Immunomodulators, compositions and methods thereof

A compound and chelate technology, applied in the direction of drug combination, active ingredient of heterocyclic compound, pharmaceutical formulation, etc.

Pending Publication Date: 2021-03-26
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 thereof
  • Immunomodulators, compositions and methods thereof
  • Immunomodulators, compositions and methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] The synthesis of embodiment 1 compound 1

[0172] ((8-((2,2'-Dimethyl-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)amino)-1,7- Naphthyridin-3-yl)methyl)glycine

[0173]

[0174] Step 1: Preparation of 8-chloro-3-vinyl-1,7-naphthyridine (M1)

[0175]

[0176] Toluene (30 mL), EtOH (10 mL), 10% Na 2 CO 3 solution (10 mL) was added Pd(dppf)Cl 2 . DCM (420 mg). 4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.1 g) was added dropwise under nitrogen protection. The mixture was stirred at 100°C for 16 hours. The reaction was quenched with water (50 mL) and extracted 3 times with EtOAc. The organic phases were combined and washed with brine. The resulting solution was concentrated and purified on a silica gel column (gradient from 8:1 to 5:1 with hexane-EtOAc) to afford 8-chloro-3-vinyl-1,7-naphthyridine (1.1 g) 88%).

[0177] Step 2: Preparation of 8-chloro-1,7-naphthyridine-3-carbaldehyde (M2)

[0178]

[0179] To a solution of 8-chloro-3-vinyl-1,7-naphth...

Embodiment 2

[0198] The synthesis of embodiment 2 compound 2

[0199] ((8-((2-Methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine

[0200]

[0201] Step 1: Preparation of ((8-((2-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine methyl ester

[0202]

[0203] This compound was prepared using a method similar to that described for M5 in Example 1, substituting phenylboronic acid for M7. The obtained compound was purified by preparative-TLC (EtOC:n-hexane=1:1) to obtain ((8-((2-methyl-[1,1'-biphenyl]-3-yl]amino]-1,7- Naphthyridin-3-yl)methyl)glycine methyl ester (150 mg) was a yellow solid.

[0204] Step 2: ((8-((2-Methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine (Compound 3)

[0205]

[0206] This compound was prepared using a method similar to that described in Compound 1. The resulting compound was purified by RP column (mobile phase: MeCN:water (0.1% HCl) with a gradient of 40:60 to 50:50) to give ((8-((2-methy...

Embodiment 3

[0209] The synthesis of embodiment 3 compound 5

[0210] 1-((8-((2,2'-dimethyl-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)amino)-1, 7-naphthyridin-3-yl)methyl)piperidine-2-acetic acid

[0211]

[0212] Step 1: Preparation of (8-chloro-1,7-naphthyridin-3-yl)methanol (M11)

[0213]

[0214] The above aldehyde (620 mg) was dissolved in MeOH. Add NaBH at one time 4 (400mg). The mixture was stirred at room temperature for 2 hours and then quenched with water (30 mL). The mixture was extracted 3 times with DCM (20 mL) and the organic phase was passed through Na 2 SO 4 dry. The resulting solution was concentrated and purified by silica gel column (n-Hexane-EtOAc gradient eluted from 2:1 to 1:1) to give (8-chloro-1,7-naphthyridin-3-yl)methanol (500 mg) as brown solid.

[0215] Step 2: Preparation of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (M12)

[0216]

[0217] To a microwave reaction vial was added 3-bromo-2-methylaniline (370 mg), (8-ch...

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PUM

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Abstract

The invention relates to 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 as cancer or infections.

Description

technical field [0001] The present invention relates to pharmaceutically active compounds. The invention provides the compound, its composition and application method. The compound modulates the PD-1 / PD-L1 protein / protein interaction and can be used to treat 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 receptor-mediate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/40C07D471/04A61K31/47A61K31/519A61P31/00
CPCA61P31/00C07D471/04
Inventor 张垚王义乾付邦陈洁王家炳丁列明
Owner BETTA PHARM CO LTD
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