Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia

• US 6,251,936 B1
• Filed: 05/10/1999
• Issued: 06/26/2001
• Est. Priority Date: 05/12/1998
• Status: Expired due to Fees

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Wrobel, Jay E., Dietrich, Arlene J., Antane, Madelene M.
• Primary Examiner(s): Gerstl, Robert
• Application Number:
  US09/307,687
• Time in Patent Office: 778 Days
• Field of Search: 548/427, 549/43, 549/48, 549/458, 544/146, 514/443, 514/410, 514/468, 514/232.8
• US Class Current: 514/443
• CPC Class Codes: C07D 307/92 Naphthofurans; Hydrogenated naphthofurans
• CPC Class Codes: C07D 333/56 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/74 Naphthothiophenes

Abstract

This invention provides compounds of Formula I having the structure

E is S, SO, SO₂, O, or NR^1c;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^2b or —COR^2c;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^1a, —NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —CH═CR⁹—CR¹⁰═CR¹¹—;

or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Claims

1. A compound of formula I having the structure

A is hydrogen, halogen, or OH;

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, —

NR¹CO₂R^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —

COR^1b or OR;

R is hydrogen, alkyl of 1-6 carbon atoms, —

COR¹, —

(CH₂)_nCO₂R¹, —

CH(R^1a)CO₂R¹, —

SO₂R¹, —

(CH₂)_mCH(OH)CO₂R¹, —

(CH₂)_mCOCO₂R¹, —

(CH₂)_mCH═

CHCO₂R¹, or —

(CH₂)_mO(CH₂)_oCO₂R¹;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH₂CO₂R^1′

;

R¹′

is hydrogen or alkyl of 1-6 carbon atoms

E is S, SO, SO₂, or O;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —

OCH₂CO₂R^2b or —

COR^2c;

Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, —

OR³, SR³, NR³R^3a, —

COR^3b, morpholine or piperidine;

R^1a, R², R^2a R³, R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

R^1b is alkyl of 1-6 carbon atoms or aryl;

R^2b is hydrogen, alkyl of 1-6 carbon atoms;

R^2c and R^3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

C is hydrogen, halogen or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R₅)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, or —

(CH2)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —

CH₂(3-pyridyl), —

CH₂CO₂H, or —

(CH₂)_nG;

G is NR^6aR^7a, NR^6aCOR^7a,

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —

PO₃(R⁶)₂, —

CH₂OH, —

CONR^6bCHR^7b, —

CH₂NR^6bCHR^7bCO₂R⁶;

—

CH₂OCHR^7bCO₂R⁶—

CH₂Br, or —

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R⁷, R^7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R^6b is hydrogen or —

COR^6c;

R^6c is alkyl of 1-6 carbon atoms or aryl;

R^7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CR¹¹—

;

R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms;

m is 1 to 4;

n is 1 or 2;

p is 1 to 4;

q is 1 to 4;

with the proviso that when E is O, Y is hydrogen, Ar is

and A, B, C, and D are hydrogen,

then Z¹, Z², and X are not all hydrogen,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein

A is hydrogen or halogen

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR;

R is hydrogen or alkyl of 1-6 carbon atoms;

E is S, or O;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, or 2-N,N-dimethylaminoethylsulfanyl;

R¹, R^1a, R², R^2a, R³, and R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

Y is hydrogen, halogen, OR³, SR³, NR³R^3a, or morpholine;

C is hydrogen, halogen, or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R⁵)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, —

(CH₂)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —

CH₂(3-pyridyl);

W is CO₂R⁶, —

CONH₂, —

CONHOH, 5-tetrazole, or —

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R^6b, R⁷, R^7a, and R^7b are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CH—

;

R⁹ and R¹⁰ are each, independently, hydrogen, or alkyl of 1-6 carbon atoms;

p is 1 to 4;

q is 1 to 4;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein

A is hydrogen;

B and D are each, independently, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8 carbon atoms;

E is S or O;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, arylsulfanyl;

Y is hydrogen, —

NR¹R², or morpholine;

R¹ and R² are each, independently, hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

C is OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R⁵)W, or 5-thiazolidine-2,4-dione;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl);

W is —

CO₂R⁶, —

CONH₂, —

CONHOH, 5-tetrazole, —

PO₃(R⁶)₂, or —

CONR⁶CHR⁶CO₂R⁶;

R⁶ is hydrogen or alkyl of 1-6 carbon atoms;

Z¹ and Z² are taken together as a diene unit having the formula —

CH═

CH—

H═

CH—

;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, which is (R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, which is (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, which is (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, which is [4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-acetic acid or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, which is (R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6sec-butyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, which is (R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, which is (R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, which is (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, which is (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyric acid or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, which is (S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyric acid or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, which is 2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionic acid or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, which is [2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, which is 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4yl)-phenol or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, which is 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, which is (R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, which is (2R)-2-[4-9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionic acid.

25. The compound of claim 1, which is (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionic acid.

26. The compound of claim 1, which is {(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-acetic acid.

27. The compound of claim 1, which is {(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-acetic acid.

28. The compound of claim 1, which is (2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, which is (2S)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, which is {(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-acetic acid or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, which is (R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, which is (R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionic acid or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, which is (R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionic acid or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1, which is (R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1, which is 2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, which is (R)-2-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, which is (R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, which is (2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1, which is 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol;

4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

4-(9-bromo-3-methyl-2-morpholin-4-yl)methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate;

4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

2-amino-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

2-amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-acetic acid;

(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenoxy]-propanoic acid;

2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionic acid;

2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol;

(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionic acid;

(R)-2-[2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid;

(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid;

(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionic acid;

(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionic acid;

(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionic acid;

3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine;

or [3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-acetic acid;

(2R)-2-[4-(9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid;

(R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionic acid;

4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol;

4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyric acid;

2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-]furan-4-yl)-phenol;

Acetic acid 2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenyl ester;

(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionic acid;

4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyric acid;

4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6ethyl-phenoxy]-butyramide;

4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol;

[9-Bromo-4-(4-methoxy-3,5-dimethylphenyl)-3-methylnaphtho[2,3-b]thien-2-yl]methyl acetate;

4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenyl acetate;

Acetic acid 4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester;

2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid;

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, which is acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

methanesulfonic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

methanesulfonic acid 4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

acetic acid 4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid methyl ester;

[3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-hydroxy-phenyl]-carbamic acid tert-butyl ester;

9-bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene;

or [3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-acetic acid methyl ester.

41. A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

A is hydrogen, halogen, or OH;

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, —

NR¹CO₂R^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —

COR^1b or OR;

R is hydrogen, alkyl of 1-6 carbon atoms, —

COR¹, —

(CH₂)_nCO₂R¹, —

CH(R^1a)CO₂R¹, —

SO₂R¹, —

(CH₂)_mCH(OH)CO₂R¹, —

(CH₂)_mCOCO₂R¹, —

(CH₂)_mCH═

CHCO₂R¹, or —

(CH₂)_mO(CH₂)_oCO₂R¹;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH₂CO₂R¹;

R^1′

is hydrogen or alkyl of 1-6 carbon atoms

E is S, SO, SO₂, O, or NR^1c;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —

OCH₂CO₂R^2b or —

COR^2c;

Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, —

OR³, SR³, NR³R^3a, —

COR^3b, morpholine or piperidine;

R^1a, R^1c, R², R^2a R³, R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

R^1b is alkyl of 1-6 carbon atoms or aryl;

R^2b is hydrogen, alkyl of 1-6 carbon atoms;

R^2c and R^3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

C is hydrogen, halogen or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R₅)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, or —

(CH₂)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —

CH₂(3-pyridyl), —

CH₂CO₂H, or —

(CH₂)_nG;

G is NR^6aR^7a, NR^6aCOR^7a,

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —

PO₃(R⁶)₂, —

CH₂OH, —

CONR^6bCHR^7b, —

CH₂NR^6bCHR^7bCO₂R⁶, —

CH₂OCHR^7bCO₂R⁶ or —

CH₂Br,—

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R⁷, R^7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R^6b is hydrogen or COR^6c;

R^6c is alkyl of 1-6 carbon atoms or aryl;

R^7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CR¹¹—

;

R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

m is 1 to 4

n is 1 or 2;

p is 1 to 4;

q is 1 to 4;

or a pharmaceutically acceptable salt thereof.

42. A method of treating or inhibiting type II diabetes in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

A is hydrogen, halogen, or OH;

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, —

NR¹CO₂R^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —

COR^1b or OR;

R is hydrogen, alkyl of 1-6 carbon atoms, —

COR¹, —

(CH₂)_nCO₂R¹, —

CH(R^1a)CO₂R¹, —

SO₂R¹, —

(CH₂)_mCH(OH)CO₂R¹, —

(CH₂)_mCOCO₂R¹, —

(CH)_mCH═

CHCO₂R¹, or —

(CH₂)_mO(CH₂)_oCO₂R¹;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH₂CO₂R^1′

;

R^1′

is hydrogen or alkyl of 1-6 carbon atoms

E is S, SO, SO₂, O, or NR^1c;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —

OCH₂CO₂R^2b or —

COR^2c;

Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, —

OR³, SR³, NR³R^3a, —

COR^3b, morpholine or piperidine;

R^1a, R^1c, R², R^2a R³, R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

R^1b is alkyl of 1-6 carbon atoms or aryl;

R^2b is hydrogen, alkyl of 1-6 carbon atoms;

R^2c and R^3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

C is hydrogen, halogen or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R₅)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, or —

(CH₂)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —

CH₂(3-pyridyl), —

CH₂CO₂H, or —

(CH₂)_nG;

G is NR^6aR^7a, NR^6aCOR^7a,

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —

PO₃(R⁶)₂, —

CH₂OH, —

CONR^6bCHR^7b, —

CH₂NR^6bCHR^7bCO₂R⁶, —

CH₂OCHR^7bCO₂R⁶ —

CH₂Br, or —

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R⁷, R^7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R^6b is hydrogen or —

COR^6c;

R^6c is alkyl of 1-6 carbon atoms or aryl;

R^7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CR¹¹—

;

R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

m is 1 to 4

n is 1 or 2;

p is 1 to 4;

q is 1 to 4;

or a pharmaceutically acceptable salt thereof.

43. A method of modulating glucose levels in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

A is hydrogen, halogen, or OH;

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, —

NR¹CO₂R^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —

COR^1b or OR;

R is hydrogen, alkyl of 1-6 carbon atoms, —

COR¹, —

(CH₂)_nCO₂R¹, —

CH(R^1a)CO₂R¹, —

SO₂R¹, —

(CH₂)_mCH(OH)CO₂R¹, —

(CH₂)_mCOCO₂R¹, —

(CH₂)_mCH═

CHCO₂R¹, or —

(CH₂)_mO(CH₂)_oC₂R¹;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH₂CO₂R^1′

;

R^1′

is hydrogen or alkyl of 1-6 carbon atoms

E is S, SO, SO₂, O, or NR^1c;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —

OCH₂CO₂R^2b or —

COR^2c;

Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, —

OR³, SR³, NR³R^3a, —

COR^3b, morpholine or piperidine;

R^1a, R^1c, R², R^2a R³, R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

R^1b is alkyl of 1-6 carbon atoms or aryl;

R^2b is hydrogen, alkyl of 1-6 carbon atoms;

R^2c and R^3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

C is hydrogen, halogen or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R₅)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, or —

(CH2)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —

CH₂(3-pyridyl), —

CH₂CO₂H, or —

(CH₂)_nG;

G is NR^6aR^7a, NR^6aCOR^7a,

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —

PO₃(R⁶)₂, —

CH₂H, —

CONR^6bCHR^7b, —

CH₂NR^6bCHR^7bCO₂R⁶, —

CH₂OCHR^7bCO₂R⁶ —

CH₂Br, or —

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R⁷, R^7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R^6b is hydrogen or —

COR^6c;

R^6c is alkyl of 1-6 carbon atoms or aryl;

R^7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CR¹¹;

R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁹, R¹⁰, and R¹ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

m is 1 to 4

n is 1 or 2;

p is 1 to 4;

q is 1 to 4;

or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition which comprises a compound of formula I having the structure

A is hydrogen, halogen, or OH;

B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, —

NR¹CO₂R^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —

COR^1b or OR;

R is hydrogen, alkyl of 1-6 carbon atoms, —

COR¹, —

(CH₂)_nCO₂R¹, —

CH(R^1a)CO₂R¹, —

S₂R¹, —

(CH₂)_mCH(OH)CO₂R¹, —

(CH₂)_mCOCO₂R¹, —

(CH₂)_mCH═

CHCO₂R¹, or —

(CH₂)_mO(CH₂)_oCO₂R¹;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH₂CO₂R¹;

R¹ is hydrogen or alkyl of 1-6 carbon atoms

E is S, SO, SO₂, O or NR^1c;

X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;

arylalkoxy, nitro, amino, NR²R^2a, NR²COR^2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —

OCH₂CO₂R^2b or —

COR^2c;

Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkyl of 6-12 carbon atoms, —

OR³, SR³, NR³R^3a, —

COR^3b, morpholine or piperidine;

R^1a, R^1c, R², R^2aR³, R^3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

R^1b is alkyl of 1-6 carbon atoms or aryl;

R^2b is hydrogen, alkyl of 1-6 carbon atoms;

R^2c and R^3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

C is hydrogen, halogen or OR⁴;

R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —

CH(R₅)W, —

C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —

CH(R⁷)(CH₂)_mCO₂R⁶, —

COR⁶, —

PO₃(R⁶)₂, —

SO₂R⁶, —

(CH₂)_pCH(OH)CO₂R⁶, —

(CH₂)_pCOCO₂R⁶, —

(CH₂)_pCH═

CHCO₂R⁶, or —

(CH2)_pO(CH₂)_qCO₂R⁶;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —

CH₂(1H-imidazol-4-yl), —

CH₂(3-1H-indolyl), —

CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —

CH₂CH₂(1-oxo-,1,3-dihydro-isoindol-2-yl), —

CH₂(3-pyridyl), —

CH₂CO₂H, or —

(CH₂)_nG;

G is NR^6aR^7a, NR^6aCOR^7a,

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —

PO₃(R⁶)₂, —

CH₂OH, —

CONR^6bCHR^7b, —

CH₂NR^6bCHR^7bCO₂R⁶, —

CH₂OCHR^7bCO₂R⁶ —

CH₂Br, or —

CONR^6bCHR^7bCO₂R⁶;

R⁶, R^6a, R⁷, R^7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R^6b is hydrogen or —

COR^6c;

R^6c is alkyl of 1-6 carbon atoms or aryl;

R^7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;

Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —

NR¹R^1a, —

NR¹COR^1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unit having the formula —

CH═

CR⁹—

CR¹⁰═

CR¹¹;

R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

m is to 4

n is 1 or 2;

p is 1 to 4;

q is to 4;

or a pharmaceutically acceptable salt thereof.