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Quinoline derivatives used as SMO inhibitors

A kind of compound, selected technology, applied in the field of quinoline derivatives

Inactive Publication Date: 2015-09-30
GUANGDONG ZHONGSHENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although there are some SMO inhibitors in the prior art, they need to be improved in terms of activity, solubility, pharmacokinetics, druggability, etc.

Method used

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  • Quinoline derivatives used as SMO inhibitors
  • Quinoline derivatives used as SMO inhibitors
  • Quinoline derivatives used as SMO inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0238]

[0239] 4-(2-(4-((3R,5R)-3,5-dimethylpiperidin-1-yl)phenyl)-4-methyl-1-oxo-1,2-dihydroiso Quinolin-5-yl)benzonitrile

[0240]

[0241] Step 1: Dissolve compound 1-1 (60g, 0.36mol) in ice water (900mL), acetone (300mL) and aqueous HCl (180mL, 2.23mol), and slowly add it dropwise to sodium nitrite (50g, 0.72mol) in aqueous solution (360mL), the temperature was kept at 0-10°C. After stirring for 2 hours, solid potassium iodide (120g, 0.72mol) was added directly, and the temperature was kept at 7-10°C for 30 minutes, then the reaction solution was heated to 80-90°C until the purple gas disappeared, and cooled to room temperature. The mixture was filtered to obtain compound 1-2 (85 g, yield 85%) as a yellow solid. MS ESI calculated value C 8 h 7 IO 3 [M+H] + 279, the measured value is 279.

[0242] Step 2: Dissolve compound 1-2 (34.5g, 0.12mol) in DCM (300mL), add DMF (0.1mL), then add compound 1-3 (12mL, 0.135mol) dropwise, and stir the reaction solution for 1...

Embodiment 14

[0256]

[0257] 4-(2-(4-((3R,5R)-4-benzoyl-3,5-dimethylpiperazin-1-yl)phenyl)-4-methyl-1-oxo-1 ,2-Dihydroisoquinolin-5-yl)benzonitrile

[0258]

[0259] Step 1: Compound 14-1 (75g, 0.4mol) and triethylamine (60mL, 0.45mol) were dissolved in THF (500mL) solution and cooled to -30°C, and isobutyl chloroformate (54mL, 0.42mol) A solution in THF (100 mL) was added dropwise and the reaction was stirred at -30 °C for 0.5 h, then allowed to warm to room temperature, then stirred for an additional 5 h. The reactant was cooled to 0°C again, and the Bn 2 NH (88 mL, 0.43 mol) and TEA (70 mL, 500 mmol) were dissolved in THF (100 mL) and added dropwise, and the reactant was stirred at room temperature for 10 hours. The reaction mixture was checked by LC-MS. The mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 14-2 as a white solid (84 g, yield 60...

Embodiment 33

[0275]

[0276] 4-(4-Methyl-1-oxo-2-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1,2-dihydroisoquinoline-5 -yl)benzonitrile

[0277]

[0278] Compound 33-1 (200mg, 0.45mmol), formaldehyde (41mg, 1.35mmol) and NaBH 3 CN (43 mg, 0.675 mmol) was dissolved in THF (5 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was checked by LC-MS. The crude product was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.43 (d, J = 8.0Hz, 1H), 7.91 (d, J = 8.0Hz, 2H), 7.61-7.54 (m, 4H), 7.35 (d, J = 8.8Hz, 2H), 7.19(s, 1H), 7.14(d, J=8.4Hz, 2H), 4.01(d, J=12.8Hz, 2H), 3.35(d, J=6.4Hz, 2H), 2.85 (t, J=12.4Hz, 2H), 1.52(s, 3H), 1.34(d, J=6.4Hz, 6H), 1.19(t, J=6.4Hz, 3H). MS ESI calculated value C 30 h 30 N 4 O[M+H] + 463, the measured value is 463.

[0279] Compounds shown in Table 3 can be synthesized from compound 33-1 and the corresponding aldehyde

[0280]

[0281]

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Abstract

The invention discloses a type of quinoline derivatives. The quinoline derivatives are used as inhibitors for hedgehog channels, and in particular, used as SMO inhibitors. The compounds disclosed by the invention can be used for treating hedgehog channel-related diseases comprising cancers.

Description

technical field [0001] The invention relates to a class of quinoline derivatives. As inhibitors of the hedgehog pathway, especially as SMO inhibitors, the compounds of the invention can be used to treat diseases related to the hedgehog pathway including cancer. Background technique [0002] Hedgehog proteins are secreted signaling proteins originally discovered in Drosophila, and they are highly hydrophobic proteins that play a crucial role in embryonic development. Three homologous hedgehog proteins have been identified in humans, namely Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dh h). Among them, Shh is not only crucial in embryonic development, but many evidences show that it also plays an important role in the carcinogenic mechanism of some cancers including basal cell carcinoma (Caro, I. and J.A. Low, Clin Cancer Res, 2010.16 (13): 3335 -9). Shh synthesizes a precursor protein with a molecular weight of 45kDa in vivo, and produces an N-terminal ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10C07D401/14C07D401/12C07D413/10C07D491/08C07D498/08C07D487/04C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D215/38C07D405/12C07D487/08C07D471/08A61K31/4725A61P35/00A61K31/5377A61K31/496A61K31/5383A61K31/4985
Inventor 吴颢林军李云辉韦昌青陈曙辉
Owner GUANGDONG ZHONGSHENG PHARMA
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