Substituted naphthyl p38α mitogen-activated protein kinase inhibitors
Substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating diseases are disclosed.
1. A compound having the structure of Formula (6):
or a pharmaceutically acceptable salt thereof, wherein,
R 1 is selected from C 1-4 alkanediyl, C 1-4 heteroalkanediyl, substituted C 1-4 alkanediyl, and substituted C 1-4 heteroalkanediyl;
R 2 is substituted morpholin-4-yl;
R 3 is selected from —C(═O)— and —S(═O) 2 —; and
R 4 is —N(R 5 ) 2 wherein each R 5 is independently selected from hydrogen and C 1-4 alkyl,
wherein each substituent is independently selected from —OH, ═O, —NH 2 , —NO 2 , C 1-6 alkyl, C 1-6 cycloalkyl, C 6 aryl, C 1-6 heteroalkyl, C 1-6 heterocycloalkyl, and C 5-6 heteroaryl.
2. The compound of claim 1 , wherein R 1 is C 1-4 alkanediyl.
3. The compound of claim 1 , wherein R 2 is mono-substituted morpholin-4-yl.
4. The compound of claim 1 , wherein R 2 is 3-substituted morpholin-4-yl.
5. The compound of claim 4 , wherein each substituent is independently selected from —OH, ═O, and —NH 2 .
6. The compound of claim 3 , wherein each substituent is ═O.
7. The compound of claim 1 , wherein R 3 is —S(O) 2 —.
8. The compound of claim 1 , wherein R 4 is bonded to the 5-position of the naphthyl moiety.
9. The compound of claim 1 , wherein,
R 1 is methane-diyl;
R 3 is —S(O) 2 —; and
R 4 is —N(R 5 ) 2 wherein each R 5 is independently selected from hydrogen and methyl.
10. The compound of claim 9 , wherein R 2 is 3-substituted 4-morpholinyl.
11. The compound of claim 9 , wherein in the moiety of R 2 , the substituent is ═O.
12. The compound of claim 1 , wherein the compound is selected from:
4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide; and
6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;
or a pharmaceutically acceptable salt of any of the foregoing.
13. The compound of claim 1 , wherein the compound is 5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (5) or a pharmaceutically acceptable salt thereof:
14. The compound of claim 1 , wherein the compound is 5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (2) or a pharmaceutically acceptable salt thereof:
15. The compound of claim 1 , wherein the compound is 5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide (3) or a pharmaceutically acceptable salt thereof:
16. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is treated by inhibiting the p38α MAPK receptor.
18. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is cancer, wherein the cancer is selected from breast cancer and melanoma.
19. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is an inflammatory disease, wherein the inflammatory disease is selected from acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis/acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesteremia, pain, diabetes, and rheumatoid arthritis.
20. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is an autoimmune disease, wherein the autoimmune disease is selected from lupus, graft-versus-host disease, hepatitis C-induced vasculitis, Type I diabetes, multiple sclerosis, spontaneous loss of pregnancy, an atopic disease, and an inflammatory bowel disease.
21. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is an age-related disease, wherein the age-related disease is selected from hearing loss, muscle degeneration, Werner's syndrome, cellular aging, and Alzheimer's disease.
22. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).