Antibacterial agents: aryl myxopyronin derivatives

Patent metadata

Field	Value
Publication number	US-2016263083-A1
Application number	US-201615064452-A
Country	US
Kind code	A1
Filing date	Mar 8, 2016
Priority date	Jun 19, 2012
Publication date	Sep 15, 2016
Grant date	—

Abstract

The invention provides compounds of 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

1 - 20 . (canceled)

21 . A method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with 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 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 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, 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″ , 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.

22 . The method of claim 21 , comprising contacting the bacterial RNA polymerase with 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 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 8 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 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″ 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 ar

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

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D417/06 Primary

  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

• A61K31/381

  having five-membered rings · CPC title

• C07D309/38

  one oxygen atom in position 2 or 4, e.g. pyrones · CPC title