Substituted pyrrolo[2,3-b]pyrazines and substituted pyrazolo[3,4-b]pyridines as ITK and JAK kinase inhibitors
The present invention relates to compounds described by Formula I: salts thereof, their synthesis, and their use as ITK and JAK3 inhibitors including such compounds and methods of using said compounds in the treatment of various diseases and or disorders such disease associated with abnormal cell growth such as autoimmune, inflammation, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's, metabolic and cancer diseases. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions and processes for preparing the compounds of the invention.
1. A compound according to Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N and X 2 is CH;
L 1 is
R 1 is independently H, halo, C 1-4 alkyl, or C 1-4 alkoxy;
Z is
optionally substituted with 1-3 independent halo or C 1-4 alkyl substituents;
R 2 is independently H, halo, C 1-4 alkyl, cyano-C 1-4 alkyl,
and
m is 0, 1, 2 or 3.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl.
3. The compound according to claim 1 , wherein R 2 is independently cyano-C 1-4 alkyl,
4. A method of modulating Janus kinase activity and/or interleukin-2-inducible T-cell kinase activity in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1 .
5. The method according to claim 4 , wherein said mammal suffers from a disease selected from rheumatoid arthritis, psoriasis, lupus erythematosus, systemic lupus erythematosus, idiopathic thrombocytopenia purpura, restenosis, angioplasty, tumor, atherosclerosis, chronic allograft rejection, acute allograft rejection, chronic graft versus host disease, asthma, allergic acute rhinitis, psoriatic arthritis, systemic sclerosis, atopical dermatitis, erythemas, alopecia, or multiple sclerosis.
6. The method according to claim 4 , wherein said mammal suffers from an immunodeficiency disorder.
7. The method according to claim 4 , wherein said mammal suffers from a myeloproliferative disorder, cancer, acute leukemia, or gain of function mutations associated with inherited polycythemia.
8. The method according to claim 4 , wherein said mammal suffers from psoriasis, psoriatic arthritis, or atopical dermatitis.
9. A compound selected from the group consisting of
and pharmaceutically acceptable salts thereof.
10. A method of modulating Janus kinase activity and/or interleukin-2-inducible T-cell kinase activity in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 9 .
11. The method according to claim 10 , wherein said mammal suffers from a disease selected from rheumatoid arthritis, psoriasis, lupus erythematosus, systemic lupus erythematosus, idiopathic thrombocytopenia purpura, restenosis, angioplasty, tumor, atherosclerosis, chronic allograft rejection, acute allograft rejection, chronic graft versus host disease, asthma, allergic acute rhinitis, psoriatic arthritis, systemic sclerosis, atopical dermatitis, erythemas, alopecia, or multiple sclerosis.
12. The method according to claim 10 , wherein said mammal suffers from an immunodeficiency disorder.
13. The method according to claim 10 , wherein said mammal suffers from a myeloproliferative disorder, cancer, acute leukemia, or gain of function mutations associated with inherited polycythemia.
14. The method according to claim 10 , wherein said mammal suffers from psoriasis, psoriatic arthritis, or atopical dermatitis.
15. A compound selected from the group consisting of
and pharmaceutically acceptable salts thereof.
16. A method of modulating Janus kinase activity and/or interleukin-2-inducible T-cell kinase activity in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 15 .
17. The method according to claim 16 , wherein said mammal suffers from a disease selected from rheumatoid arthritis, psoriasis, lupus erythematosus, systemic lupus erythematosus, idiopathic thrombocytopenia purpura, restenosis, angioplasty, tumor, atherosclerosis, chronic allograft rejection, acute allograft rejection, chronic graft versus host disease, asthma, allergic acute rhinitis, psoriatic arthritis, systemic sclerosis, atopical dermatitis, erythemas, alopecia or multiple sclerosis.
18. The method according to claim 16 , wherein said mammal suffers from an immunodeficiency disorder.
19. The method according to claim 16 , wherein said mammal suffers from a myeloproliferative disorder, cancer, acute leukemia, or gain of function mutations associated with inherited polycythemia.
20. The method according to claim 16 , wherein said mammal suffers from psoriasis, psoriatic arthritis, or atopical dermatitis.