Heterocyclic kinase modulators

A technology of heterocycloalkyl and heteroaryl, applied in the field of inhibitors of homologous proteins

Inactive Publication Date: 2010-03-24
SGX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These heterocyclic kinase modulators are described in detail below

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0817] The following examples illustrate but do not limit the invention. The preparation of embodiments of the invention is described in the following examples. In certain embodiments, the provided chemical reactions and synthetic methods can be modified to prepare various other compounds of the invention. In other embodiments, where compounds of the invention are not exemplified, those of ordinary skill in the art will appreciate that such compounds can be prepared by modification of the synthetic methods provided herein.

[0818] Intermediate 1: (7-Fluoro-quinolin-6-yl)-acetic acid

[0819]

[0820] Step 1: 6-Bromo-7-fluoro-quinoline

[0821] 4-Bromo-3-fluoro-phenylamine (2.85g, 15mmol), ferrous sulfate (0.95g), glycerol (5.658g, 4.5ml), nitrobenzene (1.125g, 0.93ml) and concentrated sulfuric acid ( 2.61 mL) of the mixture was heated slightly. After the first vigorous reaction, the mixture was heated to reflux for 7 hours. The nitrobenzene was evaporated in vacuo. T...

Embodiment 2

[1005] Example 2: General Method A

[1006] Reaction scheme 1

[1007]

[1008] where R 4 Compounds of formula (I) as defined herein are either commercially available or prepared using transformations known to those skilled in the art.

[1009] where L and B 1 Compounds of general formula (II) as defined herein are either commercially available or prepared using the methods described for the synthesis of intermediate 5 and transformations known to those skilled in the art.

[1010] The compound of general formula (III) can be prepared by the compound of formula (I) and the compound of general formula (II) by method step (i), described method comprises aminothiol (II) and formic acid (I) in POCl 3 Heated in presence.

Embodiment 2A

[1011] Example 2A: 6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thia Oxadiazol-3-ylmethyl]-quinoline

[1012]

[1013] 4-Amino-5-quinolin-6-ylmethyl-4H-[1,2,4]triazole-3-thiol (0.78g, 3.03mmol), 1-methylpyrazole-4-carboxylic acid (0.39 g, 3.03 mmol) in phosphorus oxychloride (7.5 mL) was refluxed for 6 hours. The reaction mixture was cooled to room temperature, then 30 g of crushed ice were added with stirring, followed by solid potassium hydroxide until the pH of the mixture was 8. The mixture was left to stand in an ice bath for 2 hours. The formed precipitate was filtered, washed with water, placed in boiling ethanol, and refluxed for 30 minutes, then cooled. The resulting solid was filtered and dried to afford the title compound as an off-white solid (195 mg, 18.5%).

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Abstract

The present disclosure provides heterocyclic protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 60 / 939,313, filed May 21, 2007, entitled "Heterocyclic Kinase Modulators," the disclosure of which is incorporated herein by reference in its entirety. Background of the invention [0003] Mammalian protein kinases are important regulators of cellular function. Since dysregulation of protein kinase activity is associated with several diseases and conditions, protein kinases are targets for drug development. [0004] The tyrosine kinase receptor, FMS-like tyrosine kinase 3 (FLT3), is implicated in cancers, including leukemias such as acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplasia. About one-tenth to one-third of the time AML patients have FLT3 mutations that lead to constitutive activation of the kinase and downstream signaling pathways. While in normal humans FLT3 is predominantly expressed by normal myeloid a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61P19/02C07D215/00
CPCC07D471/04C07D513/04C07D487/04A61P19/02A61P35/00A61P35/02A61P43/00A61K31/47C07D513/02
Inventor P·-Y·布诺C·R·史密斯E·A·杰斐逊J·亨德尔P·S·李A·M·萨耶G·C·赫斯特
Owner SGX PHARMA INC
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