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Substituted 2-morpholinopyridine derivatives as ATR kinase inhibitors

A compound, i-a technology, applied in drug combinations, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of rapidly proliferating tissues and stem cell populations, etc.

Pending Publication Date: 2022-03-11
REPARE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ATR-deficient mice are embryonic lethal, however, adult mice with conditional knockout of ATR are viable, with effects on rapidly proliferating tissue and stem cell populations

Method used

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  • Substituted 2-morpholinopyridine derivatives as ATR kinase inhibitors
  • Substituted 2-morpholinopyridine derivatives as ATR kinase inhibitors
  • Substituted 2-morpholinopyridine derivatives as ATR kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0703] Embodiment 1. The preparation of compound

[0704] Compound 1

[0705] Step 1. Use vacuum / N 2 A suspension of 4-chloro-7-azaindole (25 g) in DMA (140 mL) was gas sparged (3 cycles). Then add zinc powder (1.07g), zinc cyanide (11.26g), dppf (2.72g) and Pd 2 (dba) 3 (2.39g). Vacuum again / N 2 The mixture was gas-swept (3 cycles) and heated to 120 °C for 4 h. The reaction mixture was cooled to 100 °C and water (428 mL) was added within 30 min. The mixture was then cooled to rt within 2h. The crude product was filtered and washed with water (2 x 95 mL), then added to 3N HCl (150 mL), and the mixture was stirred at rt for 2 h. Insolubles were removed by filtration. To the filtrate was added 50% aqueous NaOH until pH 12 was reached. Filtration and drying afforded 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (11.6 g) as a tan solid.

[0706] Step 2. A mixture of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (10.4 g) and NaOH (29 g) in water (100 mL) and EtOH (100 mL) was heat...

Embodiment 2

[0823] Embodiment 2.ATR / ATRIP enzymatic assay

[0824] Detection of ATR kinase activity The AlphaScreen system was used to measure the phosphorylation of the substrate protein p53. In assay buffer (50mM Hepes pH 7.4, 0.1mM vanadate, 0.5mM DTT, 0.1mM EGTA, 5mM MnCl 2 , 0.01% Brij-30, 1% Glycerol, 0.05% BSA) recombinant purified ATR / ATRIP (Eurofins cat. no. 14-953) at a final concentration of 0.63 nM was mixed with serially diluted compounds in 10% DMSO. The final DMSO concentration was 1.25%. A premix of GST-tagged p53 (full-length, Enzo Life Sciences cat. no. BML-FW9370) and 5'-adenosine triphosphate (Sigma-Aldrich cat. no. 10519979001, Roche Diagnostic) in assay buffer was added to the enzyme:compound In the mixture, the final concentration was 25 nM GST-p53 and 3 μM ATP. The reaction was allowed to proceed for 1 hour at room temperature, and was then reacted by adding a final dilution of 1:3000 phosphorylated p53 (Ser 15) antibody (New England Biolabs cat# 9284S), buffer ...

Embodiment 3

[0825] Example 3. ATR assay in Hela cells

[0826] HeLa S3 cells were plated in a 384-well format at a density of 16K cells per 25 μL well in regular medium F-12K 10% FBS, and incubated at 37 °C, 5% CO 2 Incubate overnight. Then, the medium was replaced by 20 μL Opti-MEM (without phenol red) per well, and 5 μL of serially diluted compounds were added to the assay plate at a final concentration of 0.5% DMSO. Cells and compounds were incubated at room temperature for 20 min before adding 5 μL of gemcitabine at a final concentration of 1.5 μM. Incubate the plate at 37 °C, 5% CO 2 Incubate for 3.5 to 4 hours. Media was removed and cells were lysed in 15 μL of PerkinElmer Lysis Buffer for 10-20 min; 4 μL of lysate was then transferred to 384 format proxi white plates (PerkinElmer Life Sciences cat# 6008280). Phosphorylation of CHK1 at Ser345 was quantified using Alphascreen SureFire CHK1 p-Ser345 (PerkinElmer Life Sciences Cat. No. TGRCHK1S10K) and Alphascreen protein A. (Perki...

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Abstract

Disclosed are compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein-is a single bond and each Y is N or CR4; or-absent and each Y is NRY, carbonyl or C (RY) 2 wherein each R1 is H or optionally substituted C1-6 alkyl; r1 is optionally substituted C1-6 alkyl or H; r3 is an optionally substituted heteroaryl group with 1 to 9 carbon atoms or an optionally substituted heteroaryl group with 1 to 6 alkyl groups with 1 to 9 carbon atoms; each R4 is hydrogen, halogen, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, or an optionally substituted C2-6 alkynyl group; x is hydrogen or halogen; and R2 is as defined in claim 1. Also disclosed are pharmaceutical compositions containing the compounds of formula (I) and methods of making the same. The compounds of formula (I) may be inhibitors of ataxia telangiectasia and RAD-3 associated protein kinase (ATR) and are useful in the treatment of diseases or conditions such as cancer.

Description

technical field [0001] The present invention relates to compounds and pharmaceutical compositions, their preparation, and their usefulness in the treatment of diseases or disorders (e.g., cancer) and, in particular, those diseases or disorders that depend on the activity of ataxia telangiectasia and RAD-3-related protein (ATR) kinase. Use in a Disorder (eg, Cancer). Background technique [0002] DNA damage continues to occur in cells due to environmental insults including ultraviolet radiation, X-rays, and endogenous stress factors such as reactive oxygen species and hydrolysis by alkalis. Cancer cells experience a higher rate of DNA damage, which is essentially induced by a higher rate of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved stepwise in a highly coordinated manner to help repair DNA damage and act as cellular checkpoints to prevent cellular replication of damaged DNA, allowing repair functions to occur before damaged DNA i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/5377A61P35/00
CPCA61P35/00C07D471/04C07D519/00A61K31/5377
Inventor S·N·克兰V·L·张A·阿波多利J-F·特鲁顿C·布莱克S·多里奇L·法德S·拉努瓦P·琼斯M·圣-昂格A·皮卡德C·M·拉贝
Owner REPARE THERAPEUTICS INC
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