168395-26-4|(S)-Tetrahydrofuran-3-carboxylic acid| Ambeed

Structure of 168395-26-4

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Quality Control of [ 168395-26-4 ] Purity: 97% SDS Specification

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Product Details of [ 168395-26-4 ]

CAS No. :	168395-26-4
Formula :	C₅H₈O₃
M.W :	116.12
SMILES Code :	O=C(O)[C@H]1CCOC1
MDL No. :	MFCD07369984
InChI Key :	BOTREHHXSQGWTR-BYPYZUCNSA-N
Pubchem ID :	40784874

Safety of [ 168395-26-4 ]

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

Computational Chemistry of [ 168395-26-4 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.91
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.26
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.11
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.38
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.54
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.33
Solubility	54.3 mg/ml ; 0.468 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.26
Solubility	64.0 mg/ml ; 0.551 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.18
Solubility	177.0 mg/ml ; 1.52 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.19 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.46

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.

Downstream synthetic route of [ 168395-26-4 ]

[ 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).

References: [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).

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

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

References: [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 ]

References: [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 ]

References: [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 ]

References: [1]Patent: US2013/165436,2013,A1 .

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

References: [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).

References: [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

References: [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)

References: [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.

References: [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

References: [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) .

References: [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.

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

15
[ 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.

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

16
[ 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.

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

17
[ 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+].

References: [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.