Nuclear transport modulators and uses thereof
The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula I or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.
1. A compound, represented by structural formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from optionally substituted heteroaryl and optionally substituted aryl.
2. The compound of claim 1 , wherein R 2 is an optionally substituted C 5 -C 15 heteroaryl.
3. The compound of claim 1 , wherein R 2 is an optionally substituted 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
4. The compound of claim 3 , wherein R 2 is an optionally substituted 5-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
5. The compound of claim 4 , wherein R 2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.
6. The compound of claim 3 , wherein R 2 is an optionally substituted 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
7. The compound of claim 6 , wherein R 2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.
8. The compound of claim 1 , wherein R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
9. The compound of claim 8 , wherein R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, —CF 3 , amino and cyano.
10. A compound of structural formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R b is selected from —
C(O)OH, —C(O)NH 2 , —C(O)—N(R 7 )—N(R 5 )(R 6 ), —C(O)—N(R 7 )—N(R 7 )—C(O)—R 4 and —C(O)—N(R 7 )—N(R 7 )—S(O) 1-2 —R 4 ; wherein:
R 4 is selected from —N(H)(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-carbocyclyl, —(C 0 -C 4 alkylene)-heterocyclyl, -(C 0 -C 4 alkylene)-aryl, and —(C 0 -C 4 alkylene)-heteroaryl;
R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or
R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl; and
each R 7 is independently hydrogen or C 1 -C 4 alkyl; and
R 2 is an optionally substituted C 5 -C 15 heteroaryl, wherein:
unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
11. The compound of claim 10 , wherein:
R b is selected from:
—C(O)—OH; or
—C(O)—NH 2 ; or
—C(O)—NH—NH(R 6 ), and R 6 is an optionally substituted heteroaryl; or
—C(O)—NH—NH—C(O)—R 4 or —C(O)—NH—NH-S(O) 1-2 —R 4 , and R 4 is selected from optionally substituted —N(H)(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl and —(C 0 -C 4 alkylene)-heteroaryl.
12. The compound of claim 10 , wherein R 2 is an optionally substituted 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
13. The compound of claim 12 , wherein R 2 is an optionally substituted 5-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
14. The compound of claim 12 , wherein R 2 is an optionally substituted 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
15. The compound of claim 10 , wherein R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
16. A compound represented by any one of the following structural formulas:
or a pharmaceutically acceptable salt of any of the foregoing.
17. A pharmaceutically acceptable composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 .