[ CAS No. 14714-24-0 ] {[proInfo.proName]}

Name: 14714-24-0|6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid|97%
Brand: Ambeed
SKU: A117372
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Quality Control of [ 14714-24-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 14714-24-0 ]

Product Details of [ 14714-24-0 ]

CAS No. :	14714-24-0	MDL No. :	MFCD04974055
Formula :	C₇H₄ClN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HTUZJYQXKFDVLT-UHFFFAOYSA-N
M.W :	197.58	Pubchem ID :	2794637
Synonyms :

Calculated chemistry of [ 14714-24-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	44.96
TPSA :	67.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.16
Log Po/w (XLOGP3) :	1.15
Log Po/w (WLOGP) :	1.08
Log Po/w (MLOGP) :	0.83
Log Po/w (SILICOS-IT) :	0.45
Consensus Log Po/w :	0.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.24
Solubility :	1.15 mg/ml ; 0.00581 mol/l
Class :	Soluble
Log S (Ali) :	-2.16
Solubility :	1.36 mg/ml ; 0.00689 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.71
Solubility :	3.88 mg/ml ; 0.0196 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.03

Safety of [ 14714-24-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H317-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 14714-24-0 ]

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

Upstream synthesis route of [ 14714-24-0 ]
Downstream synthetic route of [ 14714-24-0 ]

[ 14714-24-0 ] Synthesis Path-Upstream 1~2

1
[ 75-89-8 ]
[ 64067-99-8 ]
[ 14714-24-0 ]

Reference： [1] Patent: WO2017/123860, 2017, A1, . Location in patent: Page/Page column 310

2
[ 64067-99-8 ]
[ 14714-24-0 ]

Reference： [1] Farmaco, 1997, vol. 52, # 4, p. 213 - 217

[ 14714-24-0 ] Synthesis Path-Downstream 1~30

1
[ 64067-99-8 ]
[ 14714-24-0 ]

Reference： [1]Il Farmaco,1997,vol. 52,p. 213 - 217

4
[ 623-33-6 ]
[ 14714-24-0 ]
[ 215530-72-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 17A Production of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl]glycine Ethyl Ester 0.593 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 7.5 ml of N,N-dimethylformamide; 0.535 g of N,N'-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.457 ml of triethylamine was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.749 g of the title compound. Melting point: 190-191 C.; Elemental analysis (for C11H11N4O3Cl): Calculated (%): C, 46.74; H, 3.92; N, 19.82; Found (%): C, 46.70; H, 4.03; N, 19.75.
	With triethylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	Reference Example 17 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl]glycine ethyl ester 0.593 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 7.5 ml of N,N-dimethylformamide; 0.535 g of N,N'-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.457 ml of triethylamine was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.749 g of the title compound. Melting point: 190-191 C. Elemental analysis (for C11H11N4O3Cl):
	With triethylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	Reference Example A17 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester <strong>[14714-24-0]6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (0.593 g) was suspended in N,N-dimethylformamide (7.5 ml); N,N'-carbonyldiimidazole (0.535 g) and glycine ethyl ester hydrochloride (0.46 g) were added thereto, followed by stirring at room temperature for 30 minutes. To this mixture, triethylamine (0.457 ml) was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystals precipitated were collected by filtration, washed with water and dried to give the title compound (0.749 g). melting point: 190-191C elemental analysis for C11H11N4O3Cl Calculated (%): C,46.74; H,3.92; N,19.82 Found (%): C,46.70; H,4.03; N,19.75

Reference： [1]Patent: US6627630,2003,B1
[2]Patent: US6248740,2001,B1
[3]Patent: EP1243271,2002,A1

5
[ 4244-84-2 ]
[ 14714-24-0 ]
N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 32A Production of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl) beta-Alanine Ethyl Ester 1.98 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 25 ml of N,N-dimethylformamide; 1.78 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 1 hour. To this mixture, 1.69 g of beta-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 2.57 g of the title compound. Melting point: 132-134 C.; Elemental analysis (for C12H13N4O3Cl): Calculated (.%): C, 48.58; H, 4.42; N, 18.88; Found (%): C, 48.43; H, 4.33; N, 18.68.

Reference： [1]Patent: US6627630,2003,B1

6
[ 17288-15-2 ]
[ 14714-24-0 ]
N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 21A Production of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine Ethyl Ester 1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound. 1H-NMR (CDCl3) delta ppm: 1.28 (3H, t, J=7.2 Hz), 1.70 (6H, s), 4.25 (2H, q, J=7.0 Hz), 7.13 (1H, d, J=9.4 Hz), 7.87 (1H, brs), 7.89 (1H, d, J=9.6 Hz), 8.41 (1H, s).
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example 21 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound. 1H-NMR (CDCl3) delta ppm: 1.28 (3H, t, J=7.2 Hz), 1.70 (6H, s), 4.25 (2H, q, J=7.0 Hz), 7.13 (1H, d, J=9.4 Hz), 7.87 (1H, brs), 7.89 (1H, d, J=9.6 Hz), 8.41 (1H, s).
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example A21 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid (1.28 g) was suspended in N,N-dimethylformamide (12 ml); N,N'-carbonyldiimidazole (1.16 g) was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture, <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> (1.20 g) and triethylamine (1.00 ml) were added, followed by stirring at room temperature for 16 hours. Water was added, the crystals precipitated were collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with brine and dried over magnesium sulfate. The extract was concentrated under reduced pressure; the residue was combined with the above crystals collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fractions were collected and concentrated under reduced pressure to give the title compound (1.20 g). 1H-NMR(CDCl3)delta ppm: 1.28(3H,t,J=7.2Hz), 1.70(6H,s), 4.25(2H,q,J=7.0Hz), 7.13(1H,d,J=9.4Hz), 7.87(1H,brs), 7.89(1H,d,J=9.6Hz), 8.41(1H,s).

Reference： [1]Patent: US6627630,2003,B1
[2]Patent: US6248740,2001,B1
[3]Patent: EP1243271,2002,A1

7
N,N'-dicarbonylimidazole [ No CAS ]
[ 4244-84-2 ]
[ 14714-24-0 ]
N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	Reference Example 32 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)beta-alanine ethyl ester 1.98 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 25 ml of N,N-dimethylformamide; 1.78 g of N,N'-dicarbonylimidazole was added, followed by stirring at room temperature for 1 hour. To this mixture, 1.69 g of beta-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 2.57 g of the title compound. Melting point: 132-134 C. Elemental analysis (for C12H13N4O3Cl):
	With triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	Reference Example A32 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl) beta-alanine ethyl ester <strong>[14714-24-0]6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (1.98 g) was suspended in N,N-dimethylformamide (25 ml); N,N'-dicarbonylimidazole (1.78 g) was added thereto, followed by stirring at room temperature for 1 hour. To this mixture, beta-alanine ethyl ester hydrochloride (1.69 g) and triethylamine (1.53 ml) were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystals precipitated were collected by filtration, washed with water and dried to give the title compound (2.57 g). melting point: 132-134C elemental analysis for C12H13N4O3Cl Calculated (%): C,48.58; H,4.42; N,18.88 Found (%): C,48.43; H,4.33; N,18.68

Reference： [1]Patent: US6248740,2001,B1
[2]Patent: EP1243271,2002,A1

8
[ 14714-24-0 ]
[ 1162680-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.5h;	Step 1. 6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl chloride To a 250-mL, round-bottomed flask was added <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (2.0 g, 10 mmol, Maybridge, Cornwall, UK) and CH2Cl2 (40 mL). To the mixture was added oxalyl chloride (20 mL, 40 mmol, 2 M in CH2Cl2) and DMF (8.0 muL, 0.10 mmol). The mixture was stirred for 1.5 h at 25 C. Toluene (10 mL) was added and the mixture was concentrated to afford the title compound which was taken on to the next step without further purification.

Reference： [1]Patent: US2009/163489,2009,A1 .Location in patent: Page/Page column 18

9
[ 14714-24-0 ]
[ 21103-33-3 ]
N-4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butyl-6-chloroimidazo[1,2-b]pyridazin-2-ylcarbamide [ No CAS ]

Reference： [1]Patent: WO2006/15737,2006,A1 .Location in patent: Page/Page column 83

10
[ 14714-24-0 ]
[ 1337910-09-4 ]

Reference： [1]Patent: US2011/237570,2011,A1

11
[ 14714-24-0 ]
[ 1337910-29-8 ]

Reference： [1]Patent: US2011/237570,2011,A1

12
[ 14714-24-0 ]
[ 1337911-44-0 ]

Reference： [1]Patent: US2011/237570,2011,A1

13
[ 14714-24-0 ]
[ 1337911-49-5 ]

Reference： [1]Patent: US2011/237570,2011,A1

14
[ 14714-24-0 ]
[ 1337911-22-4 ]

Reference： [1]Patent: US2011/237570,2011,A1

15
[ 14714-24-0 ]
[ 1337911-48-4 ]

Reference： [1]Patent: US2011/237570,2011,A1

16
5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide [ No CAS ]
[ 14714-24-0 ]
[ 1337911-50-8 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.61 g), and the mixture was heated at 80 C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on an 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2M ammonia-methanol in DCM. 4.4 g of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 457.8. 1H NMR (400 MHz, DMSO-d6) delta 11.85-12.45 (2H, m) 9.08 (1H, s) 8.36 (1H, d) 7.93-8.04 (2H, m) 7.83 (1H, s) 7.67-7.75 (2H, m) 7.49-7.64 (3H, m).

Reference： [1]Patent: US2011/237570,2011,A1 .Location in patent: Page/Page column 26

17
5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide [ No CAS ]
[ 14714-24-0 ]
[ 1337911-53-1 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 1h;	A mixture of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (600 mg), HBTU (900 mg), DIEA (1 mL) and 5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (794 mg) in DMF (5 mL) was heated at 80 C. for 1 hour with stirring. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution was added, and the mixture was stirred for 30 minutes at room temperature. The solid was filtered, washed with water, and dried under vacuum to get <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (890 mg). LCMS (m/z): 491.8.

Reference： [1]Patent: US2011/237570,2011,A1 .Location in patent: Page/Page column 27; 28

18
5-(3-chloro-5-fluorophenyl)-1H-benzoimidazol-2-ylamine hydrobromide [ No CAS ]
[ 14714-24-0 ]
[ 1337911-54-2 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.46 g), and the mixture was heated at 80 C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on a 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2 M ammonia-methanol in DCM. 4.4 g of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 441.9. 1H NMR (400 MHz, DMSO-d6) delta 12.18 (2H, br. s.) 9.08 (1H, s) 8.32-8.39 (1H, m) 7.82 (1H, s) 7.46-7.64 (6H, m).

Reference： [1]Patent: US2011/237570,2011,A1 .Location in patent: Page/Page column 28

19
5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide [ No CAS ]
[ 14714-24-0 ]
[ 1337911-58-6 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.78 g), and the mixture was heated at 80 C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on an 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2M ammonia-methanol in DCM. 4.7 g of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> [5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 473.9. 1H NMR (400 MHz, DMSO-d6) delta 12.14 (2H, br. s.) 9.08 (1H, s) 8.35 (1H, d) 7.81 (1H, s) 7.73 (1H, d) 7.47-7.65 (5H, m) 7.34 (1H, d).

Reference： [1]Patent: US2011/237570,2011,A1 .Location in patent: Page/Page column 29

20
5-(3-chlorophenyl)-1H-benzoimidazol-2-ylamine hydrobromide [ No CAS ]
[ 14714-24-0 ]
[ 1337911-60-0 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (400 mg), HBTU (900 mg) and DIEA (1 mL) in DMF (5 mL) was heated at 80 C. for 10 minutes. To this reaction mixture 5-(3-chlorophenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (265 mg) was added, and the mixture was heated at 80 C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution was added, and the mixture was stirred for 30 minutes. The mixture was filtered, washed with water, and purified on silica gel column to obtain <strong>[14714-24-0]6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid</strong> [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (635 mg). LC-MS (m/z).

Reference： [1]Patent: US2011/237570,2011,A1 .Location in patent: Page/Page column 29

21
4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butan-1-amine [ No CAS ]
[ 14714-24-0 ]
[ 1596371-82-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7042 - 7060

22
2-(((aR)-6-aminospiro[3.3]heptan-2-yl)oxy)nicotinamide [ No CAS ]
6-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid [ No CAS ]
[ 76-05-1 ]
[ 14714-24-0 ]
N-((aR)-6-((3-carbamoylpyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)-6-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazine-2-carboxamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.1%		Combined Example 42C (13 mg, 0.053 mmol) with a mixture of 6-(2,2,2- roethoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid and 6-(-chloroimidazo[1,2-dazine-2-carboxylic acid (13.73 mg, 0.053 mmol), BOP (23.25 mg, 0.053 mmol) , DMF mL) and DIEA (0.046 mL, 0.263 mmol). After stirring 18h, the reaction was acidified with diluted with DMF, filtered and purified by reverse phase HPLC to afford 2 products, one xample 61 (8.3 mg, 0.014 mmol, 26.1 % yield). LCMS(ESI) m/z 491.2 (M+H)+. 1H NMR MHz, DMSO-d6) delta 8.56 (br d, J=7.9 Hz, 1H), 8.42 (s, 1H), 8.33 - 8.24 (m, 1H), 8.17 (dd, 1.5 Hz, 1H), 8.13 (d, J=10.1 Hz, 1H), 7.68 (br s, 1H), 7.61 (br s, 1H), 7.16 (d, J=9.8 Hz, 7.11 (dd, J=7.5, 5.0 Hz, 1H), 5.22 (quin, J=7.0 Hz, 1H), 5.05 (q, J=8.9 Hz, 2H), 4.38 (sxt, Hz, 1H), 2.66 (dt, J=11.5, 5.7 Hz, 1H), 2.47 (br d, J=5.8 Hz, 1H), 2.41 (br dd, J=10.8, 7.2H), 2.34 - 2.22 (m, 3H), 2.19 (br dd, J=11.7, 7.5 Hz, 1H). Analytical HPLC: RT = 1.56 min od A) and RT = 1.56 min (Method B), purity 100%.

Reference： [1]Patent: WO2017/123860,2017,A1 .Location in patent: Page/Page column 310; 311

23
[ 75-89-8 ]
[ 64067-99-8 ]
6-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid [ No CAS ]
[ 14714-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide monohydrate; water; at 100℃; for 0.25h;Microwave irradiation;	To <strong>[64067-99-8]ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate</strong> (0.206 g, 0.913 mmol) was LiOH.H2O (1.826 mL, 1.826 mmol) in 2,2,2-trifluoroethanol (2 mL, 27.8 mmol)/ H2O (7nd the mixture was heated to 100 C in microwave for 15 min. The reaction producedd ether product and hydrolysized starting material. The reaction mixture was concentrated,ied with 1H HCl and solid filtered to collect 0.2g brown solid mixture of 2 products. MS(ESI) m/z 198.0-199.9 and 262.0 (M+H)+. The mixture was carried onto the next step as

Reference： [1]Patent: WO2017/123860,2017,A1 .Location in patent: Page/Page column 310

24
[ 4244-84-2 ]
[ 14714-24-0 ]
N-[6-[3-[4-(diphenylmethoxy)-piperidino]propylamino]imidazo[1,2-b]pyridazine-2-carbonyl]-β-alanine ethyl ester [ No CAS ]