Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors

• US 8,946,245 B2
• Filed: 03/30/2011
• Issued: 02/03/2015
• Est. Priority Date: 12/13/2005
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Shepard, Stacey, Fridman, Jordan S., Vaddi, Krishna
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US13/076,176
• Publication Number:
  US 20110224157A1
• Time in Patent Office: 1,406 Days
• Field of Search: 544/280, 514/265.1
• US Class Current: 514/265.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 31/12 Antivirals
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Claims

1. A method of treating a disease selected from cachexia, polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), multiple myeloma, leukemia, lymphoma, breast cancer, acute myelogenous leukemia, acute lymphoblastic leukemia, and Castleman'"'"'s disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound that is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and a further therapeutic agent wherein said treating refers to ameliorating or inhibiting the disease in the patient.

2. The method according to claim 1, wherein said compound is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein said further therapeutic agent is a chemotherapeutic agent.

4. The method according to claim 3, wherein said method comprises administering said compound, or said salt, and said chemotherapeutic agent simultaneously to the patient.

5. The method according to claim 3, wherein said method comprises administering said compound, or said salt, and said chemotherapeutic agent sequentially to said patient.

6. The method according to claim 3, wherein about 5 to about 1000 mg of said compound or said salt is administered to said patient.

7. The method according to claim 2, wherein said disease is polycythemia vera (PV).

8. The method according to claim 2, wherein said disease is essential thrombocythemia (ET).

9. The method according to claim 2, wherein said disease is myeloid metaplasia with myelofibrosis (MMM).

10. The method according to claim 2, wherein said disease is chronic myelogenous leukemia (CML).

11. The method according to claim 2, wherein said disease is chronic myelomonocytic leukemia (CMML).

12. The method according to claim 2, wherein said disease is multiple myeloma.

13. The method according to claim 2, wherein said disease is leukemia.

14. The method according to claim 2, wherein said disease is lymphoma.

15. The method according to claim 2, wherein said disease is breast cancer.

16. The method according to claim 2, wherein said disease is acute myelogenous leukemia.

17. The method according to claim 3, wherein said chemotherapeutic agent is lenalidomide.

18. The method according to claim 17, wherein said method further comprises administering a corticosteroid to said patient.

19. The method according to claim 18, wherein said corticosteroid is prednisone.

20. The method according to claim 3, wherein said chemotherapeutic agent is a DNA-damaging agent.

21. The method according to claim 20, wherein said DNA-damaging agent is selected from melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, and carmustine.

22. The method according to claim 2, wherein said further therapeutic agent is selected from melphalan plus prednisone, doxorubicin, dexamethasone, and bortezomib.

23. The method according to claim 2, wherein said disease is cachexia.

24. The method according to claim 2, wherein said cachexia results from or is associated with cancer.

25. The method according to claim 2, wherein the disease is Castleman'"'"'s disease.

26. The method according to claim 2, wherein the disease is acute lymphoblastic leukemia.