Thienodiazepine derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical composition including the same as an active ingredient

Abstract

The present invention relates to novel thienodiazepine derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutical composition including the same. The thienodiazepine derivatives or pharmaceutically acceptable salts thereof exhibit selective inhibition activities against protein kinases such as c-Kit, FLT3, FMS, LYN, RAF1, VEGFR3, PDGFRa, PDGFRb, RET, etc., and thus can be used as a pharmaceutical composition for prevention or treatment of abnormal cell growth diseases.

Claims

1. A compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: ##STR00060## in Chemical Formula 1, Ar is C6-20 arylene or heteroarylene, wherein the heteroarylene is a divalent group derived from one aromatic compound selected from the group consisting of pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, and 1,2,3,5-tetrazine, carbazole, indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazineimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquinoline, acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine, quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, phenanthridine, phenanthroline, thieno[2,3-b]thiophene, thieno[3,2-b]thiophene, dithienothiophene, dithienopyridine, isobenzothiophene, dibenzothiophene, and benzothiadiazothiophene; L is NR.sup.1C(O), C(O)NR.sup.1, C(O)NR.sup.1C(O), NR.sup.1C(O)NR.sup.2, or NR.sup.1C(O)NR.sup.2C(O); R.sup.1 and R.sup.2 are each independently hydrogen, a C1-5 alkyl, a C2-6 unsaturated alkyl, or a C1-5 alkylamine; R.sup.a is 3-chloro-4-(trifluoromethyl)phenyl, 4-chloro-4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl, 3-(morpholin-4-yl)-5-(trifluoromethyl)phenyl, 4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl, 3-(morpholin-4-yl)-4-(trifluoromethyl)phenyl, 3-(morpholin-3-yl)-5-(trifluoromethyl)phenyl, biphenyl-4-yl, biphenyl-2-yl, 1-phenyl-5-(trifluoromethyl)-pyrazole-4-yl, 1-acetylpiperidin-4-yl, bis(4-chlorophenyl)methyl, 2-chloro-5-(4-chlorobenzyl)phenyl, pyridinyl, pyrazinyl, 6-fluorophenyl-methyl, 3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)phenyl), 3-(4-hydroxylpiperazine-1-yl)-5-(trifluoromethyl)phenyl, 4-(4-ethylpiperazine-1-yl)-3-(trifluoromethyl)phenyl, 4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-(1-methylpiperazine-4-yloxy)-3-(trifluoromethyl)phenyl, chlorophenyl, 1H-indol-3-yl-methyl, 2-[(2-cyanophenyl)sulfanyl]phenyl, quinolinyl, biphenyl-4-yl-methyl, 2,4-dimethylphenyl, 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl, 2,3-dichlorophenyl, 4-[(4-ethylpiperazine-1-yl)methyl]-3-(trifluoromethyl)phenyl, fluorophenyl, 1H-benzotriazol-5-yl, 5-(4-methoxyphenyl)furan-2-yl, dihydro-1H-indol-2-yl, 3,4-di-methoxyphenyl)methyl, naphthyl, benzothienyl, pyranyl, isoxazolyl, pyrazolyl, pyridazinyl, thiazolyl, thienyl, pyrimidinyl, imidazolyl, pyrolyl, dihydropyrolyl, oxazolyl, triazolyl, thidiazolyl, benzimidazolyl, quinolyl, tetrahydroquinolyl, benzothiazolyl, benzothiazophenyl, benzodioxolyl, indolyl, or dihydrobenzofuranyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Chemical Formula 1 is one or more compounds selected from the group consisting of the following compounds: 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)-3-(trifluoromethyl)benzamide; 3-(4-methyl-1H-imidazol-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 3-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 4-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide; N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide; N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide; N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-acetyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)piperidine-4-carboxamide; 2,2-bis(4-chlorophenyl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine -4-yl)phenyl)acetamide; N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)isonicotinamide; N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide; 3-(4-methylpiperazine-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)benzamide; 2-(1H-indol-3-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide; 2-(2-cyanophenylthio)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide; 2-(biphenyl-4-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide; 3,5-dimethyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide; 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide; 3-(4-methyl-1H-imidazol-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 3-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 4-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-acetyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)piperidine-4-carboxamide; 2,2-bis(4-chlorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine -4-yl)phenyl)acetamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)isonicotinamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide; 3-(4-methylpiperazine-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide; 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide; 2-(1H-indol-3-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide; 2-(2-cyanophenylthio)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide; 2-(biphenyl-4-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide; 3,5-dimethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide; 2-(2-fluorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)quinoline-2-carboxamide; N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)quinoline-3-carboxamide; (R)-6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)chroman-2-carboxamide; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(4-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3,4-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3,5-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(2-fluorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(4-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3,4-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; 1-(3,5-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea; and 1-(2-fluorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea.

3. A pharmaceutical composition comprising an effective amount of a compound represented by Chemical Formula 1 according to claim 1 and a pharmaceutically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 shows schemes for the synthesis of the thienodiazepine derivative according to one embodiment of the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

(2) Hereinafter, the actions and effects of the invention will be explained through specific examples. However, these examples are presented only as the illustrations of the invention, and the scope of the invention is not limited thereby.

EXAMPLE 1

Synthesis of 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide

(Step 1) Synthesis of 2,2-dimethyl-5-(4-nitrobenzoyl)-1,3-dioxane-4,6-dione

(3) ##STR00003##

(4) Meldrum's acid (3 g, 20.8 mmol) and N,N-dimethyl amino pyridine (4.8 g, 26 mmol) were dissolved in methylene chloride, nitrobenzoyl chloride (5 g, 42 mmol) was then slowly dripped thereto, and the solution was stirred for 4 hours. After the completion of the reaction was confirmed, it was extracted three times with methylene chloride and washed with water, and then dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the concentrated residue was purified and separated through column chromatography (silica gel, methylene chloride: MeOH=10:1) to obtain a target compound B (2,2-dimethyl-5-(4-nitrobenzoyl)-1,3-dioxane-4,6-dione, 2.3 g, 40%).

(Step 2) Synthesis of ethyl 3-(4-nitrophenyl)-3-oxopropanoate

(5) ##STR00004##

(6) The compound B (2.3 g, 7.8 mmol) was dissolved in EtOH and then stirred under reflux at 100 C. for 10 hours. After the completion of the reaction was confirmed, the solvent was removed under reduced pressure, the filtrate was distilled under reduced pressure, and the concentrated residue was purified and separated through column chromatography (silica gel, methylene chloride) to obtain a target compound C (ethyl 3-(4-nitrophenyl)-3-oxopropanoate, 1.7 g, 83%).

(7) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.27 (2 H, d, J=9.2), 7.93 (2 H, d, J=9.2), 5.76 (1 H, s), 4.30 (2 H, q, J=7.2), 1.35 (3 H, t, J=7.2)

(Step 3) Synthesis of thiophene-3,4-diamine

(8) ##STR00005##

(9) 2,5-dibromo-3,4-dinitrothiophene 4a (1.8 g, 5.4 mmol) was dissolved in HCl (23 ml), and then tin metal (4.5 g, 37.8 mmol) was slowly added thereto. After the completion of the reaction was confirmed, the solution was filtered to obtain a white precipitate, and then pH was adjusted to about 78 while slowly introducing an aqueous solution of KOH, thus obtaining a target compound D (thiophene-3,4-diamine, 172.8 mg, 29%).

(10) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.29 (d, J=1.6 Hz, 1 H), 8.06 (d, J=8.8 Hz, 1 H), 7.67 (dd, J=1.6, 8.8 Hz, 1 H), 4.47 (q, J=7.2 Hz, 2 H), 1.41 (t, J=7.2 Hz, 3 H).

(Step 4) Synthesis of 4-(4-nitrophenyl)-1H-thieno[3,4-b][1,4]diazepine-2(3H)-one

(11) ##STR00006##

(12) The compound C (239 mg, 1.0 mmol) and the compound D (172.8 mg, 1.5 mmol) obtained in the above processes were dissolved in xylene, reacted in a 500 W microwave for 10 minutes, and the reaction mixture was extracted with methylene chloride three times and washed with water and then dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the concentrated residue was purified and separated through column chromatography (silica gel, ethyl acetate:hexane=1:1) to obtain a target compound E (4-(4-nitrophenyl)-1H-thieno[3,4-b][1,4]diazepine-2(3H)-one, 244 mg, 56%).

(13) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.94 (1 H, t, J=1.6 Hz), 8.37-8.32 (2 H, m), 8.23 (1 H, s), 7.66 (1 H, t, J=8.0 Hz), 7.45 (1 H, d, J=3.6 Hz), 6.91 (1 H, d, J=3.6 Hz), 3.73 (2 H, s)

(14) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.59 (1 H, s), 8.36 (2 H, d, J=8.8 Hz), 8.24 (2 H, d, J=8.8 Hz), 7.65 (1 H, d, J=3.6 Hz), 7.06 (1 H, d, J=3.6 Hz), 3.67 (2 H, s)

(Step 5) Synthesis of 4-(4-aminophenyl)-1H-thieno[3,4-b][1,4]diazepine-2(3H)-one

(15) ##STR00007##

(16) The above-obtained compound E (224 mg, 0.8 mmol) and ammonium chloride (165.8 mg, 3.1 mmol) were dissolved in 4 ml of ammonium chloride:water (3:1), and then Fe (173.1 mg, 3.1 mmol) was added thereto. After the completion of the reaction was confirmed, the solvent was removed under reduced pressure, and the reaction mixture was extracted with methylene chloride three times and washed with water, and then dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the concentrated residue was purified and separated through column chromatography (silica gel, methylene chloride:MeOH=10:1) to obtain a target compound F (4-(4-aminophenyl)-1H-thieno[3,4-b][1,4]diazepine-2(3H)-one, 178 mg, 87%).

(17) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.50 (1 H, s), 7.45 (1 H, d, J=3.6 Hz), 7.26 (1H, t, J=4.0 Hz), 7.14-7.12 (2 H, m), 6.99 (1 H, d, J=3.6 Hz), 5.30 (2 H, s), 3.50 (2 H, s)

(18) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.34 (1 H, s), 7.45 (2 H, d, J=8.4 Hz), 7.31 (1 H, d, J=3.6 Hz), 6.95 (1 H, d, J=4.0 Hz), 6.61 (2 H, d, J=8.8 Hz), 5.79 (2 H, s), 3.50 (2 H, s)

(Step 6) Synthesis of 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide

(19) ##STR00008##

(20) The above-obtained compound F (22 mg), 3-trifluoromethyl-4-chloro benzoic acid (35.2 mg), EDCl (40.6 mg), HOBt (25 mg), and triethylamine (40 L) were dissolved in a solvent of N,N-dimethylformamide, and then the solution was stirred at 70 C. for 12 hours. After cooling it to room temperature, ethyl acetate was added thereto, followed by washing with an aqueous solution of sodium bicarbonate. The organic layer was dried with sodium sulfite and filtered, and then the solvent was removed under reduced pressure. The residue was recrystallized with ethyl acetate and hexane to obtain a target compound 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide (18 mg, 92%).

(21) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.79 (1 H, s), 10.52 (1 H, s), 8.42 (1 H, d, J=2.0 Hz), 8.29 (1 H, dd, J=8.2 Hz), 8.07 (2 H, d, J=8.8 Hz), 7.94 (3 H, m), 7.51 (1 H, d, J=3.6 Hz), 7.02 (1 H, d, J=3.6 Hz), 3.61 (2 H, s)

(22) (m/z 464.0431)

Example 2

Synthesis of 3-(4-methyl-1H-imidazol-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(23) ##STR00009##

(24) 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (10 mg, 0.030 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22 mg, 0.058 mmol), and TEA (7.9 mg, 0.078 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, and then the compound F (10 mg, 0.030 mmol) was added, followed by stirring the solution at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added, and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 3-(4-methyl-1H-imidazol-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (10.3 mg, 67%).

(25) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.77 (1 H, s), 10.53 (1 H, s), 8.49 (1 H, s), 8.43 (1 H, s), 8.27 (1 H, s), 8.19 (1 H, s), 8.09 (2 H, d, J=8.8 Hz), 7.95 (2 H, d, J=8.8 Hz), 7.75 (1 H, s), 7.52 (1 H, d, J=4.0 Hz), 7.02 (1 H, d, J=3.6 Hz), 3.61 (2 H, s), 2.19 (3 H, s)

(26) (Exact mass 509.11, m/z 510.1193)

Example 3

Synthesis of 3-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(27) ##STR00010##

(28) 3-morpholino-5-(trifluoromethyl)benzoic acid (10.7 mg, 0.038 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22 mg, 0.058 mmol), and TEA (7.9 mg, 0.078 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, and then the compound F (10 mg, 0.038 mmol) was added thereto, followed by stirring the solution at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with an aqueous solution of saturated NaCl. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (10 mg, 51%).

(29) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.59 (1 H, s), 10.48 (1 H, s), 8.06 (2 H, d, J=8.8 Hz), 7.93 (2 H, d, J=8.8 Hz), 7.74 (1 H, s), 7.68 (1 H, s), 7.50 (1 H, d, J=8.8 Hz), 7.41 (1 H, s), 7.02 (1 H, d, J=8.8 Hz), 3.78 (4 H, t, J=4.8 Hz), 3.61 (2 H, s)

(30) (Exact mass 514.13, m/z 515.1342)

Example 4

Synthesis of 4-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide

(31) ##STR00011##

(32) 4-morpholino-3-(trifluoromethyl)benzoic acid (10.7 mg, 0.038 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22 mg, 0.058 mmol), and TEA (7.9 mg, 0.078 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, and then the compound F (10 mg, 0.038 mmol) was added, followed by stirring the solution at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 4-morpholino-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide (15.1 mg, 77%).

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.60 (1 H, s), 10.48 (1 H, s), 8.28-8.26 (2 H, m), 8.05 (2 H, d, J=8.8 Hz), 7.93 (2 H, d, J=8.8 Hz), 7.67 (1 H, d, J=8.0 Hz), 7.50 (1 H, d, J=3.6 Hz), 7.02 (1 H, d, J=3.6 Hz), 3.74 (4 H, t, J=4.4 Hz), 3.60 (2 H, s), 2.98 (4 H, t, J=4.2 Hz)

(34) (Exact mass 514.13, m/z 515.1344)

Example 5

Synthesis of N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide

(35) ##STR00012##

(36) 2-(biphenyl-4-yl)acetic acid (9 mg, 0.045 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (21.7 mg, 0.057 mmol), and TEA (7.7 mg, 0.076 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, and then the compound F (10 mg, 0.038 mmol) was added thereto, followed by stirring the solution at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide (9.4 mg, 56%).

(37) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.54 (1 H, s), 10.52 (1 H, s), 8.48 (1 H, s), 8.11 (2 H, d, J=8.4 Hz), 8.04 (1 H, d, J=7.2 Hz), 7.86 (2 H, d, J=8.8 Hz), 7.79-7.75 (3 H, m), 7.55-7.52 (4 H, m), 7.43 (1 H, d, J=7.2 Hz), 7.04 (1 H, d, J=4.0 Hz), 3.61 (2 H, s), 3.62 (2 H, s)

(38) (Exact mass 437.12, m/z 438.1254)

Example 6

Synthesis of N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide

(39) ##STR00013##

(40) Biphenyl-2-carboxylic acid (8.3 mg, 0.041 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (21.7 mg, 0.057 mmol), and TEA (7.7 mg, 0.076 mmol) were dissolved in DMF (0.2 ml), followed by stirring the solution at 45 C. for 30 minutes, and then the compound F (9.8 mg, 0.038 mmol) was added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide (8 mg, 48%).

(41) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (1 H, s), 10.47 (1 H, s), 7.94 (2 H, d, J=8.8 Hz), 7.66 (2 H, d, J=8.8 Hz), 7.62-7.57 (2 H, m), 7.53-7.47 (3 H, m), 7.45-7.43 (2 H, m), 7.37 (2 H, t, J=7.6 Hz), 7.31-7.27 (1 H, m), 7.00 (1 H, d, J=3.6 Hz), 3.56 (2 H, s)

(42) (Exact mass 437.12, m/z 438.1254)

Example 7

Synthesis of N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

(43) ##STR00014##

(44) 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (10 mg, 0.039 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (20 mg, 0.052 mmol), and TEA (7.1 mg, 0.070 mmol) were dissolved in DMF (0.3 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (9.1 mg, 0.035 mmol) was added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (4.5 mg, 27%).

(45) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.78 (1 H, s), 10.47 (1 H, s), 8.36 (1 H, s), 8.05 (2 H, d, J=8.8 Hz), 7.87 (2 H, d, J=8.8 Hz), 7.63-7.61 (3 H, m), 7.56-7.55 (2 H, m), 7.50 (1 H, d, J=4.0 Hz), 7.02 (1 H, d, J=3.6 Hz)

(46) (Exact mass 495.10, m/z 496.1016)

Example 8

Synthesis of 1-acetyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)piperidine-4-carboxamide

(47) ##STR00015##

(48) 1-acetylpiperidine-4-carboxylic acid (6.9 mg, 0.040 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (20.8 mg, 0.056 mmol), and TEA (7.5 mg, 0.070 mmol) were dissolved in DMF (0.3 ml), and the solution was stirred at 45 C. for 30 minutes, and then the compound F (9.4 mg, 0.037 mmol) was added and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-acetyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)piperidine-4-carboxamide (11 mg, 72%).

(49) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.53 (1 H, s), 9.97 (1 H, s), 7.98 (1 H, d, J=8.0 Hz), 7.74 (1 H, d, J=8.0 Hz), 7.47 (1 H, d, J=3.6 Hz), 7.00 (1 H, d, J=3.6 Hz), 4.43-4.39 (1 H, m), 3.89-3.86 (1 H, m), 3.57 (2 H, s), 3.10-3.04 (1 H, m), 2.61-2.59 (2 H, m), 2.01 (3 H, s), 1.85-1.80 (2 H, m), 1.64-1.54 (1 H, m), 1.49-1.39 (1 H, m)

(50) (Exact mass 410.14, m/z 411.1467)

Example 9

Synthesis of 2,2-bis(4-chlorophenyl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(51) ##STR00016##

(52) 2,2-bis(4-chlorophenyl)acetic acid (10 mg, 0.032 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (18.25 mg, 0.048 mmol), and TEA (6.52 mg, 0.064 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (8.3 mg, 0.032 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2,2-bis(4-chlorophenyl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide (12 mg, 72%).

(53) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.71 (1 H, s), 10.45 (1 H, s), 7.99 (2 H, d, J=8.8 Hz), 7.74 (2 H, d, J=8.8 Hz), 7.47 (1 H, d, J=3.6 Hz), 7.42 (4 H, d, J=8.8 Hz), 7.37 (4 H, d, J=8.8 Hz), 7.00 (1 H, d, J=3.6 Hz), 5.23 (1 H, s), 3.56 (2 H, s)

(54) (Exact mass 519.06, m/z 521.0682)

Example 10

Synthesis of N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)isonicotinamide

(55) ##STR00017##

(56) The compound F (20 mg, 0.077 mmol), isonicotinoyl chloride (10 mg, 0.077 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in THF (0.64 ml), and then the solution was stirred at 65 C. for 12 hours. After the reaction was completed, ethyl acetate was added, and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with magnesium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)isonicotinamide (7 mg, 25%).

(57) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.76 (s, 1 H), 10.51 (s, 1 H), 8.81 (dd, J=4.6, 1.4 Hz, 2 H), 8.06 (d, J=8.9 Hz, 2 H), 7.94 (d, J=8.9 Hz, 2 H), 7.89 (dd, J=4.5, 1.6 Hz, 2 H), 7.51 (d, J=3.7 Hz, 1 H), 7.02 (d, J=3.7 Hz, 1 H), 3.61 (s, 2 H).

(58) (Exact m/z 362.08, m/z 362.41)

Example 11

Synthesis of N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide

(59) ##STR00018##

(60) Pyrazine-2-carboxylic acid (9.5 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (43 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), and the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide (8 mg, 28%).

(61) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.00 (1 H, s), 10.50 (1 H, s), 9.33 (1 H, s), 8.96 (1 H, d, J=2.4 Hz), 8.84 (1 H, dd, J=2.5, 1.5 Hz), 8.10-8.03 (4 H, m), 7.51 (1 H, d, J=3.7 Hz), 7.02 (1 H, d, J=3.7 Hz), 3.61 (2 H, s).

(62) (Exact m/z 363.08, m/z 364.08)

Example 12

Synthesis of 3-(4-methylpiperazine-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(63) ##STR00019##

(64) 3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzoic acid (54 mg, 0.19 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (108 mg, 0.28 mmol), and TEA (3 8 mg, 0.38 mmol) were dissolved in DMF (1.5 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (50 mg, 0.19 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3-(4-methylpiperazine-1-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (10 mg, 10%).

(65) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.587 (s, 1 H), 10.496 (s, 1 H), 8.03 (d, J=9.2 Hz, 2 H), 7.91 (d, J=9.2 Hz, 2 H), 7.73 (s, 1 H), 7.63 (s, 1 H), 7.25 (d, J=3.6 Hz, 1 H), 7.39 (s, 1 H), 7.01 (d, J=3.6 Hz, 1 H), 3.60 (s, 2 H), 2.55-2.44 (m, 8 H), 2.24 (s, 3 H).

(66) (Exact m/z 527.16, m/z 528.96)

Example 13

Synthesis of 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(67) ##STR00020##

(68) 4-chlorobenzoic acid (9 mg, 0.058 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (33 mg, 0.087 mmol), and TEA (11 mg, 0.116 mmol) were dissolved in DMF (0.48 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (15 mg, 0.058 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 4-chloro-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide (9 mg, 39%).

(69) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.58 (s, 1 H), 10.50 (s, 1 H), 8.04-8.02 (m, 2 H), 8.01 (t, J=1.9 Hz, 2 H), 7.94 (d, J=9.0 Hz, 2 H), 7.63 (dd, J=7.2, 1.5 Hz, 2 H), 7.50 (d, J=3.7 Hz, 1 H), 7.02 (dd, J=3.5, 1.9 Hz, 1 H), 3.60 (s, 2 H).

(70) (Exact mass 395.05, m/z 395.86)

Example 14

Synthesis of 2-(1H-indol-3-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(71) ##STR00021##

(72) 2-(1H-indol-3-yl)acetic acid (13 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (43 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(1H-indol-3-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide (17 mg, 53%).

(73) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.94 (1 H, s), 10.46 (1 H, s), 10.39 (1 H, s), 7.97 (2 H, d, J=8.9 Hz), 7.75 (2 H, d, J=8.9 Hz), 7.61 (1 H, d, J=7.9 Hz), 7.47 (1 H, d, J=3.7 Hz), 7.35 (1 H, d, J=8.0 Hz), 7.27 (1 H, d, J=2.3 Hz), 7.09-7.05 (1 H, m), 7.01-6.98 (2 H, m), 3.77 (2 H, s), 3.56 (2 H, s)

(74) (Exact mass 414.12, m/z 415.12)

Example 15

Synthesis of 2-(2-cyanophenylthio)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(75) ##STR00022##

(76) 2-(2-cyanophenylthio)benzoic acid (19.6 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(2-cyanophenylthio)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide (7 mg, 18%).

(77) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.90 (1 H, d, J=1.2 Hz), 7.88 (1 H, d, J=1.1 Hz), 7.73-7.66 (4 H, m), 7.52-7.34 (7 H, m), 7.25-7.22 (1 H, m), 3.06 (2 H, q, J=7.1 Hz).

(78) (Exact mass 494.09, m/z=494.71)

Example 16

Synthesis of 2-(biphenyl-4-yl)-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazebine-4-yl)phenyl)acetamide

(79) ##STR00023##

(80) 2-(biphenyl-4-yl)acetic acid (16.3 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 5p (26 mg, 74%).

(81) .sup.1H NMR (400 MHz, DMSO-d6) 10.48 (2 H, d, J=7.3 Hz), 7.99 (1 H, d, J=8.9 Hz), 7.75 (1 H, d, J=8.9 Hz), 7.68-7.60 (4 H, m), 7.59 (1 H, t, J=2.0 Hz), 7.51 (1 H, t, J=2.2 Hz), 7.48 (1 H, d, J=3.6 Hz), 7.47-7.41 (3 H, m), 7.38-7.30 (2 H, m), 7.00 (1 H, d, J=3.7 Hz), 3.72 (2 H, dd, J=14.4, 6.7 Hz), 3.57 (2 H, s).

(82) (Exact mass 451.14, m/z 452.21)

Example 17

Synthesis of 3,5-dimethyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(83) ##STR00024##

(84) 3,5-dimethylbenzoic acid (8 mg, 0.058 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (33 mg, 0.087 mmol), and TEA (11 mg, 0.116 mmol) were dissolved in DMF (0.48 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3,5-dimethyl-N-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide (9 mg, 39%).

(85) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.49 (s, 1 H), 10.43 (s, 1 H), 8.03 (d, J=8.9 Hz, 2 H), 7.94 (d, J=8.9 Hz, 2 H), 7.59 (s, 2 H), 7.50 (d, J=3.7 Hz, 1 H), 7.24 (s, 1 H), 7.01 (d, J=3.7 Hz, 1 H), 3.60 (s, 2 H), 2.37 (s, 6 H).

(86) (Exact mass 389.12, m/z 389.47)

Example 18

Synthesis of 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide

(87) ##STR00025##

(88) 4-chloro-3-(trifluoromethyl)benzoic acid (9.6 mg, 0.042 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22.2 mg, 0.059 mmol), and TEA (7.2 mg, 0.078 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10 mg, 0.039 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide (13.4 mg, 74%).

(89) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.73 (1 H, s), 10.53 (1 H, s), 8.44 (1 H, d, J=2.0 Hz), 8.41 (1 H, t, J=1.8 Hz), 8.30 (1 H, dd, J=8.4, 2.0 Hz), 8.03 (1 H, dd, J=7.2, 1.2 Hz), 7.94 (1 H, d, J=8.4 Hz), 7.78 (1 H, d, J=8.4 Hz), 7.56-7.52 (2 H, m), 7.03 (1 H, d, J=3.6 Hz), 3.61 (2 H, s)

(90) (Exact mass 463.04, m/z 464.0418)

Example 19

Synthesis of 3-(4-methyl-1H-imidazol-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(91) ##STR00026##

(92) 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (12 mg, 0.0436 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22.6 mg, 0.059 mmol), and TEA (7.2 mg, 0.078 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10.2 mg, 0.039 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 3-(4-methyl-1H-imidazol-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (15.6 mg, 78%).

(93) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.71 (1 H, s), 10.53 (1 H, s), 8.49 (1 H, s), 8.43-8.42 (2 H, m), 8.26 (1 H, s), 8.22 (1 H, s), 8.06 (1 H, dd, J=8.2, 1.4 Hz), 7.79 (1 H, d, J=8.0 Hz), 7.73 (1 H, s), 7.58-7.54 (2 H, m), 7.04 (1 H, d, J=4.0 Hz), 3.61 (2 H, s), 2.20 (3 H, s)

(94) (Exact mass 509.11, m/z 510 10.1186)

Example 20

Synthesis of 3-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(95) ##STR00027##

(96) 3-morpholino-5-(trifluoromethyl)benzoic acid (12 mg, 0.043 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22.6 mg, 0.059 mmol), and TEA (8 mg, 0.079 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10 mg, 0.039 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (12.6 mg, 62%).

(97) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.56 (1 H, s), 10.53 (1 H, s), 8.40 (1 H, s), 8.02 (1 H, d, J=9.2 Hz), 7.77-7.75 (2 H, m), 7.70 (1 H, s), 7.55-7.51 (2 H, s), 7.41 (1 H, s), 7.03 (1 H, d, J=3.6 Hz), 3.78 (4 H, t, J=4.6 Hz), 3.61 (2 H, s)

(98) (Exact mass 514.13, m/z 515.1331)

Example 21

Synthesis of 4-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide

(99) ##STR00028##

(100) 4-morpholino-3-(trifluoromethyl)benzoic acid (12 mg, 0.043 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (22.6 mg, 0.059 mmol), and TEA (8 mg, 0.079 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10 mg, 0.039 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 4-morpholino-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)-3-(trifluoromethyl)benzamide (5 mg).

(101) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.57 (1 H, s), 10.52 (1 H, s), 8.42 (1 H, t, J=1.8 Hz), 8.30-8.27 (2 H, m), 8.02 (1 H, dd, J=8.0, 1.2 Hz), 7.76 (1 H, d, J=7.6 Hz), 7.66 (1 H, d, J=8.4 Hz), 7.54-7.50 (2 H, m), 7.03 (1 H, d, J=3.6 Hz), 3.74 (4 H, t, J=4.4 Hz), 3.61 (2 H, s), 2.97 (4 H, t, J=4.4 Hz)

(102) (Exact mass 514.13, m/z 515.1335)

Example 22

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide

(103) ##STR00029##

(104) Biphenyl-4-carboxylic acid (6.2 mg, 0.031 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (16 mg, 0.042 mmol), and TEA (5.7 mg, 0.056 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10 mg, 0.039 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-4-carboxamide (2.5 mg, 14%).

(105) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.54 (1 H, s), 10.52 (1 H, s), 8.48 (1 H, s), 8.11 (2 H, d, J=8.4 Hz), 8.04 (1 H, d, J=7.2 Hz), 7.86 (2 H, d, J=8.8 Hz), 7.79-7.75 (3 H, m), 7.55-7.52 (4 H, m), 7.43 (1 H, d, J=7.2 Hz), 7.04 (1 H, d, J=4.0 Hz), 3.62 (2 H, s)

(106) (Exact mass 437.12, m/z 438.1255)

Example 23

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide

(107) ##STR00030##

(108) Biphenyl-2-carboxylic acid (6 mg, 0.030 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (15 mg, 0.040 mmol), and TEA (5.5 mg, 0.054 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (7 mg, 0.027 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)biphenyl-2-carboxamide (6.5 mg, 55%).

(109) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.49 (1 H, s), 10.43 (1 H, s), 8.25 (1 H, s), 7.68 (2 H, d, J=8.0 Hz), 7.61-7.57 (2 H, m), 7.52 (1 H, d, J=3.6 Hz), 7.49-7.41 (4 H, m), 7.40-7.36 (3 H, m), 7.30 (1 H, t, J=7.2 Hz), 7.01 (1 H, d, J=3.6 Hz), 3.55 (2 H, s)

(110) (Exact mass 437.12, m/z 438.1258)

Example 24

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

(111) ##STR00031##

(112) 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (7.1 mg, 0.028 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (16 mg, 0.042 mmol), and TEA (5.7 mg, 0.056 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (7.1 mg, 0.028 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (12 mg, 86%).

(113) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.74 (1 H, s), 10.54 (1 H, s), 8.38 (1 H, s), 8.36 (1 H, s), 7.94 (1 H, d, J=8.4 Hz), 7.76 (1 H, d, J=8.4 Hz), 7.63-7.61 (4 H, m), 7.56-7.50 (3 H, m), 7.04 (1 H, d, J=4.0 Hz), 3.61 (2 H, s)

(114) (Exact mass 459.10, m/z 496.102)

Example 25

Synthesis of 1-acetyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)piperidine-4-carboxamide

(115) ##STR00032##

(116) 1-acetylpiperidine-4-carboxylic acid (5.1 mg, 0.03 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (15.5 mg, 0.041 mmol), and TEA (5.5 mg, 0.054 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (7 mg, 0.027 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-acetyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)piperidine-4-carboxamide (8.5 mg, 76%).

(117) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.52 (1 H, s), 10.15 (1 H, s), 8.26 (1 H, t, J=1.6 Hz), 7.83 (1 H, d, J=8.0 Hz), 7.67 (1 H, d, J=8.4 Hz), 7.53 (1 H, d, J=3.6 Hz), 7.44 (1 H, t, J=8.0 Hz), 7.02 (1 H, d, J=3.6 Hz), 3.89-3.86 (1 H, m), 3.55 (2 H, s), 3.11-3.04 (1 H, m), 2.63-2.56 (3 H, m), 2.04 (3 H, s), 1.64-1.54 (2 H, m), 1.46-1.2 (2 H, m)

(118) (Exact mass 410.14, m/z 411.1473)

Example 26

Synthesis of 2,2-bis(4-chlorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(119) ##STR00033##

(120) 2,2-bis(4-chlorophenyl)acetic acid (8.2 mg, 0.029 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (15 mg, 0.040 mmol), and TEA (5.3 mg, 0.052 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (6.8 mg, 0.026 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2,2-bis(4-chlorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide (4 mg, 29%).

(121) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.69 (1 H, s), 10.52 (1 H, s), 8.23 (1 H, t, J=1.8 Hz), 7.83 (1 H, dd, J=8.0, 1.2 Hz), 7.70 (1 H, d, J=8.4 Hz), 7.52 (1 H, d, J=3.6 Hz), 7.44-7.41 (5H, m), 7.38-7.36 (4 H, m), 7.02 (1 H, d, J=3.6 Hz), 3.56 (2 H, s)

(122) (Exact mass 519.06 m/z 520.0677)

Example 27

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)isonicotinamide

(123) ##STR00034##

(124) Isonicotinic acid (9.4 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl) isonicotinamide (8 mg, 28%).

(125) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.43 (s, 1 H), 10.72 (s, 1 H), 8.79 (d, J=5.5 Hz, 2 H), 8.29 (dd, J=4.4, 2.6 Hz, 2 H), 8.21 (d, J=8.1 Hz, 1 H), 7.86 (dd, J=4.4, 1.6 Hz, 2 H), 7.74 (dd, J=6.6, 1.6 Hz, 1 H), 7.59 (t, J=7.9 Hz, 1 H), 7.05 (d, J=3.3 Hz, 1 H), 3.51 (d, J=0.8 Hz, 2 H).

(126) (Exact mass 362.08, m/z 362.41)

Example 28

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide

(127) ##STR00035##

(128) Pyrazine-2-carboxylic acid (13 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (43 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)pyrazine-2-carboxamide (29 mg, 99%).

(129) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.97 (1 H, s), 10.53 (1 H, s), 9.33 (1 H, d, J=1.5 Hz), 8.95 (1 H, d, J=2.5 Hz), 8.84 (1 H, dd, J=2.5, 1.5 Hz), 8.63 (1 H, s), 8.07 (1 H, dd, J=8.1, 1.3 Hz), 7.80 (1 H, d, J=8.5 Hz), 7.57-7.50 (2 H, m), 7.03 (1 H, d, J=3.7 Hz), 3.62 (2 H, s)

(130) (Exact mass 363.08, m/z 364.08)

Example 29

Synthesis of 3-(4-methylpiperazine-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide

(131) ##STR00036##

(132) 3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzoic acid (33.6 mg, 0.116 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (66.1 mg, 0.17 mmol) and TEA (23.6 mg, 0.23 mmol) were dissolved in DMF (0.96 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (30 mg, 0.116 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3-(4-methylpiperazine-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)-5-(trifluoromethyl)benzamide (39 mg, 63%).

(133) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.55 (s, 1 H), 10.53 (s, 1 H), 8.40 (t, J=3.6 Hz, 1 H), 8.00 (d, d, J=1.2, 1.2 Hz, 1 H), 7.73 (d, J=2.4 Hz, 2 H), 7.65 (s, 1 H), 7.54-7.50 (t, s, J=7.6 Hz, 2 H), 7.38 (s, 1 H), 7.01 (d, J=4 Hz, 1 H), 3.61 (s, 2 H), 2.55-2.45 (m, 8 H), 2.23 (s, 3 H)

(134) (Exact mass 527.16, m/z 528.99)

Example 30

Synthesis of 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(135) ##STR00037##

(136) 4-chlorobenzoic acid (7.1 mg, 0.045 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (23.3 mg, 0.061 mmol), and TEA (8.3 mg, 0.082 mmol) were dissolved in DMF (0.2 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (10.5 mg, 0.041 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 4-chloro-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide (5 mg).

(137) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.54 (2 H, s), 8.43 (1 H, t, J=1.6 Hz), 8.04-8.00 (3 H, m), 7.75 (1 H, d, J=8.0 Hz), 7.63 (2 H, d, J=8.8 Hz), 7.55-7.49 (2 H, m), 7.03 (1 H, d, J=3.6 Hz), 3.61 (2 H, s)

(138) (Exact mass 395.05, m/z 396.0547)

Example 31

Synthesis of 2-(1H-indol-3-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(139) ##STR00038##

(140) 2-(1H-indol-3-yl)acetic acid (13 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (43 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(1H-indol-3-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide (30 mg, 93%).

(141) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.93 (1 H, s), 10.51 (1 H, s), 10.33 (1 H, s), 8.25 (1 H, t, J=1.8 Hz), 7.88-7.82 (1 H, m), 7.63 (1 H, dd, J=16.6, 8.1 Hz), 7.52 (1 H, d, J=3.7 Hz), 7.43 (1 H, t, J=8.0 Hz), 7.35 (1 H, dt, J=8.1, 0.9 Hz), 7.27 (1 H, d, J=2.3 Hz), 7.07 (1 H, ddd, J=8.1, 7.0, 1.2 Hz), 7.01 (1 H, dd, J=5.1, 2.4 Hz), 6.99-6.96 (1 H, m), 3.75 (2 H, s), 3.56 (2 H, s).

(142) (Exact mass 414.12, m/z 415.12)

Example 32

Synthesis of 2-(2-cyanophenylthio)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(143) ##STR00039##

(144) 2-(2-cyanophenylthio)benzoic acid (19.6 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(2-cyanophenylthio)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide (25 mg, 65%).

(145) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.72 (1 H, s), 10.53 (1 H, s), 8.40 (1 H, s), 7.94-7.88 (1 H, m), 7.77-7.75 (1 H, m), 7.70-7.66 (2 H, m), 7.55 (1 H, d, J=3.7 Hz), 7.52-7.48 (4 H, m), 7.44 (2 H, dd, J=7.9, 2.9 Hz), 7.20-7.16 (1 H, m), 7.03 (1 H, d, J=3.7 Hz), 3.59 (2 H, s)

(146) (Exact mass 494.09, m/z 495.09)

Example 33

Synthesis of 2-(biphenyl-4-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(147) ##STR00040##

(148) 2-(biphenyl-4-yl)acetic acid (16.3 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(biphenyl-4-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)acetamide (31 mg, 89%).

(149) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.52 (1 H, s), 10.44 (1 H, s), 8.26 (1 H, t, J=1.8 Hz), 7.85 (1 H, dd, J=8.1, 1.2 Hz), 7.66 (1 H, d, J=1.4 Hz), 7.64 (2 H, s), 7.62 (1 H, d, J=1.8 Hz), 7.52 (1 H, d, J=3.7 Hz), 7.47 (1 H, d, J=1.7 Hz), 7.46 (2 H, d, J=1.3 Hz), 7.43 (2 H, d, J=2.0 Hz), 7.38-7.36 (1 H, m), 7.35 (1 H, d, J=1.8 Hz), 7.02 (1 H, d, J=3.7 Hz), 3.71 (2 H, d, J=4.4 Hz), 3.57 (2 H, s)

(150) (Exact mass 451.14, m/z 452.14)

Example 34

Synthesis of 3,5-dimethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)benzamide

(151) ##STR00041##

(152) 3,5-dimethylbenzoic acid (11 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 3,5-dimethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)benzamide (26 mg, 86%).

(153) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.54 (1 H, s), 10.38 (1 H, s), 8.43 (1 H, t, J=1.8 Hz), 8.05-8.00 (1 H, m), 7.75-7.72 (1 H, m), 7.62-7.47 (6H, m), 7.24 (2 H, d, J=5.9 Hz), 7.04 (2 H, dd, J=8.2, 3.5 Hz), 6.98-6.96 (1 H, m), 6.92-6.89 (1 H, m), 3.61 (2 H, s)

(154) (Exact mass 389.12, m/z 390.12)

Example 35

Synthesis of 2-(2-fluorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)acetamide

(155) ##STR00042##

(156) 2-(2-fluorophenyl)acetic acid (11 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 2-(2-fluorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)acetamide (24 mg, 79%).

(157) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.52 (1 H, s), 10.45 (1 H, s), 8.29-8.26 (1 H, m), 7.81 (1 H, ddd, J=7.8, 1.8, 0.7 Hz), 7.68 (1 H, ddd, J=7.9, 1.8, 1.1 Hz), 7.52 (1 H, d, J=3.7 Hz), 7.46 (1 H, d, J=8.0 Hz), 7.41-7.39 (1 H, m), 7.32-7.29 (1 H, m), 7.19-7.17 (2 H, m), 7.02 (1 H, d, J=3.7 Hz), 3.76 (2 H, s), 3.57 (2 H, s)

(158) (Exact mass 393.09, m/z 394.10)

Example 36

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)quinoline-2-carboxamide

(159) ##STR00043##

(160) Quinoline-2-carboxylic acid (13 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl) quinoline-2-carboxamide (21 mg, 66%).

(161) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.98 (1 H, s), 10.55 (1 H, s), 8.64 (1 H, t, J=8.3 Hz), 8.55 (1 H, s), 8.48 (1 H, d, J=8.5 Hz), 8.27 (1 H, dd, J=11.3, 2.8 Hz), 8.14 (1 H, dd, J=15.4, 6.7 Hz), 8.04 (1 H, d, J=8.4 Hz), 7.97-7.91 (1 H, m), 7.85-7.74 (1 H, m), 7.71-7.65 (1 H, m), 7.63 (1 H, d, J=8.5 Hz), 7.60-7.53 (1 H, m), 7.04 (1 H, d, J=3.7 Hz), 3.66 (2 H, s).

(162) (Exact mass 412.10, m/z 413.10)

Example 37

Synthesis of N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)quinoline-3-carboxamide

(163) ##STR00044##

(164) Quinoline-3-carboxylic acid (13.3 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)quinoline-3-carboxamide (28 mg, 88%).

(165) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.85 (1 H, s), 10.56 (1 H, s), 9.39 (1 H, dd, J=6.2, 2.2 Hz), 9.02 (1 H, d, J=2.0 Hz), 8.87 (1 H, d, J=2.2 Hz), 8.48 (1 H, t, J=2.0 Hz), 8.43 (1 H, d, J=2.1 Hz), 8.19-8.05 (1 H, m), 7.96-7.89 (1 H, m), 7.84 (1 H, ddd, J=8.5, 6.9, 1.4 Hz), 7.77-7.72 (1 H, m), 7.71-7.66 (1 H, m), 7.57-7.55 (1 H, m), 7.04 (1 H, d, J=3.7 Hz), 3.63 (2 H, s).

(166) (Exact mass 412.10, m/z 413.10)

Example 38

Synthesis of (R)-6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)chroman-2-carboxamide

(167) ##STR00045##

(168) (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (19 mg, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (45 mg, 0.115 mmol), and TEA (56 mg, 0.154 mmol) were dissolved in DMF (0.64 ml), the solution was stirred at 45 C. for 30 minutes, the compound F (20 mg, 0.077 mmol) was then added, and the solution was stirred at 45 C. for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound (R)-6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)chroman-2-carboxamide (34 mg, 90%).

(169) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (1 H, s), 9.50 (1 H, s), 8.31 (1 H, t, J=1.9 Hz), 7.77 (1 H, ddd, J=8.2, 2.0, 0.8 Hz), 7.69 (1 H, ddd, J=7.8, 1.6, 1.0 Hz), 7.56-7.50 (3 H, m), 7.43 (1 H, t, J=8.0 Hz), 7.03 (1 H, dd, J=9.0, 3.5 Hz), 3.57 (2 H, s), 2.19 (3 H, d, J=3.0 Hz), 2.09-2.04 (7 H, m), 1.54-1.49 (5 H, m)

(170) (Exact mass 489.17, m/z 490.18).

Example 39

Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(171) ##STR00046##

(172) The compound F (10 mg, 0.038 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (8.6 mg, 0.038 mmol) were dissolved in THF (0.4 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (17 mg, 93%).

(173) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.46 (1 H, s), 9.25 (1 H, s), 9.19 (1 H, s), 8.13 (1 H, d, J=2.0 Hz), 7.98 (2 H, d, J=8.8 Hz), 7.68-7.60 (4 H, m), 7.47 (1 H, d, J=3.6 Hz), 7.00 (1 H, d, J=3.6 Hz), 3.57 (2 H, s)

(174) (Exact mass 478.05, m/z 479.0538)

Example 40

Synthesis of 1-(4-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(175) ##STR00047##

(176) Then compound F (10 mg, 0.039 mmol) and 1-chloro-4-isocyanatobenzene (7.1 mg, 0.046 mmol) were dissolved in DMF (0.3 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(4-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (8.2 mg, 51%).

(177) .sup.1H NMR (400 MHz, DMSO-d.sub.6)10.45 (1 H, s), 9.05 (1 H, s), 8.91 (1 H, s), 7.97 (2 H, d, J=8.8 Hz), 7.59 (2 H, d, J=8.8 Hz), 7.51-7.49 (2 H, m), 7.46 (1 H, d, J=3.6 Hz), 7.35-7.33 (2 H, m), 7.00 (1 H, d, J=3.6 Hz), 3.57 (2 H, s)

(178) (Exact mass 410.06, m/z 411.066)

Example 41

Synthesis of 1-(3-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(179) ##STR00048##

(180) The compound F (10 mg, 0.039 mmol) and 1-chloro-3-isocyanatobenzene (7.1 mg, 0.047 mmol) were dissolved in DMF (0.3 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(3-chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (14 mg, 87%).

(181) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (1 H, s), 10.27 (1 H, s), 10.20 (1 H, s), 7.96 (2 H, d, J=9.2 Hz), 7.70 (1 H, s), 7.60 (2 H, d, J=8.8 Hz), 7.46 (1 H, d, J=3.6 Hz), 7.31-7.30 (2 H, m), 7.02-7.00 (2 H, m), 3.56 (2 H, s)

(182) (Exact mass 410.06, m/z 411.0682)

Example 42

Synthesis of 1-(3,4-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(183) ##STR00049##

(184) The compound F (8.9 mg, 0.035 mmol) and 1,2-dichloro-4-isocyanatobenzene (7.2 mg, 0.038 mmol) were dissolved in DMF (0.3 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(3,4-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (5 mg, 32%).

(185) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.45 (1 H, s), 9.16 (1 H, s), 9.09 (1 H, s), 7.98 (2 H, d, J=8.8 Hz), 7.90 (1 H, d, J=2.8 Hz), 7.60 (2 H, d, J=8.8 Hz), 7.53 (1 H, d, J=8.8 Hz), 7.47 (1 H, d, J=4.0 Hz), 7.35 (1 H, dd, J=8.8, 2.4 Hz), 7.00 (1 H, d, J=3.6 Hz), 3.57 (2 H, s)

(186) (Exact mass 444.02, m/z 446.0302)

Example 43

Synthesis of 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(187) ##STR00050##

(188) The compound F (9.5 mg, 0.038 mmol), 4-nitrophenyl 3-(4-ethylpiperazine-1-yl)-5-(trifluoromethyl)phenylcarbamate (19.3 mg, 0.042 mmol), and TEA (7.7 mg, 0.076 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (5.2 mg, 23%).

(189) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.45 (1 H, s), 9.20 (2 H, s), 7.99-7.97 (3 H, m), 7.63-7.59 (4 H, m), 7.47 (1 H, d, J=3.6 Hz), 7.00 (1 H, d, J=3.6 Hz), 3.57 (2 H, s), 3.53 (2 H, s), 2.39-2.28 (10 H, m), 0.98 (3 H, t, J=7.2 Hz)

(190) (Exact mass 570.20, m/z 571.2081)

Example 44

Synthesis of 1-(3,5-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(191) ##STR00051##

(192) The compound F (10 mg, 0.038 mmol) and 1,3-dichloro-5-isocyanatobenzene (8 mg, 0.043 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(3,5-dichlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (14 mg, 80%).

(193) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.46 (1 H, s), 9.22 (1 H, s), 9.13 (1 H, s), 7.98 (2 H, d, J=8.8 Hz), 7.60 (2 H, d, J=8.8 Hz), 7.55 (2 H, d, J=2.0 Hz), 7.47 (1 H, d, J=3.6 Hz), 7.19 (1 H, t, J=1.6 Hz), 7.00 (1 H, d, J=4.0 Hz), 3.57 (2 H, s)

(194) (Exact mass 444.02, m/z 446.0299)

Example 45

Synthesis of 1-(2-fluorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(195) ##STR00052##

(196) The compound F (15 mg, 0.058 mmol) and 1-fluoro-2-isocyanatobenzene (8 mg, 0.058 mmol) were dissolved in THF (6 l), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(2-fluorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (6 mg, 26%).

(197) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.48 (s, 1 H), 9.40 (s, 1 H), 8.65 (d, J=2.5 Hz, 1 H), 8.16 (td, J=8.3, 1.7 Hz, 1 H), 7.99 (d, J=8.9 Hz, 2 H), 7.60 (d, J=8.9 Hz, 2 H), 7.47 (d, J=3.7 Hz, 1 H), 7.25 (ddd, J=11.6, 8.2, 1.4 Hz, 1 H), 7.18-7.13 (m, 1 H), 7.07-6.99 (m, 2 H), 3.57 (s, 2 H).

(198) (Exact mass 394.09, m/z 395.42)

Example 46

Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(199) ##STR00053##

(200) The compound F (10 mg, 0.038 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (8.6 mg, 0.038 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (16 mg, 87%).

(201) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (1 H, s), 9.17 (1 H, s), 9.12 (1 H, s), 8.14 (1 H, t, J=1.8 Hz), 8.12 (1 H, d, J=2.4 Hz), 7.70-7.61 (4 H, s), 7.54 (1 H, d, J=3.6 Hz), 7.44 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=3.6 Hz), 3.58 (2 H, s)

(202) (Exact mass 478.05, m/z 479.053)

Example 47

Synthesis of 1-(4-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(203) ##STR00054##

(204) The compound F (10.2 mg, 0.039 mmol), and 1-chloro-4-isocyanatobenzene (7.3 mg, 0.047 mmol) were dissolved in DMF (0.3 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(4-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)urea (13.2 mg, 82%).

(205) .sup.1H NMR (400 MHz, DMSO-d.sub.6)10.51 (1 H, s), 8.96 (1 H, s), 8.81 (1 H, s), 8.13 (1 H, t, J=1.8 Hz), 7.64-7.61 (2 H, m), 7.53 (1 H, d, J=3.6 Hz), 7.52-7.49 (2 H, m), 7.43 (1 H, t, J=8.0 Hz), 7.35-7.31 (2 H, m), 7.02 (1 H, d, J=4.0), 3.58 (2 H, s)

(206) (Exact mass 410.06, m/z 411.0654)

Example 48

Synthesis of 1-(3-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(207) ##STR00055##

(208) The compound F (10.2 mg, 0.039 mmol) and 1-chloro-3-isocyanatobenzene (7.2 mg, 0.047 mmol) were dissolved in DMF (0.4 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(3-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)urea (14.3 mg, 89%).

(209) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (1 H, s), 9.01 (1 H, s), 8.89 (1 H, s), 8.14 (1 H, t, J=1.6 Hz), 7.73 (1 H, s), 7.62 (2 H, dd, J=7.8, 1.8 Hz), 7.54 (1 H, d, J=3.6 Hz), 7.44 (1 H, t, J=8.0 Hz), 7.31-7.29 (2 H, m), 7.04-7.01 (2 H, m), 3.58 (2 H, s)

(210) (Exact mass 410.06, m/z 411.0651)

Example 49

Synthesis of 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(211) ##STR00056##

(212) The compound F (9.5 mg, 0.038 mmol), 4-nitrophenyl 3-(4-ethylpiperazine-1-yl)-5-(trifluoromethyl)phenylcarbamate (19.3 mg, 0.042 mmol) and TEA (7.7 mg, 0.076 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was crystallized to obtain a target compound 1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (5.2 mg, 23%).

(213) .sup.1H NMR (400 MHz, DMSO-d.sub.6)10.54 (1 H, s), 9.19 (1 H, s), 9.18 (1 H, s), 8.15 (1 H, t, J=1.6 Hz), 7.93 (1 H, d, J=2.0 Hz), 7.65-7.58 (4 H, m), 7.54 (1 H, d, J=3.6 Hz), 7.43 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=3.6 Hz), 3.58 (2 H, s), 3.52 (2 H, s), 2.38-2.28 (10 H, m), 0.98 (3 H, t, J=7.2 Hz) (m/z 571.2061)

Example 50

Synthesis of 1-(3,4-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(214) ##STR00057##

(215) The compound F (10 mg, 0.038 mmol) and 1,2-dichloro-4-isocyanatobenzene (10.2 mg, 0.054 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(3,4-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)urea (15.9 mg, 35%).

(216) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.53 (1 H, s), 9.08 (1 H, s), 9.01 (1 H, s), 8.15 (1 H, t, J=2.0 Hz), 7.90 (1 H, t, J=2.4 Hz), 7.64-7.61 (2 H, m), 7.55-7.52 (2 H, s), 7.44 (1 H, t, J=8.0 Hz), 7.35 (1 H, dd, J=8.0, 2.4 Hz), 7.03 (1 H, d, J=3.6 Hz), 3.58 (2 H, s)

(217) (Exact mass 444.02, m/z 446.0292)

Example 51

Synthesis of 1-(3,5-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(218) ##STR00058##

(219) The compound F (10 mg, 0.038 mmol) and 1,3-dichloro-5-isocyanatobenzene (10.2 mg, 0.054 mmol) were dissolved in DMF (0.2 ml), and then the solution was stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(3,5-dichlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4] diazepine-4-yl)phenyl)urea (12.6 mg, 72%).

(220) .sup.1H NMR (400 MHz, DMSO-d.sub.6)10.53 (1 H, s), 9.16 (1 H, s), 9.07 (1 H, s), 8.15 (1 H, t, J=2.0 Hz), 7.65-7.61 (2 H, m), 7.56-7.54 (3 H, m), 7.44 (1 H, t, J=7.8 Hz), 7.18 (1 H, t, J=1.8 Hz), 7.03 (1 H, d, J=3.6 Hz), 3.58 (2 H, s)

(221) (Exact mass 444.02, m/z 446.029)

Example 52

Synthesis of 1-(2-fluorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea

(222) ##STR00059##

(223) The compound F (20 mg, 0.077 mmol), and 1-fluoro-2-isocyanatobenzene (10 mg, 0.077 mmol) were dissolved in THF (0.2 ml), and then the solution was stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate was added and the reaction mixture was washed with a saturated aqueous NaCl solution. The organic layer was dried with sodium sulfate anhydrous and filtered, and then the solvent was removed under reduced pressure. The residue was purified through column chromatography (silica gel, ethyl acetate:Hex=1:1) to obtain a target compound 1-(2-fluorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea (30 mg, 98%).

(224) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.53 (s, 1 H), 9.33 (s, 1 H), 8.56 (d, J=2.5 Hz, 1 H), 8.19-8.11 (m, 2 H), 7.63 (ddd, J=5.8, 4.8, 1.9 Hz, 2 H), 7.54 (d, J=3.7 Hz, 1 H), 7.44 (t, J=7.9 Hz, 1 H), 7.25 (ddd, J=11.6, 8.2, 1.4 Hz, 1 H), 7.15 (t, J=7.2 Hz, 1 H), 7.05-7.00 (m, 2 H), 3.58 (s, 2 H).

(225) (Exact m/z 394.04, m/z 394.94)

Experimental Example 1

(226) Measurement of Proliferation Inhibition Activity Against A375P Cell Line (Melanoma)

(227) An A375P cell line purchased from ATCC was cultured in a DMEM medium [containing 10% FBS, 1% penicillin/streptomycin] at 37 C. in the presence of 5% CO.sub.2. The cultured A375P cell line was taken using 0.05% trypsin-0.02% EDTA, and seeded into a 96-well plate at a density of 5103 cells per well.

(228) Cell viability was measured using an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (CellTiter 96 Assay, Promega) as follows. 15 l of dye was placed per well, the cells were cultured for 2 hours, and then treated with 100 l of a stop solution, and after 24 hours, absorbance was measured. One day after plating, they were treated with compounds. For treatment with compounds, 10 M of stock was prepared, and serially diluted to one-third in dimethyl sulfoxide (DMSO) to prepare a 12-point test compound plate, and 0.5 l was added (final concentration DMSO 0.5%). Readings were conducted at a wavelength of 590 nm using EnVision2103, a proliferation inhibition activity value (GI.sub.50) was calculated using GraphPad Prism 4.0 software, and the results are shown in the following Tables 1 to 3 (maximum potency showed less than 60% of total growth).

(229) In the following Tables 1 to 3, in a case of GI.sub.50 being 10 to 30 M, it was indicated as (+), in a case of it being 1 to 10 M, it was indicated as (++), and in case of being less than 1 M, it was indicated as (+++).

(230) TABLE-US-00001 TABLE 1 A375P Compound Substitution (GI.sub.50, M) Example 1 4-amide ++ Example 2 4-amide +++ Example 3 4-amide +++ Example 4 4-amide ++ Example 5 4-amide +++ Example 6 4-amide + Example 7 4-amide ++ Example 8 4-amide + Example 9 4-amide + Example 10 4-amide + Example 11 4-amide + Example 12 4-amide + Example 13 4-amide + Example 14 4-amide + Example 15 4-amide + Example 16 4-amide + Example 17 4-amide + Example 18 3-amide ++ Example 19 3-amide + Example 20 3-amide +++

(231) TABLE-US-00002 TABLE 2 A375P Compound Substitution (GI.sub.50, M) Example 21 3-amide ++ Example 22 3-amide + Example 23 3-amide + Example 24 3-amide + Example 25 3-amide + Example 26 3-amide + Example 27 3-amide + Example 28 3-amide + Example 29 3-amide + Example 30 3-amide + Example 31 3-amide + Example 32 3-amide + Example 33 3-amide + Example 34 3-amide + Example 35 3-amide + Example 36 3-amide + Example 37 3-amide + Example 38 3-amide + Example 39 4-urea +++ Example 40 4-urea ++

(232) TABLE-US-00003 TABLE 3 A375P compound Substitution (GI.sub.50, M) Example 41 4-urea + Example 42 4-urea ++ Example 43 4-urea +++ Example 44 4-urea +++ Example 45 4-urea + Example 46 3-urea ++ Example 47 3-urea ++ Example 48 3-urea +++ Example 49 3-urea +++ Example 50 3-urea ++ Example 51 3-urea + Example 52 3-urea +

(233) Referring to Tables 1 to 3, it appears that in the compounds of the examples, the tail groups of R.sup.a have an important influence on the activities, which shows that the activities of the compounds of the examples are more sensitive to a secondary hydrophobic pocket.

(234) Among the compounds of the examples, particularly, the compounds of Examples 2, 3, 5, 20, 39, 43, 44, 48, and 49, they showed significant effects against A375P. Among them, the compound of Example 43 showed a GI.sub.50 value against A375P of 1.45 M, and thus exhibited better efficacy than Sorafenib (2.74 M).

Experimental Example 2

(235) Evaluation of Activities on Various Kinases

(236) Using the compound of Example 43 (1-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepine-4-yl)phenyl)urea), kinase panel screening was conducted against 35 kinds of kinases at a concentration of 10 M, and the results are shown in the following Tables 4 and 5 (percentages of enzymatic inhibitions exerted by compound 43 (10 M) on 30 selected protein kinases).

(237) Further, the IC.sub.50 values (50% inhibition concentration) of the compound of Example 43 against various kinases were calculated using GraphPad Prism 4.0 software, and the results are shown in the following Table 6.

(238) TABLE-US-00004 TABLE 4 Kinase % Inhibition AKT1 3.23 ALK 41.0 Aurora A 20.4 BRAF 32.0 BRAF (V599E) 43.9 c-Kit 85.9 c-MET 21.7 c-Src 55.2 CDK1/cyclin B 2.68 CDK2/cyclin E 0.28 EGFR 24.8 ERK1 1.22 FAK/PTK2 41.2 FGFR2 29.9 FGFR3 45.0 FLT3 98.9 FMS 100 GSK3b 8.62 IGF1R 1.34 KDR/VEGFR2 60.2

(239) TABLE-US-00005 TABLE 5 Kinase % Inhibition LCK 79.3 LYN 89.4 MEK1 5.26 P38a/MAPK14 89.9 RAF1 86.2 ROS/ROS1 3.71 SYK 57.4 FGFR1 34.4 FLT1/VEGFR1 79.1 FLT4/VEGFR3 95.8 ITK 20.7 PDGFRa 85.9 PDGFRb 96.1 RET 99.1 TIE2/TEK 64.9 / /

(240) TABLE-US-00006 TABLE 6 Kinase IC.sub.50 (M) Kinase % Inhibition c-Kit 8.73E07 FLT4/VEGFR3 7.35E07 FLT3 2.79E08 PDGFRa 3.68E07 FMS 3.73E09 PDGFRb 6.34E08 LYN 1.18E06 RET 7.16E08 RAF1 5.32E07 / /

(241) Referring to Tables 4 to 6, it was confirmed that, particularly, the compound of Example 43 has strong anticancer activity.