[ CAS No. 115619-01-7 ] {[proInfo.proName]}

Name: 115619-01-7|4-(4-Ethylpiperazin-1-yl)phenylamine|98%
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SKU: A169399
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Quality Control of [ 115619-01-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 115619-01-7 ]

CAS No. :	115619-01-7	MDL No. :	MFCD00702246
Formula :	C₁₂H₁₉N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KEPUOYACJXZYTQ-UHFFFAOYSA-N
M.W :	205.30	Pubchem ID :	936738
Synonyms :

Calculated chemistry of [ 115619-01-7 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	2
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	71.91
TPSA :	32.5 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.21
Log Po/w (XLOGP3) :	1.54
Log Po/w (WLOGP) :	0.66
Log Po/w (MLOGP) :	1.4
Log Po/w (SILICOS-IT) :	1.13
Consensus Log Po/w :	1.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.25
Solubility :	1.16 mg/ml ; 0.00566 mol/l
Class :	Soluble
Log S (Ali) :	-1.83
Solubility :	3.02 mg/ml ; 0.0147 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.62
Solubility :	0.495 mg/ml ; 0.00241 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	2.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 115619-01-7 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 115619-01-7 ]

* 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 [ 115619-01-7 ]
Downstream synthetic route of [ 115619-01-7 ]

[ 115619-01-7 ] Synthesis Path-Upstream 1~6

1
[ 115619-00-6 ]
[ 115619-01-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 9 h; Inert atmosphere; Schlenk technique	General procedure: The nitrophenyl analogue 7a–7e (7.5 mmol) was dissolved in ethanol (50 mL), and to this solution was added 10percent Pd/C (0.2 g). The reaction mixture was stirred at room temperature under an atmosphere of H₂ for 9 h. After completion of the reaction, the resulting mixture was filtered through Celite. The filtrate was concentrated under high vacuum to afford the desired aniline derivatives 8a–8e.
78%	With hydrogenchloride; tin In chloroform; waterReflux	General procedure: Concisely,1-(4-Nitro phenyl)-4-substitued piperazine derivatives (1-18) were refluxed for 3-4 h in chloroform (20 ml) with theSn/HCl solution. The solution was prepared before by dissolving tin (15mM) in30ml Con. HCl. The reaction mixture was cooled under tap water and neutralizedwith 15percent NaOH solution. The resulting compound was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate andevaporated under reduced pressure to afford of 4-(4-substitutedpiperazin-1-yl)-phenylamine derivatives (19-36)as solid compounds.

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[2] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[4] Patent: US2004/122237, 2004, A1, . Location in patent: Page 180
[5] Patent: WO2006/420, 2006, A1, . Location in patent: Page/Page column 210
[6] Patent: WO2006/108640, 2006, A1, . Location in patent: Page/Page column 84
[7] Patent: WO2007/71752, 2007, A2, . Location in patent: Page/Page column 73
[8] Patent: WO2011/71821, 2011, A1, . Location in patent: Page/Page column 21
[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2917 - 2929
[10] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[11] Patent: WO2015/117547, 2015, A1, . Location in patent: Page/Page column 16; 17
[12] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
[13] Patent: WO2009/141386, 2009, A1, . Location in patent: Page/Page column 67

2
[ 5308-25-8 ]
[ 115619-01-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2917 - 2929
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[5] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[6] Patent: WO2015/117547, 2015, A1,
[7] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
[8] Patent: WO2009/141386, 2009, A1,

3
[ 586-78-7 ]
[ 115619-01-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[2] Patent: WO2015/117547, 2015, A1,
[3] Patent: WO2009/141386, 2009, A1,

4
[ 350-46-9 ]
[ 115619-01-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[2] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[3] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617

5
[ 636-98-6 ]
[ 115619-01-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2917 - 2929

6
[ 100-00-5 ]
[ 115619-01-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56

[ 115619-01-7 ] Synthesis Path-Downstream 1~79

1
[ 147594-47-6 ]
[ 115619-01-7 ]
[4-(4-Ethyl-piperazin-1-yl)-phenyl]-(2-methyl-2H-[1,2,3]triazolo[4,5-f]quinolin-9-yl)-amine; hydrochloride [ No CAS ]

Reference： [1]Il Farmaco,1995,vol. 50,p. 47 - 54

2
[ 463-71-8 ]
[ 115619-01-7 ]
[ 611225-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In acetone; at 0℃;	Step 3.Synthesis of 4-(4-ethylpiperazinyl)benzeneisothiocyanate To 4-(4-ethylpiperazinyl)phenylamine in acetone at 0 C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq).The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water.The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 4-(4-ethylpiperazinyl)benzeneisothiocyanate. MS: MH+=247.

Reference： [1]Patent: US2004/122237,2004,A1 .Location in patent: Page 180

3
[ 115619-00-6 ]
[ 115619-01-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 9h;Inert atmosphere; Schlenk technique;	General procedure: The nitrophenyl analogue 7a-7e (7.5 mmol) was dissolved in ethanol (50 mL), and to this solution was added 10% Pd/C (0.2 g). The reaction mixture was stirred at room temperature under an atmosphere of H2 for 9 h. After completion of the reaction, the resulting mixture was filtered through Celite. The filtrate was concentrated under high vacuum to afford the desired aniline derivatives 8a-8e.
78%	With hydrogenchloride; tin; In chloroform; water;Reflux;	General procedure: Concisely,1-(4-Nitro phenyl)-4-substitued piperazine derivatives (1-18) were refluxed for 3-4 h in chloroform (20 ml) with theSn/HCl solution. The solution was prepared before by dissolving tin (15mM) in30ml Con. HCl. The reaction mixture was cooled under tap water and neutralizedwith 15% NaOH solution. The resulting compound was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate andevaporated under reduced pressure to afford of 4-(4-substitutedpiperazin-1-yl)-phenylamine derivatives (19-36)as solid compounds.
	With hydrogen;palladium; In methanol;	The mixture containing 4-ethyl-1-(4-nitrophenyl)piperazine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(4-ethylpiperazinyl)phenyl-amine. MS: MH+=205.

	With hydrogen;nickel; In methanol; at 20℃; for 7h;	A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 ml_) is stirred for 7 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MHf; TLC: R, = 0.15 (DCM/MeOH + 1 % NH3aq, 9:1).
	With hydrogen;nickel; In methanol; at 20℃; for 7h;	Step 50.1 : 4-(4-Ethylpiperazin-1-yl)-aniline; A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a violet solid: ESI-MS: 206.1 [MH]+; TLC: Rf = 0.15 (CH2CI2/MeOH + 1 % NH3aq, 9:1).
	With hydrogen;nickel; In methanol; at 20℃; for 7h;	4-(4-Ethylpiperazin-1-yl)-anilineA suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a violet solid: ESI-MS: 206.1 [MH]+; TLC: Rf = 0.15 (DCM/MeOH + 1 % NH3aq, 9:1 ).
	With hydrogen; In methanol; at 20℃; for 7h;	A suspension of l-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MH]+; TLC: Rf = 0.15 (DCM/MeOH + 1 % NH3aq, 9:l).
	With palladium 10% on activated carbon; hydrogen; under 2585.81 Torr;	General procedure: The substituted nitrobenzenes were reduced to the corresponding anilines by catalytic reduction (50 psi, 10% Pd/C (5% w/w)) on a Parr hydrogenator as previously described [19] The anilines (not characterized) were then condensed with 6,9-dichloro-2-methoxyacridine or 4,7-dichloroquinoline (Section 6.2.) to give 1-3, 10.
	With hydrogen;nickel; In methanol; at 20℃; for 7h;	A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (Step 1.10) (6.2 g, 26.35 mmol) and Raney nickel (2 g) in MeOH (120 ml.) was stirred for 7 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [M+H]+; TLC: Rf = 0.15 (DCM/MeOH + 1 % NH3aq, 9:1 ).
	With 5%-palladium/activated carbon; hydrogen; In ethanol; water; at 20℃;	General procedure: The substituted nitro compound 11 (1 equiv in a mixture of EtOH-H2O, 95:5, 20mL) was treated with 10% Pd-carbon (5% w/w). The reaction was subjected to hydrogenation under hydrogen gas at room temperature and the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a Celite bed and concentrated in a vacuum to afford product 12.
	With palladium on activated charcoal; hydrogen; at 20℃; for 7h;	According to scheme I, to a 250-mL flash were added Compound Ia-1, i.e. 2,6-dichloro-3,5-dimethoxyaniline (10mmol) and AcOH (24ml), and added dropwisely under an ice-bath a solution of sodium nitrite (15mmol) in sulphuric acid (5.8ml) . The mixture was stirred at 25C until the solution became clear. The resulting dark yellow solution was poured into 150ml of an ice-water, and urea (6mmol) was added. The mixture was stirred and filtered. An aqueous solution of potassium iodide (15mmol) was added to the above dark-yellow solution. The mixture was heated at 85C for 2 hours, and cooled to room temperature. NaHSO3 (3.4 mmol) was added, and the mixture was stirred for 10 minutes. The resulting yellow solid was filtered, dried, and separated by column chromatography to produce Compound Ib-1 (8mmol). Compound Ib-1 (4 mmol), and Compound A-1, i.e. 4-piperidinone ethylene ketal (6 mmol) were dissolved in 50ml toluene, and palladium acetate (0.4 mmol), BINAP (0.48 mmol), and cesium carbonate (18 mmol) were added. The mixture was refluxed under the nitrogen protection for 3 days, and separated by column chromatography to produce Compound Ic-1. Compound Ic-1 (2.5 mmol) was dissolved in 10ml THF, and 10% aqueous H2SO4 solution (10ml) was added. The mixture was heated at 60C overnight, and separated by column chromatography to produce Compound Id-1. Compound Id-1 (1.0 mmol) was dissolved in 10ml dioxane, and DMF.DMA (6.0 mmol) and triethylamine (1.0 mmol) were added. The mixture was refluxed under the nitrogen protection for 2 days, and separated by thin layer chromatography to produce Compound Ie-1. Compound B-1, i.e., 1-fluoro-4-nitrobenzene (10 mmol) was dissolved in 20ml DMF, and C-1, i.e., N-ethylpiperazine (11 mmol), and potassium carbonate (30 mmol) were added. The mixture was reacted at 70C overnight. After cooling, the mixture was poured into ice-water, and filtered to produce Compound If-1. Compound If-1 (10 mmol) was dissolved in 20ml methanol or ethanol, and palladium/carbon (1mmol) was added. The mixture was hydrogenated at room temperature for 7 hours. The mixture was separated by column chromatography to produce Compound Ig-1. Compound Ig-1 (2.6 mmol) was dissolved in 10ml dioxane, and cyanoamine (2.73 mmol), and concentrated hydrochloric acid (3.9 mmol) were added. The mixture was stirred under reflux overnight to produce Compound Ih-1. Compound Ie-1 (1mmol) and Compound Ih-1 (1.05mmol) were dissolved in 8ml ethanol, and sodium acetate (2mmol) and triethylamine (1.05mmol) were added. The mixture was stirred under flux for 7 hours, ethanol concentrated, and water and dichloromethane were added. The organic phase was separated, dried over anhydrous sodium sulphate, and separated by thin layer chromatography to produce Compound I-1 (0.1mmol) in a yield of 10%.H1-NMR(deuterated MeOH) : delta8.11(s, 1H), delta7.56(d, 2H), delta6.99(d, 2H), delta6.72(s, 1H), delta4.25(s, 2H), delta3.93(s, 6H), delta3.56(t, 2H), delta3.23(m, 4H), delta2.92(t, 2H), delta2.8(m, 4H), delta2.64(m, 3H), delta1.2(t, 3H). ESI(+)m/z: 543

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7066 - 7083
[2]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 1863 - 1873
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1092 - 1099
[4]Patent: US2004/122237,2004,A1 .Location in patent: Page 180
[5]Patent: WO2006/420,2006,A1 .Location in patent: Page/Page column 210
[6]Patent: WO2006/108640,2006,A1 .Location in patent: Page/Page column 84
[7]Patent: WO2007/71752,2007,A2 .Location in patent: Page/Page column 73
[8]Patent: WO2011/71821,2011,A1 .Location in patent: Page/Page column 21
[9]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2917 - 2929
[10]European Journal of Medicinal Chemistry,2014,vol. 75,p. 43 - 56
[11]Patent: WO2015/117547,2015,A1 .Location in patent: Page/Page column 16; 17
[12]Archives of Pharmacal Research,2016,vol. 39,p. 603 - 617
[13]Patent: WO2009/141386,2009,A1 .Location in patent: Page/Page column 67
[14]European Journal of Medicinal Chemistry,2019,vol. 163,p. 690 - 709
[15]Patent: EP3466948,2019,A1 .Location in patent: Paragraph 0069-0071

5
[ 872513-02-5 ]
[ 115619-01-7 ]
[ 872513-04-7 ]

Yield	Reaction Conditions	Operation in experiment
33.24%	With N-ethyl-N,N-diisopropylamine; In ethanol; for 2.5h;Reflux;	A mixture of 5 (0.10g, 0.48mmol), DIPEA (0.08ml, 0.48mmol) and EtOH (5ml) was mixed with the 85 (0.07g, 0.48mmol) and refluxed for 2.5hrs. The reaction was quenched by saturated NaHCO3 (aq.) and the mixture was extracted by ethyl acetate (30ml x 3). The residue was purified by flash column over silica gel (dichloromethane: methanol = 9: 1, Rf = 0.28) to afford 89 (0.05g, 33.24%) as a pale yellow solid. 1H-NMR (300MHz, CDCl3): delta 1.13 (t, J= 7.2 Hz, 3H), 2.46 (q, J= 7.2 Hz, 2H), 2.62 (t, J= 5.1 Hz, 4H), 2.98 (d, J= 5.1 Hz, 3H), 3.19 (t, J= 5.1 Hz, 4H), 5.17-5.29 (m, 1H), 5.55 (br, 1H), 6.91 (d, J= 8.7 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H), 7.46 (s, 1H), 8.20 (d, J= 44.7 Hz, 1H).
	With N-ethyl-N,N-diisopropylamine; sodium iodide; In ethanol; at 80℃; for 3h;	A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00 mmol), Nal (28 mg)and <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (410 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 ul, 2.0 mmol) is heated to 80C for 3 h under a nitrogen atmosphere.The reaction mixture is cooled to RT, concentrated partially in vacuo and diluted with hexaneat 0 C. The precipitate is filtered off, washed with Et2O and re-dissolved in EE and water.The separated off aqueous phase is extracted twice with EE, the organic layer washed withwater and brine, dried (Na2SO4) and concentrated, yielding the title compound: ESI-MS: 314[MH]*; TLC: Rf = 0.10 (DCM/MeOH 9:1).

Reference： [1]Patent: WO2017/15400,2017,A1 .Location in patent: Paragraph 0065
[2]Patent: WO2006/420,2006,A1 .Location in patent: Page/Page column 281

6
[ 5305-59-9 ]
[ 115619-01-7 ]
[ 872511-66-5 ]

Yield	Reaction Conditions	Operation in experiment
		mixture of 6-chloro-pyrimidin-4-yl)-amine (500 mg, 3.87 mmol, 1.3 eq.) and <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (611 mg, 2.98 mmol) in water (3.0 ml) and glacial acetic acid (10ml) is heated to 100C for 15h. The reaction mixture is diluted with DCM and brine. Theaqueous layer is made basic by addition of sodium bicarbonate. The aqueous layer isseparated and extracted with DCM. The organic phase is washed with brine, dried (sodiumsulfate), filtered and concentrated. Purification of the crude product by trituration in EEaffords the title compound: ESI-MS: 299.2 [MHf; tR= 1.05 min (gradient J).

Reference： [1]Patent: WO2006/420,2006,A1 .Location in patent: Page/Page column 223-224

7
[ 934496-80-7 ]
[ 115619-01-7 ]
[ 934496-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 100℃; for 16h;Product distribution / selectivity;	[00236] To a 15 mL pressure tube was added 8-ethyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (70.0 mg, 0.202 mmol), 1 mL dimethylsulfoxide (dmso), and 4-morpholinoaniline (Aldrich, 72.9 mg, 0.409 mmol, 2 eq,) was added. The reaction mixture was heated to 1000C for 16 h. The reaction was diluted with EtOAc, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The crude material was purified by preparative hplc using 20 - 90% ACN in H2O with 0.05% THF. The desired product containing fractions were combined, diluted with EtOAc, and washed with saturated NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4 and solvent was removed on a rotary evaporator to a colorless film. The film was dissolved in 2 mL ACN and 2 mL H2O, frozen and lyophilized overnight, yielding 8.7 mg (10% yield) of 6-Bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrido[2,3- EPO <DP n="77"/>phiyrimidin-7(8H)-one as a colorless powder: 1H NMR (400 MHz, CDCl3): delta 8.13 (s, IH),7.56 (d, J= 8.8 Hz5 2H), 7.22 (s, IH)5 6.94 (d, J= 9.2 Hz5 2H), 4.50 (q, J= 7.2 Hz5 2H), 3.88(t, J= 4.4 Hz, 4H)5 3.15 (t, J= 5.2 Hz5 4H)5 1.58 (s, 3H)5 1.35 (t, J= 6.8 Hz, 3H)5 MS (EI) forC20H22BrN5O2: 444.3 (MH+)
	at 170℃; for 0.166667h;Product distribution / selectivity;	Example 59; 6-Acetyl-8-ethyl-2-[4-(4-ethylpiperazin-l-yl)phenylamino]-4-methylpyrido[2,3-c(jpyrimidin-7(8H)-one; [00246] A mixture of 6-bromo-8-ethyl-4-methyl-2-(methylsulfonyl)-6- phenylpyrido[2,3-J]pyrimidin-7(8H)-one from above (502 mg, 1.46 mmol) and 4-(4- ethylpiperazin-l-yl)aniline (3.45 g, 16.8 mmol) were heated (the neat mixture melted upon heating) at 170 C for ten minutes and cooled to room temperature. The reaction was partitioned between aqueous and organic layers with ethyl acetate and H2O. The organic layer was dried with anhydrous magnesium sulfate, filtered and evaporated, and directly applied to prep-LC to provide product (320 mg, 46.5 % yield); 471.0 [M+H].

Reference： [1]Patent: WO2007/44698,2007,A1 .Location in patent: Page/Page column 75; 76
[2]Patent: WO2007/44698,2007,A1 .Location in patent: Page/Page column 85

8
[ 934494-58-3 ]
[ 115619-01-7 ]
[ 934496-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 100℃; for 12h;	[00239] Anhydrous DMSO (4.0 mL) was added to a pressure tube charged with the above sulfone (253 mg, 0.702 mmol) and 4-(4-ethylpiperazin-l-yl)phenylamine (159 mg, 0.773 mmol). The pressure tube was sealed and heated to 100 C. After 12 hours, the reaction was cooled to room temperature and poured into water (100 mL) and diluted with ethyl acetate (100 mL). The aqueous phase was separated and washed with an additional amount of ethyl acetate (100 mL). The organic layers were pooled, washed with brine, and dried over Na2SO4, filtered and concentrated in vacuo to afford 6-bromo-2-(4-(4-ethylpiperazin-l- yl)phenylamino)-4-methyl-8-(l-methylethyl)pyrido[2,3-</]pyrimidin-7(8H)-one. The compound was used in the next step without further purification.

Reference： [1]Patent: WO2007/44698,2007,A1 .Location in patent: Page/Page column 79

9
[ 934496-69-2 ]
[ 115619-01-7 ]
8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidm-7(8H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In dimethyl sulfoxide; at 100℃;	Example 46; 8-Ethyl-2- { [4-(4-ethylpiperazin- 1 -yl)phenyl] amino } -4-methyl-6-phenylpyrido [2,3 - d]pyrimidm-7(8H)-one[00242] 8-Ethyl-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-cdpyrimidin-7(8H)- one (275 mg, 0.80 mmol) and 4-(4-ethylpiperazin-l-yl)aniline (197 mg, 1.2 equiv.) were added to dimethyl sulfoxide (5 mL) and the resulting mixture was heated to 100 0C and stirred overnight. After cooling to room temperature, the reaction was partitioned between aqueous and organic layers with ethyl acetate and H2O, organic layer was dried with anhydrous magnesium sulfate, filtered and evaporated, and directly applied to prep-LC to EPO <DP n="84"/>provide the title compound in (210.0 mg, 56 % yield): 1H NMR (400 MHz, CDCl3): delta 7.80(s, IH), 7.62 (d, 2H), 7.60 (d, 2H)5 7.40 (m, 2H), 7.18 (s, 1eta), 6.95 (d, 2H)5 4.50 (q, 2H)5 3.22(m, 4H)5 2.70 (m, 4H)5 2.60 (s, 3H)5 2.50 (m, 2H)5 1.40 (t, 3H)5 1.20 (t, 3H); MS (EI) forC28^2N6O: 469.10 (MH4).

Reference： [1]Patent: WO2007/44698,2007,A1 .Location in patent: Page/Page column 82

10
[ 65766-32-7 ]
[ 115619-01-7 ]
[ 872511-35-8 ]

Yield	Reaction Conditions	Operation in experiment
80.20%	With water; acetic acid;Reflux;	A mixture of 5 (0.49g, 2.39mmol), H2O (0.75ml) and AcOH (3ml) was mixed with the 83 (0.15g, 3.13mmol) and refiuxed for overnight. The reaction was quenched by saturated NaHCO3 (aq.) and the mixture was extracted by ethyl acetate (30ml x 3). The residue was purified by flash column over silica gel (dichloromethane: methanol = 9: 1, Rf = 0.25) to afford 87 (0.60g, 80.20%) as a pale orange solid. 1H-NMR (300MHz, CDCl3): delta 1.16 (t, J= 7.2 Hz, 3H), 2.48 (q, J= 7.2 Hz, 2H), 2.64 (t, J= 5.1 Hz, 4H), 2.81 (d, J= 5.4 Hz, 3H), 3.22 (t, J= 5.1 Hz, 4H), 4.86 (s, 1H), 5.54 (s, 1H), 6.69 (s, 1H), 6.95 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 8.7 Hz, 2H), 8.14 (s, 1H).
	With hydrogenchloride; In 1,4-dioxane; at 150℃; for 5h;Product distribution / selectivity;	N-f4-(4-ethyl-piperazin-1-yl)-phenyll-N'-methvi-pyrimidine-4,6-diamine A mixture of <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (1 g, 4.88 mmol) (prepared in analogy to Example 238, Step 238.1), (6-chloro-pyhmidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.) and 4N HCI in dioxane (15 ml) is heated in a sealed tube to 150DC for 5h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM, The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR= 1.10 min (system 1); TLC: Rf = 0.21 (DCM/MeOH, 93:7).

Reference： [1]Patent: WO2017/15400,2017,A1 .Location in patent: Paragraph 0063
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 7066 - 7083
[3]Patent: WO2007/71752,2007,A2 .Location in patent: Page/Page column 88

11
[ 945756-13-8 ]
[ 115619-01-7 ]
C₂₄H₂₈N₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 90℃; for 16h;Under nitrogen atmosphere;	To a flask containing a solution of 1 (0.25g, 1 mmol), 4-(4-ethylpiperazin-l- yl)aniline (0.23g, 1.1 mmol), cesium carbonate (0.5g, 1.5 mmol), racemic-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (95mg, 0.15 mmol) in N,N-dimethylacetamide (5mL) purged with N2 was added tris(dibenzylideneacetone)dipalladium(0) (0.14g, 0.15 mmol). This reaction was heated to 90 0C for 16 h under N2. At this time the reaction was concentrated and the residue was purified via silica gel column chromatography. The column was eluted with ethyl acetate to remove the impurities and then with 85:10:5 (ethyl acetate/methanol/7M ammonia in methanol) to elute the desired product. The solid obtained was sonicated first in acetone (5mL) and then in ether (1OmL) to yield intermediate 2 (0,23g, 48% yield) as a yellow solid. LCMS: m/z 417 (MH+). To a flask containing 2 (0.23g, 0.45 mmol) was added 4N HCl in dioxane (5mL) and the solution was heated at 50 0C for 4 h. To the cooled solution was added a 2N aqueous solution of sodium hydroxide (1OmL) and the resulting precipitate was filtered and dried to yield 3 (0.2g, 99% yield) as a yellow solid. LCMS: m/z 375 (M+H)+. To a flask with 3 (0.3g, 0.8 mmol), phenylacetic acid (0.125mL, 1 mmol), triethylamine (0.97mL, 7 mmol), and DMF (5mL) was added O-(7-azabenzotriazole- l-yO-N.iV.JV'.N'-tetramethyluronium hexafluorophosphate (HATU) (0.46g, 1.2 mmol). The reaction mixture was stirred at ambient temperature for 1 h then diluted with 5% aqueous <n="281"/>solution of lithium chloride (10OmL) and extracted with ethyl acetate (3 x 5OmL). The combined organic layers were washed with an aqueous 5% sodium bicarbonate solution, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography (98:2 ethylacetate/methanol) to provide Compound 329 (0.25g, 63% yield) as an off-white solid.

Reference： [1]Patent: WO2007/89768,2007,A2 .Location in patent: Page/Page column 278-281

12
[ 1030626-93-7 ]
[ 115619-01-7 ]
[ 1030626-94-8 ]

Yield	Reaction Conditions	Operation in experiment
63.8%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 110℃; for 20h;	5-Chloro-N-(4-(4-ethylpiperazin-l-yl)phenyl)-[l,2,4]triazolo[l,5-a]pyridin-8-amine <n="76"/>[0342] To a mixture of 5-chloro-8-iodo-[l,2,4]triazolo[l,5-alpha]pyridine (279.5 mg, 1.0 mmol), 4-(4-ethylpiperazin-l-yl)aniline (246 mg, 1.2 mmol, 1.2 eq), BINAP (62.3 mg, 0.1 mmol, 0.1 eq.) and cesium carbonate (1.3 g, 4.0 mmol, 4 eq.) in toluene (10 mL) under an argon atmosphere, is added palladium acetate (22.4 mg, 0.10 mmol, 0.1 eq.). The reaction mixture is stirred at 110 0C overnight (20 h). After cooling to rt, the reaction mixture is filtered, and the solids are washed with DCM/MeOH (9: 1, 20 mL). The combined organic solution is evaporated to provide a black residue that is purified by silica gel column chromatography (1-3% 2N NH3 in MeOH/DCM) to afford the title product as a grey solid (228 mg, yield 63.8%). 1H NMR (300 MHz, OMSO-d6): delta 8.56 (s, IH), 8.49 (s, IH), 7.21 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, IH), 6.95 (d, J= 9.0 Hz, 2H), 6.86 (d, J= 8.1 Hz, IH), 3.11 (m, 4H), 2.45 (m, 4 H), 2.39 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H); LCMS-ESI (m/z): calcd for Ci8H21ClN6 Ci6H16ClN5O 356.1; [M+H]+ found, 357.2.

Reference： [1]Patent: WO2008/65198,2008,A1 .Location in patent: Page/Page column 75

13
[ 1197333-35-9 ]
[ 115619-01-7 ]
[ 1197331-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; propylphosphonic anhydride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	A mixture of propylphosphonic anhydride (50% in DMF, 0.41 ml_, 0.70 mmol, 2 equiv), 5- (2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1 ) (132 mg, 0.35 mmol), <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (Step 1.9) (79 mg, 0.39 mmol, 1.1 equiv), DMAP (3 mg), and Et3N (0.49 ml_, 3.5 mmol, 10 equiv) in DMF (3 ml_), was stirred for 16 h at rt, under an argon atmosphere. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration in EtOAc to afford the title compound as a yellow solid: ES-MS: 564.9 / 566.9 [M+H]+; tR= 4.45 min (System 1 ).

Reference： [1]Patent: WO2009/141386,2009,A1 .Location in patent: Page/Page column 161-162

14
[ 1197331-89-7 ]
[ 115619-01-7 ]
[ 1197329-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	With propylphosphonic anhydride; triethylamine;dmap; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	A mixture of propylphosphonic anhydride (50% in DMF, 0.31 ml_, 0.53 mmol, 2 equiv), 8- (2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (100 mg, 0.26 mmol) (Step 1.1 ), <strong>[115619-01-7]4-(4-ethylpiperazin-1-yl)-aniline</strong> (Step 1.9) (65 mg, 0.32 mmol, 1.2 equiv), DMAP (2 mg), and Et3N (0.37 ml_, 2.65 mmol, 10 equiv) in DMF (2.0 ml_), was stirred for 18 h at rt, under an argon atmosphere. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration in Et2O to afford the title compound as a yellow solid: ES-MS: 565.9 [M+H]+; tR= 4.26 min (System 1 ).

Reference： [1]Patent: WO2009/141386,2009,A1 .Location in patent: Page/Page column 59; 65

15
C₂₂H₂₅Cl₃N₆O₄ [ No CAS ]
[ 115619-01-7 ]
[ 1197165-02-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2648 - 2653

16
C₂₂H₂₄Cl₃N₅O₄ [ No CAS ]
[ 115619-01-7 ]
[ 1197164-96-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2648 - 2653

17
[ 1159883-71-2 ]
[ 115619-01-7 ]
[ 1160061-38-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2452 - 2455

18
[ 1152261-56-7 ]
[ 115619-01-7 ]
[ 76-05-1 ]
5-bromo-N₂-[4-(4-ethylpiperazin-1-yl)phenyl]-N₄-[2-(trifluoromethyl)-1H-benzimidazol-5-yl]pyrimidine-2,4-diamine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		EXAMPLE IB5-bromo-N2-[4-(4-ethylpiperazin-l-yl)phenyl]-N4-[2-(trifluoromethyl)-lH-benzimidazol-5-yl]pyrimidine-2,4-diamineA scintillation vial was charged with EXAMPLE IA (98 mg, 0.25 mmol), 4- (4- ethylpiperazin-l-yl)aniline (66.7 mg, 0.325 mmol), n-butanol (4 ml) and 4 N hydrogen chloride in dioxane (62.5 muL, 0.250 mmol). The mixture was stirred at 80 0C overnight. The reaction mixture was cooled and quenched with water (10 mL), adjusted to pH -135089667 1 with slow addition of cone. aq. NaOH. The mixture was extracted with ethyl acetate and the extract was concentrated. The crude product was purified with HPLC on a Cl 8 reverse-phase column using a gradient of water and acetonitrile with 0.1% TFA as a buffer. The title compound was obtained as the TFA salt as an off-white solid (100 mg, 51%). MS: (ESI(+)) m/e 561.2, 563.2 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta ppm 9.53 (bs, IH), 9.39 (s, 1 H), 8.99 (s, IH), 8.22 (s, IH), 7.94 (s, IH), 7.73 (d, IH), 7.57 (d, IH), 7.43 (d, 2H), 6.76 (d, 2H), 6.51 (s, IH), 3.66-3.53 (m, 4H), 3.21-3.09 (m, 4H), 2.87 (U H), 1.26 (q, 3H).

Reference： [1]Patent: WO2010/138578,2010,A1 .Location in patent: Page/Page column 50-51

19
[ 1170678-89-3 ]
[ 115619-01-7 ]
[ 1170678-28-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 120℃; for 4h;Microwave irradiation;	48.3 1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-[4-(4-ethylpiperazin-1-yl)-phenylamino]-5-iodo-1,3-dihydroindol-2-one4-(4-Ethylpiperazin-1-yl)phenylamine (44 mg, 0.21 mmol) was added to a solution of 3-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-iodo-1,3-dihydroindol-2-one (110 mg, 0.18 mmol) in dichloromethane (15 ml). The reaction mixture was agitated in a Biotage microwave vial at 120 C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Purification by chromatography (silica gel, 0-8% methanol in dichloromethane) resulted in 16 mg of the title compound (11% yield).ESI-MS: 784.20 [m+H]+ 1H-NMR (500 MHz, d6-DMSO): delta [ppm] 8.15 (m, 1H); 8.05 (d, 1H); 7.85 (d, 1H); 7.75 (d, 1H); 7.50 (d, 1H); 7.30 (s, 1H), 7.10 (dd, 1H); 6.70 (d, 1H); 6.65 (s, 1H); 6.45 (d, 2H); 6.40 (d, 2H); 4.05 (m, 2H); 3.85 (s, 3H); 3.55 (s, 3H); 2.95 (bs, 4H); 2.45 (bs, 4H); 2.35 (m, 2H); 1.00 (t, 3H); 0.90 (t, 3H).

Reference： [1]Patent: US2011/105454,2011,A1 .Location in patent: Page/Page column 38

20
[ 933702-18-2 ]
[ 115619-01-7 ]
[ 872511-35-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 150℃; for 5h;sealed tube;	A mixture of 4-(4-ethylpiperazin-l-yl)-aniline (1 g, 4.88 mmol), (6-chloro- pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.), and 4N HC1 in dioxane (15 ml) is heated in a sealed tube to 150C for 5h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR= 1.10 min (gradient J); TLC: Rf = 0.21 (DCM/MeOH, 93:7).

Reference： [1]Patent: WO2011/71821,2011,A1 .Location in patent: Page/Page column 21

21
[ 5308-25-8 ]
[ 115619-01-7 ]

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2917 - 2929
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 7066 - 7083
[3]European Journal of Medicinal Chemistry,2014,vol. 75,p. 43 - 56
[4]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1092 - 1099
[5]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 1863 - 1873
[6]Patent: WO2015/117547,2015,A1
[7]Archives of Pharmacal Research,2016,vol. 39,p. 603 - 617
[8]Patent: WO2009/141386,2009,A1
[9]European Journal of Medicinal Chemistry,2019,vol. 163,p. 690 - 709
[10]Patent: EP3466948,2019,A1

22
[ 636-98-6 ]
[ 115619-01-7 ]

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2917 - 2929

23
[ 86-38-4 ]
[ 115619-01-7 ]
[ 1313481-14-9 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: A previously described method [19] was followed for the syntheses of 1-5, 7, 8, 10 and 20. Briefly, equimolar quantities of the amine and the acridine/quinoline were dissolved in ethanol, 2 drops of conc. HCl were added and the mixture refluxed for ca 24 h. On cooling, NaOH (1 M) or ammonia solution (25%) was added, followed by dichloromethane to extract the product. Alternatively, if the product precipitated out of solution on alkalinization, it was removed by filtration and purified by column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2917 - 2929

24
[ 586-78-7 ]
[ 115619-01-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7066 - 7083
[2]Patent: WO2015/117547,2015,A1
[3]Patent: WO2009/141386,2009,A1

25
[ 1364846-40-1 ]
[ 115619-01-7 ]
[ 1364847-21-1 ]