Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10167290-B2
Application number	US-201715680688-A
Country	US
Kind code	B2
Filing date	Aug 18, 2017
Priority date	Oct 27, 2008
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

Provided herein are methods for the preparation of substituted pyrazino[2,3-b]pyrazines of the formula (II):

the method comprising contacting a compound of formula (VI):

with R 1 —Y in a solvent, in the presence of a palladium catalyst, wherein said contacting occurs in the presence of a base, wherein R 1 -R 3 , Y, the palladium catalyst and the base are as defined herein.

First claim

What is claimed is:

1. A method for preparing a compound of formula (II):

the method comprising contacting a compound of formula (VI):

with R 1 —Y in a solvent, in the presence of a palladium catalyst, wherein said contacting occurs in the presence of a base,
wherein Y is B(OR + ) 2 or Sn(R ++ ) 3 ;
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
R 2 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;
R 3 is H, or a substituted or unsubstituted C 1-8 alkyl; and
each R + is hydrogen, or each R + , together with the boron atom and the atoms to which they are attached, form a cyclic boronate;
each R ++ is independently C 1-3 alkyl;
the palladium catalyst is bis(dibenzylideneacetone)palladium(0)/tri-o-tolylphosphine, or palladium (II) acetate/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and
substituted means substituted with a substituent selected from the group consisting of chloro; iodo; bromo; fluoro; alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl; alkylsulfonyl; sulfonamide; acyl; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo; B(OH) 2 , O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

2. The method of claim 1 , wherein each R ++ is CH 3 .

3. The method of claim 1 , wherein the B(OR + ) 2 is B(OH) 2 or

4. The method of claim 1 , wherein the solvent is dimethylformamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethyl sulfoxide, acetone, methanol, methyl t-butyl ether or a combination thereof, optionally with the presence of water.

5. The method of claim 1 , wherein the contacting occurs in the presence of a base and the base is sodium carbonate, triethylamine, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, or sodium hydroxide.

Assignees

• Signal Pharm Llc

Inventors

• Elsner Jan
• Harris Roy L
• Lee Branden Gingsee
• Mortensen Deborah
• Packard Garrick K
• Papa Patrick
• Parnes Jason
• Perrin-Ninkovic Sophie
• Riggs Jennifer
• Sapienza John
• Shevlin Graziella I
• Tehrani Lida
• Zhao Jingjing

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title