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Triazolo-pyridazine protein kinase modulators

An unsubstituted, CH2 technology that can be used in drug combinations, active ingredients of heterocyclic compounds, organic chemistry, etc., and can solve problems such as unclear tractability and lack of kinase activity.

Inactive Publication Date: 2009-10-14
SGX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

RYK is also expressed in some cancers, but it is an atypical orphan receptor tyrosine kinase that lacks detectable kinase activity, so its tractability as a target for small molecule cancer therapies is unclear

Method used

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  • Triazolo-pyridazine protein kinase modulators
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  • Triazolo-pyridazine protein kinase modulators

Examples

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Embodiment

[0374] The following examples are offered to illustrate but not limit the claimed invention. The preparation of embodiments of the invention is described in the following examples. Those of ordinary skill in the art will appreciate that the chemical reactions and synthetic methods provided can be modified to prepare many other compounds of the invention. Where compounds of the invention are not exemplified, those of ordinary skill in the art will recognize that such compounds can be prepared by modifying the synthetic methods set forth herein, as well as by employing synthetic methods known in the art.

[0375] General formula (XII) and (XI) compound, wherein Q, R 1 , X, T and U are described herein and can be prepared according to general reaction scheme 1. Compounds of formula (I) and (II) are either commercially available or prepared from commercially available compounds using standard chemical reactions and transformations known to those skilled in the art.

[0376] Com...

Embodiment 99

[0519] Make 3-[3-(1-quinolin-6-yl-ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-benzonitrile (1.2g ) was dissolved in isopropyl alcohol (10 g / L) and eluted by chiral HPLC on a Chiralpak AS 20 μM (8 cm id x 25 cm L) column with 50% methanol / ethanol (25 °C), 150 g / min, 325 nM To separate the enantiomers, Example 126 (0.56 g, ee > 99.9%) and Example 127 (0.56 g, ee 97%) were recovered. The analytical method was performed on an AS-H 4.6mm ID x 250mm S / NASHSAEE001-409291 column, eluted with 50% methanol / ethanol (25°C), 1 mL / min, 225nM. Compound 99 had a retention time of 4.6 minutes and compound 100 had a retention time of 5.8 minutes. Analytical data are shown in Table 1.

[0520] To a degassed (nitrogen bubbled through for 15 min) mixture of water (1 mL) and 1,4-dioxane (2 mL) was added 6-(6-chloro-[1,2,4]triazolo [4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-quinoline (117mg, 0.31mmol), vinylboronic acid pinacol Ester (59 μl, 0.35 mmol), potassium carbonate (0.93 ...

Embodiment 103

[0523] Make 3-[3-(1-benzothiazol-6-yl-ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-benzonitrile (5.27 g) Dissolve in dichloromethane (200 mL) and separate the enantiomers on a Berger super critical fluid multigram II system. Separation was carried out on a Chiralcel OD-H (2x15cm) column with 40% methanol / CO 2 (100 bar), 50 mL / min, eluted at 220 nM, recovered Example 103 (2.1 g, retention time 5.31 min, ee>99%) and Example 104 (2.2 g, retention time 6.30, ee>99%).

[0524] Add 52mgs (0.295mmol) of (1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid, 1.2eq. (0.354mmol) of O-(7-azabenzotri Azol-1-yl)-N,N,N,N'-tetramethyluronium hexafluoro-phosphate, 1.5eq.(0.443mmol)[6-(1-methyl-1H-pyrazole-4- yl)-pyridazin-3-yl]-hydrazine and 4eq. (1.18mmol) N,N-diisopropylethylamine and dissolved in 4mls dimethyl-formamide. The reaction mixture was stirred at room temperature for 18 hours. After this time, dimethylformamide was removed in vacuo, acetic acid (4mls) was added to the residue and heate...

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Abstract

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

Description

[0001] Cross References to Related Applications [0001] This application claims U.S. Provisional Patent Application Serial No. 60 / 862,552, entitled "Triazolopyridazine Protein Kinase Modulators," filed October 23, 2006, January 4, 2007, and April 24, 2007, respectively. , 60 / 883,468 and 60 / 913,752 interests. Priority is hereby claimed as of the filing date, and the contents of these applications are hereby incorporated by reference in their entirety. Background of the invention [0002] Mammalian protein kinases are important regulators of cellular function. Since dysfunction of protein kinase activity is associated with diseases and disorders, protein kinases are targets for drug development. The family of tyrosine kinases, and in particular a subset of receptor tyrosine kinases, have been shown to be enriched in cancer and are thus putative targets of cancer. Receptor tyrosine kinases (RTKs) such as EGFR, HER2, KIT and KDR are well characterized as proteins with well est...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5025A61K31/53A61P35/00C07D519/00
Inventor C·R·史密斯P·布诺E·A·杰斐逊P·S·李E·托雷斯
Owner SGX PHARMA INC
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