LSD1 inhibitors and medical uses thereof

Patent metadata

Field	Value
Publication number	US-10517849-B2
Application number	US-201716345011-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 26, 2016
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

Provided are novel compounds of Formula (I or Ia′): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with LSD1. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I or Ia′), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with LSD1.

First claim

The invention claimed is:

1. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein
n is 1 or 2;
m is 1 or 2;
o is 0 or 1;
q is 0, 1, 2, or 3;
R 1 is hydrogen or (C 1 -C 6 )alkyl;
R 2 is hydrogen or (C 1 -C 6 )alkyl optionally substituted with OH or (C 1 -C 6 )alkoxy;
R 3 and R 4 , if present are each independently selected from hydrogen, halo, OH, and (C 1 -C 6 )alkyl;
R 5 is selected from NH 2 , —NH(SO 2 )(C 1 -C 6 )alkyl, —NH(SO 2 )(C 1 -C 6 )alkylO(C 1 -C 6 )alkyl, —NHC(O)(C 1 -C 6 )alkyl, —NH(SO 2 )(C 3 -C 6 )cycloalkyl, OH, —O(C 1 -C 6 )alkyl, —SO 2 NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N[(C 1 -C 6 )alkyl] 2 , —C(O)NH(SO 2 )(C 1 -C 6 )alkyl, —C(O)NH(C 1 -C 6 )alkyl(SO 2 )(C 1 -C 6 )alkyl, —C(O)NH(SO 2 )(C 3 -C 6 )cycloalkyl, —C(O)NH(C 1 -C 6 )alkylOH, —C(O)NH(C 1 -C 6 )alkylO(C 1 -C 6 )alkyl, and (C 1 -C 4 )alkyl substituted with OH; and
R 6 , if present, is selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, halo, and cyano;
provided the compound is not of the Formula:

 or a salt or stereoisomer thereof.

2. The compound of claim 1 , wherein the compound is of the Formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of the Formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxy(C 1 -C 4 )alkyl.

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

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , —NH(SO 2 )(C 1 -C 4 )alkyl, —NH(SO 2 )(C 1 -C 4 )alkylO(C 1 -C 4 )alkyl, —NHC(O)(C 1 -C 4 )alkyl, —NH(SO 2 )(C 3 -C 6 )cycloalkyl, OH, —SO 2 NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 )alkyl, —C(O)NH(SO 2 )(C 1 -C 4 )alkyl, —C(O)NH(C 1 -C 4 )alkyl(SO 2 )(C 1 -C 4 )alkyl, —C(O)NH(C 1 -C 4 )alkylOH, or (C 1 -C 2 )alkyl substituted with OH.

7. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 5 is C(O)NH 2 , OH, —SO 2 NH 2 , or —NH(SO 2 )CH 3 .

8. The compound of claim 1 , wherein the compound is of a formula selected from

or a pharmaceutically acceptable salt thereof.

9. A compound of the Formula

or a pharmaceutically acceptable salt thereof.

10. A compound of the Formula

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the compound is a single enantiomer having an enantiomeric purity of at least 95%.

12. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration about the cyclopropyl ring is 1R,2S.

13. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration about the cyclopropyl ring is 1S,2R.

14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

15. A method of treating a disease that is treatable by inhibiting LSD1 wherein said disease is selected from HIV, prostate cancer, esophageal squamous cell, neuroblastoma, ovarian cancer, bladder cancer, lung cancer, colorectal cancer, squamous cell carcinomas, breast cancer, glioblastoma multiforme, chondrosarcoma, Ewing's sarcoma, osteogenic sarcoma, rhabdomyosarcoma, melanoma, or medulloblastoma comprising the step of administering to a subject in need thereof a compound of claim 9 , or a pharmaceutically acceptable salt thereof.

16. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , —NH(SO 2 )(C 1 -C 4 )alkyl, —NH(SO 2 )(C 1 -C 4 )alkylO(C 1 -C 4 )alkyl, —NHC(O)(C 1 -C 4 )alkyl, —NH(SO 2 )(C 3 -C 6 )cycloalkyl, OH, —SO 2 NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 )alkyl, —C(O)NH(SO 2 )(C 1 -C 4 )alkyl, —C(O)NH(C 1 -C 4 )alkyl(SO 2 )(C 1 -C 4 )alkyl, —C(O)NH(C 1 -C 4 )alkylOH, or (C 1 -C 2 )alkyl substituted with OH.

17. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)NH 2 , OH, —SO 2 NH 2 , or —NH(SO 2 )CH 3 .

18. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the compound is a single enantiomer having an enantiomeric purity of at least 95%.

19. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration about the cyclopropyl ring is 1R,2S.

20. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration about the cyclopropyl ring is 1S,2R.

21. A pharmaceutical composition comprising an effective amount of a compound of claim 9 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising an effective amount of a compound of claim 10 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

23. A method of treating a disease that is treatable by inhibiting LSD1 wherein said disease is selected from HIV, prostate cancer, esophageal squamous cell, neuroblastoma, ovarian cancer, bladder cancer, lung cancer, colorectal cancer, squamous cell carcinomas, breast cancer, glioblastoma multiforme, chondrosarcoma, Ewing's sarcoma, osteogenic sarcoma, rhabdomyosarcoma, melanoma, or medulloblastoma comprising the step of administering to a subject in need thereof a compound of claim 10 .

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Brucelle Francois
• Gehling Victor S
• Khanna Avinash

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/22

  for herpes viruses · CPC title

• C07D205/12 Primary

  condensed with carbocyclic rings or ring systems · CPC title