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Isoquinoline derivatives as perk inhibitors

A technology for mammals and diseases, applied in the field of substituted isoquinoline derivatives, which can solve the problems of inability to synthesize important proteins, cell death, etc.

Inactive Publication Date: 2019-05-21
GLAXOSMITHKLINE INTPROP DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cells that tolerate ER stress can restore proteostasis and return to normal, or if the stress is insurmountable, sustained PERK activation may result in cell death driven by ATF4 / CHOP-driven autophagy and failure to synthesize important protein

Method used

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  • Isoquinoline derivatives as perk inhibitors
  • Isoquinoline derivatives as perk inhibitors
  • Isoquinoline derivatives as perk inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0729] 5-(3-Benzylisoquinolin-7-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0730]

[0731]

[0732] Step 1: To a stirred solution of 2-iodobenzoic acid (10.0 g, 40.32 mmol, 1 equiv) in MeOH (100 mL) was added dropwise H at 0 °C 2 SO 4 (10 mL). The reaction mixture was warmed to 90 °C and stirred for 8 hours. The reaction mixture was cooled and concentrated. The residue was basified with saturated sodium bicarbonate at 0 °C and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with water and brine solution then dried over sodium sulfate and evaporated to give methyl 2-iodobenzoate as a colorless liquid (9.0 g, 85%).

[0733] 1 H NMR (400MHz, CDCl 3 )δppm 3.93(s, 3H), 7.15(t, J=8.0Hz, 1H), 7.40(t, J=7.2Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.99(d, J = 8.0Hz, 1H).

[0734] Step 2: To a stirred solution of methyl 2-iodobenzoate (5.0 g, 19.08 mmol, 1 equiv) and NBS (3.73 g, 20.99 mmol, 1.1 equiv) in acetic acid (10 mL) was dropped at 20-40 °C Ad...

Embodiment 2

[0741] 5-(3-(3,5-Dimethylbenzyl)isoquinolin-7-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0742]

[0743]

[0744] Step 1: To a stirred solution of 4-bromophthalic acid (9.0 g, 37.55 mmol, 1 equiv) in THF (90 mL) was added BH dropwise at 0 °C 3 .DMS (35 mL, 375 mmol, 10 equiv). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled and quenched slowly with MeOH, then evaporated to give the crude product, which was purified by flash column chromatography on silica gel. Compound eluted in 1.5% MeOH:DCM. Fractions with product were evaporated to give (4-bromo-1,2-phenylene)dimethanol as a white solid (6.0 g, 75.9%).

[0745] 1 H NMR (400MHz, DMSO-d 6 )δppm 4.45(d, J=5.2Hz, 2H), 4.51(d, J=5.2Hz, 2H), 5.12(t, J=5.6Hz, 1H), 5.20(t, J=11.4Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.54 (s, 1H).

[0746] Step 2: A solution of oxalyl chloride (14.2 mL, 165 mmol, 6.0 equiv) in DCM (120 mL) was cooled ...

Embodiment 3

[0757] 5-(3-Benzyl-8-fluoroisoquinolin-7-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0758]

[0759] Step 1: To a stirred solution of 1-bromo-2-fluoro-4-iodobenzene (5.0 g, 16.66 mmol, 1 equiv) in THF (50 mL) was added dropwise LDA (8.3 mL, 16.66 mmol, 1.0 equivalent). The reaction mixture was stirred for 1 h, then dry ice was added portionwise at -78 °C. The reaction mixture was warmed and stirred overnight at room temperature. The reaction mixture was quenched with 1N HCl and extracted with 5% MeOH in DCM (3 x 60 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-bromo-2-fluoro-6-iodobenzoic acid (3.5 g, 61.4%) as a brown solid. LCMS (ES) m / z = 344.0, 346.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.53 (t, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 14.18 (s, 1H).

[0760] Step 2: To a stirred solution of 3-bromo-2-fluoro-6-iodobenzoic acid (3.3 g, 9.59 mmol, 1 equiv) in DCM (50 mL) was added SOCl dropwise at 0 °C 2(...

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Abstract

The invention is directed to substituted isoquinoline derivatives and uses thereof. Specifically, the invention is directed to compounds according to Formula I and the use of compounds of Formula (I)in treating disease states: (I) wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Str ussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, ather osclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The inventionis still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

technical field [0001] The present invention relates to substituted isoquinoline derivatives which are inhibitors of the activity of protein kinase R (PKR)-like ER kinase (PERK). The present invention also relates to pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer, precancerous syndromes, and diseases / injuries associated with activated unfolded protein response pathways, such as Alzheimer's disease, Spinal cord injury, traumatic brain injury, ischemic stroke, apoplexy, Parkinson's disease, diabetes mellitus, metabolic syndrome, metabolic disease, Huntington's disease, Creutzfeldt-Jakob disease, fatal familial insomnia, Grünster-Schörr syndrome, and Associated prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, hepatic steatosis, liver fibrosis, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4725A61K31/519C07D471/04C07D487/04A61P35/00
CPCA61K31/4725A61K31/519C07D471/04A61P25/28A61P35/00A61P27/02C07D487/04A61P27/06A61K45/06
Inventor J.阿克斯滕R.R.凯蒂里R.克里斯塔姆C.文卡特莎帕
Owner GLAXOSMITHKLINE INTPROP DEV LTD