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Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof

A solvate, independent technology, applied in the field of medicinal chemistry, can solve the problem of few reports of PI3Kγ inhibitors

Inactive Publication Date: 2020-01-14
INNOVENT BIOLOGICS (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although PI3Kγ inhibitors have been reported in the past ten years, there are still few reports on highly selective PI3Kγ inhibitors in vivo (WO2017214269, WO2016054491, CN106456628, WO2015051241)

Method used

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  • Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof
  • Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof
  • Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0437] The present invention provides the preparation method of above-mentioned formula I compound, it comprises:

[0438] 1) The preparation method of formula IA compound, concrete steps are as follows:

[0439]

[0440] S1: Replace X in compound IA-1-1 with R 3 (preferably by coupling reaction or substitution reaction), to obtain compound IA-1-2;

[0441] S2: Compound IA-1-2 is reacted with compound IA-a (preferably by condensation reaction) to obtain compound IA-1-3;

[0442] S3: Compound IA-1-3 is reacted with compound IA-b (preferably in the presence of Grignard reagent and metal organic compound, more preferably in the presence of isopropylmagnesium chloride and n-butyllithium), to obtain compound IA-1 -4;

[0443] S4: Compound IA-1-4 is reacted with compound IA-c (preferably by condensation reaction) to obtain the compound of formula IA;

[0444] Wherein: X is chlorine, bromine or iodine; X 4 for CH or CR 7 ;X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12...

Embodiment 1

[0540] Example 1: Synthesis of Compounds 1-3.

[0541] S1: in N 2 Under protective conditions, dimethylphosphine oxide (1.25mmol, 1eq), 2-iodo-6-methylbenzoic acid (compound 1-1) (1.35mmol, 1.08eq), triethylamine were added successively to the reaction vessel (1.44mmol, 1.15eq) and 1,4-dioxane (1.5mL), then add Pd 2 (dba) 3 (4mmol, containing 8μmol of Pd) and the bisphosphine ligand Xantphos (8μmol), the solution was stirred at 80°C for 2h, the reaction was complete by TLC, filtered, and separated by silica gel column chromatography to obtain compound 1-2. ESI-MS: m / z 213.06, [M+H] + .

[0542] S2: To a stirred mixture of compound 1-2 (1.5 mmol, 1 eq) and N,N-dimethylformamide (0.2 mL) in dichloromethane (12 mL) was added oxalyl chloride (1.65 mL) within 5 min at room temperature mmol, 1.1 eq), and stirred at room temperature for 2 h, the mixture was concentrated in vacuo, and the concentrated residue (containing compound 1-3) was dissolved in dichloromethane (15 mL), and...

Embodiment 2

[0550] Example 2: Synthesis of Compounds 4-6.

[0551] Referring to Example 1, compound 1-2 is replaced by the following compounds:

[0552] The synthetic process of compound 4 is similar to compound 1, and the difference is that 2-dimethylphosphoryl-6-methylbenzoic acid (compound 1-2) in the synthetic process of compound 1 is replaced by 2-methyl-6- (Pentafluoro-λ 6 -sulfanyl)benzoic acid to obtain compound 4. ESI-MS: m / z 551.12, [M+H] + .

[0553] The synthetic process of compound 5 is similar to that of compound 4, except that tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate is replaced by (R)-1-(methyl tert-butyl oxy(methyl)amino)-1-oxopropan-2-ylcarbamate.

[0554] The synthetic process of compound 6 is similar to compound 4, the difference is that tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate is replaced by (S)-1-(methyl tert-butyl oxy(methyl)amino)-1-oxopropan-2-ylcarbamate.

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PUM

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Abstract

The invention belongs to the field of pharmaceutical chemistry and relates to a novel phosphoinositide 3-kinase inhibitor, a preparation method and an application thereof. Specifically, the present invention provides a compound having the structure of formula I, which can be used as an efficient PI3K inhibitor and has various pharmacological activities such as tumor resistance, resistance to neurodegenerative diseases (such as Alzheimer's disease), inflammatory resistance, etc.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to an effective phosphoinositide 3-kinase (PI3K) inhibitor, a preparation method thereof, a pharmaceutical composition containing it, and a medical application thereof, especially in preparation for preventing and / or Use in a medicament for the treatment of a disease at least in part mediated by PI3K. Background technique [0002] Phosphoinositide 3-kinases (PI3Ks) are a large class of enzymes whose main function is the phosphorylation of the inositol ring of phosphoinositides. PI3Ks are divided into three classes (I, II, and III) based on structural similarity, type of regulatory subunit, and specificity of various phosphoinositide substrates (Marone R, et al., Biochim. Biophys. Acta, 2008; 1784:159-185), among which the research on class I PI3K is the most extensive. All members of this class consist of a catalytic subunit and an associated regulatory moiety that catalyze the ph...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07D487/04C07D519/00C07F9/6584A61K31/519A61K31/675A61K31/549A61K31/5415A61P35/00A61P25/28A61P29/00A61P31/00
CPCA61P25/28A61P29/00A61P31/00A61P35/00C07D487/04C07D519/00C07F9/65616C07F9/65846C07F9/65848
Inventor 张龙宋国伟
Owner INNOVENT BIOLOGICS (SUZHOU) CO LTD
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