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Immunomodulators, compositions and methods there of

A technology of compounds and chelates, applied in the field of pharmaceutically active compounds

Pending Publication Date: 2021-04-13
BETTA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, small molecule inhibitors directly targeting PD-1 or PD-L1 are still not approved, and only CA170 has been clinically evaluated

Method used

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  • Immunomodulators, compositions and methods there of
  • Immunomodulators, compositions and methods there of
  • Immunomodulators, compositions and methods there of

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] The synthesis of embodiment 1 compound 1

[0204] (S)-1-((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl) Methyl)piperidine-2-carboxylic acid

[0205]

[0206] Step 1: Preparation of methyl 4-hydroxy-2-(methylthio)-5-nitrobenzoate

[0207]

[0208] Methyl 2-fluoro-4-hydroxybenzoate (20.00g) was dissolved in 200mL of acetic acid, cooled to 0-10°C in an ice bath, and concentrated nitric acid (10.1ml, 0.236mol) was dissolved in 40mL of acetic acid and slowly added dropwise to The above reaction solution; after the dropwise addition, remove the ice bath and naturally rise to room temperature and stir for 4-6h. The reaction solution was poured into ice water to quench the reaction. After stirring for 0.5h, the solid was completely precipitated, filtered, the filter cake was washed 2-3 times with water, dried, and the crude product was purified by flash chromatography (A. n-hexane; B.EA; B% from 0 to 30%, 20 minutes) to obtain 13.00 g Methyl 2-f...

Embodiment 2

[0228] The synthesis of embodiment 2 compound 2

[0229] ((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L- proline

[0230]

[0231] Compound 2 was prepared essentially as described in Example 1 using the corresponding intermediate. For example, "L-proline" is used instead of "(S)-piperidine-2-carboxylic acid" in the last step above (step 7).

[0232] Basically according to the method described in Example 1, use instead of in step 1 of Example 29 To prepare the following examples (shown in Table 1), in some examples, the (S)-piperidine-2-carboxylic acid in step 7 above was replaced with other amic acids (such as L-proline).

[0233] Table 1

[0234]

[0235]

[0236]

[0237]

Embodiment 29

[0238] Synthesis of Example 29 Compound 29

[0239] (S)-1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5- base) methyl) piperidine-2-carboxylic acid

[0240]

[0241] Step 1: Preparation of methyl 2,4-dihydroxy-5-nitrobenzoate

[0242]

[0243] Methyl 2,4-dihydroxybenzoate (850 g, 5.06 mol) was dissolved in AcOH (3.6 L) and Ac 2 O (900mL) in the mixture. After cooling the clear solution to 10 °C (ice bath), add HNO within 1 h 3 (65%) (455ml) in AcOH (500mL). After the addition was complete, the temperature of the reaction mixture was raised to 15-20°C and stirring was continued for 1 hour. Until the raw materials are substantially completely reacted and the reaction is terminated. The reaction solution was poured into H 2 O (3 L), then the addition of the mixture was continued for 30 minutes without stirring. The precipitate was filtered and washed with a small amount of H 2 O rinse. The crude product was then poured into MeOH (2 L) wi...

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Abstract

Provided herein is compounds of Formula I, methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

Description

technical field [0001] The present invention relates to pharmaceutically active compounds. The present invention provides compounds, compositions and methods of use thereof. The compounds modulate PD-1 / PD-L1 protein / protein interactions and are useful in the treatment of various diseases including infectious diseases and cancer. Background technique [0002] The immune system plays an important role in controlling and eliminating diseases such as cancer. However, cancer cells often employ strategies to evade or suppress the immune system, thereby promoting their growth. One such mechanism is the altered expression of co-stimulatory and co-inhibitory molecules on immune cells (Postowetal, J. Clinical Oncology 2015, 1-9). Blocking the signaling of inhibitory immune checkpoints such as PD-1 has proven to be a promising, effective form of treatment. [0003] The interaction between PD-1 and PD-L1 leads to a decrease in tumor-infiltrating lymphocytes, a decrease in T cell rec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/02C07D413/00A61K31/423A61P35/00
CPCA61P35/00C07D413/06C07D263/57C07D413/14C07D498/04C07D498/14C07D413/04A61K31/454A61K31/423A61K31/5377
Inventor 王义乾张垚付邦王家炳
Owner BETTA PHARM CO LTD
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