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Indazole compounds containing nitrogen substituents, and application of same as IDO inhibitors

A compound and solvate technology, applied in the field of IDO inhibitors, can solve the problems of reducing tryptophan concentration, stagnation of synthesis, inhibiting killing effect, etc., and achieving excellent inhibitory effect.

Active Publication Date: 2018-10-23
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissue

Method used

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  • Indazole compounds containing nitrogen substituents, and application of same as IDO inhibitors
  • Indazole compounds containing nitrogen substituents, and application of same as IDO inhibitors
  • Indazole compounds containing nitrogen substituents, and application of same as IDO inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The synthesis of embodiment 1 compound LWQ-121, LWQ-122, LQW-145, LQW-146, LQW-149, LQW-150, LQW-151 and LQW-152

[0046] The synthetic route is as follows:

[0047]

[0048] (1) Synthesis of Compound LWQ-145

[0049] 1 Synthesis of compound 2a:

[0050] In an ice bath, the KNO 3(1.146g, 11.34mmol) was slowly added to compound 1a (500mg, 4.53mmol). After the addition was complete, it was moved to room temperature and stirred for 12h. TLC showed that the reaction of the raw materials was complete, and finally 50mg of a white solid was obtained. Yield: 5.5%.

[0051] 1 H NMR (400MHz, CDCl 3 ,ppm): δ8.36(d,J=7.9Hz,2H,),2.41(s,3H).

[0052] 2 Synthesis of Compound 3a:

[0053] The raw material 2a (200mg, 1mmol) was dissolved in methanol (5mL) 1,4-dioxane (2.5mL), and 10N HCl (1mL) Fe (41.9mg, 3mmol) was added under ice-cooling. After the addition was complete, it was stirred at 80°C for 3h. TLC showed the starting material was completely reacted. Finally, 42 mg o...

Embodiment 2

[0070] The synthesis of embodiment 2LQW-123, LQW-147, LQW-148, LWQ-221 and LWQ-222

[0071] The synthetic route is as follows:

[0072]

[0073] (1) Synthesis of Compound LWQ-145

[0074] 1 Synthesis of compound 4a:

[0075] At room temperature, the raw material TCCA (640mg, 2.74mmol) was slowly added to the concentrated sulfuric acid (25mL) solution of 2d (1g, 5.49mmol). Powder 872.6 mg, yield: 73.6%.

[0076] 2 Synthesis of Compound 5a:

[0077] Dissolve raw material 4a (5.9g, 23.60mmol) in methanol (10mL) 1,4-dioxane (5mL), add 10N HCl (12mL) Fe (3.96g, 70.80mmol) under ice-cooling, after addition, 80°C After stirring for 3h, TLC showed that the raw material was completely reacted. Finally, 3.55 g of light yellow powder was received, yield: 68.4%.

[0078] 3 Synthesis of compound LWQ-147:

[0079]The raw material 5a (3.55g, 16.13mmol) was dissolved in AcOH (15mL), and an aqueous solution (5mL) of sodium nitrite (2.23g, 32.26mmol) was added at 0°C. After the additi...

Embodiment 3

[0092] The synthesis of embodiment 3 compound LQW-161

[0093] The synthetic route is as follows:

[0094]

[0095] 1 Synthesis of Intermediate 8

[0096] Dissolve compound 7 (50 mg, 0.24 mmol) and compound acetone (85 μL, 1.18 mmol) in 1.5 mL of dichloroethane, add molecular sieves, and place in a microwave reactor. Set the power to 650W and the time to 540min. After the reactor was stopped, the molecular sieves were filtered out, and the molecular sieves were washed with dichloromethane for several times. The filtrates were combined and concentrated, and the crude product was purified by column chromatography to obtain compound 8 (38 mg, 0.16 mmol) as a white solid with a yield of 67%.

[0097] 2 Synthesis of compound LWQ-161

[0098] Compound 8 (30 mg, 0.16 mmol) and DMF (3 μL, 0.03 mmol) were dissolved in dichloromethane and placed at 0°C. Under the protection of Ar gas, add diluted HSiCl 3 (20 μL, 0.19 mmol) in dichloromethane. After addition, stir at the same t...

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Abstract

The invention discloses nitrogen substituent-containing indazole compounds as shown in a formula (I) which is described in the specification, a preparation method for the compounds, and application ofthe compounds as IDO inhibitors. The compounds provided by the invention can be used for preventing and / or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections relatedto cellular immune activation, autoimmune diseases, AIDS, cancers, depression, the metabolic disorder of tryptophan or the like.

Description

technical field [0001] The invention relates to an indazole compound containing a nitrogen substituent, a preparation method thereof and an application as an IDO inhibitor. Background technique [0002] Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) catalyzes the epoxidation and cleavage of indole in indoleamine molecules such as tryptophan, making it catabolized by the kynuric acid pathway. fast enzyme. [0003] IDO plays an important role in tumor immune immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissues. At the s...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61K31/416A61P25/28A61P27/12A61P25/24A61P31/18A61P37/06A61P35/00A61P29/00A61P3/00
CPCC07D231/56
Inventor 王周玉钱珊李国菠李超陈杨王伟杨羚羚赖朋
Owner XIHUA UNIV
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