Aminopyrazoles as selective janus kinase inhibitors
The instant invention provides compounds of formula I which are selective JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer.
1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
2. The compound of claim 1 , wherein the compound is
3. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier.
4. A method for the treatment of a JAK-1 mediated disease selected from the list consisting of allergic dermatitis, atopic dermatitis, arthritis, and keratoconjunctivitis sicca, comprising administering to a mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
5. The method of claim 4 wherein the JAK-1 mediated disease in the mammal is one that can be ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2 and JAK 3.
6. The method according to claim 4 , wherein the disease is atopic dermatitis.
7. The method of claim 4 , wherein the disease is arthritis.
8. The method of claim 5 wherein the mammal is a companion animal mammal.
9. The method of claim 8 wherein the companion animal is a dog, a cat, or a horse.
10. The method according to claim 4 , wherein the disease is keratoconjuncivitis sicca.
11. The method of claim 5 , wherein the administration is orally, parenterally or topically.
12. The method of claim 5 , wherein the selective inhibition is of Janus kinase JAK1 relative to JAK 2.
13. The method of claim 5 , wherein the selective inhibition is of Janus kinase JAK1 relative to JAK 3.
14. The method of claim 12 , wherein the ratio of JAK2(IC 50 )/JAK1(IC 50 ) is at least 5.
15. The method of claim 4 , wherein the daily dose of the compound is from about 0.001 mg/kg to about 100 mg/kg.
16. The method of claim 13 , wherein the ratio of JAK3(IC 50 )/JAK1(IC 50 ) is at least 500.
17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier.
18. A method for the treatment of a JAK-1 mediated disease selected from the list consisting of allergic dermatitis, atopic dermatitis, arthritis, and keratoconjunctivitis sicca, comprising administering to a mammal in need thereof the pharmaceutical composition of claim 17 .