1H-indazole derivatives and application of same as IDO inhibitors

A compound and solvate technology, applied in the field of 1H-indazole derivatives, can solve the problems of reducing tryptophan concentration, inhibiting killing effect, and stagnant synthesis.

Active Publication Date: 2018-03-27
XIHUA UNIV
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  • Abstract
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  • Claims
  • Application Information

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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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  • 1H-indazole derivatives and application of same as IDO inhibitors
  • 1H-indazole derivatives and application of same as IDO inhibitors
  • 1H-indazole derivatives and application of same as IDO inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of intermediate raw materials

[0048] (1) Synthesis of 5a and 5b

[0049]

[0050] Synthesis of 2,5-Dimethyl-1,3-Dinitrobenzene (2a)

[0051] Take a dry 50mL pear-shaped flask, dissolve xylene (1a) (2.00mL, 16.23mmol) with 20mL of concentrated sulfuric acid, slowly add potassium nitrate (4.91g, 48.68mmol) under stirring at room temperature, after the addition, stir at room temperature for 2h, The reaction solution was slowly poured into ice water, filtered, and the filter cake was dried in vacuum, and then purified by column chromatography (PE:EA=80:1) to obtain a pale yellow solid (2a) (1.62 g, yield 51%). Structure Identification: 1 H-NMR (400MHz, CDCl 3 ,ppm):δ13.0(br,1H,NH),7.42(s,2H,Ar-H), 2.45(s,6H,CH 3 ).ESI-MS:197.05[M+H].

[0052] Synthesis of 2-methyl-5-trifluoromethyl-1,3-dinitrobenzene (2b)

[0053] Using 4-trifluoromethyl-toluene (1b) (CAS: 6140-17-6, purchased from Chengdu Ruioke Reagent Company) as raw material, according to the preparation o...

Embodiment 2

[0069] Example 2 Synthesis of compounds N1, N2, N3, N4 and N5 of the present invention

[0070]

[0071] 6-Bromo-N-(3-trifluoromethylbenzyl)-1H-indazol-4-amine (N1).

[0072] Amine 5c (0.28mmol) and benzaldehyde 6 (0.24mmol) were dissolved in dichloromethane (DCM, 3mL), DHP (83.5mg, 0.33mmol) and appropriate amount (840.2 mg), trifluoroacetic acid (TFA, 17.6 μL, 0.24 mmol) was added dropwise, and refluxed at 40° C. for 12 hours, the reaction solution was filtered, spin-dried, and passed through a column (PE:EA=10:1) to obtain compound N1. Yield 53.9%; red powdery solid; 1 H-NMR(400MHz,d 6 -CDCl 3 , ppm): δ8.00 (s, 1H, indazole-H3), 7.69 (s, 1H, Ar-H), 7.63-7.50 (m, 3H, Ar-H), 7.06 (s, 1H, Ar-H ),6.34(s,1H,Ar-H),4.56(d,2H,J=4.4Hz,benzyl-CH 2 ). 13 C-NMR(100MHz,d 6 -CDCl 3 ,ppm):δ141.9,141.7,139.2,131.7,131.4,130.8,129.4,124.6,124.3,122.9,112.5,103.5,102.2,47.6.ESI-MS:370.01[M+H].

[0073] Select the corresponding aldehyde raw materials and prepare the compounds N2, N3, N4, N5 accord...

Embodiment 3

[0082] Example 3 Synthesis of compounds N6 and N7 of the present invention

[0083]

[0084] 4-((6-Methyl-1H-indazole-4-amino)methyl)benzoic acid (N6).

[0085] Compound N6 was synthesized according to the similar method in Example 2, except that compound 5a was substituted for compound 5c to obtain compound N6. Yield 42.0%; light yellow powdery solid; 1 H-NMR(400MHz,d 6 -DMSO, ppm): δ12.72 (s, 2H, COOH and indazole-NH), 8.12 (s, 2H, indazole-H3 and NH), 7.91 (d, 2H, J = 8.1 Hz, Ar-H), 7.50 (d,2H,J=8.1Hz,Ar-H),6.47(s,1H,Ar-H),5.77(s,1H,Ar-H),4.50(s,2H,benzyl-CH 2 ),2.21(s,3H,CH 3 ),ESI-MS:282.12[M+H].

[0086] 4-((6-Methyl-1H-indazole-4-amino)methyl)benzyl alcohol (N7).

[0087]

[0088] Select the corresponding aldehyde raw materials, and prepare compound N7 according to a similar method with a yield of 53.7%; a light yellow powdery solid; 1 H-NMR(400MHz,d 6 -DMSO, ppm): δ9.23(s,2H,indazole-NH and OH), 8.12(s,1H,indazole-H), 7.19(d,2H,J=8.4Hz,Ar-H), 6.72( d, 2H, J = 8.4 Hz, Ar-H), ...

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Abstract

The invention discloses 1H-indazole derivatives and a preparation method thereof, and application of the derivatives as IDO inhibitors. The derivatives 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 or the metabolic disorder of tryptophan.

Description

Technical field [0001] The present invention relates to 1H-indazole derivatives, as well as its preparation method and its use as IDO inhibitors. Background technique [0002] Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is to catalyze the cleavage of indole epoxidation in indoleamine molecules such as tryptophan, so that it can be catabolized according to the kynuric acid pathway. Speed ​​enzyme. [0003] IDO plays an important role in tumor immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, while most tumor cells will form a high expression of IDO, which converts L-tryptophan to N-formylkynurenine, reducing the color in the cell microenvironment. The concentration of amino acid makes tryptophan-dependent T cell synthesis stagnate in the G1 phase, and T cell proliferation is inhibited, thereby inhibiting the body's immune system from killing tumor tissues. At the same time, the metabolites of tryptophan under t...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D403/12C07D401/12C07D409/12A61K31/416A61K31/454A61P25/28A61P27/12A61P25/24A61P37/02A61P31/18A61P35/00
CPCC07D231/56C07D401/12C07D403/12C07D409/12
Inventor 钱珊杨羚羚王周玉赖朋李国菠刘思言李会周袁陈高成
Owner XIHUA UNIV
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