Granted Patent B2

US 7,732,455 · App. 11/956,876 · Granted Jun 8, 2010

Abstract

Claims (233)

1. A compound of formula I:

wherein:

R is H, (C 1 -C 5 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 5 )alkenyl, or (C 3 -C 5 )alkynyl;

R 1 and R 2 are independently H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heterocycle, (C 4 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, or (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-;

X is selected from: imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyrimidinyl, indolyl, isoquinolyl, and quinolyl;

Z is —OR 3 , —SR 3 , halo, —S(O) m —NR 4 R 5 , —NR 4 R 5 , or (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 1 -C 8 )alkyl, (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

each Z 1 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —OR 6 , —SR 6 , halo, R 6 O(C 1 -C 8 )alkyl, R 7 R 8 N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR 7 R 8 , R 7 R 8 N(C 1 -C 8 )alkyl, —C(O)R 6 , —COOR 6 , and —C(O)NR 7 R 8 ;

R 3 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —C(O)R 6 , or —C(O)NR 7 R 8 ;

R 4 and R 5 are independently H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 6 -C 18 )polycycloalkyl, (C 6 -C 18 )polycycloalkyl(C 1 -C 8 )alkyl-, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, —NR 7 R 8 , (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —((CH 2 ) 2-4 )Y) q —(CH 2 ) 2-4 —X 1 , —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 , or —S(O) 2 NR 7 R 8 ; or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )— in the ring, and wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 , or —NR 7 R 8 ; and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )—;

wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocycle or heteroaryl groups of R 1 , R 2 , R 3 , R 4 and R 5 groups are optionally substituted with one or more substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

wherein R 6 is H, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl, (C 4 -C 10 )heteroaryl(C 1 -C 8 )alkyl-; wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

wherein R 7 , R 8 and R 9 are independently H, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl; —COOR a , —C(O)R a , or —C(O)NR b R c wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine —N(R b )— in the ring;

R a is H, or (C 1 -C 6 )alkyl; R b and R c are each independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkylthio, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring; and

where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, or 2; and q is 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R is H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl.

3. The compound of claim 1 , wherein R is H, methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br, or —CH 2 —CH 2 —CH 2 —F.

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

5. The compound of claim 1 , wherein R 1 is H, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, or phenyl(C 1 -C 4 )alkyl.

6. The compound of claim 1 , wherein R 1 is (C 3 -C 6 )cycloalkyl and (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-.

7. The compound of claim 1 , wherein R 1 is cyclopropyl or cyclopropylmethyl.

8. The compound of claim 1 , wherein R 1 is H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, benzyl, or (methoxyphenyl)ethyl.

9. The compound of claim 1 , wherein R 1 is ethyl, n-propyl or allyl.

10. The compound of claim 1 , wherein R 2 is H, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, phenyl(C 1 -C 4 )alkyl, or (methoxyphenyl)ethyl.

11. The compound of claim 1 , wherein R 2 is (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-.

12. The compound of claim 1 , wherein R 2 is cyclopropyl or cyclopropylmethyl.

13. The compound of claim 1 , wherein R 2 is H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, or benzyl.

14. The compound of claim 1 , wherein R 2 is ethyl, n-propyl or allyl.

15. The compound of claim 1 , wherein Z is —O(C 1 -C 4 )alkyl, —O(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-O—, —NR 4 R 5 , F, Cl, Br, or I.

16. The compound of claim 1 , wherein R 4 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl-, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

17. The compound of claim 1 , wherein R 4 is H, (C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

18. The compound of claim 1 , wherein R 4 is H, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

19. The compound of claim 1 , wherein R 4 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

20. The compound of claim 1 , wherein R 5 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl-, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

21. The compound of claim 1 , wherein R 5 is H, (C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

22. The compound of claim 1 , wherein R 5 is H, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

23. The compound of claim 1 , wherein R 5 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

24. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen to which they are attached, is a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

25. The compound of claim 1 , wherein R 6 is (C 1 -C 6 )alkyl, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )-alkyl-, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, nitro, (C 1 -C 8 )alkyl, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R a N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

26. The compound of claim 1 , wherein R 6 is (C 6 -C 10 )aryl, (C 5 -C 6 )heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, nitro, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —COOR a , and —C(O)NR b R c .

27. The compound of claim 1 , wherein R 6 is pyridyl, optionally substituted with F, Cl, Br, I, CF 3 , cyano, nitro, —COOR a , or —CONHR a .

28. The compound of claim 1 , wherein R 1 and R 2 are independently H, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, or phenyl(C 1 -C 4 )alkyl.

29. The compound of claim 1 , wherein R is H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl; and R 1 and R 2 are independently H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, phenyl, phenethyl, or benzyl.

30. The compound of claim 1 , wherein R is H, methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br, or —CH 2 —CH 2 —CH 2 —F; and R 1 and R 2 are independently H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, or (methoxyphenyl)ethyl.

31. The compound of claim 1 , wherein Z is O(C 1 -C 4 )alkyl, —OC(O)NR 7 R 8 , —NR 4 R 5 , F, Cl, Br, or I, wherein R 4 and R 5 are independently H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 7 -C 12 )aralkyl, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 6 R 7 .

32. The compound of claim 1 , wherein Z is —NR 4 R 5 .

33. The compound of claim 1 , wherein R 4 and R 5 together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

34. The compound of claim 1 , wherein R 4 and R 5 are independently H, (C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

35. The compound of claim 1 , wherein R 4 and R 5 are independently H, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

36. The compound of claim 1 , wherein R 6 is methyl, methoxy, or pyridyl, and R 7 is phenyl, fluorophenyl, or methoxyphenyl.

37. The compound of claim 1 , wherein:

R is H, methyl, or ethyl;

R 1 and R 2 are independently methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl; and

Z is (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

38. The compound of claim 1 , wherein Z is selected from the group consisting of:

39. The compound of claim 1 , wherein R 1 and R 2 are n-propyl; R is hydrogen and n is zero.

40. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 1 ; and

(b) a pharmaceutically acceptable excipient.

41. A method for treating asthma comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

42. A method for improving insulin sensitivity and diabetic retinopathy, comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

43. A compound of formula I:

wherein:

R is selected from H, (C 1 -C 5 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 5 )alkenyl, and (C 3 -C 5 )alkynyl;

R 1 and R 2 are independently H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 4- C 10 )heterocycle, (C 4- C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5- C 10 )heteroaryl, or (C 5- C 10 )heteroaryl(C 1 -C 8 )alkyl-;

X is selected from: imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyrimidinyl, indolyl, isoquinolyl, and quinolyl;

Z is —NR 4 R 5 or (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 1 -C 8 )alkyl, (C 6- C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

each Z 1 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —OR 6 , —SR 6 , halo, R 6 O(C 1 -C 8 )alkyl, R 7 R 8 N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR 7 R 8 , R 7 R 8 N(C 1 -C 8 )alkyl, —C(O)R 6 , —COOR 6 , and —C(O)NR 7 R 8 ;

R 3 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —C(O)R 6 , or —C(O)NR 7 R 8 ;

R 4 and R 5 are independently (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 6 -C 18 )polycycloalkyl, (C 6 -C 18 )polycycloalkyl(C 1 -C 8 )alkyl-, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, —NR 7 R 8 , (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —((CH 2 ) 2-4 )Y) q —(CH 2 ) 2-4 —X 1 , —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 , or —S(O) 2 NR 7 R 8 ; or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )— in the ring, and wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 , or —NR 7 R 8 ; and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )—;

wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocycle or heteroaryl groups of R 1 , R 2 , R 3 , R 4 and R 5 groups are optionally substituted with one or more substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

wherein R 6 is H, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl, (C 4 -C 10 )heteroaryl(C 1 -C 8 )alkyl-; wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

wherein R 7 , R 8 and R 9 are independently H, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl; —COOR a , —C(O)R a , or —C(O)NR b R c wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine —N(R b )— in the ring;

R a is H, or (C 1 -C 6 )alkyl; R b and R c are each independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkylthio, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, heteroaryl, or heteroaryl(C i -C 6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring; and

where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, or 2; and q is 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof

44. The compound of claim 43 , wherein R is H.

45. The compound of claim 43 , wherein R 1 is cyclopropyl or cyclopropylmethyl.

46. The compound of claim 43 , wherein R 2 is cyclopropyl or cyclopropylmethyl.

47. The compound of claim 43 , wherein R 4 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

48. The compound of claim 43 , wherein R 5 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

49. The compound of claim 43 , wherein R 4 and R 5 taken together with the nitrogen to which they are attached, is a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6- C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

50. The compound of claim 43 , wherein R 6 is pyridyl, optionally substituted with F, Cl, Br, I, CF 3 , cyano, nitro, —COOR a , or —CONHR a .

51. The compound of claim 43 , wherein R 4 and R 5 together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6- C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

52. The compound of claim 43 , wherein R 6 is methyl, methoxy, or pyridyl, and R 7 is phenyl, fluorophenyl, or methoxyphenyl.

53. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 2 ; and

(b) a pharmaceutically acceptable excipient.

54. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 3 ; and

(b) a pharmaceutically acceptable excipient.

55. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 4 ; and

(b) a pharmaceutically acceptable excipient.

56. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 5 ; and

(b) a pharmaceutically acceptable excipient.

57. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 6 ; and

(b) a pharmaceutically acceptable excipient.

58. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 7 ; and

(b) a pharmaceutically acceptable excipient.

59. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 8 ; and

(b) a pharmaceutically acceptable excipient.

60. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 9 ; and

(b) a pharmaceutically acceptable excipient.

61. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 10 ; and

(b) a pharmaceutically acceptable excipient.

62. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 11 ; and

(b) a pharmaceutically acceptable excipient.

63. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 12 ; and

(b) a pharmaceutically acceptable excipient.

64. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 13 ; and

(b) a pharmaceutically acceptable excipient.

65. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 14 ; and

(b) a pharmaceutically acceptable excipient.

66. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 15 ; and

(b) a pharmaceutically acceptable excipient.

67. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 16 ; and

(b) a pharmaceutically acceptable excipient.

68. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 17 ; and

(b) a pharmaceutically acceptable excipient.

69. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 18 ; and

(b) a pharmaceutically acceptable excipient.

70. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 19 ; and

(b) a pharmaceutically acceptable excipient.

71. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 20 ; and

(b) a pharmaceutically acceptable excipient.

72. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 21 ; and

(b) a pharmaceutically acceptable excipient.

73. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 22 ; and

(b) a pharmaceutically acceptable excipient.

74. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 23 ; and

(b) a pharmaceutically acceptable excipient.

75. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 24 ; and

(b) a pharmaceutically acceptable excipient.

76. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 25 ; and

(b) a pharmaceutically acceptable excipient.

77. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 26 ; and

(b) a pharmaceutically acceptable excipient.

78. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 27 ; and

(b) a pharmaceutically acceptable excipient.

79. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 28 ; and

(b) a pharmaceutically acceptable excipient.

80. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 29 ; and

(b) a pharmaceutically acceptable excipient.

81. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 30 ; and

(b) a pharmaceutically acceptable excipient.

82. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 31 ; and

(b) a pharmaceutically acceptable excipient.

83. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 32 ; and

(b) a pharmaceutically acceptable excipient.

84. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 33 ; and

(b) a pharmaceutically acceptable excipient.

85. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 34 ; and

(b) a pharmaceutically acceptable excipient.

86. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 35 ; and

(b) a pharmaceutically acceptable excipient.

87. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 36 ; and

(b) a pharmaceutically acceptable excipient.

88. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 37 ; and

(b) a pharmaceutically acceptable excipient.

89. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 38 ; and

(b) a pharmaceutically acceptable excipient.

90. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 39 ; and

(b) a pharmaceutically acceptable excipient.

91. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 43 ; and

(b) a pharmaceutically acceptable excipient.

92. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 44 ; and

(b) a pharmaceutically acceptable excipient.

93. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 45 ; and

(b) a pharmaceutically acceptable excipient.

94. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 46 ; and

(b) a pharmaceutically acceptable excipient.

95. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 47 ; and

(b) a pharmaceutically acceptable excipient.

96. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 48 ; and

(b) a pharmaceutically acceptable excipient.

97. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 49 ; and

(b) a pharmaceutically acceptable excipient.

98. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 50 ; and

(b) a pharmaceutically acceptable excipient.

99. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 51 ; and

(b) a pharmaceutically acceptable excipient.

100. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 52 ; and

(b) a pharmaceutically acceptable excipient.

101. A method for treating asthma comprising administering an effective amount of a compound of claim 43 to a mammal in need of such treatment.

102. A method for improving insulin sensitivity and diabetic retinopathy, comprising administering an effective amount of a compound of claim 43 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

Assignments (10)