89283-92-1|5-Bromo-4-chloropyridin-3-amine| Ambeed

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Quality Control of [ 89283-92-1 ] Purity: 98% SDS Specification

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Product Details of [ 89283-92-1 ]

CAS No. :	89283-92-1
Formula :	C₅H₄BrClN₂
M.W :	207.46
SMILES Code :	NC1=C(Cl)C(Br)=CN=C1
MDL No. :	MFCD12828485
InChI Key :	KAJRLYHBOIPDLW-UHFFFAOYSA-N
Pubchem ID :	53418432

Safety of [ 89283-92-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 89283-92-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	41.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.4
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	1.49
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	1.19
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	2.03
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.64

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.56
Solubility	0.574 mg/ml ; 0.00277 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.	-1.91
Solubility	2.53 mg/ml ; 0.0122 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-3.14
Solubility	0.15 mg/ml ; 0.000724 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.	-6.51 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	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)	1.69

Application In Synthesis of [ 89283-92-1 ]

* 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 [ 89283-92-1 ]

[ 89283-92-1 ] Synthesis Path-Downstream 1~24

2
[ 140-89-6 ]
[ 89283-92-1 ]
[ 108724-10-3 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5352 - 5362.

3
[ 89283-92-1 ]
8-(7-bromothiazolo[5,4-b]pyridin-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5352 - 5362.

4
[ 89283-92-1 ]
{2-[6-amino-8-(7-bromothiazolo[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-ethyl}-phosphonic acid diethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5352 - 5362.

5
[ 31872-63-6 ]
[ 89283-92-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With iron; ammonium chloride; In ethanol; water; at 80℃; for 2.0h;	To a solution of 3-bromo-4-chloro-5-nitropyridine (9.50 g, 40.01 mmol) in EtOH (500 mL) was added NH4CI (13.27 g, 248 mmol), water (50 ml), and Fe (22.39 g, 401 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80°C. Whenthe reaction was done, the solids were filtered off. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with 0percent to 60percent EtOAc in petrol ether to yield 5-bromo-4- chloropyridin-3-amine as a yellow oil (5.94 g, 72percent). MS: m/z = 209.2 [M+H].
	With ammonium chloride; zinc; In tetrahydrofuran; at 40℃; for 1.0h;	5-bromo-4-chloro-3-nitropyridine (5.0 g, 0.021 mol)Was dissolved in 50 mL of tetrahydrofuran,150 mL of saturated ammonium chloride solution and zinc dust (13 g, 0.21 mol) were added,Heated at 40 ° C for 1 hour,Cold to room temperature,Dispensing,The aqueous phase was washed with 100 mL of ethyl acetate,Combine organic phase,Washed with water (100 mL * 2 times) and saturated brine (50 mL * 2 times)Organic phase concentration,4.1 g of crude oil,Yield 92percent.

References: [1]Patent: WO2019/25099,2019,A1 .Location in patent: Page/Page column 142.
[2]Patent: CN106146533,2016,A .Location in patent: Paragraph 0475; 0477; 0478.

6
[ 89283-92-1 ]
ethyl 7-bromothiazolo[4,5-c]pyridine-2-carboxylate [ No CAS ]

References: [1]Patent: CN106146533,2016,A .

7
[ 89283-92-1 ]
[ 4755-77-5 ]
C₉H₈BrClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1.0h;	5-Bromo-4-chloro-3-aminopyridine (4.1 g, 0.020 mol)Was dissolved in 100 mL of tetrahydrofuran,Triethylamine (2.4 g, 0.024 mol) was added,The system was placed in an ice bath at 0 ° C,A solution of oxalyl chloride monoethyl ester (3.0 g, 0.022 mol)In tetrahydrofuran solution,Reaction at room temperature for 1 hour,Concentrated under reduced pressure,Ethyl acetate (100 mL) was added,Washed with saturated sodium bicarbonate solution (50 mL * 2 times)Dispensing,The organic phase was dried over anhydrous sodium sulfate,Concentrated under reduced pressure to dry,To give 5.5 g of crude solid,Yield 90.0percent.

References: [1]Patent: CN106146533,2016,A .Location in patent: Paragraph 0475; 0479; 0480.

8
4-(5-cyano-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)benzamide [ No CAS ]
[ 89283-92-1 ]
4-(3-(5-amino-4-chloropyridin-3-yl)-5-cyano-6-methyl-1H-indol-1-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 mg	With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; tricyclohexylphosphine; In water; isopropyl alcohol; at 100℃; for 2.0h;Inert atmosphere;	To a solution of 21 .3 (70 mg, 0.174 mmol), <strong>[89283-92-1]5-bromo-4-chloropyridin-3-amine</strong> (36.2 mg, 0.174 mmol), Na2C03 (37.0 mg, 0.349 mmol), Pd2(dba)3 (8 mg, 8.72 muetaiotaomicronIota) and tricyclophexylphosphine (10 mg, 0.035 mmol) in 2-Propanol (10 mL) was added water (3 mL). The mixture was stir at 100 °C for 2 hr under nitrogen protection. Remove most organic solvent in vacuum, then the residue was re-dissolved in DCM, washed with water; the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by CombiFlash, eluted with methanol in DCM (0-5percent, 30 min). Collected the desired fraction to afford 40 mg brown syrup, it was further purified by basic Prep-HPLC (0.1 percent NH4OH/ACN/H20).Collected the desired fraction and lyophilized to afford 10 mg title compound as off-white powder. 1 H NMR (400 MHz, Methanol-^) delta 8.22 - 8.05 (m, 3H), 7.96 (d, J= 15.9 Hz, 1 H), 7.87 (s, 2H), 7.79 - 7.71 (m, 2H), 7.65 (d, J = 0.9 Hz, 1 H), 2.63 (d, J= 0.8 Hz, 3H). LC-MS: [M+H]+ = 401 .8, 402.8.

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00216.

9
2,6-dimethyl-1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
3-(5-amino-4-chloropyridin-3-yl)-2,6-dimethyl-1-(phenylsulfonyl)-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 80℃; for 5.0h;Inert atmosphere;	In a 25 mL round-bottomed flask were added K3P04 (63.2 mg, 0.298 mmol), 25.2 (65 mg, 0.149 mmol), xphos Pd G2( 20mg, 0.025mmol) and R1 (30.9 mg, 0.149 mmol) . The reaction was evacuated and filled with N2 for three times. Dioxane (4 mL) and water (1 mL) were added. The reaction was heated to 80 °C for 5h under N2 protection. The reaction was cooled to r.t. and quenched with NH4CI (aq). The combined organic phase was washed with brine and dried over Na2S04, concentrated and purified by column chromatography on silica gel (eluent: PE/EA=10:1 -2:1 ) to give the title compound (30mg, 46percent) as a yellow solid. LC-MS: [M+H]+= 436.9.

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00234.

10
2,6-dimethyl-1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
3-(5-amino-4-chloropyridin-3-yl)-2,6-dimethyl-1H-indole-5-carbonitrile [ No CAS ]

References: [1]Patent: WO2018/234978,2018,A1 .

11
trans-6-methyl-1-(3-(methylsulfonyl)cyclopentyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
trans-3-(5-amino-4-chloropyridin-3-yl)-6-methyl-1-(3-(methylsulfonyl)cyclopentyl)-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.8%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; at 100℃; for 3.0h;Inert atmosphere;	A solution of 37.4 (170 mg, 0.278 mmo), Na2C03 (58.9 mg, 0.556 mmol) 5- bromo-4-chloropyridin-3-amine (57.6 mg, 0.278 mmol), Pd(PPh3)2CI2 (19.50 mg, 0.028 mmol) in 2-Propanol (3 mL) was added water (1 mL). The mixture was degassed with nitrogen three times. Then the mixture was stirred at 100 °C for 1 hr under nitrogen protection. The mixture was diluted with ethyl acetate, washed with water; the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue purified with basic Prep-HPLC (0.1 percent NH4OH/ACN/H20). Collected the desired fraction and lyophilized to afford the title compound (8.2 mg, 6.8percent) as white powder. 1 H NMR (400 MHz, Methanol-^) delta 8.06 (s, 1 H), 7.86 (s, 1 H), 7.78 (s, 1 H), 7.73 (s, 1 H), 7.59 (s, 1 H), 5.17 (p, J= 7.4 Hz, 1 H), 4.08 - 3.87 (m, 1 H), 3.01 (s, 3H), 2.76 (ddd, J= 13.8, 7.8, 5.4 Hz, 1 H), 2.65 (s, 3H), 2.53 - 2.12 (m, 5H). LC-MS: [M+H]+ = 428.9, 430.9.

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00264.

12
1-((1r,3r)-3-cyanocyclobutyl)-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
3-(5-amino-4-chloropyridin-3-yl)-1-((1r,3r)-3-cyanocyclobutyl)-6-methyl-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; at 100℃; for 3.0h;Inert atmosphere;	To a solution of 1 .7 (200 mg, 0.526 mmol), Na2C03 (1 1 1 mg, 1 .05 mmol), Pd(PPh3)2CI2 (36.9 mg, 0.053 mmol) and 3-bromo-4-fluoro-2-methylaniline (204 mg, 0.526 mmol) in 2-Propanol (5 mL) was added water (1 .5 mL). The mixture was stirred at 100 °C for 3 hr under nitrogen protection. Removed the most organic solvents in vacuum, the residue was extracted with DCM twice, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by CombiFlash, eluted with methanol in DCM (0-5percent, 30 min). Collected the desired fraction to afford a brown solid, it was further purified by acidic Prep-HPLC (0.1percent (0672) TFA/ACN/H20). The desired fraction was lyophilized to give the title compounds

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00237; 00273.

13
6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
3-(5-amino-4-chloropyridin-3-yl)-6-methyl-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; at 100℃; for 2.0h;Inert atmosphere;	To a solution of 43.1 (1 .3 g, 4.61 mmol), <strong>[89283-92-1]5-bromo-4-chloropyridin-3-amine</strong> (1 .004 g, 4.84 mmol), Na2C03 (0.977 g, 9.22 mmol), Pd(PPh3)2CI2 (0.323 g, 0.461 mmol) in 2-Propanol (25 mL) was added water (8 mL). The mixture was stir at 100 °C for 2 hr under nitrogen protection. Then the mixture was diluted with DCM, washed with water, brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by CombiFlash, eluted with methanol in DCM (0-5percent, 30 min). Collected the desired fraction and concentrated in vacuum to afford the title compound (1 .1 g, 84percent) as off-white solid. 1 H NMR (400 MHz, DMSO-d6) delta 11.89 (d, J = 2.6 Hz, 1 H), 8.07 (s, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H), 7.72 (d, J = 2.5 Hz, 1 H), 7.49 (s, 1 H), 5.73 (s, 2H), 2.56 (s, 3H). LC-MS: [M+H]+ = 283.1 , 285.1 .

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00286.

14
1-(4-hydroxycyclohexyl)-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
3-(5-amino-4-chloropyridin-3-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-6-methyl-1H-indole-5-carbonitrile [ No CAS ]
3-(5-amino-4-chloropyridin-3-yl)-1-((1s,4s)-4-hydroxycyclohexyl)-6-methyl-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.4%; 1.9%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; at 100℃; for 3.0h;Inert atmosphere;	To a solution of 1 .7 (200 mg, 0.526 mmol), Na2C03 (1 1 1 mg, 1 .05 mmol), Pd(PPh3)2CI2 (36.9 mg, 0.053 mmol) and <strong>[89283-92-1]5-bromo-4-chloropyridin-3-amine</strong> (109 mg, 0.526 mmol) in 2-propanol (5 mL) was added water (1 .5 mL). The mixture was stirred at 100 °C for 3 r under nitrogen protection. Removed the most organic solvents in vacuum, the residue was extracted with DCM twice, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by CombiFlash, eluted with methanol in DCM (0-5percent, 30 min). Collected the desired fraction to afford a brown solid, it was further purified by acidic prep-HPLC. Collected the desired fractions and lyophilized to afford the title compound Example 1 (36.7 mg, 13.4percent) and the title compound Example 2 (5.3 mg,1 .9percent) as pink powder. (0381) Example 1 : 1 H NMR (400 MHz, Methanol-^) delta 8.14 (s, 1 H), 8.08 (s, 1 H), 7.94 - 7.86 (m, 2H), 7.66 (s, 1 H), 4.51 (td, J= 10.5, 9.4, 6.3 Hz, 1 H), 3.83 - 3.61 (m, 1 H), 2.66 (s, 3H), 2.21 - 2.06 (m, 4H), 2.04 - 1 .87 (m, 2H), 1 .63 (q, J = 12.4, 1 1 .9 Hz, 2H). LC-MS: [M+H]+ = 380.9, 382.0. (0382) Example 2: 1 H NMR (400 MHz, Methanol-^) delta 8.1 1 (d, J= 12.5 Hz, 2H), 7.91 (s, 2H), 7.67 (s, 1 H), 4.53 (t, J = 12.3 Hz, 1 H), 4.1 1 (d, J= 3.1 Hz, 1 H), 2.66 (s, 3H), 2.38 - 2.19 (m, 2H), 2.00 (d, J= 13.6 Hz, 2H), 1 .94 - 1 .81 (m, 4H). LC-MS: [M+H]+ = 380.9, 382.0. Example 3: 3-(5-amino-4-(difluoromethyl)pyridin-3-yl)-1 -((1 R,4R)-4-hydroxycyclohexyl)-6- methyl-1 H-indole-5-carbonitrile

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00154.

15
trans-1-(3-hydroxycyclohexyl)-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carbonitrile [ No CAS ]
[ 89283-92-1 ]
trans-3-(5-amino-4-chloropyridin-3-yl)-1-(3-hydroxycyclohexyl)-6-methyl-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; at 100℃; for 3.0h;Inert atmosphere;	To a solution of 1 .7 (200 mg, 0.526 mmol), Na2C03 (1 1 1 mg, 1 .05 mmol), Pd(PPh3)2CI2 (36.9 mg, 0.053 mmol) and <strong>[89283-92-1]5-bromo-4-chloropyridin-3-amine</strong> (109 mg, 0.526 mmol) in 2-propanol (5 mL) was added water (1 .5 mL). The mixture was stirred at 100 °C for 3 r under nitrogen protection. Removed the most organic solvents in vacuum, the residue was extracted with DCM twice, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by CombiFlash, eluted with methanol in DCM (0-5percent, 30 min). Collected the desired fraction to afford a brown solid, it was further purified by acidic prep-HPLC. Collected the desired fractions and lyophilized to afford the title compound Example 1 (36.7 mg, 13.4percent) and the title compound Example 2 (5.3 mg,1 .9percent) as pink powder. (0381) Example 1 : 1 H NMR (400 MHz, Methanol-^) delta 8.14 (s, 1 H), 8.08 (s, 1 H), 7.94 - 7.86 (m, 2H), 7.66 (s, 1 H), 4.51 (td, J= 10.5, 9.4, 6.3 Hz, 1 H), 3.83 - 3.61 (m, 1 H), 2.66 (s, 3H), 2.21 - 2.06 (m, 4H), 2.04 - 1 .87 (m, 2H), 1 .63 (q, J = 12.4, 1 1 .9 Hz, 2H). LC-MS: [M+H]+ = 380.9, 382.0. (0382) Example 2: 1 H NMR (400 MHz, Methanol-^) delta 8.1 1 (d, J= 12.5 Hz, 2H), 7.91 (s, 2H), 7.67 (s, 1 H), 4.53 (t, J = 12.3 Hz, 1 H), 4.1 1 (d, J= 3.1 Hz, 1 H), 2.66 (s, 3H), 2.38 - 2.19 (m, 2H), 2.00 (d, J= 13.6 Hz, 2H), 1 .94 - 1 .81 (m, 4H). LC-MS: [M+H]+ = 380.9, 382.0. Example 3: 3-(5-amino-4-(difluoromethyl)pyridin-3-yl)-1 -((1 R,4R)-4-hydroxycyclohexyl)-6- methyl-1 H-indole-5-carbonitrile

References: [1]Patent: WO2018/234978,2018,A1 .Location in patent: Paragraph 00154; 00175.

16
[ 89283-92-1 ]
4-methoxymethyl-N-[4-methoxy-7-(1-methyl-1H-pyrazol-4-yl)thiazolo[4,5-c]pyridin-2-yl]benzamide [ No CAS ]