Inhibitors of Rho/MRTF/SRF-mediated gene transcription and methods for use of the same
AssigneesThe Regents of the University of Michigan, Board of Trustees of Michigan State University
InventorsScott D. Larsen, Richard Neubig, Kim Hutchings, Dylan Kahl, Erika Mathes Lisabeth
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Abstract
Disclosed herein are inhibitors of Rho/MRTF/SRF-mediated gene transcription, and methods for their use in treating or preventing diseases such as cancer and fibrosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.
Claims17
A compound, or a pharmaceutically acceptable salt thereof, having a structure:
- wherein:
- R2 is OH or Cl;
- and
- R3 and R4 are each independently selected from the group consisting of H, C1-5fluoroalkyl, OCF(CH3)2, OCH2CF3, C0-3alkylene-C3-5cycloalkyl, and OC0-3alkylene-C3-5cycloalkyl wherein the cycloalkyl is optionally substituted with one or more fluorine atoms, and;
- at least one of R3 and R4 is not H.
A compound, selected from the group consisting of:
- A1
- A2
- 4-(5-(2-chloro-4-cyclopropylphenyl)-
- 4-((5-(2-chloro-4-(trifluoromethyl)phenyl)-
- 1,3,4-oxadiazol-2-yl)thio)butanoic acid,
- 1,3,4-oxadiazol-2-yl)thio)butanoic acid,
- A3
- A7
- 4-((5-(2-chloro-3-cyclopropylphenyl)-
- 4-((5-(2-chloro-4-
- 1,3,4-oxadiazol-2-yl)thio)butanoic acid,
- (cyclopropylmethoxy)phenyl)-1,3,4-
- oxadiazol-2-yl)thio)butanoic acid,
- A8
- A12
- 4-((5-(2-chloro-4-cycloproboxyphenyl)-
- 4-((5-(2-chloro-4-(2,2,2-
- 1,3,4-oxadiazol-2-yl)thio)butanoic acid,
- trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-
- yl)thio)butanoic acid,
- A21
- A25
- 4-((5-(2-chloro-4-(2-fluoroproban-2-
- 4-((5-(2-chloro-3-(2,2,2-
- yl)phenyl)-1,3,4-oxadiazol-2-
- trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-
- yl)thio)butanoic acid,
- yl)thio)butanoic acid,
- A26
- A27
- 4-((5-(2-chloro-3-hydroxyphenyl)-1,3,4-
- 4-((5-(2-chloro-4-hydroxyphenyl)-1,3,4-
- oxadiazol-2-yl)thio)butanoic acid, and
- oxadiazol-2-yl)thio)butanoic acid,
- or a pharmaceutically acceptable salt thereof.
A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- wherein:
- X is C3-6cycloalkylenyl;
- R1 is H or C1-3alkyl;
- R2 is H, OH, Cl, F, or CF3;
- and
- R3, R4, and R5 are each independently selected from the group consisting of H, halo, C1-7alkyl, OC1-7alkyl, C3-7cycloalkyl, OC3-7cycloalkyl, C2-4heterocycloalkyl, and OC2-4heterocycloalkyl, wherein one or two carbon atoms of the alkyl group can optionally be replaced with oxygen, and the heterocycloalkyl group comprises one oxygen ring atom.
A compound selected from the group consisting of:
- B1
- B2
- trans-3-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-
- cis-3-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-
- 2-yl)thio)cyclobutanecarboxylic acid,
- yl)thio)cyclobutanecarboxylic acid,
- B3
- B4
- cis-3-((5-(2-chloro-4-cyclopropylphenyl)-
- trans-3-((5-(2-chloro-4-cyclopropylphenyl)-
- 1,3,4-oxadiazol-2-
- 1,3,4-oxadiazol-2-
- yl)thio)cyclobutanecarboxylic acid,
- yl)thio)cyclobutanecarboxylic acid,
- B5
- B6
- cis-3-((5-(2-chloro-4-(trifluoromethyl)phenyl)-
- trans-3-((5-(2-chloro-4-
- 1,3,4-oxadiazol-2-
- (trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-
- yl)thio)cyclobutanecarboxylic acid,
- yl)thio)cyclobutanecarboxylic acid,
- B7
- B8
- cis-3-((5-(2,4-dichlorophenyl)-1,3,4-
- trans-3-((5-(2,4-dichlorophenyl)-1,3,4-
- oxadiazol-2-yl)thio)cyclopentanecarboxylic acid,
- oxadiazol-2-yl)thio)cyclopentanecarboxylic acid,
- B9
- B10
- cis-4-((5-(2,4-dichlorophenyl)-1,3,4-
- trans-4-((5-(2,4-dichlorophenyl)-1,3,4-
- oxadiazol-2-yl)thio)cyclohexanecarboxylic acid, and
- oxadiazol-2-yl)thio)cyclohexanecarboxylic acid,
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.