221681-75-0|6-Chloro-1H-indazol-5-amine| Ambeed

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Quality Control of [ 221681-75-0 ] Purity: 98% SDS Specification

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Product Details of [ 221681-75-0 ]

CAS No. :	221681-75-0
Formula :	C₇H₆ClN₃
M.W :	167.60
SMILES Code :	NC1=CC2=C(NN=C2)C=C1Cl
MDL No. :	MFCD08690108
InChI Key :	ZUCDYBREEPULBI-UHFFFAOYSA-N
Pubchem ID :	22022411

Safety of [ 221681-75-0 ]

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

Computational Chemistry of [ 221681-75-0 ] 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	1.0
Num. H-bond donors	2.0
Molar Refractivity	45.51
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	54.7 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.91
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	1.5
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.81
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.	1.11
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	1.95
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.43
Solubility	0.623 mg/ml ; 0.00372 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.	-2.26
Solubility	0.929 mg/ml ; 0.00554 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	-3.16
Solubility	0.116 mg/ml ; 0.00069 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	Yes
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.	-6.26 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)	1.47

Application In Synthesis of [ 221681-75-0 ]

* 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 [ 221681-75-0 ]

[ 221681-75-0 ] Synthesis Path-Downstream 1~17

1
[ 101420-98-8 ]
[ 221681-75-0 ]

References: [1]Journal of the Chemical Society,1955,p. 2412,2419.

2
[ 267891-86-1 ]
[ 221681-75-0 ]
[ 381694-55-9 ]

References: [1]Patent: EP1280799,2004,B1 .Location in patent: Page/Page column 8.

3
[ 864082-31-5 ]
[ 221681-75-0 ]
N-(6-chloro-1H-indazol-5-yl)-4-(4-chlorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20.0℃; for 18.0h;	Example 55;. N- (6-Chloro-lH-indazol-5-yl)-4- (4-chlorophenyl)-2-methyl-6-oxo- 1, 4,5, 6-tetrahydro-3-pyridinecarboxamide;. 6-Chloro-lH-indazol-5-amine (64 mg, 0.382 mmol, 1.0 equiv) was combined with the product from Example 4, Step 2 (101 mg, 0. 382 mmol, 1.0 equiv), EDC (88 mg, 0.458 mmol, 1.2 equiv) and Et3N (64, ut, 0.458 mmol, 1.2 equiv) in DMF (ImL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HC1, once with satd. NaHC03, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (0-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (15-98% CH3CN/H20, adjusted to pH 10 w/NH40H over 13 minutes, retention time 6.56 min) to provide 40 mg (25%) of the title compound as a white solid. MS (ES+) m/e 416 [M+H]+

References: [1]Patent: WO2005/82890,2005,A1 .Location in patent: Page/Page column 64.

4
[ 267891-86-1 ]
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium [ No CAS ]
[ 221681-75-0 ]
[ 381694-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In N-methyl-acetamide; water;	EXAMPLE 2 N-(6-Chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-Benzoic Acid Amide 194 mg (0.85 mmol) of 2-(4-pyridylmethyl)aminobenzoic acid is mixed in 8 ml of dimethylformamide with 283 mg (1.69 mmol) of <strong>[221681-75-0]5-amino-6-chloroindazole</strong>. Under argon and in a moisture-free environment, 215 mg (2.13 mmol) of N-methylmorpholine and 386 mg (1.02 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophophate are added to this solution. This mixture is stirred for 4 hours at room temperature. It is then diluted with about 40 ml of water and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol-10:1 as an eluant. 97 mg (30.2% of theory) of N-(6-chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-benzoic acid amide with a melting point of 222.8 C. is obtained. Similarly produced are:

References: [1]Patent: US2004/102441,2004,A1 .

5
(RS)-ethyl 4-chloro-5, 6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate [ No CAS ]
[ 221681-75-0 ]
ethyl 4-[(6-chloro-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35 mg	With hydrogenchloride; In 1,4-dioxane; ethanol; for 16.0h;Molecular sieve; Reflux;	To a mixture of ethyl 4-(1 H-indazol-5-ylamino)-5, 6,7,8- tetrahydro[1 ]benzothieno[2, 3-d]pyrimidine-7-carboxylate (650 mg) and 5-amino-6- chloroindazole (422 mg, 1 .15 eq) in ethanol (8.0 mL) were added 4A molecular sieves (2 g), followed by a 4 N solution of hydrogen chloride in dioxane (821 muIota_, 1 .5 eq). The mixture was heated to reflux for 16 h and added to water after cooling to room temperature. The precipitate was isolated by filtration and triturated with DMSO. Insolubles were removed by filtration, the filtrate was concentrated in vacuo to give the crude product which was purified by preparative HPLC (Method P4) yielding 35 mg of the target compound.1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1 .22 (t, 3H), 1 .89 - 2.05 (m, 1 H), 2.16 - 2.31 (m, 1 H), 2.89 - 3.30 (m, 5H, partly overlapped with water signal), 4.14 (q, 2H), 7.77 (s, 1 H), 8.07 - 8.16 (m, 2H), 8.25 (s, 1 H), 8.29 (s, 1 H), 13.21 (br. s. , 1 H).MS (ESIpos) m/z = 428 (35Cl), 430 (37Cl) [M+H]+.

References: [1]Patent: WO2013/174744,2013,A1 .Location in patent: Page/Page column 99; 100.

6
[ 24424-99-5 ]
[ 221681-75-0 ]
tert-butyl 5-amino-6-chloro-1H-indazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25.0℃; for 18.0h;	Intermediate 12-1 tert-Butyl 5-amino-6-chloro-1H-indazole-1-carboxylate (1275) (1276) 2.1 ml (11.8 mmol) of N,N-diisopropylethylamine and 2.34 g (10.7 mmol) of di-tert-butyl dicarbonate were added to 1.80 g (10.7 mmol) of <strong>[221681-75-0]6-chloro-1H-indazole-5-amine</strong> (CAS No. 221681-75-0) in 18 ml of tetrahydrofuran, and the mixture was stirred at 25 C. for 18 h. The mixture was concentrated and the residue was taken up in ethyl acetate and, during concentration, adsorbed on Isolute. The Isolute was applied to a Biotage SNAP cartridge (100 g; KP-Sil) pre-equilibrated with hexane and chromatography was carried out using the Isolera flash purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 50 ml/min; gradient: isocratic 100:0 (5 min), 100:0->75:25 (20 min), isocratic 75:25 (5 min), 75:25->50:50 (15 min), isocratic 50:50 (5 min), 50:50->0:100 (15 min)) The combined product fractions were concentrated and dried under reduced pressure. This gave 1.23 g (43% of theory) of the title compound. (1277) UPLC-MS (Method A1): Rt=1.16 min (1278) MS (ESIpos): m/z=268 (M+H)+

References: [1]Patent: US2016/311833,2016,A1 .Location in patent: Paragraph 1275; 1276; 1277; 1278.

7
[ 221681-75-0 ]
N-(6-chloro-2-{2-oxo-2-[(3R)-piperidin-3-ylamino]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide [ No CAS ]