Inhibitors of myocardin-related transcription factor and serum response factor (MRTF/SRF)-mediated gene transcription and methods for use of the same
Disclosed herein are inhibitors of gene transcription mediated by myocardin-related transcription factor and serum response factor, or both myocardin-related transcription factor and serum response factor (“MRTF/SRF”), and methods for their use in treating or preventing cancer and fibrosis. In particular, disclosed herein are compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof: wherein the substituents are as described.
1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof:
wherein:
X is
HET is 3-pyridyl, benzoimidazolyl, indolyl, or indazolyl;
m is 1 or 2;
n is 0, 1, or 2;
R 1 is pyrrolyl, furanyl, thiophenyl, pyridyl, or pyrimidinyl;
each R 2 independently is halo, C 1-6 alkyl, OC 1-6 alkyl, OC 0-6 alkylene-aryl, OC 0-6 alkylene-heteroaryl, SO 2 NR 5 2 , CN, or SO 2 C 1-3 alkyl;
R 3 is H, halo, OH, C 1-3 alkyl, or OC 1-3 alkyl;
each R 5 independently is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 3-6 alkylene-ether, C 0-6 alkylene-aryl, C 0-6 alkylene-heteroaryl, or two R 5 together with a nitrogen to which they are attached form a 3-7 atom heterocyclic ring; and
R 6 is H, halo, C 1-3 haloalkyl, or OC 1-3 haloalky R 7 is H or C 1-3 alkyl.
2. The compound of claim 1 , wherein X is
3. The compound of claim 2 , wherein HET is:
4. The compound of claim 1 , wherein X is
5. The compound of claim 1 , wherein X is selected from the group consisting of:
6. The compound of claim 1 , wherein R 3 is H or Me.
7. The compound of claim 1 : wherein
(a) m is 1 and R 2 is Cl; or
(b) at least one R 2 is F, CN, SO 2 Me, or Me.
8. The compound of claim 1 selected from the group consisting of:
9. A pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
10. A method of inhibiting MRTF/SRF-mediated gene transcription in a cell, comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount to inhibit the gene transcription.
11. The method of claim 10 , wherein the contacting comprises administering to a patient suffering from a disease associated with dysfunction of MRTF/SRF-mediated gene transcription.
12. The compound of claim 8 selected from the group consisting of E-019, E-041, E-068, and E-096, or a pharmaceutically acceptable salt thereof.