Nuclear transport modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-10722497-B2
Application number	US-201916414479-A
Country	US
Kind code	B2
Filing date	May 16, 2019
Priority date	May 9, 2012
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

Compounds of formula I:

and pharmaceutically acceptable salts, hydrates, or solvates thereof, pharmaceutical compositions comprising the compounds of formula I, and methods of using such compounds and compositions to treat various disorders associated with CRM1 activity.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
R 1 is selected from hydrogen and C 1 -C 4 alkyl;
R 2 is selected from O and S; and
R 3 is selected from N(R 4 )(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any alkyl or alkylene portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of oxo and —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;
any heterocyclyl portion of R 3 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl and oxo; and
any heteroaryl portion of R 3 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C 1 -C 4 alkyl; and
R 4 is selected from hydrogen and C 1 -C 4 alkyl.

2. The compound of claim 1 , wherein, R 1 is selected from hydrogen and methyl.

3. The compound of claim 2 , wherein R 1 is hydrogen.

4. The compound of claim 1 , wherein R 2 is O.

5. The compound of claim 1 , wherein R 4 is hydrogen.

6. The compound of claim 1 , wherein R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 3 -C 6 alkyl, —(C 0 -C 1 alkylene)-heterocyclyl, and —(C 0 -C 1 alkylene)-heteroaryl, wherein:
any alkyl or alkylene portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of oxo and —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;
any heterocyclyl portion of R 3 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl and oxo; and
any heteroaryl portion of R 3 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C 1 -C 4 alkyl.

7. The compound of claim 6 , wherein R 3 is —(C 0 -C 1 alkylene)-heterocyclyl.

8. The compound of claim 7 , wherein R 3 is —(C 1 alkylene)-heterocyclyl.

9. The compound of claim 1 , wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl.

10. The compound of claim 9 , wherein the heterocyclyl is morpholinyl R 3 is selected from —C(CH 3 ) 3 , —NH-cyclopropyl, —CH 2 -pyrazin-2-yl, -pyrazin-2-yl, —CH 2 -morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl.

11. The compound of claim 1 , wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl or C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl.

12. The compound of claim 1 , wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted with an amino group having the formula —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl.

13. The compound of claim 1 , wherein:
any heteroaryl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl; and
any alkyl, alkylene or heterocyclyl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of oxo, —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl.

14. The compound of claim 1 , wherein R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 3 -C 6 alkyl, —(C 0 -C 1 alkylene)-heterocyclyl, and —(C 0 -C 1 alkylene)-heteroaryl, wherein:
any alkyl or alkylene portion of R 3 is optionally substituted with —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;
any heterocyclyl, and heteroaryl portion of R 3 comprises at least one nitrogen atom in a ring; and
any heterocyclyl, and heteroaryl portion of R 3 is optionally substituted with C 1 -C 4 alkyl.

15. The compound of claim 14 , wherein R 3 is selected from —C(CH 3 ) 3 , —CH(NH 2 )—CH(CH 3 ) 2 , —NH-cyclopropyl, —(CH 2 ) 0-1 -pyrazinyl, piperidinyl, hydroxypiperidinyl, N-methylpiperidinyl, —CH 2 -morpholin-4-yl, and methylpyrazolyl.

16. The compound of claim 15 , wherein R 3 is selected from —C(CH 3 ) 3 , —CH(NH 2 )—CH(CH 3 ) 2 , —NH-cyclopropyl, —(CH 2 ) 0-1 -pyrazin-2-yl, piperidin-3-yl, —CH 2 -morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl.

17. The compound of claim 16 , wherein R 3 is selected from —C(CH 3 ) 3 , —NH-cyclopropyl, —CH 2 -pyrazin-2-yl, -pyrazin-2-yl, —CH 2 -morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl.

18. A compound represented by any one of the structural formulas set forth below:

Cmpd

No.
Compound Structure

1

2

3

4

5

6

7

Assignees

• Biogen Ma Inc

Inventors

• Sandanayaka Vincent
• Shechter Sharon
• Shacham Sharon
• Mccauley Dilara
• Baloglu Erkan

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D249/08 Primary

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title