INHIBITORS OF JANUS KINASES

• US 20110166129A1
• Filed: 04/09/2009
• Published: 07/07/2011
• Est. Priority Date: 04/21/2008
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Zabierek, Anna A., Altman, Michael D., Konrad, Kaleen M., Machacek, Michelle R., Haidle, Andrew
• Granted Patent: US 8,278,335 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.

Claims

1. A compound of the formula

2. The compound of claim 1 wherein R¹ is substituted aryl, wherein said aryl is substituted with one to three substituents selected from the group consisting of halo and (C_1-6 alkyl)OH, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound of claim 2 wherein R² is hydrogen or (C_1-6 alkyl)OH or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound of claim 3 wherein W is CR³;

R³ is hydrogen or C_1-6 alkyl, wherein said alkyl group is optionally substituted with one to three substituents independently selected from hydroxyl and heterocyclyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound of claim 1 wherein R¹ is substituted heteroaryl, wherein said heteroaryl group is substituted with heterocyclyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The compound of claim 1 wherein m is two;

or a pharmaceutically acceptable salt or stereoisomer thereof.

7. The compound of claim 1 selected from:

2-(4-Chlorophenyl)-5-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-(4-Chlorophenyl)-5-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-(4-Chlorophenyl)-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-(4-Chlorophenyl)-5-{[6-(1,2-dihydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

5-({6-[1-(1,1-Dioxidothiomorpholin-4-yl)-2-hydroxyethyl]pyridin-2-yl}amino)-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide;

1-{[6-({4-(Aminocarbonyl)-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazol-5-yl}amino)pyridin-2-yl]methyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide;

5-{[6-(Cyanomethyl)pyridin-2-yl]amino}-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-[(6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)amino]-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

5-{[5-(1-Hydroxy-1-methylethyl)-6-methylpyridin-2-yl]amino}-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide;

2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[5-(methylsulfonyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[6-(1-hydroxy-1-methylethyl)pyridazin-3-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[5-(methylsulfonyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[5-(1-hydroxy-1-methylethyl)-6-methylpyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-({6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}amino)-1,3-thiazole-4-carboxamide;

5-{[6-(2-Hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide;

5-{[5-(1-Hydroxy-1-methylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide;

5-{[5-(1-Hydroxy-1-methylethyl)-6-methylpyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide;

2-[2-Fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

2-[2-Fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-{[5-(1-hydroxy-1-methylethyl)-6-methylpyridin-2-yl]amino}-1,3-thiazole-4-carboxamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

8. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

9. A method of treating myeloproliferative disorders or cancer in a mammal in need thereof with a pharmaceutically acceptable amount of a compound according to claim 1.