Cyclopropylamines as LSD1 inhibitors

• US 10,174,030 B2
• Filed: 04/26/2017
• Issued: 01/08/2019
• Est. Priority Date: 02/13/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, He, Chunhong, Wang, Xiaozhao, Courter, Joel R., Zhang, Fenglei, Yao, Wenqing
• Primary Examiner(s): O'Dell, David K
• Application Number:
  US15/497,887
• Publication Number:
  US 20170342070A1
• Time in Patent Office: 622 Days
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/16 with acylated ring nitrogen atom
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems

Abstract

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1. A compound of formula:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹ is independently selected from halo and —

O—

(C_1-6 alkyl).

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹ is independently selected from F and methoxy.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is H.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from H and C_1-4 alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is methyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is —

(CH₂)_r—

, wherein r is 1, 2, or 3.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is —

CH₂—

.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclobutyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl, phenyl-C_1-4 alkyl-, or (5-6 membered heteroaryl)-C_1-4 alkyl, wherein said C_1-4 alkyl, phenyl-C_1-4 alkyl-, or (5-6 membered heteroaryl)-C_1-4 alkyl, are each optionally substituted by CN, halo, C_1-6 alkoxy, or C_1-4 cyanoalkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl or phenyl-C_1-4 alkyl-, wherein said C_1-4 alkyl and phenyl-C_1-4 alkyl- are each optionally substituted by CN, halo, C_1-6 alkoxy, or C_1-4 cyanoalkyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is phenyl-C_1-4 alkyl- substituted by fluoro or cyanomethyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl substituted by methoxy or CN.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is (5-6 membered heteroaryl)-C_1-4 alkyl substituted by methoxy or F.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is methyl, cyanomethyl, methoxymethyl, 4-fluorophenylmethyl or 4-(cyanomethyl)phenylmethyl.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is methyl, cyanomethyl, methoxymethyl, ethoxymethyl, 4-fluorophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 6-methoxypyridin-3-yl)methyl, 4-cyano-2-fluorobenzyl, (5-fluoropyridin-2-yl)methyl, 4-methoxyphenylmethyl, or 4-(cyanomethyl)phenylmethyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl substituted by CN.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is cyanomethyl.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is methoxymethyl.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a trans configuration with respect to the di-substituted cyclopropyl group depicted in the formula of claim 1.

25. The compound of claim 1 selected from:

1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid; and

1-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

or a pharmaceutically acceptable salt of any one of the aforementioned.

26. The compound of claim 1 selected from:

1-{[4-({[(1R,2S)-2-(2-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-({[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-(methoxymethyl)-4-({[2-(2-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-(methoxymethyl)-4-({[2-(4-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

1-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid; and

1-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

or a pharmaceutically acceptable salt of any one of the aforementioned.

27. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, further comprising another therapeutic agent.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopentyl.