CYCLOBUTANE AND METHYLCYCLOBUTANE DERIVATIVES AS JANUS KINASE INHIBITORS

• US 20110207754A1
• Filed: 02/18/2011
• Published: 08/25/2011
• Est. Priority Date: 02/18/2010
• Status: Abandoned Application

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Li, Yun-Long
• Application Number:
  US13/030,682
• Publication Number:
  US 20110207754A1
• Time in Patent Office: Days
• US Class Current: 514/265.1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to cyclobutane and methylcyclobutane derivatives, as well as their salts, compositions, and methods of use, which are Janus kinase (JAK) inhibitors useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer and myeloproliferative disorders.

Claims

1. A compound which is 3-cyclobutyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is (R)-3-cyclobutyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 which is (S)-3-cyclobutyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

11. The phosphoric acid salt of the compounds of claim 1 or 4.

12. A composition comprising the compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

13. A method of treating an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

14. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

15. A method of treating a myeloproliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

16. A method of treating an inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

17. A method of treating organ transplant rejection in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

18. A method of treating dry eye in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 or 4, or a pharmaceutically acceptable salt thereof.

4. A compound which is 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 which is 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((trans)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 which is (3R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((trans)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 which is (3S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((trans)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 4 which is 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((cis)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 which is (3R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((cis)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8 which is (3S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-((cis)-3-methylcyclobutyl)propanenitrile, or a pharmaceutically acceptable salt thereof.