ANTI-INFLAMMATORY AND ANTIOXIDANT CONJUGATES USEFUL FOR TREATING METABOLIC DISORDERS

BACKGROUND Oxidative stress and inflammation are implicated in the pathogenesis of metabolic diseases, diabetes, obesity, dyslipidemia and their associated cardiovascular complications. For example, oxidative stress is a common pathogenic factor leading to insulin resistance, β-cell dysfunction, impaired glucose tolerance, and type 2 diabetes mellitus. With regard to inflammation, clinical studies suggest that acute hyperglycemia results in elevated levels of circulating inflammatory cytokines such as TNFα, IL6, and ILl 8.

During hyperglycemia and/or hyperlipidemia, mitochondria generate cellular energy through TCA cycle activity and the associated electron transport chain of the inner mitochondrial membrane. However, while mitochondria generate elevated ATP production, mitochondria can also generate significant reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cells are equipped with several antioxidant enzymes to neutralize ROS and RNS. For example, superoxide anions are enzymatically converted to hydrogen peroxide by a manganese superoxide dismutase (MnSOD) within mitochondria. Hydrogen peroxide can then be rapidly removed by the mitochondrial enzyme glutathione (GSH) peroxidase. A further antioxidant enzyme, catalase, is the hydrogen peroxide detoxifying enzyme founded exclusively in peroxisomes. Glutathione (GSH) is probably the most important defense with which the cell is equipped, for scavenging ROS generated by mitochondria metabolism and excess free radicals produced secondary to hyperglycemia and hyperlipidemia.

However, while cells have a number of available anti-oxidant mechanisms, damage most likely occurs when the ROS is excessive and/or anti-oxidant pathways are overwhelmed as is frequently the case in diabetes. In diabetic patients, the levels of antioxidant enzymes responsible for scavenging free radicals are diminished. Glutathione pools become depleted in diabetic patients following frequent and severe hyperglycemic episodes. It is now widely accepted that overproduction of reactive oxygen species (ROS) contributes to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes, insulin resistance, and obesity.

In particular, compared to several other cells of the body, pancreatic β-cells have relatively low levels of free radical detoxification and redox regulating enzymes such as superoxide dismutase, glutathione peroxidase, catalase and thioredoxin. The consequence of limited scavenging systems is that ROS concentration in β-cells may increase rapidly, damaging the β-cells. Thus, under hyperglycemic conditions, the production of ROS, and subsequent oxidative stress, contributes to β-cell deterioration observed in type 2 diabetes. ROS is also considered a strong stimulus for the release of cytokines and increased superoxide can promote inflammation through NF-kB activation. Thus the role of oxidative stress and associated activation of NF-kB leading to chronic inflammation and insulin resistance is essential in the processes implicated in the pathogenesis of diabetes and its progression. Administration of glutathione, a powerful antioxidant, completely suppresses cytokine elevation, providing further support that an oxidative stress mechanism mediates the inflammatory effects of hyperglycemia in humans.

Salicylates, or aspirin-like drugs, are some of the most commonly used anti-inflammatory agents. For more than two decades, the anti-inflammatory properties of aspirin have been almost exclusively attributed to blocking prostaglandin synthesis via inhibition of cyclo-oxygenase activity. Recently, aspirin and sodium salicylate have been found to inhibit the activation of the transcription factor NF-kB. High doses of salicylate are thought to inhibit NF-kB and its upstream activator, the 1KB kinase β (IKKβ).

Also, high doses of salicylic acid lower blood glucose levels. Recent studies report that diabetic animals given salicylates or salsalate showed a decrease in IKKβ activity, accompanied by improvement in insulin sensitivity. High doses of Salicylate (120mg/kg/day) administered by subcutaneous infusion in Zucker fa/ fa rats or ob/ob mice for 3-4 weeks exhibited anti-diabetic effects, reduction in fasting blood glucose, and glucose tolerance improvement. Beneficial effects of high doses of salicylic acid have been recently reported in human diabetic patients treated with 4.5g/day of salsalate. However, at this high dose, side effects, such as tinnitus, are enhanced by 66% and the long term risk of gastric bleeding and ulceration is also increased.

Thus, there remains a need in the art for compounds for treating metabolic disorders by way of ameliorating the inflammatory and oxidative processes associated with such disorders, particularly diabetes.

SUMMARY OF THE INVENTION

The present invention relates to conjugates comprised of an anti-inflammatory agent and an anti-oxidant agent. The conjugates of the present invention are useful for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders, such as any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, hyperglycemia, and insulin sensitivity. The conjugates are also useful for reducing advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFα and IL6 levels, and for delaying or preventing cardiovascular complications associated with atherosclerosis. Also, the conjugates of the present invention are useful for protecting pancreatic β-cells, preventing their impairment or failure and subsequent lower insulin secretion. The anti-inflammatory agent and antioxidant agent as provided herein are covalently bonded directly to each other or covalently bonded directly to the same linker. In particular, the present invention is exemplified by the use of conjugates comprised of salicylic acid and N-acetyleysteine (NAC) or diflunisal and NAC. for treating the disorders disclosed herein.

The compounds of the present invention, in particular Example 1 (salnacedin) and Example 13 (conjugate comprised of diflunisal and NAC), show additive or synergistic effects relative to treatment with an antioxidant agent alone or an anti- inflammatory agent alone. The additive or synergistic effect improves the anti-diabetic effect while reducing side effects associated with monotherapy. In particular, treatment with Example 1 or Example 13 improves anti-diabetic effects while lowering the risk of gastric bleeding, associated with salicylic acid, and/or tinnitus, associated with N-acetylcysteine.

The present invention provides compounds of Formula (I)-(XXII), as defined herein, In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (I)- (XXIl) and at least one pharmaceutically acceptable carrier. The compounds of Formula (I)-(XXII) and the pharmaceutical compositions comprised of Formula (I)-(IX) and at least one pharmaceutically acceptable carrier are useful for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance. The compounds and pharmaceutical compositions of the present invention are useful for protecting pancreatic β-cells, preventing their impairment or failure and subsequent lower insulin secretion. Also, the compounds and pharmaceutical compositions of the present invention are also useful for reducing free fatty acids (FfA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TN Fa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis,

In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(IX) or a pharmaceutical composition comprised of a compound of Formula (I)-(IX) and at least one pharmaceutically acceptable carrier. The present invention also provides methods for reducing free fatty acids (FFA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFα and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XXII) or a pharmaceutical composition comprised of a compound of Formula (I)-(XXII) and at least one pharmaceutically acceptable carrier. Also, the present invention provides methods for protecting pancreatic β-cells, preventing their impairment or failure and subsequent lower insulin secretion in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XXII) or a pharmaceutical composition comprised of a compound of Formula (I)-(XXII) and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides uses for compounds of Formula (I)-(XXII), or pharmaceutical compositions comprised of a compound of Formula (I)-(XXII) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders. Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient The present invention also provides uses for compounds of Formula (I)-(XXlI), or pharmaceutical compositions comprised of a compound of Formula (I)-(XXIl) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for reducing free fatty acids (FFA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFα and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient. The present invention also provides uses for compounds of Formula (I)-(XXII), or pharmaceutical compositions comprised of a compound of Formula (I)-(XXII) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for protecting pancreatic β- cells. preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient, Specific embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is directed to the chemical stability of conjugates of the present invention in neutral, acidic, and basic solutions. The conjugates were tested in their free acid form and as lysine salts and include: salicylic acid-(L) N-acetyl cysteine (GMC-3a), diflunisal-(L) N-acetyl cysteine (GMC-3b), and dexibuprofen-(L) N-acetyl cysteine (GMC-3d).

Figures 2-4 are graphical illustrations of the cleavage efficiency for salicylic acid-(L) N-acetyl cysteine (GMC-3a) and diflunisal-(L) N-acetyl cysteine (GMC-3b) in rat and human.

Figure 5 is a graphical illustration of the cleavage efficiency for salicylic acid-(L) N-acetyl cysteine (GMC-3a), diflunisal-(L) N-acetyl cysteine (GMC-3b) in vivo in rats.

Figure 6 is a graphical illustration of the effects of salicylic acid-(L) N-acetyl cysteine (GMC- 1.3a) and diflunisal-(L) N-acetyl cysteine (GMC-Ub) ₅ as lysine salts, at protecting beta-cells in vivo in the alloxan model. 1 he alloxan model is a well known model of β-ccll dysfunction that mimicks the biochemical events involved in type 2 diabetes, including inflammation and oxidative stress. The results in Figure 6 indicate that both conjugates reduce the effect of alloxan on 0-cells. Further, the preservation of insulin levels in alloxan rats treated with GMC-3a, as shown in Figure 6, indicates a beta cell protection mechanism of action, Figure 7 is a graphical illustration of the comparative effects of the conjugate salicylic acid- (L) N-acetyl cysteine (GMC- 1.3 a) as the lysine salt, salicylate, and NAC, on free fatty acid and triglyceride levels in db/db mice (ip administration).

Figures 8-10 is a graphical illustration of the acute and chronic effects of the conjugate diflunisal-(L) N-acetyl cysteine (GMC- 1.3b), as the lysine salt, on hyperglycemia in db/db mice subsequent (oral administration).

Figure 11 is a graphical illustration of the effect of the conjugates salicylate-(L) N-acetyl cysteine (GMC-3a) and diflunisal-(L) N-acetyl cysteine (GMC-3b), as the lysine salt, on plasma insulin levels, free fatty acid levels, and triglyceride levels in db/db mice (chronic oral administration).

Figure 12 is a graphical illustration of the effects of the conjugates salicylic acid-(L) N-acetyl cysteine (GMC-3a) and diflunisal-(L) N-acetyl cysteine (GMC-3b) on body weight gain in db/db mice (chronic oral administration).

Figure 13 is a graphical illustration of the effects of the conjugates salicylic acid-(L) N-acetyl cysteine (GMC-3a) and diflunisal-(L) N-acetyl cysteine (GMC-3b) on fluid and food intake in db/db mice (chronic oral administration).

Figure 14 illustrates the protocol used in Figures 8, 9, 10, 11, 12, and 13.

Figure 15 is a graphical illustration of in vitro and in vivo cleavage data for several conjuages where lighter colors indicate positive results (white indicates not tested).

Figure 16 is a graphical illustration comparing diflunisal and NAC plasma levels in mice following oral administration (20 mg/kg) of the conjugate diflunisal-NAC and the combination of diflunisal + NAC.

Figure 17 is a graphical illustration comparing the beta-cell protective effects of the conjugate salicylate-NAC to the combination of salicylate + NAC in cd-1 male mice. Figure 18 is a graphical illustration comparing the effects of the conjugate salicylate-NAC to the combination of salicylate + NAC at reducing Free Fatty Acids in db/db mice.

Figure 19 is a graphical illustration of the effects of the conjugate diflunisal-NAC at reducing glycemia in db/db mice (oral administration). Figure 19B illustrates the reduction of glycemia during the insulin tolerance test (ITT). Figure 19C illustrates the reduction of glycemia during the glucose tolerance test (GTT).

Figure 20 is a graphical illustration of the effects of the conjugate diflunisal-NAC on weight gain in mice following chronic oral administration.

Figure 21 is a graphical illustration comparing the glycemic effects of the conjugate diflunisal-NAC to metformin in db/db mice (oral administration).

Figure 22 is a graphical illustration of the effects of the conjugate diflunisal-NAC at reducing Free Fatty Acids and Triglycerides in db/db mice after four weeks of oral administration (0.5 mmol/kg/day).

Figure 23 is a graphical illustration of the effects of the conjugate diflunisal-NAC at increasing both plasma insulin and total pancreatic insulin in db/db mice after four weeks of oral administration (0.5 mmol/kg/day).

Figure 24 is a graphical administration of the effects of the conjugate diflunisal-NAC at increasing both insulin expression and islet size without affecting pancreatic weight in db/db mice after four weeks of oral administration (0.5 mmol/kg/day).

Figure 25 is a graphical illustration comparing the effects of the conjugate diflunisal-NAC (0.5 mmol/kg/day) to metformin HCl (100 mg/kg/day) at increasing both pancreatic insulin levels and islet size in db/db mice after four weeks of oral administration (0.5 mmol/kg/day).

Figure 26 is a graphical illustration of the cleavage efficiency for the conjugate difiunisaHipoic acid in vivo in rats. Figure 27 Is a graphical Illustration of insulin islet sizes following oral administration of dlflunsal-NAC conjugate in db/db mice. A and B are representative islets from the vehicle group (A) and the treated group (B). Also, diflunsal-NAC conjugate did not affect the weight of the treated db/db, a good index of health state (Figure 20 in) nor the epididimal adipose tissue weight (respectively 1.7 ± 0.09 and 1.8 ± 0.07 g, In a preliminary experiment with control animals, the same oral dose of diflunsal-NAC conjugate (0.5 mmol/kg) did not affect these two parameters. Finally, it is important to note that diflunsal-NAC conjugate treatment did not induce any macroscopic lesions of the gastro intestinal system.

DETAILED DESCRIPTION

The present invention provides compounds, reagents, pharmaceutical compositions and methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R _& is formula (i); and R _T , Rg, RQ, XI, and L are as defined in Formula (I) of the Summary section,

In certain embodiments, the inventive methods include treating dyslipidemia. insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or

2,4-difluorophenyl; R ₆ is formula (i): and R ₇ . Rs. R ₉ , Xj, and L are as defined In Formula (I) of the Summary section.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R] is hydrogen or acetyl; R->. R-?, R ₄ , and R< are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl: R ₆ is formula (i); and R ₇ , R ₈ , R ₉ , X ₁ , and L are as defined in Formula (I) of the Summary section.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R», and R ₅ are independently hydrogen, trifluoromethyl, or

2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R9, Xi, and L are as defined in Formula (I) of the Summary section.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R$ is formula (i); and R ₇ , R ₈ , R ₉ , Xi, and L are as defined in Formula (I) of the Summary section.

In another aspect of the present invention, a method is provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z ₁₀ wherein Z ₉ and Z ₁₀ are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xj is S; and L is CH ₂ .

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z ₁₀ wherein Z ₉ and Zio are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ . In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z1 ₀ wherein Z ₉ and Zio are hydrogen; Rg is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xj is S; and L is CH ₂ .

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Cj-C ₆ )alkoxy, hydroxy, Or NZ ₉ Zi _O wherein Z ₉ and Zio are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ . In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z] ₀ wherein Z ₉ and Zi ₀ are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ . In another aspect of the present invention, a method is provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R5 are independently hydrogen, trifiuoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifiuoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; X ₁ is S; and L is CH ₂ .

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifiuoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; X ₁ is S; and L is CH ₂ . In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifiuoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; R ₈ is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In accordance with the present invention, a method is provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N-acetylcysteine.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N- acetylcysteine.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N-acetylcysteine. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N-acetylcysteine. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N- acetylcysteine.

In accordance with the present invention, a method is provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C)-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ JaIkOXy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydro xy(Cι-C _ό )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Zg)carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (C ₁ -C ₆ )alkyl, (d-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C _! -C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ JaIlCyI, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C6)alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C ₁ -C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-Cβjalkyl, (C _! -C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C ₁ -C _ό )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (d-C _ό Jalkylcarbonyl.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , Rj, and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (d-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(d-C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(d-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (C ₁ -C ₆ JaIlCyI, (d-C ₆ )alkylcarbonyl, (Cι-C6)alkylcarbonyloxy, (d-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

The present invention fiirter provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R», and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (d-C ₆ )alkylcarbonyl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci -C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (C ₁ -C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C _ό jalkyl, (Ci-C ₆ )alkylcarbonyl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C _! -C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Cι-C ₆ )alkyl, (Ci-C _ό jalkylcarbonyl.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Q-CfOalkyl, (Cj-C ₆ )alkylcarbonyl.

The present invention additionally provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R) is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

The present invention also provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z5 is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (d-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (d-C ₆ )alkyl, (C i-C ₆ )alky lcarbonyl, (d-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(d-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Zg)carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZsZ ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Cj-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (d-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (d-C ₆ )alkylthio, carboxy, cyano, formyl, halo(d-C ₆ )alkoxy, halo(Cι-C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Zg)carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C6)alkyl, or (d-C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (d-CβJalkoxycarbonyl, (C ₁ -C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (d-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(d-C ₆ )alkoxy, halo(d-C ₆ )alkyl, halogen, hydroxy, hydro Xy(Ci -C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Zg)carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ JaIkOXy, (Ci-C ₆ )alkoxycarbonyl, (Ci-Cejalkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Zg)carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, halo(d-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (d-C _ό Jalkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (d-CeJalkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl.

The present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R», and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Cj-C ₆ )alkyl or halogen.

In accordance with the present invention, methods are provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R ₆ is -NZsZ ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; Re is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R5 are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; RO is -NZ ₅ Z ₆ ; Z5 is hydrogen; Z^ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In accordance with the present invention, methods are provided for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders. Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzami de or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2- hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)ρhenylcarbamoyl)-4-chlorophenyl acetate.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula {I) or Formula (YV) is N-(3,5-bis(trifluoromethyl)phenyi)-5-chk>ro-2- hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chloro phenyl acetate, In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutical!} acceptable carrier and a conjugate of Formula (1) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2- hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzami de or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13. 14, 15, 16, 17, or 18.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxϊdatϊen of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound selected from Example L 2, 3. 4 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 15, 16, 17» or 18. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free tatty acids, elevated triglycerides, β-ccll dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type f arid type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a natient comnrisine administering to the patient in need of such treatment a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound selected from Example 1, 2, 3, 4, 5, 6, 7,

8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, or 18.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound selected from Example 1, 2,

3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive

Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 1 (salnacedin). In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of

Example 1. In certain embodiments, the present invention provides methods for treating β-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 1 (salnacedin).

In certain embodiments, the present invention provides methods for treating hyperglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 1 (salnacedin).

In certain embodiments, the present invention provides methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 1 (salnacedin).

In certain embodiments, the present invention provides methods for reducing triglycerides in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 1 (salnacedin).

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to. oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 1.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1.

In certain embodiments, the present invention includes methods for treating β-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1 (salnacedin).

In certain embodiments, the present invention includes methods for treating hyperglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1 (salnacedin).

In certain embodiments, the present invention includes methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1 (salnacedin).

In certain embodiments, the present invention includes methods for reducing triglycerides in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1 (salnacedin). In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patieni comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 1.

In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovasculai diseases, anil metabolic disorder in «» mammal «r natient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 4.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 4.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and, or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 4.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 4.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to. oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 4. In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders. Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 7, In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free tatty acids, elevated triglycerides, β-ccll dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes arid Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 7.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 7.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 7.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 7. In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 10. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic svndrome. and anv form of diabetes rnelHtus including tvne I and tvoe II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 10. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 10.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 10.

In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive

Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 13.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, metabolic syndrome, and any form of diabetes mellitus including type ϊ and type II diabetes and Latent Autoimmune Diabetes of Adulthood, and any form of diabetes mellitus including type I and type II diabetes, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 13.

In certain embodiments, the present invention provides methods for reducing advanced grvcated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 13.

In another aspect, the present invention provides methods for treating β-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 13.

In another aspect, the present invention provides methods for treating hyperglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically In another aspect, the present invention provides methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 13.

In another aspect, the present invention provides methods for reducing triglycerides in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 13.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13. In certain embodiments, present invention includes methods for treating β-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13.

In certain embodiments, present invention includes methods for treating hyerglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13.

In certain embodiments, present invention includes methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13.

In certain embodiments, present invention includes methods for reducing triglycerides in a patient comprising administering to the patient in need υf such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 13.

In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders. Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 16.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, and any form of diabetes mellitus including type I and type II diabetes, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of Example 16.

In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 16.

In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 16. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 16,

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or ror the manuiacture of, a medicament for treating atherosclerosis, ncuiυpathy. nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R ₉ , Xi, and L are as defined in Formula (I) of the Summary section.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R9, Xi, and L are as defined in Formula (I) of the Summary section.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R ₉ , Xi, and L are as defined in Formula (I) of the Summary section. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R ₉ , Xi, and L are as defined in Formula (I) of the Summary section. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluorornethyl, or 2,4-difluorophenyl; R ₆ is formula (i); and R ₇ , R ₈ , R ₉ , Xi, and L are as defined in Formula (I) of the Summary section.

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z1 ₀ wherein Z ₉ and Z ₁₀ are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZ ₉ Z10 wherein Z ₉ and Zi ₀ are hydrogen; R ₈ is hydrogen; R9 is (Ci-C ₆ )alkylcarbonyl; Xj is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZgZ ₁₀ wherein Z ₉ and Zj ₀ are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Re is formula (i); R ₇ is (Ci-C ₆ )alkoxy, hydroxy, or NZgZ ₁₀ wherein Z ₉ and Zio are hydrogen; R ₈ is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; X ₁ is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is (d-C ₆ )alkoxy, hydroxy, or NZgZ ₁₀ wherein Z ₉ and Zio are hydrogen; Rg is hydrogen; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is S; and L is CH ₂ .

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; R ₈ is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; R ₈ is hydrogen; R9 is acetyl; Xi is S; and L is CH ₂ .

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R ₉ is acetyl; Xi is S; and L is CH2.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R _∑ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is formula (i); R ₇ is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R9 is acetyl; Xi is S; and L is CH ₂ .

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R$ is (L) N-acetylcysteine.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, and any form of diabetes mellitus including type I and type II diabetes, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and Re is (L) N-acetylcysteine.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R& is (L)

N-acetylcysteine.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ₆ is (L) N-acetylcysteine.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difiuoro phenyl; and R _O is (L) N-acetylcysteine. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

In certain embodiments, the present invention provides uses for conjugates of Formula (i) for preparing, or for ihe manufacture of. a medicament tor treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type Ii diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of

Formula (I) is selected from Example ! « 2, 3, 4, 5, 6, 7. 8. 9. 10, 1 1, 12, 13. 14, 15, 16. 17, or 18.

In certain embodiments, the present invention provides uses for conjugates of Formula (1) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. 17, or 18.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is selected from Example 1, 2. 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. 16, 17, or 18.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, or 18. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is Example 1 (salnacedin). In certain embodiments, the present invention pro\ides uses for conjugates of Formula

(I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, β-ceii dysfunction, metabolic syndrome, and any form of diabetes mellitus including type I and type Il diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of formula (I) is Example 1 (salnacedin). In certain embodiments, the present invention provides uses tor conjugates of Formula

(I) for preparing, or for the manufacture of, a medicament tor treating hyperglycemia in a patient, wherein the conjugate of Formula (I) is Example 1 (salnacedin). In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing free free fatty acids in a patient, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing triglycerides in a patient, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 1 (salnacedin),

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing free fatty acids in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of. a medicament for reducing triglycerides in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 1 (salnacedin). In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 1 (salnacedin).

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is Example 4.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (I) is Example 4.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 4.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type 11 diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof wherein the conjugate of formula (I) is Example 4.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to. oxidation of knv-ciensity lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 4.

In another aspect, the present invention provides the uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis. neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive

Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is Example 7.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (1) is Example 7.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 7.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 7.

In certain embodiments, the present invention provides uses for pharmaceutical compositions tor preparing, or for the manufacture of. a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to. oxidation of low -density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 7«

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of ^* a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders. Chronic Obstructive Pulmonary Disease. cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is Example 10.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 10.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia. insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes inellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (I) is Example 10.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type 1 and type 11 diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 10.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and ^; or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 10. In another aspect, the present invention provides uses rbr conjugates of formula (U for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of formula (I) is Example 13.

In certain embodiments, the present im ention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia. insulin resistance, β-cell dysfunction, metabolic syndrome, and any form of diabetes meiiitu^ including type I and t}ψe II diabetes, in a patient, wherein the conjugate of Formula (1) is Example 13.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing free fatty acids in a patient, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing triglycerides in a patient, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidernia, insulin resistance, β-cell dysfunction, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) u> Eλdiiiple 13.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing free fatty acids in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 13

In certain embodiments, the present invention provides uses for pharmaceutical eomposiuops ioi prcparinj.,, ««r to ^r the nidrmiacturc of. α medicament for rcilutinii triglycerides in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 13.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 13. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is Example 16.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (I) is Example 16.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is Example 16.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable caπier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 16. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example 16. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (d-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ )alkoxy, (Cι-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (d-C ₆ )alkylcarbonyl, (d-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C ₁ -C ₆ )alkoxy, halo(C _! -C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides uses for conjugates of Formula

(I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (d-C ₆ )alkyl, (C ₁ -C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyI(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently (d-C ₆ )alkoxy, (d-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C t-C^alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci -C ₆ JaIkVl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZsZ ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Cj-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Cj-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (d-CeJalkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C ₁ -Ce)alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci -C ₆ JaDcO xy, (Ci-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyL, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Cι-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(C!-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Zg)carbonyl; and Z ₇ and Zg are independently hydrogen, (C i -C ₆ )alkyl, or (C i-C ₆ )alkylcarbonyl.

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or halogen; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (CrC ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl. In certain embodiments, the present invention provides uses for conjugates of Formula

(I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C!-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (d-C^alkylcarbonyl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (d-CβJalkylcarbonyl.

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R$ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen. In certain embodiments, the present invention provides uses for conjugates of Formula

(I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Cj-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Q-C^alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Cι-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(C!-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (d-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(C ₁ -C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (d-C ₆ )alkyl, or (Cι-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ )alkoxy, (Ci-C _ό )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (d-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C ₁ -C ₆ )alkoxy, ImIo(C ₁ -C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Cι-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R _& is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl ₅ (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C _! -C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (d-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C6)alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ JaIkOXy, (d-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (d-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (C ₁ -C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(C ₁ -C ₆ )alkoxy, halo(d-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Zg)carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (d-C ₆ )alkylcarbonyl.

In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(d-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen. In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Cj-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(C ₁ -C ₆ )alkyl or halogen. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, hakKCt-CsJalkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently ImIo(C ₁ -C ₆ )alkyl or halogen. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZsZ ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R^ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Zf, Is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

In another aspect, the present invention provides uses for conjugates of Formula (I) or Formula (IV) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzami de or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate. In certain embodiments, the present invention provides uses for conjugates of Formula

(I) or Formula (IV) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5- chloro-2-hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In certain embodiments, the present invention provides uses for conjugates of Formula (I) or Formula (IV) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low ^r -density lipoproteins in a patient, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzami de or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, β-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (1) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydrox>benz amide or 2-(3,5-bis(trifluorornethyl)phenylcarbamoyl)-4-chlorophcnyl acetate. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzami de or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate.

In another aspect, the present invention provides conjugates of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R ₁ is hydrogen, (Ci-C ₆ )alkylcarbonyl, or A; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, (Cι-C ₆ )alkoxy, (C ₁ -C ₆ )alkoxycarbonyl,

(Q-C _ό jalkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C^alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (C ₁ -C ₆ JaIlCyItWo, carboxy, cyano, formyl, halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₁ Z ₂ , or (NZ ₁ Z ₂ )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C ₁ -C ₆ JaIkOXy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (C ₁ -OOaIlCyI, (C ₁ -C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alk;yl, mercapto, nitro, phenyl, -NZ ₃ Z ₄ , (NZ ₃ Z ₄ )carbonyl;

Zi, Z ₂ , Z ₃ , and Z ₄ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl; R ₆ is hydroxy, -NZ ₅ Z ₆ ,

provided that when R ₆ is hydroxy, then Ri is A;

Z ₅ and Z ₆ are independently hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH2)-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )aDcylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-Cβjalkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zg, or (NZ ₇ Z ₈ )carbonyl;

Z ₇ and Zg are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl; R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbony1, (Ci-C ₆ )alkyl, (Ci-QOalkylcarbonyl, (C ₁ -C ₆ )alkylcarbonyloxy, carboxy, cyano, formyl, 1IaIo(C ₁ -C ₆ )BIkOXy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl;

R ₈ is hydrogen or (Ci-C ₆ JaIlCyI;

R ₉ is hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl;

Rio is (Ci-C ₆ )alkoxy, (d-C^alkyl, (Ci-C ₆ )alkylthio, hydroxy, Or -NZ ₉ Zi ₀ ;

Z ₉ and Zio are independently hydrogen, (d-C^alkyl, or (Ci-C ₆ )alkylcarbonyl;

Xi and X ₂ are independently O or S;

L is (Ci-C ₆ )alkylene;

A is

Ru is hydrogen, (Ci-C ₆ )alkylcarbonyl, or B; R2a, R3a, R4a, and R ₅ a are independently hydrogen, (Ci-Cβ)alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-Cβjalkylcarbonyl, (C ₁ -C6)alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZi _a Z _2a , or (NZi _a Z _2a )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-C ₆ )alkoxy, (CrCiOalkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (C ₁ -C ₆ )BUCyI, (Ci-Cβjalkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo (C i-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C6)alkyl, mercapto, nitro, phenyl, -NZ ₃₈ Zj ₃ , or (NZ3 _a Z _4a )carbonyl;

Zt _a , Z _2a , Z _3a , and Z _4a are independently hydrogen, (Ci-C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl; B is

Ri _b is hydrogen, (Ci-C ₆ )alkylcarbonyl, or C;

R2 _b , R _3b , R4 _b , and Rsb are independently hydrogen, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-Cβjalkylcarbonyloxy, (Ci-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Cι-C ₆ )alkoxy, halo(Ci-C ₆ )aDcyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZit,Z _2b , or (NZi _b Z2 _b )carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-C ₆ )alkoxy, (Ci-Cβjalkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-Cβjalkylcarbonyl, (Ci-Cejalkylcarbonyloxy, (Ci-C6)alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, hab(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C6)aIkyl, mercapto, nitro, phenyl, -NZs _b ZU _b , or (NZ _3b Z _4b )carbonyl;

Zi _b , Z2 _b , Z _3b , and Z4b are independently hydrogen, (Ci-Cβjalkyl, or (Ci-Cβjalkylcarbonyl; and

C is

provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are hydrogen; and Re is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine; also provided that Formula (I) does not encompass N-acetyl-S-[(2',4'-difluoro-4-hydroxy[ 1 , 1 '-biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester; N-acetyl-S-[(2',4'-difluoro-4-hydroxy[l , 1 '-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[l,r-biphenyI]-3-yl)c arbonyl]-L-cysteine methyl ester; and N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[l , 1 '-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester..

In another aspect, the present invention provides conjugates of Formula (I) wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, halogen, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-C ₆ )alkoxy, (Cj-Cή^lkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (C ₁ -C ₆ )alkylcarbonyl, (C ₁ -C ₆ )alkylcarbonyloxy, (C ₁ -C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(d-C ₆ )alkyl, halogen, hydroxy, hydroxy(d-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₃ Z ₄ , or (N ₃ Z4)carbonyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ; R ₈ is hydrogen or (Ci-C ₆ )alkyl; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is O or S; L is (Ci-C ₆ )alkylene; and Z ₃ , Z ₄ , Z ₉ , and Zio are independently hydrogen, (d-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are hydrogen; and R ₆ is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine.

In another aspect, the present invention provides conjugates of Formula (I) wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R4, and R5 are independently hydrogen or phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkyl, or halogen; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy or hydroxy; Rg is hydrogen or (Ci-C ₆ JaIkVl; R ₉ is (C ₁ -C ₆ )alkylcarbonyl; Xi is O or S; and L is (Ci-C ₆ )alkylene; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are hydrogen; and R ₆ is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R5 are independently hydrogen or phenyl, wherein the phenyl is optionally substituted with 1 or 2 halogen groups; R ₆ is formula (i); R ₇ is ethoxy, methoxy, or hydroxy; Rg is hydrogen or methyl; R ₉ is acetyl; Xi is O or S; and L is CH ₂ ; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are hydrogen; and R ₆ is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; one of R ₂ , R ₃ , R ₄ , and R ₅ is 2,4-difluorophenyl and the rest are hydrogen; R ₆ is formula (i); R ₇ is hydroxy; R« is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ . In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are independently hydrogen, halo(C ₁ -C ₆ )alkyl, or halogen; R ₆ is formula (i); R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (d-C ₆ )alkyIthio, hydroxy, or -NZ ₉ Z ₁₀ ; Re is hydrogen or (Ci-C ₆ )alkyl; R ₉ is (Ci-C ₆ )alkylcarbonyl; Xi is O or S; L is (Ci-C ₆ )alkylene; and Z ₉ , and Zi ₀ are independently hydrogen, (Ci-C ₆ )alkyl, or

(Ci-C ₆ )alkylcarbonyl; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R3, R ₄ , and R5 are hydrogen; and Re is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R3, R ₄ , and R ₅ are independently hydrogen or halo(Ci-C ₆ )alkyl; R ₆ is formula (i); R ₇ is (Ci-C ₆ )a0coxy or hydroxy; Re is hydrogen or (Ci-C ₆ )afleyl; R ₉ is (Ci-C^alkylcarbonyl; Xi is O or S; and L is (Ci-C ₆ )alkylene; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are hydrogen; and Re is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine. In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and Rs are independently hydrogen or trifluoraiethyl; R ₆ is formula (i); R ₇ is ethoxy, methoxy, or hydroxy; Rg is hydrogen or methyl; R ₉ is acetyl; Xi is O or S; and L is CH ₂ ; provided that Formula (I) does not encompass Ri is hydrogen or acetyl; R2, R3, R ₄ , and R5 are hydrogen; and Re is (L) N-acetylcysteine, (D) N-acetylcysteine, or (±) N-acetylcysteine.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; one of R ₂ , R ₃ , R ₄ , and Rs ais trifluormethyl and the rest are hydrogen; Re is formula (i); R ₇ is hydroxy; Rg is hydrogen; R ₉ is acetyl; Xi is S; and L is CH ₂ .

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R3, R ₄ , and R ₅ are independently hydrogen, halo(Ci-Ce)alkyl, or halogen; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, phenyl, phenyl(CH ₂ )-, or phenyl(CH ₂ ) ₂ -, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-Ce)alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (Ci-Cβjalkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, haIo(Cι-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Zs, or (NZ ₇ Zg)carbonyl; and Z ₇ and Z ₈ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl. In another aspect, the present invention provides conjugates of Formula (I) wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or halogen; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or Cl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; and Z ₆ is hydrogen.

In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(Ci-C ₆ )alkyl, or halogen; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy,

(Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkoxysulfonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, (d-C ₆ )alkylsulfonyl, (Ci-C ₆ )alkylthio, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, hydroxy(Ci-C ₆ )alkyl, mercapto, nitro, phenyl, -NZ ₇ Z ₈ , or (NZ ₇ Z ₈ )carbonyl; and Z ₇ and Zg are independently hydrogen, (Ci -C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

In another aspect, the present invention provides conjugates of Formula (I) wherein R ₁ is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halo(d-C ₆ )alkyl, or halogen; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C ₆ )alkyl or halogen. In another aspect, the present invention provides conjugates of Formula (I) wherein Rj is hydrogen or acetyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, trifluoromethyl, or Cl; R ₆ is -NZ ₅ Z ₆ ; Z ₅ is hydrogen; Z ₆ is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl.

Representative conjugates of Formula (I) include, but are not limited to, the compounds shown below, wherein Ri is hydrogen or acetyl.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (I), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (II)

wherein R2, R3, R4, R5, R& Ria, R2a, R3* R»a, and R _5a are as defined in Formula (I) of the Summary section, provided that when R ₆ is hydroxy then Ru is B, as defined in Formula (I) of the Summary section.

In another aspect, the present invention provides conjugates of Formula (II) wherein R ₂ , R ₃ , R ₄ , R ₅ , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is as defined in Formula (I) of the Summary section; R _la is hydrogen or acetyl; and R2 _a , R3a, R _J8 , and Rs _a , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl. In another aspect, the present invention provides conjugates of Formula (II) wherein R ₂ , R ₃ , R ₄ , Rs, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Rg is N-acetylcysteine, (L) N-acetylcysteine, or (D) N-acetylcysteine; Ri _a is hydrogen or acetyl; and one of R _2a , R _3a , R ₄₃ , and Rs ₈ is C(O)-Re ₈ and the rest are hydrogen; and R ₆₈ is as defined in Formula (I).

Representative conjugates of Formula (II) include, but are not limited to, the compounds shown below, wherein Ri ₈ is hydrogen or acetyl.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (II), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (III)

wherein R ₂ , R3, R*, Rs, Re, R2a, R3a, R4a, Rsa, Rib, R2b, R31* Rib, and R ₅ b are as defined in Formula (I) of the Summary section, provided that when R ₆ is hydroxy then Ri _b is C, as defined in Formula (I) of the Summary section.

In another aspect, the present invention provides conjugates of Formula (III) wherein R2, R3, R4, R5, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ₆ is (L) N-acetylcysteine; R ₂₈ , R3a, R4a, and Rs ₈ , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R _2b , R3b, R4 _b , and R _5b , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and Ri _b is hydrogen or acetyl.

Representative conjugates of Formula (III) include, but are not limited to, the compounds shown below, wherein R^ is hydrogen or acetyl.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (III), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (IV)

wherein R ₁ is hydrogen, (Ci-C ₆ )alkylcarbonyl,

Representative conjugates of Formula (IV) include the compounds shown below, wherein RΪ is hydrogen or acetyl.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (IV), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (V)

wherein R ₆ is

R ₇ is (Ci-C ₆ )a]koxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or S groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )a]koxycarbonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl; Re is hydrogen or (C i -C ₆ )alkyl;

R ₉ is hydrogen, (Ci-Cβjalkyl, or (Ci-C ₆ )alkylcarbonyl; Rio is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ; Xi and X ₂ are independently O or S; L is (Ci-C ₆ )alkylene; and Z ₉ and Zio are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-Cejalkylcarbonyl.

Representative conjugates of Formula (V) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (V), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (VI)

wherein R ₆ is

or

R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-Cβjalkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl; Rg is hydrogen or (Ci-C _ό jalkyl;

R ₉ is hydrogen, (Ci-Cβjalkyl, or (Ci-Cβjalkylcarbonyl; Rio is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ; Xi and X ₂ are independently O or S; L is (Ci-C ₆ )alkylene; and Z ₉ and ZJ ₀ are independently hydrogen, (Ci-Cβjalkyl, or (Ci-C ₆ )alkylcarbonyl.

Representative conjugates of Formula (VI) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (VI), as shown above, and at least one pharmaceutically acceptable carrier. In another aspect, the present invention provides conjugates of Formula (VII)

wherein R ₆ is

R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Cι-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl;

Rg is hydrogen or (Ci-C ₆ )aDcyl;

R ₉ is hydrogen, (Ci-Cβjalkyl, or (Ci-Cβjalkylcarbonyl;

Rio is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ;

Xi and X ₂ are independently O or S;

L is (Ci-C ₆ )alkylene; and

Z ₉ and Zio are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

Representative conjugates of Formula (VII) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (VII), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (X)

wherein R ₆ is

R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (C ₁ -C ₆ )BDCyItMo, hydroxy, -NZ ₉ Z ₁₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C ₁ -C ₆ )OIkOXy, (Ci-C ₆ )alkoxycarbonyl, (d-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(d-C ₆ )alkyl, halogen, hydroxy, or hydroxy(C ₁ -C ₆ )alkyl;

R ₈ is hydrogen or (Cι-C ₆ )alkyl;

R ₉ is hydrogen, (Ci-C ₆ )alkyl, or (C ₁ -C ₆ )alkylcarbonyl;

Rio is (d-CβJalkoxy, (Ci-C ₆ )alkylthio, hydroxy, Or-NZ ₉ Z ₁₀ ;

Xi and X ₂ are independently O or S;

L is (Ci-C ₆ )alkylene; and

Z ₉ and Z ₁₀ are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

Representative conjugates of Formula (VIII) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (VIII), as shown above, and at least one pharmaceutically acceptable carrier. In another aspect, the present invention provides conjugates of Formula (IX)

wherein Re is

R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-Cβjalkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C ₆ )alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl; R ₈ is hydrogen or (Ci-C ₆ )alkyl;

R ₉ is hydrogen, (Ci-C ₆ )alkyl, or (C _! -C ₆ )alkylcarbonyl;

R ₁₀ is (Ci-C ₆ )alkoxy, (d-C^alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ;

Xi and X ₂ are independently O or S;

L is (Ci-C ₆ )alkylene; and

Z ₉ and Zio are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C ₆ )alkylcarbonyl.

Representative conjugates of Formula (IX) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (IX), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (X)

wherein R ₆ is

Representative conjugates of Formula (X) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (X), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (XI)

wherein R ₆ is

R ₇ is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylthio, hydroxy, -NZ ₉ Zi ₀ , or-O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkylcarbonyloxy, carboxy, cyano, formyl, halo(Ci-C6)alkoxy, halo(Ci-C ₆ )alkyl, halogen, hydroxy, or hydroxy(Ci-C ₆ )alkyl;

R ₈ is hydrogen or (Ci-Cβjalkyl;

R ₉ is hydrogen, (Ci-Cβjalkyl, or (Ci-Cβjalkylcarbonyl;

Rio is (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkylthio, hydroxy, Or-NZ ₉ Zi ₀ ;

Xi and Xj are independently O or S; L is (Ci-Cβjalkylene; and

Z ₉ and Zio are independently hydrogen, (Ci-C ₆ )alkyl, or (Ci-C _δ jalkylcarbonyl. Representative conjugates of Formula (Xl) Include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XI), as shown above, and at least one pharmaceutically acceptable carrier,

The present invention also provides conjugates of Formula (XII)

A-L-B

(XlI), wherein

A is

, or

R20 is (Ci-C ₄ )alkoxy, hydroxy, or NZ20Z21;

Z ₂₀ and Z ₂ I are independently hydrogen or (Ci-C ₄ )alkyl;

L is selected from

n is 2, 3, or 4; Y is O, S, S-S, NH, NCH ₃ ;

R21 is hydrogen or (Ci-C ₄ )alkyl;

R ₂₂ is hydrogen, CH ₃ , CH(CHs) ₂ , CH ₂ CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ CH ₃ ; CH ₂ OH, CH(OH)CH ₃ , CH ₂ SH, CH ₂ COOH, CH ₂ CH ₂ COOH, CH ₂ C(O)NH ₂ , CH ₂ CH ₂ CH ₂ NHC(=NH)NH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ SCH ₃ , CH ₂ CH ₂ C(=O)NH ₂ ,

R ₂₃ and R ₂₄ are independently hydrogen or (Ci-C ₆ )alkyl;

R25 is (Ci-C4)alkoxy, hydroxy, or NZ22Z2 ₃ ;

Z22 and Z23 are independently hydrogen or (Ci-C-Oalkyl; and

R ₂₆ is hydrogen, (Ci-Cβjalkyl, or (Ci-Cejalkylcarbonyl.

Representative conjugates of Formula (XII) include, but are not limited to, the compounds shown below.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XII), as shown above, and at least one pharmaceutically acceptable carrier.

The present invention provides compounds of Formula (XIII):

or a pharmaceutically acceptable salt thereof, wherein Ri is OR ₆ or NR ₄ R ₅ ; R ₂ is H or 2,4-difluorophenyl; R ₃ is

R ₄ and R ₅ are independently H, (Ci-C ₆ )alkyl, (C ₃ -Cg)cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (d-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cyeloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1. 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxy(Ci-Cs)alkyl, (Ci-C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 halogens; or R4 and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine. piperazine, N-methylpiperazine, morpholine, or azepane;

R ₆ is H, (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(C _r C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cyeloalkyl, and (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy. (Ci-C ₆ )alkoxy(Ci-C6)alkyl, (Ci-Cό)alkoxycarbonyl, (Ci-C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ ₂ , or phenyl, wherein the phenyl is optionally substituted with 1. 2, 3, 4, or 5 halogens; and

Zi and Z ₂ are independently H or (Ci-Q,)alkyl.

Representative compounds of Formula (XIIl) include, but are not limited to, the compounds shown below:

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XIII), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XIV) or a pharmaceutically acceptable salt thereof, wherein

Ri Is OR ₆ Or NR ₄ R ₅ ; Ri is H or 2,4-difluorophenyl;

R ₃ is H or (Ci-C ₆ )alkyl;

R ₄ and R ₅ are independently H, (Ci-C _& )alkyl, (C ₃ -Cg)cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (C _r C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyL and (C ₃ -Cg)cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C _ό )alkoxy, (Ci-C ₆ )alkoxy(Ci-C ₆ )alkyl, (Cj-C _ό )alkoxycarbonyl,

(C]-C ₆ )alkylthio, halogen, hydroxy, hydro xycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; R ₆ is H, (Ci-C ₆ )alkyl, (C _r C ₈ )cycloaϊkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )aIkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cyc1oa1kyl, and (C ₃ -Cβ)cycloalkyl(C,-C ₆ )alky1 are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxy(Ci-C6)alkyl, (Ci -Cή)alko xycarbonyl, (Ci-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ ₁ Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; and

Zi and Z ₂ are independently H or (Ci-C ₆ )alkyl,

Representative compounds of Formula (XIV) include, but are not limited to, the compounds shown below: In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XIV), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XV)

or a pharmaceutically acceptable salt thereof, wherein

Ri is OR ₃ OrNR ₄ R ₅ ; R ₂ is H or 2,4-difluorophenyl;

R ₃ is H, (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )CyClOaIlCyI(C ₁ -C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci -C ₆ JaIkO xy, (Ci-C ₆ )alkoxy(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxycarbonyl, (d-C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ ₂ , or phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 halogens;

R ₄ and R ₅ are independently H, (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C i -C ₆ )alkoxy, (C i -C ₆ )alkoxy(C i -C ₆ )alkyl, (C i -C ₆ )alkoxycarbonyl,

(Ci-C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ ₂ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and Z ₁ and Z ₂ are independently H or (Ci-C _ό jalkyl.

Representative compounds of Formula (XV) include, but are not limited to, the compounds shown below:

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XV), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides a compound of Formula (XVI)

or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XVI), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XVII)

or a pharmaceutically acceptable salt thereof, wherein

Ri is OR ₂ or NR ₄ R ₅ ; R ₂ is H, (Ci-C ₆ )alkyl, (C ₃ -C ₃ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-Cό)alkyl. (C ₃ ~C ₈ )cyeloalkyl, and (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ ₂ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4. or 5 halogens;

R ₄ and R ₅ are independently H, (Ci-C6)alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -Cg)cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C3-C ₈ )cycloalkyl(Ci-C6)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxy(Cj-C ₆ )alkyl, (Ci-C ₆ )alkoxycarbonyl, (Ci-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ ₁ Z ₂ , or phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 halogens; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and

Zi and Zz are independently H or (Cι-Cf,)alkyl.

Representative compounds of Formula (XVII) include, but are not limited to, the compounds shown below:

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XVII), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XVIII)

or a pharmaceutically acceptable salt thereof, wherein Ri is OR ₂ or NR ₄ R ₅ ;

R ₂ is H, (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyL or (C ₃ -C ₈ )cycloalkyl(Cι-C ₆ )alk>l, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1 , 2, 3, or 4 substituents that are independently (Ci-C _ό )alkoxy, (Ci-0,)alkoxy(Cϊ-Cό)alkyL (Ci-C6)alkoxycarbonyl. (Cι-C ₆ )alkylthio, halogen, hydroxy, hydro xycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens;

R ₃ is

R ₄ and R5 are independently H, (Ci-C ₆ )alkyl, (C ₃ -Cg jcycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cyeloalkyl, and (C3-Cg)cycloalkyl(Ci-C6)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C6)alkoxy, (Ci-C ₆ )alkoxy(Ci-C ₆ )alkyl, (Ci -C6)alko xycarbonyl, (Ci-C ₆ )alkylthio. halogen, hydroxy, hydro xycarbonyl, NZ ₁ Z ₂ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and

Zi and Z ₂ are independently H or (Ci-C ₆ )alkyl.

Representative compounds of Formula (XVIII) include, but are not limited to, the compounds shown below:

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XVIII), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XIX) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XIX), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XX)

or a pharmaceutically acceptable salt thereof, wherein Ri is OR ₂ , NR4R5, or

R ₂ is (Ci-Cβjalkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the

(Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cycloalkyl(Cι-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-Cβ)alkoxy, (C i-C ₆ )aHcoxy(Ci -Chalky 1, (Ci-C ₆ )alkoxycarbonyl, (Ci-Cβjalkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ ₂ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens;

Zi and Z ₂ are independently H or (C]-C ₆ )alkyl; R ₃ is H or C(O)R ₆ ; R4 and R5 are independently H, (d-C ₆ )alkyl, (C ₃ -Cg)CyC Io alkyl, or (C3-C ₈ )cycloalkyl(Ci-C6)alkyl, wherein the (Ci-C ₆ )alkyl, (QrCgJeycloalkyl, and (C3-C8)cycloalkyl(C]-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C ₆ )alkyl, (C _t -C ₆ )alkoxyearbonyl« (Ci-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ ₁ Z ₂ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane;

R ₆ is H, (Ci-C _ό )alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )eyeloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )eycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-Cή)alkoxy, (Ci-C ₆ )alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (C ₁ -C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ ₃ Z ₄ , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; Z ₃ and Z ₄ are independently H or (Ci-C ₆ )alkyl; and

R ₇ Js OR ₂ Or NR ₄ R ₅ ; provided that the compound is not

N-acctyl-S-[(2',4'-difluoro-4-hydroxy[l , 1 '-biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester: N-acetyl-S-[(2',4'-difluoro-4-hydroxy[l , 1 '-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; N-acetyl-S-[(2 ⁱ ,4 ⁱ -difluoro-4-acetyloxy[ 1 , 1 ^f -biphenylj-3-yI)carbonyl J-L-cysteine methyl ester; and N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[l,r-biphenyl]-3-yl)c arbonyll-L-cysteine ethyl ester.

Representative compounds of Formula (XX) include, but are not limited to, the compounds shown below;

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XX), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides compounds of Formula (XXI)

wherein

X is absent, halogen, HSO ₄ , HPO ₄ , CH ₃ CO ₂ , or CF ₃ CO ₂ ;

R _I iS OR ₃ OrNR ₄ R ₅ ;

R ₂ is H or 2,4-difluorophenyl; R ₃ is H, (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (Ci-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkoxy(Ci-C ₆ )alkyl, (Ci-C _ό jalkoxycarbonyl, (€i-C _ό )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ ₁ Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens;

R ₄ and R ₅ are independently H, (Ci-Cβjalkyl, (C ₃ -C8)cycloalkyl, or (C ₃ -C ₈ )cycloalkyl(Ci-C ₆ )alkyl, wherein the (d-C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, and (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C ₆ )alkoxy, (C ₁ -C6)alkoxy(Ci-C6)alkyl, (Cj-C ₆ )alkoxycarbonyl, (Ci-C ₆ )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R4 and R ₅ together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and

Zi and Z ₂ are independently H or (Ci-Q,)alkyl.

Representative compounds of Formula (XXI) include, but are not limited to, the compounds shown below, wherein X is absent, Cl, Br, I, HSO4, or CH ₃ CO2:

;52

In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XXI), as shown above, and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides conjugates of Formula (XXII)

wherein Ri is

R2 is (Ci-C4)alkoxy, hydroxy, orNZiZ ₂ j and Zi and Z ₂ are independently hydrogen or (Ci -Chalky!;

Representative conjugates of Formula (XXII) include, but are not limited to, the compounds shown below.

In another aspect, the present Invention provides pharmaceutical compositions comprised of a compound of Formula (XXII), as shown above, and at least one pharmaceutically acceptable caiτier. For each of the compounds of Formulae (I -XXII) set forth herein, the invention provides in separate aspects methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I- XXII), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I- XXII) and at least one pharmaceutically acceptable carrier. For each of the compounds of Formulae (I-XXII) set forth herein, the invention provides in separate aspects methods for treating type II diabetes mellitus, metabolic syndrome, dyslipidemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XXII), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I-XXII) and at least one pharmaceutically acceptable carrier, For each of the compounds of Formulae (I-XXII) set forth herein, the invention provides in separate aspects provides methods for reducing free fatty acids, triglycerides, advanced glycated end products, ROS. lipid peroxidation, tissue and plasma TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XXII). as shown above, or a pharmaceutical composition comprised of a compound of Formulae < I-XXII) and at least one pharmaceutically acceptable carrier. For each of the compounds of formulae (I-XXII) set forth herein, the invention provides in separate aspects provides provides methods for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effeetπe amount of a compound of Formulae (I-XXII), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I-XXIIj and at least one pharmaceutical)} acceptable carrier For each of the compounds of Formulae (1-XXII) set forth herein, the invention provides in separate aspects provides provides uses for compounds of Formulae (I -XXII), or pharmaceutical compositions comprised of a compound of Formulae (I-XXII) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, COPD, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, LADA, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient. The present invention also provides uses for compounds of Formulae (I-XXII), or pharmaceutical compositions comprised of a compound of Formulae (I-XXII) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for reducing free fatty acids, triglycerides, advanced glycated end products, ROS, lipid peroxidation, tissue and plasma TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient. The present invention also provides uses for compounds of Formulae (I- XXII), or pharmaceutical compositions comprised of a compound of Formulae (I-XXII) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for protecting pancreatic b-cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient.

In another aspect, the present invention provides methods for treating adipocyte dysfunction related diseases, carbohydrate metabolism related diseases, vascular diseases, neurodegenerative diseases _^ cancers, arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer's disease, Parkinson's diseases, cystic fibrosis, dysfunctions of the immune system, stroke, multiple sclerosis, migraine, pain, inflammatory eye conditions including uveitis, glaucoma and conjunctivitis, degenerative bone or joint conditions including osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed joints, chronic inflammatory skin conditions, including allergic lesions, lichen planus, pityriasis rosea, eczema, psoriasis, and dermatitis, diseases and disorders of the gastrointestinal tract, including inflammatory bowel disease, Crohn's disease, atrophic gastritis, gastritis varialo forme, ulcerative colitis, coeiiac disease, regional ileitis, peptic ulceration, particularly irritable bowel syndrome, reflux oesophagitis, and damage to the gastrointestinal tract resulting lroni infections, tor example, by Helicobacter priori. inflammatory lung disorders such as asthma, bronchitis, particularly chronic obstructive pulmonary disease, farmer's lung, acute respiratory distress syndrome; bacteraemia, endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis, particularly pain, including inflammatory pain, neuropathic pain, acute pain or pain of a central origin; meningitis and pancreatitis, and other conditions associated with inflammation, central nervous system inflammatory conditions and diseases, including ischaemia-reperfusion injury associated with ischemic stroke; vascular diseases, such as atheromatous and nonatheromatous, ischemic heart disease, and Raynaud's Disease and Phenomenon in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formulae (I-XXII), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides uses for conjugates of Formula (I-XXII) for preparing, or for the manufacture of, a medicament for treating the diseases/disorders listed above.

In another aspect, the present invention provides methods for treating adipocyte dysfunction related diseases, carbohydrate metabolism related diseases, vascular diseases, neurodegenerative diseases, cancers, arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer's disease, Parkinson's diseases, cystic fibrosis. dysfunctions of the immune system, stroke, multiple sclerosis, migraine, pain, inflammatory eye conditions including uveitis, glaucoma and conjunctivitis, degenerative bone or joint conditions including osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed joints, chronic inflammatory skin conditions, including allergic lesions, lichen planus, pityriasis rosea, eczema, psoriasis, and dermatitis, diseases and disorders of the gastrointestinal tract, including inflammatory bowel disease, Crohn's disease, atrophic gastritis, gastritis vaπalo forme, ulcerative colitis, coeliac disease, regional ileitis, peptic ulceration, particularly irritable bowel syndrome, reflux oesophagitis, and damage to the gastrointestinal tract resulting from infections, for example, by Helicobacter pylori, inflammatory lung disorders such as asthma, bronchitis, particularly chronic obstructive pulmonary disease, farmer's lung, acute respiratory distress syndrome; bacteraemia. endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis, particularly pain, including inflammatory pain, neuropathic pain, acute pain or pain of a central origin; meningitis and pancreatitis, and other conditions associated w ith inflammation, central nervous system inflammatory conditions and diseases, including ischaemia-repetfusion injury associated with ischemic stroke; vascular diseases, such as atheromatous and nonatheromatous. ischemic heart disease, and Raynaud's Disease and Phenomenon in in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I-XXII), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating the diseases/disorders listed above, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I-XXII), or a pharmaceutically acceptable salt thereof.

Definitions

As used throughout this specification and the appended claims, the following terms have the following meanings: The term "(Ci-C ₆ )alkoxy" as used herein, means a (Ci-C ₆ )alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of (Ci-C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "(Ci-C6)alkoxycarbonyl" as used herein, means a (Ci-C _ό )alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (Ci -C ₆ )alkoxy carbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and teit-butoxycarbonyl.

The term "(Ci-C ₆ )alkoxysulfonyl" as used herein, means a (Ci-C ₆ )alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (Ci-C _ό )alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.

The term "(Ct-€ήlalkyP ^* as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of (Ci-C _ft )alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl. isopentyl. neopentyl, n-hexyl. 3-rnethylhexyl. 2,2-dimethylpentyl, and hexyl.

The term "(Ci-C6)alkylcarbonyl" as used herein, means a (C;-C _ό )alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (Ci-Ce)alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term "(Ci-C ₆ )alkylcarbonyloxy" as used herein, means a (Cj-C ₆ )alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of (Cj-C ₆ )alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.

The term "(Ci-C ₆ )alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 6 carbon atoms. Representative examples of (Ci-C ₆ )alkylene include, but are not limited to, -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, and -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

The term "(C ₁ -C ₆ )alkylsulfonyl" as used herein, means an (Ci-C ₆ )alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (Ci-C ₆ )alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "(d-C ₆ )alkylthio" as used herein, means a (Ci-C ₆ )alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of (Ci-C ₆ )alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.

The term "carbonyl" as used herein, means a -C(O)- group. The term "carboxy" as used herein, means a -CO ₂ H group.

The term "cyano" as used herein, means a -CN group.

The term "formyl" as used herein, means a -C(O)H group. .

The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F.

The term "halo(Ci-C ₆ )alkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-C ₆ )alkoxy group, as defined herein. Representative examples of halo(Ci -C ₆ JaIkO xy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term "halo(C i-C^alkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-C ₆ )alkyl group, as defined herein. Representative examples of halo(Ci-C ₆ )alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term "HTB" as used herein means 2-hydroxy-4-(trifluoromethyl)benzoic acid, a metabolite of triflusal. Conjugates comprised of HTB and one or more antioxidants are specifically contemplated by the present invention. The term "hydroxy" as used herein, means an -OH group.

The term "hydroxy(Ci-C ₆ )alkyl" as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (Ci-Cejalkyl group, as defined herein. Representative examples of hydro xy(Ci-C6)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2,3-dihydroxypentyl.

The term "mercapto" as used herein, means a -SH group.

The term "nitro" as used herein, means a -NO ₂ group.

The term "sulfonyl" as used herein, means a -SO ₂ - group.

Compounds of the present invention include α-amino acids, or derivatives thereof such as esters or amides, that can exist as stereoisomers, wherein the asymmetric or chiral center is present at the α-carbon. The chiral center is designated (L) or (D) based on the Fischer projections of (L) or (D) aldose. Ernest L. Eliel and Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, page 1 12, 1994. Further, compounds of the present invention may contain a stereocenter that is not an α-carbon of an α-amino acid (or derivative thereof). This center is designated (R) or (S), depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution, a technique well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) formation of a diastereomeric salt followed by selective i eci y stalli/ation υf one υf the diastereomeπc saits.

The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration. The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The present invention provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans (patients) and other mammals orally, rectally, parenterally , intracisternally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions, Examples of suitable aqueous and nonaqueous earners, diluents, solvents or vehicles include water, ethanoi polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of the present invention can be incorporated into slow-release or target ed-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use

The active compounds can also be in micro -encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art, In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tablet ing lubricants and other tab let ing aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S, P, and isotonic sodium chloride solution.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, free fatty acids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose. alginates, gelatin, porvvύrvlpyrrolidinone, sucrose. and acacia; c) hurnectatits such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds: g) wetting agents such as cctyl alcohol and glycerol monostearate: h) absorbents such as kaolin and bcntonitc clav; and i) lubricants such as talc, calcium stearate. magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. in the case of capsules, tablets and pitls. ilie dosage fomi mav also comprise buffei ing agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyltbrmamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and free fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chloro fluorohydro carbons.

Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,

Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.

The phrase "therapeutically effective amount" of the compound of the present invention means a sufficient amount of the compound to treat metabolic disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response tor a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. The total daily dose of the compounds of this invention administered to a mammal, and particularly a human, from about 0.03 to about 20 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.1 to about 10 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

The term "pharmaceutically acceptable salt," as used herein, means a positively- charged inorganic or organic cation that is generally considered suitable for human consumption. Examples of pharmaceutically acceptable cations are alkali metals (lithium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammmonium, and choline. Cations may be interchanged by methods known in the art, such as ion exchange. Where compounds of the present invention are prepared in the carboxylic acid form, addition of a base (such as a hydroxide or a free amine such as an alpha amino acid) will yield the appropriate salt form, (L) lysine is a preferred free amine for preparing salts of the present invention.

The present invention contemplates pharmaceutically active metabolites formed by in vivo biotransformation of conjugates of Formula (I). The term pharmaceutically active metabolite, as used herein, means a compound formed by the in vivo biotransformation of conjugates of Formula (I). The present invention contemplates conjugates of Formula (I) and metabolites thereof. A thorough discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition).

All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety for any purpose.

The following Schemes and Examples are provided for the purposes of illustration and are not intended to limit the scope of the present invention. The invention is not limited in scope by the exemplified embodiments, which are intended as illustrations of individual aspects of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Preparation of Compounds of the Invention Scheme 1

Conjugates of Formula (I), wherein Ri, R2, R3, R4, Rs, R7, Re, R9, and L are as defined in the Summary section herein, are prepared as described EP 0 080229, BE 900328, or Scheme 1. Acids of formula (1) are treated with an alcohol or mercaptan of formula (2) in an appropriate solvent optionally with heating and optionally with one or more coupling reagents to provide conjugates of Formula (I). Coupling reagents useful for preparing compounds of the present invention include, but are not limited to, dimethylaminopyridine (DMAP), 1,3-di- tert-butylcarbodiimide, 1,1 '-carbonyldiimidazo Ie (CDI), lj'-thiocarbonyldiimidazole, 1,1'- carbonylbis(2-methylimidazole), l-(3-dimethylaminopropyl)-3-ethylcarbodϋmide hydrochloride (EDCI), benzotriazol-1-yl-oxy-tris-pyrrolidino- phosphoniumhexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop), O-(-7-azabenzotriazol-l -yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate, N-t(dimethylamino)(3H-[l ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylene]-N-methylmethanaminium, benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPCl), l^-dicyclohexylcarbodiimide (DCC), 1-Hydroxy- 7-azabenzotriazole (HOAT), 1-hydroxybenzotriazole hydrate (HOBT), 3-hydroxy- 1,2,3- benzotriazin-4(3H)-one (HOOBT), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol- 1 -yl-N,N,N\N'- tetramethyluronium hexafluorophosphate (HBTU), and O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU).

Scheme 2

Alternatively, conjugates of Formula (I), wherein R], R ₂ , R ₃ , R4, R ₅ , R ₇ , Rg, R9, and L are as defined in Formula (1) of the Summary section herein, are prepared as described in Scheme 2. Acids of formula (1) are treated with a chlorinating reagent such as thionyl chloride (or PCI ₃ ) in an appropriate solvent to provide acid chlorides of formula (3). Conjugates of Formula (3) are treated with a base such as triethylamine (or diisopropylethylamine) and an alcohol or thiol of formula (2) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (1).

Scheme 3

Conjugates of Formula (II), wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R _la , R _2a , R _3a , R ₄₃ , and R _5a , are as defined in Formula (I) of the Summary section herein, are prepared as described in Scheme 3. Conjugates of Formula (I) are treated with a benzoic acid of formula (4) in the presence of one or more coupling reagents, as disclosed in Scheme 1, in an appropriate solvent to provide conjugates of Formula (II). Alternatively, a conjugate of Formula (4) can be treated with a chlorinating agent (see Scheme 2) and a base including, but not limited to triethylamine or diisopropylethylamine, to provide the corresponding acid chloride. The acid chloride is treated with a conjugate of Formula (I) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (II).

Scheme 4

Conjugates of Formula (III), wherein R ₂ , R ₃ , R ₄ , R5, R ₆ , R2a, R3a, R4a, R-5a, Rib, R∑b,

R _3b , R» _b , and Rsb are as defined in Formula (I) of the Summary section herein, are prepared as described in Scheme 4. Conjugates of Formula (II) are treated with a benzoic acid of formula (5) in the presence of one or more coupling reagents, as disclosed in Scheme 1, in an appropriate solvent to provide conjugates of Formula (III). Alternatively, a conjugate of Formula (S) can be treated with a chlorinating agent (see Scheme 2) and a base including, but not limited to triethylamine or diisopropylethylamine, to provide the corresponding acid chloride. The acid chloride is treated with a conjugate of Formula (II) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (III).

Scheme 5

Compounds of Formula (XIII), wherein R ₂ is H or 2,4-difluorophenyl and Ri is as denned herein, are prepared as described in Scheme S. Lipoic acid is treated with a chlorinating agent (such as thionyl chloride or POCI ₃ or PCI ₃ ) to provide the corresponding acid chloride. Phenols of formula (A) are treated with the acid chloride of lipoic acid in the presence of base, such as triethylamine or diisopropylethylamine, to provide compounds of Formula (XIII).

Scheme 6

Compounds of Formula (XIV) and (XV), wherein R2 is H or 2,4-difluorophenyl and

Ri and R3 are as defined herein, are prepared as described in Scheme 6. Compounds of Formula (II) are prepared by treating phenols of formula (A) with 4-nitrophenyl carbonochloridatβ to provide carbonates of formula (B). Carbonates of formula (B) are treated with derivatives of N-acetylcysteine (compounds of formula (C)) to provide compounds of Formula (XIV). Bioυrganic Med, Chem., 13 (19) pg 5592 (2005), Alternatively, acyl chlorides of formula (D), prepared using similar methodology as disclosed in Bull, Chem, Sυc. Japan, 37 (2) pgs 242-244, (1964), are treated with phenols of formula (A) to provide compounds of Formula (XIV). Compounds of Formula (XV) are prepared by treating taurine with carbonates of formula (B), Scheme 7

The compound of Formula (XVI) and compounds Formula (XVII) are prepared as described in Scheme 7. The compound of Formula (XVI) are prepared by treating 4-nitrophenyl carbonochloridate with acetaminophen (paracetamol) to provide the compound of formula (E). The compound of formula (E) is treated with taurine to provide the compound of Formula (XVI). Bioorganic Med. Chem., 13 (19) pg 5592 (2005).

Compounds of Formula (XVII), wherein R ₃ is as defined herein, are prepared by treating 4-nitrophenyl carbonochloridate (compound of formula (E)) with a compound of formula (C) to provide compounds of Formula (XVII). Alternatively, acyl chlorides of formula (D), prepared in a similar manner as disclosed in Bull. Chem. Sot: Japan, 37 (2) pgs 242-244. (1964), are treated with acetaminophen to provide compounds of Formula (XVIl). Scheme 8

Compounds of Formula (XVIII) and the compound of Formula (XIX) are prepared as described in Scheme 8. Lipoic acid is treated with a chlorinating agent (such as thionyl chloride or POCb, or PCI ₃ ) to provide the corresponding acid chloride. Amines of formula (F) are treated with the acid chloride of lipoic acid in the presence of base, such as triethylamine or diisopropylethylamine, to provide compounds of Formula (XVIII) wherein Ri is as defined herein.

The compound of Formula (XIX) is prepared by treating

2-(2,6-dichlorophenylamino)benzoic acid with taurine in the presence of coupling reagents. Coupling reagents useful for preparing the compound of Formula (XIX) include, but are not limited to, dimethylaminopyridine (DMAP), 1,3-di-tert-butylcarbodiimide, 1,1 '-carbonyldiimidazole (CDI), 1 , 1 '-thiocarbonyldiimidazole, 1 , 1 '-carbonylbis(2- methylimidazole), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), benzotriazol-1 -yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP), bromo- tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop), O-(-7-azabenzotriazol-l-yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate, N-[(dimethylamino)(3H- [ 1 ,2,3]tria2»lo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmeth anaminium, benzotriazol- 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPCl), l^-dicyclohexylcarbodiimide (DCC), 1 -Hydro xy- 7-azabenzotriazole (HOAT), 1 -hydro xybenzotriazole hydrate (HOBT), 3-hydro xy- 1,2,3- benzotria2in-4(3H)-one (HOOBT), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU), and O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU). Alternatively, the compound of Formula (XIX) is prepared by treating 2-(2,6-dichlorophenylamino)benzoyl chloride with taurine.

Scheme 9

Compounds of Formula (XX), wherein Ra is H or 2,4-difluorophenyl and Rj is as defined herein, are prepared as described in Scheme 9. Acids of formula (G) are treated with a chlorinating reagent such as thionyl chloride (or PCl ₃ ) in an appropriate solvent to provide acid chlorides of formula (H). Acid chlorides of formula (H) are treated with compounds of formula (J) and a base such as triethylamine (or diisopropylethylamine) to provide compounds of Formula (XX). Alternatively, the compounds of formula (XX) are prepared using similar methodology as that described in European patent application no, 881 12028.1 (publication no. EP O 301 474 A2). Scheme 10

Compounds of Formula (XXI), wherein Ro is H or 2,4-difiuorophenyl and Ri is as defined herein, are prepared as described in Scheme 10. (3-Carboxy-2- hydroxypropyl)trimethyl ammonium is treated with a reagent such as methoxymethyl chloride, (chloromethyl)(methyl)sulfane, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, or benzyl bromide in the presence of a base such as triethylamine, diisopropylethylamine, imidazole, or sodium hydride to provide a compound of formula (K), wherein PG is a hydroxy protecting group. The compound of formula (K) is treated with a chlorinating agent (such as thionyl chloride or POCI ₃ or PCl ₃ ) to provide the corresponding acid chloride of formula (L). Phenols of formula (A) are treated with an acid chloride of formula (L) in the presence of base, such as triethylamine or diisopropylethylamine, to provide compounds of formula (M). The hydroxy protecting group is removed from compounds of formula (M) to provide compounds of Formula (XXI). In particular, the methoxymethyl, methylthiomethyl. tert-butyldimethylsilyl, tert- butyldiphenylsilyl, or benzyl protecting groups are removed by treating compounds of formula (M) with: Ph ₃ ⁴ BF ₄ ^' in CH ₂ Cl ₂ : HgCi ₂ in CH ₃ CN; Bu ₄ NT ^' in THF; Bu ₄ NT ^" in THF; and BF ₃ Et ₂ O NaI in CFI ₃ CN, respectively. Scheme 1 1

Compounds of Formula (I), wherein R2 is H or 2,4-difluorophenyl, are prepared as described in Scheme 1 1 . A compound of formula (N) is treated with 2,2,2-trichloroethyl- chlorocarbonate and a base such as triethylamine in acetone at -3 ⁰ C to provide the anhydride of formula (O). Compounds of formula (O) are treated with L-N-acetylcysteine and triethylamine dropwise in acetone at O ⁰ C to provide compounds of formula (P). Compounds of formula (P) in glacial acetic acid are treated with Zn (powder) and hydrogen gas to provide compounds of Formula (1).

(R)-2-acetamido-3 -(2-hydroxybenzo ylthio )propano ic acid The title compound is prepared using the procedures described in EP O 080 229, Example 2

(R)-methyl 2-acetamido-3-(2-hydroxybenzoylthio)propanoate

The title compound is prepared using similar procedures as described in EP O 080 229.

Example 3

(R)-ethyl 2-acetamido-3~(2-hydroxybenzoylthio)propanoate

The title compound is prepared using similar procedures as described in EP O 080 22929.

Example 4

(R)-2-acetamido-3-.(2-acetoxybenzoylthio)propanoic acid The title compound is prepared using similar procedures as described in EP 0 080 229. Example 5

(IP-methyl 2-acetamido-3-(2-acetoxybenzoylthiotøropanoate

The title compound is prepared using similar procedures as described in EP 0 080 229.

Example 6

The title compound is prepared using similar procedures as described in EP 0 080229.

Example 7

(R ^" )-2-acetamido-3-(2-hvdroxy-4-(trifluoromethynbenzoylth io)propanoic acid The title compound is prepared using similar procedures as described in EP 0 080 229.

Example 8

(R)-methyl 2-acetamido-3-(2-hydroxy-4-(trifluoromethyl)benzoylthio)prop anoatg The title compound is prepared using similar procedures as described in EP O 080 229.

(R)-ethyl 2-acetamido-3-(2-hydroxy-4-(trifluoromethyl)benzoylthio)prop anoate

The title compound is prepared using similar procedures as described in EP 0 080 229.

Example 10

(R)-2-acetamido-3-(2-acetoxy-4-(triflupromethyl)bcnzoylth io)propanoic acid The title compound is prepared using similar procedures as described in EP O 080 229.

(R)-methyl 2-aeetamido-3-(2-aeetoxy-4-(trifluoromethyl)benzoylthio)prop anoate The title compound is prepared using similar procedures as described in EP 0 080 229.

(R)-ethyl 2-acetamido-3-(2-aeetoxy-4-(trifluoromethyl)benzoylthio)prop anoate

The title compound is prepared using similar procedures as described in EP O 080 229.

(R)-2-acetamido-3-(2',4'-difluoro-4-hydroxybiphenylcarbon ylthio)propanoic acid

The title compound is prepared using the procedures described in BE 900328. The title compound was also commercially available. However, alternatively the compound was synthesized as follows.

Example 13a

To a solution of 2'.4 ^t -difluoro-4-hydroxy-l , l '-diphenyl-?-carboxylic acid (Difliinlsal, 82,5 g, 0.329 mol) dissolved in acetone (450 mL) and cooled to -10 ^C C ^* (refrigerant mixture: temperature: from -8 ^C C to 9 ⁰ C). To the resulting solution was added 2,2.2-trichloroethyl chloro formate (100 tnL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below O ⁰ C: from -10 ⁰ C to 0 ⁰ C). The mixture was stirred for 1 h at 0 ⁰ C (a white precipitate of triethylamine hydrochloride was gradually formed). At the end of the reaction, the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4x180 niL) and the filtrate was evaporated under vacuum at 30 ⁰ C. The oily residue was taken with Et ₂ O (150 niL) and the suspension was evaporated again under vacuum. The operation was repeated three times to remove excess of chlorocarbonate. The residue was dissolved in acetone (180 mL), and added to a refrigerated solution of N- acetyl-Z-cysteine (JV-Ac-Cys, 53.81 g, 0.329 mol) and Et ₃ N (46 mL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 15°C: from 0 ^C C to 15 ^C C). The reaction mixture was stirred at 15 ^C C for 4 h. The mixture was cooled to -12 ¹³ C (internal temperature), and Et ₃ N (115 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12 ⁰ C (internal temperature), and at the end of the reaction, the mixture was filtered under vacuum and the precipitate was washed with acetone (3x150 mL). The oily precipitate was suspended in CH2CI2 (400 mL), cooled to 0 ⁰ C and an aqueous HCl solution (15% v:v) was added with vigorous stirring until the pH was lowered to 3. Ethanol (80 mL) was added, and the aqueous phase was extracted with CH2CI2 (2x400 mL). The combined organic layers were washed with a 10% HCl aqueous solution (1x500 mL) and with water (2x600 mL), were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration with Et ₂ θ (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et2θ (100 mL) and stirred at room temperature for 20 min. The solid was filtered under vacuum and was washed with Et ₂ O (3x100 mL), to afford 31.33 g of the title compound GMC-3b (R/= 0.3 CH ₂ Cl ₂ /Me0H/Ac0H 95:5: 1 ), white solid, 24% yield, 96.22% HPLC purity); Purity was determined by NMR analysis and mass spectrometry to conform to the following parameters: IH-NMR (CD ₃ OD, 250 MHz, δ): 8.00 (m, I H, ArH); 7,66 (dm, J - 8.2 Hz, I H, ArH), 7.50 (m, IH, ArH); 7.06 (m. 3H, ArH); 4.74 (m. IH, CH); 3.77 (dd, J = 4.7 and 13.7 Hz, IH, CH); 3.40 (m, I H, CH); 1.98 (s, 3H, CH ₁ ); MS-EI+ m/z: 396.00 (MxI); LC-MS: M+l : 396.00; purity: 96.52% (HPLC method: SunFire Cl 8 3.5 urn, 2.1x100 mm, flow: 0.3 mL/min, gradient: A:B 3 mm 10:90 ^■ + from 10 ^* 90 to 95.5 in 17 min - 10 min 95 ^* 5; A- CH ₃ CN ¹ MeOH 1 : 1 : B; NH ₄ OAc buffer 5 mM pH 7).

.81 Example 13b

Synthesis of (2R)-2-(Acetylamino)-3-{[(2',4'-difluoro-4-hydroxy-l,l'- biphenyl-3- yl)carbonyl]thio}propanoic acid L-Lysine Salt

Starting material (GMC-3b, 18.33 g, 46.37 mmol, Example 13a) was dissolved in acetone (300 mL) and Z-Lysine (L-Lys, 6.44 g, 44.05 mmol) dissolved in H ₂ O (60 mL) was added. Acetone (100 mL) was added and the mixture was stirred at room temperature for 1 h. The resulting solid was filtered under vacuum, washed with acetone (3x100 mL), Et ₂ O (2x80 mL), and hexanes (2x80 mL). The solid was dried at room temperature to give 22.01 g of title salt GMC-3b L-Lys as a white solid. (92% yield, 99.59% HPLC purity). ¹ H- NMR (D ₂ 0, 250 MHz) δ 7.77 (m, 1 H, ArH); 7.50 (d, J= 8.5 Hz, IH, ArH); 7.23 (m, 1 H, ArH); 6.90 (m, 3H, ArH); 4.47 (m, 1 H, CH); 3.73-3.59 (m, 2H, CH); 3.25 (m, 1 H, CH); 2.97 (t, J =7.4 Hz, 2H, CH ₂ ); 1.94 (s, 3H, CH ₃ ); ); 1.84 (m, 2H, CH ₂ ); 1.67 (m, 2H, CH ₂ ); 1.44 (m, 2H, CH ₂ ); MS-EI ⁺ m/z: 396.00 (M+1-L-Lys); LC-MS: M+l l-£-Lys: 396.00; purity: 99.59% (HPLC method: SunFire Cl 8 3.5 um, 2.1x100 mm, flow: 0.3 mL/min, gradient: A:B 3 min 10:90 + from 10:90 to 95:5 in 17 min + 10 min 95:5; A: CH ₃ CN:MeOH 1:1; B: NH ₄ OAc buffer 5 mM pH 7).

Example 14

(R)-methyl 2-acetamido-3-(2\4'-difluoro-4-hydroxybiphenylcarbonylthio)p ropanoate The title compound is prepared using similar procedures as described in BE 900328.

(^-ethy^-acetamido-S-ri'^'-difluoro- _' Φ-hydroxybiphenylcarbonylthiolpropanoate The title compound is prepared using similar procedures as described in BE 900328.

(R)-2-acetamido-3-(4-acetoxy-2'.4'-difluorobiphenylcarbon ylthio)propanoic acid The title compound is prepared using similar procedures as described in BE 900328.

(RVmethyl 2-acetamido-3-(4-acetoxy-2',4'-difluorobiphenylcarbonylthio) propanoate The title compound is prepared using similar procedures as described in BE 900328.

(R)-ethyl 2-acetamido-3-(4-acetoxy-2',4'-difluorobiphenylcarbonylthio) propanoate The title compound is prepared using similar procedures as described in BE 900328.

Example 19

Methyl 2-(5-((R)- 1 ,2-dithiolan-3-yl)pentanoyloxy)benzoate

Lipoyl chloride (commercially available, 300 mg) was added slowly to a solution of Meth\l 2-hydroxybenzoate (commercially available, 260 mg) and triethylamine (300 mg) in dichloromethane. The reaction was stirred at room temperature for 12 h. The reaction was then concentrated and the residue purified by column chromatography to obtain the desired compound ( 160 mg) as a pale yellow solid. ¹ H-NMR (DMSO) δ: 1.29 (m, 2H); 1.55 (m. 4H); 1.80 (m, 4H); 2.23 (m, 2H); 2.58 (m, 3H); 3.80 (s, 3H); 7.18 (m, 2H); 7.44 (m, IH); 7.94 (m, IH).

Example 20 lett-Bulyl 2-(5-((R)- 1 ,2-dithiolan-3-yl)pentanoyioxy)benzoate

The title compound was prepared in a similar manner as that described in Example 19 except using tert-butyl 2-hydroxybenzoate instead of methyl 2-hydroxyben7oate. ¹ H-N ¹ VtR (DMSO) 6: 1.29 (m, 2H); 1.40 (s, 9H); 1.55 (m, 4H); 1.80 (m, 4H); 2.23 (m, 2H); 2.58 (m, 3H); 7.18 (m, 2H); 7.44 (m, IH); 7.94 (m, IH).

Example 21

Benzyl 2-(5-((R)-1 ,2-dithiolan-3-yl)pentanoyloxy)benzoate

The title compound was prepared in a similar manner as that described in Example 19 except using benzyl 2-hydroxybenzoate instead of methyl 2-hydroxybenzoate. ¹ H-NMR (DMSO) δ: 1.29 (m, 2H); 1.55 (m, 4H); 1.80 (m, 4H); 2.23 (m, 2H); 2.58 (m, 3H); 5.51 (m, 2H); 7.18 (m, 7H); 7.44 (m, 1 H); 7.94 (m, 1 H).

Experimental Methods for Figures 1-27

The experiments described herein illustrate beneficial embodiments of the invention comprising distinct antioxidat-antiinflammatory agent conjugates. The advantageous and beneficial properties of alternative conjugates as provided by this invention can be demonstrated using substantially the same experiments and assays.

Animals. Male cd-1 mice weighing 25-30 g were purchased from Charles River Laboratories Spain. The animals were housed in animal quarters at 22 ⁰ C with a 12-h light / 12-h dark cycle and fed ad libitum. 5 -weeks old Male mice C57BL/Ks bearing the db/db mutation (The Jackson Laboratories) were purchased from Charles River Laboratories Spain (Sant Cugat del Valles, Spain).

Chemicals, The chemicals N- Acetyl-cysteine and Sodium Salicylate were purchase from Sigma (Sigma Aldrich, St. Louis. MO, USA) and PBS was purchase from Invitrogen. The compounds of diflunisal, dexibuprofen, and salnacedin (GMC-Ua). and their lysine salts were purchase from Galchimia, S. L. (Galchimia S. L., A Corona, Spain). All the compounds were dissolved in PBS. with lysine salt when indicated, and the pH of the compounds without hsine was adjusted with NaOH 6N until pH ~.

ϊii vitro U-cell protection model INS-IE j8-cells were cultivated in the presence of a high glucose concentration (11 mM) and a high palmitate concentration (0.4 mM bound to BSA 0.5 %) in order to promote glucotoxicity and lipotoxicity. The combination of both stressors promote the apoptosis of the _/ S-cells. INS- 1 E cells were seeded at a density of 80.000 cells / cni2 in 96 wells plates 4 days before the beginning of the treatment. At 60-80 % of confluence, cells were fasted with RPMI 5mM of glucose + FBS 10%. 8 h later, antioxidants and anti-inflammatory agents, alone or in combination were added overnight at the indicated concentrations. The day after, fasting medium was changed by the stressing medium (glucose 25 mM + palmitate 0.4 mM bound to BSA 0.5 %). Medium, and tested agents when present, were changed every 24 h. 48 h after the addition of the stressing medium, apoptosis was measured with Apo-One Homogeneous Caspase 3/7 Assay (Promega) which determine the activity of easpase 3 and 7. Cells were frozen at -80"C for 2 hours, defrost at room temperature and incubated in the presence of 100 μl of caspase reactive for 20 hours. Resulting fluorescence was read at 485/530 (excitation/ emission wave lenght). The background apoptosis, in absence of stressing condition, was determined with INSl E cells cultured in the presence of fasting medium

(RPMI 5 mM glucose + FBS 10 %). Staurosporine 0.2 % in the presence of 0.5 % BSA was used as a positive control of apoptosis.

In vivo Beta cell protection model Beta-cell destruction was induced in ed-1 mice after 3 hours of fasting by a single intraperitoneal injection of a freshly prepared solution of alloxan 200mg/kg (Sigma- Aldrich, San Luis, MO) that was dissolved in NaCl 0.9%. Single intraperitoneal drug administration was 1 hour before the alloxan administration. Animals received the different drugs dissolved in PBS pH 7.4, and the animals that not received any drug were injected with the vehicle, in this case PBS pH 7.4. At the end of the treatment, at day 4, animals were killed and the plasma collected and kept at -20 ⁰ C until used.

Mjci^)gomal _^ cjeayj|gej|tsavs

IB vitro cleavage experiments were performed substantiallas described in Singh et al, 1996, in vitro metabolism of a potent HIV-protease inhibitor (141 W94) using rat, monkey and human Hv εr S9, Rapid Commun. Mass Spectrom. 10: 1019-1026. Briefly, conjugate compounds of the invention were incubated at a final concentration of 1 micro M for I hour in the presence of human or rat liver microsome S9 (obtained from Xenotech). At the end of incubation at each of the time points reported, an equal volume of an organic mixture (acetonitrile'methanol, 50/50, v/v) was added to the incubation mixture followed by centriftigation. At this time blank microsomal extract was spiked with metabolites to create calibration standards for each metabolite at the following concentrations: 0 (blank), 0.05, 0.1, 0.5 and 1 micro M. All samples were analyzed by HPLC-MS/MS and the peak areas corresponding to the expected metabolites (generally, antioxidant and anti-inflammatory cleavsasge products) were determined by HPLC-MS/MS. The amount of each metabolite present in the 60 minute incubation samples was determined from the corresponding calibration curve.

Chronic treatment in db/db mice. 5-weeks old Male mice C57BL/Ks bearing the db/db mutation (The Jackson Laboratories) were purchased from Charles River Laboratories Spain (Sant Cugat del Valles, Spain). The animals were housed in animal quarters at 22°C with a 12-h light / 12-h dark cycle and fed ad libitum. The animals were treated with the indicated drugs for a month. The administration route was a single intraperitoneal injection. The glycemia levels were determined in blood from the Tail Vein, using a rapid glucose analyzer (Accu-Chek A viva; Roche) 3 times per week, as body weight measure too. The food and water intake were measured twice a week. At the end of the treatment, the mice were sacrificed, in feeding state, with CO2 euthanasia, and the blood was extracted from the Inferior Cave Vein, using heparin as an anticoagulant, and maintained at 4°C until the preparation of plasma.

Intraperitoneal Insulin Tolerance Test.

At the third week of treatment, an Insulin Tolerance Test was done to the mice in feeding state. The animals received an ip injection of Insulin 2 Uϊ/kg (Humulin®). The glycemia levels were determined at the indicated time in blood from the Tail Vein, after the Insulin injection using a rapid glucose analyzer.

Intraperitoneal GIueose Tolerance Test.

At the fourth week of treatment, a Glucose Tolerance Test was done to the mice after an overnight fasting. The animals received an ip injection of Glucose 0.5 g/kg (Glucosmon 50 "M)), The glycemia levels were determined in blood at the indicated time from the Tail Vein after the Glucose injection using a rapid glucose analvzer,

Determination of biochemical parameters. The circulating glucose concentration was determined by a rapid glucose analyzer (Accu- Chek Aviva; Roche). Plasma triglycerides and non esterified fatty acids were determined with standard colorimetric methods (Biosystems, Barcelona, Spain, and Wako Chemicals, Neuss, Germany, respectively). Plasma insulin concentration was determined by enzyme-linked immunosorbent assay method (CrystalChem, Downers Grove, IL). Total pancreas insulin content has been determined after extraction of insulin with a mixture Ethanol (70 %) / HCl (0.15 N) from pancreas homogenates.

Preparation of pancreas sections and immunohistochemical analyses. The pancreas was removed from each mouse and fixed overnight in a solution of 4% formalin. Fixed tissues were processed routinely for paraffin embedding, and 6-μm sections were prepared and mounted on slides treated with xilane. For detection of insulin, the avidin- biotin complex (ABC) method was performed using Vectastain ABC Kit (Vector Laboratories). Deparaffmized and dehydrated sections were microwaved in citrate buffer (pH 6.0) for antigen retrieval, then were incubated in Tris 100 mM pH 7.4 containing 3% BSA, and 0.01% Triton, to permeabilize and block nonspecific staining, for 30 min, and after that, were incubated with the guinea pig polyclonal anti-insulin antibody (Dako), diluted 1/500 in blocking solution for 2 hours. Negative controls were incubated with blocking solution without the primary antibody. The sections were then incubated with biotinylated antiguinea pig IgG (Vector Laboratories), diluted 1 :100 in PBS containing donkey serum 10%, for 45 min. The sections were then incubated with ABC reagent for 45 min, and positive reactions were visualized by incubation with the peroxidase substrate solution containing 3,3'- diaminobenzidine tetrahydro chloride (DAB) (Vector Laboratories). The sections were mounted using Fluoromount G (Electron Microscopy Sciences). Sections were then examined using a Nikon E-600 upright microscope, and microscopic pictures were obtained with a digital camera Olympus DP 72 using Olympus-SIS Cell F software. This program and Fiji Software were used to measure pancreas sections and islets areas.

Statistical analysis. Statistical comparisons between groups were established by two-way ANOVA using Prism 4 (GraphPad, San Diego, CA), A p value of less than 0.05 was considered to be statistically significant. Statisticaly significant differences arc indicated as follow: *. P < 0,05: **. P < 0.01 ; ***. P < 0.001. Biological Data

Exemplary experimental results showing the efficacy of certain embodiments of the combinations of the invention are set forth in the drawings. Stability studies were performed on thioester conjugates of N-acetylcysteine and salicylate, diflunisal or dexibuprofen, at neutral (pH 7), acidic, or basic (9) pH in phosphate-buffered saline (PBS). The free acid as well as the lysine salt of salicylate-NAC was tested at room temperature (RT) ; under basic conditions only the lysine salt showed any (sparing) detectable conjugate after a 3 hour incubation. In contrast, the lysine salt was stable after 3 hours under acidic conditions, while the free acid in the absence of lysine lost stability during a 3-day timecourse. Diflunisal-NAC conjugates were tested for 3 or 24 hours under the same neutral, acidic and basic conditions, at room temperature or 4°C, and in PBS or mixture of water and methanol. Under these conditions, the free acid was stable over 3 and 24 hours in the water/methanol mixture at neutral pH and room temperature, as was the lysine salt in PBS at neutral pH and room temperature after 3 hours (but not after 24 hours). However, the lysine salt did not show comparable stability in the water/methanol mixture. Dexibuprofen-NAC conjugates were stable as lysine salts under neutral pH conditions at room temperature or 4°C ; the free acid was stable for 3- and 24-hour incubation as the free acid in in water/methanol. These results are shown in Figure 1.

The capacity for conjugates of the invention to be cleaved was tested in vitro using rat or human liver microsomes. As shown in Figure 2, salicylate-NAC and diflunisal-NAC thioester conjugates were incubated for 1 hour in the presence of microsomes and the amout of free salicylate or diflunisal assayed. Rat microsomes were found to be more potent in cleaving these conjugates, and a higher percentage of diflunisal that salicyalte was released by both rat and human liver microsomes. Similar experiments were performed in plasma from rat or human for salicylate-NAC or diflunisal-NAC conjugates ; these results are shown in Figures 3 and 4, respectively.

Cleavage of conjugates of the invention in vivo was assayed by oral adminstration of salicylate- H AC or diflunisal-NAC conjugates to rats. As shown in Figure 5, both the conjugate and the NAC components were quickly cleared from the systemic circulation (within 8 hours), while both salicylate and diflunisal persisted between 8 and 24 hours after administration. The effects of salicylate- NAC or diflunisal-NAC conjugates on glycemia or lnsulemla in vivo was assayed using alloxan- treated cd-1 mice. The alloxan model is a well-known model of /3-cell dysfunction that mimicks the biochemical events involved in type 2 diabetes, including inflammation and oxidative stress. Conjugates were administered as lysine salts i.p . over a 4-day timecourse, and both conjugates showed statistically-significant reductions in glycemia, as shown in Figure 6. In addition, salicylate-NAC conjugate showed an increase in plasma insulin levels in alloxan-treated mice, indicating that the conjugate protected these mice from the beta-cell toxicity of alloxan.

The conjugates were also tested in mouse diabetes model, specifically db/db mice. As shown in Figure 7, free fatty acid and plasma triglyceride levels were significantly improved in mice administered salicylate-NAC conjugate (0.75 mmol/kg/day as the lysine salt), compared with separate administration of either component of the conjugate.

Mice (db/db) used as a mouse model for human diabetes were tested using a protocol set forth in Figure 14. The effects of oral administration of salicylate-NAC or diflunisal-NAC conjugates to db/db mice on glycemia is shown in Figure 8, wherein lysine (1.5 mmol/kg/day), salicylate-NAC (1.5 mmol/kg/day, as the lysine salt) or diflunisal-NAC (0.5 mmol/kg/day, as the lysine salt) was administered to mice over 35-day course of treatment. Although glucose concentrations increased over the course of the experiment, mice treated with the diflusinal-NAC conjugate showed lower glycemia levels.

Intraperitoneal insulin tolerance tests were performed on db/db mice in the feeding state by injecting mice i.p with 2IU/kg human insulin (Humulin®). Tail vein blood was assayed for glucose concentration in mice treated with lysine (1.5 mmol/kg/day), salicylate- NAC (1.5 mmol/kg/day, as the lysine salt) or diflunisal-NAC (0.5 mmol/kg/day, as the lysine salt). The diflunisal-NAC conjugate showed the greatest sustained insulin sensitivity over the 3-hour time course of these experiments, as shown in Figure 9.

Intraperitoneal glucose tolerance tests were also performed onb db/db mice after an overnight fast. The animals received an ip injection of Glucose 0.5 g/kg (Glucosmon 50 JC) and glycemia levels were determined from tail vein blood. Lysine (1.5 mmol/kg/day), salicylate-NAC (1.5 mmol/kg/day. as the lysine salt) or diflunisal-N 4C (0.5 mmol/kg/day. as the lysine salt) were administered and showed reductions in plasma glucose over the 120 minute experimental timecourse, with the diflunisal-NAC conjugate having the greatest effect.

Chronic oral administration of conjugates of the invention was shown to have beneficial effects on insulin, triglyceride and free fatty acid levels in db/db mice. Statistically- significant increase in plasma insulin, and decreases in free fatty acid and triglycerides were detected after administation of diflunisal-NAC (0.5 mmol/kg/day, as the lysine salt), and significant reductions in triglycerides was detected in db/db mice administered salicylate- NAC (1.5 mmol/kg/day, as the lysine salt). These results are shown in Figure 11. Weight gain in db/db mice was also assayed after chronic oral administration of lysine (1.5 mmol/kg/day), salicylate-NAC (1.5 mmol/kg/day, as the lysine salt) or diflunisal-NAC (0.5 mmol/kg/day, as the lysine salt). These results are shown in Figure 12, wherein mice administered the diflunisal-NAC conjugate showed the greatest effect on weight gain. Mice administered the diflunisal-NAC conjugate also showed reduced consumption of food and water, as shown in Figure 13.

A comparison of diflunisal and NAC levels in blood after oral administration was performed in rats by administration of the diflunisal-NAC conjugate (GMC-252) or the individual components separately (Le., not chemically conjugated). Conjugate (20 mg/kg) or the equivalent amount of difliunisal and NAC were administered and blood assayed over a 7- hour timecourse. In contrast with the blood plasma profiles of diflunical and NAC administered separately, the conjugate showed a more gradual increase in plasma concentrations (albeit the final concentrations were the same whether administered as a conjugate or as separate components, as shown in Figure 16.

Pancreatic beta-cell protection of conjugates of the invention was assayed using alloxan-treated cd-1 mice. In these experiments, salicylate-NAC (0.38 mmol/kg) or an equivalent amount of the combination of salicylate + NAC was administered to male cd-1 mice and glycemia assayed over a 4-day timecourse. As shown in Figure 17, both the conjugate and the combination reduced glycemia, although only the conjugate showed a statistically-significant reduction. Similar results are shown for diflunisal-NAC conjugate administration (0.38 mmol/kg). In addition, the conjugate showed statistically-significant potection of pancreatic beta-cell function (as assessed by plasma insulin levels) in mice treated with alloxan. Similar experiments were performed comparing the effects of salicylate- NAC (0.38 mmol/kg/day or 0.75 mmol/kg/day) or an equivalent amount of the combination of salicylate ^ NAC on free fatty acid levels in db/db mice, wherein statistically- significant reductions were found at 0.75 mmol/kg/day for both the conjugate and the combination, but free fatty acid levels were lowered significantly only by the conjugate when administered at 0.38 mmol/kg/day. These results are shown in Figure 18.

Chronic oral administration of the diflunisal-NAC conjugate (GMC-252, 200mg/kg/day) was shown to significantly reduce glycemia in db/db mice over 30 days of treatment, shown in Figure 19. In addition, this conjugate showed reduced glycemia during an insulin tolerance (ITT) test and during s glucose tolerance test. Similarly, weight gain improvements were detected in these mice over 25 days of chronic adminisrtation (shown in Figure 20). This treatment was also found to reduce plasma triglcerides and free fatty acids, as shown in Figure 22, and was found to increase plasma insulin levels in these mice as well (Figures 23 and 24). These results were achieved wherein both insulin expression and islet size were increased without affecting pancreatic weight.

The effects of diflunisal-NAC (GMC-252) oral administration on glycemia were compared with the effects on metformin, a conventional Type II Diabetes drug. As shown in

Figure 21, the diflunisal-NAC conjugate (GMC-252) showed a statistically-significant lowering of plasma glycemia compaied with this conventional Type II Diabetes drag.

The effects of the combination of metformin HCl (100 mg/kg/day) administration and administration of a diflunical-NAC conjugate (0.5 mmol/kg/day) are shown in Figure 25, wherein beta-cell areas in the pancreas increased as assayed by immunohistochemistry and islet cell function improved as assayed by ELISA for pancreatic insulin.

Several parameters of certain conjugates of the invention were assayed and the results of these assays shown in Figure 15.

The data above shows the beneficial effects of compounds of the present invention, including salnacedin, in Type 2 diabetic animal models as compared to control or to animals treated with salicylate or an antioxidant alone (e.g. salicylic acid alone or N -acetylcysteine alone). The data described herein further provides that conjugates of Formula (I), such as salicylate-NAC and difiusinal-NAC. possess strong hypolipidemic and ant'-diahetic effects ^;» % well as antioxidant properties in different animal models of diabetes useful in preventing the development of β-cell failure and aggravation of the diabetic status leading to cardiovascular complications. This data supports the therapeutic utility of conjugates comprising an antioxidant agent and an anti- inflammatory agent, such as salicylate-NAC and diflusinal- NAC.

Moreover the additive and/or synergism effects of these conjugates allow for the decrease dosing of each independent active ingredient. These additive and/or synergistic effects reduce the liability of side effects associated with a salicylate agent, gastric bleeding, or an antioxidant, tinnitus, given to a patient alone.