67938-76-5|(5-Chloropyridin-2-yl)methanamine| Ambeed

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Quality Control of [ 67938-76-5 ] Purity: 95% SDS Specification

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Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors

Giri R. Gnawali ; Koichi Okumura ; Karolina Perez ; Rosa Gallagher ; Julia Wulfkuhle ; Emanuel F. Petricoin , et al.

DOI: 10.1007/s00044-022-02904-z PubMed ID: 36389181 Med. Chem. Res.,2022,31(7):1154-1175.

Abstract: Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-chloro (GRG-1-34, 6e), 4-Bromo (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1–34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 h after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.

Keywords: Quinoline derivatives ; Pim kinase ; Antitumor activity ; mTORC

Purchased from AmBeed: 180748-30-5 ; 4837-01-8 ; 589-10-6 ; 6627-60-7 ; 31106-82-8 ; 1260903-05-6 ; 872577-05-4 ; 865156-50-9 ; 188637-63-0 ; 103-67-3 ; 3731-51-9 ; 164341-39-3 ; 67938-76-5 ; 22921-76-2 ; 1241725-81-4 ; 131052-62-5 ; 184637-50-1

Product Details of [ 67938-76-5 ]

CAS No. :	67938-76-5
Formula :	C₆H₇ClN₂
M.W :	142.59
SMILES Code :	NCC1=NC=C(Cl)C=C1
MDL No. :	MFCD10697658
InChI Key :	KQJKUOYVWLBSDN-UHFFFAOYSA-N
Pubchem ID :	21069929

Safety of [ 67938-76-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 67938-76-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	36.92
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.57
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	0.37
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.04
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.	0.49
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	1.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.02

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.38
Solubility	5.88 mg/ml ; 0.0413 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.	-0.75
Solubility	25.2 mg/ml ; 0.177 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	-2.66
Solubility	0.311 mg/ml ; 0.00218 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	Yes
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.	-6.91 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.	0.55

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)	1.47

Application In Synthesis of [ 67938-76-5 ]

* 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 [ 67938-76-5 ]

[ 67938-76-5 ] Synthesis Path-Downstream 1~25

2
[ 89809-64-3 ]
[ 67938-76-5 ]

Yield	Reaction Conditions	Operation in experiment
51%	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h;	A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4x25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) ? ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).
51%	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h;	A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1 H, br d), 7.66-7.60 (1 H, m), 7.28-7.14 (1 H, m), 3.97 (2H, s), 1.72 (2H, s).
51%	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h;	(5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04. found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).

51%

(5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile(3.8 g, 27.43 mmol), cone. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4 X 25 mL). The combined CH2Cl2 layers were dried <n="142"/>(Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (IH, br d), 7.66-7.60 (IH, m), 7.28-7.14 (IH, m), 3.97 (2H, s), 1.72 (2H, s).

References: [1]Patent: US2005/267105,2005,A1 .Location in patent: Page/Page column 63.
[2]Patent: US2007/111984,2007,A1 .Location in patent: Page/Page column 29.
[3]Patent: US2007/129379,2007,A1 .Location in patent: Page/Page column 21-22.
[4]Patent: WO2007/64316,2007,A1 .Location in patent: Page/Page column 140 - 141.

3
[ 1168138-38-2 ]
[ 67938-76-5 ]
[ 1168138-54-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5568 - 5572.

4
[ 67938-76-5 ]
(5-chloropyridin-2-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; dichloromethane; at 0 - 5℃; for 1.0h;Inert atmosphere;	The compound <strong>[67938-76-5]2-(aminomethyl)-5-chloropyridine</strong> (18 g, 0.13 mol, from Step D) was dissolved in dichioromethane (50 mL) and hydrochloric methanol solution (5 M, 50 mL) was added. After stirring for several min a white solid began to precipitate. The mixture was stirred for 1 h at 0-5 °C, and the solid was collected by filtration and the filtrate was evaporated in vacuo to give some off-white solid. The combined solid was washed with a small amount of cold DCM. The product was dried in vacuo to yield the indicated compound as the hydrochloric salt. -NMR (DMSO-de, 400 MHz) 6 8.70 (s, 3H), 8.62 (s5 1H), 8.0 (dd, 7=2.5, 6 Hz, 1H), 7.60 (d, J=8.5 Hz, lH), 4.15 (m, 2H).

References: [1]Patent: WO2011/149921,2011,A1 .Location in patent: Page/Page column 88.

5
[ 67938-69-6 ]
[ 67938-76-5 ]

Yield	Reaction Conditions	Operation in experiment
		Diethyl (5-chloro-2-pyridyl) acetamidomalonate (70 g, 0.21 mol, Step C) was dissolved in 95percent ethanol (200 mL). To the stirred solution (2 °C) was added sodium hydroxide solution (105 mL, 8 N). After 2 hours, the mixture was cooled to 5 °C and acidified to pH 2 with hydrochloric acid (6 N, -40 mL). The ethanol was evaporated under reduced pressure to give a mixture containing some solid. The mixture was treated with hydrochloric acid (5 N, 150 mL) and heated to 80 °C for 4 hours, and then maintained at room temperature overnight. Sodium hydroxide solution (4 N) was slowly added to the mixture to adjust pH 10. The mixture was extracted with DCM (4 x 200 mL), the organic phases were combined, dried over anhydrous Na2S04, and filtered. The solvent was evaporated to give the indicated product as a pale yellow oil.
		Diethyl (5-chloro-2-pyridyl) acetamidomalonate (70 g, 0.21 mol) was dissolved in 95percent ethanol (200 mL). To the stirred solution (2 °C) was added sodium hydroxide solution (105 mL, 8 N). After 2h, the mixture was cooled to 5 °C and acidified to pH 2 with hydrochloric acid (6 N, ?40 mL). The ethanol was evaporated in vacuum to give a mixture containing some solid. The mixture was mixed with hydrochloric acid (5 N, 150 mL) and heated to 80 °C for 4 hr, and then maintained at room temperature overnight. Sodium hydroxide solution (4 N) was slowly added to the mixture to adjust pH 10. The mixture was extracted with DCM (4 x 200 mL), and then the combined organic phases were dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the indicated product as a pale yellow oil.

References: [1]Patent: WO2011/149921,2011,A1 .Location in patent: Page/Page column 88.
[2]Patent: EP2373317,2016,B1 .Location in patent: Paragraph 0144-0145.

6
N-(3-(1H-imidazol-1-yl)propyl)-2-bromo-1,3-thiazole-5-carboxamide [ No CAS ]
[ 67938-76-5 ]
C₁₆H₁₇ClN₆OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 120℃;	General procedure: Example 6A (2 g, 6.35 mmol) and (4-fluorophenyl)methanamine (0.794 g, 6.35 mmol) in acetonitrile (10 ml) were stirred at 120 °C overnight. The reaction mixture was cooled, concentrated, taken into ethyl acetate and washed with saturated aqueous NaHC03 and brine. The combined aqueous layers were extracted twice with ethyl acetate. The combined organic extracts were dried (MgS04) and filtered. The filtrate was concentrated until solid material precipitated. The mixture was filtered to provide the title compound.

References: [1]Patent: WO2013/170118,2013,A1 .Location in patent: Page/Page column 129.

7
[ 67938-76-5 ]
[ 610-14-0 ]
C₁₃H₁₀ClN₃O₃ [ No CAS ]

References: [1]PLoS ONE,2015,vol. 10.

8
[ 67938-76-5 ]
[ 407-25-0 ]
C₈H₄ClF₃N₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3202 - 3206.

9
[ 67938-76-5 ]
(5-chloropyridin-2-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; dichloromethane; at 0 - 5℃;	The compound <strong>[67938-76-5]2-(aminomethyl)-5-chloropyridine</strong> (18 g, 0.13 mol) was dissolved in dichloromethane (50 mL) and hydrochloric methanol solution (5 M, 50 mL) was added. After stirring for several min a white solid began to precipitate. The mixture was stirred for 1 h at 0-5 °C, and the solid was collected by filtration and the filtrate was evaporated in vacuo to give some off-white solid. The combined solid was washed with a small amount of cold DCM. The product was dried in vacuo to yield the indicated compound as the hydrochloric salt. 1H-NMR (d6-DMSO, 400 MHz) delta 8.70 (s, 3H), 8.62 (s, 1H), 8.0 (dd, J=2.5, 6 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 4.15 (m, 2H).

References: [1]Patent: EP2373317,2016,B1 .Location in patent: Paragraph 0146-0147.

10
11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid 5,5-dioxide [ No CAS ]
[ 67938-76-5 ]
N-((5-chloropyridin-2-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5,5-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;Inert atmosphere;	[000132] To a stirring solution of 30 (1 g, 3.30 mmol) in DMF (20 mL) under inert atmosphere were added EDCI.HC1 (945 g, 4.90 mmol), HOBt (668 mg, 4.95 mmol), ((5- chloropyridin-2-yl) methanamine 98 (470 mg, 3.30 mmol) and diisopropylethylamine (1.63 mL, 9.90 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-3percent MeOH/ CH2CI2 to afford compound 99 (1.2 g, 85percent) as an off-white solid. TLC: 10percent MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-

References: [1]Patent: WO2017/48954,2017,A1 .Location in patent: Paragraph 000132.

11
[ 67938-76-5 ]
[ 1262618-95-0 ]