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Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

A technology of compounds and hydrates, applied in the field of small molecule drugs, can solve the problems of only injectable administration, not oral administration, and high production costs

Pending Publication Date: 2021-03-09
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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  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0133] The preparation of formula I compound

[0134] 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 in the present invention can be obtained by the following method 1 or 2.

[0135] Method 1 includes the following steps:

[0136]

[0137] (a) Based on halide 1-1 and a suitable coupling reagent 1-2 (like boronic acid, borate ester, tin reagent or Grignard reagent), palladium or copper catalyzed coupling reaction (like Suzuki, Stille or Kumada coupling) to obtain intermediate compound 1-3;

[0138] (b) using intermediate 1-3 as a raw material, reacting with carboxylic acid 1-4 under the action of a condensing agent (like HATU, EDCI or HBTU) to obtain amide intermediate 1-5;

[0139] (c) using intermediate 1-5 as raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 1-6;

[0140] (d) using interme...

Embodiment 1

[0185] The synthesis of embodiment 1 compound LW1005-001

[0186]

[0187] Step 1-1:

[0188]

[0189] Compound 1 (51g, Journal of Medicinal Chemistry, 2019, 62, 276-287), 2-methyl-3-bromobenzoic acid (95.56g) was sequentially added to PPA (500g), and the reaction was carried out under mechanical stirring at 140°C for 6 hours. After the reaction is complete, pour ice water into the reaction bottle, pour out the slurry after dilution for 30 minutes, and filter. Add 500ml of water to the filtered solid, add solid sodium hydroxide under mechanical stirring, adjust the water phase to pH=6-8, and filter. The filter cake solid was dried at 55° C. to obtain 80 g of off-white solid product. MS-APCI:305[M+H] + .

[0190] Step 1-2:

[0191]

[0192] 3 (2.0g), DMAP (805mg) was added to DMF (30mL), the turbid liquid was added to Boc2O, the solid was dissolved, and the reaction was heated at 40°C overnight. TLC showed a small amount of 1 remaining. The reaction solution was...

Embodiment 2

[0197] The synthesis of embodiment 2 compound LW1005-002

[0198]

[0199] Step 2-1:

[0200]

[0201] Compound 3 (10g) was dissolved in DMF (150ml), and 6 (14.3g; Macromolecules, 2015, 48, 1688-1702) and Cs2CO3 (21.4g) were added and reacted overnight at room temperature. TLC detects that the reaction is complete. After filtration, the filtrate was added with water and then extracted with EtOAc. The organic phase was spin-dried and slurried with HEP:EtOAc=10:1 to obtain 11 g of white solid 7. MS-APCI:587.1[M+H]+

[0202] 1H NMR (400MHz, Chloroform-d) δ8.05(dd, J=7.9, 1.3Hz, 1H), 7.75(dd, J=8.0, 1.3Hz, 1H), 7.54(dt, J=6.7, 1.5Hz, 4H),7.49(d,J=7.3Hz,1H),7.41–7.35(m,2H),7.34–7.27(m,4H),7.22(t,J=7.9Hz,1H),6.58(d,J =7.3Hz, 1H), 4.26(t, J=4.7Hz, 2H), 4.05(dd, J=5.5, 4.1Hz, 2H), 2.92(s, 3H), 1.05(s, 9H).

[0203] Step 2-2:

[0204]

[0205] 7 (11 g) was dissolved in THF (110 mL) at room temperature, 1NTBAF / THF (20.7 mL) was added, and reacted for 2 hours. TLC showed ...

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Abstract

The invention provides a nitrogen-containing heterocyclic compound as well as a preparation method, a pharmaceutical composition and an application thereof, and particularly provides a compound as shown in a formula I which is described in the specification, or an optical isomer, a hydrate and a solvate thereof, or a pharmaceutically acceptable salt thereof; wherein the definition of each group isas shown in the specification. The compounds of formula I can be used to treat diseases associated with PD-1 / PD-L1 signaling pathways.

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): C07D519/00C07D491/048C07D471/04C07D498/04A61K31/4375A61K31/519A61K31/4545A61K31/437A61K31/4355A61K31/497A61K31/444A61P35/00A61P35/02A61P31/04A61P31/12A61P37/06A61P3/10A61P1/04A61P1/00A61P21/04A61P11/00A61P13/12A61P1/16A61P25/00A61P7/06A61P5/14A61P5/16A61P31/20
CPCC07D519/00C07D491/048C07D471/04C07D498/04A61P35/00A61P35/02A61P31/04A61P31/12A61P37/06A61P3/10A61P1/04A61P1/00A61P21/04A61P11/00A61P13/12A61P1/16A61P25/00A61P7/06A61P5/14A61P5/16A61P31/20C07B2200/07A61K31/4355A61K31/437A61K31/4375A61K31/444A61K31/4545A61K31/497A61K31/519Y02P20/55
Inventor 王喆潜安然李德亮张基勇曾志宏
Owner SHANGHAI LONGWOOD PHARMA
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