Triazolopyridines and triazolopyrazines as LSD1 inhibitors

• US 9,758,523 B2
• Filed: 07/09/2015
• Issued: 09/12/2017
• Est. Priority Date: 07/10/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, Wang, Xiaozhao, Yao, Wenqing, Zhang, Colin
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Michelson, Ben S
• Application Number:
  US14/795,532
• Publication Number:
  US 20160009721A1
• Time in Patent Office: 796 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention is directed to [1,2,4]triazolo[4,3-a]pyridine and [1,2,4]triazolo[4,3-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1. A compound of Formula IVa:

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

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4.

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

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is H, C_1-4 alkyl, or C_1-6 haloalkyl, wherein said C_1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, F, phenyl, C_3-7 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C(O)NH₂, phenoxy, and dimethylamino, wherein said phenyl is optionally substituted by CN and said 5-6 membered heteroaryl is optionally substituted by methyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is H, methyl, cyanomethyl, cyanoethyl, cyclopentylmethyl, tetrahydrofuranylmethyl, (1-methyl-1H-pyrazol-3-yl)methyl, morpholinylethyl, aminocarbonylmethyl, 3,3,3-trifluoro-2-hydroxypropyl, piperidinylmethyl, phenoxyethyl, dimethylaminoethyl, benzyl, cyanophenyl, or hydroxyethyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^A is CN.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^B is C_1-6 alkyl.

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

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^a1 is pyrrolidinylmethyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁴ is phenyl, cyclopentyl, tetrahydrofuranyl, pyrazolyl, morpholinyl, or piperidinyl, each optionally substituted by one substituent independently selected from methyl and CN.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁵ is pyrrolidinyl.

13. The compound of claim 1 selected from:

4-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-methyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

(R)-4-(2-(cyanomethyl)-3-oxo-8-(pyrrolidin-3-ylmethoxy)-5-p-tolyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzonitrile;

4-{2-(2-cyanoethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(cyclopentylmethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{5-(4-methylphenyl)-2-(2-morpholin-4-ylethyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

2-[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl]acetamide;

4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-3-oxo-2-(piperidin-4-ylmethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{5-(4-methylphenyl)-3-oxo-2-(2-phenoxyethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-[2-(dimethylamino)ethyl]-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-benzyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(4-cyanobenzyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(2-hydroxyethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

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