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Novel tricyclic protein kinase modulators

A solvate and compound technology, applied in the field of new tricyclic protein kinase regulators, can solve problems such as dependence and MM cell cytotoxicity

Inactive Publication Date: 2012-08-22
CYCLENE PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The survival of multiple myeloma cells has been shown to depend on the high activity of CK2, and CK2 inhibitors are cytotoxic to MM cells

Method used

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  • Novel tricyclic protein kinase modulators
  • Novel tricyclic protein kinase modulators
  • Novel tricyclic protein kinase modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0163] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0164]

[0165] in:

[0166] A is an optionally substituted saturated or partially saturated 5, 6 or 7 membered ring;

[0167] Indicates a single or double bond;

[0168] when When representing a single key, Z 1 and Z 2 independently N or C with the proviso that Z 1 and Z 2 not all N; and

[0169] when When representing a double bond, Z 1 and Z 2 is C;

[0170] L is a linker selected from bond, NR 3 , O, S, CR 4 R 5 、CR 4 R 5 -NR 3 、CR 4 R 5 -O-, and CR 4 R 5 -S;

[0171] R 1 , R 2 , R 3 , R 4 and R 5 each independently is H, or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkyne Group, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 aralkyl and C6-C12 hete...

Embodiment 1

[0349]The chemistry described in Scheme 1 can be used to prepare intermediate 4 with a tetrahydrothiopyran ring. Compound 2 preparation was previously described in WO2009061131. Compound 3 can be formed using the method described in WO2009061131 by heating commercially available isocyanate 1 and compound 2 in toluene and by subsequent treatment of the reaction mixture with acid. Compound 3 can be converted to compound 4 using an acid such as sulfuric acid.

[0350] plan 1

[0351]

Embodiment 2

[0353] The chemistry described in Example 1 can be applied to other substituted isocyanates 2 (Scheme 2) to prepare analog 6 with various substitutions on the phenyl ring. Isocyanate 2 can be commercially available or prepared from commercially available aniline 1 .

[0354] Scenario 2

[0355]

[0356] The chemistry can also be applied to substituted 2-bromoanilines 4 to obtain compounds 6. Compound 6 can be converted to compound 3 in two steps by treatment with a cyanide reagent, followed by hydrolysis and esterification.

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PUM

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Abstract

The invention provides compounds that inhibit CK2 and / or Pim kinases and compositions containing such compounds. These tricyclic compounds and compositions containing them are useful for treating proliferative disorders such as cancer, as well as other kinase-associated conditions including inflammation, pain, pathogenic infections, and certain immunological disorders.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 243,104, filed September 16, 2009, entitled "NOVEL TRICYCLIC PROTEIN KINASE MODULATORS," the contents of which are hereby incorporated by reference in their entirety for all purposes. field of invention [0003] The present invention relates in part to molecules having biological activities including, but not limited to, inhibition of cell proliferation, modulation of serine-threonine protein kinase activity, and modulation of tyrosine kinase activity. Molecules of the invention can modulate casein kinase (CK) activity (e.g., CK2 activity) and / or Pim kinase activity (e.g., PIM-1 activity), and / or Fms-like tyrosine kinase (Flt) activity (e.g., Flt-3 activity). Such compounds are useful in the treatment of a variety of physiological disorders due to their activity as kinase inhibitors. The invention also relates in part to methods of using such mole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/14
CPCC07D221/10C07D221/16C07D471/04C07D487/04C07D491/048C07D495/04C07D513/04A61P25/04A61P27/02A61P29/00A61P31/00A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P33/02A61P33/06A61P33/12A61P35/00A61P43/00A61P9/00A61K31/519A61K31/4985A61K31/435
Inventor M·哈达齐F·皮埃尔
Owner CYCLENE PHARM INC
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