Bicyclic pyridines and analogs as sirtuin modulators

Patent metadata

Field	Value
Publication number	US-9556201-B2
Application number	US-201013504134-A
Country	US
Kind code	B2
Filing date	Oct 29, 2010
Priority date	Oct 29, 2009
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

First claim

The invention claimed is:

1. A compound of Formula (I):

wherein:
each Z 1 and Z 2 independently is selected from N and CR;
wherein:
at least one of Z 1 and Z 2 is CR; and
each R independently is selected from hydrogen, halo, —OH, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl; C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 3 )(R 3 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 3 )(R 3 ), and —N(R 3 )(R 3 );

W is —N(C 1 -C 4 alkyl)-;
each R 6 is independently selected from hydrogen, C 1 -C 4 alkyl and fluoro-substituted C 1 -C 4 alkyl; or
two R 6 bound to the same carbon atom are taken together to form ═O;
R 1 is selected from an aliphatic carbocycle and a heterocycle;
wherein:
R 1 is optionally substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 2 alkyl, —O—R 3 , —S—R 3 , —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 );

R 2 is selected from a carbocycle and a heterocycle;
wherein:
R 2 is optionally substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 3 , —S—R 3 , —SO 2 —R 3 , ═O, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ), —O-phenyl, phenyl, and a second heterocycle, and when R 2 is phenyl;
R 2 is also optionally substituted with —O-(saturated heterocycle), 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R 2 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl, and —N—(C 1 -C 4 ) 2 alkyl;

each R 3 is independently selected from hydrogen and —C 1 -C 4 alkyl; or
two R 3 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O;
wherein:
when R 3 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 3 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at any carbon atom with —OH, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and optionally substituted at any substitutable nitrogen atom with hydrogen, —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;

p is 2; and
X 2 is selected from —C(═O)-†, —C(═O)—O†, —S(═O) 2 -†, and —C(═O)—NH-†,
wherein:
† represents where X 2 is bound to R 1 ; and

a corresponding tautomer or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (VI):

wherein:
each of Z 1 and Z 2 is independently selected from N and CR;
wherein:
at least one of Z 1 and Z 2 is CR; and
each R is independently selected from hydrogen, halo, —OH, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl; C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 3 )(R 3 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 3 )(R 3 ), and —N(R 3 )(R 3 );

W is —N(C 1 -C 4 alkyl)-;
wherein:
each R 6 is independently selected from hydrogen, halogen, C 1 -C 4 alkyl and fluoro-substituted C 1 -C 4 alkyl, or two R 6 bound to the same carbon atom are taken together to form ═O,

R 1 is substituted with a spiro bicycle;
wherein:
R 1 is optionally further substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 2 alkyl, —O—R 3 , —S—R 3 , —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ); and
when R 1 is phenyl, R 1 is also optionally further substituted with —O-(saturated heterocycle), —O-(fluoro-substituted saturated heterocycle), C 1 -C 4 alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy;

R 2 is selected from a carbocycle and a heterocycle;
wherein:
R 2 is optionally substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 3 , —S—R 3 , —SO 2 —R 3 , ═O, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ), —O-phenyl, phenyl, and a second heterocycle;
when R 2 is phenyl, R 2 is also optionally substituted with —O-(saturated heterocycle), 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy;
wherein:
any phenyl, saturated heterocycle, or second heterocycle substituent of R 2 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl, and —N—(C 1 -C 4 ) 2 alkyl;

each R 3 is independently selected from hydrogen and —C 1 -C 4 alkyl; or
two R 3 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O;
wherein:
when R 3 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 ;
when two R 3 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at any carbon atom with —OH, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and optionally substituted at any substitutable nitrogen atom with hydrogen, —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;

p is 2;
X 2 is selected from —C(═O)-†, —C(═O)—O†, —S(═O) 2 -†, and —C(═O)—NH-†;
wherein:
† represents where X 2 is bound to R 1 ; or

a corresponding tautomer or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 1 is a heterocycle.

Assignees

• Ng Pui Yee
• Blum Charles
• Mcpherson Lauren
• Perni Robert B
• Vu Chi B
• Ahmed Mohammed Mahmood
• Disch Jeremy S
• Glaxosmithkline Llc

Inventors

• Ng Pui Yee
• Blum Charles
• Mcpherson Lauren
• Perni Robert B
• Vu Chi B
• Ahmed Mohammed Mahmood
• Disch Jeremy S

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title