Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors
The present invention provides a compound having the following structure: Compositions and methods for using the same in the treatment of skin disorders and other Pim kinase-associated conditions are also disclosed.
1. A pharmaceutical composition comprising a compound having the following structure:
or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable salt is a hydrochloric acid salt.
3. The pharmaceutical composition of claim 1 , wherein the one or more additional therapeutic agents are selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an anti-hormone, an antiangiogenic agent, an anti-androgen, a platinum coordination complex, a substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, a hormone, a hormone antagonist, an aromatase inhibitor, and a natural product-based chemotherapeutic agent.
4. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is an alkylating agent selected from the group consisting of a pyrimidine analog, an alkyl sulfonate, an aziridine, an ethyleneimine, a methyl melamine, a nitrogen mustard, and a triazine.
5. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is an antiangiogenic agent selected from the group consisting of a matrix metalloproteinase inhibitor and a cyclooxygenase-2 inhibitor.
6. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is a natural product-based chemotherapeutic agent selected from the group consisting of a vinca alkaloid, an epipodophyllotoxin, an antibiotic chemotherapeutic agent, and an enzymatic chemotherapeutic agent.
7. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is a protein kinase inhibitor.
8. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is a mitotic inhibitor.
9. A method for inhibiting proviral insertion in murine kinase activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
10. The method of claim 9 , wherein the subject has a chronic leukemia.
11. The method of claim 9 , wherein the subject has a hyperproliferative disorder.
12. The method of claim 9 , wherein the subject has a proviral insertion in murine kinase-expressing cancer.
13. The method of claim 9 , wherein the proviral insertion in murine kinase activity is inhibited in hematopoietic cells.
14. The method of claim 9 , wherein the proviral insertion in murine kinase activity is inhibited in the bone marrow.
15. The method of claim 9 , wherein the pharmaceutically acceptable salt is a hydrochloric acid salt.
16. The method of claim 9 , wherein the one or more additional therapeutic agents are selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an anti-hormone, an antiangiogenic agent, an anti-androgen, a platinum coordination complex, a substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, a hormone, a hormone antagonist, an aromatase inhibitor, and a natural product-based chemotherapeutic agent.
17. The method of claim 9 , wherein the additional therapeutic agent is an alkylating agent selected from the group consisting of a pyrimidine analog, an alkyl sulfonate, an aziridine, an ethyleneimine, a methyl melamine, a nitrogen mustard, and a triazine.
18. The method of claim 9 , wherein the additional therapeutic agent is an antimetabolite selected from the group consisting of a folic acid analog and a purine analog.
19. The method of claim 9 , wherein the additional therapeutic agent is an antiangiogenic agent selected from the group consisting of a matrix metalloproteinase inhibitor and a cyclooxygenase-2 inhibitor.
20. The method of claim 9 , wherein the additional therapeutic agent is a natural product-based chemotherapeutic agent selected from the group consisting of a vinca alkaloid, an epipodophyllotoxin, an antibiotic chemotherapeutic agent, and an enzymatic chemotherapeutic agent.
21. The method of claim 9 , wherein the additional therapeutic agent is a protein kinase inhibitor.
22. The method of claim 9 , wherein the additional therapeutic agent is a mitotic inhibitor.
23. A method for treating a skin disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 , wherein the skin disorder is selected from the group consisting of angiodema, conjunctivitis, dermatitis, lichen planus, pruritus, psoriasis, urticaria, uveitis, a chronic skin ulcer, a corneal ulcer, a cutaneous eosinophilia, an erythema, and a vasculitide.
25. The method of claim 23 , wherein the skin disorder is selected from the group consisting of dermatitis and psoriasis.
26. The method of claim 23 , wherein the skin disorder is dermatitis.
27. The method of claim 23 , wherein the pharmaceutically acceptable salt is a hydrochloric acid salt.
28. The method of claim 23 , wherein the method further comprises administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.