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Heterobicyclic pyrazole compounds and methods of use

A compound, heterocyclic group technology, applied in the field of heterobicyclic pyrazole compounds, can solve the problem of tumor growth deceleration and other problems

Inactive Publication Date: 2009-05-20
ARRAY BIOPHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of Met leads to tumor growth deceleration in a mouse model of tumor xenografts

Method used

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  • Heterobicyclic pyrazole compounds and methods of use
  • Heterobicyclic pyrazole compounds and methods of use
  • Heterobicyclic pyrazole compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0551] N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylcarbamoyl)-2-phenyl Preparation of acetamide

[0552]

[0553] As described, and / or by routine modification of reaction conditions. Additionally, other reactions disclosed herein or known in the art should be recognized as applicable to the preparation of other compounds of the invention.

[0554] In the examples described below, all temperatures are expressed in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and were used without further purification unless otherwise stated.

[0555] Reactions described below are generally performed in anhydrous solvents under positive pressure of nitrogen or argon, or using drying tubes (unless otherwise stated), and reaction flasks are generally fitted with rubber septa for introduction of substrates and reagents via syringes.

[0556] Glassware is oven-dried and / ...

Embodiment 2

[0576] N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane - Preparation of 1,1-dicarboxamide

[0577]

[0578] Step A: N-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N- Preparation of (4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0579] To stirred 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoroaniline (73 mg, 0.20 mmol; obtained from In step D) of Example 1 and ((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (49mg, 0.220mmol; from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using WO 2005 / 030140 and Shih and Rankin, Synth.Comm.1996, 26 (4), prepared by the method of 833-836) in DMA (2mL) mixture, add N1-((ethylimino) methylene)-N3, N3 - Dimethylpropane-1,3-diamine hydrochloride (EDCI) (77 mg, 0.400 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc (10ml) and water (10ml). The phases were separated and the orga...

Embodiment 3

[0585] N-(3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)ring Preparation of propane-1,1-dicarboxamide

[0586]

[0587] Step A: Preparation of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine:

[0588] in N 2 Next, stirred 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (27.6g, 70.0 mmol; obtained from Example 1, step C) and TFA (53.9 mL, 700 mmol) was heated at reflux for 18 hours. The reaction was cooled to room temperature, then concentrated in vacuo and azeotroped with toluene (4 x 100 mL) to remove residual TFA. The resulting residue was diluted with EtOAc (200 mL) and washed with saturated NaHCO 3 Aqueous solution (100 mL) was carefully neutralized (pH=8-9). The biphasic suspension was stirred at room temperature for 30 minutes. The suspension is filtered. The resulting solid was azeotropically dried with toluene (2 x 200 mL) to afford the product (18.7 g, 97%).

[0589] 1 H NMR (DMSO-d6, ...

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Abstract

Compounds of Formulas (Ia) and (Ib), and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

Description

[0001] Priority of the invention [0002] This application claims priority to US Provisional Application No. 60 / 779,805, filed March 7, 2006, and US Provisional Application No. 60 / 874,832, filed December 14, 2006. The entire contents of these provisional applications are hereby incorporated by reference. field of invention [0003] The present invention relates to heterobicyclic pyrazole compounds having protein tyrosine kinase activity. Heterobicyclic pyrazole compounds are useful in the treatment of hyperproliferative diseases, such as cancer, in mammals. The invention also relates to pharmaceutical compositions and formulations, methods of synthesis and methods of use such as in the treatment of hyperproliferative disorders. Background of the invention [0004] Met tyrosine kinase is a high affinity transmembrane receptor for hepatocyte growth factor (HGF, Bottaro et al. (1991) Science 251:802-804). Met has been cloned, named (Cooper et al. (1984) 311:29-33) and identi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00A61K31/437
Inventor J·F·布莱克S·A·博伊德F·科亨J·德米斯方建朝J·J·高迪诺T·卡普兰A·L·马罗徐廷法A·A·托马斯田红旗W·B·杨
Owner ARRAY BIOPHARMA
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