[ CAS No. 955369-56-9 ] {[proInfo.proName]}

Name: 955369-56-9|2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one|95%
Brand: Ambeed
SKU: A272272
Rating: 96 (30 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 955369-56-9 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 955369-56-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 955369-56-9 ]

SDS Specification

Alternatived Products of [ 955369-56-9 ]

Product Details of [ 955369-56-9 ]

CAS No. :	955369-56-9	MDL No. :	MFCD19443207
Formula :	C₁₇H₁₉N₅O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CTAHQYLRFXBFKB-UHFFFAOYSA-N
M.W :	357.43	Pubchem ID :	67170189
Synonyms :

Calculated chemistry of [ 955369-56-9 ]

Physicochemical Properties

Num. heavy atoms :	25
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.29
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	98.67
TPSA :	111.13 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.02
Log Po/w (XLOGP3) :	2.14
Log Po/w (WLOGP) :	2.0
Log Po/w (MLOGP) :	1.8
Log Po/w (SILICOS-IT) :	2.05
Consensus Log Po/w :	2.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.52
Solubility :	0.108 mg/ml ; 0.000303 mol/l
Class :	Soluble
Log S (Ali) :	-4.11
Solubility :	0.028 mg/ml ; 0.0000784 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.12
Solubility :	0.0271 mg/ml ; 0.0000759 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.34

Safety of [ 955369-56-9 ]

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

Application In Synthesis of [ 955369-56-9 ]

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

Upstream synthesis route of [ 955369-56-9 ]
Downstream synthetic route of [ 955369-56-9 ]

[ 955369-56-9 ] Synthesis Path-Upstream 1~4

1
[ 955369-56-9 ]
[ 16153-81-4 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	Stage #1: With 3-chloro-benzenecarboperoxoic acid In toluene for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene	817 mg of m-chloroperbenzoic acid (> 65percent) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) δ: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501
1.2 g	Stage #1: With 3-chloro-benzenecarboperoxoic acid In toluene for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene	Step 3) Production of 2-allyl-l-[6-(l -hydroxy- l-methylethyl)pyridin-2-yl]-6- [4-(4- methylpiperazin- 1 -yl)phenyl] amino} - 1 ,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin- 3 -one: 817 mg of m-chloroperbenzoic acid (> 65percent) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred fro 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) δ: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 29-30
[3] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 30-31
[4] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 32
[5] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2013/39854, 2013, A1, . Location in patent: Page/Page column 28
[7] Patent: WO2014/62454, 2014, A1, . Location in patent: Page/Page column 32
[8] Patent: US2016/8361, 2016, A1, . Location in patent: Paragraph 0164

2
[ 638218-78-7 ]
[ 955368-90-8 ]
[ 955369-56-9 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: US2016/8361, 2016, A1, . Location in patent: Paragraph 0163
[3] ACS Chemical Biology, 2016, vol. 11, # 4, p. 921 - 930
[4] Patent: WO2017/75629, 2017, A2, . Location in patent: Page/Page column 34; 35

3
[ 26218-75-7 ]
[ 955369-56-9 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: WO2017/75629, 2017, A2,
[3] Patent: US2016/8361, 2016, A1,

4
[ 5909-24-0 ]
[ 955369-56-9 ]

Reference： [1] ACS Chemical Biology, 2016, vol. 11, # 4, p. 921 - 930
[2] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[3] Patent: WO2017/75629, 2017, A2,

[ 955369-56-9 ] Synthesis Path-Downstream 1~88

Yield	Reaction Conditions	Operation in experiment
81%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 80 - 95℃; for 18h;	General procedure: (0225) General procedure for the preparation of pyridyl pyrazolopyrimidinones. N,N'- Dimethylethylenediamine (2.0 equiv.) was added to a solution of the relevant pyrazolopyrimidine (1.0 equiv.), the relevant bromopyridine (1.3 equiv.), copper iodide (1.0 equiv.) and K2C03 (1.4 equiv.) in 1,4-dioxane (2 mL/mmol) at 80 C. The resultant suspension was heated at 95 C for 18 h, over which time a color change of orange to dark green occurred. The reaction mixture was cooled to RT and diluted with NH4OH (10 ml) before being extracted with EtOAc (2 x 10 mL/mmol). The combined organic extracts were washed with brine (10 mL/mmol), dried (MgS04) and evaporated to dryness before the crude material was purified via chromatography on silica. Synthesis of 1 -(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 1-(6-(2-Hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (0.177 g, 0.90 mmol), 2-(6-bromopyridin-2-yl)propan-2-ol (0.253 g, 1.17 mmol), copper iodide (0.172 g, 0.90 mmol), K2C03 (0.174 g, 1.26 mmol) and L/,L/'-dimethylethylenediamine (194 pL, 1.80 mmol) were reacted in 1,4-dioxane (2 mL) according to the described general procedure. Purification on silica gel (19:1 DCM:MeOH) gave the desired compound as a white solid (0.215 g, 0.65 mmol, 72%). Rf 0.34 (19:1 DCM:MeOH); M.p. 155-158 C; IR (cm 1) 3432, 2973, 2928, 1683, 1604, 1562; 1H NMR (400 MHz, DMSO-d6) 1.46 (6H, s, C(CH3)2), 2.56 (3H, s, SCH3), 3.49 (3H, s, N2-CH3), 5.35 (1 H, s, OH), 7.67 (1 H, dapp, J = 7.7 Hz, H-5'), 7.79 (1 H, dapp, J = 8.2 Hz, H-3'), 8.06 (1 H, ddapp, J = 8.2, 7.7 Hz, H-4'), 9.00 (1 H, s, H-4); 13C NMR (100 MHz, DMSO- e) 14.4 (SCH3), 30.9 (C(CH3)2), 32.8 (N2-CH3), 72.8 (C(CH3)2), 104.8, 1 16.6, 1 17.5, 139.7, 146.8, 154.7, 158.3, 160.4, 168.4, 175.9; MS [M + H]+ m/z 332.6.
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	General procedure: Production of 2-allyl-6-(methylthio)- 1 -pyridin-2-yl-3 H-pyrazolo [3 ,4-d]pyrimidin-3 -one : 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(memyltWo)-l,2-dmydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3,80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. iH-NMR (400 MHz, CDCI3) 5: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s).
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	General procedure: Preparative Example 1-1 Production of 2-allyl-6-(methylthio)-l-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one: 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. lH-NMR (400 MHz, CDCI3) delta: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s).

With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere;

General procedure: Cuprous iodide (599.92 mg, 3.15 mmol), N,N-dimethylethylenediamine (310.99 mg, 3.53 mmol, 379.26 muL) and potassium carbonate (600.80 mg, 4.35 mmol) were added separately into compound I1 (700.00 mg, 3.15 mmol) and 2-bromopyridine (497.59 mg, 3.15 mmol, 299.75 muL) in dioxane solution. Under nitrogen atmosphere, the reaction mixture was stirred at 95C for 48 hours and then added 40 mL ammonia after concentration, then extracted by EtOAc 350 mL (70 mL×5), and washed by saturated brine 150 mL, dried over anhydrous sodium sulfate, then filtered to give the crude compound 3-A. MS m/z: 300.0[M+H]+

2
[ 955369-56-9 ]
[ 16153-81-4 ]
[ 67-63-0 ]
2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-([4-(4-methylpiperazin-1-yl)phenyl]amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one isopropanol solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		Example 1 :Production of 2-allyl-l-[6-(l-hvdroxy-l-methylethyl)pyridin-2-yl]-6-[4-(4-methylpiperazin-l- yl)phenyl]amino\|-1.2-dihvdro-3H-pyrazolo[3,4-d1pyrimidin-3-one monohvdrate (Form G)To a stirred solution of 2-allyl-l-[6-(l-hydroxy-l-methylethyl)-2-pyridinyl]-6- (methylthio)-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (2.17 g, 92.2 wt%, 2.00 g assay, 5.60 mmol) in toluene (30 mL) was added m-chloroperbenzoic acid (1.66 g) below 30 C and the mixture was stirred at the same temperature for 30 minutes. Then N,N-diisopropylethylamine (2.92 mL) and 4-(4-methylpiperazin-l-yl)aniline (1.19 g) were added below 30C and the slurry was stirred at ambient temperature for more than 2 hours. Then toluene (30 mL) and isopropanol (50 mL) were added, and washed with aqueous IN sodium hydroxide solution (20 mL) and 15% aqueous sodium chloride solution (10 mL). The aqueous layer was extracted with toluene (20 <n="34"/>mL). The combined organic layers were concentrated to 40 mL and isopropanol (40 mL) was added. The mixture was concentrated to 4OmL and aged at ambient temperature for overnight. The crystal was collected by filtration, washed with isopropanol (20 mL) and dried in vacuo at ambient temperature for overnight to obtain the isopropanol solvate (2.99 g, 75.6 wt%) as a pale yellowish crystal in 81 % yield.

Reference： [1]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 32-33

3
[ 955369-56-9 ]
[ 16153-81-4 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
		3) Production of 2-allyl-l -[6-(I -hydroxy-1 -methylethyl)pyridin-2-yl]-6- [4-(4-methylpiperazin- 1 -yl)phenyl]amino}-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one: <n="31"/>817 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N5N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. IH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.
		Reference Example 3:Production of Form A of Compound A733 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (30 mL) solution of 1.02 g of 2-allyl-l-[6-(l-hydroxy-l-methylethyl)-2-pyridinyl]-6-(methylthio)-l,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 20 minutes. 1.45 mL of N,N- diisopropylethylamine and 710 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was crystallized from ethyl acetate to obtain the entitled compound contaminated with a impurity. This impurity was removed by re-purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2) and collected the fractions not contaminated with the impurity. After concentrated, this was dissolved in ethyl acetate (10 mL) under reflux and the solution was stand over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 655 mg of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (13.8, 1039), (26.4, 544), (6.9, 162), (11.2, 484), (12.4, 135), (20.7, 137), (24.0, 151). DSC: <n="32"/>When DSC of Form A was measured using a TA Instruments DSC QlOOO instrument, the extrapolated melting temperature onset of Form A was 154C with an enthalpy of fusion of 86.4 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 155C.
		Reference Example 5:Production of Form H of Compound A817 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (20 mL) solution of 1.10 g of 2-allyl-l-[6-(l-hydroxy-l-methylethyl)-2-pyridinyl]-6-(methylthio)-l,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 20 minutes. 1.61 mL of N5N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2, chloroform/methanol = 10/1). After the solvent was evaporated away, the residue was re-purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was dissolved in ethyl acetate under reflux and the solution was stand over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 1.20 g of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (5.8, 777), (11.5, 189), (11.6, 217), (5.2, 133), (16.6, 119), (23.3, 80.9), (24.0, 60.8). DSC:When DSC of Form H was measured using a TA Instruments DSC QlOOO instrument, the extrapolated melting temperature onset of Form H was 131C with an enthalpy of fusion of 43.1 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 134C. Before melting, a broad endotherm peak with form conversion was detected at ~100C.

		Reference Example 4:Production of Form D of Compound A20.0 g of m-chloroperbenzoic acid (> 65 %) was added to toluene (500 mL) solution of 24.3 g of 2-allyl-l -[6-(I -hydroxy- l-methylethyl)-2-pyridinyl]-6-(methylthio)- 1,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 40 minutes. 35.5 mL of N,N- diisopropylethylamine and 14.3 g of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Tetrahydrofuran (500 mL) and aqueous saturated sodium hydrogen carbonate solution were added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 11.Og of the crude entitle compound. The filtrate was concentrated and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1 and chloroform/methanol = 1/0 to 7/1). After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 16.9g of the entitle compound. The filtrate was concentrated and the residue was purified through silica gel basic column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 2.5Og of the entitle compound. The combined crude title compounds (30.4g) was recrystallized from isopropanol (300 mL) to obtain 32.2g of the entitled compound as 1 isopropanol adduct. The entitled compound 1 isopropanol adduct (32.2g) was dissolved in ethyl acetate (300 mL) under reflux and the solution was stirred over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 21.2g of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (6.5, 71.0), (10.3, 61.5), (9.3, 40.8), (14.6, 22.5), (18.7, 22.0), (19.5, 55.9), (22.2, 32.2). DSC:When DSC of Form D was measured using a TA Instruments DSC Ql 000 instrument, the extrapolated melting temperature onset of Form D was 173C with an enthalpy of fusion of 66.2 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 174C. Before melting, a small endotherm peak with form conversion was detected at 135~150C.
1.2 g		817 mg of m-chloroperbenzoic acid (> 65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501
1.2 g		Step 3) Production of 2-allyl-l-[6-(l -hydroxy- l-methylethyl)pyridin-2-yl]-6- [4-(4- methylpiperazin- 1 -yl)phenyl] amino} - 1 ,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin- 3 -one: 817 mg of m-chloroperbenzoic acid (> 65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred fro 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.
		817 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N-diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-1-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1, ethyl acetate/ethanol=98/2). After concentrated, this was recrystallized from ethyl acetate to obtain the entitled compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.8 Hz), 7.75 (1H, d, J=7.3 Hz), 7.49 (1H, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (1H, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (1H, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (1H, d, J=10.0 Hz), 4.94 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 29-30
[3]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 30-31
[4]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 32
[5]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 31
[6]Patent: WO2013/39854,2013,A1 .Location in patent: Page/Page column 28
[7]Patent: WO2014/62454,2014,A1 .Location in patent: Page/Page column 32
[8]Patent: US2016/8361,2016,A1 .Location in patent: Paragraph 0164

4
[ 26218-75-7 ]
[ 955369-56-9 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: WO2017/75629,2017,A2
[3]Patent: US2016/8361,2016,A1
[4]Patent: WO2019/165204,2019,A1

5
[ 955369-56-9 ]
[ 99-98-9 ]
2-allyl-6-((4-(dimethylamino)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3Hpyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: mCPBA (0.34 mmol) was added to a solution of pyrazolopyrimidinones 9a-c (0.31 mmol) in toluene (5 ml) and the resulting mixture was stirred at RT for 1 h. DIPEA (1.63 mmol) and the relevant substituted aniline 10a-e (0.40 mmol) were added, and the reaction mixture was stirred at RT for 18 h. Saturated NaHC03 solution (15 ml) was added, and the mixture was extracted with EtOAc (2 x 15 ml). The combined organic extracts were washed with brine (10 ml), dried (MgS04) and concentrated in vacuo. The resultant residue was purified via chromatography on silica (19:1 DCM:MeOH) to give the target compound as a yellow solid (55-72%). 2-Allyl-6-((4-(dimethylamino)phenyl)amino)-1 -(6-(2-hydroxypropan-2-yl)pyridin-2- yl)-1,2-dihydro-3Hpyrazolo[ 3,4-d]pyrimidin-3-one (11a). Rf 0.37 (19:1 DCM:MeOH), M.p. 173-175 C; IR (cm-1) 3325, 3245, 3172, 3056, 2964, 2922, 2357, 1669, 161 1, 1568, 1542, 1516; 1 H NMR (400 MHz, DMSO-d6) 1.47 (6H, s, C(CH3)2), 2.88 (6H, s, N(CH3)2), 4.68 (2H, dapp, J = 6.0 Hz, N2-CH2), 4.83 (1 H, dapp, J = 17.2 Hz, allyl CHtrans), 5.00 (1 H, dapp, J = 10.1 Hz, allyl C-Hcis), 5.32 (1 H, s, OH), 5.67 (1 H, ddW = 17.2, 10.1, 6.0 Hz, allyl C- H), 6.73 (2H, d, J = 8.6 Hz, H-3"/5"), 7.49-7.57 (1 H, m, H-5'), 7.60 (2H, d, J = 8.6 Hz, H- 2"/6"), 7.76 (1 H, dapp, J = 7.3 Hz, H-5'), 8.03 (1 H, dd, J = 7.6, 7.5 Hz, H-4'), 8.81 (1 H, s, H- 4), 10.08 (1 H, br, C6-NH); 13C NMR (125 MHz, DMSO-d6) 30.9 (C(CH3)2), 41.0 (N(CH3)2), 47.1 (N2-CH2), 72.8 (C(CH3)2), 1 13.0, 1 16.0, 1 16.7, 1 18.7, 122.1, 129.0, 132.7, 139.2, 147.5, 168.0; MS [M + H] + m/z 446.3.

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930
[2]Patent: WO2017/75629,2017,A2 .Location in patent: Page/Page column 37

6
[ 2359-60-6 ]
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(piperidin-1-yl)phenyl)amino)-1,2-dihydro-3Hpyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930

7
[ 2524-67-6 ]
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-morpholinophenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930

8
[ 955369-56-9 ]
methyl 4-(4-aminophenyl)piperazine-1-carboxylate [ No CAS ]
methyl 4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930

9
[ 5909-24-0 ]
[ 955369-56-9 ]

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930
[2]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[3]Patent: WO2017/75629,2017,A2
[4]Patent: US2019/106427,2019,A1
[5]Patent: WO2019/165204,2019,A1
[6]Patent: WO2019/165204,2019,A1
[7]Patent: CN110872296,2020,A

10
[ 955369-56-9 ]
2-allyl-6-amino-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: WO2019/28008,2019,A1

11
[ 955369-56-9 ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

12
[ 955369-56-9 ]
[ 2836-04-6 ]
2-allyl-6-((3-(dimethylamino)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

13
[ 955369-56-9 ]
[ 27958-77-6 ]
2-allyl-6-((3-((dimethylamino)methyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

14
[ 955369-56-9 ]
[ 33322-60-0 ]
3-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N,N-dimethylbenzamide [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

15
[ 955369-56-9 ]
[ 5636-52-2 ]
2-allyl-6-((4-(2-(dimethylamino)ethyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

16
[ 955369-56-9 ]
[ 62345-76-0 ]
2-allyl-6-((4-(2-(dimethylamino)ethoxy)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

17
[ 955369-56-9 ]
[ 2393-23-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-methoxybenzyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

18
[ 955369-56-9 ]
[ 62-53-3 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(phenylamino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

19
[ 955369-56-9 ]
[ 1092794-11-0 ]
2-allyl-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-6-((2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of Intermediate 1 (1 eq) in toluene (0.2 to 0.5 M), was added mCPBA (2.0 eq). The reaction was stined at RT for 1 h. DIPEA (5.0 eq) and the conesponding amine (1.0 eq) were added. The reaction was stined at RT for 24 h. NaHCO3 was added, and the mixture was extracted 3x with EA. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography or reverse phase HPLC to give Product Formula (I).

Reference： [1]Patent: WO2019/28008,2019,A1 .Location in patent: Paragraph 0121; 0130

20
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((7-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

21
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

22
[ 955369-56-9 ]
2-allyl-6-((4,4-difluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

23
[ 955369-56-9 ]
tert-butyl 7-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

24
[ 955369-56-9 ]
tert-butyl 7-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,4,4-trimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

25
[ 955369-56-9 ]
tert-butyl (R)-7-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,4,4-trimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]
tert-butyl (S)-7-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,4,4-trimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

26
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Oxone; In tetrahydrofuran; water; at 20℃; for 1h;	General procedure: To a solution of Intermediate 1 (1 eq) in THF/Water (0.2 to 0.5 M) was added oxone (3 eq) at RT (room temperature), and the reaction was stined for 1 h. The reaction was diluted with water and extracted with EA. The combined organic layers were dried (Na2504), filtered and concentrated in vacuo to afford Intermediate B as a pale yellow semi-solid. To a stined solution of Intermediate B (1 eq) in toluene (0.3 to 0.5 M) was added DIPEA (3 eq) and Intermediate C (1 eq). The reaction was stined at RT for 16 h. The reaction was diluted with water, extracted with EA, dried (Na2504), filtered and concentrated. The crude residue was purified by column chromatography or reverse phase HPLC to give Product Formula (I).
1.8 g	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;Cooling with ice;	To a solution of compound Int-1 (2.0 g) in DCM (50 mL) was added m-CPBA (2.95 g) in an ice-water bath, stirred at room temperature overnight, diluted with water, and extracted with 100 mL of DCM. The organic phase was washed with sodium bicarbonate After 3 times, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH, 45: 1, v / v) to give the target product Int-2 (1.8g) as a pale yellow color

Reference： [1]Patent: WO2019/28008,2019,A1 .Location in patent: Paragraph 0120
[2]Patent: CN110872296,2020,A .Location in patent: Paragraph 0140; 0148-0149

27
[ 955369-56-9 ]
7-((2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2019/28008,2019,A1

28
[ 164148-92-9 ]
[ 955369-56-9 ]
tert-butyl 6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		Step-1: Synthesis of tert-butyl 6-(2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a stirred solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (300 mg, 0.84 mmol, 1.0 eq) in toluene (5 mL) was added m-CPBA (361 mg, 2.10 mmol, 2.5 eq) and allowed to stir at RT for 30 min. tert-Butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (208 mg, 0.84 mmol, 1.0 eq) and DIPEA (433 mg, 3.36 mmol, 4.0 eq) were added and allowed to stir at RT for 12 h. Progress of reaction was monitored by LCMS. After completion of reaction, precipitated compound was filtered off, washed with toluene (3 mL) and dried under reduced pressure to obtain tert-butyl 6-(2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (220 mg, 47.00%).

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0305-0307

29
[ 955369-56-9 ]
[ 171049-41-5 ]
tert-butyl 7-(2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Step-4: Synthesis of tert-butyl 7-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylate To a stirred solution of 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidin-3-one (240 mg, 0.67 mmol, 1.0 eq) in 5 mL of toluene was added mCPBA (232 mg, 1.34 mmol, 2.0 eq) and allowed to stir at RT for 20 minutes. Tert-butyl 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (216 mg, 0.87 mmol, 1.3 eq) and DIPEA (260 mg, 2.10 mmol, 3.0 eq) were added and allowed to stir at RT for overnight. Solvent was removed under reduced pressure; residue was diluted with water and extracted with ethyl acetate (30 mL*3). Organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product which was purified by flash chromatography to afford 200 mg (53%) of tert-butyl 7-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylate.

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0252; 0260; 0261

30
[ 645418-66-2 ]
[ 955369-56-9 ]
7-((2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41.4%	With N-ethyl-N,N-diisopropylamine; 3-chloro-benzenecarboperoxoic acid; In toluene; at 20℃; for 16h;	Step-1: Synthesis of tert-butyl 7-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-4,4-dimethyl-1,3-dihydroisoquinoline-2-carboxylate To a stirred solution of 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidin-3-one (500 mg, 1.40 mmol, 1.0 eq) in 5 mL of toluene was added mCPBA (172 mg, 2.80 mmol, 2.0 eq) and allowed to stir at RT for 30 minutes. Tert-butyl 7-amino-4,4-dimethyl-1,3-dihydroisoquinoline-2-carboxylate (424 mg, 1.69 mmol, 1.20 eq) and DIPEA (541 mg, 4.2 mmol, 3.0 eq) were added and allowed to stir at RT for overnight. After completion of reaction, solvent was removed under reduced pressure. Residue was diluted with water and extracted with ethyl acetate (50 mL*2). Combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product which was purified by flash chromatography to afford 340 mg (41.4%) of tert-butyl 7-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-4,4-dimethyl-1,3-dihydroisoquinoline-2-carboxylate.
150 mg		To a toluene solution (15 mL) of compound Int-1 (168 mg) was added m-CPBA (219 mg), and the mixture was stirred at room temperature overnight, and then compound 2 (100 mg) and DIEA (187 mg) were added, and overnight at room temperature. It was diluted with water and extracted with ethyl acetate. The organic phase was washed three times with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, the solvent was removed under vacuum from the filtrate, and the residue was prepared by reversed phase to obtain the final product 3 (150 mg).

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0269-0271
[2]Patent: CN110872296,2020,A .Location in patent: Paragraph 0265-0268

31
ethyl 4-([[(tert-butoxy) carbonyl](prop-2-en-1-yl)amino]amino)-2-(methylsulfanyl)pyrimidine-5-carboxylate [ No CAS ]
[ 955369-56-9 ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: WO2019/165204,2019,A1
[3]Patent: CN110872296,2020,A

32
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one hydrochloride [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

33
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

34
[ 955369-56-9 ]
2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

35
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-6-((1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: CN110872296,2020,A

36
[ 955369-56-9 ]
2-allyl-6-((2-(2-hydroxyacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

37
[ 955369-56-9 ]
2-allyl-6-((4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: CN110872296,2020,A

38
[ 955369-56-9 ]
2-allyl-6-((2-(2-hydroxy-2-methylpropanoyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

39
[ 955369-56-9 ]
2-allyl-6-[(4,4-dimethyl-2,3-dihydro-1H-isoquinolin-7-yl)amino]-1-[6-(1-hydroxy-1-methylethyl)-2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

40
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: CN110872296,2020,A

41
[ 955369-56-9 ]
2-allyl-6-[[2-(2-hydroxyacetyl)-4,4-dimethyl-1,3-dihydroisoquinolin-7-yl]amino]-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1

42
[ 955369-56-9 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-methanesulfinyl-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo [3,4-d] pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.4 mg	With 3-chloro-benzenecarboperoxoic acid; In toluene; at 20℃; for 0.5h;	Into a 8-mL vial, was placed l-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(prop-2-en-l-yl)- lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one (30 mg, 0.084 mmol, 1 equiv), toluene (2 mL, 0.022 mmol, 0.26 equiv), m-CPBA (14.48 mg, 0.084 mmol, 1.00 equiv). The resulting solution was stirred for 2 hr at room temperature. The resulting mixture was concentrated. This resulted in 36.4 mg (116.13%) of l-[6-(2-hydroxypropan-2-yl) pyridin-2-yl]-6- methanesulfinyl-2-(prop-2-en-l-yl)-lH, 2H, 3H- pyrazolo [3, 4-d] pyrimidin-3-one as a white solid. LC-MS (ES, m/z) 374[M+l] +

Reference： [1]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 42

43
[ 955369-56-9 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-([1-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazol-4-yl]amino)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

44
[ 955369-56-9 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-([1-[1'-(propan-2-yl)-[1,4-bipiperidin]-4-yl]-1H-pyrazol-4-yl]amino)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

45
[ 955369-56-9 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-[[1-(propan-2-yl)-1H-pyrazol-4-yl]amino]-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

46
[ 955369-56-9 ]
6-[(1-cyclopentyl-1H-pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride: [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

47
[ 955369-56-9 ]
6-[(1-cyclohexyl-1H-pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

48
[ 955369-56-9 ]
[ 1201935-36-5 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]amino]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%		Into a 50-mL round-bottom flask, was placed a solution of l-[6-(2-hydroxypropan-2- yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(prop-2-en-l-yl)-lH,2H,3H-pyrazolo[3,4-d]pyrimidin- 3-one (50.0 mg, 0.14 mmol, 1.00 equiv, ordered from BePharm Ltd.) in toluene (2 mL), MCPBA (24.0 mg, 1.00 equiv). The resulting solution was stirred for 0.5 h at room temperature. Then DIEA (54.0 mg, 0.42 mmol, 3.00 equiv), l-(l-methylpiperidin-4-yl)-lH- pyrazol-4-amine (30.0 mg, 0.17 mmol, 1.20 equiv) was added. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. (0210) The crude product was purified by Prep-HPLC with the following conditions (0211) (SHIM ADZU (HPLC- 10)): Column, X Bridge Prep C18 OBD Column 19*150mm 5umC- 0013; mobile phase, A: Water(l0 mmon/L NH4HC03); B:ACN (6 min in 31% B, 20 mL/min); Detector, 254 nm. This resulted in 16.3 mg (19%) of l-[6-(2-hydroxypropan-2- yl)pyridin-2-yl]-6-[[l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl]amino]-2-(prop-2-en-l-yl)- lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one as a off-white solid. LC-MS-PH-PHNW-3-2-0 (ES, m/z): [M+H] +: 490. H-NMR-PH-PHNW-3-2-0(300 MHz, CDCl3, ppm): d 8.85 (bs, 1H), 8.80-7.82 (m, 2H), 7.74-7.71 (m, 1H), 7.62-7.56 (m, 2H), 7.45-7.42 (m, 1H), 5.77-5.66 (m, 1H), 5.06 (d, J= 9.9 Hz, 1H), 4.97-4.91 (m, 1H), 4.73 (d, J= 6.3 Hz, 2H), 4.19 (bs, 1H), 3.11- 3.08 (m, 2H), 2.44 (s, 3H), 2.25 (br, 4H), 2.10 (br, 3H), 1.61 (s, 6H).

Reference： [1]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 29-30

49
[ 955369-56-9 ]
1-{4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-1H-pyrazol-4-amine [ No CAS ]
6-[(1-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-1H- pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.7 mg	With N-ethyl-N,N-diisopropylamine; In toluene; at 20℃; for 2h;	Into a 8-mL vial, was placed l-[6-(2- hydroxypropan-2-yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(prop-2-en-l-yl)-lH,2H,3H- pyrazolo[3,4-d]pyrimidin-3-one (50 mg, 0.140 mmol, 1 equiv), toluene (5 mL), l-[4-[4- (cyclopropylmethyl)piperazin-l-yl]cyclohexyl]-lH-pyrazol-4-amine (50.94 mg, 0.168 mmol, 1.20 equiv), DIEA (54.24 mg, 0.420 mmol, 3 equiv). The resulting solution was stirred for 2 hr at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, X-bridge RP18; mobile phase, 0.05% ammonia in water and CH3CN (45% CH3CN up to 60% in 5 min); Detector, (0267) UV 254 nm. This resulted in 8.7 mg (10.15%) of 6-[(l-[4-[4-(cyclopropylmethyl)piperazin-l- yl]cyclohexyl]-lH-pyrazol-4-yl)amino]-l-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2- en-l-yl)-lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one as a white solid. LC-MS-0: (ES, m/z): 613 [M+l] + , 1H NMR (300 MHz, Chloroform-d, ppm) d 8.85 (s, 1H), 7.90-7.85 (m, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.40-7.35 (m, 2H), 5.83 - 5.60 (m, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.94 (d, / = 17.4 Hz, 1H), 4.74 (d, / = 6.3 Hz, 2H), 4.09-4.01 (m, 1H), 3.89 (s, 1H), 2.75 (s, 7H), 2.50-2.20 (m, 5H), 2.20 - 1.95 (m, 3H), 1.89-1.70 (m, 2H), l.53-l.39(m, 3H), 1.29 (s, 5H), 0.90 (s, 1H), 0.57 (d, J = 7.5 Hz, 2H), 0.13 (d, / = 23.4 Hz, 2H).

Reference： [1]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 40-41

50
[ 955369-56-9 ]
C₁₇H₂₁N₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 10 wt% Pd(OH)2 on carbon; hydrogen; In ethanol; at 25℃; under 775.743 Torr; for 12h;	Pd(OH)2/C (100.00 mg, 131.66 mumol, 20% purity) was added into the compound 24-A (100.00 mg, 279.78 mumol) in ethanol (8.00 mL) solution. The reaction mixture was stirred under hydrogen (15 Psi) at 25C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove the solvent so as to give the compound 24-B. MS m/z: 360.2 [M+H]+

Reference： [1]Patent: EP3572413,2019,A1 .Location in patent: Paragraph 0208-0209; 0211

51
[ 955369-56-9 ]
[ 1093095-00-1 ]
C₃₂H₄₀N₈O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		m-Chloroperoxybenzoic acid (117.40 mg, 578.28 mumol, purity:85%) was added into the 24-A (206.69 mg, 578.28 mumol) in toluene (15.00 mL) solution, the mixture was stirred at 20-25C for 1 hour and then added I2 (86.65 mg, 334.06 mumol) and N,N-diisopropylethylamine (224.21 mg, 1.73 mmol, 302.99 muL). After further stirring for 14 hours, the product was concentrated to give the crude compound, the crude compound was purified by preparative HPLC (neutral condition) to give the compound 29. 1H NMR (400 MHz, DMSO-d6) delta1.47 (s, 6 H) 1.47 - 1.50 (m, 4 H) 1.54 (br s, 4 H) 2.17 (s, 3 H) 2.30 (br s, 4 H) 3.09 (br s, 4 H) 4.69 (br d, J=5.02 Hz, 2 H) 4.83 (br d, J=17.07 Hz, 1 H) 5.00 (br d, J=10.04 Hz, 1 H) 5.34 (s, 1 H) 5.60 - 5.79 (m, 1 H) 6.92 (br d, J=8.53 Hz, 2 H) 7.50 - 7.67 (m, 3 H) 7.76 (br d, J=7.53 Hz, 1 H) 8.06 (br s, 1 H) 8.83 (s, 1 H) MS m/z: 569.3 [M+H]+

Reference： [1]Patent: EP3572413,2019,A1 .Location in patent: Paragraph 0229-0231

52
[ 955369-56-9 ]
4-((3-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

53
[ 955369-56-9 ]
4-((3-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)propyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

54
[ 955369-56-9 ]
N-(3-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)propyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propenamide [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

55
[ 955369-56-9 ]
C₂₉H₃₇N₉O₂*C₂HF₃O₂ [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

56
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(piperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

57
[ 955369-56-9 ]
C₃₉H₅₅N₉O₇ [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

58
[ 955369-56-9 ]
C₃₇H₅₁N₉O₄ [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

59
[ 955369-56-9 ]
C₃₄H₄₅N₉O₄ [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

60
[ 955369-56-9 ]
4-((2-(2-(2-(2-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

61
[ 955369-56-9 ]
4-((6-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)hexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

62
[ 955369-56-9 ]
[ 170911-92-9 ]
C₃₁H₃₈N₈O₄ [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 57 - 9,65

63
[ 955369-56-9 ]
[ 264916-06-5 ]
tert-butyl 5-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73 mg		To a toluene solution (15 mL) of compound Int-1 (200 mg) was added m-CPBA (242 mg), and the mixture was stirred at room temperature overnight, and then 5-aminoisoindolin-2-carboxylic acid tert-butyl ester (157 mg) and DIEA (217 mg) at room temperature overnight. It was diluted with water and extracted with ethyl acetate. The organic phase was washed three times with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, the solvent was removed under vacuum from the filtrate, and the residue was prepared by reversed phase to obtain the final product 2 (73 mg).

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0256-0259

64
2-methylisoindolin-5-amine [ No CAS ]
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((2-methylisoindolin-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 mg		Add m-CPBA (121 mg) to a toluene solution (7 mL) of compound 1-1 (100 mg) in an ice-water bath, and stir at room temperature overnight, then add 1-2 (93 mg) and DIEA (180 mg) at 60 C. Stir for 5 hours. Cool to room temperature, dilute with water, extract three times with DCM, wash the combined organic phases with sodium bicarbonate, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated to prepare the target product HY-B022 (1.0 mg) as a white solid.

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0262-0264

65
[ 955369-56-9 ]
2-(2-((tert-butyldimethylsilyl)oxy)ethyl)isoindoline-5-amine [ No CAS ]
2-allyl-6-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)isoindolin-5-yl)amino)-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 mg		To a toluene solution (10 mL) of compound Int-1 (200 mg) was added m-CPBA (291 mg), and the mixture was stirred at room temperature overnight, then compound 3 (163 mg) and DIEA (361 mg) were added, and the mixture was stirred overnight at room temperature. Dilute with water and extract with ethyl acetate. The combined organic phases are washed three times with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo from the filtrate. The residue is passed through a silica gel chromatography column (PE: EA (v / v ) = 2: 1) The target product 4 (60 mg) was isolated and purified as a yellow solid

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0285-0286; 0291-0292

66
[ 69189-26-0 ]
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-6-((2-methyl-3-oxoisoindolin-5-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.6mg		To a toluene solution (5 mL) of compound Int-1 (100 mg), m-CPBA (146 mg) was added and stirred at room temperature overnight to obtain a solution A. NaH (56 mg) was added to a DMF (5 mL) solution in which Compound A-31 (59 mg) was dissolved, and stirred at room temperature for 30 minutes to obtain a mixture B. Then A was slowly added to B and stirred overnight at room temperature. The reaction solution was poured into a saturated ammonium chloride solution, a white solid was precipitated, and the filter cake was purified by thin layer chromatography TLC (dichloromethane: methanol (v / v) = 20: 1) to obtain the standard product HY-B031 (2.6 mg) as a white solid.

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0301-0303

67
[ 61964-08-7 ]
[ 955369-56-9 ]
2-allyl-6-((1,3-dihydroisobenzofuran-5-yl)amino)-1-(6-(2-hydroxyprop-2-yl)pyridine-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23 mg		To a toluene solution containing the compound Int-1 (100 mg) was added m-CPBA (72 mg), followed by stirring at room temperature overnight. DIEA (108 mg) and compound A02 (45 mg) were added to the solution, and then stirred at room temperature for another 8 hours. Ethyl acetate (50 mL) was added, and the organic phase was washed three times with a saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate in vacuo. Ethyl acetate (2 mL) was added to the residue, a white solid was precipitated, filtered, and the solid was dried to give the target product HY-B002 (23 mg).

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0153-0155

68
[ 955369-56-9 ]
[ 22013-33-8 ]
2-allyl-6-((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)-1-(6-( 2-hydroxypropane-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]