[ CAS No. 1346575-64-1 ] {[proInfo.proName]}

Name: 1346575-64-1|3-(Aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one|97%
Brand: Ambeed
SKU: A128735
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Quality Control of [ 1346575-64-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1346575-64-1 ]

SDS Specification

Alternatived Products of [ 1346575-64-1 ]

Product Details of [ 1346575-64-1 ]

CAS No. :	1346575-64-1	MDL No. :	MFCD25541770
Formula :	C₁₀H₁₆N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JBKWKHWTUAUEFI-UHFFFAOYSA-N
M.W :	180.25	Pubchem ID :	67124140
Synonyms :

Calculated chemistry of [ 1346575-64-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	54.28
TPSA :	58.88 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.82
Log Po/w (XLOGP3) :	0.89
Log Po/w (WLOGP) :	0.94
Log Po/w (MLOGP) :	1.01
Log Po/w (SILICOS-IT) :	2.69
Consensus Log Po/w :	1.47

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.66
Solubility :	3.93 mg/ml ; 0.0218 mol/l
Class :	Very soluble
Log S (Ali) :	-1.71
Solubility :	3.5 mg/ml ; 0.0194 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.56
Solubility :	0.0495 mg/ml ; 0.000275 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.06

Safety of [ 1346575-64-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1346575-64-1 ]

* 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.

Upstream synthesis route of [ 1346575-64-1 ]
Downstream synthetic route of [ 1346575-64-1 ]

[ 1346575-64-1 ] Synthesis Path-Upstream 1~3

1
[ 5609-09-6 ]
[ 1346575-64-1 ]

Reference： [1] Patent: WO2011/140325, 2011, A1,
[2] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 12, p. 1091 - 1096

2
[ 5609-09-6 ]
[ 1346575-64-1 ]

Reference： [1] Patent: WO2016/73956, 2016, A1,

3
[ 1346575-64-1 ]
[ 1346704-33-3 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 12, p. 1091 - 1096

[ 1346575-64-1 ] Synthesis Path-Downstream 1~87

Yield	Reaction Conditions	Operation in experiment
60%	With sodium tetrahydroborate; iodine; In tetrahydrofuran; for 3.5h;Cooling with ice; Reflux;	General procedure: 3b) 3-(Aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone To an ice-bath cooled THF (100 mL) solution of the product from step 1 (2 g, 9.26mmol) was added NaBH4 (0.81 g, 21.3 mmol) and h (2.3 g, 9.26 mmol), and the mixturestirred for 30 min The reaction mixture was then heated at reflux for 3 h, and then allowedto cool to room temperature. After cooling to 0 C, the reaction mixture was acidified byslow addition of 3 N HCl (1 mL). The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase HPLC to give 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone as a solid (0.5 g, 25%).
60%	With sodium tetrahydroborate; iodine; In tetrahydrofuran; for 3.5h;Inert atmosphere; Cooling with ice; Reflux;	General procedure: To an ice-bath cooled THF (100 mL) solution of the product from step 1 (2 g, 9.26 mmol) was added NaBH4 (0.81 g, 21.3 mmol) and I2 (2.3 g, 9.26 mmol), and the mixture stirred for 30 min. The reaction mixture was then heated at reflux for 3 h, and then allowed to cool to room temperature. After cooling to 0 C., the reaction mixture was acidified by slow addition of 3 N HCl (1 mL). The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase HPLC to give 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone as a solid (0.5 g, 25%). LCMS E-S (M+H)=221.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.8-11.9 (br s, 1H), 7.80-7.93 (br s, 3H), 6.07 (s, 1H), 3.69 (s, 2H), 2.67-2.75 (m, 1H), 2.17 (s, 3H), 1.58-1.72 (m, 5H), 1.19-1.41 (m, 5H).
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 4h;	General procedure: Tert-butyl ((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamate (40 g, 0.27 mol)was added into dioxane/HCl (1 L)and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtrated and concentrated to give crude product. The crude was washed with ethyl acetate (lOOmL x 2) and EtOH (50mL x 1) and concentrated to afford the title compound as its HCI salt (15 g, 40 %). LCMS (M + H+) m/z: calc'd. 152.19; found153.1. 1H NMR (DMSO, 400MHz) delta 11.84 (s, 1H), 8.07 (s, 3H), 5.96 (s, 1H), 3.76-7.75(d, J = 5.6 Hz, 2H), 2.21 (s, 3H), 2.15 (s, 3H).

With borane-THF; In tetrahydrofuran; at 85℃; for 2h;

General procedure: Step 1: To a solution of compound 12a-1 (2 g, 10 mmol) in THF (5 mL) was added dropwise borane-tetrahydrofuran (100 mL, 1M) at room temperature, the system was slowly raised to 85 C. and stirred for 2 hours. The mixture was cooled to room temperature, quenched with methanol and concentrate to give 1.95 g of white solid compound 12a-2. MS m/z (ESI): 204 [M+H]+.

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[ 1346575-64-1 ]
[ 1346575-63-0 ]
[ 1346575-01-6 ]

Yield	Reaction Conditions	Operation in experiment
19%		c) 6-(2-Dimethylamino-ethoxy)-l-isopropyl-lH-indole-4-carboxylic acid (6-methyl-2-oxo-4- propyl-1 , 2-dihydro-pyridin-3-ylmeth l)-amide To a cooled (0 C) mixture of 6-(2-dimethylamino-ethoxy)-l-isopropyl-lH-indole-4- carboxylic acid (400 mg, 1.37 mmol) in DMF (10 mL) was added EDC.HC1 (310 mg, 1.65 mmol) and HOBt.H20 (250 mg, 1.65 mmol). The reaction was stirred for 15 min, then DIPEA (1.2 mL, 6.89 mmol) and 3-aminomethyl-6-methyl-4-propyl-lH-pyridin-2-one (240 mg, 1.37 mmol) were added. The reaction was allowed to warm to RT and stirred for 16 h, at which time it was diluted with water (20 mL) and extracted with DCM (2x15 mL). The combined DCM layer was dried over Na2S04 and concentrated. The residue was purified by flash column chromatography eluting with 3% MeOH in chloroform and then further purified by preparative HPLC to furnish 6-(2-dimethylamino-ethoxy)-l-isopropyl-lH-indole-4- carboxylic acid (6-methyl-2-oxo-4-propyl-l,2-dihydro-pyridin-3-ylmethyl)-amide (120 mg, 19%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): delta 0.92-0.88 (t, 3H), 1.43-1.41 (d, J = 6.8 Hz, 6H), 1.56 (m, 2H), 2.12 (s, 3H), 2.22 (s, 6H), 2.55-2.53 (m, 2H), 2.06 (m, 2H), 4.11-4.09 (t, 2H), 4.36-4.34 (d, J = 4.8 Hz, 2H), 4.76-4.73 (m, 1H), 5.90 (s, 1H), 6.74-6.73 (d, J = 2.8 Hz, 1H), 7.04 (s, 1H), 7.20 (s, 1H), 7.43-7.42 (d, J=3.2 Hz, 1H), 8.10-8.07 (bs, 1H), 11.55 (bs, 1H). LCMS (ES+): m/z= 453.23[M+H].
19%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	To a cooled (0 C.) mixture of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg, 1.37 mmol) in DMF (10 mL) was added EDC.HCl (310 mg, 1.65 mmol) and HOBt.H2O (250 mg, 1.65 mmol). The reaction was stirred for 15 min, then DIPEA (1.2 mL, 6.89 mmol) and <strong>[1346575-64-1]3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one</strong> (240 mg, 1.37 mmol) were added. The reaction was allowed to warm to RT and stirred for 16 h, at which time it was diluted with water (20 mL) and extracted with DCM (2×15 mL). The combined DCM layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 3% MeOH in chloroform and then further purified by preparative HPLC to furnish 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (120 mg, 19%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): delta 0.92-0.88 (t, 3H), 1.43-1.41 (d, J=6.8 Hz, 6H), 1.56 (m, 2H), 2.12 (s, 3H), 2.22 (s, 6H), 2.55-2.53 (m, 2H), 2.06 (m, 2H), 4.11-4.09 (t, 2H), 4.36-4.34 (d, J=4.8 Hz, 2H), 4.76-4.73 (m, 1H), 5.90 (s, 1H), 6.74-6.73 (d, J=2.8 Hz, 1H), 7.04 (s, 1H), 7.20 (s, 1H), 7.43-7.42 (d, J=3.2 Hz, 1H), 8.10-8.07 (bs, 1H), 11.55 (bs, 1H). LCMS (ES+): m/z=453.23 [M+H].

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 104
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0613

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[ 1346575-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;Inert atmosphere;	e) l-(l-Methylethyl)-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydro-3-pyridinyl)methyl]-7- (methyloxy)-lH-indole-4-carboxamideAdded l-(l-methylethyl)-7-(methyloxy)-lH-indole-4-carboxylic acid (160 mg, 0.686 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(lH)-pyridinone (186 mg, 0.857 mmol), 1- hydroxy-7-azabenzotriazole (187 mg, 1.372 mmol), EDC (263 mg, 1.372 mmol) and N- methylmorpholine (0.302 mL, 2.74 mmol) to DMSO (10 mL) and stirred mixture at RT for 16 h. Added 25 ml of water and stirred for 10 minutes. Filtered off solids and dried in vacuo. The solids were purified by column chromatography (Biotage; 0% to 15% gradient MeOH:DCM; 10g-HP- silica gel column) to give 165 mg of l-(l-methylethyl)-N-[(6-methyl- 2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-7-(methyloxy)- lH-indole-4-carboxamide. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.01 (t, 3 H), 1.45 (d, J=6.57 Hz, 6 H), 1.63 (m, J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2 H), 2.24 (s, 3 H), 2.74 (t, J=7.58 Hz, 2 H), 3.96 (s, 3 H), 4.64 (br. s., 2 H), 5.45 (quin, J=6.63 Hz, 1 H), 5.97 (s, 1 H), 6.62 (d, J=8.08 Hz, 1 H), 6.94 (d, J=3.28 Hz, 1 H), 7.24 (d, J=3.28 Hz, 1 H), 7.53 (d, J=8.08 Hz, 1 H), 7.74 (br. s., 1 H), 12.46 (br. s., 1 H). MS(ES) [M+H]+ 395.7.
165 mg	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;Inert atmosphere;	Added 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylic acid (160 mg, 0.686 mmol), <strong>[1346575-64-1]3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone</strong> (186 mg, 0.857 mmol), 1-hydroxy-7-azabenzotriazole (187 mg, 1.372 mmol), EDC (263 mg, 1.372 mmol) and N-methylmorpholine (0.302 mL, 2.74 mmol) to DMSO (10 mL) and stirred mixture at RT for 16 h. Added 25 ml of water and stirred for 10 minutes. Filtered off solids and dried in vacuo. The solids were purified by column chromatography (Biotage; 0% to 15% gradient MeOH:DCM; 10 g-HP-silica gel column) to give 165 mg of 1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-7-(methyloxy)-1H-indole-4-carboxamide. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.01 (t, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.63 (m, J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2H), 2.24 (s, 3H), 2.74 (t, J=7.58 Hz, 2H), 3.96 (s, 3H), 4.64 (br. s., 2H), 5.45 (quin, J=6.63 Hz, 1H), 5.97 (s, 1H), 6.62 (d, J=8.08 Hz, 1H), 6.94 (d, J=3.28 Hz, 1H), 7.24 (d, J=3.28 Hz, 1H), 7.53 (d, J=8.08 Hz, 1H), 7.74 (br. s., 1H), 12.46 (br. s., 1H). MS(ES) [M+H]+ 395.7.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 136-137
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0700

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[ 1346575-88-9 ]
[ 1346575-49-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	b) 6-Chloro- 1 -isopropyl-2,3-dimethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)- lH-indole-4-carboxamide To a stirred solution of methyl 6-chloro- l-isopropyl-2,3-dimethyl-lH-indole-4-carboxylate (320 mg, 1.144 mmol) in Methanol (12 mL) and Tetrahydrofuran (THF) (4 mL) was added 1 N NaOH (4 mL, 4.00 mmol). The reaction was refluxed (70 C oil bath) for 18 h. The reaction was concentrated under vacuum, diluted with water, acidified with 1 N HC1 (4 mL), filtered, washed with water and dried under vacuum to give the carboxylic acid (0.30 g, 1.14 mmol, 100%) as a light yellow solid. MS(ES)+ m/e 266.1 [M+H]+. To the carboxylic acid above was added 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)- one (230 mg, 1.276 mmol), HOAt (160 mg, 1.176 mmol), Dichloromethane (12 mL) and N,N- Dimethylformamide (4.00 mL) to dissolve. With stirring was added EDC free base (210 mg, 1.353 mmol) and the reaction stirred at RT for 3 hr. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum then purified by silica gel chromatography (SF25- 40 g, 50 to 100% EtOAc in CH2C12) (streaked off). The pure fractions were combined and evaporated under vacuum. The remaining solid was triturated with 25% CH2C12 in hexanes, filtered, washed with hexanes and dried under vacuum to give the product 6-chloro- l-isopropyl-2,3-dimethyl-N-((6- methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-4-carboxamide (431 mg, 1.007 mmol, 88% yield) as an off-white solid. lB NMR (400MHz ,DMSO-d6) delta = 1 1.49 (s, 1 H), 8.16 (t, J = 5.1 Hz, 1 H), 7.58 (d, J= 1.8 Hz, 1 H), 6.82 (d, J= 1.8 Hz, 1 H), 5.89 (s, 1 H), 4.75 (dt, J= 6.9, 13.9 Hz, 1 H), 4.31 (d, J= 5.1 Hz, 2 H), 2.52 ( 2H under DMSO), 2.33 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 3 H), 1.61 - 1.51 (m, 2 H), 1.49 (d, J= 6.8 Hz, 6 H), 0.94 (t, J= 7.3 Hz, 3 H). MS(ES)+ m/e 428.3[Mu+Eta .
88%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	To the carboxylic acid above was added <strong>[1346575-64-1]3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one</strong> (230 mg, 1.276 mmol), HOAt (160 mg, 1.176 mmol), Dichloromethane (12 mL) and N,N-Dimethylformamide (4.00 mL) to dissolve. With stirring was added EDC free base (210 mg, 1.353 mmol) and the reaction stirred at RT for 3 hr. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum then purified by silica gel chromatography (SF25-40g, 50 to 100% EtOAc in CH2Cl2) (streaked off). The pure fractions were combined and evaporated under vacuum. The remaining solid was triturated with 25% CH2Cl2 in hexanes, filtered, washed with hexanes and dried under vacuum to give the product 6-chloro-1-isopropyl-2,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamide (431 mg, 1.007 mmol, 88% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta=11.49 (s, 1H), 8.16 (t, J=5.1 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 5.89 (s, 1H), 4.75 (dt, J=6.9, 13.9 Hz, 1H), 4.31 (d, J=5.1 Hz, 2H), 2.52 (2H under DMSO), 2.33 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.61-1.51 (m, 2H), 1.49 (d, J=6.8 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H). MS(ES)+ m/e 428.3 [M+H]+.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 138-139
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0709

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6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride [ No CAS ]
[ 1346575-50-5 ]

Yield	Reaction Conditions	Operation in experiment
63.2%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; for 2h;Inert atmosphere;	c) 6-Chloro-2-((dimethylamino)methyl)- 1 -isopropyl-3 -methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-4-carboxamide To 6-chloro-2-((dimethylamino)methyl)- 1 -isopropyl-3 -methyl- 1 H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol), 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one (0.22 g, 1.221 mmol), HOAt (0.17 g, 1.249 mmol) was added Dichloromethane (16 mL), N,N- Dimethylformamide (4 mL) and N-methylmorpholine (135 1.228 mmol). The mixture was stirred and EDC free base (0.20 g, 1.288 mmol) was added. After stirring for 2 hr LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum and purified by silica gel chromatography (Analogix, SF25-60g, 0 to 8% (5% NH4OH in MeOH) in CH2C12). The pure fractions were combined, evaporated to dryness then taken up in 20% EtOAc in hexanes.Scratching crystallized out the product which was filtered and washed with hexanes to give the product 6-chloro-2-((dimethylamino)methyl)- 1 -isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-4-carboxamide (362 mg, 0.769 mmol, 63.2% yield) as an off- white solid. ¾ NMR (400MHz ,DMSO-d6) delta = 1 1.49 (s, 1 H), 8.24 (t, J= 4.9 Hz, 1 H), 7.61 (d, J = 1.8 Hz, 1 H), 6.83 (d, J= 1.8 Hz, 1 H), 5.89 (s, 1 H), 4.91 (quin, J= 7.0 Hz, 1 H), 4.31 (d, J= 5.1 Hz, 2 H), 3.47 (s, 2 H), 2.52 (2H under DMSO), 2.14 (s, 6 H), 2.12 (s, 3 H), 2.10 (s, 3 H), 1.62 - 1.53 (m,2 H), 1.51 (d, J = 7.1 Hz, 6 H), 0.94 (t, J = 7.3 Hz, 3 H). MS(ES)+ m/e 471.3 [M+H]+.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 140-141

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[ 1346575-64-1 ]
[ 1346576-82-6 ]
[ 1346576-80-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	b) 2-(2-Aminoethyl)-6-chloro- l-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-4-carboxamide 3) 4 N HCI/dioxane 3 -Methyl- lH-indole-4-carboxylate (140 mg, 0.342 mmol) in Methanol (9 mL) andTetrahydrofuran (3 mL) was added 1 N NaOH (2 mL, 2.000 mmol). The reaction was refluxed (70 C oil bath) for 18 h (reaction proceeded very slowly at 60 C with only 1 mL 1 N NaOH). The reaction was concentrated under vacuum, diluted with water, acidified with 1 N HC1 (2 mL), filtered, washed with water and dried under vacuum to give the carboxylic acid (0.14 g, 0.354 mmol, 100%) as a white solid. MS(ES)+ m/e 395.0 [M+H]+. To the carboxylic acid above was added 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)- one (80 mg, 0.444 mmol), HOAt (60 mg, 0.441 mmol), Dichloromethane (12 mL) and N,N- Dimethylformamide (3.00 mL) to dissolve. With stirring was added EDC free base (70 mg, 0.451 mmol) and the reaction stirred at RT overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum then purified by silica gel chromatography (SF25- 40g, 50 to 100% EtOAc in CH2C12) to give the Boc protected final product (0.20 g, 3.59 mmol, 100%) as a white solid. MS(ES)+ m/e 557.3 [M+H]+. The above was dissolved with MeOH (5 mL) then treated, while stirring, with a solution of 4 N HCl in dioxane (10 mL, 40.0 mmol). The reaction was stirred for 30 minutes then evaporated to dryness under vacuum. The solid was triturated with Et20, filtered, washed with hexanes and dried under vacuum to give the product 2-(2-aminoethyl)-6-chloro- l-isopropyl-3-methyl-N-((6-methyl-2- oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-4-carboxamide hydrochloride salt (161 mg,0.326 mmol, 95% yield) as a light yellow solid. MS(ES)+ m/e 457.2 [M+H]+.
100%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To the carboxylic acid above was added <strong>[1346575-64-1]3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one</strong> (80 mg, 0.444 mmol), HOAt (60 mg, 0.441 mmol), Dichloromethane (12 mL) and N,N-Dimethylformamide (3.00 mL) to dissolve. With stirring was added EDC free base (70 mg, 0.451 mmol) and the reaction stirred at RT overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum then purified by silica gel chromatography (SF25-40g, 50 to 100% EtOAc in CH2Cl2) to give the Boc protected final product (0.20 g, 3.59 mmol, 100%) as a white solid. MS(ES)+ m/e 557.3 [M+H]+.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 142-143
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0722

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[ 5609-09-6 ]
[ 1346575-64-1 ]

Reference： [1]Patent: WO2011/140325,2011,A1
[2]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1091 - 1096

8
[ 1346575-64-1 ]
[ 1346704-24-2 ]

Reference： [1]Patent: WO2011/140325,2011,A1

9
[ 1346575-64-1 ]
[ 1347232-05-6 ]

Reference： [1]Patent: WO2011/140325,2011,A1

10
[ 1346575-64-1 ]
[ 1346702-73-5 ]

Reference： [1]Patent: WO2011/140325,2011,A1

11
[ 1346575-64-1 ]
[ 1346702-87-1 ]

Reference： [1]Patent: WO2011/140325,2011,A1

12
[ 1346575-64-1 ]
[ 1346702-88-2 ]

Reference： [1]Patent: WO2011/140325,2011,A1

13
[ 1346575-64-1 ]
[ 1346702-54-2 ]
[ 1346702-61-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃;Inert atmosphere;	Example 1016-Bromo-l-(l-methylethyl)-N-[(6-methyl-2-oxo-4^ropyl-l,2-dihydro-3-pyridinyl)methyl]-lH- indazole-4-carboxamide6-Bromo-l-(l-methylethyl)-lH-indazole-4-carboxylic acid (80 mg, 0.28 mmol), 3- (aminomethyl)-6-methyl-4-propyl-2(lH)-pyridinone (112 mg, 0.38 mmol) and l-hydroxy-7- azabenzotriazole (57.7 mg, 0.42 mmol) were stirred in 3 mL of DMSO for 10 min under nitrogen. N- Methylmorpholine (0.12 ml, 1.13 mmol) was added along with EDC (81 mg, 0.42 mmol) and the mixture was stirred at room temperature overnight under nitrogen. Ice-water was added and solids crashed out. Then 10% K2C03 was added to adjust the pH to about 8-9. Then the reaction was stirred at room temperature for 10 min and let stand for 10 min. Solids were filtered off, dissolved in DMF and water was added. Solids that precipitated out were filtered off, air-dried for 15 min and dried in vacuum oven for 2 h to give the title compound (94 mg, 73%). ¾ NMR (400 MHz, DMSO-J6) delta ppm 11.54 (s, 1 H) 8.62 (t, J=4.93 Hz, 1 H) 8.37 (s, 1 H) 8.20 (s, 1 H) 7.69 (d, J=1.26 Hz, 1 H) 5.91 (s, 1 H) 5.06 (dt, J=13.14, 6.57 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.14 (s, 3 H) 1.48 - 1.56 (m, 2 H) 1.47 (s, 3 H) 1.45 (s, 3 H) 0.89 (t, J=7.33 Hz, 3 H); MS(ES) [M+H]+ 445.1, 446.9.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 124
[2]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1091 - 1096

14
[ 1346575-64-1 ]
[ 1346702-94-0 ]
[ 1346702-92-8 ]

Yield	Reaction Conditions	Operation in experiment
		c) N-((l,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-l-isopropyl-6-(lH-pyrazol-4- yl)-lH-indazole-4-carboxamideTo a stirred solution of N-((l,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-l-isopropyl-6- (lH-pyrazol-4-yl)-lH-indazole-4-carboxamide (550 mg, 2.037mmol) in DCM (20 mL) were added EDC HCl (466 mg, 2.44 mmol), HOBT (374 mg, 2.44 mmol) and DIPEA (1.8 mL, 10.18 mmol) and the contents stirred at room temperature for 15 min. To the resulting mixture 3-(amino methyl)-4,6- dimethylpyridin-2(lH)-one (338 mg, 2.037 mmol) was added and stirred at RT for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL). The DCM layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford 200 mg of crude product. The crude product was diluted with DCM (5 mL), filtered, and dried to afford N-((l,2-dihydro-6-methyl- 2-oxo-4-propylpyridin-3 -yl)methyl)- 1 -isopropyl-6-(l H-pyrazol-4-yl)- 1 H-indazole-4-carboxamide as an off-white solid (80 mg, 10%).^ NMR(DMSO-d6, 400 MHz): delta 0.907-0.87 l(t, 3H, J = 14.4 Hz), 1.55-1.48 (m, 8H), 2.134 (s, 3H), 2.555 (s, 2H), 4.417-4.406 (d, 1H, J = 4.4 Hz), 5.059 (m, 1H), 5.913 (s, 1H), 7.830 (s, 1H), 8.047 (s, 1H), 8.080 (s, 1H), 8.306 (s, 2H), 8.462 (s, 1H), 1 1.53 (s, 1H), 13 (bs, 1H). LCMS (ES+) m/z = 433.17.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 63

15
[ 1346575-64-1 ]
[ 1346702-47-3 ]
[ 1346702-45-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃;	c) 6-chloro-l-(l-methylethyl)-lH-indazole-4-carboxylic acid (.10 g, 0.419 mmol), 3-(aminomethyl)- 6-methyl-4-propyl-2(lH)-pyridinone (0.109 g, 0.503 mmol), 1 -hydroxy-7-azabenzotriazole (0.080 g, 0.587 mmol), and then EDC (0.112 g, 0.587 mmol) were added to DMSO (4.0 mL). N- methylmorpholine (0.184 mL, 1.676 mmol) was quickly added via syringe. The contents were stirred at RT overnight Additional HOAT and EDC were added, and the contents were stirred for another 6h. The contents were slowly poured onto 45 mL of ice-water wherein solid precipiatation occurred. The contents were stirred for 10 min., and then allowed to stand for another 10 min. The contents were filtered, the collected solid washed with ca. 5 mL of water. The solid was air dried for 15 min. then dried in vacuum oven at 45 C for 24h. The title compound was collected as a white solid (0.160g, 93 % yield). :H NMR (400 MHz, DMSO- 6) delta ppm 0.89 (t, J=7.33 Hz, 3 H) 1.42 - 1.58 (m, 8 H) 2.14 (s, 3 H) 2.52 - 2.58 (m, 1 H) 4.36 (d, J=5.05 Hz, 2 H) 5.04 (quin, J=6.57 Hz, 1 H) 5.91 (s, 1 H) 7.59 (d, J=1.52 Hz, 1 H) 8.06 (s, 1 H) 8.38 (s, 1 H) 8.61 (t, J=4.80 Hz, 1 H) 11.54 (s, 1 H); MS(ES) [M+H]+ 400.9.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 38

16
[ 1346575-64-1 ]
[ 1346703-02-3 ]
[ 1346703-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; for 48h;	c) 6-(4-(dimethylamino)piperidin-l-yl)-l-isopropyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl)-lH-indazole-4-carboxamideTo a solution of 6-[4-(dimethylamino)-l-piperidinyl]-l-(l-methylethyl)-lH-indazole-4-carboxylic acid (34 mg, 0.103 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-6-methyl-4-propyl-2(lH)- pyridinone (29.0 mg, 0.134 mmol), N-methylmorpholine (0.045 mL, 0.412 mmol), l-hydroxy-7- azabenzotriazole (28.0 mg, 0.206 mmol) and EDC (39.5 mg, 0.206 mmol), and the mixture was stirred for 48h. The mixture was purified using reverse-phase HPLC to afford the title compound as a pale yellow solid (34 mg). .H NMR (400 MHz, DMSO-i¾) delta ppm 0.77 - 0.96 (m, 3 H), 1.43 (d, J = 6.57 Hz, 6 H), 1.46 - 1.66 (m, 4 H), 1.89 (m, 2 H), 2.13 (s, 3 H), 2.31 (s, 6H), 2.33( m, 2 H), 2.55 (s, 3 H), 2.65 - 2.84 (m, 2 H), 3.86 (m. 2 H), 4.38 (m, 2 H), 4.85 - 5.04 (m, 1 H), 5.91 (s, 1 H), 7.07 (s, 1 H), 7.32 (m, 1 H), 8.15 (m, 1 H), 8.25 (br. s., 1 H), 8.44 (t, J= 4.93 Hz, 1 H); LCMS: (M+H)+=493.2

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 66

17
[ 1346575-64-1 ]
[ 1346703-17-0 ]
[ 1346703-14-7 ]

Yield	Reaction Conditions	Operation in experiment
32%		Step 2: To a stirred suspension of 6-bromo-l-ethyl-lH-indazole-4-carboxylic acid, 4 (450 mg, 1.67 mmol) in DCM (50 mL) were added EDC.HC1 (384 mg, 2.00 mmol), HOBt.H20 (306 mg, 2.00 mmol) and then stirred for 15 min at RT. To the resulting mixture, DIPEA (1.2 mL, 5.59 mmol) followed by 3-aminomethyl-6-methyl-4-propyl-lH-pyridin-2-one (301 mg, 1.67 mmol) were added and the contents stirred for 18 h at RT. The reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL), 10% aq citric acid solution (2x50 mL), saturated aq NaHCCh solution (2x30 mL) and brine (2x50 mL). The organic layer was dried over Na SO/i, filtered, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether (2 x 50 mL) to afford the title compound as a white solid (230 mg, 32 %). XH NMR (400 MHz, DMSO-d6): delta 0.83-0.79 delta (t, 3H), 1.38 (t, 3H), 1.55 (m, 2H), 2.15 (s, 3H), 2.49 (s, 2H), 4.38 (d, 2H), 4.43 (m, 2H), 5.90 (s, 1H), 7.64 (d, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 8.61 (m, 1H), 1 1.51 (bs, 1H). LCMS (ES+): m/z = 431.15.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 73

18
1,2-dihydro-6-methyl-2-oxo-4-propylpyridine-3-carbonitrile [ No CAS ]
[ 1346575-64-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; water; at 20℃;	A mixture of the above 3 (1.5 g) in THF (20 mL) was added Pd/C (10%, 1.5 g) and conc. HCl (1 mL). The mixture was stirred at room temperature overnight under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtration was concentrated in vacuo. the residue was recrystallized from PE/EA (v/v = 10) to give 1.4 g of 4 (91% yield) as a tan-yellow solid. MS: m/z 181.1 (M+H)+; 164.1 (M-NH3+H)+; 1H NMR (500 MHz, DMSOd6) delta 11.87 (br s, 1H), 8.12 (s, 3H), 6.49 (br s, 1H), 6.00 (s, 1H), 3.78 (m, 2H), 2.18 (s, 3H), 1.50 (m, 2H), 0.92 (t, J = 7.0 Hz, 3H) ppm.
81.6%	With ammonia; hydrogen; In methanol; under 5171.62 Torr; for 48h;	The Raney Ni (1.5 g) was dissolved in 100 mL of MeOH, and the starting material S34 (3.0 g, 17.0 mmol) and 200 mL of MeOH-NH3 were added and reacted under H2 (100 psi). After 48 h, the celite was filtered and washed with methanol. In addition to solvent, column chromatography separation,DCM: MeOH = 10:1 to DCM: MeOH - NH3 = 3:1,A pale yellow solid S35 (2.7 g, yield 81.6%) was obtained.
39%	With ammonia; hydrogen;Raney Ni; In methanol; at 20℃; under 3102.97 Torr; for 48h;	Step 2To a suspension of Raney Ni (2 g) in methanol (250 mL) was added I ,2-dihydro-6-methyl-2-oxo-4- propyipyridine-3-carbonitrile (5 g, 28.4 mmol) and methanolic ammonia (750 mL). The reaction mixture was stirred at room temperature under hydrogen pressure (60 psi) for 48 hrs. The reaction mixture was filtered through celite pad and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure to afford the crude product (5.1 g). The crude product was purified by column chromatography by using a short column of silica gel (60-120 mesh) treated with methanolic NH3, (eluant: 0-25% methanol in DCM) and isolated to afford the desired product 3- (amino methyl)-6-methyl-4-propylpyridin-2(lH)-one as an off white solid (2 g , 39 % yield). lB NMR (DMSO, 400 MHz) : delta 0.921(t, 3H, J = 7.2 Hz), 1.518 (m, 2H),2.09 ( s, 3H), 2.418 (t, 2H,J=7.6 Hz), 3.451 (s,2H), 4-5.6 (br s, 2H, exchangeable), 5.822(s, lH). LCMS E-S (M+H) = 181.22.

Reference： [1]Patent: WO2016/73956,2016,A1 .Location in patent: Paragraph 00353
[2]Patent: CN110016014,2019,A .Location in patent: Paragraph 0107; 0108; 0110
[3]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 143
[4]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1091 - 1096

19
[ 1346575-64-1 ]
[ 1346702-80-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1091 - 1096

20
[ 1346575-64-1 ]
[ 1346704-33-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1091 - 1096

21
[ 851175-95-6 ]
[ 1346575-64-1 ]
[ 1427853-73-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃;	Example 130l-isopropyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-6-phenyl- lH-pyrazolo [3,4-b] pyridine-4-carboxamideEthyl l-(l-methylethyl)-6-phenyl-lH-pyrazolo[3,4-b]pyridine-4-carboxylate (270 mg, 0.873 mmol) was suspended in THF (1913 mu?) and Methanol (6378 mu?). To the mixture was added 3N NaOH (436 mu?, 1.309 mmol) and the contents heated on an aluminum block at 55 C overnight. The solvent was removed in vacuo. The remaining orange residue was dissolved with water (10 mL) and cooled with stirring in an ice bath. The contents were acidifed by dropwise addition IN HCl until precipitation ceased. The white solid was collected via vacuum filtration and the filter cake was dried open to the air, under vacuum overnight. The white solid was added to a 20 mL vial followed by 3-(aminomethyl)-6- methyl-4-propyl-2(lH)-pyridinone (208 mg, 0.960 mmol), N-[3-(dimethylamino)propyl]- N'-ethylcarbodiimide hydrochloride (251 mg, 1.309 mmol), 3H-[l,2,3]triazolo[4,5- b]pyridin-3-ol hydrate (202 mg, 1.309 mmol) and DMSO (4 ml). To the same was added a magnetic stir bar and 4-methylmorpholine (618 mg, 6.11 mmol). The reaction was stirred at room temperature overnight. The reaction contents were slowly poured onto an aqueous solution of sat Na2C03 (6 mL) and water (20 mL) and stirred in an ice bath. The resulting suspension was stirred 20 minutes. The solid was collected by vacuum filtration and dried under high vacuum overnight. The title compound was obtained as an off- white solid (388 mg, 99%). 1H NMR (400 MHz, DMSO-56) delta 9.00 (t, J = 3.92 Hz, 1H), 8.38 (s, 1H), 8.23 - 8.29 (m, 2H), 8.16 (s, 1H), 7.46 - 7.62 (m, 3H), 5.93 (s, 1H), 5.34 (quin, J = 6.63 Hz, 1H), 4.45 (d, J = 4.55 Hz, 2H), 2.55 (s, 2H), 2.14 (s, 3H), 1.56 (d, J = 6.57 Hz, 6H), 1.45 - 1.54 (m, 2H), 0.88 (t, J = 7.20 Hz, 3H). LCMS(ES) [M+H]+ 444.3

Reference： [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 195

22
[ 1346575-64-1 ]
[ 1118787-47-5 ]
[ 1427853-82-4 ]

Yield	Reaction Conditions	Operation in experiment
70 mg	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;	b) 6-cyclopropyl-l-(l,l-dimethylethyl)-3-methyl- V-[(6-methyl-2-oxo-4-propyl-l,2- dihydro-3-pyridinyl)methyl]-lH-pyrazolo[3,4-6]pyridine-4-carboxamide6-cyclopropyl- 1 -( 1 , 1 -dimethylethyl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine-4-carboxylic acid (53 mg, 0.194 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(lH)-pyridinone (71.3 mg, 0.242 mmol), l-hydroxy-7-azabenzotriazole (52.8 mg, 0.388 mmol), EDC (74.3 mg, 0.388 mmol) and N-methylmorpholine (0.085 mL, 0.776 mmol) were suspended in Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Added 25 mL of water and stirred for 10 minutes. The contents were filtered and dried, and collected as 70 mg. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.93 (t, J=7.33 Hz, 3 H), 0.96 - 1.09 (m, 4 H), 1.54 (m, J=7.52, 7.52, 7.52, 7.52, 7.33 Hz, 2 H), 1.68 (s, 9 H), 2.12 (s, 2 H), 2.17 - 2.27 (m, 1 H), 2.33 (s, 3 H), 2.5(2H), 4.34 (d, J=5.05 Hz, 2 H), 5.89 (s, 1 H), 7.01 (s, 1 H), 8.54 (t, J=4.80 Hz, 1 H), 11.50 (s, 1 H). LCMS(ES) [M+H]+ 436.1

Reference： [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 202

23
[ 1346575-64-1 ]
[ 1427853-85-7 ]
[ 1427853-83-5 ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;	f ) 1 ,6-dicyclopropyl-3-methyl- V- [(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3- pyridinyl)methyl]-lH-pyrazolo[3,4-6]pyridine-4-carboxamide l,6-dicyclopropyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-4-carboxylic acid (125 mg, 0.486 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(lH)-pyridinone (126 mg, 0.583 mmol), 1- hydroxy-7-azabenzotriazole (132 mg, 0.972 mmol), EDC (186 mg, 0.972 mmol) and N- methylmorpholine (0.214 mL, 1.943 mmol) were suspended in Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Added 25 mL of water and let stir for 10 minutes. The contents were filtered and dried. The product was collected as 200 mg. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.92 (t, J=7.07 Hz, 3 H), 1.04 (d, J=6.06 Hz, 8 H), 1.45 - 1.73 (m, 2 H), 2.12 (s, 3 H), 2.24 (br. s., 1 H), 2.33 (s, 3 H), 3.79 (br. s., 1 H), 4.34 (d, J=3.79 Hz, 2 H), 5.89 (br. s., 1 H), 6.99 (s, 1 H), 8.57 (br. s., 1 H), 11.51 (br. s., 1 H). MS(ES) [M+H]+ 420.2

Reference： [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 205

24
[ 1346575-64-1 ]
[ 1016682-77-1 ]
[ 1354821-01-4 ]

Yield	Reaction Conditions	Operation in experiment
24%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Example 11l-(l-Methylethyl)- V-[(6-methyl-2-oxo-4-propyl-l,2-dihydro-3-pyridinyl)methyl]-6-(4- pyridinyl)-l -pyrazolo[3,4-6]pyridine-4-carboxamidel-(l-Methylethyl)-6-(4-pyridinyl)-l H-pyrazolo [3, 4-b]pyridine-4-carboxylic acid (150 mg, 0.531 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(lH)-pyridinone (1 15 mg, 0.531 mmol), EDC (122 mg, 0.638 mmol), HOAt (72.3 mg, 0.531 mmol), and N- methylmorpholine (0.233 mL, 2.12 mmol) were suspended in DMF (5 mL) and stirred at room temperature overnight, water was added to the reaction mixture, and the contents were filtered. The filter cake was washed with addional water (2x). The crude solid was purified by reverse phase HPLC (mobile phase: 10-30% ACN in H20, 0.1% TFA). The isolated solid was then neutralized with saturated NaHC03, and washed with EtOAc (5 x 15 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as an off-white solid, 0.060 g (24%). LCMS E-S (M+H) = 445.3. 1H NMR (400 MHz, DMSO-d6) ? ppm 0.84 - 0.92 (m, 3 H), 1.47 - 1.54 (m, 2 H), 1.57 (d, J=6.82 Hz, 6 H), 2.14 (s, 3 H), 2.48 - 2.52 (m, 2 H), 4.42 - 4.49 (m, 2 H), 5.33 - 5.43 (m, 1 H), 5.90 - 5.96 (m, 1 H), 8.28 - 8.37 (m, 3 H), 8.44 - 8.48 (m, 1 H), 8.82 - 8.87 (m, 2 H), 8.99 - 9.04 (m, 1 H), 11.58 (s, 1 H).

Reference： [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 65; 66

25
[ 1346575-64-1 ]
5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoic acid [ No CAS ]
5-bromo-2-methyl-3-[(1-methylethyl)amino]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.6%	With 4-methyl-morpholine; benzotriazol-1-ol; 1,2-dichloro-ethane; In dimethyl sulfoxide; at 20℃; for 72h;	To a 50 ml round bottom was added 5-bromo-2-methyl-3-[(1-methylethyl)amino]benzoic acid (270 mg, 0.992 mmol), 1-hydroxy-7-azabenzotriazole(203 mg, 1.488 mmol) and EDC (285 mg, 1.488 mmol) followed by dimethyl sulfoxide(DMSO) (20 mL). N-methylmorpholine (0.327 mL, 2.98 mmol) was added to the reactionfollowed by <strong>[1346575-64-1]3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone</strong> (232 mg, 1.290mmol). The reaction stirred at rt for 72 h. The reaction was poured onto ice water (10 mL) and was stirred for 20 min (rested for 10 min) and filtered. The solid was rinsed with water(10 mL) followed by MeOH I ice water (10 mL I 10 mL) to provide the title compound as a tan solid. (299 mg, 0.661 mmol, 66.6% yield). 1H NMR (400 MHz, DMSO-d6) 8 ppm11.48 (br. s., 1 H) 8.08 (t, J=4.67 Hz, 1 H) 6.66 (s, 1 H) 6.52 (d, J=1.52 Hz, 1 H) 5.88 (s, 1H) 4.74 (d, J=7.83 Hz, 1 H) 4.24 (d, J=4.80 Hz, 2 H) 3.54- 3.67 (m, 1 H) 2.45- 2.48 ( m,2H) 2.12 (s, 3 H) 1.96 (s, 3 H) 1.47- 1.56 (m, 2 H) 1.16 (d, J=6.32 Hz, 6 H) 0.90-0.94 (m, 3 H). MS(ES) [M+Ht 434.0.

Reference： [1]Patent: WO2013/173441,2013,A2 .Location in patent: Page/Page column 74; 75

26
[ 1346575-64-1 ]
6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride [ No CAS ]
[ 1346575-50-5 ]

Yield	Reaction Conditions	Operation in experiment
362 mg	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; for 2h;Inert atmosphere;	To 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol), <strong>[1346575-64-1]3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one</strong> (0.22 g, 1.221 mmol), HOAt (0.17 g, 1.249 mmol) was added Dichloromethane (16 mL), N,N-Dimethylformamide (4 mL) and N-methylmorpholine (135 muL, 1.228 mmol). The mixture was stirred and EDC free base (0.20 g, 1.288 mmol) was added. After stirring for 2 hr LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum and purified by silica gel chromatography (Analogix, SF25-60g, 0 to 8% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness then taken up in 20% EtOAc in hexanes. Scratching crystallized out the product which was filtered and washed with hexanes to give the product 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamide (362 mg, 0.769 mmol, 63.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta=11.49 (s, 1H), 8.24 (t, J=4.9 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H), 5.89 (s, 1H), 4.91 (quin, J=7.0 Hz, 1H), 4.31 (d, J=5.1 Hz, 2H), 3.47 (s, 2H), 2.52 (2H under DMSO), 2.14 (s, 6H), 2.12 (s, 3H), 2.10 (s, 3H), 1.62-1.53 (m, 2H), 1.51 (d, J=7.1 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H). MS(ES)+ m/e 471.3 [M+H]+.

Reference： [1]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0716

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[ 1346575-64-1 ]
1-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-4-(pyrido[2,3-b]pyrazin-7-yl)-1H-indole-6-carboxamide [ No CAS ]