[ CAS No. 168395-26-4 ] {[proInfo.proName]}

Name: 168395-26-4|(S)-Tetrahydrofuran-3-carboxylic acid|97%
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Quality Control of [ 168395-26-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 168395-26-4 ]

CAS No. :	168395-26-4	MDL No. :	MFCD07369984
Formula :	C₅H₈O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BOTREHHXSQGWTR-BYPYZUCNSA-N
M.W :	116.12	Pubchem ID :	40784874
Synonyms :

Calculated chemistry of [ 168395-26-4 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	26.89
TPSA :	46.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.19 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.91
Log Po/w (XLOGP3) :	-0.26
Log Po/w (WLOGP) :	0.11
Log Po/w (MLOGP) :	-0.38
Log Po/w (SILICOS-IT) :	0.54
Consensus Log Po/w :	0.18

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.33
Solubility :	54.3 mg/ml ; 0.468 mol/l
Class :	Very soluble
Log S (Ali) :	-0.26
Solubility :	64.0 mg/ml ; 0.551 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.18
Solubility :	177.0 mg/ml ; 1.52 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.46

Safety of [ 168395-26-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338+P310-P312-P332+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H303-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 168395-26-4 ]

* 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 [ 168395-26-4 ]
Downstream synthetic route of [ 168395-26-4 ]

[ 168395-26-4 ] Synthesis Path-Upstream 1~3

1
[ 1002728-73-5 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 23, p. 6072 - 6075[2] Angew. Chem., 2013, vol. 125, # 23, p. 6188 - 6191

2
[ 797038-33-6 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 23, p. 6072 - 6075[2] Angew. Chem., 2013, vol. 125, # 23, p. 6188 - 6191

3
[ 797038-34-7 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 23, p. 6072 - 6075[2] Angew. Chem., 2013, vol. 125, # 23, p. 6188 - 6191

[ 168395-26-4 ] Synthesis Path-Downstream 1~27

1
[ 168395-26-4 ]
[ 124506-31-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 5 5-Butyl-9-[1-(2,4-dimethyl-pyridine-3-carbonyl)-4-methyl-piperidin-4-yl]-3-[(R)-1-(tetrahydro-furan-3-yl)methyl]-3,9-diaza-spiro[5.5]undecan-2-one (I-14) step 1-(S)-Tetrahydro-3-furanoic acid (3.3 g, 29.1 mmol) was dissolved in freshly distilled THF (15 mL) and added to a slurry of NaBH4 (2.6 g, 69 mmol) in freshly distilled THF (15 mL) cooled to 0 C. and maintained under a N2 atmosphere. The mixture was stirred for 10 min and then a solution of I2 (7.3 g, 29 mmol) in anhydrous THF (15 mL) was added dropwise over a 30 min period. When gas evolution ceased the solution was heated at reflux for 12 h. The reaction mixture was cooled, the solvent evaporated and the residue was taken up in 20% aqueous KOH and stirred for 4 h at RT. The aqueous solution was continuously extracted with DCM for 2 d and the resulting extract was dried (MgSO4), filtered and evaporated to afford 2.5 g of (R)-20: MS=(M+H)=103; NMR=1H nmr δ 3.93-3.51 (m, 6H), 2.2-2.0 (m, 1H), 1.98-1.71 (m, 2H).

Reference： [1]Patent: US2009/281133,2009,A1 .Location in patent: Page/Page column 17

2
[ 168395-26-4 ]
[ 935854-67-4 ]
(S)-tetrahydro-furan-3-carboxylic acid {4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-fluoro-phenyl}-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 29 (S)-Tetrahydro-furan-3-carboxylic acid {4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-fluoro-phenyl}-amide A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and DCC (1.0 mmol) in DCE (10 mL) was stirred at rt for 1 h, then was treated with (S)-tetrahydro-furan-3-carboxylic acid (1.0 mmol), and was stirred at rt for 16 h. The mixture was concentrated, and the residue was purified by PTLC to provide the title compound (74 mg, 51%). MS (ESI): mass calcd. for C27H35FN4O3, 482.27; m/z found, 483.4 [M+H]+. 1H NMR (CDCl3): 7.75-7.60 (m, 1H), 7.55-7.26 (m, 5H), 7.10-7.00 (m, 1H), 6.84 (t, J=9.0, 1H), 4.21 (s, 1H), 4.05-3.72 (m, 4H), 3.50-3.10 (m, 4H), 3.10-2.95 (m, 5H), 2.73-2.60 (m, 4H), 2.28-2.18 (m, 2H), 1.14-1.02 (m, 6H).

Reference： [1]Patent: US2007/100141,2007,A1 .Location in patent: Page/Page column 34

3
[ 1002728-73-5 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 6072 - 6075
Angew. Chem.,2013,vol. 125,p. 6188 - 6191

4
[ 797038-33-6 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 6072 - 6075
Angew. Chem.,2013,vol. 125,p. 6188 - 6191

5
[ 797038-34-7 ]
[ 66838-42-4 ]
[ 168395-26-4 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 6072 - 6075
Angew. Chem.,2013,vol. 125,p. 6188 - 6191

6
[ 89364-31-8 ]
[ 168395-26-4 ]

Reference： [1]Patent: US2013/165436,2013,A1

7
[ 1445651-64-8 ]
[ 168395-26-4 ]

Reference： [1]Patent: US2013/165436,2013,A1

8
[ 130193-90-7 ]
[ 168395-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 18h;	c) (S)-Tetrahydro-furan-3-carboxylic acid/(R)-Tetrahydro-furan-3-carboxylic acidA solution of an enantiomerically pure tetrahydro-furan-3-carboxylic acid benzyl ester (peak 1 or peak 2, 200 mg, 0.97 mmol), Pd/C (103 mg, 0.97 mmol) in EtOH (2 ml) was hydrogenated with H2 at rt for 18 h. Filtration of the reaction mixture and concentration of the filtrate afforded the title compound as colourless oil (125 mg (Peak 1), 111 mg (Peak 2), crude). [0808] 1H NMR (both enantiomers) (400 MHz, DMSO-d6): δ 12.40 (br s, 1H), 3.84-3.59 (m, 4H), 3.00 (m, 1H), 2.08-1.92 (m, 1H).

Reference： [1]Patent: US2013/165436,2013,A1 .Location in patent: Paragraph 0806; 0807; 0808

9
[ 168395-26-4 ]
(S)-N-(5-chloro-2-methyl-3-((3-methylpiperazin-1-yl)methyl)phenyl)-3-cyanobenzamide [ No CAS ]
N-(5-chloro-2-methyl-3-(((S)-3-methyl-4-((S)-tetrahydrofuran-3-carbonyl)piperazine-1-yl)methyl)phenyl)-3-cyanobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of (S) -N- (5-chloro-2-methyl-3- ( (3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52 150 mg) in DMF (50 mL) was added (S) -tetrahydrofuran-3-carboxylic acid (54.6 mg) HATU (149 mg) and DIPEA (0.137 mL) . The mixture was stirred at RT for 2 hours. Water was added. The solution was extracted with EA (3×50 mL) . The filtrate was washed with sat. NaHCO3solution water and brine. The resulting solution was dried over MgSO4. After filtration the residue was purified by chiral preparative HPLC to afford the title compound (20 mg) as a white solid.1H NMR (400 MHz CDCl3) 8.19 (s 1H) 8.15 (d J 7.8 Hz 1H) 7.89 (d J 7.8 Hz 1H) 7.82 (brs 1H) 7.76 (d J 7.5 Hz 1H) 7.68 (t J 7.8 Hz 1H) 7.18 (d J 2.0 Hz 1H) 4.77 (brs 0.5H) 4.39 (d J 14.1 Hz 0.5H) 4.07-3.79 (m 4.5H) 3.64 (d J 13.6 Hz 0.5H) 3.52-3.32 (m 2.5H) 3.27-3.14 (m 1H) 2.98-2.66 (m 2.5H) 2.32 (s 3H) 2.26-2.00 (m 4H) 1.36-1.22 (m 3H) . MS (ESI) C26H29ClN4O3requires 480 found 481 [M+H]+.
20 mg	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	In the containment (S)-3-cyano-N-(5-chloro-methyl-3-((3-methylpiperazin-1-yl)methyl)phenyl)benzamide (D52, 150 mg) of DMF (50 mL) was added <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (54.6 mg)(149 mg) and DIPEA (0.137 mL) were stirred at room temperature for 2 hours. Add water. The solution was extracted using ΕΑ (3 x 50 mL). The filtrate was washed with saturated NaHC03 solution, water and brine. The resulting solution was dehydrated by MgS04. After filtration, the residue was purified by palm preparative HPLC to give the title compound (20 mg) as a white solid

Reference： [1]Patent: WO2015/180614,2015,A1 .Location in patent: Page/Page column 58
[2]Patent: TW2017/14884,2017,A .Location in patent: Paragraph 0147

10
[ 168395-26-4 ]
(R)-N-(5-chloro-2-methyl-3-((3-methylpiperazine-1-yl)methyl)phenyl)-5-fluoro-6-methylnicotinamide ditrifluoroacetate [ No CAS ]
N-(5-chloro-2-methyl-3-(((R)-3-methyl-4-((S)-tetrahydrofuran-3-carbonyl)piperazine-1-yl)methyl)phenyl)-5-fluoro-6-methylnicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;	To a solution of (R) -N- (5-chloro-2-methyl-3- ( (3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide 2 Trifluoroacetic acid salt (D92 415 mg) in DMF (4 mL) (S) -tetrahydrofuran-3-carboxylic acid (137.4 mg 97ee) solution in DMF (1 mL) was added then HATU (741.3 mg) and DIPEA (0.55 ml) were added. The reaction mixture was stirred overnight. The mixture was purified by preparative HPLC and further purified by chiral SFC to afford the title compound (20 mg) .1H NMR (400 MHz MeOD-d4) 8.87 (s 1H) 8.07 (dd J9.8 1.7 Hz 1H) 7.36 (d J2.2 Hz 1H) 7.31 (d J2.0 Hz 1H) 4.67 (brs 0.5H) 4.32 (d J13.7 Hz 0.5H) 4.24 (brs 0.5H) 4.06-3.75 (m 4.5H) 3.57-3.46 (m 2H) 3.46-3.34 (m 1.5H) 3.05-2.95 (m 0.5H) 2.86 (d J11.2 Hz 1H) 2.79-2.70 (m 1H) 2.60 (d J2.9 Hz 3H) 2.31 (s 3H) 2.26-1.97 (m 4H) 1.40-1.19 (m 3H) .19F NMR (376 MHz MeOD-d4) -126.9. MS (ESI) C25H30ClFN4O3requires 488 found 489 [M+H]+.
20 mg	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;	In the containment (R)-N-(5-chloro-2-methyl-3-((3-methylpiperazine-1-yl)methyl)phenyl)-5-fluoro-6-methylnicotinamide ditrifluoroacetate (D92, 415 mg) of DMF (4 mL) was added <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (137.4 mg, 97% from) of DMF (1 mL) solution, add HATU (741.3 mg) with DIPEA (0.55 ml). The reaction mixture was stirred overnight. The mixture was purified by preparative HPLC Purified with palm SFC to give the title compound (20 mg)

Reference： [1]Patent: WO2015/180614,2015,A1 .Location in patent: Page/Page column 83-84
[2]Patent: TW2017/14884,2017,A .Location in patent: Paragraph 0174

11
[ 168395-26-4 ]
(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
(S)-N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		A solution of <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (0.036 g, 0.31 mmol), HATU (0.12 g, 0.31 mmol) and triethylamine (0.11 mL, 0.77 mmol) in DMF (2 mL) was stirred under nitrogen for 20 minutes. Then (1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide (0.10 g, 0.26 mmol; prepared according to Example 14 using 5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole prepared as described in Example 23) in DMF (1 mL) was added, and the resulting mixture was stirred under these conditions for 30 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was purified by flash C18 chromatography, elution gradient 20 to 60% MeCN in water containing 1% NH4OH. Pure fractions were concentrated under reduced pressure to afford (S)-N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide (0.10 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6, 30 C.) 1.05-1.16 (1H, m), 1.21-1.41 (9H, m), 1.72-1.83 (3H, m), 1.87-2.04 (3H, m), 2.57-2.66 (1H, m), 2.82-2.91 (3H, m), 3.54-3.77 (4H, m), 3.83 (1H, t), 3.95 (2H, s), 7.83 (1H, d), 7.99 (1H, s), 8.25 (1H, s), 8.35 (1H, s), 10.54 (1H, s). m/z: ES+[M+H+]486.

Reference： [1]Patent: US2016/376287,2016,A1 .Location in patent: Paragraph 0767

12
[ 168395-26-4 ]
(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide dihydrochloride [ No CAS ]
(S)-N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 17 - 25℃; for 3h;	HATU (140 mg, 0.37 mmol) was added to a solution of (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide dihydrochloride (150 mg, 0.34 mmol; prepared according to Example 3 b), <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (43 mg, 0.37 mmol) DIPEA (0.18 mL, 1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h. The reaction was diluted with EtOAc and washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in hexane, to afford (S)-N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide (70 mg, 44%). 1H NMR (300 MHz, CDCl3, 27 C.) 1.09-1.26 (m, 1H), 1.38-1.59 (m, 3H), 1.87-2.05 (m, 5H), 2.07-2.21 (m, 4H), 2.29 (1H, d), 2.38-2.58 (1H, m), 2.82-2.99 (4H, m), 3.78-4.00 (4H, m), 4.24 (2H, t), 5.63 (1H, d), 7.92 (1H, s), 8.25 (1H, s), 8.27 (1H, s), 8.40 (1H, br s). m/z: ES+[M+H]+ 472. Optical Rotation: (0881) Concentration: 0.1 g/dL Lamp: Sodium Wavelength: 589 nm Temperature: 20 C. (0882) Path length: 10 cm Cell volume: 1 mL Solvent: DMSO (0883) [α]=+60.4

Reference： [1]Patent: US2016/376287,2016,A1 .Location in patent: Paragraph 0880-0883

13
[ 168395-26-4 ]
(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide [ No CAS ]
5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((S)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	A solution of (R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- thia-3,5,8-triazaacenaphthylene-2-carboxamide (Example 869, 120 mg, 0.24 mmol), (35)- tetrahydrofuran-3-carboxylic acid (100 mg, 0.86 mmol), HATU (150 mg, 0.40 mmol), and triethylamine (80 mg, 0.79 mmol) in DMF (5 mL) was reacted at rt for 2 h. The reaction was quenched with H20 (10 mL), extracted with DCM, dried over anhydrous Na2SC>4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound as an off white solid (57 mg, 40% yield). MS (ESI): mass calcd. for C32H31N5O5S, 597.7; m/z found, 598.2 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.32-8.27 (m, 1H), 7.42-7.29 (m, 3H), 7.19-7.09 (m, 1H), 7.09-7.00 (m, 3H), 6.97-6.90 (m, 1H), 6.04-5.98 (m, 1H), 4.60-4.31 (m, 1H), 4.26-4.08 (m, 1H), 3.94-3.85 (m, 1H), 3.85-3.66 (m, 4H), 3,52-3.37 (m, 1H), 3.15-2.92 (m, 1H), 2.81 -2.59 (m, 1H), 2.15-1.97 (m, 6H), 1.89-1.73 (m, 1H), 1.73-1.41 (m,2Η).
40%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	A solution of (R) -5- (2-methyl-4-phenoxyphenyl) -4-oxo-N- (piperidin-3-yl) -4, 5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide (Example 869, 120 mg, 0.24 mmol) , (3S) -tetrahydrofuran-3-carboxylic acid (100 mg, 0.86 mmol) , HATU (150 mg, 0.40 mmol) , and triethylamine (80 mg, 0.79 mmol) in DMF (5 mL) was reacted at rt for 2 h. The reaction was quenched with H2O (10 mL) , extracted with DCM, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound as an off white solid (57 mg, 40yield) . MS (ESI) : mass calcd. for C32H31N5O5S, 597.7 m/z found, 598.2 [M+H]+.1H NMR (400 MHz, CD3OD) : δ 8.32-8.27 (m, 1H) , 7.42-7.29 (m, 3H) , 7.19-7.09 (m, 1H) , 7.09-7.00 (m, 3H) , 6.97-6.90 (m, 1H) , 6.04-5.98 (m, 1H) , 4.60-4.31 (m, 1H) , 4.26-4.08 (m, 1H) , 3.94-3.85 (m, 1H) , 3.85-3.66 (m, 4H) , 3.52-3.37 (m, 1H) , 3.15-2.92 (m, 1H) , 2.81-2.59 (m, 1H) , 2.15-1.97 (m, 6H) , 1.89-1.73 (m, 1H) , 1.73-1.41 (m, 2H) .

Reference： [1]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 324
[2]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 323-324

14
[ 168395-26-4 ]
3-amino-4-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]amino}quinoline-6-carbonitrile [ No CAS ]
1 -[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-2-[(3R)-tetrahydrofuran-3-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 15h;	3-am ino-4-[(2 R, 4R)-2-m ethyltetrahydro-2 H-pyran-4-yl]am ino}qu md ine-6-carbonitrile (50 mg, 0.18 mmcl) and <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (30.8 mg,0.266 mmcl) were added into DMF (2 mL), followed by T3P in DMF (0.277 mL, 0.44 mmol, 1.6 M) and finally DIEA (68 mg, 0.531 mmol). The mixture was then heated to110 C for 15 hours. LCMS showed the reaction was complete. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3), the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, then purified by preparative HPLC (Waters XBridge Prep OBD C18 150 x 30 mm, 5u; water (0.05% ammonia hydroxide v/v) ACN 25 mL/min). Concentrated andthen lyophilized to afford the desired product as white solid (12.2 mg, 19% yield). 1H NMR (400 MHz, DMSO-d6) O 1.25 (d, J = 6.1 Hz, 3H), 1.90-2.27 (m, 3H),2.29-2.41 (m, 1H), 2.41-2.49 (m, 2H), 3.78 (dd, J = 25.7, 13.5 Hz, 2H), 3.91 (q, J = 7.4Hz, 1H), 4.00 (t, J = 7.5 Hz, 2H), 4.10 (t, J = 7.5 Hz, 1H), 4.18 (m, 1H), 4.25 (t, J = 7.7Hz, 1 H), 5.31 (b, 1 H), 8.03 (dt, J = 8.8, 2.0 Hz, 1 H), 8.31 (dd, J = 8.7, 2.9 Hz, 1 H), 9.02(5, 1H), 9.34 (d, J = 2.1 Hz, 1H). LCMS Column: Waters XBridge C18 50 x 2.0 mm, 5um; Mobile phase: A) 0.1% FA in Water; B) 0.1% FA in ACN. Gradient: 1% B increase to 5% B within 0.6 mm; 5% B increase to 100% B within 3.4 mm; Flow rate 0.8 mL/min MS Ionization: ESI. HPLC: HPLC-AE Ultimate XB-C18, 3um, 3.0 x 50 mm; Mobile phase: 1.0% ACN in water (0.1% TFA) to 5% ACN in water (0.1%TFA) in 1 mm, thenfrom 5% ACN in water (0.1% TFA) to 100% ACN (0.1% TFA) in 5 minutes; hold at100% ACN (0.1% TFA)for2 minutes; Flow rate: 1.2 mL/min.

Reference： [1]Patent: WO2018/163030,2018,A1 .Location in patent: Page/Page column 98

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[ 168395-26-4 ]
6-(difluoromethyl)-N<SUP>4</SUP>-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)quinoline-3,4-diamine [ No CAS ]
8-(difluoromethyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-((R)-tetrahydrofuran3-yl)-1H-imidazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In toluene; at 60 - 100℃; for 5.5h;	To a Toluene (3.00 mL, c=0.108 M) solution 6-(difluoromethyl)-N4-((2R,4R)-2- methyltetrahydro-2H-pyran-4-yl)quinoline-3,4-diamine (0.100 g, 0.325 mmol) was added <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> (0.039 g, 0.342 mmol, 1.05 eq.), N-ethyl-Nisopropylpropan-2-amine (0.046 g, 0.358 mmol, 1.10 eq.), and lastly 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.228 g, 0.358 mmol, 1.10 eq.). Theresulting solution was heated to 60 C for 90 mm. Then the temperature of the reaction was increased to 100 C and the reaction mixture was stirred at that temperature over4h. The reaction mixture was partitioned between EtOAc (10 mL) and NaHCO3 (aq., sat’d., 10 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a dark orange oily residue. Purificationvia regular silica column chromatography (0 to 15% of MeOH in DCM) yielded 8-(difluorom ethyl)-1 -((2R,4R)-2-m ethyltetrahydro-2 H-pyran-4-yl)-2-(( R)-tetrahydrofuran-3-yl)-1H-imidazo[4,5-c]quinoline as an off-white solid (0.065 g, 0.168 mmol, 52% yield).HNMR 400 MHz, CD3OD) O ppm 1.36 (d, J=6.53 Hz, 3 H) 1.97-2.23 (m, 2 H) 2.38-2.53(m, 2 H) 2.40-2.66 (m, 3 H) 2.80 (br s, 1 H) 3.81-3.93 (m, 2 H) 4.00-4.09 (m, 1 H) 4.11-4.25 (m, 3 H) 4.29-4.39 (m, 2 H) 5.33 (br s, 1 H) 6.94-7.26 (m, 1 H) 7.92 (d, J=8.53 Hz,1 H) 8.34 (d, J=8.53 Hz, 1 H) 8.84 - 9.10 (m, 1 H) 8.99 (br s, 1 H) 9.24 (5, 1 H)); 19F NMR 376 MHz, CD3OD) O ppm -113.72 to -108.29 (m, 1 F); LCMS MS 388.0 M+H.

Reference： [1]Patent: WO2018/163030,2018,A1 .Location in patent: Page/Page column 101

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[ 168395-26-4 ]
N⁴-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-6-(trifluoromethyl)quinoline-3,4-diamine [ No CAS ]
1-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-2-[(3R)-tetrahydrofuran-3-yl]-8-(trifluoromethyl)-1H-imidazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 110℃; for 2h;	General procedure: To a solution of an appropriate acid (i.e. R1CO2H, 0.422 mmol) in N,Ndimethylformamide (2 mL) was added diamine (137 mg, 0.421 mmol), N,Ndiisopropylethylamine (161 mg, 1.25 mmol), and 2,4,6-tripropyl-1 3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (50% solution in ethyl acetate, 0.39 mL, 0.655 mmol).The reaction mixture was stirred for 2 hours at 110 C, whereupon it was diluted with water (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were concentrated in vacuo and purified by reversed phase HPLC (Column: Agela Durashell, 5 pm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B:acetonitrile), providing the product as a pale grey or white solid. 1H NMR (400 MHz, CDCI3) O 1.37 (d, J = 6.1 Hz, 3H), 1.81 -2.19 (m, 2H), 2.39-2.65 (m, 3H), 2.80 (b, 1H), 3.65-3.81 (m, 2H), 3.85 (b, 1H), 4.07 (dt, J = 8.5, 7.1 Hz,1H), 4.18 (q, J = 7.4 Hz, 2H), 4.26-4.47 (m, 2H), 5.02 (b, 1H), 7.87 (dd, J = 8.8, 1.9 Hz,1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.99 (b, 1 H), 9.39 (5, 1 H). LCMS: MS 406.0 M+H. Mobilephase: A) 0.1% FA in Water; B) 0.1% FA in ACN. Gradient: 1% B increase to 5% Bwithin 0.6 mm; 5% B increase to 100% B within 3.4 mm; Flow rate 0.8 mL/min. HPLC:3.87/10 mm, 95.87% purity. HPLC-AE Ultimate XB-C18, 3um, 3.0 x 50 mm. Mobile phase:1.0% ACN in water (0.1% TFA) to 5% ACN in water (0.1% TFA) in 1 mm; then from 5% ACN in water (0.1% TFA) to 100% ACN (0.1% TFA) in 5 minutes; hold at 100% ACN (0.1% TFA)for2 minutes; Flow rate 1.2 mL/min.

Reference： [1]Patent: WO2018/163030,2018,A1 .Location in patent: Page/Page column 103; 104

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[ 168395-26-4 ]
(S)-azetidin-1-yl(2-((1-(5-fluoropyridin-3-yl)ethyl)amino)-6-methylthieno[3,2-d]pyrimidin-4-yl)methanone [ No CAS ]
(S)-N-(1-(2-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-6-methylthieno[3,2-d]pyrimidine-4-carbonyl)azetidin-3-yl)tetrahydrofuran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: A mixture of (3R)-tetrahydrofuran-3-carboxylic acid (4.5 mg, 0.039 mmol) (3568) (commercially obtained from Ark Pharm, Arlington Heights, IL) and HATU (15 mg, 0.039 mmol) in DMF (0.5 mL) was added to a solution of (S)-(3-aminoazetidin-l-yl)(2-((l-(5- fluoropyridin-3-yl)ethyl)amino)-6-methylthieno[3,2-<i]pyrimidin-4-yl)methanone (3569) trihydrochloride (15 mg, 0.03 mmol) and DIEA (37 uL, 0.21 mmol) in DMF (0.3 mL). The resulting mixture was stirred at room temperature for 3 hours, concentrated on rotary evaporator, and the residue was purified by flash chromatography on silica gel eluting with 0% to 10% methanol in DCM to provide compound 598 (70% yield). NMR (400 MHz, CDCb) δ 1.62 (3H, dd, J= 7.2 Hz), 2.17-2.21 (2H, m), 2.60 (3H, t, J= 0.8 Hz), 2.94-2.98 (1H, m), 3.80-4.03 (5H, m), 4.15-4.40 (1H, m), 4.55 (1H, t, J= 9.2 Hz), 4.66-4.71 (1H, m), 4.65-5.05 (1H, m), 5.15 (1H, q, J= 7.2 Hz), 5.34 (1H, dd, J= 19.2, 6.4 Hz), 6.21 (1H, dd, J = 49.6, 6.4 Hz), 6.84 (1H, d, J= 0.8 Hz), 7.40 (1H, m), 8.33 (1H, d, J= 2.8 Hz), 8.47 (1H, d, J= 6.4 Hz) ppm. MS m/z = 485.1 [M+H+].

Reference： [1]Patent: WO2019/46784,2019,A1 .Location in patent: Paragraph 2061; 2062; 2063; 2064

18
[ 168395-26-4 ]
6-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylpyrazolo[1,5-a]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-ium 2,2,2-trifluoroacetate [ No CAS ]
(S)-2-((2-ethyl-5-(6-(tetrahydrofuran-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 10 (S)-2-((2-ethyl-5-(6-(tetrahydrofuran-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Compound 10) The title compound was prepared was prepared from 9c (58 mg, 0.1 mmol) and <strong>[168395-26-4](S)-tetrahydrofuran-3-carboxylic acid</strong> in a manner analogous to Example 9. The Compound 10 was isolated as a light brown solid (50 mg, 85%) and the spectra were the same as Compound 9.