Antibacterial agents: aryl myxopyronin derivatives

Patent metadata

Field	Value
Publication number	US-9315495-B2
Application number	US-201314409407-A
Country	US
Kind code	B2
Filing date	Jun 19, 2013
Priority date	Jun 19, 2012
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The invention provides compounds of formula la, lb and Ic: [Formula Ia, Ib, and Ic] and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.

First claim

What is claimed is:

1. A compound of formula Ia, Ib or Ic:

or a salt thereof, wherein:
W is sulfur, oxygen, or nitrogen;
X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;
one of R 1 and R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a N b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or
one of R 1 and R 2 is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1 and R 2 is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;
R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least three of V′, W′, X′, Y′, and Z′ are carbon;
one of R 1′ and R 2′ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or
one of R 1′ and R 2′ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1′ and R 2′ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;
R 3′ , R 4′ , and R 5′ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
W″ is sulfur, oxygen, or nitrogen;
U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;
one of R 1″ and R 2″ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or
one of R 1″ and R 2″ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1″ and R 2″ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;
R 3′ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
R 4″ , R 5″ , and R 6″ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
R 5 and R 6 are individually H or methyl;
G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ;
R 7 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 8 ) 2 ;
each R 8 is independently one of hydrogen or —C 1 -C 6 alkyl;
R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;
each R a is C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; and
each R b is H or C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy.

2. The compound of formula Ia′, Ib′ or Ic′:

or a salt thereof, wherein:
W is sulfur, oxygen, or nitrogen;
X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;
one of R 1 and R 2 is C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, alkoxy, or furanyl; and the other of R 1 and R 2 is absent or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
V′, W, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least four of V′, W′, X′, Y′, and Z′ are carbon;
one of R 1′ and R 2′ is C 1 -C 5 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl; and the other of R 1′ and R 2′ is absent, or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
R 3′ , R 4′ , and R 5′ each is absent, or each of R 3′ , R 4′ , and R 5′ is one of is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
W″ is sulfur, oxygen, or nitrogen;
U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;
one of R 1″ and R 2″ is C 1 -C 8 alkyl or C 1 -C 5 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl; and the other of R 1 ″ and R 2 ″ is absent, or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;
R 4″ , R 5″ , and R 6″ each is absent, or each of R 4″ , R 5″ , and R 6″ is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl; and
R 5 and R 6 are individually H or methyl;
G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 , R 7 is one of C 1 -C 6 alk

Assignees

• Univ Rutgers
• Provid Pharmaceuticals Inc

Inventors

• Ebright Richard H
• Ebright Yon W
• Shen Juan
• Bacci James
• Hiebel Anne-Cecile
• Solvibile William
• Self Christopher
• Olson Gary

Classifications

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D309/36

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title