Anti-fibrotic pyridinones

1. A method of treating a fibrotic condition selected from pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis, comprising administering a therapeutically effective amount of a compound having the structure of Formula (III):

or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein

R 1 is selected from the group consisting of C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;

R 3 is selected from the group consisting of hydrogen, —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n —(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;

ring A is

optionally substituted with one or more R 4 , wherein R 17 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C-carboxy, acyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 ,

each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;

each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;

each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;

each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , —CN, and —NO 2 ;

each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;

each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;

each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;

each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;

R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;

R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;

each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;

Z is selected from oxygen and sulfur;

each n is 0; and

the bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.

2. The method of claim 1 , wherein

R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ; and

each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 .

3. The method of claim 1 , wherein R 1 is selected from C 6-10 aryl optionally substituted with one or more R 4 , or 5 to 6 membered heteroaryl optionally substituted with one or more R 4 .

4. The method of claim 3 , wherein R 1 is phenyl optionally substituted with one or more R 4 .

5. The method of claim 3 , wherein R 1 is pyridazinyl optionally substituted with one or more R 4 .

6. The method of claim 3 , wherein R 1 is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .

7. The method of claim 1 , wherein R 3 is —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .

8. The method of claim 7 , wherein R 3 is phenyl, optionally substituted with one or more R 9 .

9. The method of claim 7 , wherein R 3 is unsubstituted.

10. The method of claim 8 , wherein R 9 is selected from cyano, halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.

11. The method of claim 10 , wherein R 9 is selected from cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

12. The method of claim 1 , wherein R 17 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, —(CH 2 ) 2 F, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 2 H 5 , —(CH 2 ) 2 OC 3 H 7 , —C(O)O-t-Bu, —C(O)CH 3 or benzyl.

13. The method of claim 1 , wherein R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or C 7-14 aralkyl optionally substituted with one or more R 11 , or two geminal R 4 together are oxo.

14. The method of claim 13 , wherein R 4 is selected from fluoro, methyl, trifluoromethyl, —(CH 2 ) 2 OH, benzyl, or two geminal R 4 together are oxo.

15. The method of claim 1 , wherein ring A is unsubstituted.

16. The method of claim 1 , wherein Z is oxygen.

17. The method of claim 1 , wherein the bonds represented by a solid and dashed line are double bonds.

18. The method of claim 1 , wherein the compound is selected from the group consisting of

or pharmaceutically acceptable salts thereof.

19. The method of claim 18 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The method of claim 18 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

21. The method of claim 18 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. The method of claim 18 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the fibrotic condition is idiopathic pulmonary fibrosis.

24. The method of claim 1 , wherein the compound is administered by inhalation.