[ CAS No. 1003298-87-0 ] {[proInfo.proName]}

Name: 1003298-87-0|2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol|97%
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SKU: A244939
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Quality Control of [ 1003298-87-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1003298-87-0 ]

Product Details of [ 1003298-87-0 ]

CAS No. :	1003298-87-0	MDL No. :	MFCD20526385
Formula :	C₁₂H₁₅BCl₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IAVSUBSFIDLDNW-UHFFFAOYSA-N
M.W :	288.96	Pubchem ID :	66715127
Synonyms :

Calculated chemistry of [ 1003298-87-0 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	74.96
TPSA :	38.69 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.81
Log Po/w (WLOGP) :	3.0
Log Po/w (MLOGP) :	2.2
Log Po/w (SILICOS-IT) :	2.63
Consensus Log Po/w :	2.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.21
Solubility :	0.0177 mg/ml ; 0.0000613 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.32
Solubility :	0.0139 mg/ml ; 0.0000482 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.65
Solubility :	0.0065 mg/ml ; 0.0000225 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.9

Safety of [ 1003298-87-0 ]

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 [ 1003298-87-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1003298-87-0 ]

[ 1003298-87-0 ] Synthesis Path-Downstream 1~53

1
[ 1984-65-2 ]
[ 25015-63-8 ]
[ 1003298-87-0 ]

Yield	Reaction Conditions	Operation in experiment
	(Ind)Ir(COD); 1,2-bis(dimethylphosphanyl)ethane; at 150.0℃; for 16.0h;	2,6-Dichloro-1,4-hydroquinone (9): The general process was applied to 2,6-dichloroanisole (177 mg, 1.0 mmol). The borylation step was carried out neat with HBPin (320 mg, 2.5 mmol) and dmpe (3.0 mg, 0.02 mmol, 2 mol %) at 150 C. for 16 hours. The oxidation step was then performed, after which the crude material was dissolved in ether and passed through a plug of silica gel (pentane/ether 2:1). Evaporation of solvent gave 140 mg material containing 120 mg hydroquinone 9 (67%) and 20 mg water. Sublimation at 90 C. under 0.08 mmHg or recrystallization from CH2Cl2 afforded analytically pure 9 as a white solid; mp 160-161 C. (lit. 164). 1H NMR (300 MHz, acetone-d6): delta8.43 (brs, 1 H), 8.24 (brs, 1 H), 6.83 (s, 2 H); 13C NMR (75 MHz, acetone-d6): delta150.7, 142.3, 122.3, 115.5; IR (KBr): 3349, 1591, 1482, 1213, 953, 791 cm-1; LRMS: m/e 178 (M+), 142, 114, 86. Anal. Calcd for C6H4Cl2O2: C, 40.26; H, 2.25. Found C, 40.58; H, 2.17. For a previous preparation see Kulkarni and Kate, J. Chem. Soc., Perkin. Trans. 1: 4242-4244 (2000) (photoreduction of 2,6-dichloro-1,4-benzoquinone with a vitamin C derivative, 87% yield). This material is also available from Apin.

Reference： [1]Patent: US2004/30197,2004,A1 .Location in patent: Page 14; 17-18

2
[ 1003298-87-0 ]
1-(6-bromo-4-((trans-4-((dimethyl-d6-amino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone [ No CAS ]
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((trans-4-((dimethyl-d6-amino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Example 864l -(6-(3,5-dichloro-4-hydroxyphenyl)-4-((tra»5-4-((dimethyl-ii6-amino)methyl)cyclohexyl))quinolin-3-yl)ethanone dihydrochlorideTo a suspension ofl -(6-bromo-4-((ira«i'-4-((dimethyl-< 6-amino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone (273 mg, 0.67 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (289 mg, 1.0 mmol) and Pd(dppf)Cl2 (49 mg, 0.067 mmol) in dioxane (20 mL) was added Cs2C03 (1.0 M in H20, 2 mL, 2 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHC03 solution and extracted with a mixture of CHCl3/isopropanol (3: 1 ). The combined organic layers were dried over anhydrous sodium sulfate. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (20 mL) and HC1 (1.25 M in methanol, 8.0 mL, 12 mmol) was added. The resultant solution was concentrated to give the desired product (245 mg, 75%) as a light brown solid. NMR (500 MHz, MeOD) 5 9.1 1 (s, 1H), 8.47 (s, 1 H), 8.27 (dd, J = 8.8, 1 .8 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1H), 7.73 (s, 2H), 4.54 (br s, 1 H), 3.08 (d, J = 6.6 Hz, 2H), 2.74 (s, 3H), 2.46 (d, J = 12.3 Hz, 2H), 2.10 - 2.00 (m, 3H), 1.87 - 1 .75 (m, 2H), 1 .36 (q, J= 12.9 Hz, 2H).ESI MS m/z 492 [C26H23D6C12N302 + H]+; HPLC >99% (AUC), tR = 9.81 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 462

3
[ 1003298-87-0 ]
[ 1356951-19-3 ]
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		Example 836l -(6-(3,5-dichloro-4-hydroxyphenyl)-4-((l -(l -methylpiperidin-4-yl)-l H-pyrazol-4-yl)amino)qui nolin-3-yl)ethanone dihydrochlorideTo a suspension ofl -(6-bromo-4-((l -(l -methylpiperidin-4-yl)-l H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (50 mg, 0.1 16 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2C03 (1.0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHC03 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (4 mL) and HC1 (1 .25 M in methanol, 1 .0 mL, 1 .25 mmol) was added. The resultant solution was concentrated to give the desired product (18.6 mg, 27%) as a yellow solid. NMR (500 MHz, MeOD) delta 9.26 (s, 1 H), 8.25 - 8.1 8 (m, 1 H), 8.1 8 - 8.07 (m, 2H), 8.00 (d, J= 8.8 Hz, 1 H), 7.71 (s, 1 H), 7.36 - 7.32 (m, 2H), 4.70 - 4.61 (m, 1 H), 3.68 (d, 2H), 3.53 - 3.45 (m, 1 H), 3.41 - 3.22 (m, 1 H), 2.94 (s, 3H), 2.80 (s, 3H), 2.53 - 2.33 (m, 4H). ESI MS m/z 510 [C26H25C12N502 + H]+; HPLC 97.4% (AUC), tK = 9.46 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 460-461

4
[ 1003298-87-0 ]
[ 1356951-21-7 ]
cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-((6-(3-(methylamino)piperidin-1-yl)pyridin-3-yl)amino)quinolin-3-yl)methanone trihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		Example 807cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyI)-4-((6-(3-(methylamino)piperidin-l -yl)pyridin-3-y l)amino)quinolin-3-yl)methanone trihydrochlorideTo a suspension of tert-butyl(l -(5-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)(met hyl)carbamate (80 mg, 0.137 mmol),2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2C03 (1.0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHC03 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a brown solid. This solid was dissolved in THF (3 mL) and TFA (2 mL). The reaction mixture was heated at 65 C for 16 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (CI 8 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (8 mL) and HC1 (6 M in water, 1 .0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (39.6 mg, 43%) as an orange solid. NMR (500 MHz, MeOD) delta 9.39 (s, 1 H), 8.29 - 8.21 (m, 2H), 8.19 (s, 1H), 8.04 (d, J= 8.8 Hz, 1 H), 7.78 (dd, /= 9.3, 2.7 Hz, 1H), 7.40 (s, 2H), 7.25 (d, J = 9.3 Hz, 1H), 4.44 (br s, 1H), 4.00 - 3.92 (m, 1H), 3.61 (br s, 1H), 3.48 - 3.36 (m, 1H), 3.37 - 3.32 (m, 1H), 2.89 - 2.81 (s, 1 H), 2.80 (s, 3H), 2.28 - 2.22 (m, 1 H), 2.02 - 1 .94 (m, 1H), 1.87 - 1 .69 (m, 2H), 1.24 - 1.16 (m, 4H). ESI MS m/z 561 [C3oH29Cl2N502 + H]+; HPLC 97.8% (AUC), tR = 10.73 min

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 456-457

5
[ 1003298-87-0 ]
[ 1356951-22-8 ]
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Example 814l -(6-(3,5-dichloro-4-hydroxyphenyl)-4-((l -(l -methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)amino) quinolin-3-yl)ethanone dihydrochloride To a suspension ofl -(6-bromo-4-((l -(l -methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)amino)quinolin-3-yl)eth (80 mg, 0.19 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2C03 (1.0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHC03 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by columnchromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was further purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The resultant residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (66.2 mg, 60%) as a yellow solid. NMR (500 MHz, MeOD) delta 9.27 (br s, 1 H), 8.26 - 8.17 (m, 2H), 8.1 1 (s, 1 H), 8.02 (d, J= 8.8 Hz, l H), 7.79 (s, 1 H), 7.37 (s, 2H), 5.41 (br s, 1 H), 4.25 - 3.93 (m, 2H), 3.84 - 3.32 (m, 2H), 3.21 - 3.03 (m, 3H), 2.82 - 2.78 (br s, 1H), 2.80 (3, 3H), 2.39 (br s, 1 H). ESI MS m/z 496 [C25H23C12N502 + H]+; HPLC >99% (AUC), tR = 9.56 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 457-458

6
[ 1003298-87-0 ]
(6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone [ No CAS ]
cyclopropyl (6-(3,5-dichloro-4-hydroxyphenyl)-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino)quinolin-3-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80.0℃; for 2.0h;Inert atmosphere;	Example 584cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl) -((tran^-4-(pyrrolidin-l -ylmethyl)cyclohexyl)a mino)quinolin-3-yl)methanoneTo a suspension of(6-bromo-4-((tmra-4-(pyrrolidin-l -ylmethy])cyclohexyl)anriino)quinolin-3-y])(cyclopropyl)meth anone (46 mg, 0.10 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.015 mmol) in dioxane (4 mL) was added CS2CO3 (1.0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to roomtemperature, then directly subjected to column chromatography (silica, 0-20%methanol/dichloromethane). The resultant residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the desired product (22.1 mg, 41 %) as a yellow solid. *H N R (500 MHZ, MeOD) delta 9.09 (s, 1 H), 8.28 (d, J= 2.1 Hz, 1 H), 7.97 - 7.91 (m, 1 H), 7.84 (d, J= 8.7 Hz, 1 H), 7.55 (s, 2H), 4.19 - 4.10 (m, 1 H), 3.14 - 3.07 (m, 4H), 2.89 - 2.78 (m, 3H), 2.31 (d, J = 12.6 Hz, 5H), 2.04 - 1 .97 (m, 4H), 1 .83 - 1.79 (m, 1 H), 1 .57 (q, J = 12.3 Hz, 4H), 1 .32 - 1.04 (m, 6H). ESI MS m/z 538 [C30H33CI2N3O;. + H]+; HPLC >99% (AUC), tR = 1 1 .29 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 438

7
[ 1003298-87-0 ]
(6-bromo-4-((trans-4-((3-methoxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone [ No CAS ]
cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-((trans-4-((3-methoxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80.0℃; for 2.0h;Inert atmosphere;	Example 598cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-((tr<3 75-4-((3-methoxypyrrolidin- l -yl)methyl)c yclohexyl)amino)quinolin-3-yl)methanone To a suspension of(6-bromo-4-((tra«5-4-((3-methoxypyrrolidin-l -yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclo propyl)methanone (49 mg, 0.10 mmol),2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.01 5 mmol) in dioxane (4 mL) was added Cs2C03 (1.0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to room temperature, then directly subjected to column chromatography (silica, 0-20% methanol/dichloromethane). The resultant residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the desired product (30.6 mg, 54%) as a yellow solid. NMR (500 MHz, MeOD + TFA-d) delta 9.36 (br s, 1 H), 8.47 (br s, 1H), 8.27 (dd, J = 8.7, 1 .8 Hz, 1H), 7.98 (d, J= 8.7 Hz, 1H), 7.75 - 7.71 (s, 2H), 4.53 - 4.49 (br s, 1 H), 4.19 (d, J = 18.9 Hz, 1 H), 3.85 - 3.74 (m, 2H), 3.35 (s, 3H), 3.28 - 3.26 (m, 1 H), 3.25 - 3.12 (m, 3H), 2.84 (br s, 1H), 2.45 - 2.29 (m, 3H), 2.20 - 1 .97 (m, 4H), 1.80 - 1.73 (m, 2H), 1 .37 -1.18 (m, 6H). ESI MS m/z 568 [C3iH35CI2N303 + H]+; HPLC >99% (AUC), / = 1 1 .42 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 438-439

8
[ 1003298-87-0 ]
(6-bromo-4-((trans-4-((methylamino)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone [ No CAS ]
cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-((trans-4-((methylamino)methyl)cyclohexyl)amino)quinolin-3-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80.0℃; for 2.0h;Inert atmosphere;	Example 685cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-((tro«5-4-((methylamino)methyl)cyclohexyl)a mino)quinolin-3-yl)methanone To a suspension of(6-bromo-4-((tra«5-4-((methylamino)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)meth anone (42 mg, 0.10 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yI)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (1 1 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2C03 (1 .0 M in H20, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80 C for 2 h. The solution was allowed to cool to roomtemperature, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by preparative HPLC (CI 8 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (14.7 mg, 29%) as a yellow solid. NMR (500 MHz, MeOD + TFA-d) delta 9.35 (br s, 1 H), 8.47 (br s, 1 H), 8.27 (dd, J= 8.8, 1 .8 Hz, 1 H), 7.98 (d, J= 8.7 Hz, 1 H), 7.74 (s, 2H), 4.52 (br s, 1 H), 2.94 (d, J = 6.9 Hz, 2H), 2.83 (br s, 2H), 2.73 (s, 3H), 2.46 - 2.42 (br s, 2H), 2.05 (d, J= 13.0 Hz, 2H), 1.88 (br s, 1H), 1 .77 - 1.68 (m, 2H), 1.36 - 1.19 (m, 6H). ESI MS m/z 498 [C27H29C12N302 + H]+; HPLC >99% (AUC), tR = 1 1 .08 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 442-443

9
[ 1003298-87-0 ]
[ 1356951-43-3 ]
cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-(trans-4-((dimethylamino)methyl)cyclohexylamino)quinolin-3-yl)methanone hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure F (6-position substitution)To a suspension of intermediates F (1.0 equiv), the requisite boronic ester ( 1.5-2.0 equiv) and Pd(dppf)Cl2 (0.1-0.2 equiv) in dioxane was added Cs2C03 ( 1 .0 M in H20, 3.0 equiv). The reaction mixture was degassed with nitrogen followed by heating at 80 C for 2 - 3 h. The reaction mixture was cooled, diluted with ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product.; Example 416l-(6-(3,5-dichloro-4-hydroxyphenyl)-4-(4-(pyrrolidin-l -ylmethyl)phenylamino)quinolin-3- l ethanone h dr bromideFollowing general procedure F, l -(6-bromo-4-(4-(pyrrolidin-l -ylmethyl)phenylamino)quinoline -3-yl)ethanone (4.0 g, 9.42 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenol (4.0 g, 14.13 mmol) to obtain the free base. The purified product was suspended in dichloromethane / methanol (1 :1 , 40 mL) and HBr gas was bubbled through the suspension until a solution formed. The solution was concentrated to dryness and the resultant solid was triturated with diethyl ether. The mixture was filtered, washed with diethyl ether, and dried to obtain desired product (3.37 g, 52% over two steps) as a yellow solid: NMR (300 MHz, DMSO-< ) delta 12.03 (br s, 1 H), 10.59 (br s, 1H), 10.08 (br s, 1 H), 9.27 (s, 1 H), 8.43 - 8.27 (m, 2H), 8.1 12 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 2H), 7.59 - 7.47 (m, 4H), 4.47 (d, J = 5.3 Hz, 2H), 3.40 - 3.24 (m, 2H), 3.19 - 3.02 (m, 2H), 2.56 (s, 3H), 2.13 - 1 .81 (m, 4H); APCI MS m/z 506 [C28H25C12N302 + H]+; HPLC >99% (AUC), fR = 4.97 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 256; 349-350

10
[ 1003298-87-0 ]
tert butyl 1-(((1R,4R)-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexyl)methyl)piperidin-3-ylcarbamate [ No CAS ]
1-(4-((1R,4R)-4-((3-aminopiperidin-1-yl)methyl)cyclohexylamino)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-3-yl)ethanone trihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		Example 810l -(4-(lR,4R)-4-((3-aminopiperidin-l-yl)methyl)cyclohexylamino)-6-(3,5-dichloro-4-hydroxy phenyl)quinolin-3-yl)ethanoneTo a suspension of tert-butyl1 -((1 R,4R)-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexyl)methyl)piperidin-3-ylcarbamate (80 mg, 0.173 mmol), 2,6-dichIoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.260 mmol) and Pd(dppf)Cl2 (12 mg, 0.017mmol) in dioxane (4 mL) was added Cs2C03 (260 muL·, 2.0 M solution in H20). N2 gas was bubbled through the reaction mixture and the vessel was sealed. The mixture was then heated under microwave irradiation conditions to 140 C for 30 min. The solution was allowed to cool to it, then directly subjected to purification by preperatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HCl solution in diethyl ether to afford the product (26 mg, 23%) as an off-white solid: 'H NMR (500 MHZ, MeOD) 5 9.01 (s, l H), 8.37 (s, 1 H), 8.17 (dd, J= 8.7, 1 .9 Hz, 1 H), 7.89 (d, J= 8.7 Hz, 1H), 7.62 (s, 2H), 4.45 (s, 1H), 3.73 (s, 2H), 3.61 (s, 1 H), 3.1 1 (d, J= 6.1 Hz, 2H), 2.97 (s, 1H), 2.65 (s, 3H), 2.36 (s, 2H), 2.08 (m, 6H), 1 .72 (q, J = 12.4 Hz, 2H), 1.62 (s, 1H), 1.31 (q, J= 1 1.9 Hz, 2H); ESI MS m/z 541 , [C29H34C12N402 + H]+; HPLC 98.3% (AUC), /R = 9.34 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 476-477

11
[ 1003298-87-0 ]
[ 1356954-20-5 ]
4-(4-(6-(3-aminopiperidin-1-yl)pyridin-3-ylamino)-3-(methylsulfonyl)quinolin-6-yl)-2,6-dichlorophenol trihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		Example 9134-(4-(6-(3-aminopiperidin-l -yl)pyridin-3-ylamino)-3-(methylsulfonyl)quinolin-6-yl)-2,6-dichlorophenolTo a suspension of tert-butyl l-(5-(6-bromo-3-(methylsulfonyl)quinolin-4-ylamino)pyridin-2-yl) piperidin-3-ylcarbamate (70 mg, 0.121 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenol (40 mg, 0.142 mmol) and Pd(dppf)Cl2 (9 mg, 0.012 mmol) in dioxane (4 mL) was added Cs2C03 (182 muL, 2.0 M solution in H20). N2 gas was bubbled through the reaction mixture, the vessel was sealed and the mixture was then heated imicrowave irradiation conditions to 140 C for 30 min. The solution was allowed to cool to rt, then directly subjected to purification by preperatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HCl solution in diethyl ether to afford the product (8.2 mg, 10%) as an orange solid: NMR (500 MHz, MeOD) delta 9.03 (s, 1 H), 8.27 (d, J= 2.7 Hz, IH), 8.24 (dd, J=8.8, 1.9 Hz, I H), 8.01 (d, J= 8.8 Hz, IH), 7.93 (d, J= 1.9 Hz, IH), 7.74 (dd, J= 9.2, 2.7 Hz, IH), 7.22 (s, 2H), 7.1 1 (d, J- 9.2 Hz, IH), 4.60(s, 1 H), 4.05 (d, J= 13.5 Hz, 1 H), 3.45 (s, 3H), 3.26 (m, 3H), 2.19 (d, J= 1 1 .1 Hz, IH), 1.94 (d, J= 1 1.0 Hz, IH), 1.71 (m, 2H); ESI MS m/z 558,[C26H25Cl2N503S + H]+; HPLC 98.9% (AUC), iR = 10.14 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 484

12
[ 1003298-87-0 ]
(S)-tert-butyl 2-((1r,4S)-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
(S)-N-((1R,4S)-4-(3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino)cyclohexyl)pyrrolidine-2-carboxamide dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		Example 920(S)-N-(( l R,4S)-4-(3-acetyI-6-(3,5-dichloro-4-hydroxyphenyI)quinolin-4-ylamino)cyclohexyl)pyrrolidine-2-carboxamide To a suspension of (S)-tert-butyl 2-((l r,4S)-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexyl carbamoyl)pyrrolidine-l -carboxylate (70 mg, 0.125 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.150 mmol) and Pd(dppf)Cl2 (9 mg, 0.013 mmol) in dioxane (4 mL) was added Cs2C03 (187 mu, 2.0 M solution in H20). N2 gas was bubbled through the reaction mixture and the vessel was sealed. The mixture was then heated under microwave irradiation conditions to 140 C for 30 min. The solution was allowed to cool to rt, then directly subjected to purification by preperatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HC1 solution in diethyl ether to afford the product (40 mg, 52%) as a yellow solid: NMR (500 MHz, MeOD) delta 9.12 (s, 1 H), 8.51 (s, 1 H), 8.30 (dd, J = 8.8, 1 .8 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.75 (s, 2H), 4.57 (s, 1 H), 4.24 (m, 1 H), 3.90 (t, J= 1 1.8 Hz, 1 H), 3.44 (dt, J= 1 1.5, 6.9 Hz, 1 H), 3.36 (m, 1 H), 2.76 (s, 3H), 2.46 (m, 3H), 2.19 (d, J= 12.2 Hz, 2H), 2.05 (m, 3H), 1.87 (q, J= 13.5 Hz, 2H), 1 .58 (p, J= 13.7, 13.2 Hz, 2H); ESI MS m/z 541, [C28H30Cl2N4O3 + H]+; HPLC 97.7% (AUC), tK = 9.94 min.

Reference： [1]Patent: WO2012/16082,2012,A1 .Location in patent: Page/Page column 486-487

13
[ 1003298-87-0 ]
(S)-(4-(6-(3-aminopiperidn-1-yl)pyridin-3-ylamino)-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl)(cyclopropyl)methanone trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/109388,2013,A2

14
[ 1003298-87-0 ]
[ 1448361-66-7 ]
1-{6-(3,5-dichloro-4-hydroxyphenyl)-4-[trans-4-(dimethylamino)cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		General procedure: To a suspension of intermediate L ( 1.0 equiv), the requisite boronic ester ( 3.5 - 2.0 equiv) and Pd(dppf)Cl2 (0.1 - 0.2 equiv) in dioxane (0.1 - 0.2 M) was added Cs2C03 (1.0 M in H2O, 3.0 - 4.0 eq). The reaction mixture was degassed with nitrogen and stirred with heat at 80 C for 2 - 24 h. The reaction mixture was cooled, poured onto satd. aq. sodium bicarbonate and extracted with 3: 1 chloroform/isopropanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by chromatography (norma phase silica using meihanol/dichloromethane or reverse phase silica using water/aceton strile containing 0.025% TFA) to afford the target compound. In some instances the product was diluted in methanol followed by the addition of excess HCl (2.9 - 5.0 equiv as a solution in ether, methanol, dioxane or water). After 5 min the mixture was concentrated to dryness to obtain the HCl salt of the target compound.

Reference： [1]Patent: WO2013/109388,2013,A2 .Location in patent: Page/Page column 78; 81

15
[ 1003298-87-0 ]
(S)-tert-butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylnmino]pyridin-2-yl}piperidin-3-ylcarbamate [ No CAS ]
[ 1448361-79-2 ]

Yield	Reaction Conditions	Operation in experiment
60%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80.0℃;Inert atmosphere;	General procedure: To a suspension of intermediate L ( 1.0 equiv), the requisite boronic ester ( 3.5 - 2.0 equiv) and Pd(dppf)Cl2 (0.1 - 0.2 equiv) in dioxane (0.1 - 0.2 M) was added Cs2C03 (1.0 M in H2O, 3.0 - 4.0 eq). The reaction mixture was degassed with nitrogen and stirred with heat at 80 C for 2 - 24 h. The reaction mixture was cooled, poured onto satd. aq. sodium bicarbonate and extracted with 3: 1 chloroform/isopropanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by chromatography (norma phase silica using meihanol/dichloromethane or reverse phase silica using water/aceton strile containing 0.025% TFA) to afford the target compound. In some instances the product was diluted in methanol followed by the addition of excess HCl (2.9 - 5.0 equiv as a solution in ether, methanol, dioxane or water). After 5 min the mixture was concentrated to dryness to obtain the HCl salt of the target compound.

Reference： [1]Patent: WO2013/109388,2013,A2 .Location in patent: Page/Page column 78; 164; 165

16
[ 3217-15-0 ]
[ 73183-34-3 ]
[ 1003298-87-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; for 26.0h;Inert atmosphere; Heating;	To a roundbottom flask that was flame dried, cooled under hi-vac, and purged with nitrogen was added 4-bromo-2,6-dichloro-phenol (S26, 2.90 g, 12.0 mmol), 1,4-dioxane (48.0 mL, 0.25 M), KOAc(2.36 g, 24.0 mmol) and bis(pinacolato)diboron (3.35 g, 13.2 mmol). The solution was degassedwith nitrogen via bubbling for 10 minutes, then Pd(dppf)Cl2?CH2Cl2 (0.245 g, 0.3000 mmol) wasadded and the reaction was degassed via bubbling for an additional 5 minutes. The resultingsolution was heated to 90 C under nitrogen for 26 h. The reaction was cooled to 23 C, dilutedwith hexanes (100 mL) and filtered through a 1 × 2 inch pad of silica gel, washing with 100 mLof 4:1 hexanes:EtOAc. The solvent was removed by rotary evaporation and the resulting oil waspurified by flash chromatography (9:1 to 4:1 hexanes/EtOAc). The fractions containing thedesired product were combined and the solvent was removed via rotary evaporation. Theresulting oil was diluted with hexanes (15 mL) and cooled at -20 C for 6 h. The liquid waspipetted off and the solid was rinsed with an additional 10 mL of cold hexanes to afford 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (S27, 2.58 g, 74% yield, Rf =0.50 in 4:1 hexanes/EtOAc) as a white solid.
44%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90.0℃; for 16.0h;Inert atmosphere;	A flask was charged with 4-bromo-2,6-dichloropbenol (45 g, 0.20 mol), KOAc (39 g, 0.40 mol), bis(pinacoiato)diboron (61 g, 0.22 mol) and Pd(dppf)Cl3 (8.1 g, 0.010 mol) followed by the addition of 1 ,4-dioxane (1200 nuL). T he reaction mixture was degassed with nitrogen and stirred with heat at 90 C for 16 h. The reaction mixture was cooled, diluted with methylene chloride, filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography (silica, hexanes/ethyl acetate) to obtain a yeilow oil which was treated with hexanes and the resulting solids were filtered to obtain the desired product (24 g, 44%) as a white solid: NMR (500 MHz, CDClj) delta 7.57 (t, J= .3 Hz, 1 H), 7.42 (dd, J - 10.2, 1 .3 Hz, 1H), 1 -33 (s, I2H).

Reference： [1]Bioorganic and Medicinal Chemistry,2020,vol. 28
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 8337 - 8352
[3]Patent: WO2013/109388,2013,A2 .Location in patent: Page/Page column 156; 157

17
[ 1003298-87-0 ]
methyl 5-phenyl-4-(3-trifluoromethylsulfonyloxyphenyl)isoxazole-3-carboxylate [ No CAS ]
methyl 4-(3',5'-dichloro-4'-hydroxy-3-biphenyl)-5-phenylisoxazole-3-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8337 - 8352

18
[ 1003298-87-0 ]
methyl 5-methyl-4-(3-trifluoromethanesulfonyloxyphenyl)-isoxazole-3-carboxylate [ No CAS ]
methyl 4-(3',5'-dichloro-4'-hydroxy-3-biphenyl)-5-methylisoxazole-3-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8337 - 8352

19
[ 1003298-87-0 ]
4-(3',5'-dichloro-4'-hydroxy-3-biphenyl)-5-methylisoxazole-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8337 - 8352

20
[ 1003298-87-0 ]
5-bromo-6-phenylpyrazin-2-amine [ No CAS ]
4-(5-amino-3-phenylpyrazin-2-yl)-2,6-dichlorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg	In 1,4-dioxane; water; at 80.0℃; for 18.0h;Inert atmosphere;	To a solution of 5-bromo-6-phenylpyrazin-2-amine (100 mg, 0.40 mmol, 1 eq.) in 1,4-dioxane-water (10 mL, 4:1) was added <strong>[1003298-87-0]2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol</strong> (174 mg, 0.48 mmol, 1.2 eq.), Cs2CO3 (391 mg, 1.20 mmol, 3.0 eq.), PdCl2(dppf)CH2Cl2 complex (32 mg, 0.04 mmol, 0.05 eq.). The reaction mixture was deoxygenated using N2 atmosphere and the reaction mixture was allowed to stir at 80 C. overnight. The progress of reaction was monitored by TLC and LCMS and found to be complete after 18 h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted using ethyl acetate (3*50 mL). Combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave crude which was purified by SFC to afford 15 mg (11 of 4-(5-amino-3-phenylpyrazin-2-yl)-2,6-dichlorophenol. LCMS: 332 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 6.28 (s, 2H), 6.64 (s, 1H), 7.10 (s, 2H), 7.38 (s, 4H), 7.90 (s, 1H).

Reference： [1]Patent: US2019/23666,2019,A1 .Location in patent: Paragraph 0337; 0338

21
[ 1003298-87-0 ]
C₁₈H₂₄ClN₅O [ No CAS ]
[ 76-05-1 ]
6-(3,5-dichloro-4-hydroxyphenyl)-4-(((trans)-4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridine-3-carboxamide trifluoroacetic acid salt [ No CAS ]