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Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors

A technology of substituents and alkyl groups, applied in the field of novel compounds, can solve problems such as undisclosed pyrroline compounds

Inactive Publication Date: 2006-09-13
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] So far, no indazolyl-substituted pyrroline compounds of the present invention have been disclosed

Method used

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  • Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors
  • Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors
  • Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] 3-(5-Chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-imidazol-1-yl-propyl)-1H-indazol-3-yl]-

[0203] Pyrrole-2,5-dione (Compound 1)

[0204] Pyridine (1.024g, 12.95mmol) and methanesulfonic anhydride (1.3g, 7.45mmol) were added to compound 1a (1.62g, 3.7mmol, prepared see WO 02 / 46183) in THF (5OmL). The mixture was heated at 50°C for 3 hours and then cooled to room temperature. Additional THF (10 mL) was added, followed by 1N HCl (10 mL). The mixture was stirred for 15 minutes, then extracted several times with EtOAc. The combined EtOAc layers were washed once with 1N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), dried (Na 2 SO 4 ) and evaporated in vacuo to obtain compound 1b (1.6 g, 84%) as a reddish solid. ES-MS mz 513 (MH + ).

[0205] 75% NaH (3.74 mg, 0.117 mmol) was added to a mixture of imidazole (7.96 mg, 0.117 mmol) in DMF (5 mL) at 0 °C, and the mixture was heated to reflux for 30 min. The solution was then cooled to room temperatur...

Embodiment 2

[0208] 3-(5-Chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-[1,2,3]triazol-1-yl-propyl)-1H- Indazole-

[0209] 3-yl]-pyrrole-2,5-dione (compound 2)

[0210] 75% NaH (3 mg, 0.093 mmol) was added to a mixture of triazole (5 mg, 0.072 mmol) in DMF (4 mL) at 0°C. The mixture was heated to reflux for 30 minutes. The solution was then cooled to room temperature. Compound 1b (20 mg, 0.03 mmol) in DMF (1 mL) was added dropwise. The mixture was heated to 80 °C for 1 h, then stirred at room temperature overnight. TLC showed some starting material was also contained. The mixture was heated to 90°C overnight. The solvent was evaporated in vacuo to a dark oil. The oil was purified by preparative TLC to obtain compound 2 (3 mg) as an orange solid. 1 HNMR (CDCl 3 )δ8.08(s, 1H), 7.70(d, J=8.2Hz, 1H), 7.64(s, 1H), 7.43(m, 3H), 7.17(m, 2H), 7.01(dd, J=1.9 , 8.7Hz, 1H), 6.12(d, J=1.8Hz, 1H), 4.31(t, J=6.2Hz, 2H), 4.12(t, J=6.5Hz, 2H), 3.86(s, 3H), 2.40 (m, 2H). ES-MS m / z 486 (MH ...

Embodiment 3

[0214] 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-tetrazol-2-yl-propyl)-1H-indazol-3-yl]

[0215] Pyrrole-2,5-dione

[0216] and

[0217] 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-tetrazol-1-yl-propyl)-1H-indazol-3-yl] -

[0218] Pyrrole-2,5-dione (compound 3 and compound 4)

[0219] 3% tetrazole CH 3 CN solution (10.15 mL, 3.4 mmol) was diluted with DMF (10 mL), potassium carbonate (0.47 g, 3.4 mmol) was added, and the mixture was heated to 90° C. for 2 h. Cool the mixture to room temperature. Compound 1b (350 mg, 0.68 mmol) in DMF (5 mL) was added dropwise. The mixture was heated to 80°C overnight. The solvent was evaporated. Water (10 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H 2 O and brine washed, dried (Na 2 SO 4 ) and evaporated in vacuo to a dark oil. The oil was purified by flash column chromatography (96:4:0.4; DCM:MeOH:NH 4 OH), ...

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Abstract

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I): Formula (I), R<2> is selected from the group consisting of -C1-8alkyl-Z, -C2-8alkenyl-Z and -C2-8alkynyl-Z; wherein the -C1-8alkyl-Z, -C2-8alkenyl-Z and -C2-8alkynyl-Z and Z is a 5 to 6 member aromatic monocyclic heteroaryl ring having from 2 to 4 heteroatoms. These compounds are useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

Description

[0001] This application claims priority to Provisional Patent Application No. 60 / 478,516 filed June 13, 2003, which is incorporated herein by reference. field of invention [0002] The present invention relates to some novel compounds, methods for preparing them and methods for treating or improving kinase or dual kinase-mediated diseases. More particularly, the present invention relates to indazolyl-substituted pyrroline compounds useful as selective kinase or dual kinase inhibitors, methods of preparing these compounds and methods of treating or ameliorating kinase or dual kinase mediated diseases. Background of the invention [0003] U.S. Patent 5,057,614 (Davis, et.al.) introduces the substituted pyrrole compounds of the following structural formula I and the substituted pyrrole compounds of the following structural formula I as therapeutically active drugs for the control or prevention of inflammatory diseases, immune diseases, b...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D401/14A61K31/416A61P25/00
CPCC07D401/14C07D403/14A61P11/06A61P13/12A61P17/02A61P17/06A61P17/14A61P19/02A61P25/00A61P25/04A61P25/08A61P25/18A61P25/24A61P25/28A61P27/02A61P29/00A61P31/18A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P43/00A61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P9/14A61P3/10
Inventor H·-C·张B·E·玛丽亚诺夫H·叶
Owner JANSSEN PHARMA NV
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