Nuclear transport modulators and uses thereof
View Patent ↗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 the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 , if present, is independently selected from —CF 3 , —CN, halo, —OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 3-18-membered heterocyclyl, —NH 2 , halo-C 1 -C 3 alkyl, —NO 2 , —NH(C 1 -C 3 alkyl), —C(O)O—(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), —C(O)OH, —C(O)—(C 1 -C 3 alkyl), —O—(C 1 -C 3 alkyl), —O—(C 1 -C 3 haloalkyl), and —S—(C 1 -C 3 alkyl);
R 2 is a 6-18-membered aryl substituted with one or more substituents, wherein at least one substituent is —S(O) 1-2 —R 8 or N(H)S(O) 1-2 —R 8 ;
R b is selected from —C(O)—N(R 5 )(R 6 ), —C(O)—O—R 3 , —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 3 is selected from hydrogen, —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, C 3 -C 18 s carbocyclyl, C 6 -C 18 aryl, 3-18-member heterocyclyl and 5-18-member heteroaryl;
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)-C 3 -C 18 carbocyclyl, —(C 0 -C 4 alkylene)-3-18-member heterocyclyl, —(C 0 -C 4 alkylene)-C 6 -C 18 aryl, and —(C 0 -C 4 alkylene)-5-18-member 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, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-member heterocyclyl and 5-18-member heteroaryl; or
R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-member heterocyclyl or 5-18-member heteroaryl; and
each R 7 is independently hydrogen or —C 1 -C 4 alkyl;
R 8 is selected from —N(R 9 )—R 10 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —(C 0 -C 4 alkylene) C 3 -C 18 carbocyclyl, and —(C 0 -C 4 alkylene)-3-18-member heterocyclyl;
R 9 is hydrogen or —C 1 -C 4 alkyl;
R 10 is selected from —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 0 -C 4 alkylene)-C 3 -C 18 carbocyclyl and —(C 0 -C 4 alkylene)-3-18-member heterocyclyl; or
R 9 and R 10 are taken together with the nitrogen atom to which they are commonly attached to form a 4-7-membered heterocyclyl;
n is 0, 1, 2, 3, 4 or 5, wherein:
unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
2. The compound of claim 1 , wherein R b is selected from
C(O)—NH 2 , —C(O)—OH, —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 .
3. The compound of claim 2 , wherein R b is —C(O)NH 2 .
4. The compound of claim 1 , wherein R 2 is phenyl.
5. The compound of claim 1 , wherein the at least one substituent of R 2 is —S(O) 1-2 —R 8 .
6. The compound of claim 1 , wherein the at least one substituent of R 2 is —N(H)S(O) 1-2 —R 8 .
7. The compound of claim 5 , wherein R 8 is —N(Me)-Me or —N(H)-cyclopropyl.
8. The compound of claim 1 , wherein R 8 is —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 0 -C 4 alkylene-C 3 -C 18 carbocyclyl, or —(C 0 -C 4 alkylene)-3-18-member heterocyclyl wherein each alkyl, carbocyclyl and heterocyclyl is optionally substituted.
9. The compound of claim 8 , wherein R 8 is optionally substituted cyclopropyl.
10. The compound of claim 1 , wherein R 8 is an optionally substituted 3-12-membered heterocyclyl.
11. The compound of claim 1 , wherein R 8 is substituted with 1, 2 or 3 substituents independently selected from halo, hydroxyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy.
12. The compound claim 10 , wherein R 8 is selected from:
13. The compound of claim 1 , wherein n is 1 or 2 and each R 1 is independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and —O—(C 1 -C 4 )alkyl.
14. The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1a and R 1b are independently selected from —CF 3 , —CN, halo, —OH, (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, 3-12-membered heterocyclyl, halo-(C 1 -C 3 )alkyl, —NH 2 , —NO 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)—(C 1 -C 3 alkyl), —O—(C 1 -C 3 alkyl), —O—(C 1 -C 3 haloalkyl), and —S—(C 1 -C 3 alkyl); and
m is 0 or 1.
15. The compound of claim 14 , wherein R 1a is halo or (C 1 -C 3 )haloalkyl.
16. The compound of claim 14 , wherein R 1b is (C 1 -C 3 )haloalkyl or —O(C 1 -C 3 )alkyl.
17. The compound of claim 14 , wherein R 1a is —CF 3 and R 1b is —CF 3 .
18. A pharmaceutically composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. A method for treating a disorder associated with CRM1 activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
20. A compound represented by any one of the structural formulas selected from:
or a pharmaceutically acceptable salt thereof.