1035093-81-2|(S)-Chroman-4-amine hydrochloride| Ambeed

Structure of 1035093-81-2

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Product Details of [ 1035093-81-2 ]

CAS No. :	1035093-81-2
Formula :	C₉H₁₂ClNO
M.W :	185.65
SMILES Code :	N[C@H]1CCOC2=C1C=CC=C2.[H]Cl
MDL No. :	MFCD08752571
InChI Key :	BVMKYKMJUZEGBU-QRPNPIFTSA-N
Pubchem ID :	56973613

Safety of [ 1035093-81-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1035093-81-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	50.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	1.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.95
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.	1.44
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	1.63
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.44
Solubility	0.667 mg/ml ; 0.00359 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.08
Solubility	1.56 mg/ml ; 0.00839 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-2.36
Solubility	0.814 mg/ml ; 0.00439 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	Yes
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.	-6.21 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)	2.29

Application In Synthesis of [ 1035093-81-2 ]

* 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 [ 1035093-81-2 ]

[ 1035093-81-2 ] Synthesis Path-Downstream 1~24

1
[ 53981-38-7 ]
[ 6290-49-9 ]
[ 730980-58-2 ]
[ 1035093-81-2 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 4-aminochromane hydrochloride (27.8 g, 0.15 mol) and aqueous sodium hydroxide (2N) was extracted with ethyl acetate and the organic layer dried (sodium sulfate) and evaporated to give racemic 4-aminochromane (14.2 g, 0.095 mol). To this was added methyl 2-methoxyacetate (10.94 g, 0.105 mol) and 2.5 g Novozym 435 (Aldrich Corp.) in tert-butyl methyl ether, and the mixture heated at reflux for 2 hours. A further addition of Novozym 435 (0.5 g) was made and heating continued until the reaction was complete as judged by hplc. Dichloromethane was added, the biocatalyst filtered off and the organic layer dried (sodium sulfate) and evaporated. The residue was dissolved in the minimum of dichloromethane, and ethanolic hydrochloric acid solution (8N) was added to give (4S)4-aminochromane hydrochloride which was filtered off, and the filtrate evaporated to give N-[(4R)4-chromanyl]-2-methoxyacetamide (8.2 g), mp. 109-112 C.

References: [1]Patent: US2004/157739,2004,A1 .Location in patent: Page 14.

2
[ 1035093-81-2 ]
[ 74124-79-1 ]
[ 913296-58-9 ]
[ 1034770-56-3 ]

Yield	Reaction Conditions	Operation in experiment
		Di(N-succinimidyl) carbonate (538 mg, 2.1 mmol) was suspended in acetonitrile (5 mL), and Example 1G (555 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) and pyridine (0.17 mL, 2.1 mmol) was added. After stirring for 15 minutes at ambient temperature, <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (J&W PharmLab, 371 mg, 2.0 mmol) and diisopropylethylamine (1.05 mL, 6.0 mmol) was added and the mixture stirred for 30 minutes. The mixture was filtered through a silica gel plug, rinsed with 1/1 ethyl acetate/hexane, and concentrated under reduced pressure to afford 1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((S)-chroman-4-yl)urea.

References: [1]Patent: US2008/153871,2008,A1 .Location in patent: Page/Page column 19-20.

3
[ 1035093-81-2 ]
3-bromo-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.25h;	At 0C to a solution of 3-bromo-7-isopropyl-2-methylpyrazolo[i ,5-a]pyrim idine-6-carboxylic acid (0.90 g, 2.78 mmol), (S)-chroman-4-ylamine hydrochloride (0.52 g, 2.78 mmol) and N,Ndiisopropylethylamine (0.43 g, 3.33 mmol, 0.57 mL) in dry N,N-dimethylformamide (30 mL) andwere added N-(3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (0.59 g, 3.05 mmol) and i-hydroxy-7-azabenzotriazole (0.04 g, 0.28 mmol). The mixture was stirred at 0C for 15 mm and at room temperature for 2 h. Water (90 mL) was added and the resulting precipitate was filtered off and dried in vacuo at 50C overnight. 1.04 g (2.43 mmol; 88% of theory) of the title compound were obtained.LC-MS (Method Li): R1= 2.11 mm; m/z = 429/431 (M+H)1H NMR (300 MHz, Chloroform-d, Method M2) 6 8.39 (s, 1H), 7.27 (s, 1H), 7.26 - 7.17 (m,1H), 6.94 (m, 1H), 6.90-6.83 (m, 1H), 6.16 (d, J = 7.5 Hz, 1H), 5.39-5.29 (m, 1H), 4.35 (m,1H), 4.19 (m, 1H), 4.05 (p, J = 7.1 Hz, 1H), 2.52 (s, 3H), 2.47 -2.32 (m, 1H), 2.22 (m, 1H), 1.60(dd, J = 7.0, 6.0 Hz, 6H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 102.

4
[ 1035093-81-2 ]
3-bromo-7-methoxy-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-7-methoxy-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.6%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 48h;	To a stirred mixture of 3-bromo-7-methoxy-2-methylpyrazolo[1 ,5-a]pyrim idine-6-carboxylic acid (crude material 75% purity 126 mg, 0.33 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (54.2 mg, 0.36 mmol) and N,N-diisopropylethylamine (64 mg, 0.49 mmol) in dichlromethane (15 mL) were added T3P (Propylphosphonic anhydride solution 50 % in DMF, 210 mg, 0.33 mmol) at room temperature. The resulting mixture was stirred for 48 h. The reaction mixture was dilutedwith more dichloromethane and mixed with 1 N sodium hydroxide. The dichloromethane phase was separated via a Whatman cartridge. The aqueous phase was extracted again with dichloromethane. The combined extracts were dried via a sodium sulfate /silica gel cartridge and concentrated in vacuo. Purification by flash chromatography with an ethyl acetate I cyclohexane gradient afforded 100mg (67.6%) of the title compound.1H NMR (400 MHz, DMSO-d6, Method Ml): 69.12(d, 1H, NH), 8.73 (s, 1H), 7.24-7.17(m,2H), 6.89 (t, 1H), 6.83 (d, 1H), 5.25-5.20 (m, 1H), 4.32-4.27 (m, 1H), 4.19-4.16 (m, 1H),4.15 (s, 1 H), 2.32 (s, 3H), 2.22-2.18 (m, 1 H), 2.07 -2.03 (m, 1 H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 139.

5
[ 1035093-81-2 ]
3-bromo-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
3-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.8%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a stirred mixture of 3-bromo-2-methyl-7-(morphol in-4-yl)pyrazolo[1 ,5-a]pyrimidi ne-6-carboxylic acid (crude material 60% purity 430 mg, 0.75 mmol), (S)-chroman-4-aminehydrochloride (168 mg, 0.9 mmol) and N,N-diisopropylethylamine (195 mg, 1.51 mmol) in dichlromethane (15 mL) were added N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (145 mg, 0.75 mmol), 1-hydoxy-1H-benzotriazole (51 mg, 0.37 mmol) and 4- N,N-dimethylamino pyridine (46.2 mg, 0.37 mmol) at room temperature. The resulting mixturewas stirred overnight. The reaction mixture was mixed with water (50 mL) and the dichloromethane phase was separated via a Whatman cartridge. The aqueous phase was extracted again with dichloromethane. The combined extracts were dried via a sodium sulfate /silica gel cartridge and concentrated in vacuo. Purification by flash chromatography with an ethyl acetate I cyclohexane gradient afforded 310 mg (86.8 %) of the title compound.1H NMR (400 MHz, DMSO-d6, Method Ml): 69.05 (d, 1H, NH), 8.35 (s, 1H), 7.34 (d, 1H),7.19 (t, 1 H), 6.92 (t, 1 H), 6.81 (d, 1 H), 5.22-5.18 (m, 1 H), 4.30-4.20 (m, 2H), 3.82-3.79 (m,4H), 3.59 - 3.58 (m, 4H), 2.40 (s, 3H), 2.23 - 2.17 (m, 1 H), 2.08 - 2.03 (m, 1 H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 143.

6
[ 1035093-81-2 ]
2-chloro-3-(2,3-difluorophenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
2-chloro-N-((S)-chroman-4-yl)-3-(2,3-difluorophenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; ethyl cyanoglyoxylate-2-oxime; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	Under nitrogen atmosphere N-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60mg, 0.31 mmol) and ethyl cyanoglyoxylate-2-oxime (4 mg, 0.03 mmol) were added to a stirredmixture of 2-chloro-3-(2,3-d ifl uorophenyl)-7-isopropylpyrazolo[i ,5-a]pyrimidi ne-6-carboxylic acid (100 mg, 0.28 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (55 mg, 0.30 mmol) and triethylamine (35 mg, 0.34 mmol, 0.05 mL) in dry N,N-dimethylformamide (2 mL) at 0CC. N-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol) and ethyl cyanoglyoxylate-2-oxime (4 mg, 0.03 mmol). The resulting mixture was stirred overnight while warming to room temperature. The reaction mixture was poured out into water (20 mL) andwas extracted with ethyl acetate (3x10 mL). The combined organic extracts were washed with brine (3x10 mL), dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L6; 12 g; heptane, 5%-50% ethyl acetate) afforded 80 mg (0.17 mmol; 58% of theory) of the title compound.LC-MS (Method L2): R1 = 4.30 mm; mlz = 483 (M+1)1H NMR (400 MHz, DMSO-d6, Method M2) 69.26 (d, J = 8.0 Hz, 1H), 8.63 (s, 1H), 7.61 -7.48(m, 1H), 7.47-7.31 (m, 3H), 7.24-7.12 (m, 1H), 6.99-6.88 (m, 1H), 6.81 (d, J = 8.2 Hz, 1H),5.23 (q, J = 5.6 Hz, 1H), 4.36-4.14 (m, 2H), 3.97 -3.84 (m, 1H), 2.28-2.15 (m, 1H), 2.12 -2.00 (m, 1H), 1.55(m, 6H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 90; 91.

7
[ 1035093-81-2 ]
3-bromo-7-cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-7-cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	To a suspension of 3-bromo-7-cyclopropyl-2-methylpyrazolo[i ,5-a]pyrim idine-6-carboxylic acid(750 mg, 2.53 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (495 mg, 2.67 mmol) and triethylamine (384 mg, 3.80 mmol, 0.53 mL) in dry N,N-dimethylformamide (25 mL) at 0 C were added N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (534 mg, 2.79 mmol) and i-hydroxy-7-azabenzotriazole (35 mg, 0.25 mmol). The reaction mixture was allowed to warm to room temperature and stirring was continued for 18 h. N-(3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol) was added. The reaction mixture was stirred for 24 h and was poured out into water (300 mL). The mixture was stirred for 15 minutes. The resulting precipitate was filtered off, washed with water (2x40 mL) and diisopropyl ether (2x40 mL) and was dried on air to afford 857 mg (2.01 mmol; 79% of theory) of the title compound.LC-MS (Method Li): R1 = 1 .98 mm; m/z = 427/429 (M+H)1H NMR (400 MHz, DMSO-d6, Method M2) 69.14 (d, J = 7.9 Hz, 1H), 8.49 (s, 1H), 7.40-7.10(m, 2H), 7.03 - 6.67 (m, 2H), 5.22 (d, J = 6.7 Hz, 1 H), 4.38 - 4.08 (m, 2H), 2.54 (m, 1 H), 2.44(s, 3H), 2.31 - 1.95 (m, 2H), 1.49 - 1.09 (m, 4H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 105.

8
[ 1035093-81-2 ]
3-bromo-2-(difluoromethyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-2-(difluoromethyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; ethyl cyanoglyoxylate-2-oxime; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	N-(3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (1 .43 g, 7.47 mmol) and ethyl cyano(hydroxyimino)acetate (0.10 g, 0.68 mmol) were added under nitrogen atmosphere to astirred mixture of 3-bromo-2-(d ifluoromethyl)-7-isopropylpyrazolo[i ,5-a]pyrimidi ne-6-carboxylic acid (2.27 g, 6.79 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (1.26 g, 6.79 mmol) and triethylamine (0.83 g, 8.15 mmol, 1.13 mL) in dry N,N-dimethylformamide (50 mL) at 000. The resulting mixture was stirred while warming up to room temperature overnight. The reaction mixture was poured out into hydrochloric acid (1 .0 M; 500 mL) and extracted with ethyl acetate(3x150 mL). Combined extracts were washed with brine (3x100 mL), dried with sodium sulfate and concentrated in vacuo. Purification by trituration in ethyl acetate (10 mL) and diisopropyl ether (5 mL) afforded 1 .95 g (4.20 mmol; 62% of theory) of the title compound.LC-MS (Method Li): R1 = 2.12 mm; m/z = 465/467 (M--i)1H NMR (400 MHz, DMSO-d6, Method M2) 69.25 (d, J = 8.0 Hz, 1H), 8.70 (s, 1H), 7.49-7.15(m, 3H), 6.98-6.90 (m, 1H), 6.85-6.78 (m, 1H), 5.29-5.18 (m, 1H), 4.35-4.16 (m, 2H), 3.91 (hept, J = 7.0 Hz, 1 H), 2.29 - 2.16 (m, 1 H), 2.13 -2.00 (m, 1 H), 1.51 (dd, J = 9.2, 7.1 Hz, 6H).

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 106.

9
[ 1035093-81-2 ]
3-bromo-7-ethyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-7-ethyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; ethyl cyanoglyoxylate-2-oxime; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	To a suspension of 3-bromo-7-ethyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1000mg, 3.52 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (653 mg, 3.52 mmol) and triethyl amine(534 mg, 5.28 mmol, 0.73 mL) in dry N,N-dimethylformamide (35 mL) at 0 00 were added N(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (810 mg, 4.22 mmol) and ethyl (hydroxyimino)cyanoacetate (50 mg, 0.352 mmol). The reaction mixture was allowed to warmroom temperature and stirring was continued for 18 h. The mixture was poured out intowater (300 mL). The mixture was stirred for 15 minutes. The resulting white precipitate was filtered off, washed with water and dried on air. The solid was coevaporated with dichloromethane to afford 1312mg (3.16 mmol, 90% of theory) of the title compound.LC-MS (Method Li): R1 = 2.03 mm; m/z = 415/417 (M+H)

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 106.

10
[ 1035093-81-2 ]
3-bromo-7-cyclopropyl-2-(difluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ No CAS ]
(S)-3-bromo-N-(chroman-4-yl)-7-cyclopropyl-2-(difluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.97 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; ethyl cyanoglyoxylate-2-oxime; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (1 .84 g, 9.61 mmol) and ethyl cyano(hydroxyimino)acetate (0.12 g, 0.87 mmol) were added at 0C under nitrogen atmosphere to a stirred mixture of 3-bromo-7-cyclopropyl-2-(d ifl uoromethyl)pyrazolo[1 ,5- a]pyrimidine-6-carboxylic acid (2.90 g, 8.73 mmol), <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (1.62 g, 8.73 mmol) and triethylamine (1.06 g, 10.48 mmol, 1.46 mL) in dry N,N-dimethylformamide(75 mL). The resulting mixture was stirred while warming up to room temperature overnight. The reaction mixture was poured into hydrochloric acid (1.0 M; 500 mL) and extracted with ethyl acetate (3x150 mL). Combined extracts were washed with brine (3x100 mL), dried with sodium sulfate and concentrated in vacuo. Purification by trituration in ethyl acetate (10 mL) and diisopropyl ether (5 mL) afforded 0.97 g (2.09 mmol; 23% of theory over two steps) of thetitle compound.LC-MS (Method Li): R1 = 2.12 mm; m/z = 463/465 (M+i)1H NMR (400 MHz, DMSO-d6, Method M2) 6 9.18 (d, J = 8.0 Hz, 1H), 7.49 - 7.14 (m, 3H),6.97 - 6.90 (m, 1H), 6.81 (dd, J = 8.2, 1.1 Hz, 1H), 5.28 - 5.19 (m, 1H), 4.35-4.26 (m, 1H),4.26 -4.17 (m, 1H), 2.60 -2.51 (m, 2H), 2.28-2.17 (m, 1H), 2.13 -2.01 (m, 1H), 1.38 - 1.30(m, 2H), 1.27- 1.18 (m, 2H).Br

References: [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 107.

11
[ 1035093-81-2 ]
8-bromo-4-chloroquinoline-3-carboxylic acid [ No CAS ]
8-bromo-4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 45 - 50℃; for 0.5h;	8-Bromo-4-chloroquinoline-3-carboxylic acid (step i) (7.00 g, 24.4 mmol) was dissolved in THFby stirring in an oilbath of 50C for iO mm. The heating was removed, (45)-chroman-4-aminehydrochloride (5.44 g, 29.3 mmol), N,N-diisopropyl-ethyl-amine (i7 ml, 98 mmol) and a solution of 2,4,6-tripropyl-i ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (23 ml, 50 % content, 39 mmol) were added, which caused an increase in temperature to 45C. Stirring was continued for 30 mm and water (300 ml) was added under continuous stirring tosupport precipitation of a solid. The precipitate was collected, washed with water and dried in vacuo.Yield: 9.50 g(93 % of th.)LC-MS (Method Li): R1 = i.oi mm; MS (ESIneg): mlz = 4i7 [M+H]1HNMR Peaklist (400 MHz, DMSO-d6) 6 [ppm]: 2.047 (0.74), 2.054 (0.99), 2.063 (i.54), 2.070(i.66), 2.08i (i.85), 2.088 (i.86), 2.097 (2.49), 2.i04 (2.i8), 2.ii3 (i.49), 2.i20 (i.08), 2.i97(i.06), 2.206 (i.6i), 2.2i8 (2.4i), 2.23i (2.i7), 2.239 (2.iO), 2.252 (i.56), 2.264 (i.Oi), 2.273(0.7i), 2.328 (0.42), 2.670 (0.47), 4.205 (i.i8), 4.2i2 (i.43), 4.233 (3.76), 4.240 (2.80), 4.253(3.08), 4.26i (2.42), 4.277 (2.42), 4.285 (3.i2), 4.293 (2.75), 4.302 (3.iO), 4.3i3 (i.33), 4.32i(i.40), 4.329 (i.04), 5.266 (i.5i), 5.28i (3.35), 5.300 (3.35), 5.3i5 (i.47), 6.793 (5.60), 6.8i4(6.35), 6.922 (2.99), 6.940 (6.44), 6.959 (3.78), 7.i62 (3.04), 7.i65 (3.ii), 7.i83 (5.i5), 7.20i(2.48), 7.382 (5.42), 7.40i (5.04), 7.7i3 (4.62), 7.733 (8.03), 7.754 (5.29), 8.3i2 (6.79), 8.324(8.26), 8.327 (8.69), 8.345 (6.64), 9.042 (i6.00), 9.264 (4.77), 9.285 (4.67).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 162.

12
[ 1035093-81-2 ]
ethyl 8-bromo-4-(dimethylamino)-7-fluoroquinoline-3-carboxylate hydrochloride [ No CAS ]
8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(dimethylamino)-7-fluoroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		To a solution of 8-bromo-4-(dimethylamino)-7-fluoroquinoline-3-carboxylic acid hydrochloride(step 4) (2.00 g, 5.7 mmol) in N,N-dimethylformamide (50 mL) were added 1-[bis(dimethylamino)-methylene]-1 H-i ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (2.18 g, 5.7 mmol) and N,N-diisopropylethylamine (4.21 g, 32.6 mmol, 5.7 mL). The mixture was stirred at room temperature for 1 h. (4S)-Chroman-4-amine hydrochloride (1 .06 g, 5.7 mmol) was added. The reaction mixture was stirred for 16 hat room temperature. The mixturewas poured out into water (200 mL). Solids were filtered off, washed with water and were dried in vacuo. After co-evaporation with toluene and ethyl acetate the title compound was obtained.Yield: 1.90 g (4.3 mmol, 75% of th.)LC-MS (Method L2): R1 = 1 .78 mi m/z = 444/446 (M+H)1H-NMR (400 MHz, DMSO-d6) 6 9.12 (d, J = 8.1 Hz, 1H), 8.70 (s, 1H), 8.23 (dd, J = 9.4, 6.1Hz, 1H), 7.59 (dd, J = 9.3, 8.3 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.98 -6.90 (m, 1H), 6.81 (dd, J = 8.2, 1.0 Hz, 1H), 5.29-5.20 (m, 1H), 4.34-4.19 (m, 2H), 3.06 (s,6H), 2.27-2.15 (m, 1H), 2.11 -2.00 (m, 1H).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 167.

13
[ 1035093-81-2 ]
8-(2,3-dichlorophenyl)-4-[methyl(oxetan-3-yl)amino]quinoline-3-carboxylic acid [ No CAS ]
8-(2,3-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-[methyl(oxetan-3-yl)amino]quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	A flask was charged with 8-(2,3-dichlorophenyl)-4-[methyl(oxetan-3-yl)amino]quinoline-3- carboxylic acid (step 3) (260 mg, 0.645 mmol), <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (131.7 mg, 0.71 mmol), N,N-diisopropyl ethylamine (250 mg, 1 .93 mmol), 4-(N,N-dimethylamino)pyridine (39.4 mg, 0.32 mmol), 1-hydroxy-1H-benzotriazole (43.5 mg, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123.6 mg, 0.645 mmol) in 10 mL dichloromethane. The reaction mixture was stirred at ambient temperature overnight, then mixed with water, the dichloromethane phase was separated, dried via a sodium sulfate I silica gel cartridge and the solvent was removed under reduced pressure. The residue was purifiedby reverse phase column chromatography (eluent water I acetonitrile gradient) to obtain the title compound.Yield: 130mg (0.24 mmol, 37% of th.)1H-NMR Peaklist (399,9532 MHz, DMSO): 6=9.1403(1.94); 9.1288 (2); 9.1208 (2.32); 9.1103(1.85); 8.6012 (10.54); 8.4715 (0.58); 8.3155 (1.57); 8.2143 (2.25); 8.1975 (2.56); 8.1729(1.06); 7.7323 (2.07); 7.7127 (5.31); 7.6894 (10.46); 7.6737 (1.95); 7.4635 (1.67); 7.4521(1.74); 7.4433 (2.94); 7.4332 (2.77); 7.4235 (2.08); 7.4143 (1.65); 7.3824 (1.86); 7.3618 (4.63);7.3428 (4.44); 7.3225 (1.63); 7.1895 (1.81); 7.171 (3.64); 7.1535 (2.27); 6.9433 (2.6); 6.9255(4.32); 6.9084 (2.02); 6.8059 (4.77); 6.7848 (4.45); 6.5782 (0.9); 5.2488 (1.97); 5.237 (2);4.725 (1.91); 4.697 (7.04); 4.6722 (5.48); 4.6575 (5.6); 4.5955 (1.22); 4.5844 (1.61); 4.2921(2.17); 4.2752 (3.94); 4.2675 (3.64); 4.2552 (2.23); 4.2471 (2.41); 4.2281 (0.89); 3.3183(319.34); 3.2701 (0.87); 3.2496 (0.61); 3.1747 (0.71); 3.081 (16); 3.0759 (15.54); 2.9497(1.08); 2.6703 (8.96); 2.5893 (0.63); 2.5051 (1239.6); 2.5012 (1583.24); 2.4971 (1204.24);2.3276 (9.3); 2.2832 (0.88); 2.2475 (1.34); 2.2286 (1.72); 2.2205 (1.78); 2.1313 (0.96); 2.074(5.92); 2.0168 (0.96); 1.2694 (0.87); 1.169 (4.47); 1.0034 (0.71); 0.9887 (0.75); 0.1463 (2.93);-0.0001 (642.47); -0.0792 (0.67); -0.1497 (3.13); -3.3083 (0.55).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 170; 171.

14
[ 1035093-81-2 ]
8-bromo-4-chloro-2-methylquinoline-3-carbonyl chloride [ No CAS ]
8-bromo-4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2-methylquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
766 mg	With triethylamine; In acetonitrile; at 0 - 20℃;	8-Bromo-4-chloro-2-methylquinoline-3-carbonyl chloride (raw product from step 2) (1 g, 3,13 mmol) was dissolved in 60 mL acetonitril and mixed with <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (582 mg, 3,13 mmol) and triethylamine (951 mg, 9,4 mmol) at 0 00. The rection mixture was allowed to warm to room temperature and stirred until complete conversion. The solvent was removed under reduced pressure; the remaining solution was extracted twice withdichloromethane. The combined organic layers were dried over sodium sulfate, filtered and reduced in vacuo. The resulting residue was purified by silica gel flash chromatography (eluent cyclohexane/ethyl acetate gradient).Yield: 766 mg (1.77 mmol, 55% of th.)1H-NMR (400 MHz, DMSO-d6) 6 9.29 (d, 1H, NH), 8.26 - 8.22 (t, 2H), 7.66 - 7.62 (dd, 1H),7.38 - 7.36 (d, 1 H), 7.20 - 7.16 (t, 1 H), 6.97 - 6.93 (t, 1 H), 6.82 - 6.80 (d, 1 H), 5.32 - 5.28 (m,1 H), 4.34 - 4.29 (m, 1 H), 4.23 - 4.17 (m, 1 H), 2.71 (s, 3H), 2.28 -2.22 (m, 1 H), 2.10 -2.03 (m,1 H).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 181.

15
[ 1035093-81-2 ]
8-bromo-4-(methoxymethyl)quinoline-3-carboxylic acid [ No CAS ]
8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(methoxymethyl)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
391 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; trimethylamine; In tetrahydrofuran; ethyl acetate; at 20 - 45℃;	A solution of 8-bromo-4-(methoxymethyl)quinoline-3-carboxylic acid (360 mg, 1 .22 mmol) inTHF (6 ml) was treated with (45)-chroman-4-amine hydrochloride (1:1) and trimethylamine(680 p1, 4.9 mmol). The mixture was warmed to 45C, 2,4,6-tripropyl-i,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (solution in ethyl acetate, 23 ml, 50 % content, 39 mmol)was added, the heating removed and the mixture stirred at ambient temperature overnight.After dilution with water (pH 8-9) the THF was removed in vacuo. The precipitate was filtered off and dissolved in approx. 10 ml of warm acetone. Warm water was added (10 mL) and the mixture was allowed to cool to RT. The solid was filtered off, washed with acetone/water (1:2) and dried in vacuo.Yield: 391 mg (95% purity, 72% of th.) LC-MS (Method Li): R1 = 0.96 mm; MS (ESipos): mlz = 427 [M+H]1HNMR (600 MHz, DMSO-d6) 6 [ppm]: i.235 (0.52), 2.090 (2.20), 2.230 (2.i5), 3.287 (i6.00),4.24i (2.66), 4.293 (2.83), 4.998 (8.92), 5.3i4 (2.68), 6.800 (2.83), 6.8ii (3.i3), 6.943 (3.04),7.i83 (3.03), 7.397 (3.Oi), 7.6i2 (3.03), 8.2ii (2.99), 8.22i (3.08), 8.3ii (2.87), 8.324 (2.94),8.998 (4.49), 9.207 (2.80).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 186; 187.

16
[ 1035093-81-2 ]
4-chloro-8-(3,5-dichlorophenyl)quinoline-3-carboxylic acid [ No CAS ]
4-chloro-8-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 4-chloro-8-(3,5-dichlorophenyl)quinoline-3-carboxylic acid (step 3) (7.60 g, 21.6 mmol) in THF (110 ml) were added under stirring <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (4.4 g, 23.7 mmol), triethylamine (12 ml, 86 mmol) and after 10 mm at ambient temperature a solution of 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethylacetate (19 ml,50 % content, 32 mmol), whereafter the temperature of the mixture was raised to 36C. After stirring overnight at ambient temperature further <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (0.8 g,4.3 mmol), triethylamine (3 ml, 21.5 mmol) and a solution of 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide in ethylacetate (3.85 ml, 50 % content, 6.5 mmol) were added and stirring continued at ambient temperature for another night. Then water was addedand most of the organic solvents evaporated under reduced pressure. The formed precipitate was filtered off and washed with petrolether and was dried in vacuo.Yield: 10.0 g (94% purity, 90% of th.)LC-MS (Method Li): R1 = 1 .35 mm; MS (ESIpos): mlz = 483 [M+H]1HNMR Peaklist (400 MHz, DMSO-d6) 6 [ppm]: 1.356 (1.31), 1.743 (2.45), 1.752 (3.18), 1.759(6.79), 1.768 (3.21), 1.776 (2.57), 1.988 (0.51), 2.059 (0.99), 2.066 (1.07), 2.076 (1.22), 2.084(1.26), 2.093 (1.57), 2.100 (1.38), 2.209 (1.45), 2.221 (1.33), 2.229 (1.27), 2.242 (0.90), 2.366(0.47), 3.585 (2.47), 3.601 (5.93), 3.617 (2.49), 4.221 (0.89), 4.241 (2.24), 4.249 (1.82), 4.262(2.18), 4.270 (2.80), 4.279 (2.21), 4.287 (1.82), 4.296 (1.93), 4.315 (0.75), 5.267 (0.91), 5.282(2.01), 5.301 (2.05), 5.315 (0.88), 6.791 (3.63), 6.811 (4.03), 6.917 (1.84), 6.936 (3.82), 6.955(2.20), 7.161 (2.03), 7.179 (3.22), 7.199 (1.53), 7.380 (3.39), 7.399 (3.19), 7.680 (16.00), 7.879 (0.46), 7.893 (2.16), 7.912 (3.99), 7.932 (3.43), 8.009 (4.26), 8.026 (2.94), 8.389 (3.75), 8.410 (3.33), 8.962 (9.97), 9.251 (3.23), 9.272 (3.16).

References: [1]Patent: WO2018/87036,2018,A1 .Location in patent: Page/Page column 150; 151.

17
[ 1035093-81-2 ]
[ 1401031-28-4 ]
(S)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)chroman-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.1%		R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetaldehyde 5a (80 mg, 0.31 mmol) and <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> 6a (86 mg, 0.46 mmol, prepared by a method disclosed in "") were dissolved in 10 mL of a mixture of dichloromethane and methanol (V:V=5:1), and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (263 mg, 1.24 mmol) was added, and the resulting mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromtography with elution system A to obtain the title compound 6 (36 mg, yield 32.1%) as a white viscous solid. MS m/z (ESI): 393.5 [M+1] 1H NMR (400 MHz, Methanol-d4) delta 8.55 (d, 1H), 7.80-7.76 (m, 1H), 7.53 (d, 1H), 7.26-7.25 (m, 1H), 7.05-7.01 (m, 2H), 6.78-6.70 (m, 2H), 4.17-4.10 (m, 2H), 3.79-3.63 (m, 3H), 2.56-2.42 (m, 3H), 2.19-2.10 (m, 2H), 1.92-1.82 (m, 2H), 1.80-1.44 (m, 12H).

References: [1]Patent: EP3354649,2018,A1 .Location in patent: Paragraph 0104; 0105.

18
[ 1035093-81-2 ]
7-bromo-3-isopropyl-6-methylpyrazolo[5,1-b][1,3]thiazole-2-carboxylic acid [ No CAS ]
7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-6-methylpyrazolo[5,1-b][1,3]thiazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.0 g	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	A flask was charged with 7-bromo-3-isopropyl-6-methylpyrazolo[5,l-b][l,3]thiazole-2-carboxylic acid (3.0 g, 85 % purity, 8.41 mmol), <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (1.87 g, 10.09 mmol), NN- diisopropyl ethylamine (2.17 g, 16.82 mmol), 4-(NN-dimethylamino) pyridine (513.8 mg, 4.21 mmol), 1 -hydroxy- lH-benzotriazole (568.3 mg, 4.21 mmol) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.61 g, 8.41 mmol) in 125 mL dichloromethane. The reaction mixture was stirred at ambient temperature overnight, then mixed with water, the dichloromethane phase was separated, dried via a sodium sulfate / silica gel cartridge and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent cyclohexane / ethyl acetate gradient) to obtain the title compound. Yield: 2.0 g (4.6 mmol, 54.7 % of th.) LC-MS (Method L0): Rt = 1.70 min; MS (ESIpos): m/z = 434.0; 435.9 [M+H]+. -NMR (399,95) MHz, DMSO-d6) delta [ppm]: 8.91 (d, 1H, NH), 7.20 - 7.15 (m, 2H), 6.92 - 6.89 (dd, 1H), 6.81 (d, 1H), 5.24 - 5.19 (m, 1H), 4.30 - 4.20 (m, 2H), 4.09 - 4.02 (hept, 1H), 2.32 (s, 3H), 2.16 - 2.05 (m, 2H), 1.47 (d, 6H).

References: [1]Patent: WO2018/197401,2018,A1 .Location in patent: Page/Page column 109-110.

19
[ 1035093-81-2 ]
8-bromo-4-chlorocinnoline-3-carbonyl chloride [ No CAS ]
8-bromo-4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]cinnoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	Under a nitrogen atmosphere to a stirred solution of crude 8-bromo-4-chlorocinnoline-3-carbonyl chloride (2.27 mmol) in dichloromethane (25 mL) were added triethylamine (688 mg, 6.80 mmol, 0.95 mL) and <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (463 mg, 2.49 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with dichloromethane (2x20 mL). Combined organic layers were dried with sodium sulfate and concentrated in vacuo. 922 mg (2.20 mmol, 97% of theory) of the title compound were obtained. LC-MS (Method L3): Rt = 2.07 min; m/z = 418/420 (M+l)+. JH NMR (400 MHz, DMSO-d6) delta 9.48 (d, J = 8.3 Hz, 1H), 8.49 (dd, J = 7.5, 1.1Hz, 1H), 8.36 (dd, J = 8.5, 1.1Hz, 1H), 7.99 (dd, J = 8.5, 7.5 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.24 - 7.14 (m, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.1Hz, 1H), 5.38 (q, J = 6.0 Hz, 1H), 4.40 - 4.19 (m, 2H), 2.32 - 2.19 (m, 1H), 2.19 - 2.05 (m, 1H).

References: [1]Patent: WO2019/2132,2019,A1 .Location in patent: Page/Page column 171.

20
[ 1035093-81-2 ]
8-(4-methylpentan-2-yl)-4-(morpholin-4-yl)quinoline-3-carboxylic acid [ No CAS ]
N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-8-(4-methylpentan-2-yl)-4-(morpholin-4-yl)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.2%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	A flask was charged with 8-(4-methylpentan-2-yl)-4-(morpholin-4-yl)quinoline-3-carboxylic acid (0.12g, 0.35 mmol), <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (78.1 mg, 0.42 mmol), N,N-diisopropyl ethylamine(90.6 mg, 0.70 mmol), 4-(N,N-dimethylamino) pyridine (21.4 mg, 0.17 mmol), 1-hydroxy-1H- benzotriazole (23.7 mg, 0.17 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67.2 mg, 0.35 mmol) in 8 mL dichloromethane. The reaction mixture was stirred at ambient temperature overnight, then mixed with water, the dichloromethane phase was separated, dried via asodium sulfate / silica gel cartridge and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent cyclohexane / ethyl acetate gradient) to obtain the title compound.Yield: 0.144 g (0.30 mmol, 87,2 % of th.).LC-MS (Method 17): R = 1.44 mi mlz = 474 (M+H).1H NMR (400 MHz, DMSO-d6) 9.18 - 9.15 (d, 1H, NH), 8.68 (s, 1H), 8.05 - 8.03 (d, 1H), 7.64 -7.56 (m, 2H), 7.40 - 7.39 (d, 1H), 7.20 - 7.16 (t, 1H), 6.96 - 6.92 (m, 1H), 6.81 - 6.79 (d, 1H), 5.26 (m,1H), 4.35 -4.24 (m, 3H), 3.88 - 3.80 (m, 4H), 3.25 - 3.23 (m, 4H), 2.27 -2.17 (m, 1H), 2.12 -2.01 (m, 1H), 1.76- 1.69 (m, 1H), 1.51 - 1.45 (m, 1H), 1.38- 1.31 (m, 1H), 1.24-1.21 (m, 3H), 0.85-0.82 (m,6H).

References: [1]Patent: WO2019/25341,2019,A1 .Location in patent: Page/Page column 143; 144.

21
[ 1035093-81-2 ]
8-bromo-4-(dimethylamino)quinoline-3-carboxylic acid [ No CAS ]
(S)-8-bromo-N-(chroman-4-yl)-4-(dimethylamino)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.31 g	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a stirred suspension of crude 8-bromo-4-(dimethylamino)quinoline-3-carboxylic acid (4.64 mmol) in N,N-dimethylformamide (50 mL) was added triethylamine (1,41 g, 13.92 mmol, 1.94 mL). To the resulting solution were added O-(7-azabenzotriazol- 1 -yl)-N,N,N?,N?-tetramethyluroniumhexafluorophosphate (2.12 g, 5.57 mmol) and <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (0.95 g, 5.10 mmol).The reaction mixture was stirred at room temperature for 6 hours and was poured out into water (500mL). The resulting suspension was stirred for 15 minutes. The precipitate was collected by filtration,washed with water (100 mL) and dried in vacuo to afford 1.31 g (3.07 mmol; 66% of theory over twosteps) of the title compound.LC-MS (Method 1): R = 4.65 mm; mlz = 426/428 (M+H)?H NMR (400 MHz, DMSO-d6) 9.11 (d, J = 8.1 Hz, 1H), 8.68 (s, 1H), 8.17 (m, 1H), 8.09 (m, 1H), 7.46 (m, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.98 - 6.89 (m, 1H), 6.81 (m, 1H), 5.31 -5.21 (m, 1H), 4.35 -4.19 (m, 2H), 3.05 (s, 6H), 2.28 -2.16 (m, 1H), 2.13 -2.00 (m, 1H).

References: [1]Patent: WO2019/25341,2019,A1 .Location in patent: Page/Page column 122; 123.

22
[ 1035093-81-2 ]
8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid hydrochloride [ No CAS ]
(S)-N-(chroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Finally, 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid hydrochloride is amidated with ( T) - C h r o ma n a m i n c · H C 1 via utilization of CDMT and NMM in 90% yield (>99 w% purity).In a four-necked round-bottomed flask (500 mL), equipped with a mechanical stirrer, a dropping funnel and a thermometer, was added 20.0 g of 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3- carboxylic acid hydrochloride (95 w%), 11.0 g CDMT and 160 mL of toluene. Via dosing of 25.0 g of NMM within 25 min the suspension was heated to 35 C internal temperature and was maintained afterwards with external heating. The suspension turns yellow and becomes more viscous at the end of addition. However, the viscosity decreases subsequently under stirring. After 30 min stirring 10.4 g of ( S) - C h ro m a n - 4 - a m i n c hydrochloride was added in one portion. Afterwards the suspension was stirred for another 8 hours until HPLC analysis indicated 99% conversion. After reaction completion, the reaction mixture was cooled down to room temperature (20-22 C) and was transferred into a one necked round-bottomed flask (1000 mL). Subsequently 320 mL of methylcyclohexane was added, the suspension was cooled to 0 C and stirred at this temperature for 30 min. Then the solid was filtered through a glass frit (por. 3). The filter cake was washed with 100 mL of ice-cold acetonitrile, 100 mL of aqueous sodium hydroxide (5 w%) and 300 mL of deion. water. The solid was dried under vacuum (40 C, 70 mbar). Afterwards the complete amount of 24.2 g of dry solid were suspended in 120 mL of MTBE. Some crystals of the desired polymorph were added as seeds. Afterwards the suspension was stirred at 56 C external heating for 4 hours. Finally, the suspension was cooled back to 22 C, the solid was filtered off and washed with 20 mL of MTBE. The product was then dried under vacuum (40 C, 50-10 mbar) for 2 hours. The product was obtained as a white solid.As determined via Q-NMR and Q-HPLC analysis, the remaining 22.8 g solid contained 99.1 w% of (S)- N-(Chroman-4-yl)-8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxamide, which corresponds to 21.6 g pure product and a yield of 90%.-NMR (DMSO-d6, 400 MHz) d (ppm) = 9.10 (d, J = 8.0 Hz), 8.63 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.67-7.63 (m, 4H), 7.37 (d, J= 8.0 Hz, 1H), 7.17 (dd, J= 8.0, 8.0 Hz, 1H), 6.94 (dd, J = 8.0, 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.79-5.72 (m, 1H), 4.21-4.32 (m, 2H), 3.07 (s, 6H), 2.25-2.15 (m, 1H), 2.09-2.00 (m, 1H).

References: [1]Patent: WO2019/115768,2019,A1 .Location in patent: Page/Page column 34; 38; 39.

23
[ 1035093-81-2 ]
4-chloro-8-(2,3,5-trifluorophenyl)quinoline-3-carbonyl chloride [ No CAS ]
4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 74h;Inert atmosphere;	Under argon atmosphere at 0C, to a solution of crude 4-chloro-8-(2,3,5-trifluorophenyl)quinoline-3- carbonyl chloride (17 mmol) in dry tetrahydrofuran (30 mL) was added N,N-diisopropylethylamine (15 mL, 84 mmol). The mixture was stirred for 10 min and <strong>[1035093-81-2](S)-chroman-4-amine hydrochloride</strong> (3.13 g, 17 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and was stirred for 74 h. Activated charcoal (2 g) was added and the mixture was stirred for 30 min. Solids were filtered off over a pad of kieselgur. The filter cake was washed with tetrahydrofuran (3x30 mL). At 0C, the filtrate was slowly added to hydrochloric acid (1 M; 150 mL). The resulting suspension was stirred for 30 min. Solids were filtered off, washed with water, diisopropyl ether and methyl-tert-butyl ether and were dried on air. 5.41 g (69% of theory) of the title compound were obtained. LC-MS (Method 3): Rt = 2.21 min; m/z = 469/471 (M+H)+ (0780) 1H NMR (400 MHz, DMSO-r/6) d 9.29 (d, 1H), 8.93 (s, 1H), 8.45 (dd, 1H), 8.02 - 7.91 (m, 2H), 7.74 - 7.56 (m, 1H), 7.38 (dd, 1H), 7.34 - 7.26 (m, 1H), 7.18 (td, 1H), 6.93 (td, 1H), 6.80 (dd, 1H), 5.28 (dt, 1H), 4.33 - 4.20 (m, 2H), 2.27 - 2.17 (m, 1H), 2.12 - 2.02 (m, 1H).

References: [1]Patent: WO2019/215182,2019,A1 .Location in patent: Page/Page column 79-80.

24
[ 1035093-81-2 ]
8-bromo-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid [ No CAS ]
8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		A solution of 8-bromo-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid (690 mg, 2.05 mmol) in DMF / THF (1 :3 mixture, 14 ml) was placed in an oil bath of 55C and treated with (4S)-chroman-4- amine hydrochloride (457 mg, 2.46 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.2 mmol). The heating was removed and a solution of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethylacetate (1.9 ml, 50 % content, 3.3 mmol) was added dropwise and the mixture stirred over night at ambient temperature. The reaction mixture was warmed again to 55C, <strong>[1035093-81-2](4S)-chroman-4-amine hydrochloride</strong> (152 mg, 0.82 mmol), N,N-diisopropylethylamine (0.5 ml, 2.87 mmol) was added and after removal of the heating a solution of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethylacetate (0.6 ml, 50 % content, 1.03 mmol) and stirring continued at ambient temperature for 3.5 h. Then water (80 ml) was added and the mixture stirred at 60 for 20 min. The THF was removed under reduced pressure and the mixture cooled to RT. The precipitate was filtered off, washed with water and dried in vacuo. (0801) Yield: 748 mg (78% of theory) (0802) LC-MS (Method 2): Rt = 0.97 min; MS (ESIneg): m/z = 465 [ M f (0803) -NMR (500 MHz, DMSO-d6) d [ppm]: 1.351 (0.58), 1.644 (3.27), 1.670 (3.71), 1.686 (3.38), 1.713 (3.35), 1.755 (1.16), 1.988 (0.44), 2.060 (2.11), 2.070 (2.36), 2.084 (2.76), 2.229 (2.51), 2.240 (2.55), 2.246 (2.47), 2.257 (1.85), 2.377 (4.33), 2.401 (4.40), 2.632 (0.47), 3.296 (0.44), 3.393 (1.42), 3.440 (1.96), 3.461 (3.53), 3.495 (2.87), 3.519 (4.15), 3.541 (2.36), 3.598 (1.27), 3.697 (2.22), 3.988 (5.45), 4.000 (6.33), 4.011 (5.09), 4.212 (1.89), 4.229 (4.40), 4.247 (3.20), 4.290 (3.49), 4.297 (3.31), 4.303 (3.60), 5.299 (1.82), 5.310 (4.00), 5.325 (3.85), 5.336 (1.78), 6.793 (7.02), 6.810 (7.60), 6.933 (3.49), 6.948 (7.16), 6.963 (4.07), 7.168 (3.75), 7.184 (6.29), 7.199 (3.09), 7.414 (6.47), 7.429 (6.04), 7.577 (4.11), 7.593 (7.05), 7.609 (4.36), 8.185 (7.96), 8.200 (7.64), 8.465 (6.55), 8.482 (6.18), 8.856 (16.00), 9.192 (5.85), 9.208 (5.71).

References: [1]Patent: WO2019/215182,2019,A1 .Location in patent: Page/Page column 81-82.

Historical Records

Technical Information

• Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Hydride Reductions • Leuckart-Wallach Reaction • Mannich Reaction • Petasis Reaction • Preparation of Amines • Reactions of Amines • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction

Related Functional Groups of
[ 1035093-81-2 ]

Amines

A140031 [67858-19-9]

6-Methoxychroman-4-amine hydrochloride

Similarity: 1.00

A150356 [90609-63-5]

Chroman-4-amine hydrochloride

Similarity: 1.00

A178396 [730980-59-3]

(R)-Chroman-4-amine hydrochloride

Similarity: 1.00

A305485 [1392218-82-4]

(S)-6-Methylchroman-4-amine hydrochloride

Similarity: 1.00

A206694 [188198-38-1]

(S)-Chroman-4-amine

Similarity: 0.98

Related Parent Nucleus of
[ 1035093-81-2 ]

Other Aromatic Heterocycles

A140031 [67858-19-9]

6-Methoxychroman-4-amine hydrochloride

Similarity: 1.00

A150356 [90609-63-5]

Chroman-4-amine hydrochloride

Similarity: 1.00

A178396 [730980-59-3]

(R)-Chroman-4-amine hydrochloride

Similarity: 1.00

A305485 [1392218-82-4]

(S)-6-Methylchroman-4-amine hydrochloride

Similarity: 1.00

A206694 [188198-38-1]

(S)-Chroman-4-amine

Similarity: 0.98

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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