Hydrazide containing nuclear transport modulators and uses thereof
View Patent ↗The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula I: or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, and quinoxalin-2-yl, pyrimidin-4-yl, 1,1-dioxotetrahydrothiophen-3-yl and cyclopropyl, wherein R 2 is optionally substituted with one or more substituents independently selected from methyl and halogen; or
R 1 and R 2 are taken together with their intervening atoms to form 4-hydroxypiperidin-1-yl, pyrrolidin-1-yl, azepan-1-yl, 4-benzylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-hydroxyazetidin-1-yl, or morpholin-4-yl;
R 3 is selected from hydrogen and halo; and
represents a single bond wherein a carbon-carbon double bond bound thereto is in an (E)- or (Z)-configuration.
2. The compound according to claim 1 , wherein the compound is represented by structural formula II:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein:
R 1 is selected from hydrogen and methyl; and
R 2 is selected from pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl and pyrimidin-4-yl, wherein R 2 is optionally substituted with a single substituent selected from methyl and chloro; or
R 1 and R 2 are taken together to form 4-hydroxypiperidin-1-yl.
4. The compound of any one of claims 1 - 3 , wherein R 3 is hydrogen.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by any one of the following structural formulas:
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by any one of the following structural formulas:
7. A composition comprising a compound of any one of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. The composition of claim 7 , further including a second therapeutic compound.