HISTONE DEACETYLASE INHIBITORS

• US 20070173527A1
• Filed: 01/12/2007
• Published: 07/26/2007
• Est. Priority Date: 01/13/2006
• Status: Abandoned Application

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Brown, Jason, Vu, Phong, Stafford, Jeffrey, Bressi, Jerome, Kaldor, Stephen, Gangloff, Anthony, Jennings, Andrew, Skene, Robert
• Application Number:
  US11/622,669
• Publication Number:
  US 20070173527A1
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 235/28 Sulfur atoms
• CPC Class Codes: C07D 235/30 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Compounds, pharmaceutical compositions, kits and methods are provided for use with histone deacetylases (HDACs) that comprise a compound selected from the group consisting of: wherein the variables are as defined herein.

Claims

1. A compound comprising:

2. The compound according to claim 1 comprising:

3. The compound according to claim 1 comprising:

4. The compound according to claim 1 comprising:

5. The compound according to claim 1 comprising:

6. The compound according to claim 1 comprising:

7. The compound according to claim 1 comprising:

8. The compound according to claim 1 comprising:

9. The compound according to claim 1 comprising:

10. The compound according to claim 1 comprising:

11. The compound according to claim 1 comprising:

12. The compound according to claim 1, wherein L is selected from the group consisting of (C_1-6)alkylene, (C_2-6)alkenylene, and (C_2-6)alkynylene, each substituted or unsubstituted.

13. The compound according to claim 1, wherein L is a (C_1-4)alkylene, unsubstituted or substituted.

14. The compound according to claim 1, wherein L is a (C_1-3)alkylene, unsubstituted or substituted.

15. The compound according to claim 1, wherein L is a methylene, unsubstituted or substituted.

16. The compound according to claim 1, wherein at least one of R₁ and R₂ is H.

17. The compound according to claim 1, wherein R₁ and R₂ are both H.

18. The compound according to claim 1, wherein R₃ is H.

19. The compound according to claim 1, wherein R₄ is hydrogen, halo, perhalo(C_1-3)alkyl, amino, cyano, nitro, thio, (C_1-5)alkyl, (C_3-5)cycloalkyl, hetero(C_3-5)cycloalkyl, aryl(C_1-3)alkyl, heteroaryl (C_1-3)alkyl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, alkenyl, alkynyl, carbonyl, and imino, each substituted or unsubstituted.

20. The compound according to claim 5, wherein at least one of R₁₅ and R₁₆ is H.

21. The compound according to claim 5, wherein R₁₅ and R₁₆ are both H.

22. The compound according to claim 9, wherein at least one of R₁₅ and R₁₆ is H.

23. The compound according to claim 9, wherein R₁₅ and R₁₆ are both H.

24. The compound according to claim 1, wherein A₁ is phenylene.

25. The compound according to claim 1, wherein A₁ is 1,4-phenylene.

26. The compound according to claim 1, wherein Y₂ is CR₇R₈, or NR₉ where R₉ is not H.

27. The compound according to claim 1, wherein Y₂ is CR₇R₈, or NR₉ where R₉ is not H.

29. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.

30. The compound according to claim 1, wherein the compound is present in a mixture of stereoisomers.

31. The compound according to claim 1, wherein the compound comprises a single stereoisomer.

32. A pharmaceutical composition comprising as an active ingredient a compound according to claim 1.

33. The pharmaceutical composition according to claim 1, wherein the composition is a solid formulation adapted for oral administration.

34. The pharmaceutical composition according to claim 1, wherein the composition is a liquid formulation adapted for oral administration.

35. The pharmaceutical composition according to claim 1, wherein the composition is a tablet.

36. The pharmaceutical composition according to claim 1, wherein the composition is a liquid formulation adapted for parenteral administration.

37. The pharmaceutical composition comprising a compound according to claim 1, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.

38. A kit comprising:

a compound according to claim 1;

and

instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.

39. The kit according to claim 38, wherein the kit comprises the compound in a multiple dose form.

40. An article of manufacture comprising:

a compound according to claim 33;

and

packaging materials.

41. The article of manufacture according to claim 40, wherein the packaging material comprises a container for housing the compound.

42. The article of manufacture according to claim 41, wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.

43. The article of manufacture according to claim 40, wherein the article of manufacture comprises the compound in a multiple dose form.

44. A therapeutic method comprising:

administering a compound according to claim 1 to a subject.

45. A method of inhibiting histone deacetylase comprising:

contacting histone deacetylase with a compound according to claim 1.

46. A method of inhibiting histone deacetylase comprising:

causing a compound according to claim 1 to be present in a subject in order to inhibit histone deacetylase in vivo.

47. A method of inhibiting histone deacetylase comprising:

administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits histone deacetylase in vivo, the second compound being a compound according to claim 1.

48. A method of treating a disease state for which histone deacetylase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising:

causing a compound according to claim 1 to be present in a subject in a therapeutically effective amount for the disease state.

49. A method of treating a disease state for which histone deacetylase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising:

administering a first compound to a subject that is converted in vivo to a second compound according to claim 1, wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.

50. A method of treating a disease state for which histone deacetylase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising:

administering a compound according to claim 1, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.

51. A method for treating cancer comprising administering a composition according to claim 1 to a mammalian species in need thereof.

52. The method according to claim 50, wherein the cancer is selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi'"'"'s sarcoma, glioblastoma, non small-cell lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.

53. The method for treating inflammation, inflammatory bowel disease, psoriasis, or transplant rejection, comprising administering a compound according to claim 1 to a mammalian species in need thereof.

54. A method for treating arthritis comprising administering a compound according to claim 1 to a mammalian species in need thereof.

55. A method for treating degenerative diseases of the eye comprising administering a compound according to claim 1 to a mammalian species in need thereof.

56. A method for treating multiple sclerosis, amyotrophic lateral sclerosis, thyroid neoplasm or Alzheimer'"'"'s disease comprising administering a compound according to claim 1 to a mammalian species in need thereof.

28. A compound selected from the group consisting of:

N-(2-aminophenyl)-4-((benzo[d]thiazol-2-ylamino)methyl)benzamide;

4-((1H-benzo[d]imidazol-2-ylamino)methyl)-N-(2-aminophenyl)benzamide;

4-((1H-benzo[d]imidazol-2-ylthio)methyl)-N-(2-aminophenyl)benzamide;

4-((3H-imidazo[4,5-b]pyridin-2-yloxy)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

N-(2-aminophenyl)-3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

N-(2-aminophenyl)-3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

N-(2-aminophenyl)-3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

N-(2-aminophenyl)-4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

N-(2-amino-4-fluorophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

N-(2-amino-4-fluorophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

N-(2-amino-4-fluorophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-amino-4-fluorophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

N-(2-amino-4-fluorophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

3-acetamido-N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

3-acetamido-N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

3-acetamido-N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

3-acetamido-N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

3-acetamido-N-(2-aminophenyl)-4-((1-methyl-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

N-(2-aminophenyl)-4-((1-(piperidin-3-yl)-1H-benzo[d]imidazol-2-ylamino)methyl)benzamide;

N-(2-aminophenyl)-4-((1-(piperidin-3-yl)-1H-benzo[d]imidazol-2-yloxy)methyl)benzamide;

N-(2-aminophenyl)-4-((1-(piperidin-3-yl)-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((1-(piperidin-3-yl)-1H-benzo[d]imidazol-2-ylsulfinyl)methyl)benzamide;

N-(2-aminophenyl)-4-((1-(piperidin-3-yl)-1H-benzo[d]imidazol-2-ylsulfonyl)methyl)benzamide;

4-((1H-benzo[d]imidazol-2-ylsulfinyl)methyl)-N-(2-aminophenyl)benzamide;

4-((1H-benzo[d]imidazol-2-ylsulfonyl)methyl)-N-(2-aminophenyl)benzamide;

N-(2-aminophenyl)-4-((1-isopropyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

N-(2-aminophenyl)-4-((1-cyclohexyl-1H-benzo[d]imidazol-2-ylthio)methyl)benzamide;

4-((3H-imidazo[4,5-b]pyridin-2-ylthio)methyl)-N-(2-aminophenyl)benzamide;

4-((3H-imidazo[4,5-c]pyridin-2-ylthio)methyl)-N-(2-aminophenyl)benzamide;

4-((3H-imidazo[4,5-c]pyridin-2-yloxy)methyl)-N-(2-aminophenyl)benzamide; and

5-((3H-imidazo[4,5-b]pyridin-2-yloxy)methyl)-N-(2-aminophenyl)thiophene-2-carboxamide.

57. A method comprising:

coupling a compound having the formula

to a phenylenediamine compound having the formula

under conditions that form a compound having the formula

wherein

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

A₁ is selected from the group consisting of (C_3-12)cycloalkylene, hetero(C_3-12)cycloalkylene, arylene, and heteroarylene, each unsubstituted or substituted;

L is a linker comprising a backbone chain of 1 to 10 atoms comprising C, N, O, or S and may be optionally substituted with a substituent selected from the group consisting of halo, halo(C_1-6)alkyl, amino, nitro, cyano, thio, (C_1-6)alkyl, (C_3-7)cycloalkyl, (C_1-6)alkyl(C_3-7)cycloalkyl, (C_3-7)cycloalkyl(C_1-6)alkyl, hetero(C_3-7)cycloalkyl, (C_1-6)alkylhetero(C_3-7)cycloalkyl, hetero(C_3-7)cycloalkyl(C_1-6)alkyl, (C_1-6)heteroalkyl, aryl, (C_1-6)alkylaryl, ary(C_1-6)alkyl, heteroaryl, (C_1-6)alkylheteroaryl, heteroaryl(C_1-6)alkyl, carbonyl(C_1-6)alkyl, thiocarbonyl(C_1-5)alkyl, sulfonyl(C_1-6)alkyl, sulfinyl(C_1-6)alkyl, and imino(C_1-6)alkyl;

Y₂ is selected from the group consisting of CR₇R₈, NR₉, O, and S;

R₁ and R₂ are each individually selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_4-12)bicycloaryl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_4-12)bicycloaryl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted;

each R₄ is independently selected from the group consisting of hydrogen, halo, perhalo(C_1-10)alkyl, amino, cyano, nitro, thio, (C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, aryl(C_1-10)alkyl, heteroaryl (C_1-5)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted;

each R₆ is independently selected from the group consisting of hydrogen, halo, perhalo(C_1-10)alkyl, amino, cyano, nitro, thio, (C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, aryl(C_1-10)alkyl, heteroaryl (C_1-5)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted;

R₇ and R₈ are each independently selected from the group consisting of hydrogen, halo, perhalo(C_1-10)alkyl, amino, cyano, nitro, thio, (C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, aryl(C_1-10)alkyl, heteroaryl (C_1-5)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted, or R₈ is absent when the carbon to which it is bound forms part of a double bond;

R₉ is selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_4-12)bicycloaryl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted, or R₉ is absent when the nitrogen to which it is bound forms part of a double bond; and

R₁₀ is selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_4-12)bicycloaryl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, carbonyl (C_1-3)alkyl, thiocarbonyl (C_1-3)alkyl, sulfonyl (C_1-3)alkyl, sulfinyl (C_1-3)alkyl, imino (C_1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each substituted or unsubstituted, or R₁₀ is absent when the nitrogen to which it is bound forms part of a double bond;

with the provisos that (a) when Y₂ is NH; and

R₁, R₂, and R₃ are all H;

L is not —

S—

CH₂—

;

(b) when Y₂ is O; and

R₁, R₂, and R₃ are all H;

L is not —

O—

CH₂—

;

(c) when Y₂ is S; and

R₁, R₂, and R₃ are all H;

L is not —

NH—

CH₂—

;

(d) when Y₂ is S; and

R₁, R₂, and R₃ are all H;

L is not —

NH—

CH₂—

CH═

CH—

;

(e) when A₁ is 1,4-phenylene;

L is methylene;

R₁₀ is absent;

Y₂ is NH; and

p is 1;

R₆ is not 5-F or 5-MeO; and

(f) when A₁ is 1,4-phenylene;

L is methylene;

R₁₀ is absent;

Y₂ is NH; and

p is 2;

R₆ is not 5-Cl, 6-F or 5-F, 6-Cl.

58. The method according to claim 57 further comprising:

converting a carboxylic ester having the formula

59. The method according to claim 58, wherein L is *NH—

CH₂-L^a

where

* indicates the point of attachment of L to the five membered ring containing Y₂, and

L^a is a bond or is a linker comprising a backbone chain of 1 to 8 atoms comprising C, N, O, or S and may be optionally substituted with a substituent selected from the group consisting of halo, halo(C_1-6)alkyl, amino, nitro, cyano, thio, (C_1-6)alkyl, (C_3-7)cycloalkyl, (C_1-6)alkyl(C_3-7)cycloalkyl, (C_3-7)cycloalkyl(C_1-6)alkyl, hetero(C_3-7)cycloalkyl, (C_1-6)alkylhetero(C_3-7)cycloalkyl, hetero(C_3-7)cycloalkyl(C_1-16)alkyl, (C_1-16)heteroalkyl, aryl, (C_1-16)alkylaryl, aryl(C_1-6)alkyl, heteroaryl, (C_1-6)alkylheteroaryl, heteroaryl(C_1-6)alkyl, carbonyl(C_1-6)alkyl, thiocarbonyl(C_1-5)alkyl, sulfonyl(C_1-6)alkyl, sulfinyl(C_1-6)alkyl, and imino(C_1-6)alkyl.

60. The method according to claim 57 further comprising:

reacting a compound having the formula

with a compound having the formula

under conditions to form a compound having the formula

61. The method according to claim 60, wherein L^a is a bond.

62. The method according to claim 58, wherein L is *XCH₂L^a,

where

* indicates the point of attachment of L to the five membered ring containing Y₂,

X is O or S, and

L^a is a bond or is a linker comprising a backbone chain of 1 to 8 atoms comprising C, N, O, or S and may be optionally substituted with a substituent selected from the group consisting of halo, halo(C_1-6)alkyl, amino, nitro, cyano, thio, (C_1-6)alkyl, (C_3-7)cycloalkyl, (C_1-6)alkyl(C_3-7)cycloalkyl, (C_3-7)cycloalkyl(C_1-6)alkyl, hetero(C_3-7)cycloalkyl, (C_1-6)alkylhetero(C_3-7)cycloalkyl, hetero(C_3-7)cycloalkyl(C_1-6)alkyl, (C_1-6)heteroalkyl, aryl, (C_1-6)alkylaryl, ary(C_1-6)alkyl, heteroaryl, (C_1-6)alkylheteroaryl, heteroaryl(C_1-6)alkyl, carbonyl(C_1-6)alkyl, thiocarbonyl(C_1-5)alkyl, sulfonyl(C_1-6)alkyl, sulfinyl(C_1-6)alkyl, and imino(C_1-6)alkyl.

63. The method according to claim 62 further comprising:

reacting a compound having the formula

with a compound having the formula

under conditions to form a compound having the formula

64. The method according to claim 63, wherein X is O.

65. The method according to claim 63, wherein X is S.

66. The method according to claim 65 further comprising

oxidizing the sulfide of the compound having the formula

under conditions to yield the corresponding sulfoxide compound having the formula

67. The method according to claim 66, wherein L^a is a bond.

68. The method according to claim 65 further comprising

oxidizing the sulfide of the compound having the formula

under conditions to yield the corresponding sulfone compound having the formula

69. The method according to claim 68, wherein L^a is a bond.

70. The method according to claim 58, wherein R_a is methyl.

71. The method according to claim 60, wherein R_a is methyl.

72. The method according to claim 57, wherein at least one of R₁ and R₂ is H.

73. The method according to claim 57, wherein R₁ and R₂ are both H.

74. The method according to claim 57, wherein R₃ is H.

75. The method of according to claim 57, wherein R₄ is hydrogen, halo, perhalo(C_1-3)alkyl, amino, cyano, nitro, thio, (C_1-5)alkyl, (C_3-5)cycloalkyl, hetero(C_3-5)cycloalkyl, aryl(C_1-3)alkyl, heteroaryl (C_1-3)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, imino(C_1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, alkenyl, alkynyl, carbonyl, and imino, each substituted or unsubstituted.

76. The method according to claim 57, wherein R₄ is hydrogen.

77. The method according to claim 57, wherein A₁ is phenylene.

78. The method according to claim 57, wherein A₁ is 1,4-phenylene.

79. The method according to claim 57, wherein Y₂ is CR₇R₈, or NR₉ where R₉ is not H.

80. The method according to claim 57, wherein Y₂ is CR₇R₈, or NR₉ where R₉ is not H.

81. A compound having the formula

82. A compound having the formula

83. A compound having the formula

84. The compound according to claim 83, wherein X is O.

85. The compound according to claim 83, wherein X is S.

86. A compound having the formula

87. The compound of claim 86, wherein R₁, R₂, R₃, and R₄ are all hydrogen.