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Novel tricyclic aromatic heterocyclic compound and preparation method, pharmaceutical composition and application thereof

A technology of compounds and hydrates, applied in drug combination, digestive system, organic chemistry, etc., can solve the problems of only injection administration, easy to be decomposed by protease, and inability to take orally

Pending Publication Date: 2021-11-30
SHANGHAI LONGWOOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the currently marketed and researched PD-1 monoclonal antibodies have their own defects, including injection, not oral, unstable in vivo, easy to be decomposed by protease, prone to immune cross-reaction, difficult to purify and difficult to produce. high cost

Method used

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  • Novel tricyclic aromatic heterocyclic compound and preparation method, pharmaceutical composition and application thereof
  • Novel tricyclic aromatic heterocyclic compound and preparation method, pharmaceutical composition and application thereof
  • Novel tricyclic aromatic heterocyclic compound and preparation method, pharmaceutical composition and application thereof

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Effect test

preparation example Construction

[0101] The preparation of formula I compound

[0102] In order to prepare the compound described in the general formula I of the present invention, according to the structure of the general formula I, the compound of the general formula I prepared in the present invention can be obtained through the following synthetic route.

[0103] Equation 1:

[0104]

[0105] (a) using intermediates 1 and 2 as raw materials, the target product I-1 is obtained through a coupling reaction catalyzed by a suitable palladium catalyst;

[0106] The preparation method of intermediate 1 is exemplified as follows:

[0107]

[0108] (a) Using compound 1-1 as a raw material (X is Cl, Br or I), under the conditions of a suitable palladium catalyst and ligand, a coupling reaction occurs to form intermediate 1-2;

[0109] (b) Using 1-2 as a raw material, under the catalysis of a suitable Lewis acid, shrinkage reaction with primary and secondary amines, adding an appropriate reducing agent, and ...

Embodiment 1

[0153] The synthesis of embodiment 1 compound 001

[0154] Step 1-1:

[0155]

[0156] Take raw material 1-1 (100g, 1.0eq), sodium hydroxide (27g, 1.0eq), add to water (500ml), methanol (2000ml), the brown color is slightly muddy, cool down to about -25°C in the inner bath, disposable Add NIS (151g, 1.0eq), then naturally heat up the reaction, the solids increase, and then gradually dissolve to dark brown and clear, react for 2 hours, spot the plate and LCMS tracking. Add 1000ml of water, add 2M hydrochloric acid (400ml), the system is weakly acidic, Filtrate, rinse twice with MTBE to obtain a solid: 161 g, yield: 87%. MS-APCI:275[M+H] + .

[0157] Step 1-2:

[0158]

[0159] Take DMF (1000ml, 2BV) into the reaction flask, nitrogen protection, add raw material 1-2 (500g, 1.0eq), cuprous cyanide (172g, 1.05eq), nitrogen replacement, heat up to 115°C in the inner bath, and react 6 hours, LCMS tracking; post-treatment: dilute with THF, filter, concentrate the filtrate, a...

Embodiment 2

[0178] The synthesis of embodiment 2 compound 026

[0179] Step 2-1:

[0180]

[0181] Take raw material 1-3 (110g, 1.0eq) and add it to acetic acid (660ml, 6BV), it becomes turbid, raise the temperature to 40°C in the inner bath, slowly add fuming nitric acid (84g, 2.1eq) dropwise, it becomes turbid, then keep it warm for 1 hour Left and right, LCMS tracking, 3.5% raw material remaining, post-processing: cooling to 10°C, stirring for 30 minutes, filtering, rinsing with HEP, drying to obtain 117g of solid, yield: 84%, purity 88%, raw material 8%, adding THF ( 600ml) was beaten in an external bath at 50°C for 1 hour, filtered at room temperature to obtain 106g of solid, yield: 76%. MS-APCI:219[M+H] + .

[0182] Step 2-2:

[0183]

[0184] Take raw material 2-4 (20g, 1.0eq), add TFA (12g, 1.1eq) into THF (400ml, 20BV), it is turbid, add 5% platinum carbon (10-20%), replace with hydrogen, react at room temperature, LCMS Tracking, (the reaction speed is affected by many...

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PUM

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Abstract

The invention provides a novel tricyclic aromatic heterocyclic compound and a preparation method, a pharmaceutical composition and application thereof, and particularly provides a compound as shown in the following formula I, or an optical isomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. The definition of each group is described in the specification. The compound shown in the formula I can be used for treating diseases related to a PD-1 / PD-L1 signal channel.

Description

technical field [0001] The present invention relates to the field of small molecule drugs, specifically, the present invention provides a small molecule compound that can be used to treat diseases related to PD-1 / PD-L1 signaling pathway. [0002] Background of the invention [0003] The immune system plays a vital role in the control and cure of many diseases, such as various cancers and diseases caused by viruses. But cancer cells can often evade or suppress the immune system in ways that allow them to multiply rapidly. One way of doing this is by changing the activating and inhibitory molecules expressed on immune cells. Blockade of inhibitory immune checkpoints, like PD-1, has proven to be a very effective way to suppress cancer cells. [0004] PD-1 is programmed cell death protein-1, also known as CD279. It is mainly expressed in activated T cells and B cells, and its function is to inhibit the activation of cells, which is a normal homeostasis mechanism of the immune ...

Claims

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Application Information

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IPC IPC(8): C07D413/04C07D413/14C07D307/93A61K31/4178A61K31/397A61K31/5377A61P35/00A61P37/02A61P31/04A61P31/12A61P31/20A61P35/02A61P19/02A61P9/00A61P25/00A61P1/16A61P13/12A61P1/04A61P5/14A61P3/10
CPCC07D413/04C07D413/14C07D307/93A61P35/00A61P37/02A61P31/04A61P31/12A61P31/20A61P35/02A61P19/02A61P9/00A61P25/00A61P1/16A61P13/12A61P1/04A61P3/10A61P5/14C07D263/52C07D413/10C07D405/04C07D405/14C07D263/57C07D307/78C07D407/10
Inventor 王喆白海云潜安然李德亮
Owner SHANGHAI LONGWOOD PHARMA
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