Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors
The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
1. A method for modulating a proviral insertion in murine kinase in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having one of the following structures:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the subject has an autoimmune disease or an inflammatory disease.
3. The method of claim 1 , wherein the subject has psoriasis or Crohn's disease.
4. The method of claim 1 , wherein the subject has fibrosis.
5. The method of claim 1 , wherein the subject has a hyperproliferative disorder.
6. The method of claim 1 , wherein the subject has a chronic leukemia.
7. The method of claim 1 , wherein the subject has an acute leukemia.
8. The method of claim 1 , wherein the subject has a proviral insertion in murine kinase-expressing cancer.
9. The method of claim 8 , wherein the cancer is a hematological malignancy.
10. The method of claim 9 , wherein the hematological malignancy is acute myeloid leukemia.
11. The method of claim 8 , wherein the cancer is bladder cancer.
12. The method of claim 8 , wherein the cancer is prostate cancer.
13. The method of claim 8 , wherein the cancer is a solid tumor.
14. The method of claim 1 , wherein the subject has lung cancer, non-small-cell lung cancer, oat-cell cancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head or neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, colo-rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, a gynecologic tumor, Hodgkin's disease, hepatocellular cancer, esophagus cancer, small intestine cancer, endocrine system cancer, sarcoma of soft tissues, urethra cancer, penis cancer, prostate cancer, chronic leukemia, acute leukemia, a pediatric solid tumor, hypereosinophilia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, a pediatric malignancy, a neoplasm of the central nervous system, Barrett's esophagus, neoplastic cutaneous disease, mycosis fungoides or benign prostatic hypertrophy.
15. The method of claim 1 , wherein the subject has a uterine sarcoma, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, thyroid cancer, pancreatic cancer, parathyroid cancer, adrenal gland cancer, renal cell carcinoma, carcinoma of the renal pelvis, primary central nervous system lymphoma, a spinal axis tumor, medulloblastoma, a brain stem glioma or a pituitary adenoma.
16. The method of claim 1 , wherein the subject has diabetic retinopathy, retinal ischemia, retinal neovascularization, hepatic cirrhosis, angiogenesis or atherosclerosis.
17. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 , wherein the subject has a proviral insertion in murine kinase-expressing cancer.
25. The method of claim 24 , wherein the cancer is a solid tumor.
26. The method of claim 23 , wherein the subject has lung cancer, non-small-cell lung cancer, oat-cell cancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head or neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, colo-rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, a gynecologic tumor, Hodgkin's disease, hepatocellular cancer, esophagus cancer, small intestine cancer, endocrine system cancer, sarcoma of soft tissues, urethra cancer, penis cancer, prostate cancer, chronic leukemia, acute leukemia, a pediatric solid tumor, hypereosinophilia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, a pediatric malignancy, a neoplasm of the central nervous system, Barrett's esophagus, neoplastic cutaneous disease, mycosis fungoides or benign prostatic hypertrophy.
27. The method of claim 23 , wherein the subject has a uterine sarcoma, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, thyroid cancer, pancreatic cancer, parathyroid cancer, adrenal gland cancer, renal cell carcinoma, carcinoma of the renal pelvis, primary central nervous system lymphoma, a spinal axis tumor, medulloblastoma, a brain stem glioma or a pituitary adenoma.
28. The method of claim 23 , wherein the subject has diabetic retinopathy, retinal ischemia, retinal neovascularization, hepatic cirrhosis, angiogenesis or atherosclerosis.
29. The method of claim 23 , wherein the subject has an autoimmune disease or an inflammatory disease.
30. The method of claim 23 , wherein the subject has psoriasis or Crohn's disease.
31. The method of claim 23 , wherein the subject has fibrosis.
32. The method of claim 23 , wherein the subject has a hyperproliferative disorder.
33. The method of claim 23 , wherein the subject has a chronic leukemia.
34. The method of claim 23 , wherein the subject has an acute leukemia.
35. The method of claim 24 , wherein the cancer is bladder cancer.
36. The method of claim 24 , wherein the cancer is prostate cancer.
37. The method of claim 24 , wherein the cancer is a hematological malignancy.
38. The method of claim 37 , wherein the hematological malignancy is acute myeloid leukemia.
39. The method of claim 23 , wherein the modulating is in hematopoietic cells.
40. The method of claim 23 , wherein the modulating is in bone marrow.
41. The method of claim 1 , wherein the modulating is in hematopoietic cells.
42. The method of claim 1 , wherein the modulating is in bone marrow.