440627-14-5|11-Oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid| Ambeed

Structure of 440627-14-5

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Quality Control of [ 440627-14-5 ] Purity: 95% SDS Specification

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Product Details of [ 440627-14-5 ]

CAS No. :	440627-14-5
Formula :	C₁₄H₉NO₃S
M.W :	271.29
SMILES Code :	O=C(C1=CC=C(C(N2)=C1)SC3=CC=CC=C3C2=O)O
MDL No. :	MFCD03019857
InChI Key :	OAXKROVRBSKYFV-UHFFFAOYSA-N
Pubchem ID :	23940697

Safety of [ 440627-14-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 440627-14-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	12
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	74.67
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	91.7 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.72
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.43
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.53
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.42
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.48
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.45
Solubility	0.0953 mg/ml ; 0.000351 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.0
Solubility	0.0272 mg/ml ; 0.0001 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.61
Solubility	0.00664 mg/ml ; 0.0000245 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.23 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.75

Application In Synthesis of [ 440627-14-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 440627-14-5 ]

[ 440627-14-5 ] Synthesis Path-Downstream 1~35

1
[ 440627-14-5 ]
[ 917237-09-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With phosphorus pentachloride; In toluene; at 110℃; for 2h;Product distribution / selectivity;	A solution of l l-Oxo-10,l l-dihydro-dibenzo [b,f][l,4] thiazepine-8- carboxylic acid_ (200 mg, 0.74 mmol) and phosphorus pentachloride (756 mg, 3.68mmol) in 4 mL toluene was heated to 110 0C for 2 h. Toluene and excess of phosphorus pentachloride was removed at reduced pressure to give the title compound (193 mg, 85%) as an yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.01 (d, IH, J = 2.0 Hz), 7.87 (dd, IH, J = 8.4, 2.2 Hz), 7.77 (m, IH), 7.58 (d, IH, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, IH); 13C NMR (100 MHz, CDCl3); delta 167.5, 157.1, 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 132.6, 130.3, 129.5, 129.1, 128.8;
85%	With phosphorus pentachloride; In toluene; at 110℃; for 2h;Product distribution / selectivity;	A solution of 11-Oxo-l 0,11 -dihydro-dibenzo [b,fj[1,4] thiazepine-8- carboxylic acid. (200 mg, 0.74 mmol) and phosphorus pentachloride (756 mg, 3.68mmol) in 4 mL toluene was heated to 110 C for 2 h. Toluene and excess of phosphorus pentachloride was removed at reduced pressure to give the title compound (193 mg, 85%) as an yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.01 (d, 1H, J = 2.0 Hz), 7.87 (dd, 1H, J = 8.4, 2.2 Hz), 7.77 (m, 1H), 7.58 (d, 1H, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, <n="87"/>1H); 13C NMR (100 MHz, CDCl3); delta 167.5, 157.1, 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 132.6, 130.3, 129.5, 129.1, 128.8;
85%	With phosphorus pentachloride; In toluene; at 110℃; for 2h;Product distribution / selectivity;	The typical procedure Method C for the Synthesis of Imidoyl chlorides was applied to form the title compound and the following reagents were employed: 11-Oxo- 10,l l-dihydro-dibenzo[b,f][l,4]thiazepine-8-carboxylic acid (200 mg, 0.74 mmol), PCl5 (756 mg, 3.68mmol), toluene (4 mL). This afforded 193 mg (85%) of the title compound as a yellow solid, which was sufficiently pure to be used without further purification. 1H NMR (400 MHz, CDCl3): delta 8.01 (d, IH, J = 2.0 Hz), 7.87 (dd, IH, J = 8.4, 2.2 Hz), 7.77 (m, IH), 7.58 (d, IH, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, IH). 13C NMR (100 MHz, CDCl3): delta 167.5, 157.1, 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 132.6, 130.3, 129.5, 129.1, 128.8.; Method C: A mixture of the lactam (1 eq.) and PCl5 (5 eq.) in toluene was heated at 110C for 2 hours. The reaction mixture was then cooled to room temperature and excess of PCl5 and toluene was removed at reduced pressure using oilpump to give crude product, which was used without further purification.

84%	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 80℃; for 17h;Product distribution / selectivity;	A solution of SOCl2 (25 ml), l l-Oxo-10,l l-dihydro-dibenzo [b,f][l,4] thiazepine-8-carboxylic acid (1.24 g, 4.6 mmol) and DMF (0.05 ml) in toluene (25 ml) was heated at 80 0C for 17h. Toluene and excess SOCl2 were removed at reduced pressure to give 1.18 g (84%) of the title compounds as a yellow solid, which was used in the next step without further purifications. 1H NMR (400 MHz CDCl3) delta 8.01 (d, IH, j = 2.0 Hz), 7.87 (dd, IH, J = 8.4, 2.2 Hz), 7.77 (m, IH), 7.58 (d, IH, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, IH); 13C NMR (100 MHz, CDCl3); delta 167.5, 157.1, 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 130.3, 129.5, 129.1, 128.8.
84%	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 80℃; for 17h;Product distribution / selectivity;	A solution of SOCl2 (25 ml), 1 1 -Oxo- 10,1 1 -dihydro-dibenzo [b,f][ 1 ,4] thiazepine-8-carboxylic acid (1.24 g, 4.6 mmol) and DMF (0.05 ml) in toluene (25 ml) was heated at 80 C for 17h. Toluene and excess SOCl2 were removed at reduced pressure to give 1.18 g (84%) of the title compound5 as a yellow solid, which was used in the next step without further purifications. 1H NMR (400 MHz CDCl3) delta 8.01 (d, 1H, j = 2.0 Hz), 7.87 (dd, 1H, J = 8.4, 2.2 Hz), 7.77 (m, 1H), 7.58 (d, 1H, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, 1H); 13C NMR (100 MHz, CDCl3); delta 167.5, 157.1 , 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 130.3, 129.5, 129.1, 128.8.
	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 90℃;	Examples 2 (Compounds 18-20)[0090] Compounds 18-20 of the invention were synthesized according to the following methods.[0091] To Ethyl 4-fluoro-3-nitrobenzoate (about 1 eq.) and Cs:Ctheta3 (about 1 eq.) in DMF (10.1 ml) methyl 2-mercaptobenzoate (about I eq.) dissolved in DMF (10.1 ml) was added at 40 C during 40 min.. The mixture was diluted with EtOAc and water. The water phase was extracted with EtOAc and the combined organics were dried and concentrated. The obtained crude was recrystallized from EtOAc/Heptane to give ( 13) was dissolved in THF (60 ml) followed by addition of IM lithium hydroxide (20 ml). The two phase system was stirred at 60 C for 24h. The reaction mixture was allowed to cool to room temperature and the aqueous phase treated with 2M HCl and a formed precipitate was filtered, washed with water and dried under reduced pressure. The crude product (14) was was taken up in MeOH (10 ml) and Pd/C (5%. wet) and platinum oxide was added. Hydrogen was added the reaction chamber evacuated and refilled with hydrogen several times. The mixture was stirred for 16h at room temperature under argon atmosphere. The mixture was filtered through celite and washed with MeOH and concentrated to give crude 3-amino-4-(2- carboxyphenylthio)benzoic acid ( 15) that was used in the next step without any further purification. To a mixture of 3-amino-4-(2-carboxypheny]thio)benzoic acid in THF 1 ,1 '- carbonyldiimidazole (10 eq) was added and the mixture stirred at room temperature for 18h. 2M HCl solution was added until pH 2 was obtained. A white precipitate was filtered off and washed with water to give ] l -oxo-10.1 l -dihydrodibenzo[b,fj[1.4]thiazepine-8-carboxylic acid (16). 1 l -oxo-10.1 l -dihydrodibenzo[b.fJ[l ,4]thiazepine-8-carboxylic acid (54 mg) was dissolved in toluene and SOCl2 (thionyl chloride, excess) was added dropwise followed by 2 drops of DMF. The mixture was stirred at 90 C for 6h. The mixture was cooled to room temperature and the mixture concentrated and thereafter diluted with toluene and concentrated. The crude product (1 7) ( 1.0 mmol) dissolved in DCM (4 ml) was added to the appropriate hydroxylamine hydrochloride (O-methylhydroxylamine hydrochloride, compound 18; O-ethylhydroxylamine hydrochloride, compound 19; and N, O- dimethylhydroxylamine. compound 20:) (2.5 mmol) in DCM (2 ml) at 0 C. Shaken for 4 h at room temperature. The reaction mixture was filtered through AI2O3 (acidic), eluating with DCM/EtOAc. The filtrate was concentrated at reduce pressure and the obtained imidoylchloride used in the next step without any further purification.[0092] Piperazine (100 ul) in toluene (1 ml) was added to the imidoylchloride (0.03 mmol) and the mixture was shaken for Ih at 100 C. The volatile material was removed at reduced pressure and the crude product was purified by preparative HPLC-MS to give one of the desired compound 18. 19. or 20.
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 90℃; for 6h;Product distribution / selectivity;	A solution of SOC12 (25 ml), 11-Oxo- 10,11 -dihydro- dibenzo[b,f][l,4]thiazepine-8-carboxylic acid (1.24 g, 4.6 mmol) and DMF (0.05 ml) in EPO <DP n="61"/>toluene (25 ml) was heated at 90 0C for 6h. Toluene and excess SOCl2 were removed at reduced pressure to give the title compound as a yellow solid, which was used in the next step without further purifications.

References: [1]Patent: WO2007/47737,2007,A1 .Location in patent: Page/Page column 55.
[2]Patent: WO2008/118141,2008,A2 .Location in patent: Page/Page column 85-86.
[3]Patent: WO2007/47776,2007,A1 .Location in patent: Page/Page column 55; 58.
[4]Patent: WO2007/47737,2007,A1 .Location in patent: Page/Page column 56.
[5]Patent: WO2008/118141,2008,A2 .Location in patent: Page/Page column 86.
[6]Patent: WO2007/47776,2007,A1 .Location in patent: Page/Page column 38.
[7]Organic Letters,2006,vol. 8,p. 1771 - 1773.
[8]Journal of Medicinal Chemistry,2009,vol. 52,p. 1975 - 1982.
[9]Patent: WO2010/62565,2010,A1 .Location in patent: Page/Page column 26-27.
[10]Patent: WO2007/47776,2007,A1 .Location in patent: Page/Page column 58; 59.

2
[ 440627-10-1 ]
[ 440627-14-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 16h;	CDI (4.53 g, 29 mmol, 4 eq) was added to 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (2.1 g, 7.3 mmol) dissolved in THF (30 ml). The reaction was stirred for 16h at room temperature. Water (200 ml) was then added to the mixture resulting in, after filtration and drying, 1.78g (91%) of the titled compound as a off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 10.78 (br s, IH), 7.77 (s, IH), 7.67 (m, 3H), 7.55-7.42 (m, 3H); 13C NMR (100 MHz, DMSO-d6); delta 168.9, 166.9, 140.3, 138.3, 136.0, 134.5, 133.5, 133.0, 132.9, 132.2, 132.1, 129.9, 126.5, 124.3.
91%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 16h;	CDI (4.53 g, 29 mmol, 4 eq) was added to 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (2.1 g, 7.3 mmol) dissolved in THF (30 ml). The reaction was stirred for 16h at room temperature. Water (200 ml) was then added to the mixture resulting in, after filtration and drying, l.78g (91%) of the titled compound as a off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 10.78 (br s, 1H), 7.77 (s, 1H), 7.67 (m, 3H), 7.55-7.42 (m, 3H); 13C NMR (100 MHz, DMSO-d6); delta 168.9, 166.9, 140.3, 138.3, 136.0, 134.5, 133.5, 133.0, 132.9, 132.2, 132.1, 129.9, 126.5, 124.3.
90%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	[00080] To a stirred solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphere was added CDI (86.88 g, 536.29 mmol) at 0 C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HC1 to pH4. The obtained solid was filtered and further dried by using toluene (2 x 200 mL) to afford compound 6 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH2C12 (R 0.3); 1H NMR (DMSO-d6, 400 MHz): oe 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H).

90%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	[00079] To a stirred solution of compound 26 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphere was added CDI (86.88 g, 536.29 mmol) at 0 C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HC1 to pH~4. The obtained solid was filtered and further dried by using toluene (2 x 200 mL) to afford compound 27 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H NMR (DMSO-rfs, 400 MHz): delta 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H).
90%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	To a stirred solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphere was added CDI (86.88 g, 536.29 mmol) at 0 C; warmed to RT and stirred for16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HC1 to pH-4. The obtained solid was filtered and further dried by using toluene (2 x 200 mL) to afford compound 6 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); ?H NMR (DMSO-d6, 400 MHz): oe 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H).
87%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 0 - 20℃;	A solution of 3-amino-4-(2-carboxyphenylthio)benzoic acid (4.76 g, 16.5 mmol) in THF (100 mL) was treated at 0 C with Iota,Iota'-carbonyldiimidazole (CDI) (10.7 g, 65.8 mmol) via several portions. The reaction mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into 140 mL of ice water containing concentrated HCl (20.0 mL) and stirred for 1 hr. The white precipitate was filtered, washed with water, and dried to give 3.89 g (87%) of the title compound as a white solid which was used directly in the next reaction without further purification. 1H NMR (400 MHz, DMSO- ) delta ppm 13.20 (br. s., 1 H), 10.79 (s, 1 H), 7.76 (d, 7=1.2 Hz, 1 H), 7.62 - 7.70 (m, 3 H), 7.41 - 7.57 (m, 3 H); LCMS RT = 4.55 min, m/z 271.9 [M+H+]; HRMS (ESI) m/z calcd for Ci4Hi0NO3S [M+H+] 272.0376, found 272.0376
60%	With polyphosphoric acid; at 50 - 90℃; for 10h;	Compound 4 (25 g) was added in portions to water (170 ml) KOH (31.8 g) solution, after its dissolution compound 3 (30 g) was added and the resultant mixture was stirred at 60 C for 15 h. Then the reaction mixture was cooled, acidified with HCl (10%) to pH=3, filtered, washed with water and dried. It gave compound 5, yield 70%. Compound 5 (50 g) was dissolved in aqueous ammonia (500 ml) and dithionite (80 g) was added in portions, after that the reaction mixture was refluxed for 1 h, cooled, ammonia was evaporated on rotary evaporator, and water solution was acidified with conc. HCl to pH=1, stirred for 1 h, the solid was filtered off, washed with water and dried. It gave compound 6, yield 60%. Compound 6 (45 g) was added in portions to polyphosphoric acid (200 ml) at 50C, then the reaction mixture was stirred for 10 h at 90 C, cooled and poured out on ice (500 ml), the solid was filtered off, washed with water and dried. It gave compound 7, yield 60%. Compound 7 (30 g) was dissolved in acetic acid (500 ml), 33% hydrogen peroxide (70 ml) was added, stirring was continued for night at 70C. After cooling acetic acid was evaporated on rotary evaporator and water (600 ml) was added to the residue. The precipitated solid was filtered off, washed with water and dried. It gave compound 8, yield 70%. To a solution of compound 8 (22 g) in ethanol (300 ml) thionyl chloride (8 ml) was dropped at 10C, then the mixture was refluxed for 5 h, cooled, evaporated on rotary evaporator, after that water (300 ml) was added. The precipitated solid was filtered off, washed with water and dried. It gave compound 9, yield 90%. To a solution of compound 9 (8.2 g) in DMF (80 ml) were added in turn potassium carbonate (7 g) and m-chlorobenzyl chloride (5.2 g). The reaction mixture was stirred for night at 50C, evaporated on rotary evaporator, water (200 ml) was added to the residue. The precipitated solid was filtered off, washed with water and dried. It gave compound 10, yield 90%. To a solution of compound 10 (11 g) in 50% water ethanol (150 ml) KOH (2.7 g) was added, the resultant mixture was stirred at room temperature for night. Then ethanol was evaporated on rotary evaporator, water solution was acidified with 10% HCl to pH=3. The precipitated solid was filtered off, washed with water and dried. It gave compound 11, yield 80%. To a solution of compound 11 (1.8 g) in THF (50 ml) at stirring in argon atmosphere N-hydroxysuccinimide (0.48 g) and dicyclohexylcarbodiimide (0.87g) were added. The reaction mixture was stirred for night at room temperature, the precipitated solid was filtered off, mother liquor was evaporated, the residue was purified by flash chromatography on silica (eluent-ethyl acetate). It gave compound 1(1), yield 50%. NMR Spectrum of compound 1(1) is given on Fig.1.
54%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;dmap; In acetonitrile; at 140℃; for 0.166667h;Microwaves;	The typical procedure Method C for the EDC coupling was applied to form the title compound and the following reagents were employed: 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (400 mg, 1.46 mmol), EDC (807mg, 4.22 mmol), HOBt (295 mg, 2.19 mmol), DMAP (4.3 mg, 0.03 mmol), TEA (0.90 mL, 6.57 mmol), MeCN (1.5 mL). Purification by recrystallization from EtOH afforded 211 mg (54%) as a off-white solid. 1H EPO <DP n="57"/>NMR (400 MHz, DMSOd6): delta 10.78 (br s, IH), 7.77 (s, IH), 7.67 (m, 3H), 7.55-7.42 (m, 3H). 13C NMR (100 MHz, DMSO-d6): delta 168.9, 166.9, 140.3, 138.3, 136.0, 134.5, 133.5, 133.0, 132.9, 132.2, 132.1, 129.9, 126.5, 124.3.
		Examples 2 (Compounds 18-20)[0090] Compounds 18-20 of the invention were synthesized according to the following methods.[0091] To Ethyl 4-fluoro-3-nitrobenzoate (about 1 eq.) and Cs:Ctheta3 (about 1 eq.) in DMF (10.1 ml) methyl 2-mercaptobenzoate (about I eq.) dissolved in DMF (10.1 ml) was added at 40 C during 40 min.. The mixture was diluted with EtOAc and water. The water phase was extracted with EtOAc and the combined organics were dried and concentrated. The obtained crude was recrystallized from EtOAc/Heptane to give ( 13) was dissolved in THF (60 ml) followed by addition of IM lithium hydroxide (20 ml). The two phase system was stirred at 60 C for 24h. The reaction mixture was allowed to cool to room temperature and the aqueous phase treated with 2M HCl and a formed precipitate was filtered, washed with water and dried under reduced pressure. The crude product (14) was was taken up in MeOH (10 ml) and Pd/C (5%. wet) and platinum oxide was added. Hydrogen was added the reaction chamber evacuated and refilled with hydrogen several times. The mixture was stirred for 16h at room temperature under argon atmosphere. The mixture was filtered through celite and washed with MeOH and concentrated to give crude 3-amino-4-(2- carboxyphenylthio)benzoic acid ( 15) that was used in the next step without any further purification. To a mixture of 3-amino-4-(2-carboxypheny]thio)benzoic acid in THF 1 ,1 '- carbonyldiimidazole (10 eq) was added and the mixture stirred at room temperature for 18h. 2M HCl solution was added until pH 2 was obtained. A white precipitate was filtered off and washed with water to give ] l -oxo-10.1 l -dihydrodibenzo[b,fj[1.4]thiazepine-8-carboxylic acid (16). 1 l -oxo-10.1 l -dihydrodibenzo[b.fJ[l ,4]thiazepine-8-carboxylic acid (54 mg) was dissolved in toluene and SOCl2 (thionyl chloride, excess) was added dropwise followed by 2 drops of DMF. The mixture was stirred at 90 C for 6h. The mixture was cooled to room temperature and the mixture concentrated and thereafter diluted with toluene and concentrated. The crude product (1 7) ( 1.0 mmol) dissolved in DCM (4 ml) was added to the appropriate hydroxylamine hydrochloride (O-methylhydroxylamine hydrochloride, compound 18; O-ethylhydroxylamine hydrochloride, compound 19; and N, O- dimethylhydroxylamine. compound 20:) (2.5 mmol) in DCM (2 ml) at 0 C. Shaken for 4 h at room temperature. The reaction mixture was filtered through AI2O3 (acidic), eluating with DCM/EtOAc. The filtrate was concentrated at reduce pressure and the obtained imidoylchloride used in the next step without any further purification.[0092] Piperazine (100 ul) in toluene (1 ml) was added to the imidoylchloride (0.03 mmol) and the mixture was shaken for Ih at 100 C. The volatile material was removed at reduced pressure and the crude product was purified by preparative HPLC-MS to give one of the desired compound 18. 19. or 20.

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.
[2]Patent: WO2007/47737,2007,A1 .Location in patent: Page/Page column 55.
[3]Patent: WO2008/118141,2008,A2 .Location in patent: Page/Page column 85.
[4]Journal of Medicinal Chemistry,2009,vol. 52,p. 1975 - 1982.
[5]Patent: WO2015/138895,2015,A1 .Location in patent: Paragraph 00080.
[6]Patent: WO2017/48954,2017,A1 .Location in patent: Paragraph 00079.
[7]Patent: WO2018/53157,2018,A1 .Location in patent: Page/Page column 47; 49; 142; 144.
[8]Journal of Medicinal Chemistry,2014,vol. 57,p. 3450 - 3463.
[9]Patent: WO2015/17412,2015,A1 .Location in patent: Paragraph 0106.
[10]Patent: EP2947074,2015,A1 .Location in patent: Paragraph 0039.
[11]Patent: WO2007/47776,2007,A1 .Location in patent: Page/Page column 37; 54; 55.
[12]Patent: WO2010/62565,2010,A1 .Location in patent: Page/Page column 26-27.
[13]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

3
[ 440627-14-5 ]
[ 74-88-4 ]
[ 897771-13-0 ]

Yield	Reaction Conditions	Operation in experiment
86%		A solution of ll-Oxo-10,ll-dihydro-dibenzo [b,fj[l,4] thiazepine-8- carboxylic acid (715 mg, 2.61 mmol) and Na2CO3 (1.39 g, 13.05 mmol) in DMF (20 mL) was stirred at room temperature for 0.5 hour. Then CH3I (0.81 mL, 13.05 mmol) was added and the two phase mixture was stirred for another 0.5 hour at room temperature. DMF was then removed at reduce pressure using oil pump and the resulting residue was dissolved in EtOAc. The organic phase was washed with NaHCO3 (aq. sat.), brine, dried (Na2SO3), EPO <DP n="74"/>filtered and evaporated to give crude product. Purification by recrystallization from Toluene afforded 640 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): delta 9.23 (IH, bs), 7.88-7.86 (2H, m), 7.79-7.77 (IH, m), 7.64 (IH, J = 8.0Hz), 7.52-7.50 (IH, m), 7.45-7.38 (2H, m), 3.91 (3H, s). 13C NMR (100 MHz, CDCl3): delta 169.4, 165.9, 139.6, 136.8, 136.4, 135.8, 133.3, 132.7, 132.3, 132.2, 131.8, 129.3, 127.0, 123.7, 52.7.

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.
[2]Patent: WO2007/47776,2007,A1 .Location in patent: Page/Page column 37; 71; 72.

4
[ 440627-14-5 ]
[ 887760-81-8 ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.

5
[ 440627-14-5 ]
11-butyl-dibenzo[b,f][1,4]thiazepine-8-carboxylic acid methyl ester [ No CAS ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.

6
[ 440627-09-8 ]
[ 440627-14-5 ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3450 - 3463.
[3]Patent: WO2015/17412,2015,A1 .
[4]Patent: EP2947074,2015,A1 .

7
[ 917237-08-2 ]
[ 440627-14-5 ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.

8
[ 367-80-6 ]
[ 440627-14-5 ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.

9
[ 4892-02-8 ]
[ 440627-14-5 ]

References: [1]Organic Letters,2006,vol. 8,p. 1771 - 1773.
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 3450 - 3463.
[4]Patent: WO2015/17412,2015,A1 .
[5]Patent: WO2015/138895,2015,A1 .
[6]Patent: WO2017/48954,2017,A1 .
[7]Patent: WO2018/53157,2018,A1 .

10
[ 440627-14-5 ]
N-[3-(cyclohexylmethylamino)propyl]-10-[(3-chloro-phenyl)methyl]-10,11-dihydro-11-oxo-dibenzo-[b,f][1,4]-thiazepine-8-carboxamide-5-oxide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

11
[ 440627-14-5 ]
[ 895795-22-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

12
[ 440627-14-5 ]
[ 897772-23-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

13
[ 440627-14-5 ]
[ 1319194-05-2 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

14
[ 440627-14-5 ]
[ 18107-18-1 ]
[ 897771-13-0 ]

Yield	Reaction Conditions	Operation in experiment
1.23 g	In tetrahydrofuran; at 20℃; for 1h;	Amine 47 (19.12 g, 0.0602 mol) was dissolved in THF (425 mL) containing H2O (75 mL). The mixture was cooled to 0 C and LiOH·H2O (7.58 g, 0.181 mol) was added in one portion. After 1 h, the reaction was warmed to rt. HPLC or TLC monitoring indicated that hydrolysis was complete after 36 h at rt. The pH was adjusted to 4.0 by the addition of 2 M HCl. The remaining mixture was dried to an off white powder by rotary evaporation followed by lyophilization with MeOH (6 × 300 mL). The resulting powder was further dried by rotary evaporation with toluene (3 × 300 mL) and suspended in DMF (400 mL). After cooling to -20 C, 1,1'-carbonyl-diimidazole (48.84 g, 0.301 mol) was added in portions over 3 h. The flask was equipped with a drying tube filled Drierite. The reaction was warmed to rt over 2 h. After 24 h of vigorous stirring at rt, reaction was cooled to 0 C and methanol (200 mL) was added. The reaction was warmed over 1 h to rt and stirred for an addition 12 h. The contents of the flask were then diluted in EtOAc (200 mL) and filtered with 1:10 MeOH/EtOAc (2 L) through a DCVC column charged with 250 g of Celite (packed at top of column) and 500 g of silica gel (packed at bottom of column). The elutant was concentrated on a rotary evaporator. Recrystallization from a minimal amount hot toluene followed by slow cooling to rt and storage at 4 C for 24 h provided 14.21 g (83%) of methyl ester 50 as a white powder. The remaining mother liquor contained a mixture of 50 and its corresponding acid 49 that could be converted to 50 (1.23 g, 6% yield) by treatment with 0.5 M TMSCH2N2 in THF. This recycled material was not tabulated in the yield. Mp 179-181 C, 1H NMR (500 MHz, CDCl3) delta 8.48 (s, 1H, NH), 7.85 (dd, J = 1.9, 7.4 Hz, 1H); 7.79 (d, J = 1.7 Hz, 1H); 7.77 (dd, J = 1.7, 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 1.5, 7.5 Hz, 1H), 7.40 (ddd, J = 1.6, 8.3, 11.4 Hz, 1H), 7.39 (ddd, J = 1.6, 8.4, 8.7 Hz, 1H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) delta 170.2. 166.3, 140.1, 137.2, 136.8, 136.0, 133.5, 133.0, 132.5, 132.5, 132.0, 129.6, 127.3, 124.2, 53.1; HREIMS [M+Na]+ m/z: 308.0489 (calcd for C15H11NNaO3S, 308.0357).

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

15
[ 67-56-1 ]
C₁₇H₁₁N₃O₂S [ No CAS ]
[ 897771-13-0 ]
[ 440627-14-5 ]

Yield	Reaction Conditions	Operation in experiment
14.21 g	With dmap; In N,N-dimethyl-formamide; at 0 - 20℃; for 13h;	Amine 47 (19.12 g, 0.0602 mol) was dissolved in THF (425 mL) containing H2O (75 mL). The mixture was cooled to 0 C and LiOH·H2O (7.58 g, 0.181 mol) was added in one portion. After 1 h, the reaction was warmed to rt. HPLC or TLC monitoring indicated that hydrolysis was complete after 36 h at rt. The pH was adjusted to 4.0 by the addition of 2 M HCl. The remaining mixture was dried to an off white powder by rotary evaporation followed by lyophilization with MeOH (6 × 300 mL). The resulting powder was further dried by rotary evaporation with toluene (3 × 300 mL) and suspended in DMF (400 mL). After cooling to -20 C, 1,1'-carbonyl-diimidazole (48.84 g, 0.301 mol) was added in portions over 3 h. The flask was equipped with a drying tube filled Drierite. The reaction was warmed to rt over 2 h. After 24 h of vigorous stirring at rt, reaction was cooled to 0 C and methanol (200 mL) was added. The reaction was warmed over 1 h to rt and stirred for an addition 12 h. The contents of the flask were then diluted in EtOAc (200 mL) and filtered with 1:10 MeOH/EtOAc (2 L) through a DCVC column charged with 250 g of Celite (packed at top of column) and 500 g of silica gel (packed at bottom of column). The elutant was concentrated on a rotary evaporator. Recrystallization from a minimal amount hot toluene followed by slow cooling to rt and storage at 4 C for 24 h provided 14.21 g (83%) of methyl ester 50 as a white powder. The remaining mother liquor contained a mixture of 50 and its corresponding acid 49 that could be converted to 50 (1.23 g, 6% yield) by treatment with 0.5 M TMSCH2N2 in THF. This recycled material was not tabulated in the yield. Mp 179-181 C, 1H NMR (500 MHz, CDCl3) delta 8.48 (s, 1H, NH), 7.85 (dd, J = 1.9, 7.4 Hz, 1H); 7.79 (d, J = 1.7 Hz, 1H); 7.77 (dd, J = 1.7, 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 1.5, 7.5 Hz, 1H), 7.40 (ddd, J = 1.6, 8.3, 11.4 Hz, 1H), 7.39 (ddd, J = 1.6, 8.4, 8.7 Hz, 1H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) delta 170.2. 166.3, 140.1, 137.2, 136.8, 136.0, 133.5, 133.0, 132.5, 132.5, 132.0, 129.6, 127.3, 124.2, 53.1; HREIMS [M+Na]+ m/z: 308.0489 (calcd for C15H11NNaO3S, 308.0357).

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.

16
[ 1319194-13-2 ]
[ 440627-14-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3450 - 3463.
[3]Patent: WO2015/17412,2015,A1 .
[4]Patent: WO2015/138895,2015,A1 .
[5]Patent: WO2017/48954,2017,A1 .
[6]Patent: WO2018/53157,2018,A1 .

17
[ 1319194-14-3 ]
[ 440627-14-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3956 - 3964.
[2]Patent: WO2015/138895,2015,A1 .
[3]Patent: WO2017/48954,2017,A1 .
[4]Patent: WO2018/53157,2018,A1 .

18
[ 329-59-9 ]
[ 440627-14-5 ]

19
[ 440627-14-5 ]
[ 1596117-80-4 ]
10-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid 5-(R)-oxide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3450 - 3463.
[2]Patent: WO2015/17412,2015,A1 .

20
[ 440627-14-5 ]
[ 1281892-89-4 ]