Cyclopropylamines as LSD1 inhibitors

• US 10,513,493 B2
• Filed: 11/18/2016
• Issued: 12/24/2019
• 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, Qian, Ding-Quan, Shen, Bo, Yao, Wenqing
• Primary Examiner(s): O'Dell, David K
• Application Number:
  US15/355,995
• Publication Number:
  US 20170158633A1
• Time in Patent Office: 1,131 Days
• 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 method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula,

2. The method of claim 1, wherein q is 0.

3. The method of claim 1, wherein q is 1.

4. The method of claim 1, wherein R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, 4-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.

5. The method of claim 1, 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.

6. The method of claim 1, wherein R^Z is C_1-4 alkyl.

7. The method of claim 1, wherein R^Z is C_1-4 alkyl substituted by CN or methoxy.

8. The method of claim 1, wherein R^Z is phenyl-C_1-4 alkyl-substituted by fluoro.

9. The method of claim 1, wherein R^Z is methyl, cyanomethyl, methoxymethyl, or 4-fluorophenylmethyl.

10. The method of claim 1, wherein R^Z is C_1-4 alkyl substituted by CN.

11. The method of claim 1, wherein R^Z is cyanomethyl.

12. The method of claim 1, wherein R^Z is H.

13. The method of claim 1, wherein the compound is a compound having a trans configuration with respect to the di-substituted cyclopropyl group depicted in the formula of claim 1.

14. The method 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.

15. The method of claim 1, wherein the compound is 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,2S)-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-4-0 [(1R, 2 S)-2-phenylcyclopropyl]amino methyl)piperidin-1-yl]pyridine-2-carboxamide; and

N-methyl-5-[4-methyl-4-0 [(1R, 2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

16. The method of claim 1, wherein said cancer is myelodysplasia syndrome.

17. The method of claim 1, wherein said cancer is acute myelogenous leukemia.

18. The method of claim 1, wherein said cancer is undifferentiated small cell lung cancer.

19. The method of claim 1, wherein said cancer is Ewing'"'"'s sarcoma.

20. The method of claim 1, wherein said cancer is primary myelofibrosis.