Heterocyclic LSF inhibitors and their uses

Patent metadata

Field	Value
Publication number	US-11242353-B2
Application number	US-202117155547-A
Country	US
Kind code	B2
Filing date	Jan 22, 2021
Priority date	Jan 24, 2020
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.

First claim

What is claimed is:

1. A compound of Formula (I):

or enantiomers, derivatives, and pharmaceutically acceptable salts thereof; and
none, one, or more vicinal pairs of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 each, together with the carbons to which they are attached, form a 5-8 membered cycloalkyl or heterocyle ring; and
the remaining R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 9 are each independently selected from the group consisting of hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , SO 2 R 1A , —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkenyl, aryl, and heteroaryl, and R 8 is selected from the group consisting of hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , SO 2 R 1A , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkenyl and aryl;

R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkenyl, aryl, heteroaryl, or halogen; or R 10 and one of the vicinal R 11 or R 12 groups together form a double bond between the carbon atoms they are attached to;
none or a vicinal pair of R 11 , R 12 , R 13 and R 14 together form a double bond between the carbon atoms they are attached to and the remaining R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkenyl, OR 3A , SR 3A , SO 2 R 3A , NR 3A R 4A , heteroaryl, and aryl; or
one or two of a germinal pair of R 11 , R 12 , R 13 and R 14 together form a carbonyl (═O) and the remaining R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkenyl, OR 3A , SR 3A , SO 2 R 3A , NR 3A R 4A , halogen, heteroaryl, and aryl;

wherein,
R 1A , R 2A , R 3A and R 4A are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, cycloalkyl, heterocyclyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, heteroaryl, and aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, heteroalkyl, heteroaryl, and aryl can be optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl or C 1 -C 6 alkoxy, and
any of the 5-8 membered cycloalkyl, the heterocyle ring, the alkyl, the haloalkyl, the heteroalkyl, the alkenyl, the heteroaryl, and the aryl can be optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, C 2 -C 8 alkenyl, amino (NH 2 ), mono(C 1 -C 6 alkyl)amino or di(C 1 -C 6 alkyl)amino.

2. The compound according to claim 1 , wherein at least one germinal pair of R 11 , R 12 , R 13 and R 14 together forms a carbonyl (═O).

3. The compound according to claim 1 , wherein at least one vicinal pair of R 10 and R 12 , or R 12 and R 14 together form a double bond between the carbon atoms they are attached to.

4. The compound according to claim 1 , wherein R 7 and R 8 together with the carbons to which they are attached, form a 5-8 membered cycloalkyl or heterocycle ring.

5. The compound of claim 1 , wherein the compound is of Formula (IA):

wherein
n is 1, 2 or 3; and
R 7′ and R 8′ independently are hydrogen or halogen.

6. The compound of claim 5 , wherein n is 1 or 2.

7. The compound of claim 5 , wherein R 7′ is H or F.

8. The compound of claim 5 , wherein R 8′ is H or F.

9. The compound of claim 1 , wherein R 6 is hydrogen, halogen, OR 1A NR 1A R 2A , SR 1A , or C 1 -C 6 alkyl.

10. The compound of claim 9 , wherein R 6 is hydrogen, halogen or OR 1A .

11. The compound of claim 1 , wherein R 9 is hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , or C 1 -C 6 alkyl.

12. The compound of claim 11 , wherein R 9 is hydrogen, halogen or OR 1A .

13. The compound of claim 1 , wherein R 10 is hydrogen or C 1 -C 6 alkyl.

14. The compound of claim 1 , wherein R 1 is hydrogen, halogen, OR 1A , NR 1A , R 2A , SR 1A , C 1 -C 6 alkyl or —NO 2 .

15. The compound of claim 14 , wherein R 1 is O(C 1 -C 6 alkyl).

16. The compound of claim 1 , wherein R 2 is hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , C 1 -C 6 alkyl or —NO 2 .

17. The compound of claim 16 , wherein R 2 is hydrogen or halogen.

18. The compound of claim 1 , wherein R 3 is hydrogen, halogen, OR 1A , NR 1A R 2A , C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 1 -C 6 haloalkyl, or —NO 2 .

19. The compound of claim 18 , wherein R 3 is N(C 1 -C 6 alkyl) 2 , halogen, C 1 -C 6 haloalkyl, or —NO 2 .

20. The compound of claim 1 , wherein R 4 is hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , C 1 -C 6 alkyl or —NO 2 .

21. The compound of claim 20 , wherein R 4 is hydrogen or halogen.

22. The compound of claim 1 , wherein R 5 is hydrogen, halogen, OR 1A , NR 1A R 2A , SR 1A , C 1 -C 6 alkyl or —NO 2 .

23. The compound of claim 22 , wherein R 5 is hydrogen or halogen.

24. The compound of claim 1 , wherein R 1 is O(C 1 -C 6 alkyl) and R 3 is N(C 1 -C 6 alkyl) 2 .

25. The compound of claim 1 , wherein R 2 , R 4 and R 5 are hydrogen.

26. The compound of claim 1 , wherein R 11 and R 12 , or R 13 and R 14 are hydrogen.

27. The compound of claim 1 , wherein the compound is

28. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or carrier.

29. A method for inhibiting LSF in a subject, the method comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

30. A method for treating cancer in a subject, the method comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

Assignees

• Univ Boston

Inventors

• Schaus Scott E
• Hansen Ulla
• Kavouris John A
• York Emily A
• Pokharel Niranjana

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D491/056 Primary

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title