Indazole compounds and application thereof to preparation of IDO inhibitors

A technology of compounds and mixtures, applied in the fields of drug combination, organic chemistry, antiviral agents, etc., can solve the problems of reducing tryptophan concentration, inhibiting killing effect, stagnation of synthesis, etc., and achieving excellent inhibitory effect.

Inactive 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 and application thereof to preparation of IDO inhibitors
  • Indazole compounds and application thereof to preparation of IDO inhibitors
  • Indazole compounds and application thereof to preparation of IDO inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091]The synthesis of embodiment 1 compound LWQ-137, LWQ-139, LWQ-140

[0092] The synthetic route is as follows:

[0093]

[0094] 1 Synthesis of Compound LWQ-139

[0095] Dissolve starting material 13b (50mg, 0.2994mmol), starting material 14 (50mg, 0.3892mmol) and dihydropyridine ester (110mg, 0.4192mmol) in DCM:MeOH=6:2ml, add trifluoroacetic acid (23μL, 0.2994 mmol). After addition, open to 40°C and stir at reflux for 3h. TLC showed that the reaction of the raw materials was complete, and finally 53 mg of a beige solid was obtained, with a yield of 65.3%.

[0096] 1 H NMR(400MHz,DMSO)δ12.82(s,1H),9.31(s,1H),8.22(s,1H),7.20(s,1H),6.73(d,J=8.4Hz,2H),6.67 (s,1H),5.95(s,1H),4.31(d,J=5.8Hz,2H),3.38(s,1H),2.54–2.47(m,1H). 13 C NMR (400MHz, DMSO) δ156.69, 143.40, 141.68, 133.11, 132.52, 129.79, 128.69, 115.53, 112.35, 98.61, 96.97, 46.23, 30.96. HRMS (AP-ESI) Calcd.for C 14 h 12 ClN 3 O:296.0567(M+Na) + .Found: 296.0025.

[0097] 2 Synthesis of compounds LWQ-137 a...

Embodiment 2

[0102] The synthesis of embodiment 2 compound LWQ141, LWQ-173, LWQ-175, LWQ-176, LWQ-177, LWQ-183

[0103] The synthetic route is as follows:

[0104]

[0105] Starting material 7 (212.0 mg, 1.0 mmol) and starting material m-nitrobenzaldehyde (181.2 mg, 1.2 mmol) were dissolved in DCM (10 mL) and methanol (5 mL), dihydropyridinate (354.2 mg, 1.4 mmol) was added, Trifluoroacetic acid (74.5 μL, 1.0 mmol) was added dropwise, and the reaction was refluxed at 40° C. for 6 hours. TLC detects that after the reaction of the raw materials is complete, the reaction is cooled to room temperature, and solid NaHCO is added. 3 Adjust the pH to about 7-8, add silica gel to the reaction solution, spin dry, and pass through the column (DCM:MeOH=100:1-80:1-60:1) to obtain 266.4 mg of yellow solid compound 15c with a yield of 81.5%.

[0106] Other compounds were synthesized using compound 7 and corresponding aldehyde raw materials, and were obtained by referring to the synthesis method of c...

Embodiment 3

[0114] The synthesis of embodiment 3 compound LWQ-170, LWQ-171, LWQ-172

[0115] The synthetic route is as follows:

[0116]

[0117]Synthesis of compound LWQ-171: Dissolve compound 15c (208.2mg, 0.60mmol) in ethanol (3mL) and water (3mL), add ammonium chloride (16.5mg, 0.3mmol), add iron powder (166.7mg , 2.98mmol), reacted at 80°C for 30 minutes, filtered the reaction solution while it was hot, spin-dried the solvent under reduced pressure, and passed the column (DCM:MeOH=30:1) to obtain 166.0mg of a light yellow solid with a yield of 87.3%.

[0118] Compounds LWQ-170 and LWQ-172 were prepared using compounds 15b and 15d as raw materials, respectively, according to the synthetic method of compound LWQ-171.

[0119] LWQ-170: yellow solid 22.7mg, yield 25.7%. 1 H NMR (400MHz, DMSO) δ12.90(s, 1H), 8.11(s, 1H), 6.88(d, J=8.4Hz, 2H), 6.43(d, J=8.4Hz, 2H), 6.36(s ,1H),5.89(s,2H),4.81(s,2H),4.01(s,2H). 13 C NMR(101MHz,DMSO)δ146.67,143.43,142.13,132.68,128.04,127.96,122.06,12...

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Abstract

The invention discloses indazole compounds as shown in a formula (i) or (II) which is described in the specification, and a preparation method thereof, and application of the 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 related to cellular immune activation,autoimmune diseases, AIDS, cancers, depression, the metabolic disorder of tryptophan or the like.

Description

technical field [0001] The present invention relates to indazole compounds, and also relates to their preparation method and application in the preparation of IDO inhibitor drugs. 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. A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D405/12C07D401/12C07D409/12C07D403/12A61K31/416A61K31/4178A61K31/4439A61P25/28A61P25/24A61P27/12A61P37/02A61P31/18A61P35/00
CPCC07D231/56C07D401/12C07D403/12C07D405/12C07D409/12
Inventor 杨羚羚钱珊李国菠陈丰李超何彦颖王周玉赖朋
Owner XIHUA UNIV
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