P38α mitogen-activated protein kinase inhibitors

1. A compound having the structure of Formula (1):

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; and

R 2 is selected from a moiety of Formula (2a), a moiety of Formula (2b), and a moiety of Formula (2c):

wherein,

each of B 1 , B 2 , B 3 , and B 4 is independently selected from —(CH(—R 4 )),

wherein,

each n is independently selected from, 0, 1, 2, 3, and 4;

both B 1 and B 2 are not absent;

both B 3 and B 4 are not absent; and

each R 4 is independently selected from hydrogen, —OH, —NH 2 , —NO 2 , C 1-3 alkyl, C 1-3 heteroalkyl, substituted C 1-3 alkyl, and substituted C 1-3 heteroalkyl;

D is selected from methane-diyl and ethane-diyl; and

X is selected from —O—, —CH(—OH)—, —NR 3 —, and —SO 2 —, wherein R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, C 6 aryl, C 1-6 heteroalkyl, C 1-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 1-6 alkyl, substituted C 1-6 cycloalkyl, substituted C 6 aryl, substituted C 1-6 heteroalkyl, substituted C 1-6 heterocycloalkyl, and substituted C 5-6 heteroaryl.

2. The compound of claim 1 , wherein,

R 1 is C 1-4 alkanediyl; and

R 2 is selected from a substituted or unsubstituted moiety of any one of Formula (2a.1) to (2a.4):

wherein,

R 5 is selected from hydrogen (unsubstituted), —OH, —NH 2 , —NR 2 wherein each R is independently selected from hydrogen and C 1-3 alkyl, —NO 2 , ═O, C 1-3 alkoxy, and C(═O)—R where R is C 1-3 alkyl.

3. The compound of claim 2 , wherein R 1 is C 1-4 alkane-diyl.

4. The compound of claim 2 , wherein R 1 is methane-diyl.

5. The compound of claim 2 , wherein R 2 is selected from an unsubstituted moiety of any one of Formula (2a.1) to (2a.4).

6. The compound of claim 2 , wherein R 2 is selected from a substituted moiety of any one of Formula (2a.1) to (2a.4).

7. The compound of claim 1 , wherein B 1 is —(CH 2 ) 2 —; B 2 is —CH 2 —; B 3 is —(CH 2 )n— wherein n is selected from 0, 1, 2, and 3; and X is O.

8. The compound of claim 1 , wherein the compound is selected from:

N-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)-4-chlorobenzamide (2);

N-(4-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)phenyl)-4-chlorobenzamide (4);

N-(4-((8-oxa-2-azaspiro[4.5]decan-2-yl)methyl)phenyl)-4-chlorobenzamide (5);

N-(4-((1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl)phenyl)-4-chlorobenzamide (6);

N-(4-(((1R,5S)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)methyl)phenyl)-4-chlorobenzamide (9); and

4-chloro-N-(4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H )-yl)methyl)phenyl)benzamide (10);

or a pharmaceutically acceptable salt of any of the foregoing.

9. The compound of claim 1 , wherein the compound inhibits the p38α MAPK receptor.

10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the etiology of the disease is associated with up-regulation of the p38α MAPK protein, with the down-regulation of the p38α MAPK protein, or with both the up-regulation and the down-regulation of the p38α MAPK protein.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from cancer, an inflammatory disease, and autoimmune disease, and a viral disease.

13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

14. A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

15. A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the pharmaceutical composition of claim 10 , wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

16. A compound having the structure of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

R 1 is selected from C 1-4 alkanediyl, C 2-4 heteroalkanediyl, substituted C 1-4 alkanediyl, and substituted C 2-4 heteroalkanediyl; and

R 2 is selected from a substituted or unsubstituted moiety of any one of Formula (2d.1), (2d.2), (2d.4), (2d.5), and (2d.5′):

wherein,

R 5 is selected from hydrogen (unsubstituted), —OH, —NH 2 , —NR 2 wherein each R is independently selected from hydrogen and C 1-3 alkyl, —NO 2 , ═O, C 1-3 alkoxy, and C(═O)—R where R is C 1-3 alkyl; and

R 6 is selected from C 1-6 alkyl and C 1-6 alkoxy.

17. The compound of claim 16 , wherein R 1 is C 1-4 alkanediyl.

18. The compound of claim 16 , wherein R 1 is methane-diyl.

19. The compound of claim 16 , wherein R 2 is selected from an unsubstituted moiety of any one of Formula (2d.1), (2d2), (2d.4), (2d.5) and (2d.5′).

20. The compound of claim 16 , wherein R 2 is selected from a substituted moiety of any one of Formula (2d.1), (2d2), (2d.4), (2d.5) and (2d.5′).

21. The compound of claim 16 , wherein R 2 has the structure of Formula (2d.1) or Formula (2d.2):

22. The compound of claim 16 , wherein R 2 is a moiety of Formula (2d.4):

23. The compound of claim 16 , wherein R 2 has the structure of Formula (2d.5) or Formula (2d.5′):

24. The compound of claim 16 , wherein the compound is selected from:

N-(4-((1,4-oxazepan-4-yl)methyl)phenyl)-4-chlorobenzamide (1);

4-chloro-N-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)benzamide (7); and

4-chloro-N-(4-(((2S,6S)-2,6-dimethylmorpholino)methyl)phenyl)benzamide (8),

or a pharmaceutically acceptable salt of any of the foregoing.

25. A pharmaceutical composition comprising the compound of claim 16 or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the etiology of the disease is associated with up-regulation of the p38α MAPK protein, with the down-regulation of the p38α MAPK protein, or with both the up-regulation and the down-regulation of the p38α MAPK protein.

27. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from cancer, an inflammatory disease, and autoimmune disease, and a viral disease.

28. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

29. A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

30. A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the pharmaceutical composition of claim 25 , wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.