59673-74-4|6-Amino-1H-indazol-3-ol| Ambeed

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Quality Control of [ 59673-74-4 ] Purity: 95% SDS Specification

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Product Details of [ 59673-74-4 ]

CAS No. :	59673-74-4
Formula :	C₇H₇N₃O
M.W :	149.15
SMILES Code :	OC1=NNC2=C1C=CC(N)=C2
MDL No. :	MFCD07781650
InChI Key :	RVEOZWSYDIHKIB-UHFFFAOYSA-N
Pubchem ID :	108801

Safety of [ 59673-74-4 ]

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

Computational Chemistry of [ 59673-74-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	3.0
Molar Refractivity	42.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.93 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.35
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	0.85
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.86
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.	0.6
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	0.83
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.7

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.91
Solubility	1.85 mg/ml ; 0.0124 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.	-2.01
Solubility	1.47 mg/ml ; 0.00985 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	-1.96
Solubility	1.65 mg/ml ; 0.011 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	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.	-6.61 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	1.0 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)	1.79

Application In Synthesis of [ 59673-74-4 ]

* 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 [ 59673-74-4 ]

[ 59673-74-4 ] Synthesis Path-Downstream 1~24

1
[ 7364-33-2 ]
[ 59673-74-4 ]

References: [1]Journal of the Chemical Society,1955,p. 2412,2419.
[2]Chemische Berichte,1942,vol. 75,p. 1096,1104.

2
[ 59673-74-4 ]
4-bromo-Ν-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine [ No CAS ]
4-bromo-Ν-α-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-Ν-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20.0℃; for 16.0h;	A solution of 4-bromo-Nu-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine (1500 mg, 3 mmol) and <strong>[59673-74-4]6-amino-1,2-dihydro-3H-indazol-3-one</strong> (555 mg, 24 mmol) in ethyl acetate (21 ml) was treated with N, N-diisopropylethylamine (1.4 ml, 7.8 mmol).The suspension was treated with a 2,4, 6-tripropyl-l, 3,5,2, 4,6-trioxatriphosphinane-2, 4,6 trioxide solution (50% in dimethylformamide, 2.2 ml, 3.7 mmol) and up added to the solution with dimethylformamide, and then stirred at RT for 16 h.The reaction mixture was stirred in ethyl acetate, washed twice with water and once with aqueous saturated sodium chloride solution.The organic phase was dried with sodium sulfate and the solvent removed.The crude product was stirred with acetonitrile and suction filtered.The residue was twice purified by preparative HPLC separated (eluent: acetonitrile / water with 0.1% TFA (gradient)).The crude product was stirred with methanol and sucked.This gave 202 mg (11% d. Th.) Of the title compound.
11%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20.0℃; for 16.0h;	A solution of 4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine (1500 mg, 3 mmol) and <strong>[59673-74-4]6-amino-1,2-dihydro-3H-indazole-3-one</strong> (555 mg, 24mmol) in ethyl acetate (21 ml) was treated with N, N-diisopropylethylamine (1.4 ml, 7.8 mmol). Thesuspension was treated with a 2,4, 6-tripropyl-1, 3,5,2, 4,6-trioxatriphosphinane 2, 4,6 trioxidesolution (50% in dimethylformamide, 2.2 ml, 3.7 mmol) and up added to the solution withdimethylformamide, and then stirred at RT for 16 h. The reaction mixture was stirred in ethylacetate, washed twice with water and once with sodium chloride solution. The organic phase wasdried with sodium sulfate and the solvent removed. The crude product was stirred with acetonitrileand suction filtered. The residue was twice purified by preparative HPLC separated (eluent:acetonitrile / water gradient, 0.1% TFA). The crude product was stirred with methanol and suctionfiltered. This gave 202 mg (11% theoretical value)of the title compound.
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20.0℃; for 16.0h;	Containing 4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine (1500 mg, 3 have mozambican ear) and <strong>[59673-74-4]6-amino-1,2-dihydro-3H-indazol-3-one</strong> (555 mg, 24 have mozambican ear) in ethyl acetate (21 ml) solution with in N, N-diisopropyl ethylamine (1.4 ml, 7.8 have mozambican ear) blend. For the suspension 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution (50% in DMF in, 2.2 ml, 3.7 have mozambican ear) DMF until the blending and dissolving, and then the the mixture to the stirring the mixture at room temperature for up to 16 hours. Stirring the reaction mixture in ethyl acetate, and secondary washing with water and a saturated sodium chloride aqueous solution. The organic phase with sodium sulfate drying and removing the solvent. The crude product using acetonitrile stirring and suction filtered. The residual quality by preparative HPLC to be separated and secondary (eluents: acetonitrile/water with 0.1% trifluoro acetic acid the gradient). The crude product is used for methanol stirring and suction filtered. This generating 202 mg (theoretical value of 11%) the subject compound.

With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20.0℃;

N,N-Diisopropylethylamine is added to a solution of 4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine and <strong>[59673-74-4]6-amino-1,2-dihydro-3H-indazol-3-one</strong> in ethyl acetate. A 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in dimethylformamide) is added to the reaction mixture, and the mixture is then stirred overnight at RT. The reaction mixture is worked up by methods known to those skilled in the art and the residue is separated by means of preparative HPLC. This gives the title compound.

References: [1]Patent: TW2016/5828,2016,A .Location in patent: Page/Page column 46; 47.
[2]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0206.
[3]Patent: TW2016/5809,2016,A .Location in patent: Page/Page column 47; 48.
[4]Patent: US2016/237044,2016,A1 .Location in patent: Paragraph 0548-0549.

3
[ 59673-74-4 ]
(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-[2'-chloro-4'-(isopropylcarbamoyl)biphenyl-4-yl]propanoic acid [ No CAS ]
tert-butyl [trans-4-({(2_S)-3-[4'-(isopropylcarbamoyl)-2'-methylbiphenyl-4-yl]-1-oxo-1-[(3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]propan-2-yl}carbamoyl)cyclohexyl]methyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; In ethyl acetate; for 3.0h;Reflux;	A solution of (2S ) - 2- [(trans-4- [(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - amino} -3- [4 '-(isopropylcarbamoyl) - 2'-methylbiphenyl-4-yl] propanoic acid (150 mg, 0:26 mmol) and 6-amino-l,2-dihydro-3 / i-indazol-3-one (53 mg, 0:28 mmol) in ethyl acetate (3 ml) was treated with N, Ndiisopropylethylamine(0:11 mL, 0.77 mmol). Then, 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide solution (50% in ethyl acetate, 0:46 ml, 0.77 mmol) and refluxed for 3 h , Thereaction mixture was mixed with water, the precipitate is suctioned and dried via lyophilization.This gave 102 mg (55% d. Th.) Of the title compound.

References: [1]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0431.

4
[ 59673-74-4 ]
ethyl 6-({(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-[4'-(cyclobutylcarbamoyl)-2'-methylbiphenyl-4-yl]propanoyl}amino)-1H-indol-2-carboxylate [ No CAS ]
tert-butyl [trans-4-({(2S)-3-[4'-(cyclobutylcarbamoyl)-2'-methylbiphenyl-4-yl]-1-oxo-1-[(3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]propan-2-yl}carbamoyl)cyclohexyl]methyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With 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 20.0℃;	A solution of (2S )- 2- [(ira Ae4- [(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) - carbonyl] amino} -3- [4 '-(cyclobutylcarbamoyl) - 2'-methylbiphenyl-4-yl] propanoic acid (80 mg, 0:14 mmol) in DMF (1.5mL) was added 6-amino-l, 2-dihydro-3 / i-indazol-3-one (40 mg, 0:27 mmol) and N, Ndiisopropylethylamine(0.07 mL, 0:41 mmol). The solution was treated with HATU (77 mg, 0:41mmol) and then stirred overnight at RT. The solvent was removed and the residue dissolved in alittle DMSO / acetonitrile, filtered through a Millipore filter and purified by preparative HPLC(eluent: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 28 mg (29% d.Th.) Of the title compound.

References: [1]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0477.

5
[ 59673-74-4 ]
N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-iodo-L-phenylalanine [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-iodo-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; HATU; In ethyl acetate; for 6.0h;Reflux;	N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-iodo-L-phenylalanine (1.91 g, 3.6 mmol), 6-amino-l, 2-dihydro-3 -indazol-3-one (0:55 g, 3.60 mmol) and N, N- diisopropylamine (1.9 ml, 10.8 mmol)were suspended in 23 ml of ethyl acetate and 2,4,6-tripropyl-l, 3,5,2 , 4,6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 5.73 g, 9.0 mmol). The mixture was then refluxed for 3 h,additional 6-amino-l, 2-dihydro-3 / i-indazol3-one (0.14g, 0.90 mmol), N, N-diisopropylamine (0:47ml, 2.70 mmol) and 2,4,6 added -Tripropyl1,3,5, 2,4, 6-trioxatriphosphinane-2,4,6-trioxide (50% inethyl acetate, 1:43 g, 2.25 mmol) and refluxed for another 3 h. The reaction mixture was treatedwith water, the phases were separated and the aqueous phase extracted three times with ethylacetate. The precipitated in two phases solid was suction filtered and dried under high vacuum.This gave 1:35 g (57%.

References: [1]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0350.

6
[ 59673-74-4 ]
3-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine [ No CAS ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20.0℃; for 50.0h;Reflux;	Example 150A 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide 3-Bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine, <strong>[59673-74-4]6-amino-1H-indazol-3(2H)-one</strong> and N,N-diisopropylethylamine are suspended in ethyl acetate, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate) is added. The reaction mixture is then heated under reflux for 2 h and stirred at RT for a further 48 h. The reaction mixture is worked up by methods known to those skilled in the art and the residue is separated by means of preparative HPLC. This gives the title compound.

References: [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1238; 1239.

7
[ 59673-74-4 ]
tert-butyl [trans-4-({(2S)-3-[2'-methyl-5'-(morpholin-4-ylsulphonyl)biphenyl-3-yl]-1-oxo-1-[(3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]propan-2-yl}carbamoyl)cyclohexyl]methyl}carbamate [ No CAS ]