Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors. wherein A, Y, Z, X 1 , X 2 , X 3 , R 1 , R 3 , ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
1. A method of treating an IRAK4-mediated disorder, disease, or condition in a subject, comprising administering a compound selected from:
or a pharmaceutically acceptable salt thereof to the subject.
2. The method of claim 1 , wherein the disorder or disease is cancer.
3. The method of claim 1 , wherein the disease or disorder is a hematological malignancy.
4. The method of claim 1 , wherein the disease or disorder is leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma or multiple myeloma.
5. The method of claim 1 , wherein the disease or disorder is diffuse large B-cell lymphoma (DLBCL).
6. The method of claim 1 , wherein the disease or disorder is activated B-cell-like diffuse large B-cell lymphoma (DLBCL).
7. The method of claim 1 , wherein the disease or disorder is Waldenstrom's macroglobulinemia (WM).
8. The method of claim 1 , wherein the compound is
9. The method of claim 1 , wherein the compound is
10. The method of claim 1 , wherein the compound is
11. The method of claim 1 , wherein the compound is
12. The method of claim 1 , wherein the compound is
13. The method of claim 1 , wherein the compound is
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
14. The method of claim 1 , wherein the compound is
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
15. The method of claim 1 , wherein the compound is
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
16. The method of claim 1 , wherein the compound is
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
17. The method of claim 1 , wherein the compound is
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
18. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
19. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
20. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
21. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).
22. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of
and the disease or disorder is diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia (WM).