129999-60-6|N-(2-Aminoethyl)-4-piperidinol| Ambeed

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Structure of 1-(2-aminoethyl)piperidin-4-ol
CAS No.: 129999-60-6

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Quality Control of [ 129999-60-6 ] Purity: 98% SDS Specification

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Product Details of [ 129999-60-6 ]

CAS No. :	129999-60-6
Formula :	C₇H₁₆N₂O
M.W :	144.21
SMILES Code :	OC1CCN(CCN)CC1
MDL No. :	MFCD04038390
InChI Key :	TVPOQFOCXVSORW-UHFFFAOYSA-N
Pubchem ID :	2756425

Safety of [ 129999-60-6 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H314
Precautionary Statements:	P301+P330+P331-P303+P361+P353-P363-P304+P340-P310-P321-P260-P264-P280-P305+P351+P338-P405-P501
Class:	8
UN#:	2735
Packing Group:	Ⅲ

Computational Chemistry of [ 129999-60-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	1.0
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	44.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.49 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.65
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	-0.81
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.98
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.	-0.31
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	-0.08
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.11

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.09
Solubility	117.0 mg/ml ; 0.809 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	0.25
Solubility	256.0 mg/ml ; 1.78 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-0.23
Solubility	85.7 mg/ml ; 0.594 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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.	-7.75 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

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<1.0
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)	1.24

Application In Synthesis of [ 129999-60-6 ]

* 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 [ 129999-60-6 ]

[ 129999-60-6 ] Synthesis Path-Downstream 1~35

1
[ 129999-60-6 ]
[ 605658-33-1 ]
C₃₀H₃₅ClN₈O₅S [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3914 - 3929.

2
[ 129999-60-6 ]
[ 605658-34-2 ]
4-hydroxy-1-{2-[1-methyl-4-(1-methyl-4-(1-methyl-4-(isoquinoline-3-carboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido]ethyl}piperidine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3914 - 3929.

3
[ 78503-67-0 ]
[ 129999-60-6 ]

Yield	Reaction Conditions	Operation in experiment
		ii) l-(2-Aminoethyl)piperidin-4-ol; Lithium aluminium hydride in THF (43ml, l.OM in THF) was diluted in dry THF (13 mL) and cooled to O0C under nitrogen. The product from step (i) ((4-hydroxypiperidin-l- yl)acetonitrile) (2.Og) in THF (5 mL) was added slowly via syringe. The reaction mixture was heated at reflux for 5 h then cooled to room temperature. Excess hydride was <n="169"/>destroyed by dropwise addition of 1.6 ml of water and 1.6 ml of 15% NaOH, and finally EtOAc was added dropwise until no effervescence was observed. The granular precipitate formed was filtered and washed several times with DCM and EtOAc. The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo to give the subtitle compound as a yellow oil. Yield: 2.OgThis was used in the next step without purification.1H NMR (DMSO) delta 3.44 - 3.37 (m, IH), 2.64 (t,2H), 2.57 (t, 2H), 2.25 - 2.21 (t, 2H), 1.99 - 1.94 (m, 2H), 1.70 - 1.65(m, 2H), 1.40 -1.3 l(m, 2H).

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6690 - 6695.
[2]Patent: WO2007/102771,2007,A1 .Location in patent: Page/Page column 167-168.

4
[ 134529-37-6 ]
[ 129999-60-6 ]
1-[2-(dimethylamino)ethylamino]-4-[2-(4-hydroxypiperidin-1-yl)ethylamino]-5,8-dihydroxyanthracene-9,10-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6690 - 6695.

5
[ 24424-99-5 ]
[ 129999-60-6 ]
[ 220178-83-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7013 - 7023.

6
[ 956035-15-7 ]
[ 129999-60-6 ]
C₃₅H₆₁N₃O₈ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4818 - 4831.

7
[ 129999-60-6 ]
[ 857637-31-1 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7013 - 7023.

8
[ 129999-60-6 ]
[ 857637-30-0 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7013 - 7023.

9
[ 129999-60-6 ]
[ 857637-29-7 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7013 - 7023.

10
[ 129999-60-6 ]
1-[(2-dimethylamino)ethyl]amino}-4-[2-(4-chloropiperidin-1-yl)ethyl]-amino}-5,8-dihydroxyanthracene-9,10-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7013 - 7023.

11
[ 5382-16-1 ]
[ 129999-60-6 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6690 - 6695.
[2]Patent: WO2007/102771,2007,A1 .

12
2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one [ No CAS ]
[ 129999-60-6 ]
5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-[2-(4-hydroxypiperidin-1-yl)ethyl] amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 80℃; for 2h;	102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4 (R) - methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N- (2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at [80C.] The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4: 1). The title compound is obtained: Rf (dichloromethane/methanol=4: 1) =0.16.

References: [1]Patent: WO2003/103653,2003,A1 .Location in patent: Page 200.

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; nickel; In methanol; at 55℃; under 56255.6 Torr;	General procedure: EXAMPLE 238 4-Fluoropiperidine HC1 (801 mg, 5.74 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (647 uL of a 52% aqueous solution, 6.31 mmol) at 5 C. Sodium carbonate (912 mg, 8.60 mmol) was added and the solution was stirred at 70 C for 1.5 h. The solution was cooled, diluted with water (2 mL), washed with Et20 (3 x 4 ml). The organic fraction was dried and the solvent evaporated to give 2-(4-fluoropiperidin- 1 -yl)acetonitrile as a colourless oil. The oil was then dissolved in a 7 N solution of ammonia in MeOH (25 mL) and submitted to hydrogenation on the H-Cube using 75 bar of hydrogen pressure at 55 C with a flow rate of 0.8 mL/min and using a Raney nickel catalyst cartridge. After the reaction was complete the solvent was stripped in vacuo to give 2-(4-fluoropiperidin- 1- yl)ethanamine as a translucent oil.

14
2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one [ No CAS ]
[ 129999-60-6 ]
5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a) 5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-[2-(4-hydroxypiperidin-1-yl)-ethyl]-amide 102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of <strong>[129999-60-6]N-(2-aminoethyl)-4-hydroxypiperidine</strong> are stirred for 2 hours at 80 C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16.

References: [1]Patent: US5559111,1996,A .

15
[ 129999-60-6 ]
[ 50-30-6 ]
[ 948895-18-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;	Example 44; s 2,6-Dichloro-iV-[2-(4-[(2i?)-2-hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino}piperidin-l-yl)ethyl]benzamide; i) 2,6-Dichloro-iV-[2-(4-hydroxypiperidin-l-yl)ethyl]benzamideA solution of l-(2-aminoethyl)piperidm-4-ol (0.312 g), 2,6-dichlorobenzoic acid (0.826g), 0 and triethylamine (0.61 mL) in DMF (10 mL) was treated with PyBROP (1.2Ig) at ambient temperature. After stirring for 14 h the mixture was loaded onto a SCX cartridge and eluted with acetonitrile followed by methanol. The product was then eluted off with ammonia/methanol solutions to give the subtitle compound, after solvent evaporation, as a yellow oil. Yield: 0.7g s MS APCI+ 317/319/321 [M+H]+

References: [1]Patent: WO2007/102771,2007,A1 .Location in patent: Page/Page column 130.

16
[ 98-09-9 ]
[ 129999-60-6 ]
[ 948896-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 4h;	iii) N-[2-(4-hydroxypiperidin-l-yl)ethyl]benzenesulfonamide; The product from step (ii) (l-(2-aminoethyl)piperidin-4-ol) (0.43g) was suspended in DCM (40 mL) followed by addition of triethylamine (0.84 ml) and benzenesulfonyl chloride (0.53g). The mixture was stirred for 4 h at room temperature and then partitioned between DCM and water, organics collected, dried (Na2SO4) and solvent evaporated to a leave beige solid. Purification was by silica gel chromatography eluting with 20:1 to 10:1 DCM/MeOH to give the subtitle compound as a colourless solid. Yield: 0.43g MS APCI+ 285 [M+H]+ 1HNMR (DMSO) delta 7.82 - 7.79 (m, 2H), 7.66 - 7.57 (m, 3H), 7.49 (s, IH), 4.49 (s, IH), 3.45 - 3.37 (m,lH), 2.80 (t, 2H), 2.26 (t, 2H), 1.93 (t, 2H), 1.63 - 1.60(m, 2H), 1.34 - 1.25(m, 2H).

References: [1]Patent: WO2007/102771,2007,A1 .Location in patent: Page/Page column 168.

17
[ 152120-55-3 ]
[ 129999-60-6 ]
C₂₄H₃₀N₄O₅ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1632 - 1635.

18
N-{3-[2-(2-Chloro-pyridin-4-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-3-trifluoromethyl-benzamide [ No CAS ]
[ 129999-60-6 ]
N-{3-[2-(2-[2-(4-hydroxypiperidin-1-yl)ethyl]amino}pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-3-(trifluoromethyl)benzamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6890 - 6892.

19
[ 1225380-63-1 ]
[ 129999-60-6 ]
[ 1226860-98-5 ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate; triethylamine;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 32h;Inert atmosphere; Reflux;	Example 41-[2-({6-[(5-Methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)-methyl]pyridin-3-yl}amino)ethyl]piperidin-4-ol; Under inert conditions, a mixture of 100 mg (0.190 mmol) of the compound from Example 43A, 28 mg (0.190 mmol) of <strong>[129999-60-6]1-(2-aminoethyl)piperidin-4-ol</strong> [K. Pors et al., J. Med. Chem. 2005, 48 (21), 6690-6695], 1.3 mg (0.006 mmol) of palladium(II) acetate, 3.5 mg (0.006 mmol) of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 309 mg (0.948 mmol) caesium carbonate and 1.6 mul (0.011 mmol) of triethylamine in 4 ml of toluene was heated at reflux. After 16 h, the mixture was allowed to cool to RT, and the same amounts of <strong>[129999-60-6]1-(2-aminoethyl)piperidin-4-ol</strong>, palladium(II) acetate, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, caesium carbonate and triethylamine were added again. The mixture was then once more heated under reflux for 16 h. After cooling, approx. 50 ml of water were added and the mixture was extracted three times with approx. 50 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration, the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (method K). The product fractions were combined, dissolved in methanol and freed via a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol) from the formic acid originating from the HPLC mobile phase. After the solvent had been removed on a rotary evaporator, 30 mg (30% of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.25 (d, 2H), 7.97 (d, 1H), 7.33 (d, 2H), 6.94 (d, 1H), 6.82 (dd, 1H), 6.79 (s, 1H), 5.44 (s, 2H), 4.47 (t, 1H), 3.77-3.70 (m, 1H), 3.12 (dt, 2H), 2.80-2.71 (m, 2H), 2.61 (t, 2H), 2.35 (s, 3H), 2.21-2.13 (m, 2H), 1.93-1.86 (m, 2H), 1.61-1.53 (m, 2H), 1.43 (d, 1H).HPLC (method B): Rt=4.15 min.MS (ESIpos): m/z=544 [M+H]+.

References: [1]Patent: US2011/312930,2011,A1 .Location in patent: Page/Page column 70-71.

20
C₂₀H₁₃ClF₃N₅O₃ [ No CAS ]
[ 129999-60-6 ]
[ 1226861-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere;	Example 13N-[2-(4-Hydroxypiperidin-1-yl)ethyl]-5-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)methyl]pyridine-2-carboxamide; Under inert conditions, a solution of 85 mg (0.191 mmol) of the compound from Example 55A was initially charged in 3 ml of anhydrous dichloromethane, and 83 mul (0.954 mmol) of oxalyl chloride and a small drop of DMF were added at RT. After 2 h, the reaction mixture was freed from all volatile components on a rotary evaporator, and the crude product was dried under high vacuum for 1 h. The residue was then dissolved in 2 ml of anhydrous THF and added dropwise to a solution of 41 mg (0.286 mmol) of <strong>[129999-60-6]1-(2-aminoethyl)piperidin-4-ol</strong> [K. Pors et al., J. Med. Chem. 2005, 48 (21), 6690-6695] and 67 mul (0.382 mmol) of N,N-diisopropylethylamine in 1 ml of anhydrous THF. The reaction mixture was stirred at RT for 16 h. Approx. 1 ml of water was then added and the reaction mixture was separated directly by preparative HPLC (method K). The product fractions were concentrated and then once more dissolved in methanol, and the adhering formic acid was removed via a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). 87 mg (80% of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.43 (d, 1H), 8.30 (t, 1H), 8.25 (d, 2H), 8.18 (d, 1H), 7.65 (dd, 1H), 7.33 (d, 2H), 6.85 (s, 1H), 5.53 (s, 2H), 3.76-3.69 (m, 1H), 3.54 (quart, 2H), 2.81 (dt, 2H), 2.58 (t, 2H), 2.33 (s, 3H), 2.21 (dt, 2H), 1.90 (dt, 2H), 1.60 (dt, 2H), 1.46 (broad, 1H).HPLC (method B): Rt=4.36 min.MS (ESIpos): m/z=572 [M+H]+.LC/MS (method E, ESIpos): Rt=1.42 min, m/z=572 [M+H]+.

References: [1]Patent: US2011/312930,2011,A1 .Location in patent: Page/Page column 73.

21
[ 1415397-86-2 ]
[ 129999-60-6 ]
[ 1415397-43-1 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10551 - 10563.

22
N,N’-bis{4-[(2-chIorobenzoyl)amino]phenyl}-5,10-dioxo-5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-1,6-dicarboxamide [ No CAS ]
[ 129999-60-6 ]
N⁴-{4-[(2-chlorobenzoyl)amino]phenyl}-N⁵-[2-(4-hydroxypiperidin-1-yl)ethyl]-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg	With N-ethyl-N,N-diisopropylamine; at 20℃; for 19h;	To the crude mixture of N,N?-bis{4-[(2-ch[orobenzoy[)amino]pheny[1-5, 10-dioxo-5H,1OH-diimidazo[1 ,5-a:1?,5?-d]pyrazine-1 ,6-dicarboxamide (0.2 mmo[,Intermediate 052), were added 61 mg (0.4 mmo[) 1-(2-aminoethy[)piperidin-4-o[ and 0.348 mL (2 mmo[) N-ethy[-N-isopropy[propan-2-amine and the mixture wasstirred for 19 h at room temperature.The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC chromatography to give 20 mg of the tit[e compound as a so[id materia[.1HNMR (400 MHz, DMSO-d6): 6 [ppm] = 10.49 (s, 1H), 8.63 (br. s., 1H), 8.16 (s, 1H),7.91 (s, 1H), 7.76-7.63 (m, 4H), 7.60-7.54 (m, 2H), 7.53-7.41 (m, 2H), 7.36-7.28 (m, 1H), 4.52 (br. s., 1H), 3.50-3.40 (m, 4H), 2.83-2.72 (m, 2H), 2.09 (t, 2H), 1.71 (d, 2H), 1.38 (d, 2H).LC-MS (Method 1): Rt = 0.70 mm; MS (ESIpos) m/z = 512 [M+H].

References: [1]Patent: WO2015/150449,2015,A2 .Location in patent: Page/Page column 370; 371.

23
N,N'-bis{4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}-5,10-dioxo-5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-1,6-dicarboxamide [ No CAS ]
[ 129999-60-6 ]
N₄-{4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}-N₅-[2-(4-hydroxypiperidin-1-yl)ethyl]-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13 mg	With N-ethyl-N,N-diisopropylamine; at 20℃; for 19h;	To the crude mixture of N,N?-bis{4-[(2-ch[oro-4-f[uorobenzoy[)amino]pheny[1-5,10- dioxo-5H,1OH-diimidazo[1 ,5-a:1?,5?-d]pyrazine-1 ,6-dicarboxamide (0.20 mmo[, Intermediate 005), were added 61 mg (0.4 mmo[) 1-(2-aminoethy[)piperidin-4-o[and 0.348 mL (2 mmo[) N-ethy[-N-isopropy[propan-2-amine and the mixture was stirred for 19 h at room temperature.The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC chromatography to give 13 mg of the tit[e compound as a so[id materia[.1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 10.52 (s, 1H), 7.94 (s, 1H), 7.76-7.65 (m,5H), 7.60 (dd, 1H), 7.36 (td, 1H), 4.54 (br. s., 1H), 3.50-3.41 (m, 4H), 2.82-2.73 (m, 2H), 2.09 (t, 2H), 1.72 (d, 2H), 1.39 (d, 2H).LC-MS (Method 1): R = 0.89 mm; MS (ESIpos) m/z = 530 [M+H]÷.

References: [1]Patent: WO2015/150449,2015,A2 .Location in patent: Page/Page column 382; 383.

24
N,N'-bis{4-[(4-fluorobenzoyl)amino]phenyl}-5,10-dioxo-5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-1,6-dicarboxamide [ No CAS ]
[ 129999-60-6 ]
N⁴-{4-[(4-fluorobenzoyl)amino]phenyl}-N⁵-[2-(4-hydroxypiperidin-1-yl)ethyl]-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57 mg	With N-ethyl-N,N-diisopropylamine; at 20℃; for 19h;	To the crude mixture of N,N?-bis{4-[(4-f[uorobenzoy[)amino]pheny[-5,10-dioxo-5H,1OH-diimidazo[1 ,5-a:1?,S?-d]pyrazine-l ,6-dicarboxamide (0.2 mmo[,Intermediate 018), were added 61 mg (0.4 mmo[) 1-(2-aminoethy[)piperidin-4-o[ and 0.348 mL (2 mmo[) N-ethy[-N-isopropy[propan-2-amine and the mixture was stirred for 19 h at room temperature.The reaction mixture was concentrated in vacuo and the residue was purified bypreparative HPLC chromatography to give 57 mg of the tit[e compound as a so[idmateria[.1HNMR (400 MHz, DMSO-d6): 6 [ppm] = 10.26 (s, 1H), 8.09-7.98 (m, 2H), 7.90 (s,1H), 7.80-7.64 (m, 4H), 7.40-7.30 (m, 2H), 4.51 (d, 1H), 3.44 (q, 3H), 2.81-2.71 (m,2H), 2.13-2.03 (m, 2H), 1.71 (dd, 2H), 1.45-1.32 (m, 2H).LC-MS (Method 1): R = 0.71 mm; MS (ESIpos) m/z = 495 [M+H].

References: [1]Patent: WO2015/150449,2015,A2 .Location in patent: Page/Page column 355; 356.

25
[ 1312208-19-7 ]
[ 129999-60-6 ]
1-[2-(4-hydroxypiperidin-1-yl)ethyl]amino}-3-[4-(trifluoromethyl)phenyl]benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1432 - 1448.

26
[ 64-18-6 ]
(Z)-4-(((1-acetyl-6-(methoxycarbonyl)-5-methyl-2-oxoindolin-3-ylidene)(phenyl)methyl)amino)benzoic acid trifluoroacetate [ No CAS ]
[ 129999-60-6 ]
(Z)-methyl 3-(((4-((2-(4-hydroxypiperidin-1-yl)ethyl)carbamoyl)phenyl)amino)(phenyl)methylene)-5-methyl-2-oxoindoline-6-carboxylate formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		(Z)-4-(((l -Acetyl-6-(methoxycarbonyl)-5-methyl-2-oxoindolin-3-ylidene)(phenyl)methyl)amino)benzoic acid, trifluoroacetate adduct (Intermediate E) (75 mg, 0.128 mmol), and HATU (73 mg, 0.192 mmol) in DMF (2 mL) were stirred at rt for 10 mm then Hunig?s base (179 p1, 1.03 mmol) and <strong>[129999-60-6]1-(2-aminoethyl)piperidin-4-ol</strong> (50 mg, 0.346 mmol) wereadded. The mixture was stirred at rt for 3 h and piperidine (127 p1, 1.28 mmol) was added. The mixture was stirred at rt for 18 h. The reaction mixture was partitioned between DCM (25 mL) and saturated aqueous NaHCO3 solution (10 mL). The organic layer was washed with brine (10 mL) and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (Method A, 20-50% MeCN in water) to afford the title compound(Z)-methyl 3-(((4-((2-(4-hydroxypi peridin- 1-yl)ethyl)carbamoyl) phenyl)am ino)(phenyl)methylene)-5-methyl-2-oxoindoli ne-6-carboxylate,0.8 formate as a light yellow solid (9mg, 11%); Rt 1.54 mm (Method 1); mlz 555 (M+H) (ES);1H NMR O: 1.28-1.42 (2H, overlapping m), 1.64-1.72 (2H, overlapping m), 2.02-2.11 (2H,overlapping m), 2.13 (3H, 5), 2.42 (2H, t), 2.69-2.78 (2H, overlapping m), 3.75 (3H, 5), 4.56(1H, brs), 5.62 (1H, 5), 6.87 (2H, m), 7.36 (1H, 5), 7.52 (2H, m), 7.57-7.69 (5H, overlappingm), 8.16 (0.8H, 5), 8.28 (1H, t), 10.88 (1H, 5), 12.22 (1H, 5). (Missing 3H-presumed obscured by solvent).

References: [1]Patent: WO2017/153748,2017,A1 .Location in patent: Page/Page column 39; 40.

27
[ 86-38-4 ]
[ 129999-60-6 ]
6-chloro-9-[2-(4'-hydroxypiperidin-1-yl)ethyl]amino-2-methoxyacridine [ No CAS ]