PPAR-sparing compounds for the treatment of metabolic diseases

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Each of R 1 and R 2 is independently selected from —H, —C 1-6 alkyl, aryl, 5-10 membered heteroaryl, —C 3-6 cycloaliphatic, 3-8 membered heterocycloaliphatic, —CH 2 -aryl, —CH 2 -5-10membered heteroaryl, —CH 2 —C 3-6 cycloaliphatic, —CH 2 -3-8 membered heterocycloaliphatic, each of which is optionally substituted with 1-3 groups selected from halo, —OH, or phenyl,

or R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 5-8 membered saturated or partially unsaturated heterocyclic ring that includes an N atom, an O atom, and up to 1 additional heteroatom selected from N, O, or S;

R 3 is —C 1-6 alkyl optionally substituted with 1-3 groups selected from halo, —OH, or phenyl;

each of R 4 and R 5 is independently selected from —H, —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH,

or R 4 and R 5 together form oxo or ═N—O—R 7 ;

Ring A is a 5-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from N, O, or S, wherein ring A is optionally substituted with 1-3 of R 6 ;

each R 6 is independently halo, —H, —CN, —OR 7 , —NO 2 , —C 1-6 alkyl, aryl, 5-10 membered heteroaryl, —S(O) 2 R 7 , or —C(O)R 7 , each of which is optionally substituted with 1-3 groups selected from halo or —OH; and

each R 7 is independently —H, —C 1-6 alkyl, —C 3-8 cycloalkyl, or phenyl.

2. The compound of claim 1 , wherein R 1 is —H or —C 1-6 alkyl.

3. The compound of claim 1 , wherein R 2 is —H, —C 1-6 alkyl, aryl, 5-10membered heteroaryl, —C 3-6 cycloaliphatic, or 3-8 membered heterocycloaliphatic, each of which is optionally substituted with 1-3 groups selected from halo, —OH, or phenyl.

4. The compound of claim 3 , wherein R 2 is —H or —C 1-6 alkyl.

5. The compound of claim 1 , wherein R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 5-8 membered saturated or partially unsaturated heterocyclic ring that includes an N atom, an O atom, and up to 1 additional heteroatom selected from N, O, or S.

6. The compound of claim 1 , wherein R 3 is —C 1-3 alkyl optionally substituted with 1-3 groups selected from halo, —OH, or phenyl.

7. The compound of claim 1 , wherein one of R 4 and R 5 is H and the other is independently selected from —H or —OH, or R 4 and R 5 together form oxo.

8. The compound of claim 1 , wherein ring A is a 6-membered, saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from N, O, and S, optionally substituted with 1-3 of R 6 .

9. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIa-1:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein

R 4a is independently selected from —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH.

12. The compound of claim 11 , wherein R 4a is —OH.

13. The compound of claim 1 , wherein the compound of Formula H is a compound of Formula IIb-1:

or a pharmaceutically acceptable salt thereof, wherein

R 4a is independently selected from —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH.

14. The compound of claim 13 , wherein R 4a is —OH.

15. The compound of claim 13 , wherein the compound of Formula IIb-1 is a compound of Formula IIb-1a, IIb-1b, IIb-1c, or IIb-1d:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIb-2:

or a pharmaceutically acceptable salt thereof, wherein

R 4a is independently selected from —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH.

17. The compound of claim 16 , wherein R 4a is —OH.

18. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIb-3:

or a pharmaceutically acceptable salt thereof, wherein

R 4a is independently selected from —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH.

19. The compound of claim 18 , wherein R 4a is —OH.

20. The compound of claim 1 , wherein the compound of Formula II is a compound of Formula IIb-4:

or a pharmaceutically acceptable salt thereof, wherein

R 4a is independently selected from —OH, —NH 2 , —NHC(O)R 7 , —NHC(O)OR 7 , —NHS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , —C 1-6 alkyl, each of which is optionally substituted with 1-3 groups selected from halo or —OH.

21. The compound of claim 20 , wherein R 4a is —OH.

22. A compound selected from

Compound

Structure

2

8

10

11

12

13

14

15

16

17

18

19

20

21

.

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