobutyl)carbamoyl)picolinate (311b) (62 mg, 70% yield) as a yellow oil; MS (ES-): 725.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((trans-3-hydroxycyclobutyl)carbamoyl)picolinate (311c) Compound 311c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(((trans)-3-hydroxycyclobutyl)carbamoyl)picolinate (311b) (62 mg, 0.085 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((trans-3-hydroxycyclobutyl)carbamoyl)picolinate (311c) (46 mg, 60% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 627.2 (M+1); (ES-): 625.2 (M-1).Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((trans-3-hydroxycyclobutyl)carbamoyl)picolinic acid (311d) Compound 311d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((trans-3-hydroxycyclobutyl)carbamoyl)picolinate (311c) (46 mg, 0.073 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 608 µL, 1.216 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((trans-3- hydroxycyclobutyl)carbamoyl)picolinic acid (311d) (10 mg, 13% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H, D2O exchangeable), 9.26 (d, J = 7.4 Hz, 1H, D2O exchangeable), 8.23 – 8.05 (m, 5H, 3H D2O exchangeable), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.11 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 5.15 – 5.06 (m, 1H, D2O exchangeable), 4.57 – 4.45 (m, 1H), 4.40 – 4.26 (m, 3H), 3.96 – 3.84 (m, 2H), 3.30 – 3.24 (m, 2H), 2.39 – 2.28 (m, 2H), 2.28 – 2.14 (m, 2H), 2.09 (s, 6H); MS (ES+): 613.2 (M+1); (ES-): 611.1 (M-1). Scheme 312 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinic acid (312c)Step-1: Prepar butoxycarbon ieno[2,3- d]oxepin-8-yl) Compound 3 39, from 5-(9- ((4-(((tert-but dihydrobenzo[ 0 mg, 0.122 mmol) in DM mg, 0.182 mmol), DIPE overnight to afford after w bamoyl)-3-(9- ((4-(((tert-but dihydrobenzo[ ellow oil; MS (ES-): 721.2 ( Step-2: Prepar 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinate (312b) Compound 312b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (312a) (58mg, 0.080 mmol) in DCM (10 mL) using TFA (0.5 mL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinate (312b) (36 mg, 48% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 623.2 (M+1); (ES-): 621.4 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinic acid (312c) Compound 312c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinate (312b) (36mg, 0.058 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 0.608 mL, 1.216 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (bicyclo[1.1.1]pentan-1-ylcarbamoyl)picolinic acid (312c) (18 mg, 24% yield) HCl salt as a yellow solid;1H NMR (300 MHz, DMSO-d6) δ 10.07 – 9.79 (m, 1H, D2O exchangeable), 9.58 (s, 1H, D2O exchangeable), 8.15 – 8.03 (m, 4H, 2H D2O exchangeable), 7.89 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.05 (s, 2H), 7.02 (d, J = 5.2 Hz, 1H), 6.94 – 6.88 (m, 1H), 4.30 (t, J = 4.9 Hz, 2H), 3.91 –3.78 (m, 2H), 3.23 – 3.16 (m, 2H), 2.08 (s, 6H), 2.04 – 1.95 (m, 6H), 1.17 (d, J = 6.5 Hz, 1H); MS (ES+) 609.2 (M+1), (ES-) 607.2 (M-1). Scheme 313 Preparation of 3-(9 dihydrobenzo[b]thi rbamoyl)picolinic acid (313d) Step-1: Preparation dimethylphenyl)cacyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313b) Compound 313b was prepared according to the procedure reported in step-1 of scheme 39, from 5- (9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 3-aminobicyclo[1.1.1]pentane-1-carbonitrile hydrochloride (313a) (19.73 mg, 0.182 mmol), DIPEA (106 µL, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313b) (63 mg, 69% yield) as a yellow oil; MS (ES-): 746.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313c) Compound 313c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313b) (63 mg, 0.084 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313c) (42 mg, 53% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 648.2 (M+1); (ES-): 646.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinic acid (313d) Compound 313d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinate (313c) (42 mg, 0.065 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((3- cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)picolinic acid (313d) (17 mg, 22% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H, D2O exchangeable), 9.99 (s, 1H, D2O exchangeable), 9.87 (s, 1H, D2O exchangeable), 8.30 – 8.13 (m, 4H, 3H D2O exchangeable), 8.11 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.37 (t, J = 4.9 Hz, 2H), 3.97 – 3.82 (m, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.64 (s, 6H), 2.08 (s, 6H); MS (ES+): 634.1 (M+1); (ES-): 632.2 (M-1). Scheme 314Preparation of 3-(9-((4-(aminomethyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (314d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- (trifluoromethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (314b) Compound 314b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole 66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl (4-amino-3- (trifluoromethyl)benzyl)carbamate (314a) (280 mg, 0.965 mmol; CAS# 1196702-82-5) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- (trifluoromethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (314b) (103 mg, 43% yield); MS (ES+): 739.1 (M+1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (314c) Compound 314c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (314b) (103 mg, 0.139 mmol) in DCM (5 mL) using TFA (107 µL, 1.394 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((4-(aminomethyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (314c) (44 mg, 49% yield), which was used as such without further purification; MS (ES+): 639.1 (M+1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (314d) Compound 314d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-(trifluoromethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (314c) (44 mg, 0.069 mmol) in THF (5 mL) using lithium hydroxide monohydrate (8.67 mg, 0.207 mmol) in water (1 mL) stirring overnight at RT to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- (trifluoromethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (314d) (17.9 mg, 42% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H, D2O exchangeable), 10.36 (s, 1H, D2O exchangeable), 9.16 (t, 1H, D2O exchangeable), 8.27 (s, 3H, D2O exchangeable), 8.19 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.95 – 7.86 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.37 (t, 2H), 4.11 (s, 2H), 3.31 – 3.24 (m, 4H), 1.66 -1.49 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);19F NMR (282 MHz, DMSO-d6) δ -59.54; MS (ES+): 625.2 (M+1); (ES-): 623.1 (M- 1). Scheme 315Preparation of 3-(9-((4-(aminomethyl)-2-iodophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (315d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- iodophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (315b) Compound 315b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl (4-amino-3- iodobenzyl)carbamate (315a) (280 mg, 0.804 mmol; CAS# 152918-49-5) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- iodophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (315b) (129 mg, 50% yield); MS (ES+): 797.1 (M+1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-iodophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (315c) Compound 315c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-iodophenyl)carbamoyl)-4,5-dihydroben 0.162 mmol) in D fter workup me no[2,3- d]oxepin-8 hich was used as suc Step-3: Pre dihydroben Compound from methyl 3-(9 ]oxepin-8- yl)-6-(prop m hydroxide o afford after work )-4,5- dihydroben mg, 34% yield) HCl ngeable), 10.24 (s, 1 (m, 5H, 3H D2O ex, , , , , , , , Hz, 1H), 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.37 (t, J = 4.9 Hz, 2H), 3.98 (s, 2H), 3.31– 3.24 (m, 4H), 1.67 - 1.50 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 683.1 (M+1); (ES-): 681.00 (M-1). Scheme 316Preparation of 3-(9-((4-(aminomethyl)-2-(carboxymethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (316e) Step-1: Preparation of methyl 3-(9-((2-(2-(tert-butoxy)-2-oxoethyl)-4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (316b) Compound 316b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (400 mg, 0.857 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (176 mg, 2.144 mmol), methanesulfonyl chloride (246 mg, 2.144 mmol), and tert-butyl 2-(2-amino-5-(((tert- butoxycarbonyl)amino)methyl)phenyl)acetate (316a) (288 mg, 0.857 mmol; CAS# 502481-72-3) to afford after work up and purification method-AG, methyl 3-(9-((2-(2-(tert-butoxy)-2-oxoethyl)-4- (((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinate (316b) (340 mg, 51% yield); MS (ES+): 807.3 (M+Na).Step oxo (pro (pro carb Com 8, from buto 6- (pro .33 mm buto (pro (am dihy ld), whi Step dihy Com (5- (am dihy ol) in T stirr)-2- (carboxymethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (316e) (31.2 mg, 46% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H, D2O exchangeable), 10.17 (s, 1H, D2O exchangeable), 9.13 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.23 – 8.09 (m, 4H, 3H D2O exchangeable), 8.05 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.35 – 7.28 (m, 3H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.44 – 4.30 (m, 2H), 3.97 (s, 2H), 3.60 (s, 2H), 3.30 – 3.23 (m, 4H), 1.64 - 1.50 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 615.2 (M+1); (ES-): 613.1 (M-1). Scheme 317O O O O O OH S S N LiOH N O HN O O HN O O HN O HN O O NH2NH2316c317aPreparation of 3-(9-((4-(aminomethyl)-2-(2-(tert-butoxy)-2-oxoethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (317a) Compound 317a was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-(2-(tert-butoxy)-2-oxoethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (316c) (70 mg, 0.102 mmol) in THF (5 mL) using lithium hydroxide monohydrate (12.87 mg, 0.307 mmol) in water (1 mL) stirring for 2 h at RT to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-(2- (tert-butoxy)-2-oxoethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (317a) (3.5 mg, 5% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H, D2O exchangeable), 9.15 (t, J = 5.9 Hz, 1H, D2O exchangeable), 8.24 – 8.08 (m, 4H), 8.04 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.33 – 7.26 (m, 2H), 7.26 – 7.20 (m, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.43 – 4.35 (m, 2H), 3.97 (s, 2H), 3.57 (s, 2H), 3.31 – 3.22 (m, 4H), 1.63 – 1.53 (m, 2H), 1.33 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 671.3 (M+1); (ES-): 669.2 (M-1). Scheme 318Preparation of 3-(9-((4-(aminomethyl)-2-ethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (318e) Step-1: Preparation of tert-butyl (4-amino-3-ethylbenzyl)carbamate (318b) Compound 318b was prepared according to the procedure reported in step-1 of scheme 173, from 4- amino-3-ethylbenzonitrile (318a) (0.3 g, 2.052 mmol; CAS# 170230-87-2) in MeOH (10 mL), using nickel(II) chloride.6H2O (0.366 g, 1.539 mmol), sodium borohydride (0.699 g, 18.47 mmol), di-tert- butyl dicarbonate (0.448 mL, 2.052 mmol) and diethylenetriamine (1.336 mL, 12.31 mmol) to afford after work up and purification method-AG, tert-butyl (4-amino-3-ethylbenzyl)carbamate (318b) (275 mg, 54% yield); MS (ES+): 251.2 (M+1). Step-2: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- ethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (318c) Compound 318c was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (200 mg, 0.429 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (88 mg, 1.072 mmol), methanesulfonyl chloride (123 mg, 1.072 mmol), and tert-butyl (4-amino-3- ethylbenzyl)carbamate (318b) (268 mg, 1.072 mmol) to afford after work up and purification method- AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-ethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (318c) (109 mg, 36%yield); as a white solid; MS (ES+): 721.2 (M+Na). Step-3: Preparation of methyl 3-(9-((4-(aminomethyl)-2-ethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (318d) Compound 318d was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-ethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (318c) (109 mg, 0.156 mmol) in DCM (5 mL) using TFA (120 µL, 1.560 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((4-(aminomethyl)-2-ethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (318d) (47 mg, 50% yield), which was used as such without further purification; MS (ES+): 599.2 (M+1). Step-4: Preparation of 3-(9-((4-(aminomethyl)-2-ethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (318e) Compound 318e was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-ethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinate (318d) (47 mg, 0.079 mmol) in THF (5 mL) using lithium hydroxide monohydrate (9.88 mg, 0.236 mmol) in water (1 mL) to afford after work up and purification dihydrobenz mg, 21% yield) HCl s angeable), 9.98 (s, 1H, , 8.03 (s, 1H), 7.94 (d .08 (d, J = 5.2 Hz, 1H), .47 – 2.39 (m, 2H), 1.6 585.2 (M+1); (ES-Preparation of 3-(9-((4-(aminomethyl)-2-cyanophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (319d) Step-1: Preparation of tert-butyl (4-amino-3-cyanobenzyl)carbamate (319a) To a solution of tert-butyl (4-amino-3-iodobenzyl)carbamate (315a) (2.6 g, 7.47 mmol) in DMF (5 mL) was added dicyanozinc (2.192 g, 18.67 mmol) and Pd(PPh3)4(0.863 g, 0.747 mmol) at an ambient temperature and was stirred at 130° C for 2 h. The reaction was cooled to room temperature and poured into H2O and was extracted with ethyl acetate and dried over MgSO4. The organic layer was concentrated under vacuum to afford tert-butyl (4-amino-3-cyanobenzyl)carbamate (319a) (820 mg, 44% yield) which was used as such for the next step; MS (ES+): 270.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- cyanophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (319b) Compound 319b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl (4-amino-3- cyanobenzyl)carbamate (319a) (239 mg, 0.965 mmol) to afford after work up and purificationmethod-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-cyanophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (319b) (72 mg, 32% yield); MS (ES+): 696.2 (M+1). Step-3: Preparation of methyl 3-(9-((4-(aminomethyl)-2-cyanophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (319c) Compound rom methyl 3-(9-((4-(((t dihydroben 0.103 mmol) in D ter workup methyl 3-(9 -d]oxepin- 8-yl)-6-(pro r the next step; MS (E Step-4: Pre dihydroben Compound from methyl 3-(9 -d]oxepin- 8-yl)-6-(pro ium hydroxide m d purification dihydroben mg, 43% yield) HCl s angeable), 9.16 (t, J =8.0 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 4.38 (t, J = 4.8 Hz, 2H), 4.05 (s, 2H), 3.31 – 3.25 (m, 4H), 1.64 – 1.52 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 582.2 (M+1); (ES-): 580.1 (M-1); FT-IR (CN) = 2230.8 cm-1. Scheme 320Preparation of 3-(9-((4-(aminomethyl)-2-(2-hydroxyethyl)phenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (320f) Step-1: Preparation of 4-amino-3-(2-hydroxyethyl)benzonitrile (320b) Compound 320b was prepared according to the procedure reported in step-1 of scheme 135, from 3- (2-hydroxyethyl)-4-nitrobenzonitrile (320a) (1 g, 5.20 mmol) and palladium on carbon (Pd / C) (10% wt.) (0.028 g, 0.260 mmol) in MeOH (10 mL) and stirring under a hydrogen balloon at RT for 2 h to afford after work up 4-amino-3-(2-hydroxyethyl)benzonitrile (320b) (745 mg, 88 % yield); MS (ES+): 163.1 (M+1). Step-2: Preparation of tert-butyl (4-amino-3-(2-hydroxyethyl)benzyl)carbamate (320c) Compound 320c was prepared according to the procedure reported in step-1 of scheme 173, from 4- amino-3-(2-hydroxyethyl)benzonitrile (320b) (600 mg, 3.70 mmol) in MeOH (10 mL), using nickel(II) chloride.6H2O (659 mg, 2.77 mmol), sodium borohydride (1260 mg, 33.3 mmol), di-tert- butyl dicarbonate (859 µL, 3.70 mmol) and diethylenetriamine (2408 µL, 22.20 mmol) to afford after work up and purification method-AG, tert-butyl (4-amino-3-(2-hydroxyethyl)benzyl)carbamate (320c) (827 mg, 84% yield); MS (ES+): 267.1 (M+1). Step-3: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-(2- hydroxyethyl)phenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (320d)C 2- (m ca , 0. h n m h (p St di C yl 3- di m p m di m St di C m di m to h (p 0MHz, DMSO-d6) δ 12.89 (s, 1H, D2O exchangeable), 10.12 (s, 1H, D2O exchangeable), 9.18 (t, J = 6.1 Hz, 1H), 8.27 (s, 3H, D2O exchangeable), 8.20 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.37 – 7.32 (m, 2H), 7.26 (dd, J = 8.2, 2.1 Hz,1H), 7.08 (d, J = 5.2 Hz, 1H), 7.00 (s, 1H), 5.22 (s, 1H, D2O exchangeable), 4.37 (t, J = 4.8 Hz, 2H), 3.95 (q, J = 5.7 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.32 – 3.24 (m, 4H), 2.77 – 2.66 (m, 2H), 1.66 - 1.50 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 601.3 (M+1); (ES-): 599.1 (M-1). Scheme 321NH2O O O O O O S S 321a N N NBocHNO OTFAO HO O N O HN HNClS N O NBoc 72b 321b O O O O O OH S S N N O LiOH O HN O HN O HN HN NH NH 321c 321d Preparation of 3-(9-(isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (321d) Step-1: Preparation of tert-butyl 5-(8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)isoindoline-2-carboxylate (321b) Compound 321b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl 5-aminoisoindoline-2- carboxylate (321a) (188 mg, 0.804 mmol; CAS# 264916-06-5) to afford after work up and purification method-AG, tert-butyl 5-(8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)isoindoline-2-carboxylate (321b) (183 mg, 83% yield); MS (ES+): 683.3 (M+1); (ES-): 681.2 (M-1). Step-2: Preparation of methyl 3-(9-(isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (321c) Compound 321c was prepared according to the procedure reported in step-2 of scheme 8, from tert- butyl 5-(8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxamido)isoindoline-2-carboxylate (321b) (183 mg, 0.268 mmol) in DCM (5 mL) using TFA (206 µL, 2.68 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9- (isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (321c) (138 mg, 88% yield); MS (ES+): 583.2 (M+1); (ES-): 581.1 (M- 1). Step-3: Preparation of 3-(9-(isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinic acid (321d) Compound 321d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-(isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (321c) (138 mg, 0.237 mmol) in THF (5 mL) using lithium hydroxide monohydrate (29.8 mg, 0.711 mmol) in water (1 mL) stirring overnight at RT to afford after work up and purification method-O, 3-(9-(isoindolin-5-ylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(propylcarbamoyl)picolinic acid (321d) (82.6 mg, 61% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H, D2O exchangeable), 10.73 (s, 1H, D2O exchangeable), 9.60 (s, 2H, D2O exchangeable), 9.16 (t, J = 6.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.99 - 7.86 (m, 2H), 7.70 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.44 (dd, J = 8.3, 1.9 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.42 (d, J = 5.6 Hz, 4H), 4.36 (t, J = 5.0 Hz, 2H), 3.31 – 3.23 (m, 4H), 1.66 - 1.49 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 569.2 (M+1); (ES-): 567.1 (M-1). Scheme 322 Preparation of 6-(propylcarbamoyl)-3-(9-((1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (322d) Step-1: Preparation of tert-butyl 6-(8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (322b) Compound 322b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl 6-amino-3,4- dihydroisoquinoline-2(1H)-carboxylate (322a) (200 mg, 0.804 mmol; CAS# 164148-92-9) to affordafter work up and purification method-AG, tert-butyl 6-(8-(2-(methoxycarbonyl)-6- (propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate (322b) (176 mg, 79% yield); MS (ES+): 719.2 (M+Na); (ES- ): 695.2 (M-1). Step-2: Preparation of methyl 6-(propylcarbamoyl)-3-(9-((1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (322c) Compound 322c was prepared according to the procedure reported in step-2 of scheme 8, from tert- butyl 6-(8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (322b) (176 mg, 0.253 mmol) in DCM (5 mL) using TFA (195 µL, 2.53 mmol) stirring for 16 h at RT to afford after workup methyl 6-(propylcarbamoyl)-3-(9-((1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (322c) (127 mg, 84% yield); MS (ES+): 597.2 (M+1); (ES-): 595.2 (M-1). Step-3: Preparation of 6-(propylcarbamoyl)-3-(9-((1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-4,5- dihydrobenz Compound , from methyl 6-(pr dihydrobenz (5 mL) using lithium rnight at RT to afford aft tetrahydrois linic acid (322d) (68.0 12.87 (s, 1H, D2O ex le), 9.16 (t, J = 6.1 Hz, 1 , J = 5.2 Hz, 1H), 7.45 (d 1H), 4.36 (t, J = 4.9 Hz, 2 2H), 0.91 (t, J = 7.4 HPreparation of 3-(9-((4-(aminomethyl)-2,6-difluorophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (323d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- difluorophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (323b) Compound 323b was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylic acid (72b) (150 mg, 0.322 mmol) in DCM (5 mL) using 1-methyl-1H-imidazole (66.0 mg, 0.804 mmol), methanesulfonyl chloride (92 mg, 0.804 mmol), and tert-butyl (4-amino-3,5- difluorobenzyl)carbamate (323a) (208 mg, 0.804 mmol; CAS# 2579084-64-1) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- difluorophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (323b) (182 mg, 80% yield); MS (ES+): 707.1 (M+1); (ES-): 705.1 (M- 1) Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-difluorophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (323c) Compound 323c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-difluorophenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (323b) (182 mg, 0.258 mmol) in DCM (5 mL) using TFA (198 µL, 2.58 mmol) stirring for 16 h at RT to afford after workupmethyl 3-(9-((4-(aminomethyl)-2,6-difluorophenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (323c)( 119 mg, 76% yield), which was used as such for the next s Step-3: Prepa dihydrobenz Compound 3 2, from methyl 3-(9-( o[2,3- d]oxepin-8-y L) using lithium hydr ht at RT to afford after w difluorophen (propylcarba H NMR (300 MHz, DMSO 9.18 (t, 1H, D2O exchan H), 7.90 (d, J = 8.0 Hz, 1H ), 4.37 (t, J = 5.1 Hz, 2H 3H);19F NMR (282 MScheme 324Preparation of 3-(9-((4-(aminomethyl)-2-ethoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (324f) Step-1: Preparation of 4-amino-3-ethoxybenzonitrile (324b) Compound 324b was prepared according to the procedure reported in step-1 of scheme 135, from 3- ethoxy-4-nitrobenzonitrile (324a) (1.04 g, 5.41 mmol; CAS# 1506163-71-8) and Pd / C (10% wt.) (0.029 g, 0.271 mmol) in MeOH (20 mL) and stirring under a hydrogen balloon at RT for 6 h to afford after work up and purification method-BY, 4-amino-3-ethoxybenzonitrile (324b) (863 mg, 98% yield); MS (ES+): 163.1 (M+1). Step-2: Preparation of tert-butyl (4-amino-3-ethoxybenzyl)carbamate (324c) Compound 324c was prepared according to the procedure reported in step-1 of scheme 173, from 4- amino-3-ethoxybenzonitrile (324b) (863 mg, 5.32 mmol) in MeOH (10 mL), using nickel(II) chloride.6H2O (949 mg, 3.99 mmol), sodium borohydride (1812 mg, 47.9 mmol), di-tert-butyl dicarbonate (1235 µL, 5.32 mmol) and diethylenetriamine (3463 µL, 31.9 mmol) to afford after work up and purification method-AG, tert-butyl (4-amino-3-ethoxybenzyl)carbamate (324c) (950 mg, 67% yield); MS (ES+): 267.2 (M+1). Step-3: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- ethoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (324d) Compound 324 11, from 8-(2- (methoxycarbo ]oxepine-9- carboxylic acid zole (66.0 mg, 0.804 mmol), m 3- ethoxybenzyl)c fication method-AG, m rbamoyl)-4,5- dihydrobenzo[b mg, 78% yield); MS (ES Step-4: Prepara dihydrobenzo[b Compound 324 8, from methyl 3-(9-((4-(((tert- dihydrobenzo[b mg, 0.250 mmol) in DCM rd after workup methyl b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (324e) (123 mg, 80% yield), which was used as such for the next step; MS (ES+): 615.2 (M+1); (ES-): 613.2 (M-1). Step-5: Preparation of 3-(9-((4-(aminomethyl)-2-ethoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (324f) Compound 324f was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-ethoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(propylcarbamoyl)picolinate (324e) (123 mg, 0.200 mmol) in THF (5 mL) using lithium hydroxide monohydrate (25.2 mg, 0.600 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-ethoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (324f) (65.8 mg, 55% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.34 (s, 1H, D2O exchangeable), 9.10 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.85 (s, 1H, D2O exchangeable), 8.24 (s, 3H, D2O exchangeable), 8.14 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.93 (dd, J = 8.1, 1.8 Hz, 2H), 7.61 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 - 6.88 (m, 2H), 4.36 (t, J = 5.1 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 3.31 – 3.19 (m, 4H), 1.66-1.49 (m, 2H), 1.28 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 601.2 (M+1); (ES-): 599.1 (M-1). Scheme 325 Preparation of 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (325f)Step-1: Preparation of 4-amino-3-propoxybenzonitrile (325b) Comp 4- nitro- t.) (0.02 afford g, 90% Step- Comp 4- amino chlori dicarb work up an , 69% Step- propo (prop Comp 8-(2- (meth 9- carbo mg, 0.804propoxybenzyl)carbamate (325c) (225 mg, 0.804 mmol) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-propoxyphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (325d) (174 mg, 74% yield); MS (ES+): 729.2 (M+1). Step-4: Preparation of methyl 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (325e) Compound 325e was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-propoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (325d) (174 mg, 0.239 mmol) in DCM (5 mL) using TFA (184 µL, 2.387 mmol) stirring for 16 h at RT to afford after workup methyl 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (325e) (129 mg, 86% yield), which was used as such for the next step; MS (ES+): 629.2 (M+1); (ES-): 627.3 (M-1).Step-5: Preparation of 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (325f) Compound 325f was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (325e) (129 mg, 0.205 mmol) in THF (5 mL) using lithium hydroxide monohydrate (25.8 mg, 0.616 mmol) in water (1 mL) to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-propoxyphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (325f) (55.6 mg, 44% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.24 (s, 1H, D2O exchangeable), 9.10 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.95 (s, 1H, D2O exchangeable), 8.17 (s, 3H, D2O exchangeable), 8.13 (d, 1H), 8.02 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 – 6.89 (m, 2H), 4.36 (t, J = 4.9 Hz, 2H), 3.93 (s, 2H), 3.88 (t, J = 6.8 Hz, 2H), 3.31 – 3.18 (m, 4H), 1.76 – 1.64 (m, 2H), 1.65 – 1.50 (m, 2H), 0.98 – 0.87 (m, 6H); MS (ES+): 615.2 (M+1); (ES-): 613.1 (M-1). Scheme 326 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinic acid (326d)Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3- methoxybenzyl)carbamoyl)picolinate (326b) Compound 326b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using (2,6-difluoro-3-methoxyphenyl)methanamine (326a) (27.4 mg, 0.158 mmol), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinate (326b) (58mg, 59% yield) as a yellow oil; MS (ES+): 835.2 (M+Na); (ES-): 811.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinate (326c) Compound 326c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinate (326b) (58 mg, 0.071 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinate (326c) (45 mg, 52% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 713.9 (M+1); (ES-): 711.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinic acid (326d) Compound 326d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,6-difluoro-3-methoxybenzyl)carbamoyl)picolinate (326c) (45 mg, 0.063 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,6-difluoro-3- methoxybenzyl)carbamoyl)picolinic acid (326d) (25 mg, 29% yield) HCl salt as a yellow solid;1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H, D2O exchangeable), 9.93 (s, 1H, D2O exchangeable), 9.52 (t, J = 5.6 Hz, 1H, D2O exchangeable), 8.24 – 8.04 (m, 5H, 3H D2O exchangeable), 7.95 (d, J =8.0 Hz, 1H , 2H), 4.36 (t, J = 4.9 H m, 6H); 19F NMR ( (M-1).Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinic acid (327d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5- dichlorobenzyl)carbamoyl)picolinate (327b) Compound 327b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using (2,5-dichlorophenyl)methanamine (327a) (27.8 mg, 0.158 mmol; CAS# 10541-69-2), DIPEA (47.2 mg, 0.365 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinate (327b) (80 mg, 81% yield) as a yellow oil; MS (ES+): 837.1 (M+Na); (ES-): 813.2 and 815.0 (M-1).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinate (327c) Compound 327c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinate (80mg, 0.098 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinate (327c) (62 mg, 71% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 715.2 and 717.1 (M+1); (ES-): 713.1 and 715.0 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinic acid (327d) Compound 327d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((2,5-dichlorobenzyl)carbamoyl)picolinate (327c) (62mg, 0.087 mmol) in THF / MeOH (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) stirring for 2 h at 50oC to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((2,5- dichlorobenzyl)carbamoyl)picolinic acid (327d) (51 mg, 60% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H, D2O exchangeable), 9.98 (s, 1H, D2O exchangeable), 9.74 (t, 1H, D2O exchangeable), 8.23 (d, J = 8.0 Hz, 1H), 8.18 – 8.06 (m, 4H, 3H D2O exchangeable), 7.98 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.12 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 7.00 (s, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.37 (t, J = 5.1 Hz, 2H), 3.96 – 3.86 (m, 2H), 3.27 (t, J = 4.8 Hz, 2H), 2.09 (s, 6H); MS (ES+): 701.1 and 703.1 (M+1); (ES-): 699.0 and 701.1 (M-1). Scheme 329 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(4,4-difluoropiperidine-1-carbonyl)picolinic acid (329d)Step-1: Prepa dimethylphen ropiperidine- 1-carbonyl)pi Compound 3 9, from 5-(9- ((4-(((tert-but dihydrobenzo mg, 0.122 mmol) in DM # 21987-29- 1), DIPEA (8 ght to afford after work up methyl)-2,6- dimethylphen ropiperidine- 1-carbonyl)pi a); (ES-): 759.2 (M-1). Step-2: Prepa 5- dihydrobenzo te (329c)Compound 329c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(4,4-difluoropiperidine-1-carbonyl)picolinate (329b) (35mg, 0.046 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(4,4-difluoropiperidine-1-carbonyl)picolinate (329c) (25 mg, 31% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 661.2 (M+1); MS (ES-): 659.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(4,4-difluoropiperidine-1-carbonyl)picolinic acid (329d) Compound 329d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(4,4-difluoropiperidine-1-carbonyl)picolinate (329c) (25mg, 0.038 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(4,4- difluoropiperidine-1-carbonyl)picolinic acid (329d) (9 mg, 11% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H, D2O exchangeable), 8.18 (s, 3H, D2O exchangeable), 8.06 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.13 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.36 (t, J = 5.0 Hz, 2H), 3.97 - 3.85 (m, 2H), 3.84 – 3.72 (m,2H), 3.63 – 3.51 (m, 2H), 3.26 (t, J = 5.0 Hz, 2H), 2.19 – 1.98 (m, 10H);19F NMR (282 MHz, DMSO-d6) δ -95.18; MS (ES+): 647.2 (M+1); (ES-): 645.2 (M-1). Scheme 330 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclobutyl)carbamoyl)picolinic acid (330d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclobutyl)carbamoyl)picolinate (330b) Compound 330b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 1-methylcyclobutan-1-amine hydrochloride (330a) (22.19 mg, 0.182 mmol; CAS# 174886-05-6), DIPEA (106 µL, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-methylcyclobutyl)carbamoyl)picolinate (330b) (53 mg, 60% yield) as a yellow oil; (ES-): 723.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclobutyl)carbamoyl)picolinate (330c) Compound 330c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclobutyl)carbamoyl)picolinate (330b) (80 mg, 0.122 mmol) in DCM (10 mL) using TFA (208 mg, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclobutyl)carbamoyl)picolinate (330c) (42 mg, 55% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 625.2 (M+1); MS (ES-): 623.3 (M-1).Step-3 dihyd d) Comp methy d]oxe MeO ol) and st (amin -((1- methy1H NMR e), 9.11 ( Hz, 1H), 7 Hz, 2H), 3 – 1.78 (Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(benzylcarbamoyl)picolinic acid (331d) Step-1: Preparation of methyl 6-(benzylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)- 2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (331b) Compound 331b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using phenylmethanamine (331a) (16.94 mg, 0.158 mmol; CAS# 100-46-9), DIPEA (47.2 mg, 0.365 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 6-(benzylcarbamoyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (331b) (59 mg, 65% yield) as a yellow oil; MS (ES+): 769.3 (M+Na); (ES-): 745.2 (M-1).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(benzylcarbamoyl)picolinate (331c) Compound 331c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-(benzylcarbamoyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (331b) (59mg, 0.079 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9- ((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (benzylcarbamoyl)picolinate (331c) (42 mg, 53% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 647.3 (M+1); MS (ES-): 645.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(benzylcarbamoyl)picolinic acid (331d) Compound 331d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(benzylcarbamoyl)picolinate (331c) (42 mg, 0.065 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (benzylcarbamoyl)picolinic acid (331d) (31 mg, 40% yield) HCl salt as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H, D2O exchangeable), 9.97 (s, 1H, D2O exchangeable), 9.77 (t, J = 6.3 Hz, 1H, D2O exchangeable), 8.23 (d, J = 8.0 Hz, 1H), 8.18 - 8.04 (m, 4H, 3H D2O exchangeable), 7.97 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.29 – 7.21 (m, 1H), 7.14 – 7.06 (m, 3H), 6.98 (s, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.37 (t, J = 5.0 Hz, 2H), 3.96 – 3.87 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.09 (s, 6H); MS (ES+): 633.2 (M+1); (ES-): 631.2 (M-1). Scheme 332 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinic acid (332d)Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((cyclopropylmethyl)carbamoyl)picolinate (332b) Compound 332b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (1 mL) using cyclopropylmethanamine (332a) (9.52 mg, 0.134 mmol; CAS# 2516-47- 4), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((cyclopropylmethyl)carbamoyl)picolinate (332b) (65 mg, 75% yield) as a yellow oil; MS (ES+): 711.3 (M+1); (ES-): 709.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinate (332c) Compound 332c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinate (332b) (65mg, 0.091 mmol) in DCM (1 mL) using TFA (211 µL, 2.74 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinate (332c) (44 mg, 79% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 611.2 (M+1); MS (ES-): 609.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinic acid (332d) Compound 332d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((cyclopropylmethyl)carbamoyl)picolinate (332c) (44 mg, 0.072 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 360 µL, 0.720 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((cyclopropylmethyl)carbamoyl)picolinic acid (332d) (28 mg, 65% yield) HCl salt as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H, D2O exchangeable), 9.27 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.34 – 8.05 (m, 5H, 3H is D2O exchangeable), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.17 – 7.03 (m, 3H), 6.98 (s, 1H), 4.37 (t, J = 4.8 Hz, 2H), 4.00 – 3.81 (m, 2H), 3.31 –3.18 (m, 4H), 2.08 (s, 6H), 1.14 – 1.02 (m, 1H), 0.52 – 0.41 (m, 2H), 0.31 – 0.17 (m, 2H); MS (ES+): 597.2 (M+1); (ES-): 595.2 (M-1).Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinic acid (333c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (isobutylcarbamoyl)picolinate (333a) Compound 333a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (237d) (80 mg, 0.124 mmol) in DMF (1 mL) using 2-methylpropan-1-amine (10.00 mg, 0.137 mmol), DIPEA (87 µL, 0.497 mmol) and HATU (61.4 mg, 0.162 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (isobutylcarbamoyl)picolinate (333a) (55 mg, 63% yield) as a yellow oil; MS (ES+): 699.1 (M+1); (ES-): 697.2 (M-1).Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinate (333b) Compound 333b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinate (333a) (55 mg, 0.079 mmol) in DCM (1 mL) using TFA (182 µL, 2.361 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinate (333b) (40 mg, 85% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 599.2 (M+1); MS (ES-): 597.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinic acid (333c) Compound 333c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(isobutylcarbamoyl)picolinate (333b) (40 mg, 0.067 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 334 µL, 0.668 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(isobutylcarbamoyl)picolinic acid (333c) (19 mg, 49% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H, D2O exchangeable), 9.16 (t, J = 6.2 Hz, 1H, D2O exchangeable), 8.31 – 8.10 (m, 4H, 3H D2O exchangeable), 8.04 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.32 – 7.17 (m, 3H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.00 – 3.90 (m, 2H), 3.29 – 3.25 (m, 2H), 3.17 (t, J = 6.6 Hz, 2H), 2.12 (s, 3H), 1.94 – 1.81 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H); MS (ES+): 585.1 (M+1); (ES-): 583.2 (M-1). Scheme 334Pre dih Ste dim pheCompound 334b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 1-phenylethan-1-amine (334a) (19.16 mg, 0.158 mmol; CAS# 618-36- 0), DIPEA (47.2 mg, 0.365 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinate (334b) (61 mg, 66% yield) as a yellow oil; MS (ES+): 783.2 (M+Na); (ES-): 759.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinate (334c) Compound 334c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinate (334b) (61 mg,0.080 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinate (334c) (46 mg, 57% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 661.3 (M+1); MS (ES-): 659.1 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinic acid (334d) Compound 334d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-phenylethyl)carbamoyl)picolinate (334c) (46 mg, 0.070 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- phenylethyl)carbamoyl)picolinic acid (334d) (35 mg, 45% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H, D2O exchangeable), 9.97 (s, 1H, D2O exchangeable), 9.51 (d, J = 8.5 Hz, 1H, D2O exchangeable), 8.27 – 8.06 (m, 5H, 3H D2O exchangeable), 7.96 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.40 – 7.32 (m, 2H), 7.29 – 7.22 (m, 1H), 7.13 (s, 2H), 7.10 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 5.32 – 5.21 (m, 1H), 4.38 (t, J = 5.0 Hz, 2H), 3.98 – 3.85 (m, 2H), 3.28 (t, J = 5.1 Hz, 2H), 2.10 (s, 6H), 1.57 (d, J = 7.0 Hz, 3H); MS (ES+): 647.2 (M+1); (ES- ): 645.2 (M-1). Scheme 335Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)pyridine-2,6-dicarboxylic acid (335d) and 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3- difluoropiperidine-1-carbonyl)picolinic acid (335e) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoropiperidine- 1-carbonyl)picolinate (335b) Compound 335b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 3,3-difluoropiperidine hydrochloride (335a) (28.8 mg, 0.182 mmol; CAS# 496807-97-7), DIPEA (79 mg, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(3,3-difluoropiperidine-1-carbonyl)picolinate (335b) (66 mg, 71% yield) as a yellow oil; MS (ES+): 783.2 (M+Na); (ES-): 759.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoropiperidine-1-carbonyl)picolinate (335c)Compound 335c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoropiperidine-1-carbonyl)picolinate (335b) (66 mg, 0.087 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenz (335c) (50 mg, 62% yi (M+1); MS (ES-): 6 Step-3: Prep dihydrobenz (4- (aminometh -yl)-6-(3,3- difluoropipe Compounds scheme 12, from me dihydrobenz (335c) (50 mg, 0.076 m olution; 912 µL, 1.824 m od-O, 3-(9- ((4-(aminom in-8- yl)pyridine- (aminometh -yl)-6-(3,3- difluoropipe solid; Data for 335 (s, 1H,D2O exchangeable), 8.25-8.10 (m, 4H, 3H D2O exchangeable), 8.08 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 4.36 (t, J = 4.9 Hz, 2H), 3.91 (s, 2H), 3.26 (t, J = 4.9 Hz, 2H), 2.05 (s, 6H); MS (ES+): 544.2 (M+1); (ES-): 542.2 (M-1). Data for 335e: 1H NMR (300 MHz, DMSO-d6) δ 13.19 (s, 1H, D2O exchangeable), 9.90 (s, 1H, D2O exchangeable), 8.17 (s, 3H, D2O exchangeable), 8.05 (d, J = 5.0 Hz, 1H), 7.91 (t, J = 8.2 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 3.7 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.08 – 3.84 (m, 4H), 3.75 – 3.67 (m, 1H), 3.55 – 3.47 (m, 1H), 3.26 (t, J = 5.0 Hz, 2H), 2.21 – 2.09 (m, 2H), 2.09 – 1.99 (m, 6H), 1.79 – 1.69 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ -100.37; MS (ES+): 647.2 (M+1); (ES-): 645.2 (M-1). Scheme 336Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinic acid (336d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- ((cyclohexylmethyl)carbamoyl)picolinate (336b) Compound 336b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using cyclohexylmethanamine (336a) (17.90 mg, 0.158 mmol; CAS# 3218- 02-8), DIPEA (47.2 mg, 0.365 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinate (336b) (68 mg, 74% yield) as a yellow oil; MS (ES+): 775.2 (M+Na); (ES-): 751.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinate (336c) Compound 336c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinate (336b) (68 mg, 0.090 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinate (336c) (50 mg, 63% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 653.3 (M+1); MS (ES-): 651.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((cyclohexylmethyl)carbamoyl)picolinic acid (336d) Compound 336d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)- ) in MeOH / THF (2 1.824 mmol) and stirring for - (aminomethyl)- in-8-yl)-6- ((cyclohexylme white solid;1H NMR (300 MH changeable), 9.20 (t, 1H, D2 J = 8.0 Hz, 1H), 7.61 (d, J (t, J = 5.0 Hz, 2H), 4.01 – 3.85 ), 1.78 – 1.65 (m, 4H), 1.65 – 9.2 (M+1); (ES-): 637.2 (MPreparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinic acid (337d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1- carbonyl)picolinate (337b) Compound 337b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122mmol) in DMF (4 mL) using 2-ethylpiperidine (336a) (17.90 mg, 0.158 mmol; CAS# 1484-80-6), DIPEA (79 mg, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1- carbonyl)picolinate (337b) (68 mg, 74% yield) as a yellow oil; (ES-): 751.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinate (337c) Compound 337c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinate (337b) (56mg, 0.074 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinate (337c) (42 mg, 53% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 653.3 (M+1); MS (ES-): 651.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinic acid (337d) Compound 337d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(2-ethylpiperidine-1-carbonyl)picolinate (337c) (42mg, 0.064 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-ethylpiperidine-1- carbonyl)picolinic acid (337d) (35mg, 45% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) (a mixture of rotamers) δ 13.16 (s, 1H, D2O exchangeable), 9.89 (s, 1H, D2O exchangeable), 8.18 (s, 3H, D2O exchangeable), 8.04 (s, 1H), 7.86 (dd, J = 7.9, 4.2 Hz, 1H), 7.67 – 7.56 (m, 2H), 7.13 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 1.1 Hz, 1H), 4.66-4.58 and 4.44-4.40 (2m, 1H), 4.42 – 4.30 (m, 2H), 3.98 – 3.80 (m, 2H), 3.69 – 3.56 and 3.49 - 3.38 (2m, 1H), 3.26 (t, J = 5.0 Hz, 2H), 3.08 and 2.79 (2t, J = 12.4 Hz, 1H), 2.06 (s, 6H), 1.91 – 1.37 (m, 8H), 0.89 and 0.68 (2t, J = 7.3 Hz, 3H); MS (ES+): 639.2 (M+1); (ES-): 637.3 (M-1). Scheme 338Pr di ) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-dimethylazetidine- 1-carbonyl)picolinate (338b) Compound 338b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 3,3-dimethylazetidine hydrochloride (338a) (13.46 mg, 0.158 mmol; CAS# 89381-03-3), DIPEA (79 mg, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinate (338b) (66 mg, 75% yield) as a yellow oil; MS (ES+): 747.2 (M+Na); (ES-): 723.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinate (338c) Compound 338c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinate (338b) (66 mg, 0.091 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinate (338c) (52 mg, 68% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 625.2 (M+1); MS (ES-): 623.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinic acid (338d) Compound 338d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(3,3-dimethylazetidine-1-carbonyl)picolinate (338c) (52 mg, 0.083 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3- dimethylazetidine-1-carbonyl)picolinic acid (338d) (46 mg, 62% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.10 (s, 1H, D2O exchangeable), 10.01 - 9.78 (m, 1H, D2O exchangeable), 8.25 – 8.10 (m, 3H, D2O exchangeable), 8.07 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.14 (s, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 4.43 – 4.31 (m, 4H), 3.98 – 3.88 (m, 2H), 3.78 (s, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.08 (s, 6H), 1.27 (s, 6H); MS (ES+): 611.2 (M+1); (ES-): 609.2 (M-1). Scheme 339Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine-1-carbonyl)picolinic acid (339d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine- 1-carbonyl)picolinate (339b) Compound 339b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (82 mg, 0.125 mmol) in DMF (4 mL) using 2,6-dimethylpiperidine (339a) (18.35 mg, 0.162 mmol; CAS# 504-03- 0), DIPEA (81 mg, 0.623 mmol) and HATU (61.6 mg, 0.162 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine- 1-carbonyl)picolinate (339b) (48 mg, 51% yield) as a yellow oil; (ES-): 751.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine-1-carbonyl)picolinate (339c) Compound 339c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine-1-carbonyl)picolinate (339b)(48 mg, 0.064 mmol) in DCM (10 mL) using TFA (144 µL, 1.870 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine-1-carbonyl)picolinate (339c) (35 mg, 43% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 653.3 (M+1); MS (ES-): 651.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2,6-dimethylpiperidine-1-carbonyl)picolinic acid (339d) Compound 339d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl) mol) in MeOH / THF ( 870 mmol) and stirring fo (aminomethyl n-8-yl)-6-(2,6- dimethylpiperi ellow solid;1H NMR (300 xchangeable), 8.04 (s, 3H, D H), 7.53 (d, J = 5.2 Hz, 1H), .29 (t, J = 5.0 Hz, 2H), 3.89 6H), 1.85 – 1.71 (m, 2H), 637.3 (M-1).Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(pyrrolidine-1-carbonyl)picolinic acid (340d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(pyrrolidine-1- carbonyl)picolinate (340b) Compound 340b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using pyrrolidine (340a) (11.25 mg, 0.158 mmol), DIPEA (79 mg, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(pyrrolidine-1- carbonyl)picolinate (340b) (68 mg, 79% yield) as a yellow oil; MS (ES+): 733.3 (M+Na); (ES-): 709.3 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(pyrrolidine-1-carbonyl)picolinate (340c) Compound 340c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-– 3.46 (m, 2H), 3.26 (t, J = 5.0 Hz, 2H), 2.07 (s, 6H), 1.96 – 1.77 (m, 4H); MS (ES+): 597.2 (M+1); (ES-): 595.3 (M-1). Scheme 341Preparation of 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (341d) Step-1: Preparation of methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (341b) Compound 341b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (4 mL) using 1,4'-bipiperidine (341a) (26.6 mg, 0.158 mmol; CAS# 4897-50-1), DIPEA (79 mg, 0.608 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)picolinate (341b) (59mg, 0.073 mmol, 60.0 % yield) as a yellow oil; MS (ES+): 808.3 (M+Na); (ES-): 806.3 (M-1). Step-2: Preparation of methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (341c)Compound 341c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (341b) (59 mg, 0.073 mmol) in DCM (10 mL) using TFA (141 µL, 1.824 mmol) and stirring at RT for 2 h to afford after workup methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (341c) (45 mg, 52% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 708.3 (M+1); MS (ES-): 706.3 (M-1). Step-3: Preparation of 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(aminomethyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinic acid (341d) Compound 341d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 6-([1,4'-bipiperidine]-1'-carbonyl)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)picolinate (341c) (45 mg, 0.064 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 912 µL, 1.824 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 6-([1,4'-bipiperidine]-1'-carbonyl)-3- (9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)picolinic acid (341d) (32 mg, 38% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H, D2O exchangeable), 10.50 (s, 1H, D2O exchangeable), 9.87 (s, 1H, D2O exchangeable), 8.31 (s, 3H, D2O exchangeable), 8.07 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.16 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 4.65 (d, J = 13.2 Hz, 1H), 4.36 (t, J = 4.8 Hz, 2H), 3.99 – 3.82 (m, 3H), 3.52 – 3.42 (m, 3H), 3.26 (t, J = 5.0 Hz, 2H), 3.21 – 3.08 (m, 1H), 2.99 – 2.76 (m, 3H), 2.28 – 2.18 (m, 1H), 2.07 (s, 7H), 1.94 – 1.61 (m, 7H), 1.49 – 1.30 (m, 1H); MS (ES+): 694.3 (M+1); (ES-): 692.2 (M-1). Scheme 342Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinic acid (342d) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1- carbonyl)picolinate (342b) Compound 342b was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (85 mg, 0.129 mmol) in DMF (4 mL) using 2-phenylpiperidine (342a) (27.1 mg, 0.168 mmol; CAS# 3466-80-6), DIPEA (84 mg, 0.646 mmol) and HATU (63.9 mg, 0.168 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1- carbonyl)picolinate (342b) (58 mg, 56% yield) as a yellow oil; MS (ES+): 823.3 (M+Na); (ES-): 799.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinate (342c) Compound 342c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinate (342b) (58mg, 0.072 mmol) in DCM (10 mL) using TFA (149 µL, 1.938 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinate (342c) (41 mg, 45% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 701.3 (M+1); MS (ES-): 699.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinic acid (342d) Compound 342d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(2-phenylpiperidine-1-carbonyl)picolinate (342c) (41 mg, 0.059 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 969 µL, 1.938 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(2- phenylpiperidine-1-carbonyl)picolinic acid (342d) (27 mg, 30% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) (a mixture of rotamers) δ 13.06 (s, 1H, D2O exchangeable), 10.14 – 9.68 (m, 1H, D2O exchangeable), 8.19 (s, 3H, D2O exchangeable), 8.09 - 7.96 (m, 1H), 7.93 – 7.69 (m, 2H), 7.62 – 7.54 (m, 1H), 7.48 - 7.20 (m, 5H), 7.17 - 7.02 (m, 3H), 7.01 - 6.87 (m, 1H), 5.95 – 5.81 (m, 1H), 4.52 – 4.22 (m, 2H), 3.96 – 3.76 (m, 2H), 3.59 – 3.48 (m, 1H), 3.29 – 3.22 (m, 2H), 3.04 – 2.88 (m, 1H), 2.71 – 2.52 (m, 1H), 2.47 – 2.30 (m, 1H), 2.07 (s, 3H), 1.94 (s, 3H), 1.72 – 1.35 (m, 4H); MS (ES+): 687.3 (M+1); (ES-): 685.2 (M-1). Scheme 343P d S d 1 C - ((dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (85 mg, 0.129 mmol) in DMF (4 mL) using 3,3-difluoroazetidine hydrochloride (338a) (15.64 mg, 0.168 mmol; CAS# 288315-03-7), DIPEA (84 mg, 0.646 mmol) and HATU (63.9 mg, 0.168 mmol) stirring at RT overnight to afford after work up and purification method-C, methyl 3-(9-((4-(((tert- butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinate (343b) (65 mg, 69% yield) as a yellow oil; (ES-): 731.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinate (343c)Compound 343c was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinate (343b) (65 mg, 0.089 mmol) in DCM (10 mL) using TFA (149 µL, 1.938 mmol) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinate (343c) (46 mg, 56% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 633.2 (M+1); MS (ES-): 631.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinic acid (343d) Compound 343d was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(3,3-difluoroazetidine-1-carbonyl)picolinate (343c) (46 mg, 0.073 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 969 µL, 1.938 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(3,3- difluoroazetidine-1-carbonyl)picolinic acid (343d) (4 mg, 5% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) (a mixture of rotamers) δ 10.06 – 9.79 (m, 1H, D2O exchangeable), 8.23 – 8.03 (m, 5H, 3H D2O exchangeable), 7.93 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.94 (s, 1H), 5.07 (t, J = 12.4 Hz, 2H), 4.54 (t, J = 12.5 Hz, 2H), 4.41 – 4.31 (m, 2H), 3.97 – 3.83 (m, 2H), 3.29 – 3.25 (m, 2H), 2.13 – 1.98 (m, 6H);19F NMR (282 MHz, DMSO-d6) δ -100.41; MS (ES+): 619.2 (M+1); (ES-): 617.2 (M-1). Scheme 344Preparation of 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (344c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (344a) Compound 344a was prepared according to the procedure reported in step-1 of scheme 39, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (309g) (111 mg, 0.231 mmol) in DMF (2 mL) using tert-butyl (4-amino- 3-methylbenzyl)carbamate (171a) (65.5 mg, 0.277 mmol), DIPEA (0.081 mL, 0.462 mmol) and HATU (114 mg, 0.300 mmol) stirring at RT overnight to afford after work up and purification method-BR, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-2- methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (344a) (105 mg, 65% yield) as a yellow oil; MS (ES+): 721.2 (M+Na); (ES-): 697.2 (M-1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (344b) Compound 344b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (344a) (105mg, 0.150mmol) in DCM (10 mL) using TFA (1 mL) and stirring at RT for 2 h to afford after workup and purification method-O, methyl 3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (344b) (66 mg, 48% yield) HCl salt as a white solid, which was used as such for the next step;1H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.63 (t, J = 6.2 Hz, 1H), 8.30 (s, 3H), 8.17 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.35 – 7.17 (m, 3H), 6.97 (s, 1H), 6.78 (d, J = 1.3 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.93 (s, ), 1.6 Ste dih Co me,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (344b) (66 mg, 0.110 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 1.732 mL, 3.46 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)-2- methylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinic acid (344c) (36mg, 27% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H, D2O exchangeable), 10.01 (s, 1H, D2O exchangeable), 9.14 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.25 (s, 3H, D2O exchangeable), 8.17 (d, J = 8.0 Hz, 1H), 7.98 – 7.83 (m, 2H), 7.27 (s, 1H), 7.22 (s, 2H), 6.95 (s, 1H), 6.78 (d, J = 1.3 Hz, 1H), 4.32 (t, J = 4.9 Hz, 2H), 3.98 – 3.86 (m, 2H), 3.31 – 3.24 (m, 2H), 3.18 (t, J = 5.0 Hz, 2H), 2.45 (s, 3H), 2.10 (s, 3H), 1.63 – 1.50 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 585.3 (M+1); (ES-): 583.2 (M-1). Scheme 345Preparation of 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (345c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6- methylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (345a) Compound 345a was prepared according to the procedure reported in step-1 of scheme 11, from 8-(2- (methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (309g) (120 mg, 0.250 mmol) in DCM (3 mL) using 1-methyl-1H- imidazole (51.3 mg, 0.624 mmol), methanesulfonyl chloride (71.5 mg, 0.624 mmol), and tert-butyl (4-amino-3-chloro-5-methylbenzyl)carbamate (205a) (203 mg, 0.749 mmol) to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6- methylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (345a) (142 mg, 78% yield) as a yellow oil; MS (ES+): 755.2 (M+Na): MS (ES-): 731.1 (M+1). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-2- methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (345b) Compound 345b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6-methylphenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (345a) (142mg, 0.194 mmol) in DCM (10 mL) using TFA (1 mL) and stirring at RT for 2 h to afford after workup methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (345b) (97 mg, 61% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 633.2 (M+1); MS (ES-): 631.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (345c) Compound 345c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (345b) (97 mg, 0.153 mmol) in MeOH / THF (6 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 1.87 mL, 3.75 m (a d]o id;1H e), 9.2 8.0 ), 6.7Hz, 2H), 2.46 (d, J = 1.1 Hz, 3H), 2.10 (s, 3H), 1.64 – 1.50 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES+): 619.1 and 621.1 (M+1); (ES-) 617.2 and 619.1 (M-1). Scheme 346Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3- d S m C ( d a ( m d a S d C m dmmol) in DCM (10 mL) using TFA (1 mL) and stirring at RT for 2 h to afford after workup methyl 3- (9-((4-(aminomethyl)phenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (346b) (98mg, 76% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 585.2 (M+1); MS (ES-): 583.2 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-2-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (346c) Compound 346c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)-6-(propylcarbamoyl)picolinate (346b) (98 mg, 0.168 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 1.654 mL, 3.31 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4-(aminomethyl)phenyl)carbamoyl)-2-methyl- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (346c) (79 mg, 63% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H, D2O exchangeable), 10.66 (s, 1H, D2O exchangeable), 9.15 (t, J = 6.1 Hz, 1H, D2O exchangeable), 8.23 (s, 3H, D2O exchangeable), 8.16 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.60 – 7.50 (m, 2H), 7.38 – 7.29 (m, 2H), 6.94 (s, 1H), 6.78 (d, J = 1.3 Hz, 1H), 4.32 (t, J = 4.9 Hz, 2H), 3.93 (s, 2H), 3.32 – 3.26 (m, 2H), 3.18 (t, J = 5.0 Hz, 2H), 2.45 (d, J = 1.1 Hz, 3H), 1.64 – 1.49 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 571.1 (M+1); (ES-): 569.2 (M-1). Scheme 347 Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinic acid (347c) Step-1: Preparation of methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclopentyl)carbamoyl)picolinate (347a) Compound 347a was prepared according to the procedure reported in step-1 of scheme 39, from 5-(9- ((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(methoxycarbonyl)picolinic acid (238b) (80 mg, 0.122 mmol) in DMF (1 mL) using 1-methylcyclopentan-1-amine hydrochloride (303a) (16.50 mg, 0.122 mmol), DIPEA (85 µL, 0.487 mmol) and HATU (60.1 mg, 0.158 mmol) stirring at RT overnight to afford after work up and purification method-AG, methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (347a) (63 mg, 70% yield) as a yellow oil; MS (ES+): 761.3 (M+Na). Step-2: Preparation of methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (347b) Compound 347b was prepared according to the procedure reported in step-2 of scheme 8, from methyl 3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (347a) (63 mg, 0.085 mmol) in DCM (1 mL) using TFA (197 µL, 2.56 mmol) and stirring at RT for 2 h to afford after work up methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (347b) (46 mg, 84 % yield) as a yellow oil, which was used as such for the next step; MS (ES+): 639.3 (M+1); MS (ES-): 637.3 (M-1). Step-3: Preparation of 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinic acid (347c) Compound 347c was prepared according to the procedure reported in step-6 of scheme 12, from methyl 3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-((1-methylcyclopentyl)carbamoyl)picolinate (347b) (46 mg, 0.072 mmol) in MeOH / THF (2 mL; ratio 1:1) using lithium hydroxide (2M aqueous solution; 36.0 µL, 0.072 mmol) and stirring for 2 h at 50 °C to afford after work up and purification method-O, 3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-((1- methylcyclopentyl)carbamoyl)picolinic acid (347c) (32 mg, 71% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H, D2O exchangeable), 8.55 (s, 1H), 8.24 (s, 3H, D2O exchangeable), 8.16 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.12 (s, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 4.37 (t, J = 4.9 Hz, 2H), 3.90 (s, 2H), 3.27 (t, J = 5.0 Hz, 2H), 2.19 – 2.11 (m, 2H), 2.08 (s, 6H), 1.74 – 1.61 (m, 6H), 1.45 (s, 3H); MS (ES+): 625.3 (M+1); (ES-): 623.3 (M-1); Analysis calculated for C35H36N4O5S.1.1HCl .2.5H2O: C, 59.22; H, 5.98; Cl, 5.49; N, 7.89; Found: C, 59.35; H, 5.92; Cl, 5.49; N, 8.32; Scheme 348Preparation of (S)-3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (348j) Step-1: Preparation of methyl (S)-2-bromo-5-iodo-4-((1-(thiophen-3-yl)propan-2-yl)oxy)benzoate (348b) Compound 348b was prepared according to the procedure reported in step-2 of scheme 1, from (R)-1- (thiophen-3-yl)propan-2-ol (348a) (3 g, 21.09 mmol; CAS # 851885-27-3), triphenylphosphine (5.53 g, 21.09 mmol) and methyl 2-bromo-4-hydroxy-5-iodobenzoate (68a) (6.27 g, 17.58 mmol) in DCM (1 D - (t 48 St caCompound 348c was prepared according to the procedure reported in step-3 of scheme 1, from methyl (S)-2-bromo-5-iodo-4-((1-(thiophen-3-yl)propan-2-yl)oxy)benzoate (348b) (6.675 g, 13.87 mmol) inDMSO (250 mL) using K2CO3(3.83 g, 27.7 mmol), Pd(OAc)2(0.311 g, 1.387 mmol) and triphenylphosphine (0.728 g, 2.77 mmol) and stirring for 30 min at 100 °C to afford after workup and purification method-CE, methyl (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9- carboxylate (348c) (4.88 g, 13.82 mmol, 100 % yield) as a white solid; MS (ES+): 374.9 (M+Na). Step-3: Preparation of (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (348d) Compound 348d was prepared according to the procedure reported in step-6 of scheme 12, from methyl (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (348c) (4.88 g, 13.82 mmol) in THF / MeOH (20 mL; ratio 1:1) using lithium hydroxide monohydrate (2.91 g, 69.4 mmol) in water (3 mL) and stirring overnight at RT to afford after workup (S)-8-bromo-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (348d) (4.657 g, 99% yield) as a white solid; MS (ES+): 360.9 (M+Na). Step-4: Preparation of 2-(trimethylsilyl)ethyl (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylate (348e) Compound 348e was prepared according to the procedure reported in step-1 of scheme 26, from (S)- 8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (348d) (4.657 g, 13.73 mmol) in DCM (100 mL) using 2-(trimethylsilyl)ethan-1-ol (1.623 g, 13.73 mmol), DCC (2.83 g, 13.73 mmol) and DMAP (0.335 g, 2.75 mmol) stirring for 10 h at RT to afford after work up 2- (trimethylsilyl)ethyl (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (348e) (3.765 g, 62% yield) as a white solid; MS (ES+): 461.00 (M+Na). Step-5: Preparation of methyl (S)-3-(5-methyl-9-((2-(trimethylsilyl)ethoxy)carbonyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348f) Compound 348f was prepared according to the procedure reported in step-3 of scheme 21, from 2- (trimethylsilyl)ethyl (S)-8-bromo-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylate (348e) (3.765 g, 8.57 mmol) in 2Me-THF (30 mL) using methyl 6-(propylcarbamoyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (13b) (5.97 g, 17.14 mmol), K3PO4(3M) (7.14 mL, 21.42 mmol), Pd2(dba)3(0.785 g, 0.857 mmol) and XPhos (0.817 g, 1.714 mmol) to afford after work up and purification method-A, methyl (S)-3-(5-methyl-9-((2-(trimethylsilyl)ethoxy)carbonyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348f) (3.576 g, 72% yield) as a yellow oil; MS (ES+): 581.2 (M+1). Step-6: Preparation of (S)-8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-9-carboxylic acid (348g)- Sp p y y y y methylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (348h) Compound 348h was prepared according to the procedure reported in step-1 of scheme 11, from (S)- 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (348g) (150 mg, 0.312 mmol) in DCM (5 mL) using 1-methyl-1H- imidazole (64.1 mg, 0.780 mmol), methanesulfonyl chloride (89 mg, 0.780 mmol), and tert-butyl (4- amino-3-methylbenzyl)carbamate (171a) (221 mg, 0.936 mmol) to afford after work up and purification method-AG, methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2- methylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (348h) (162 mg, 74% yield); MS (ES+): 721.2 (M+Na). Step-8: Preparation of methyl (S)-3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348i) Compound 348i was prepared according to the procedure reported in step-2 of scheme 8, from methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348h) (162 mg, 0.232 mmol) in DCM (5 mL) using TFA (179 µL, 2.318 mmol) and stirring at RT for 16 h to afford after workup methyl (S)-3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348i) (132 mg, 95% yield) as a yellow oil, which was used as such for the next step; MS (ES+): 599.2 (M+1); MS (ES-): 597.2 (M-1). Step-9: Preparation of (S)-3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (348j) Compound 348j was prepared according to the procedure reported in step-6 of scheme 12, from methyl (S)-3-(9-((4-(aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (348i) (132 mg, 0.220 mmol) in THF (5 mL) using lithium hydroxide monohydrate (27.8 mg, 0.661 mmol) in water (1 mL)and stirring overnight at RT to afford after work up and purification method-O, (S)-3-(9-((4- (aminomethyl)-2-methylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)- 6-(propylc NMR (300 MHz, , 9.15 (t, J = 6.0 Hz, 1 H), 7.95 (d, J = 8.0 H), 6.96 (s, 1H), 4.4 H), 2.12 (s, 3H), 1.6 85.2 (M+1); (E Preparationdihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (349c) Step-1: Preparation of methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (349a) Compound 349a was prepared according to the procedure reported in step-1 of scheme 11, from (S)- 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (348g) (150 mg, 0.312 mmol) in DCM (5 mL) using 1-methyl-1H- imidazole (64.1 mg, 0.780 mmol), methanesulfonyl chloride (89 mg, 0.780 mmol), and tert-butyl (4- amino-3,5-dimethylbenzyl)carbamate (172a) (234 mg, 0.936 mmol) to afford after work up and purification method-AG, methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6- dimethylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (349a) (136 mg, 61% yield); MS (ES+): 735.1 (M+Na). Step-2: Preparation of methyl (S)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (349b) Compound 349b was prepared according to the procedure reported in step-2 of scheme 8, from methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl- 4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (349a) (136 mg, 0.191mmol) in DCM (5 mL) using TFA (147 µL, 1.908 mmol) and stirring at RT for 16 h to afford after workup methyl (S)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (349b) (115 mg, 98% yield), which was used as such for the next step; MS (ES+): 613.2 (M+1); MS (ES-): 611.3 (M-1). Step-3: Preparation of (S)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (349c) Compound 349c was prepared according to the procedure reported in step-6 of scheme 12, from methyl (S)-3-(9-((4-(aminomethyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (349b) (115 mg, 0.188 mmol) in THF (5 mL) using lithium hydroxide monohydrate (20.31 mg, 0.484 mmol) in water (1 mL) and stirring overnight at RT to afford after work up and purification method-O, (S)-3-(9-((4- (aminomethyl)-2,6-dimethylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8- yl)-6-(propylcarbamoyl)picolinic acid (349c) (50.8 mg, 53% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H, D2O exchangeable), 9.97 (s, 1H, D2O exchangeable), 9.22 (t, 1H, D2O exchangeable), 8.19 (d, J = 8.0 Hz, 1H), 8.14 (s, 3H, D2O exchangeable), 8.07 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.11 (s, 2H), 7.05 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 4.39 – 4.26 (m, 1H), 3.90 (d, J = 4.9 Hz, 2H), 3.31 – 3.24 (m, 3H), 3.13 (dd, J = 17.6, 9.5 Hz, 1H), 2.08 (s, 6H), 1.65 - 1.51 (m, 2H), 1.46 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). MS (ES+): 599.3 (M+1) (ES-): 597.1 (M-1) 99.99%, Rt: 1.968 Optical Rotation: [α]D= +92.24 [MeOH, 0.245]. Scheme 350 Preparation of (S)-3-(9-((4-(aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (350c) Step-1: Preparation of methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-6- methylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6- (propylcarbamoyl)picolinate (350a) Compound 350a was prepared according to the procedure reported in step-1 of scheme 11, from (S)- 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (348g) (150 mg, 0.312 mmol) in DCM (5 mL) using 1-methyl-1H-im a d pu m (p St m C m m g, 0. af - di yi St 4, C mdihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (350b) (103 mg, 0.163 mmol) in THF (5 mL) using lithium hydroxide monohydrate (20.48 mg, 0.488 mmol) in water (1 mL) and stirring overnight at RT to afford after work up and purification method-O, (S)-3-(9-((4- (aminomethyl)-2-chloro-6-methylphenyl)carbamoyl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (350c) (74.4 mg, 74% yield) HCl salt as a white solid;1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H, D2O exchangeable), 10.26 (s, 1H, D2O exchangeable), 9.21 (t, J = 6.4 Hz, 1H, D2O exchangeable), 8.28 (s, 3H, D2O exchangeable), 8.18 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 4.39 – 4.26 (m, 1H), 3.96 (s, 2H), 3.31 – 3.22 (m, 3H), 3.13 (dd, J = 17.6, 9.4 Hz, 1H), 2.12 (s, 3H), 1.66 - 1.51 (m, 2H), 1.46 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H); MS (ES+): 619.2 (M+1); (ES-): 617.1 (M-1); Optical Rotation: [α]D= +78.13 [MeOH, 0.320]. Scheme 351Preparation of (S)-3-(9-((4-(aminomethyl)phenyl)carbamoyl)-5-methyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinic acid (351c) Step-1: Preparation of methyl (S)-3-(9-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamoyl)- 5-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-6-(propylcarbamoyl)picolinate (351a) Compound 351a was prepared according to the procedure reported in step-1 of scheme 39, from (S)- 8-(2-(methoxycarbonyl)-6-(propylcarbamoyl)pyridin-3-yl)-5-methyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-9-carboxylic acid (348g) (175 mg, 0.364 mmol) in DMF (1 mL) usin...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein: ring is a tricyclic ring system comprising at least one aromatic or heteroaromatic ring; ring is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; wherein J and ringare bonded to the same ring within the tricyclic ring system of ring ; ringis aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; J represents –NH–, –CH2–, –C(O)–, –O–, –S–, –S(O)–, –SO2–, –N(alkyl)–, –CH(alkyl)–, –CH(CF3)–, –CH(aryl)–, –C(alkyl)2–, –CH(cycloalkyl)–,, or is absent; K represents –C(O)–, –O–, –NH–, –CH2–, –S–, –S(O)–, –SO2–, –N(alkyl)–, –NHCH2–, –CH(alkyl)–, –CH(cycloalkyl)–, or is absent; wherein at least one of J and K is absent, or is –C(O)–, –CH2–, –CH(alkyl)–, or – CH(aryl)–; Y represents –H, –CH2NH2, –C(=NH)(NH2), –C(O)NH2, –NH2, –CN, halo, –CH2C(O)OH, –C(O)OH, –S(O)2NH2, –CH2CN, –NHBoc, –CH2NHCH3, –CH(CH3)NH2, –CH2NHCH=NOH, –CH2OH, amino-substituted cycloalkyl, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, or heteroarylalkyl; V is -C(O)REor H;REis –OH, –NH-OH, –O(alkyl), –C(O)(haloalkyl),T is a bond, or represents –C(O)–, –C(O)NH–, –C(O)N(alkyl)–, –C(O)O–, –CH2NH–, – CH2O–, –CH(CF3)-NH–, –NH-CH(CF3)–, or –NHC(O)–; RTrepresents H, halo, –CH2C(O)NH2, –CH2C(O)OH, or optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; RA, independently for each occurrence, represents alkyl, halo, –NHBoc, tosyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl; RB, independently for each occurrence, represents halo, –C(O)OH, –C(O)NH2, – C(O)NH(alkyl), –C(O)NH(aminoalkyl), oxo, cyano, hydroxy, or optionally substituted alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; RD, independently for each occurrence, represents hydroxy, halo, –CN, –C(O)OH, –C(O)NH(alkyl), –C(O)NH(cycloalkyl), –CH2C(O)(alkyl), –CH2C(O)ORD1, – CH2C(O)NHRD1, –O[(CH2)xO]y(alkyl), –O(CH2)xCOOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl, or haloalkyl; RD1, independently for each occurrence, represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; m, n, and q are each integers independently selected from 0-3; and x and y are each integers independently selected from 1-10.

2. The compound of claim 1, having the structure of formula (Ia):wherein:are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl; m1 and m2 are each integers selected from 0-3; and the sum of m1 and m2 is 3 or less.

3. The compound of claim 2, having the structure of formula (Ia-1):The compound of claim 3, whereinhas the following structure:.

5. The compound of claim 4, whereinselected from the group consisting of: ,The compound of claim 3, whereinhas the following structure:wherein: Z1, Z2, and Z3are each independently selected from S, CH, and CRA; and one and only one of Z1, Z2, and Z3is S. The compound of claim 6, whereinselected from the group consisting of:, , , ,. The compound of claim 6, whereinhas the following structure:. The compound of claim 6, whereinselected from the group10. The compound of claim 6, whereinhas the following structure:The compound of claim 3, wherein15. The compound of any one of claims 1-14, wherein RA, independently for each occurrence, represents alkyl.

16. The compound of any one of claims 2-15, wherein each occurrence of m1 and m2 is 17. The compound of any one of claims 1-16, wherein ringis a bicyclic ring.

18. The compound of any one of claims 1-16, wherein ringis a monocyclic ring.

19. The compound of any one of claims 1-16, whereinand W is N or CH.

20. The compound of claim 19, wherein W is N.

21. The compound of claim 19, wherein W is CH.

22. The compound of any one of claims 1-16, wherein23. The compound of any one of claims 1-22, wherein V is -C(O)RE.

24. The compound of claim 23, wherein REis –OH or –O(methyl).

25. The compound of claim 23, wherein REis –OH.

26. The compound of any one of claims 1-25, wherein n is 0.

27. The compound of any one of claims 1-26, wherein –T-RTis H.

28. The compound of any one of claims 1-26, wherein T is a bond, and RTis optionally substituted aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.

29. The compound of any one of claims 1-26, wherein T is –C(O)–, –C(O)NH–, or –C(O)N(alkyl)–.

30. The compound of any one of claims 1-26, wherein T is –C(O)–, and RTis optionally substituted heterocycloalkyl, preferably optionally substituted N-linked heterocycloalkyl.

31. The compound of any one of claims 1-26, wherein T is –C(O)NH–.

32. The compound of claim 31, wherein RTis optionally substituted alkyl, hydroxyalkyl, haloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl), arylalkyl, or heteroarylalkyl.

33. The compound of claim 32, wherein RTis optionally substituted alkyl.

34. The compound of claim 31, wherein RTis optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

35. The compound of claim 34, wherein RTis optionally substituted cycloalkyl.

36. The compound of any one of claims 1-35, wherein –J-K– is selected from the group consisting of –C(O)-NH–, –C(O)-N(CH3)–, –C(O)-NHCH2–, –CH2-O–, and –CH2-NH–.

37. The compound of claim 36, wherein –J-K– is –C(O)-NH–.

38. The compound of any one of claims 1-37, wherein ringis a bicyclic ring.

39. The compound of any one of claims 1-37, wherein ringis a monocyclic ring.

40. The compound of any one of claims 1-39, wherein ringis selected from the group consisting of phenyl, pyrazinyl, pyridinyl, pyriminyl, thiophenyl, tetrahydroisoquinolinyl, benzoimidazolyl, indolyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, cyclohexyl, isoindolinyl, isoquinolinyl, or naphthalenyl.

41. The compound of claim 40, wherein ringis phenyl.

42. The compound of claim 40, wherein ringis pyridinyl.

43. The compound of claim 40, wherein ringis benzoimidazolyl, indolyl, or isoquinolinyl.

44. The compound of any one of claims 1-37, wherein ringis represented by:

45. The compound of claim 44, wherein Y is –NH2.

46. The compound of any one of claims 1-37, wherein ringis represented by.

47. The compound of any one of claims 1-37, wherein ringis represented by.

48. The compound of claim 46 or 47, wherein Y is selected from the group consisting of –CH2NH2, –C(=NH)(NH2), and –C(O)NH2.

49. The compound of claim 48, wherein Y is –CH2NH2.

50. The compound of any one of claims 1-37, wherein ringis represented by.

51. The compound of claim 50, wherein Y is –CH2NH2.

52. The compound of any one of claims 1-51, wherein RD, independently for each occurrence, represents hydroxy, halo, –C(O)NH(alkyl), or optionally substituted alkyl, alkoxy, hydroxyalkyl, or haloalkyl.

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the following table:O S HNOHN NH2.

54. A compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein: ring and ring are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl; ringis optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; ringis aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; J represents –NH–, –CH2–, –C(O)–, –O–, –S–, –S(O)–, –SO2–, –N(alkyl)–, –CH(alkyl)–, –CH(CF3)–, –CH(aryl)–, –C(alkyl)2–, –CH(cycloalkyl)–,, or is absent; K represents –C(O)–, –O–, –NH–, –CH2–, –S–, –S(O)–, –SO2–, –N(alkyl)–, –NHCH2–, –CH(alkyl)–, –CH(cycloalkyl)–, or is absent; wherein at least one of J and K is absent, or is –C(O)–, –CH2–, –CH(alkyl)–, or – CH(aryl)–; Y represents –H, –CH2NH2,–C(=NH)(NH2), –C(O)NH2, –NH2, –CN, halo, –CH2C(O)OH, –C(O)OH, –S(O)2NH2, –CH2CN, –NHBoc, –CH2NHCH3, –CH(CH3)NH2, –CH2NHCH=NOH, –CH2OH, amino-substituted cycloalkyl, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, or heteroarylalkyl; V is -C(O)REor H; REis –OH, –NH-OH, –O(alkyl), –C(O)(haloalkyl),RArepresents H, alkyl, alkoxy, halo, –NHBoc, tosyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl;RB2and RB3each, independently for each occurrence, represent halo, –C(O)OH, –C(O)NH2, –C(O)NH(alkyl), –C(O)NH(aminoalkyl), oxo, cyano, hydroxy, or optionally substituted alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; RD, independently for each occurrence, represents hydroxy, halo, –CN, –C(O)OH, –C(O)NH(alkyl), –C(O)NH(cycloalkyl), –CH2C(O)(alkyl), –CH2C(O)ORD1, – CH2C(O)NHRD1, –O[(CH2)xO]y(alkyl), –O(CH2)xCOOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl, or haloalkyl; RD1, independently for each occurrence, represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; q, m1, and m2 are each integers independently selected from 0-3; the sum of m1 and m2 is 3 or less; and x and y are each integers independently selected from 1-10.

55. The compound of claim 54, whereinwhereinhas a structure selected from the group consisting of:

57. The compound of claim 54, whereinhas the following58. The compound of claim 57, whereinhas a structure selected from the group consisting of:

59. The compound of any one of claims 54-58, wherein RB2and RB3each, independently for each occurrence, represent halo or alkyl.

60. The compound of any one of claims 54-59, wherein V is -C(O)RE.

61. The compound of claim 60, wherein REis –OH or –O(methyl).

62. The compound of claim 60, wherein REis –OH.

63. The compound of any one of claims 54-62, wherein RArepresents H, alkyl, alkoxy, or halo.

64. The compound of claim 63, wherein RArepresents alkoxy.

65. The compound of any one of claims 54-64, wherein –J-K– is selected from the group consisting of –C(O)-NH–, –C(O)-N(CH3)–, –C(O)-NHCH2–, –CH2-O–, and –CH2-NH–.

66. The compound of claim 65, wherein –J-K– is –C(O)-NH–.

67. The compound of any one of claims 54-66, wherein ringis optionally substituted thiophenyl.

68. The compound of any one of claims 54-67, wherein ring is phenyl.

69. The compound of any one of claims 54-67, wherein ringis benzoimidazolyl, indolyl, or isoquinolinyl.

70. The compound of any one of claims 54-69, wherein ringis represented by:

71. The compound of claim 70, wherein Y is –NH2.The compound of any one of claims 54-69, wherein ring is represented by.

73. The compound of claim 72, wherein Y is selected from the group consisting of –CH2NH2, –C(=NH)(NH2), and –C(O)NH2.

74. The compound of claim 73, wherein Y is –CH2NH2.

75. The compound of claim 73, wherein Y is –C(=NH)(NH2).

76. The compound of any one of claims 54-75, wherein q is 0.

77. The compound of claim 54, or a pharmaceutically acceptable salt thereof, selected from the following table:.

78. A pharmaceutical composition, comprising a compound of any one of claims 1-77, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

79. A method of treating or preventing a disease or condition characterized by aberrant kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-77, or a pharmaceutically acceptable salt thereof.

80. The method of claim 79, wherein the disease or condition is characterized by aberrant kallikrein-related peptidase 5 (KLK5) activity.

81. The method of claim 79 or 80, wherein the disease or condition is a skin disease.

82. The method of any one of claims 79-81, wherein the disease or condition is Netherton Syndrome.

83. The method of claim 81, wherein the skin disease is eczema, atopic eczema, atopic dermatitis, ichthyosiform (scaly) erythroderma (IE), rosacea, or a skin infection.

84. The method of claim 79 or 80, wherein the disease or condition is selected from the group consisting of rhinitis, conjunctivitis, angioedema, eosinophilia, eosinophilic esophagitis, growth delay, failure to thrive, trichorrhexis invaginata (TI), respiratory tract infections, systemic infections, and gastrointestinal disorders.

85. The method of claim 79 or 80, wherein the disease or condition is selected from the group consisting of hypersensitivity of the immune system (atopy), hyper IgE syndrome, allergies (including allergies to food and airborne agents), asthma, allergic asthma, and chronic inflammation.

86. The method of claim 79 or 80, wherein the disease or condition is cancer.

87. The method of claim 86, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, bladder cancer, cervical cancer, glioblastoma multiforme, and neuroblastoma.

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