Cyclopropylamines as LSD1 inhibitors

• US 9,527,835 B2
• Filed: 02/12/2015
• Issued: 12/27/2016
• 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, Qian, Ding-Quan, Shen, Bo, Yao, Wenqing
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US14/620,853
• Publication Number:
  US 20150225375A1
• Time in Patent Office: 684 Days
• Field of Search: 514/210.1, 514/217, 514/304, 514/313, 514/318, 514/326, 514/331, 514/426, 514/451, 540/605, 546/124, 546/160, 546/194, 546/207, 546/229, 548/557, 548/953
• US Class Current: 1/1
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• 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: A61P 35/00 Antineoplastic agents
• 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 211/34 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C12N 9/0022 with oxygen as acceptor (1.4.3)
• CPC Class Codes: C12Y 104/03004 Monoamine oxidase (1.4.3.4)

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 II:

2. The compound of claim 1 having Formula Vb:

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

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

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, CN, NR^c3R^d3, C(O)OR^a3, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═

NR^e3)NR^c3R^d3, NR^c3C(═

NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, CN, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═

NR^e3)NR^c3R^d3, NR^c3C(═

NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2, wherein said C_1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, (═

NR^e2)NR^c2R^d2, NR^c2C(═

NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2.

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

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

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

12. 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 halo, CN, or OR^a4.

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

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

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

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

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

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

19. 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 Formula II.

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

{4-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}acetonitrile;

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 selected from:

6-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

5-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

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

6-[4-(methoxymethyl)-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

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

6-[4-methyl-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

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

N,N-dimethyl-5-[4-methyl-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide; and

N-methyl-5-[4-methyl-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

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