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

Patent metadata

Field	Value
Publication number	US-10683298-B2
Application number	US-201816186883-A
Country	US
Kind code	B2
Filing date	Nov 12, 2018
Priority date	Oct 27, 2008
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Provided herein are Heteroaryl Compounds having the following structure:

wherein R 1 -R 4 are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases, or cardiovascular conditions, comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.

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

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

the method further comprising cyclizing a compound of formula (VII)

in a second solvent, in the presence of a second base, or an acid, wherein said cyclization occurs under conditions suitable to provide 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):

wherein:
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; and
R 3 is H, or a substituted or unsubstituted C 1-8 alkyl;
wherein substituted means substituted with a substituent independently selected from the group consisting of oxo, alkyl, fluoro, chloro, bromo, iodo, nitro, cyano, thiol, alkylthio, alkyl sulfonyl, alkoxyalkyl, hydroxy, alkoxy, aralkyloxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, cyanate, isocyanate, thiocyanate, isothiocyanate, azido, amino, alkylamino, hydroxyamino, alkoxyamino, aralkoxyamino, sulfonamido, hydrazino, hydrazido, N-oxide, acyl, carboxy, alkoxycarbonyl, alkylthiocarbonyl, aminocarbonyl, O(alkyl)aminocarbonyl, acylamino, imino, oxime, amidino, enamino, imido, guanidino, urea, urethane, phosphonato, phosphino, boronic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;

comprising the following steps:
(i) cyclizing a compound of formula (VII):

wherein:
R is H or C 1-4 alkyl;
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; and
R 3 is H or a substituted or unsubstituted C 1-8 alkyl;
where substituted means substituted with a substituent independently selected from the group consisting of oxo, alkyl, fluoro, chloro, bromo, iodo, nitro, cyano, thiol, alkylthio, alkyl sulfonyl, alkoxyalkyl, hydroxy, alkoxy, aralkyloxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, cyanate, isocyanate, thiocyanate, isothiocyanate, azido, amino, alkylamino, hydroxyamino, alkoxyamino, aralkoxyamino, sulfonamido, hydrazino, hydrazido, N-oxide, acyl, carboxy, alkoxycarbonyl, alkylthiocarbonyl, aminocarbonyl, O(alkyl)aminocarbonyl, acylamino, imino, oxime, amidino, enamino, imido, guanidino, urea, urethane, phosphonato, phosphino, boronic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;

in the presence of potassium tert-butoxide or an acid selected from the group consisting of acetic acid, trifluoroacetic acid, hydrochloric acid and phosphoric acid, to provide a compound of formula (VI):

wherein:
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; and
R 3 is H or a substituted or unsubstituted C 1-8 alkyl;
where substituted means substituted with a substituent independently selected from the group consisting of oxo, alkyl, fluoro, chloro, bromo, iodo, nitro, cyano, thiol, alkylthio, alkyl sulfonyl, alkoxyalkyl, hydroxy, alkoxy, aralkyloxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, cyanate, isocyanate, thiocyanate, isothiocyanate, azido, amino, alkylamino, hydroxyamino, alkoxyamino, aralkoxyamino, sulfonamido, hydrazino, hydrazido, N-oxide, acyl, carboxy, alkoxycarbonyl, alkylthiocarbonyl, aminocarbonyl, O(alkyl)aminocarbonyl, acylamino, imino, oxime, amidino, enamino, imido, guanidino, urea, urethane, phosphonato, phosphino, boronic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl, and
(ii) contacting the compound of formula (VI) above with a compound of the following formula:
R 1 -Y

wherein:
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,
Y is B(OR + ) 2 or Sn(R ++ ) 3 ;
each R + is independently H; or
each R + , together with the boron atom and the oxygen atoms to which they are attached, form a cyclic boronate; and
each R ++ is independently C 1-3 alkyl;
where substituted means substituted with a substituent independently selected from the group consisting of oxo, alkyl, fluoro, chloro, bromo, iodo, nitro, cyano, thiol, alkylthio, alkyl sulfonyl, alkoxyalkyl, hydroxy, alkoxy, aralkyloxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, cyanate, isocyanate, thiocyanate, isothiocyanate, azido, amino, alkylamino, hydroxyamino, alkoxyamino, aralkoxyamino, sulfonamido, hydrazino, hydrazido, N-oxide, acyl, carboxy, alkoxycarbonyl, alkylthiocarbonyl, aminocarbonyl, O(alkyl)aminocarbonyl, acylamino, imino, oxime, amidino, enamino, imido, guanidino, urea, urethane, phosphonato, phosphino, boronic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;
in the presence of

(a) an optionally hydrous solvent selected from the group consisting of dimethylformamide, dimethylacetamide, methanol, isopropanol, isopropyl acetate, methyl tert-butyl ether, dioxane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, acetone and toluene, or a combination thereof,
(b) a base selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, diisopropylethylamine, trimethylamine, piperidine and pyridine, and
(c) a palladium catalyst selected from the group consisting of bis(dibenzylideneacetone)palladium(0)/tri-o-tolylphosphine and palladium (II) acetate/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to provide the compound of formula (II) above.

2. The method of claim 1 , wherein step (i) is performed in the presence of potassium tert-butoxide.

3. The method of claim 1 , wherein step (i) is performed in the presence of acetic acid.

4. The method of claim 1 , wherein step (i) is further performed in the presence of a solvent selected from the group consisting of methanol and water, or a combination thereof.

5. The method of claim 1 , wherein step (ii) is performed in the presence of an optionally hydrous solvent selected from the group consisting of dimethylformamide, dimethylacetamide, methanol and isopropanol, or a combination thereof.

6. The method of claim 1 , wherein step (ii) is performed in the presence of a base selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate.

7. The method of claim 1 , wherein Y is selected from the group consisting of:

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

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title