[ CAS No. 1446144-04-2 ] {[proInfo.proName]}

Name: 1446144-04-2|(S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide|99+%
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Quality Control of [ 1446144-04-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1446144-04-2 ]

CAS No. :	1446144-04-2	MDL No. :	MFCD27997886
Formula :	C₁₉H₁₈ClN₅OS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QECMENZMDBOLDR-AWEZNQCLSA-N
M.W :	399.90	Pubchem ID :	71291068
Synonyms :		Chemical Name :	(S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide

Calculated chemistry of [ 1446144-04-2 ]

Physicochemical Properties

Num. heavy atoms :	27
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.26
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	110.98
TPSA :	114.4 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.68
Log Po/w (XLOGP3) :	2.89
Log Po/w (WLOGP) :	2.97
Log Po/w (MLOGP) :	2.35
Log Po/w (SILICOS-IT) :	4.96
Consensus Log Po/w :	3.17

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.38
Solubility :	0.0166 mg/ml ; 0.0000416 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.95
Solubility :	0.00446 mg/ml ; 0.0000112 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.39
Solubility :	0.000163 mg/ml ; 0.000000408 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.23

Safety of [ 1446144-04-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1446144-04-2 ]

* 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 [ 1446144-04-2 ]

[ 1446144-04-2 ] Synthesis Path-Downstream 1~28

1
[ 1446144-04-2 ]
[ 2300923-95-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / 1,4-dioxane / 5 h / 90 °C / Sealed tube 2: PPA / 1 h / 90 °C

Reference： [1]Current Patent Assignee: HINOVA PHARMACEUTICALS - CN109503618, 2019, A

2
[ 1446144-04-2 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
18%	With silver trifluoromethanesulfonate In toluene at 90℃; for 5h; Sealed tube;	22 (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4 ,3-a][1,4] diaza-6-yl)-4methyloxazoleSynthesis of (26): Compound A (100 mg, 0.25 mmol) was added to a 10 mL sealed tube.Toluene (3 mL), B (137 mg, 1 mmol), C (128 mg, 0.5 mmol),The system was reacted at 90 ° C for 5 hours. Pour the reaction solution into 50 mL of water.Extracted with 30 mL (15 mL×3) EA, and the combined organic phases dried over anhydrous sodium sulfate.Purification by column chromatography gave compound 26 (20 mg).The yield was 18%.

Reference： [1]Current Patent Assignee: HINOVA PHARMACEUTICALS - CN109503618, 2019, A Location in patent: Paragraph 0175; 0176; 0177; 0178

3
[ 1446144-04-2 ]
[ 534-07-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
12%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 5h; Sealed tube;	23 (S) 2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4, 3-a][1,4] diaza-6-yl)-4-chloromethyloxazoleSynthesis of (27): Compound A (200 mg, 0.5 mmol) was added to a 10 mL sealed tube.Dioxane (5 mL), B (127 mg, 1 mmol),NaHCO3 (168 mg, 2 mmol) was reacted at 90 ° C for 5 hours.The reaction solution was poured into 50 mL of water, extracted with 30 mL (15 mL×3) EA, and the organic phase was combined.Drying over anhydrous sodium sulfate and purifying by column chromatography gave Compound C (30 mg).The yield was 12%.

Reference： [1]Current Patent Assignee: HINOVA PHARMACEUTICALS - CN109503618, 2019, A Location in patent: Paragraph 0180-0183

4
[ 1446144-04-2 ]
[ 2417371-50-5 ]

Yield	Reaction Conditions	Operation in experiment
71.4%	With Lawessons reagent In tetrahydrofuran at 40℃; for 2h;	xxxi To a solution of Compound 16 (840.00 mg, 2.10 mmol) in THF (50 mL) was added Lawesson's reagent (1.700 g, 4.20 mmol). The mixture was stirred at 40 °C for 2 h. The mixture was diluted with EtOAc (250 mL), washed with H20 (50 mL x 3) and brine (50 mL). The organic layer was concentrated and purified by flash column chromatography (5-10% MeOH in DCM) to give Compound 4 (630.00 mg, 71.4%) as a yellow solid. LCMS (5-95, AB, l.5min): RT (220/254nm) = 0.888 min, m/z = 416.0 [M+l]+.
71%	With Lawessons reagent In tetrahydrofuran at 40℃; for 2h;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1 Location in patent: Page/Page column 506
[2]Dragovich, Peter S.; Pillow, Thomas H.; Blake, Robert A.; Sadowsky, Jack D.; Adaligil, Emel; Adhikari, Pragya; Bhakta, Sunil; Blaquiere, Nicole; Chen, Jinhua; Dela Cruz-Chuh, Josefa; Gascoigne, Karen E.; Hartman, Steven J.; He, Mingtao; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Liu, Liang; Liu, Liling; Liu, Qi; Lu, Ying; Meng, Fanwei; Mulvihill, Melinda M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Staben, Leanna R.; Staben, Steven T.; Wai, John; Wang, Jian; Wei, Binqing; Wilson, Catherine; Xin, Jianfeng; Xu, Zijin; Yao, Hui; Zhang, Donglu; Zhang, Hongyan; Zhou, Hao; Zhu, Xiaoyu [Journal of Medicinal Chemistry, 2021, vol. 64, # 5, p. 2534 - 2575]

5
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: acetic acid; toluene-4-sulfonic acid / 1 h / 90 °C
	Multi-step reaction with 2 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: toluene-4-sulfonic acid / acetic acid / 1 h / 90 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1
[2]Dragovich, Peter S.; Pillow, Thomas H.; Blake, Robert A.; Sadowsky, Jack D.; Adaligil, Emel; Adhikari, Pragya; Bhakta, Sunil; Blaquiere, Nicole; Chen, Jinhua; Dela Cruz-Chuh, Josefa; Gascoigne, Karen E.; Hartman, Steven J.; He, Mingtao; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Liu, Liang; Liu, Liling; Liu, Qi; Lu, Ying; Meng, Fanwei; Mulvihill, Melinda M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Staben, Leanna R.; Staben, Steven T.; Wai, John; Wang, Jian; Wei, Binqing; Wilson, Catherine; Xin, Jianfeng; Xu, Zijin; Yao, Hui; Zhang, Donglu; Zhang, Hongyan; Zhou, Hao; Zhu, Xiaoyu [Journal of Medicinal Chemistry, 2021, vol. 64, # 5, p. 2534 - 2575]

6
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: acetic acid; toluene-4-sulfonic acid / 1 h / 90 °C 3: caesium carbonate / acetonitrile / 1 h / 105 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: toluene-4-sulfonic acid / acetic acid / 1 h / 90 °C 3: caesium carbonate; Pd(Cy*Phine)₂Cl₂ / acetonitrile / 1 h / 105 °C / Microwave irradiation; Inert atmosphere

7
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: acetic acid; toluene-4-sulfonic acid / 1 h / 90 °C 3: caesium carbonate / acetonitrile / 1 h / 105 °C / Microwave irradiation 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1

8
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: acetic acid; toluene-4-sulfonic acid / 1 h / 90 °C 3: caesium carbonate / acetonitrile / 1 h / 105 °C / Microwave irradiation 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C 5: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1

9
[ 202592-23-2 ]
[ 1446144-04-2 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;	xxxi To a mixture of Compound 15 (0.870 g, 2.11 mmol), NH4Cl (337.81 mg, 6.32 mmol) and HATU (1.600 g, 4.21 mmol) in DMF (20 mL) was added DIEA (1.74 mL, 10.53 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated and purified by flash column chromatography (0-5% MeOH in DCM) to give Compound 16 (0.84 g, 98.5%) as a yellow solid. LCMS (5-95, AB, l.5min): RT (220/254nm) = 0.771 min, m/z = 421.9 [M+23]+.
98%	With ammonium chloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 23℃; for 2h;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1 Location in patent: Page/Page column 505
[2]Dragovich, Peter S.; Pillow, Thomas H.; Blake, Robert A.; Sadowsky, Jack D.; Adaligil, Emel; Adhikari, Pragya; Bhakta, Sunil; Blaquiere, Nicole; Chen, Jinhua; Dela Cruz-Chuh, Josefa; Gascoigne, Karen E.; Hartman, Steven J.; He, Mingtao; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Liu, Liang; Liu, Liling; Liu, Qi; Lu, Ying; Meng, Fanwei; Mulvihill, Melinda M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Staben, Leanna R.; Staben, Steven T.; Wai, John; Wang, Jian; Wei, Binqing; Wilson, Catherine; Xin, Jianfeng; Xu, Zijin; Yao, Hui; Zhang, Donglu; Zhang, Hongyan; Zhou, Hao; Zhu, Xiaoyu [Journal of Medicinal Chemistry, 2021, vol. 64, # 5, p. 2534 - 2575]

10
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: toluene-4-sulfonic acid / acetic acid / 1 h / 90 °C 3: caesium carbonate; Pd(Cy*Phine)₂Cl₂ / acetonitrile / 1 h / 105 °C / Microwave irradiation; Inert atmosphere 4: 1,2-dichloro-ethane / 2 h / 23 °C

Reference： [1]Dragovich, Peter S.; Pillow, Thomas H.; Blake, Robert A.; Sadowsky, Jack D.; Adaligil, Emel; Adhikari, Pragya; Bhakta, Sunil; Blaquiere, Nicole; Chen, Jinhua; Dela Cruz-Chuh, Josefa; Gascoigne, Karen E.; Hartman, Steven J.; He, Mingtao; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Liu, Liang; Liu, Liling; Liu, Qi; Lu, Ying; Meng, Fanwei; Mulvihill, Melinda M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Staben, Leanna R.; Staben, Steven T.; Wai, John; Wang, Jian; Wei, Binqing; Wilson, Catherine; Xin, Jianfeng; Xu, Zijin; Yao, Hui; Zhang, Donglu; Zhang, Hongyan; Zhou, Hao; Zhu, Xiaoyu [Journal of Medicinal Chemistry, 2021, vol. 64, # 5, p. 2534 - 2575]

11
[ 1446144-04-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: Lawessons reagent / tetrahydrofuran / 2 h / 40 °C 2: toluene-4-sulfonic acid / acetic acid / 1 h / 90 °C 3: caesium carbonate; Pd(Cy*Phine)₂Cl₂ / acetonitrile / 1 h / 105 °C / Microwave irradiation; Inert atmosphere 4: 1,2-dichloro-ethane / 2 h / 23 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 23 °C

12
[ 1268524-70-4 ]
[ 1446144-04-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 1 h / 23 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; ammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 23 °C

13
[ 1446144-04-2 ]
[ 380430-68-2 ]
[ 2851988-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	1.2; S-d Step 2: A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3-[(tert-butoxy)carbonyl]amino}phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL) and Pd(Cy*Phine)2Cl2 (269 mg, 0.1 eq., 209 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give tert-butyl (S)-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate. 1H NMR (500 MHz, d6-DMSO) δ 9.43 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.56 - 7.48 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.00 - 6.95 (m, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.24 (d, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.69 (m, 3H), 1.48 (s, 9H).
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	1.2; S-d Step 2: A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3-[(tert-butoxy)carbonyl]amino}phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL) and Pd(Cy*Phine)2Cl2 (269 mg, 0.1 eq., 209 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give tert-butyl (S)-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate. 1H NMR (500 MHz, d6-DMSO) δ 9.43 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.56 - 7.48 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.00 - 6.95 (m, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.24 (d, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.69 (m, 3H), 1.48 (s, 9H).
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	1.2; S-d Step 2: A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3-[(tert-butoxy)carbonyl]amino}phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL) and Pd(Cy*Phine)2Cl2 (269 mg, 0.1 eq., 209 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give tert-butyl (S)-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate. 1H NMR (500 MHz, d6-DMSO) δ 9.43 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.56 - 7.48 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.00 - 6.95 (m, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.24 (d, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.69 (m, 3H), 1.48 (s, 9H).

Reference： [1]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0388; 0443
[2]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0388; 0443
[3]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0380; 0388; 0443

14
[ CAS Unavailable ]
[ 1446144-04-2 ]
[ 2851988-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU at 25℃; Inert atmosphere;	3-a.1 Step 1: To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (1 eq.) and ethylamine; hydrochloride (2 eq) in DMF was added DIEA (5 eq) and HATU (1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (SiO2, 0 to 100 % ethyl acetate in petroleum ether) to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N- ethylacetamide.
	With N-ethyl-N,N-diisopropylamine; HATU at 25℃; Inert atmosphere;	3-a.1 Step 1: To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (1 eq.) and ethylamine; hydrochloride (2 eq) in DMF was added DIEA (5 eq) and HATU (1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (SiO2, 0 to 100 % ethyl acetate in petroleum ether) to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N- ethylacetamide.
	With N-ethyl-N,N-diisopropylamine; HATU at 25℃; Inert atmosphere;	3-a.1 Step 1: To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (1 eq.) and ethylamine; hydrochloride (2 eq) in DMF was added DIEA (5 eq) and HATU (1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (SiO2, 0 to 100 % ethyl acetate in petroleum ether) to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N- ethylacetamide.

Reference： [1]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0391
[2]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0391
[3]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0391

15
[ 1446144-04-2 ]
[ 2851988-21-9 ]
[ 2851986-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	3-b.2 Step 2: A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (50.0 mg, 125 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 µmol), cesium carbonate (122 mg, 3 eq., 375 µmol), degassed ACN (2.5 mL) and Pd(Cy*Phine)2Cl2 (16.1 mg, 0.1 eq., 12.5 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(6-(2-amino-2- oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)benzofuran-2-carboxamide.
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	3-b.2 Step 2: A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (50.0 mg, 125 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 µmol), cesium carbonate (122 mg, 3 eq., 375 µmol), degassed ACN (2.5 mL) and Pd(Cy*Phine)2Cl2 (16.1 mg, 0.1 eq., 12.5 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(6-(2-amino-2- oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)benzofuran-2-carboxamide.
	With caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; Microwave irradiation; Sealed tube; Inert atmosphere;	3-b.2 Step 2: A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0,]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (50.0 mg, 125 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 µmol), cesium carbonate (122 mg, 3 eq., 375 µmol), degassed ACN (2.5 mL) and Pd(Cy*Phine)2Cl2 (16.1 mg, 0.1 eq., 12.5 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(6-(2-amino-2- oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)benzofuran-2-carboxamide.

Reference： [1]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0396
[2]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0396
[3]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0395; 0396

16
[ 873566-75-7 ]
[ 1446144-04-2 ]
[ 2851988-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; XPhos Pd G₂ In tetrahydrofuran; water at 25 - 90℃;	4-d.1; A.2 Step 1: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 µmol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added 3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 µmol, 1.2 eq), K3PO4 (106.2 mg, 500.1 µmol, 2.0 eq), Xphos Pd G2 (CAS : 1310584-14-5, 19.7 mg, 25.0 µmol, 0.1 eq) at 25 °C and the mixture was stirred at 90 °C for 10 hours. The residue was diluted with water (6 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with brine (6 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-2-(4-(3'-amino-4'- fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamide, which was used in the next step without purification.
	With potassium phosphate; XPhos Pd G₂ In tetrahydrofuran; water at 25 - 90℃;	4-d.1; A.2 Step 1: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 µmol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added 3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 µmol, 1.2 eq), K3PO4 (106.2 mg, 500.1 µmol, 2.0 eq), Xphos Pd G2 (CAS : 1310584-14-5, 19.7 mg, 25.0 µmol, 0.1 eq) at 25 °C and the mixture was stirred at 90 °C for 10 hours. The residue was diluted with water (6 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with brine (6 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-2-(4-(3'-amino-4'- fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamide, which was used in the next step without purification.
	With potassium phosphate; XPhos Pd G₂ In tetrahydrofuran; water at 25 - 90℃;	4-d.1; A.2 Step 1: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 µmol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added 3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 µmol, 1.2 eq), K3PO4 (106.2 mg, 500.1 µmol, 2.0 eq), Xphos Pd G2 (CAS : 1310584-14-5, 19.7 mg, 25.0 µmol, 0.1 eq) at 25 °C and the mixture was stirred at 90 °C for 10 hours. The residue was diluted with water (6 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with brine (6 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-2-(4-(3'-amino-4'- fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamide, which was used in the next step without purification.

Reference： [1]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0447; 0477
[2]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0447; 0477
[3]Current Patent Assignee: PLEXIUM INC - WO2022/221786, 2022, A2 Location in patent: Paragraph 0476; 0447; 0477

17
[ 1446144-04-2 ]
[ 2851986-61-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; bis[dicyclohexyl(2,4,6-triisopropyl[1,1':3',1"-terphenyl]-2-yl)phosphane]palladium(II) dichloride / acetonitrile / 2 h / 90 °C / Microwave irradiation; Sealed tube; Inert atmosphere 2: dichloromethane / 2 h / 20 °C