Substituted pyrrolo[2,3-
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:
both X 1 and X 2 are CH; or X 1 is CH, and X 2 is —C(═O);
L 1 is H, halo, C 1-4 alkyl, —NH—S(O) 2 (C 1-4 alkyl),
or phenyl optionally substituted with 1-3 substituents, each substituent independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, —CO—O—C 1-4 alkyl, —CO—N(C 1-4 alkyl)(C 1-4 alkyl),
R 1 is each 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 each independently cyano-C 1-4 alkyl,
m is 0, 1, 2 or 3; and
n is 0, 1 or 2,
provided that the compound is not
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CH; and
X 2 is CH, as represented by Formula (IA):
3. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl.
4. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is H.
5. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is halo.
6. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is C 1-4 alkyl.
7. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is —NH—S(O) 2 (C 1-4 alkyl).
8. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is
9. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is
10. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl; and L 1 is optionally substituted phenyl.
11. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is pyridyl.
12. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is pyridyl; and L 1 is H.
13. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is pyridyl; and L 1 is C 1-4 alkyl.
14. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is pyridyl; and L 1 is optionally substituted phenyl.
15. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is H;
X 1 is CH; and
X 2 is —C(═O).
16. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl.
17. The compound according to claim 1 wherein each R 2 is independently cyano-C 1-4 alkyl,
18. A compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
19. A compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
20. A compound according to claim 1 selected from
or a pharmaceutically acceptable salt thereof.
21. A method of modulating Janus kinase activity and/or interleukin-2-inducible T-cell activity in a mammal comprising administering an effective amount of a compound according to claim 1 .
22. The method of claim 21 , wherein said mammal suffers from a disease selected from a myeloproliferative disorder or cancer.
23. The method of claim 22 wherein said mammal suffers from a disease selected from acute leukemia, or gain of function mutations associated with inherited polycythemia.
24. The method of claim 21 , wherein said mammal suffers from a disease selected from rheumatoid arthritis, psoriasis, lupus erythematosus, systemic lupus erythematosus, atherosclerosis, idiopathic thrombocytopenia purpura, restenosis, angioplasty, tumors, atherosclerosis, or systemic lupus erythematosus.
25. The method of claim 21 , wherein said mammal suffers from a disease selected from chronic allograft rejection, acute allograft rejection, or chronic graft versus host diseases.
26. The method of claim 21 , wherein said mammal suffers from a disease selected from asthma, allergic acute rhinitis, psoriatic arthritis, systemic sclerosis, atopical dermatitis, erythemas, alopecia, multiple sclerosis, or atherosclerosis.