Pyrimidine cyclohexenyl glucocorticoid receptor modulators

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, or an isomer thereof,

wherein

R 1 is H or C 1-6 alkyl;

L 1 is C 1-4 alkylene;

Ar 1 is a C 6-12 aryl or 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1-3 R a groups;

each R a is independently H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —SO 2 R a1 , or —NR a1 R a2 ;

R a1 and R a2 are each independently H or C 1-4 alkyl; or R a1 and R a2 when attached to a nitrogen atom are combined to form a 3-6 membered heterocycle having 1-2 heteroatoms selected from N, O, and S, which is optionally substituted with 1-2 R a3 ;

each R a3 is independently H, halogen, C 1-4 alkyl, or C 1-4 alkoxy;

Ar 2 is a C 6-12 aryl or 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, wherein the aryl is substituted with 1-4 R b groups, and wherein the heteroaryl is optionally substituted with 1-4 R b groups;

each R b is independently halogen, CN, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, —OR b4 , —NR b1 R b2 , —C(O)R b1 , —C(O)OR b1 , —OC(O)R b1 , —C(O)NR b1 , R b2 , —NR b1 C(O)R b2 , —SO 2 R b1 , —SO 2 NR b1 R b2 , or C 3-6 cycloalkyl;

alternatively, two R b groups on adjacent ring atoms can be combined to form a C 5-8 cycloalkyl or a 5-8 membered heterocycle having 1-2 heteroatoms selected from N, O, and S;

R b1 and R b2 are each independently H or C 1-4 alkyl; or R b1 and R b2 when attached to a nitrogen atom are combined to form a 3-6 membered heterocycle having 1-2 heteroatoms selected from N, O, and S, which is optionally substituted with 1-2 R b3 ;

each R b3 is independently H, halogen, C 1-4 alkyl, or C 1-4 alkoxy; and

each R b4 is independently C 1-4 hydroxyalkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-C 1-4 alkyl.

2. The compound of claim 1 , having formula Ia:

3. The compound of claim 1 , wherein Ar 1 is phenyl, pyridinyl, or thiazolyl, each of which is optionally substituted with 1-2 R a groups.

4. The compound of claim 1 , wherein Ar 1 is phenyl, which is optionally substituted with 1-2 R a groups.

5. The compound of claim 1 , wherein each R a is independently H, F, Cl, CN, Me, Et, OMe, CF 3 , NH 2 , or N(Me) 2 .

6. The compound of claim 1 , wherein each R a is independently H, F, CF 3 , or 1-pyrrolidinyl.

7. The compound of claim 1 , having formula Ib:

8. The compound of claim 1 , wherein Ar 2 is phenyl, pyridinyl, pyrimidiniyl, thiazolyl, pyrazolyl, indazolyl, benzothiazolyl, benzopyrazolyl, or [1,2,4]triazolo[4,3-a]pyridinyl, wherein the phenyl is substituted with 1-2 R b groups, and wherein each pyridinyl, pyrimidiniyl, thiazolyl, pyrazolyl, indazolyl, benzothiazolyl, benzopyrazolyl, or [1,2,4]triazolo[4,3-a]pyridinyl is optionally substituted with 1-2 R b groups.

9. The compound of claim 1 , wherein Ar 2 is phenyl, which is substituted with 1-2 R b groups.

10. The compound of claim 1 , having formula Ic:

11. The compound of claim 1 , wherein Ar 2 is pyridin-3-yl, which is optionally substituted with 1-2 R b groups.

12. The compound of claim 1 , having formula Id:

13. The compound of claim 1 , wherein

each R b is independently F, Cl, CN, Me, Et, nPr, iPr, nBu, iBu, sBu, tBu, OMe, OEt, OnPr, OiPr, CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CF 3 , —CH 2 OH, —OCH 2 CH 2 OH, —O-cyclopropyl, —O-cyclobutyl, —O-cyclopentyl, —O-cyclohexyl, —O-cyclopropylmethyl, —O-cyclobutylmethyl, —O-cyclopentylmethyl, —O-cyclohexylmethyl, —NH 2 , —NHMe, —NMe 2 , —SO 2 Me, —SO 2 Et, —S(O) 2 iPr, —S(O) 2 NHMe, —S(O) 2 NMe 2 , 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, —C(O)-1-pyrrolidinyl, —C(O)-1-piperidinyl, —C(O)-1-piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein

each of 1-pyrrolidinyl, 1-piperidinyl, and 1-piperazinyl is optionally substituted with 1-2 R b3 ; and

each R b3 is independently H, F, Me, or OMe.

14. The compound of claim 1 , wherein

each R b is independently F, Cl, CN, Me, Et, iBu, OMe, OEt, OiPr, CF 3 , OCHF 2 , OCF 3 , OCH 2 CF 3 , —CH 2 OH, —OCH 2 CH 2 OH, —O-cyclopropyl, —O-cyclopropylmethyl, —NMe 2 , —S(O) 2 Me, —S(O) 2 Et, —S(O) 2 iPr, —S(O) 2 NHMe, —S(O) 2 NMe 2 , 1-pyrrolidinyl, 1-piperidinyl, 4,4-diflouro-1-piperidinyl, 3,3-dimethyl-1-piperidinyl, 3-methyl-1-piperidinyl, 3-methoxy-1-piperidinyl, —C(O)-1-pyrrolidinyl, —C(O)-4-methyl-1-piperazinyl, or cyclopropyl.

15. The compound of claim 1 , wherein each R b is independently F, Cl, CN, Me, CF 3 , OCF 3 , or —CH 2 OH.

16. The compound of claim 1 , wherein R 1 is H.

17. The compound of claim 1 , selected from the group consisting of:

18. The compound of claim 1 , selected from the group consisting of:

19. The compound of claim 1 , selected from the group consisting of:

20. The compound of claim 17 , selected from the group consisting of:

21. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a compound of claim 1 .

22. The compound of claim 17 , having the structure

23. The compound of claim 17 , having the structure

24. The compound of claim 17 , having the structure

25. The compound of claim 17 , having the structure

26. The compound of claim 17 , having the structure

27. The compound of claim 17 , having the structure

28. The compound of claim 17 , having the structure

29. The compound of claim 17 , having the structure

30. The compound of claim 17 , having the structure

31. The compound of claim 17 , having the structure

32. The compound of claim 17 , having the structure