1351813-02-9|6-Bromo-5-nitro-1H-indazole| Ambeed

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Quality Control of [ 1351813-02-9 ] Purity: 95% SDS Specification

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Product Details of [ 1351813-02-9 ]

CAS No. :	1351813-02-9
Formula :	C₇H₄BrN₃O₂
M.W :	242.03
SMILES Code :	O=[N+](C1=CC2=C(NN=C2)C=C1Br)[O-]
MDL No. :	MFCD27987808
InChI Key :	YZKXPWFCVVSHCK-UHFFFAOYSA-N
Pubchem ID :	71681986

Safety of [ 1351813-02-9 ]

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

Computational Chemistry of [ 1351813-02-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	52.62
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.5 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.85
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	2.07
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.23
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.	1.61
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	0.51
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.45

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.09
Solubility	0.196 mg/ml ; 0.000811 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.	-3.26
Solubility	0.132 mg/ml ; 0.000545 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	-3.15
Solubility	0.171 mg/ml ; 0.000708 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.	-6.31 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.	0.55

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	2.0 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)	1.95

Application In Synthesis of [ 1351813-02-9 ]

* 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 [ 1351813-02-9 ]

[ 1351813-02-9 ] Synthesis Path-Downstream 1~35

1
[ 679839-39-5 ]
[ 1351813-02-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine hydrate; In ethanol; at 80℃; for 8h;	To a cooled to 0C solution of potassium nitrate (0.55 g, 5.4 mmol) in concentrated sulfuric acid (8 mL) 4-bromo-2-fluorobenzaldehyde (1 g, 4.9 mmol) was added. The reaction mixture was stirred at room temperature for lh. Then the mixture was poured into ice water and occurred precipitate was collected by filtration. The solid was washed with water next saturated aqueous solution of sodium hydrocarbonate and air dried to give 4-bromo-2-fluoro-5-nitrobenzaldehyde (1.1 g, 90%). To the obtained product (0.1 g, 0.4 mmol) dissolved in ethanol (5 mL) hydrazine monohydrate (0.02 mL, 0.4 mmol) was dropped. The reaction mixture was heated at 80C for 8h. After cooled to room temperature the solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and next brine. Organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6-bromo-5-nitro-lH-indazole as a solid (0.09, 95%). NMR (300 MHz, DMSO) delta 13.71 (s, 1H), 8.61 (d, J = 3.1 Hz, 1H), 8.33 (s, 1H), 8.05 (s, 1H). 3.2.
93%	With hydrazine; In N,N-dimethyl-formamide; at 150℃; for 2h;	To a solution of 4-bromo-2-fluoro-5-nitrobenzaldehyde (23 g, 93.11 mmol) in DMF (350mL) was added hydrazine (6 mL, 102 mmol) and the contents were heated at 150 C for 2 h.After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the title compound (20.0 g, 93%) as a yellow solid.?H NMR (400 MHz, DMSO-d6): oe 13.70 (bs, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H).LCMS: mlz: 240 (M-1) .
93%	With hydrazine; In N,N-dimethyl-formamide; at 150℃; for 2h;	To a solution of 4-bromo-2-fluoro-5-nitrobenzaldehyde (23 g, 93.11 mmol) in DMF (350 mL) was added hydrazine (6 mL, 102 mmol) and the contents were heated at 150 C. for 2 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the title compound (20.0 g, 93%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 13.70 (bs, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H). LCMS: m/z: 240 (M-1)+.

References: [1]Patent: WO2017/68064,2017,A1 .Location in patent: Page/Page column 196; 197.
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.
[3]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 44.
[4]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0239; 0240.

2
[ 57848-46-1 ]
[ 1351813-02-9 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.
[2]Patent: WO2015/104662,2015,A1 .
[3]Patent: US2016/326151,2016,A1 .

3
[ 1351813-02-9 ]
[ 1351813-04-1 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

4
[ 1351813-02-9 ]
[ 1351813-05-2 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

5
[ 1351813-02-9 ]
[ 1351813-06-3 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

6
[ 1351813-02-9 ]
[ 1351813-08-5 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

7
[ 1351813-02-9 ]
[ 1351813-09-6 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

8
[ 1351813-02-9 ]
[ 1351813-11-0 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

9
[ 1351813-02-9 ]
[ 1351811-41-0 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

10
[ 1351813-02-9 ]
[ 76513-69-4 ]
[ 1351813-03-0 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4343 - 4356.

Yield	Reaction Conditions	Operation in experiment
86%	With hydrazine hydrate; In ethanol; at 100℃; for 2h;	General procedure: A mixture comprising 5.00 g (27.0 mmol) 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (prepared according to intermediate example 94e), 100 mL ethanol and 6.57 mL hydrazine hydrate was heated at 100 C for 2 hours. The mixture was acidified with hydrochloric acid, ethyl acetate was added, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid, brine and dried over sodium sulfate. After filtration and removal of the solvent 2.33 g (48%) of the title compound were obtained.

12
[ 1351813-02-9 ]
6-bromo-1H-indazol-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With iron; ammonium chloride; In ethanol; water; for 3h;Reflux;	A mixture comprising 10 g (41 .3 mmol) 6-bromo-5-nitro-1 H-indazole (prepared according to the Journal of Medicinal Chemistry, 2013 , vol. 56, 1 1 p. 4343 - 4356), 400 mL ethanol, 80 mL water, 23.1 g iron powder and 1 .1 1 g ammonium chloride was stirred vigorously for 3h at reflux. After filtration and washing with ethanol the reaction mixture was concentrated in vacuum and then taken up in ethyl acetate and washed with saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate, filtrated and concentrated to give 8.44 g (92%) of the title compound.

References: [1]Patent: WO2015/74986,2015,A1 .Location in patent: Page/Page column 274.

13
[ 1351813-02-9 ]
[ 74-88-4 ]
6-bromo-2-methyl-5-nitro-2H-indazole [ No CAS ]
6-bromo-1-methyl-5-nitro-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.3%; 52.95%		To a solution of 5-nitro-6-(piperidin-1-yl)-1H-indazole (334 mg, 1.35 mmol) in DMF (10 mL) was added potassium carbonate (562 mg, 4.07 mmol) and the contents were stifled for 0.5 h at RT. The reaction mixture was again cooled to 0 C and methyl iodide (0.169 mL, 2.71 mmol) was added drop wise and stifling, at room temperature, was continued for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. Afterconcentration, the residue was purified by flash chromatography (n-hexane:EtOAc; 3:1) to give1-methyl-5-nitro-6-(piperidin-1-yl)-2H-indazole (Isomer B) (215 mg, 61%) as a brown solid.?H NMR (400 MHz, CDC13): oe 8.20 (s, 1H), 7.98 (s, 1H), 6.87 (s, 1H), 4.04 (s, 3H), 3.03-3.00(m, 4H), 1.79-1.73 (m, 4H), 1.64-1.58 (m, 2H). MS (ES) mle 261 (M+1, 95 %).Further elution of column with (n-hexane:EtOAc 3:1) afforded the 2-methyl-5-nitro-6-(piperidin-1-yl)-2H-indazole (Isomer A, 87 mg, 24%) as a brown solid.Using the same reagents and conditions as described in step 5 of example 1, <strong>[1351813-02-9]6-bromo-5-nitro-1H-indazole</strong> (product of step 2 of example 5) (2.5g, 10.3 mmol) was methylated usingsodium hydride (520mg, 21.6 mmol) and methyl iodide (6.08g, 42.3 mmol) in THF (25mL) to get the crude product. This was purified by silica gel column chromatography and elution with 20% ethyl acetate in hexane gave the isomer A; 6-bromo-1-methyl-5-nitro-1H-indazole (1.4g, 52.95%).?HNMR (CDC13, 300MHz): oe 8.36 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 4.10 (s, 3H).Further elution with 50% ethyl acetate in hexane gave the isomer B; 6-bromo-2-methyl-5-nitro-2H-indazole(1. ig, 42.3%).?HNMR (DMSO-d6, 300MHz): oe 8.70 (s, 1H), 8.62 (s, 1H), 8.14 (s, 1H), 4.21 (s, 3H).

References: [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 38; 39; 55.

14
[ 1351813-02-9 ]
2-cyclopentyl-5-nitro-2H-indazole-6-carbonitrile [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

15
[ 1351813-02-9 ]
5-amino-2-cyclopentyl-2H-indazole-6-carbonitrile [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

16
[ 1351813-02-9 ]
2-cyclopentyl-6-cyclopropyl-5-nitro-2H-indazole [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

17
[ 1351813-02-9 ]
2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

18
[ 1351813-02-9 ]
N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

19
[ 1351813-02-9 ]
6-(cyclohex-1-en-1-yl)-2-methyl-5-nitro-2H-indazole [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

20
[ 1351813-02-9 ]
6-cyclohexyl-2-methyl-2H-indazol-5-amine [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

21
[ 1351813-02-9 ]
6-cyclopropyl-2-methyl-5-nitro-2H-indazole [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

22
[ 1351813-02-9 ]
6-cyclopropyl-2-methyl-2H-indazol-5-amine [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

23
[ 1351813-02-9 ]
N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

24
[ 1351813-02-9 ]
1,6-dicyclopropyl-5-nitro-1H-indazole [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

25
[ 1351813-02-9 ]
6-cyclopropyl-1-methyl-5-nitro-1H-indazole [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

26
[ 1351813-02-9 ]
6-cyclopropyl-1-methyl-1H-indazol-5-amine [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

27
[ 1351813-02-9 ]
N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

28
[ 1351813-02-9 ]
N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .
[2]Patent: US2016/326151,2016,A1 .

29
[ 1351813-02-9 ]
N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride [ No CAS ]

References: [1]Patent: WO2015/104662,2015,A1 .

30
[ 137-43-9 ]
[ 1351813-02-9 ]
6-bromo-2-cyclopentyl-5-nitro-2H-indazole [ No CAS ]
6-bromo-1-cyclopentyl-5-nitro-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%; 40%		A suspension of sodium hydride (0.160 g, 3.96 mmol) in dry DMF (5 mL) was cooled to0 C and <strong>[1351813-02-9]6-bromo-5-nitro-1H-indazole</strong> (0.8 g, 3.3 mmol) in dry DMF (5 mL) was added at thesame temperature and stined for 30 mm. Cyclopentyl bromide (0.59 g, 3.96 mmol) was added drop wise to the above mixture and continued stifling at room temperature for 12 h. After completion of reaction, reaction mixture was poured on crushed ice, extracted with EtOAc. Ethyl acetate layer was washed with water followed by brine and dried over anhydrous Na2SO4.Organic layer was concentrated under reduced pressure to obtain crude compound, the crude residue was purified by flash chromatography (n-hexane:EtOAc; 9:1) to give 6-bromo-1- cyclopentyl-5-nitro-1H-indazole (Isomer B, 0.4 g, 40 %) as a brown solid.?H NMR (400 MHz, DMSO-d6): oe 8.60 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 5.31-5.28 (m, 1H),2.18-2.11 (m, 2H), 2.01-1.86 (m, 4H), 1.73-1.67 (m, 2H). LCMS: mlz: 312 (M+1, 100 %).Further elution of the column under the same conditions gave 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (Isomer A, 0.3 g, 30 %) as a brown solid.?H NMR (400 MHz, DMSO-d6): oe 8.80 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 5.15-5.11 (m, 1H), 2.26-2.21 (m, 2H), 2. 19-2.04 (m, 2H), 1.90-1.86 (m, 2H), 1.73-1.68 (m, 2H). LCMS: mz: 312 (M+1).
30%; 40%		A suspension of sodium hydride (0.160 g, 3.96 mmol) in dry DMF (5 mL) was cooled to 0 C. and <strong>[1351813-02-9]6-bromo-5-nitro-1H-indazole</strong> (0.8 g, 3.3 mmol) in dry DMF (5 mL) was added at the same temperature and stirred for 30 min. Cyclopentyl bromide (0.59 g, 3.96 mmol) was added drop wise to the above mixture and continued stirring at room temperature for 12 h. After completion of reaction, reaction mixture was poured on crushed ice, extracted with EtOAc. Ethyl acetate layer was washed with water followed by brine and dried over anhydrous Na2SO4. Organic layer was concentrated under reduced pressure to obtain crude compound, the crude residue was purified by flash chromatography (n-hexane:EtOAc; 9:1) to give 6-bromo-1-cyclopentyl-5-nitro-1H-indazole (Isomer B, 0.4 g, 40%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): delta 8.60 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 5.31-5.28 (m, 1H), 2.18-2.11 (m, 2H), 2.01-1.86 (m, 4H), 1.73-1.67 (m, 2H). LCMS: m/z: 312 (M++1, 100%). Further elution of the column under the same conditions gave 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (Isomer A, 0.3 g, 30%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): delta 8.80 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 5.15-5.11 (m, 1H), 2.26-2.21 (m, 2H), 2.19-2.04 (m, 2H), 1.90-1.86 (m, 2H), 1.73-1.68 (m, 2H). LCMS: m/z: 312 (M+1)+.

References: [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 44; 45.
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0241; 0242; 0243.

31
[ 1351813-02-9 ]
[ 411235-57-9 ]
6-bromo-1-cyclopropyl-5-nitro-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.91%	With [2,2]bipyridinyl; copper acetylacetonate; sodium carbonate; In 1,2-dichloro-ethane; at 80℃; for 2h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the same reagents and conditions as described in step 1 of example 6, 6-bromo-5- nitro-1H-indazole (product of step 2 of example 5) (1gm, 4. 1322mmo1) was coupled with cyclopropyl boronic acid (7 10mg, 8.2644mmo1) using Cu(OAc)2 (901mg, 4.9586 mmol), 2,2-bipyridine (775mg, 4.9586mmo1) and sodium carbonate (1.314gm, 12.3966 mmol) in dichloroethane (20 mL) at 80C for 2h to get the crude compound. This was purified by silica gel column chromatography and elution with 1% methanol in DCM gave the title compound (500mg, 42.91%).?HNMR (CDC13, 300MHz): oe 8.34 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 3.64-3.57 (m, 1H), 1.25-1.24 (m, 4H). LCMS: 89.33%, mlz = 281.9 (M+1) .
42.91%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate; In dichloromethane; at 80℃; for 2h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid; Using the same reagents and conditions as described in step 1 of example 6, <strong>[1351813-02-9]6-bromo-5-nitro-1H-indazole</strong> (product of step 2 of example 5) (1 gm, 4.1322 mmol) was coupled with cyclopropyl boronic acid (710 mg, 8.2644 mmol) using Cu(OAc)2 (901 mg, 4.9586 mmol), 2,2'-bipyridine (775 mg, 4.9586 mmol) and sodium carbonate (1.314 gm, 12.3966 mmol) in dichloroethane (20 mL) at 80 C. for 2 h to get the crude compound. This was purified by silica gel column chromatography and elution with 1% methanol in DCM gave the title compound (500 mg, 42.91%). 1HNMR (CDCl3, 300 MHz): delta 8.34 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 3.64-3.57 (m, 1H), 1.25-1.24 (m, 4H). LCMS: 89.33%, m/z=281.9 (M+1)+.

References: [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 46; 72.
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0251; 0252; 0382; 0283.

32
[ 110-87-2 ]
[ 1351813-02-9 ]
6-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With toluene-4-sulfonic acid; In dichloromethane; at 5 - 20℃; for 0.333333h;	To a suspension of 6-bromo-5-nitro-1 H-indazole (1.03 g, 4.26 mmol) and DHP (717 mg, 8.25mmol) in DCM (10 mL) was added TsOH (146 mg, 0.825 mmol) at ii. The resulting mixturewas stirred at rt (5 C) for 20 mm. The reaction mixture was diluted with DCM (50 mL) and then washed with sat.Na2CO3 (30 mL) and brine, dried over MgSO4 and concentrated. The crude was purified by column chromatography (PE: EtOAc = 5: 1) to give the title compound (1.08 g, yield 78%) as an orange solid.D424 1H NMR (300 MHz, CDCI3): 6 8.35 (s, 1H), 8.14 (s, 1H), 8.00 (s, IH), 5.75-5.71 (m,1H), 4.04-3.99 (m IH), 3.82-3.74 (m, 1H), 2.54-2.41 (m, IH), 2.21-2.08 (m, 2H), 1.85-1.66 (m, 3H).
78%	With toluene-4-sulfonic acid; In dichloromethane; at 25℃; for 0.333333h;	To a suspension of 6-bromo-5-nitro-1 H-indazole (1.03 g, 4.26 mmol) and DHP (717 mg, 8.54 mmcl) in DCM (10 mL) was added TsOHH20 (146 mg, 0.77 mmol) at rt. The resulting mixture was stirred at rt (25 C) for 20 mm. The reaction mixture was diluted with DCM (50 mL) and then washed with sat. Na2CO3 (30 mL) and brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (PE:EtOAc 5:1)to give the title compound (1.08 g, yield: 78%) as an orange solid.1H NMR (300 MHz, CDCI3) 8.35 (s, 1H), 8.14 (s, IH), 8.00 (s, IH), 5.75-5.71 (m, IH),4.04-3.99 (m 1H), 3.82-3.74 (m, IH), 2.54-2.41 (m, 1H), 2.21-2.08 (m, 2H), 1.85-1.66 (m,3H).

References: [1]Patent: WO2017/12576,2017,A1 .Location in patent: Page/Page column 280.
[2]Patent: WO2018/137573,2018,A1 .Location in patent: Page/Page column 56.
[3]Patent: WO2018/137593,2018,A1 .Location in patent: Page/Page column 87.

33
[ 1142382-25-9 ]
[ 1351813-02-9 ]

References: [1]Patent: WO2017/12576,2017,A1 .
[2]Patent: WO2018/137593,2018,A1 .

34
1-(6-bromo-5-nitro-1H-indazol-1-yl)ethanone [ No CAS ]
[ 1351813-02-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;	To a solution of i-(6-bromo-5-nitro-1H-indazol-i-yl)ethanone (2.2 g, 7.8 mmol) in THF (10 mL) was added aqueous NaOH (5 M, 6 mL). The resulting mixture was stirred at rt for 1 h. DCM (100 mL) was added to extract the desired compound. The organic solution was washed with water (30 mL) and brine, dried over Na2SO4 and concentrated to give the title compound (1.0 g, yield 53%) as a brown solid which was used for next step directly.0423 1H NMR (300 MHz, DMSO-d6): 6 13.74 (s, 1H), 8.63 (s, 1H), 8.35 (s, IH), 8.07 (s, 1H).
53%	With water; sodium hydroxide; In tetrahydrofuran; at 25℃; for 1h;	To a solution of 1-(6-bromo-5-nitro-1H-indazol-1-yl)ethanone (2.2 g, 7.8 mmol) in THF (10 ml) was added aqueous NaOH (5 M, 6 ml). The resulting mixture was stirred at room temperature for 1 hour. DCM (100 mL) was added to extract the desired compound. The organic solution was washed with water (30 mL) and brine, dried over Na2SO4 and concentrated to give the title compound (1.0 g, yield: 53%) as a brown solid which was used for next step directly.1H NMR (300 MHz, DMSO-d6) O 13.74 (s, 1H), 8.63 (s, IH), 8.35 (s, 1H), 8.07 (s, 1H).

References: [1]Patent: WO2017/12576,2017,A1 .Location in patent: Page/Page column 279.
[2]Patent: WO2018/137573,2018,A1 .Location in patent: Page/Page column 56.
[3]Patent: WO2018/137593,2018,A1 .Location in patent: Page/Page column 86; 87.

35
[ 1351813-02-9 ]
(S)-(4-(6-(5-chloro-6-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indazol-1-yl)-2-methylpyrimidin-4-yl)morpholin-2-yl)methanol [ No CAS ]

References: [1]Patent: WO2017/12576,2017,A1 .

Historical Records

Technical Information

• Alkyl Halide Occurrence • General Reactivity • Grignard Reaction • Hiyama Cross-Coupling Reaction • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Dihalides • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling

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CAS No.: 1351813-02-9

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CAS No.: 1351813-02-9

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