Substituted bridged urea analogs as sirtuin modulators

Patent metadata

Field	Value
Publication number	US-2017355697-A1
Application number	US-201515528195-A
Country	US
Kind code	A1
Filing date	Nov 19, 2015
Priority date	May 13, 2013
Publication date	Dec 14, 2017
Grant date	—

Abstract

The present invention relates to novel substituted bridged urea compounds, corresponding related analogs, pharmaceutical compositions and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders, which include, but are not limited to, 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. The present invention also related to compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

First claim

1 .- 17 . (canceled)

18 . A compound of Formula (I):

or a salt thereof
wherein:
m is 1 or 2;
n is 2 or 3;
p is 0 to 4;
R 1 is selected from a carbocycle and heterocycle, wherein R 1 is optionally substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, —C≡N, —Y, —X—C(═O)—Y, —X—O—Y, —X—OR 4 , —X—C(═O)—NR 3 R 3 , —X—NH—C(═O)—Y—NR 3 R 3 , —X—NH—C(═O)—O—Y, —X—NR 3 R 3 , ═O, —NH—S(═O) 2 —R 3 , —S(═O) 2 —R 3 , —S—R 3 , —(C 3 -C 7 ) cycloalkyl, —C(═N)—NR 3 R 3 , —C(═N)—NH—X—NR 3 R 3 , —X—NH—C(═O)—Y, —C(═O)—NH—X, —NH—X, phenyl, —O-phenyl, 3- to 6-membered saturated or unsaturated heterocycle and —O-(5- to 6-membered saturated heterocycle), wherein any phenyl, 3- to 6-membered saturated or unsaturated heterocycle or —O-5- to 6-membered saturated heterocycle substituent of R 1 is optionally substituted at any substitutable carbon atom with one or more substituents selected from halo, —OR 4 , —X—O—Y, —CF 3 , —Y, —X—R 3 R 3 , —X—NH—C(═O)—Y—NR 3 R 3 , —X—NH—C(═O)—O—Y-(5- to 6-membered saturated heterocycle or carbocycle), —X—C(═N)—NR 3 R 3 and —S—Y and optionally substituted at any substitutable nitrogen atom with —Y, —C(═O)—Y, —C(═O)—O—Y, —C(═O)—OR 4 , —Y—C(═O)—Y—NR 3 R 3 , —Y—NH—C(═O)—O—Y, —Y—NH—C(═O)—OR 4 , —Y—NH 2 , —C(═O)—NH—Y or —C(═O)-3- to 5-membered saturated carbocycle;
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 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, —C≡N, —Y, —X—OR 4 , —X—O—Y, —SO 2 —R 3 , —X—NR 3 R 3 , —NH—S(═O) 2 R 3 , —C(═O)—NR 3 R 3 , —C(═O)—Y, —C(═O)—O—Y, —SO 2 —R y , —SO 2 —NH—R y , —SO 2 —NR 3 R 3 , 3- to 6-membered saturated carbocycle or heterocycle and phenyl, wherein any 3- to 6-membered saturated heterocycle substituent of R 2 is optionally substituted at any carbon atom with one or more substituents selected from halo, —CF 3 , —Y, —X—O—Y, —NH—Y and —N(Y) 2 , and is optionally substituted at any nitrogen atom with one or more substituents selected from —C(═O)—O—Y, —Y and —C(═O)—Y, and when R 2 is an N-linked 5- to 7-membered saturated or unsaturated heterocycle it is further substituted at any nitrogen atom with one or more substituents selected from —C(═O)—O—Y, —Y and —C(═O)—Y;
each R 3 is independently selected from hydrogen, —C(═N)—NH 2 , —C(═O)—Y, —Y, —Y—NH—C(═O)—O—Y, —Y—NH—C(═O)—OH, —Y—NH—C(═O)—CF 3 , —C(═O)—Y—3- to 5-membered saturated heterocycle, —C(═O)—O—Y-(3- to 5-membered saturated heterocycle), —C(═O)—CF 3 , —C(═O)—O—Y, —C(═O)—OH, —C(═O)—O—CF 3 , —S(═O) 2 —Y, —S(═O) 2 —OH;
two R 3 are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected independently from N, S, S(═O), S(═O) 2 , and O, wherein the heterocycle formed by two R 3 is optionally substituted at any carbon atom with one or more of OH, halo, Y, NH 2 , NH—Y, N(Y) 2 , O—Y, and optionally substituted at any substitutable nitrogen atom with C(═O)—O—Y, Y or C(═O)—Y;
each R 4 is independently selected from hydrogen, Y, —CF 3 , —C(═O)—Y, —C(═O)—O—Y, —Y—C(═O)—Y or —Y—C(═O)—O—Y;
R 5 and R 6 are independently selected from hydrogen, —OH, —OCF 3 , —O—Y, —O—C(═O)—Y, —O—C(═O)—O—Y, —O—C(═O)—NH—Y, —O—C(═O)—N(Y) 2 , —O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle, wherein only one of R 5 and R 6 is O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle, and when R 5 or R 6 is O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle it is further substituted with halo, —OH, Y, —O—Y, —OCF 3 or —O—C(═O)—Y; or
R 5 and R 6 can be taken together to the carbon atom to which they are bound to form ═O;
R 7 and R 8 are independently selected from hydrogen, halo, —OH, —O—Y and Y;
R 9 is selected from hydrogen, halo, —OH, —OCF 3 , —O—Y, Y, —O—C(═O)—Y, —NH—Y and —N(Y) 2 ;
each X is C 0 -C 5 straight chain or branched alkyl, alkenyl or alkynyl; and
each Y is C 1 -C 5 straight chain or branched alkyl, alkenyl or alkynyl;
wherein any Y or X is optionally substituted with one or more of —OH, —C 1 -C 4 straight chain or branched alkyl, —C 1 -C 4 alkene, —C 1 -C 4 alkynyl, —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkene), —O—(C 1 -C 4 alkynyl), —C(═O)—C 1 -C 4 straight chain or branched alkyl, —C(═O)—C 1 -C 4 alkene, —C(═O)—C 1 -C 4 alkynyl, —C(═O)—O—C 1 -C 4 straight chain or branched alkyl, —C(═O)—O—C 1 -C 4 alkene, —C(═O)—O—C 1 -C 4 alkynyl, halo, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —(C 1 -C 3 straight chain or branched alkyl)-NH—(═NH)—NH 2 , —NH(alkoxy-substituted C 1 -C 4 alkyl), —NH(hydroxy-substituted C 1 -C 4 alkyl), —N(alkoxy-substituted C 1 -C 4 alkyl)(hydroxy-substituted C 1 -C 4 alkyl), —N(hydroxy-substituted C 1 -C 4 alkyl) 2 or —N(alkoxy-substituted C 1 -C 4 alkyl) 2 ; or

a pharmaceutically acceptable salt thereof.

19 . The compound according to claim 18 , wherein the compounds or pharmaceutically acceptable salts are represented by Structural Formula (IIa):

20 . The compound or pharmaceutically acceptable salt according to claim 19 , wherein the compound is:

a pharmaceutically acceptable salt thereof.

21 . A method for treating acne, rosacea or Inflammatory Bowel Disease, which comprises administering a compound or a pharmaceutically acceptable salt thereof according to Formula (I), to a subject in need thereof; wherein Formula (I) is

wherein:
m is 1 or 2;
n is 2 or 3;
p is 0 to 4;
R 1 is selected from a carbocycle and heterocycle, wherein R 1 is optionally substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, —C≡N, —Y, —X—C(═O)—Y, —X—O—Y, —X—OR 4 , —X—C(═O)—NR 3 R 3 , —X—NH—C(═O)—Y—NR 3 R 3 , —X—NH—C(═O)—O—Y, —X—NR 3 R 3 , ═O, —NH—S(═O) 2 —R 3 , —S(═O) 2 —R 3 , —S—R 3 , —(C 3 -C 7 ) cycloalkyl, —C(═N)—NR 3 R 3 , —C(═N)—NH—X—NR 3 R 3 , —X—NH—C(═O)—Y, —C(═O)—NH—X, —NH—X, phenyl, —O-phenyl, 3- to 6-membered saturated or unsaturated heterocycle and —O-(5- to 6-membered saturated heterocycle), wherein any phenyl, 3- to 6-membered saturated or unsaturated heterocycle or —O-5- to 6-membered saturated heterocycle substituent of R′ is optionally substituted at any substitutable carbon atom with one or more substituents selected from halo, —OR 4 , —X—O—Y, —CF 3 , —Y, —X—R 3 R 3 , —X—NH—C(═O)—Y—NR 3 R 3 , —X—NH—C(═O)—O—Y-(5- to 6-membered saturated heterocycle or carbocycle), —X—C(═N)—NR 3 R 3 and —S—Y and optionally substituted at any substitutable nitrogen atom with —Y, —C(═O)—Y, —C(═O)—O—Y, —C(═O)—OR 4 , —Y—C(═O)—Y—NR 3 R 3 , —Y—NH—C(═O)—O—Y, —Y—NH—C(═O)—OR 4 , —Y—NH 2 , —C(═O)—NH—Y or —C(═O)-3- to 5-membered saturated carbocycle;
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 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, —C≡N, —Y, —X—OR 4 , —X—O—Y, —SO 2 —R 3 , —X—NR 3 R 3 , —NH—S(═O) 2 R 3 , —C(═O)—NR 3 R 3 , —C(═O)—Y, —C(═O)—O—Y, —SO 2 —R y , —SO 2 —NH—R y , —SO 2 —NR 3 R 3 , 3- to 6-membered saturated carbocycle or heterocycle and phenyl, wherein any 3- to 6-membered saturated heterocycle substituent of R 2 is optionally substituted at any carbon atom with one or more substituents

Assignees

• Glaxosmithkline Llc

Inventors

• Blum Charles A
• Caldwell Richard Dana
• Casaubon Rebecca
• Disch Jeremy S
• Fox Ryan Michael
• Koppetsch Karsten
• Miller William Henry
• Ng Pui Yee
• Oalmann Christopher
• Perni Robert B
• Szczepankiewicz Bruce G
• White Brian H

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4995

  Pyrazines or piperazines forming part of bridged ring systems · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title