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    • 专利摘要:
    The present invention is directed to methods for treating metabolic disorders with compounds that are conjugates. The conjugates of the present invention are comprised of salicylic acid, triflusal, diflusinal, salsalate, IMD-0354, ibuprofen. diclofenac, licofelone, or HTB, and one or more antioxidants.
    公开号:AU2010224866A1
    申请号:U2010224866
    申请日:2010-03-16
    公开日:2011-10-06
    发明作者:Julio Cesar Castro Palomino Laria；Silvia Garcia Vicente；Luc Marti Clauzel；Eric Mayoux；Alec Mian；Marta Serrano Munoz；Antonio Zorzano Olarte
    申请人:Genmedica Therapeutics SL；
    IPC主号:A61K31-166
    专利说明:
    WO 2010/106082 PCT/EP2010/053418 ANTI-NFLAMMAORY AN ANTIOXIDA CT CONJGATES USEFUL FOR, TREATIN MECTABOLi IC DISORDES BACKGROUND 5 Oxidativ e stress and inflammation are implicated in the pathogenesis of metabolic diseases, diabetes, obesity, dyslipidemia and their associated cardiovascular complications. For example, oxidativ stress is a common pathogenic factor leading to insulin resistance, P-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 10 circulating inflammatory cytokines such as TNFa, 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 15 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 20 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 hypergiy cemia and hyperlipidemia. Howev er, while cells have a number of available anti-oxidant mechanisms, damage 25 most likely ccur when the ROS is c -essive and/or anti-oxidant pathways are oveIhemed as is frequently the case in diabetes. In diabetic patients, the levels of antioxidant enzymes responsible for scavenging fre radicals are diminished. Glutathione pools become depleted in diabetic patients following frquent and severe hyperglyc'emic episodes. it is now widely accepted that overproduction of reactive oxygen species (ROS) contributes to cell and tissue 30 dysfunction and damage caused bly glucolipotoxicity in diabetes, insulin resistance, and In particular. compared to several other cells of the body, pancreatic p-cells have relatively low levels of free radical detoxification and redox regulating enzymes such as sueoiedsmtsguatin eoia atls an hoeoi.Tecneuneo WO 2010/106082 PCT/EP2010/053418 limited scavenging systems is that ROS concentration in p-cells may increase rapidly, damaging the p-cells. Thus, under hyperglycemic conditions, the production of ROS, and subsequent oxidative stress, contributes to p-cell deterioration observed in type 2 diabetes. ROS is also considered a strong stimulus for the release of cytokines and increased 5 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 10 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 15 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 IKB kinase P (IKKp). Also, high doses of salicylic acid lower blood glucose levels. Recent studies report that diabetic animals given salicylates or salsalate showed a decrease in IKKP activity, accompanied by improvement in insulin sensitivity. High doses of Salicylate (I 20mg/k'gday) 20 administered by subcutaneous infusion in Zuckerfa//a rats or obl/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 25 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. The present invention relates to conjugates comprised of an anti-inflammaatory agent and an anti-oxidant agent The conjugat es of the present invention are useful for treating athernsclerosis, neuropathy,. nephropahy retinopathy, inflammatoryv disorders, Chronic WO 2010/106082 PCT/EP2010/053418 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 5 products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFa 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 p-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 10 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-acetylcysteine (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 15 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 I 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. 20 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)- (XXII) and at least one pharmaceutically acceptable carrier. The compounds of Formula (I)-(XXII) and the pharmaceutical compositions comprised of 25 Formula (I)-(IX) and at least one pharmacy utically acceptable carrier are useful for treating atheroscl erosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD) cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes rmellitus, Latent Autoimmune Diabetes of Adulthood 30 compounds and pharmaceutical compositions of the present invention are useful for protecting pancreatic p3-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 faitty acids (FFA5), triglyceridcs, advanced glvcated WO 2010/106082 PCT/EP2010/053418 end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFCC 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 5 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 10 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 TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient 15 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 P-cells, preventing their impairment or failure and subsequent lower 20 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 25 (I)-(XXII), or pharmaceutical corpositions comprised of a compound of Formula (I)-(XXII) and at leaA on pharmaceutically acceptable carrier, for preparing, or for th manufacture of, anedicament for treating atherosclerosis, neuropat, nehropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular 30 Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient. The present invention also prove ides uses for compounds of Formula (I)-(XXII), or pharmaceutical compositions comprised of a compound of Formula (I)-(XXII) and at least one pharmaceutically acceptable WO 2010/106082 PCT/EP2010/053418 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 TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient. The present invention also 5 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 p cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient. 10 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, 15 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) 20 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. 25 Figure 6 is a graphical illustration of the effects of salicylic acid-(L) N-acetyl cysteine (GMC I 3a) and diflunisal-(L) N-acetyl cysteine (GMC-1 3b), as lysine salts, at protecting beta-cells in vivo in the alioxan mode, the alloxan model is a well known model of /5Scell dysfunction that mimicks the biochemical events inv olved in type 2 diabetes, including inflammation and 30 alloxan on #-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.
    WO 2010/106082 PCT/EP2010/053418 Figure 7 is a graphical illustration of the comparative effects of the conjugate salicylic acid (L) N-acetyl cysteine (GMC- 1 .3a) as the lysine salt, salicylate, and NAC, on free fatty acid and triglyceride levels in db/db mice (ip administration). 5 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 10 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 15 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 illustrtion of the effects of the conjugates saliyi acid(L) N-acety' cysteine (GMC-3a) and diflunisal-(L) N-acetyl cysteine (GMC-3b) on fluid and food intake in 20 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 25 where lighter colors indicate positive results (white indicates not tested). Figure 16 is a graphical illustration compainig diflunisal and NA Qpasmva-lvl nmc 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 prot ective effecs ofthe conjugate salicylate NA t the combination of saicylate +NAxC in ed-1 rnale mice.
    WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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). 15 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 20 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 25 mice after four weeks of oral administration (0.5 mmol/kg/day). (0. m rmol/kg/day) to metformin H-CI (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). 30 Figure 26 is a graphical illustration of the cleavage eficiency for the cojugat diflunisal-lipoic acid in vivo in rats.
    WO 2010/106082 PCT/EP2010/053418 Figure 27 is a graphical illustration of insulin islet sizes following oral administration of diflunsal-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 5 tissue weight (respectively 1.7 ± 0.09 and 1.8 1 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. 10 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 15 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 formula (i); and R 7 , R, R 9 , XI, and L are as defined in Formula (1) of the Summary section. In certain embodiments, the inventive methods include treating dyslipidemia, insulin 20 resistance, elevated free fatty acids, elevated triglycerides, p-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 therapy ally effective amount of a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein R 1 is 25 hydrogen or acetyl; R 2 , R 3 , R4, and R are independently hydrogen, trifluoromethyl, or 2,4-difuorophenyl; R(s formula (i); and R 7 , R 9 , X1, and L ar as defmed in Formula (I) oT the Summary setion. In certain embodiments, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, hut not limited to, 30 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, w herein Ri is hydrogen or acety I; R2, R 3 , R4, and Rs are independently hydrogen, trifluoromethyl, or 2,'4-difluorophenyl; WO 2010/106082 PCT/EP2010/053418
    R
    6 is formula (i); and R7, R8, 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, P-cell dysfunction, hyperglycemia, 5 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 R, is 10 hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 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 present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation 15 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, 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); and R 7 , 20 R, 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 disordrs, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders in 25 a mammal or patient which includes th step of administering to the mammal or patient in need of such treatment a therapeuticaily effective amount of' aonjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein it is hydrogen or acetyl; R(2, R&, R4 and Rs arc independently hydrogen, trifluorornethyl, or 2,4-difluorophenyl; Re, is formula (i); R 1 is 30 (CC:lvcaunl isi : n 1 sC In certain embodiments he inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated trigly cerides, pe-ell dysfunction, hyperglycemia, metabolic syndrome, and an form of diabetes nmellitus including type 1 and type II diabetes an LtntAuommn Dibees - of Adltoo (AD) inapatient cmrsn WO 2010/106082 PCT/EP2010/053418 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, is hydrogen or acetyl; R2, R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is (Ci-C 6 )alkoxy, hydroxy, or NZ 9 Zio wherein Z 9 and 5 Z 1 0 are hydrogen; R 8 is hydrogen; R 9 is (CICW)alkylcarbonyl; X, 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 10 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 formula (i); R 7 is (CI-C 6 )alkoxy, hydroxy, or NZ 9 Zio wherein Z 9 and Zio are hydrogen; Rs is hydrogen; R 9 is (CI-C 6 )alkylcarbonyl; X, is S; and L is CH 2 . In certain embodiments, the inventive methods include treating dyslipidemia, insulin 15 resistance, elevated free fatty acids, elevated triglycerides, p-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 20 conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R 4 , and R 5 are independently hydrogen, trifluoromethyl, or I formulO (; is i-Cakoxy, hydroxy, or NLg9 wherein Zan
    Z
    1 ( are hydrogen; R 8 is hydrogen; R 9 is (CI-C6)alkylcarbonyl; Xi is S; and L is CH 2 . In certain embodiments, the present invention provides methods for reducing 25 advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to th atgin in need o such treatment a therapeutical ly effective amount of a pharrmaceutical composition comprising at least one pharmaceutically aceptable carrier an d a conjugate of Fo rmula (I), or a pharmaceutically acceptable salt there f, wherein Ri is hydrogen or acetyl; R2, R, R4, and R 30are independently hydrogen, trifluoromethyl, or 2,4difluorophenyl; R 6 is formula (i); R7 is
    (C
    1 -41:alkoxy, hydroxy, or NZ9Zi wherein Z 5 and Z 1 o are hydrogen; Rs is hydrogen; RK is (CC()lkltoonl X 1 irS n sC WO 2010/106082 PCT/EP2010/053418 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 5 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 R5 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 inventive methods include treating dyslipidemia, insulin 10 resistance, elevated free fatty acids, elevated triglycerides, p-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, is hydrogen or acetyl; R 2 , R 3 , R 4 , 15 and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i);
    R
    7 is amino, ethoxy, methoxy, or hydroxy; Rs 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/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the 20 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 acety; RR Ra Rs are.indep l h o trtY, or 2,4-difluorophenyl; R6 is formula (i); R- is amino, ethoxy, methoxy, or hydroxy; Rs is hydrogen; R 9 is acetyl; Xi is S; and L is CH 2 . 25 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type l and type il 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 30 com position 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; R2, R, R4, and Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is re-i WO 2010/106082 PCT/EP2010/053418 formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R) is acetyl; X, 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 5 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 (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; R 6 is formula (i); R 7 is 10 amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R 9 is acetyl; X, 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 15 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-acetyleysteine. In certain embodiments, the inventive methods include treating dyslipidemia, insulin 20 resistance, elevated free fatty acids, elevated triglycerides, P-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, is hydrogen or acetyl; R 2 , R 3 , R 4 25 and Rs ar independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R, is (L) N acetyleysteine. In crtain embhodiments, 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 30marnmal or patient in need of such treatment a therapeutically effective arnount 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 Rs are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; i[2 WO 2010/106082 PCT/EP2010/053418 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 5 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. 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 at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a 15 pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R2, R3, R4, and Rs 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 20 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; R2, R3, R 4 , and R 5 are independently hydrogen, halo(C 1
    -C
    6 )alkyl, or phenyl wherein the phenyl is optionally 25 substituted with 1 or 2 halogens; R is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z 6 is hydrogen (CpC 6 )alkyl,
    (C
    1 -C)alkvlcarbonvl, phenyl, phenyl(CH 2 )-, or phenyl(CH 2 )2, wherein the phenyl is optionally substituted with P, 2, 13, 4, or 5 groups that are indcpendently (Ce sJaikoxy, (C Cs)alkoxycarbo nyl, (C & 6 )alkoxysulfonyl, (C 1 eC )alky i, (C 1
    C
    6 )alkylcarbonyl, 30 halo(C: ~C)alkoxy, halo(C vCs)alkyl, halogen, hydr'oxy, hydro xy(C: Cs~alkyl, mercapto, nitro, phenyl, NZ 7 Zs, or (NZyZs)carbonyL; and Z 7 and Zs are independently hydrogen,
    (C
    1 ~~ak,~CC vabn' n Ycrtain points, th inventive method ncld treating dyslipidcmia, insulin resstnce eevtedfte att aid, eevte trglceides,> Th>V p ael dyfuion,>11 IW hyprgyceia, I t~1,~,I<-~,> >. %~, ~*VA4 I tI. &>~I V V I a.V I11W WO 2010/106082 PCT/EP2010/053418 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, 5 and R 5 are independently hydrogen, halo(CI-C 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R6 is -NZ 5 Z6; Z 5 is hydrogen Z 6 is hydrogen, (CI -C 6 )alkyl, (C 1
    -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
    (C
    1
    -C
    6 )alkoxy, (C 1
    -C
    6 )alkoxycarbonyl, (C 1
    -C
    6 )alkoxysulfonyl, (C-C)alkyl, 10 (C -C 6 )alkylcarbonyl, (C 1
    -C
    6 )alkylcarbonyloxy, (C-C)alkylsulfonyl, (CC)alkylthio, carboxy, cyano, formyl, halo(C -C 6 )alkoxy, halo(C 1
    -C
    6 )alkyl, halogen, hydroxy, hydroxy(CI-C)alkyl, mercapto, nitro, phenyl, -NZ 7
    Z
    8 , or (NZ7ZS)carbonyl; and Z 7 and Z 8 are independently hydrogen, (CI-C 6 )alkyl, or (C-C 6 )alkylcarbonyl. In certain embodiments, the present invention provides methods for reducing 15 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, halo(C -C 6 )alkyl, or phenyl wherein 20 the phenyl is optionally substituted with 1 or 2 halogens; R6 is -NZ:Z6; Z 5 is hydrogen; Z6 is hydrogen, (CICr)alkyl, (C-C)alkylcarbonyl, phenyl, phenyl(CH 2 )-, or phenyl(CH 2
    )
    wherein the phe-nyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently
    (CI-C
    6 )alkoxy, (C C)alkoxycarbonyl, (C C)alkoxysulfonyl, (CI-C 6 )alkyl, (Cf-C 6 )alkylcarbonyl, (C 1 -C6)alkylcarbonyloxy, (CIC 6 )alkylsulfonyl, (Ci-C6)alkylthio, 25 carboxy, cyano, formyl, halo(CI-C 6 )alkoxy, halo(C 1 -C)alkyl, halogen, hydroxy, hydroxy(CCn)alkyl, mercapto, nitro, phe nyl, TNZ 7 Z, or (NZ 7 Zscarbonyl; and Z7 and Aar independently hydrogen, (Ce-Csalkyi, or (CeC)akylcarbonyl In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, s-cell dysfunction, hyperglycemia, metabolic syndrome, and any formi of diabetes rellitus including type 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 pharrmaceutically acceptable carrier and a con jugate of WO 2010/106082 PCT/EP2010/053418 Formula (1), 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 I or 2 halogens; R 6 is -NZsZ6; Z5 is hydrogen; Z 6 is hydrogen, (CiCs)alkyl, (CI-C 6 )alkylcarbonyl, phenyl, phenyl(CH2)-, or phenyl(CH2) 2 5 wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (CC)alkoxy, (CI-C 6 )alkoxycarbonyl, (C-C 6 )alkoxysulfonyl, (CI-C 6 )alkyl, (C( C)alkylcarbonyl, (C -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-C 6 )alkyl, mercapto, nitro, phenyl, -NZ 7
    Z
    8 , or (NZ7Zs)carbonyl; and Z 7 and Z 8 are 10 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 15 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(Cl -C 6 )aikyi, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R 6 is -NZ 5 Z; Z 5 is hydrogen; Z, is hydrogen, (C1-C)alkyl, (Ci-C 6 )alkylcarbonyl, phenyl, phenyl(CH 2 )-, or phenyl(CH 2
    )
    2 -, wherein the phenyl is 20 optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (CI-C 6 )alkoxy,
    (CI-C
    6 )alkoxycarbonyl, (C-C 6 )alkoxysulfonyl, (C -C 6 )alkyl, (CeC 6 )alkylcarbonyl, (CI-C6)alkylcarbonyloxy, (CI-C 6 )alkylsulfonyl, (C-C 6 )alkylthio, carboxy, cyano, form , halo(C 1
    -C
    6 )alkoxy, halo(C 1
    -C
    6 )alkyl, halogen, hydroxy, hydroxy(CI-C6)alkyl, mercapto, nitro, phenyl, -NZ7Z 8 , or (NZ7Zs)carbonyl; and Z 7 and Zs are independently hydrogen, 25 (C-W)alkyl, or (C-C 6 )alkylcarbonyl. The present invention furter 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 30 effective amount of a conjugate of Fornmula (I), or a pharmaceutically acceptable salt thereof. halo(C 1 salkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R( is -NZ Ze; Zs i hydrogen; Z1, is hydrogen, (C Crialkyt, (C 1 Cs)alkylcarbhonyl.
    WO 2010/106082 PCT/EP2010/053418 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 5 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; R2, R3, 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 Z6; Z 5 is hydrogen; Z 6 is hydrogen, (C C 6 )alkyl, (C-C 6 )alkylcarbonyl. 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 a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or 15 acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halo(C1-C 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z 6 is hydrogen, (CI-C 6 )alkyl, (Cp-C 6 )alkylcarbonyl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of 20 diabetes mellitus including type I and type 11 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 compr1isng least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R2, R 3 , R 4 , and R5 are independently 25 hydrogen, halo(C1C 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; RK is -NZsZ 6 ; Z 5 is hydrogen; Ze is hydrogen, (C 0
    C
    6 )alkyl, (C rC 6 )alkylearbonyl. 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 30such 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; R2, R3, R4, and Rs are independently hydrogen, halo(C& salk'yl, orphenyl wherein the phenyl is optionally 7 1- - l WO 2010/106082 PCT/EP2010/053418 substituted with 1 or 2 halogens; R 6 is -NZ 5 Z6; Z 5 is hydrogen; Z 6 is hydrogen, (CIC 6 )alkyl,
    (CI-C
    6 )alkylcarbonyl. The present invention additionally provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive 5 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, is hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is -NZ 5 Z6; Z 5 is hydrogen; and Z 6 is 10 hydrogen. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 15 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 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; and Z 6 is hydrogen. In certain embodiments, the present invention provides methods for reducing 20 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 theraputcally efci amount of a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein R, is hydrogen or acetyl; R 2 , Ri, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; 25 R 6 is -NZ 5 Z; Z 5 is hydrogen; and Z6 is hydrogen. In certain embodiments, the inventive me thods include treating dyslipidemia, insulin resistance, elevated free fatty acd, lvae tilyeies, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Auto immune Diabetes of Adulthood, in a patient comprising administering to the 30patient in need of such treatment a therapeutically effective arnount of a pharmaceutical composition comprising at least one pharmaceutically acceptable earrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ru is hydrogen or acetyv; WO 2010/106082 PCT/EP2010/053418
    R
    2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is
    -NZ
    5 Z6; Z 5 is hydrogen; and Z6 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 5 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, 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 10 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 15 effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R 2 , R3, R 4 , and R 5 are independently hydrogen, halo(C 1
    -C
    6 )alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R is-NZsZ; Zs is hydrogen; Z is phenyl, wherein the pheIIy' is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1
    -C
    6 )alkoxy, (CI-C 6 )alkoxycarbonyl, 20 (CI-C)alkoxysul fonyl, (C-C 6 )alkyi, (CI-C 6 )alkylcarbonyl, (C-C 6 )alkyicarbonyloxy (C-C)alkylsulfonyl, (C 1
    -C
    6 )alkylthio, carboxy, cyano, formyl, halo(CI-C 6 )alkoxy, halo(CI-C 6 )alkyl, halogen, hydroxy, hydroxy(C 1 C)alkyl, mercapto, nitro, phenyl, -NZ7Z 8 , or
    (NZ
    7 Zs)carbonyl; and Z 7 and Z8 are independently hydrogen, (C 1
    -C
    6 )alkyl, or
    (CI-C
    6 )alkylcarbonyl. 25 In certain mbodime nt, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, -cell dysfunction, hyperglye mia, metabolic syndrome, and any form of diabetes melitus including type i and type Il 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 30 (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R2, R 3 , R4, and RV are independently hydrogen, halo(Ce-Cr)alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R is -NZsZs; Z is hydioen; Zo is phenyl, whe<rein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups tha are independently C>, i4alkoxy, ( . ~akoycrbnyi, (CeC~ )akxsufni (Ce ~ aky V.C 10 12 WO 2010/106082 PCT/EP2010/053418
    (CI-C
    6 )alkylcarbony, (C 1
    -C
    6 )alkylcarbonyloxy, (C -C 6 )alkylsulfonyl, (Cp-C 6 )alkylthio, carboxy, cyano, formyl, halo(Ci IC 6 )alkoxy, halo(CIC 6 )alkyl, halogen, hydroxy, hydroxy(CI-C 6 )alkyl, mercapto, nitro, phenyl, -NZ 7 ZS, or (NZ 7 Zs)carbonyl; and Z 7 and Zs are independently hydrogen, (C C)alkyl, or (C 1
    -C
    6 )alkylcarbonyl. 5 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 10 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 I or 2 halogens; R 6 is -NZ 5 Z6; 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 -C 6 )alkoxy, (CI -C 6 )alkoxycarbonyl, (CI-C 6 )alkoxysulfonyl, (CC)alkyl,
    (CI-C
    6 )alkylcarbonyl, (CC)alkylcarbonyloxy, (CIW)alkylsulfonyl, (CC)alkylthio, 15 carboxy, cyano, formyl, halo(C 1
    -C
    6 )alkoxy, halo(C 1
    -C
    6 )alkyl, halogen, hydroxy, hydroxy(C 1
    -C
    6 )alkyl, mercapto, nitro, phenyl, -NZ7ZS, or (NZ 7 Zs)carbonyl; and Z7 and ZS are independently hydrogen, (-C 6 )alkyl, or (CIC)alkylcarbonyl. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, 20 metabolic syndrome, and any form of diabetes mellitus including type I and type 11 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 kast one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; 25 R 2 , R 3 , R4, and R 5 are indep ndently hydrogen, ha lo(CoC)alkyl or phenyl wherein the phenyl is optionally substituted with I or 2haloens; R is -NZZ.; Z 5 is hydrogen; Z 6 is phenyl, wvherein the pnenyl is optionally substituted with 1, 2, 3, 4,Lor 5 gro that are independently (C 1
    C
    6 )alkoxy, (C 1 eCs)alkoxycarbonyl, (Ce C 6 )alkoxysulfonyi, (C 1
    C
    6 )alkyi,
    (C
    1 ~Q)alkylcarbonyl, (C 1 CJ)alkyicarbonyloxy, (C 1 salklsulfonyl, (C 1 Cs)alkylthio, c0 arboxy, cyano, formyL, halo(CvC 6 I)alkoxy, halo(&C~)alkyl, halogen, hydroxy, hydroxy((C ~)alkyl, merecapto, nitro, phenyl, -NZ7Zs, or (NZ7Zs)carbonyl; and Z7 and Z 5 are independently hydrogen, (C 1
    C
    6 )alkyl or (C & alkyearbony. In crtanin bodiments, the present invention provides methods for reducing advnce gycaed ndprodut and lipiferoiainicuig u o iie o xdto WO 2010/106082 PCT/EP2010/053418 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 , R4, and R 5 5 are independently hydrogen, halo(CC6)alkvl, or phenyl wherein the phenvl 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, (C C)alkoxycarbonyl, (CI-C 6 )alkoxysulfonyl, (C-C 6 )alkyl, (CI -C 6 )alkylcarbonyl, (C1 C 6 )alkylcarbonyloxy, (C C 6 )alkylsulfonyl, (CI -C 6 )alkylthio, 10 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 Zs)carbonyl; and Z 7 and Z 8 are independently hydrogen, (C C)alkyl, or (CIC 6 )alkylcarbonyl. The present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, 15 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 RD i 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, 20 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(C1-C 6 )alkyl or halogen. In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 25 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 (Ior a pharma~euically acceptable satteef hriR is hydrogen or acetyl; Rk2, R3, R4, anid Rs 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 ; Zs is hydrogen; Ze, is phenyl, 30 wherein the phenyl is optionally substituted with I or 2 groups that are independently halo(C 1 eC)alkyl or halogen. In certain embodiments, the present invention provides methds fo r reducing advanced glycated end product and/or id prxdation including, but not limte to o> xidlation of lo-denityI iproeis in a miarnma! or patient comprising admiitring to the mammalii or 20 WO 2010/106082 PCT/EP2010/053418 patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (1), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R, 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(; Z 5 is hydrogen; Z 6 is phenyl, 5 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 inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 10 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 (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, halo(C-C6)alkyl, or phenyl wherein the 15 phenyl is optionally substituted with 1 or 2 halogens; R6 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 20 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, is hydrogen or acetyl; R2, R3, R4, and R 5 are independently hydrogen, halo(CI-C)alkyl, or phenyl wherein the phenyl is optionally 25 substituted with I or 2 halogens; R is -NZ 5
    Z
    6 ; Z is h hydrogen; Z is phe nyl, wherein the phenyl is optionally substituted with I or 2 groups thdt are idependently halo(CgC 6 )alkyl or nalogten, In accordance with the present invention, methods are provided for treating athe'rosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic 3)0 Obtructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of adrninistering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formnula ()ora pharmaceutiall acceptable salt thereof, wherein R sq hydogn or '~acy R_, RK.4 adR arc indepe-ndiently hydrogen, ~tiluo rehyl or 2-4,diflrp heny R, is - N>ZAe Z/ i 21 WO 2010/106082 PCT/EP2010/053418 hydrogen; Z6 is phenyl, wherein the phenyl is optionally substituted with I 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, p-cell dysfunction, hyperglycemia, 5 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 , R3, R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R 6 is -NZ 5
    Z
    6 ; Z 5 10 is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with I 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 15 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 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with I or 2 groups that are independently trifluoromethyl or Cl. 20 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty aids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metaboliC syndrome, and any form of diabetes meitus including type I and type II diab etes 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 25 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 aetyl;
    R
    2 , R, R4, and Rs are independently hydrogen, trifluorormethyl, or 2-4 ,difluorophenyl; RK is -NZsZ 6 ; Zs is hydrogen; ZA is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl 30 In certain embodirnents, the present invention provides rnethods for reducing advanced glycated end products rnd lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patint in need of such treatment a therapeutically effective amount of a pharmaceuticals composition coising WO 2010/106082 PCT/EP2010/053418 at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or acetyl; R2, R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2-4,difluorophenyl; R6 is -NZsZ6; Zs is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that 5 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 10 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)phenylcarbamoyl)-4-chlorophenyl acetate. In certain embodiments, the inventive methods include treating dyslipidemia, insulin 15 resistance, elevated free fatty acids, elevated triglycerides, p-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 ofa conjugate of Formula (I) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of 20 Formula (I) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2 hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chloropheny1 acetate. In certain embodiments. the present invention provides methods for reducing advanced glycated end products and/or lipid proxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the 25 mammal or patient in need of such treatment a therapeutically effective amount of a onjugate of Formula (1) or Formula (IV), or a pharma cutically acceptable salt thereof, wherein the conjugate ofFrua()o ormula (IV) is N-(3,bis~trifuoromethylphenyl)5-horo-2 hy droxybenzamide or 2-(3,5-bis(trifluoromethyl~phenylcarbamoyl)-4-chlorophenyl acetate. In certain embodiments, the inventive methods include treating dyslipidemnia, insulin 30 resistance, elevated free fatty acids, elevated triglycerides, -cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type t and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering 10 the patient in need of such treatment a therapeutically efeci amunt of a pharmaceutical composition comnprising at les on hracuial acetal cariran conjuateo 30; WO 2010/106082 PCT/EP2010/053418 Formula (1) 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 hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate. In certain embodiments, the present invention provides methods for reducing 5 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 10 Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide 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 15 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, 11, 12, 13, 14, 15,16 117, or 18. In certain embodiments, the inventive methods include treating dyslipidemia, insulin 20 resistance, elevated free fatty acids, elevated triglycerides, p-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 comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound s lee d from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. 25 In certain embodiments, the present invention provides methods for reducing advance 1d glycated en products and/or lipid pendat ion incding, but ot imihd 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 compound selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14i, 15, l6, 17, or 18. 30 in certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-celi dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type I1 diabetes and Latent Autoiirnune Diabetes of Adulthood, in a patient comprisig administering io the WO 2010/106082 PCT/EP2010/053418 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, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, the present invention provides methods for reducing 5 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. 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 I (salnacedin). 15 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. 20 In certain embodiments, the present invention provides methods for treating p-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of ExampIe I (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 25 therapeutically effc tive amount of Example 1 (salnacedin). In certain embodiments the present ivention provides methods for reducing free fatty acids in a patient comprisin administering to the patient in need of such treatment a therapeutically effective amo unt of Example 1 (salnaced in). therapeutically effective amount of Example I (salnacedin). In certain embhodimuents, the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, hut tnt limited to, WO 2010/106082 PCT/EP2010/053418 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 5 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 p-cell 10 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 15 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 20 pharmaceutically acceptable carrier and Example I (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 I (salnacedin). 25 in certain embodiments, the present invention pro ides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising admninistering 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 30 parrnaceutical composition comprising at least one pharmaceutically acceptable earrier and In another aspect, the present invention provides methods for treating atherosclerosis, neuropathy, ncphro pathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmnonary Disease, cardiovascular diseases, and metaholic disorders in a manma or patients of'o WO 2010/106082 PCT/EP2010/053418 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, p-cell dysfunction, hyperglycemia, 5 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, 10 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, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 15 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 20 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. 25 In another aspect, the press nt invention provides m thods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases and metabolic disorders in ma mmmal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 7. In certain ernbodinments, the inventive 30 methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type Iand type Ii diabetes and Latent Autoimmune Diabetes of j;7 WO 2010/106082 PCT/EP2010/053418 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 5 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, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 10 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 15 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 co mpri administering to the mammal or patient in need of such treatment a therapeutically effective amount of Example 10. 25 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hype rlycemia, rmetabolic syndrome, and any form of diabetes mellitus including type Iand type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the 30 tn certain embodiments, the present invention provides methods for reducing advanced glycated end prioductsand/or lipid peroxidation including, hut not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising admuinistering to the mnamrnal or patient in need of such treatment a therapeutically effective amount of Example aii WO 2010/106082 PCT/EP2010/053418 In certain embodiments, the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 5 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 10 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, 15 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 20 resistance, 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 13. In certain embodiments, the present invention provides methods for reducing 25 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 mammalI or patient in need of suchi treatment a therapeutically effective amount 0f Example 13. In another aspect, the present ivention provides methods for treating p-cel In another aspect, the present invention provides methods for treating hyperglycemia in a patient ecompr isin adinsern to the patient in need of such treatment a therapeutically e aE WO 2010/106082 PCT/EP2010/053418 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, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 10 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 15 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. 20 In certain embodiments, present invention includes methods for treating p-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 hyerglycernia 25 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 Eampe 1 In certain embodiments, present invention includes methods for reducing free fatty In certain embodiments, present invention includes methods for reducing triglycerides inapatien com prising administering to the patient in need of suchi treatment a therapeutically WO 2010/106082 PCT/EP2010/053418 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 5 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, p-cell dysfunction, hyperglycemia, 10 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 15 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 20 resistance, elevated free fatty acids, elevated triglycerides, P-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 comprising administering to the patient in need of such treatment a therapeutically fetive amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Example 16. 25 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 patient comprising administerin to tn patient in need of such tr eatmrent a therapeutically effective amount of a pharmaceutical composition comprising adintrn anothe aiet the present ofsuhnvtentio prvie thesraeutiaftean of Forua)fr ) phrpacuingao ompositianfcurisif, at east o ptreuti a cceabler, creurahy WO 2010/106082 PCT/EP2010/053418 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 R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyf; R 6 is formula (i); and R 7 , R 8 , R 9 , X 1 , and L are as defined in Formula (I) 5 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, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 10 and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein R, 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); and R 7 , R 8 , R9, X 1 , and L are as defined in Formula (I) of the Summary section. In certain embodiments, the present invention provides uses for conjugates of Formula 15 (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-difluorophenyi; 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. 20 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, l-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, 25 wh rein th pharmaceutical composition comprises at least one pharmaceutically acceptable career and a c< a t or Ola (I), or a pharmaceutically acceptable salt thereof, wherein RK is hydrogen or acetyl; R2, R 3 , R4, and Rs: are independently hydrogen, trifluoromethyL, or 24-difluorophenyl; R, is formula (i); and Ry, Rs, R 9 , X 1 , and L are as defined in Formula (I) of the umr scin 30in certain embodiments, the present invention provides uses fr pharmaceutical compositions for preparing, oir for the manufacture of, a medicament for reducing advanced gly'cated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comnprises at leat oe parmceuicllyaccptale arrerand a cnuaeo oml Io WO 2010/106082 PCT/EP2010/053418 pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R2, R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); and R 7 , R8, R 9 , X 1 , 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 5 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 , R4, 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 Zio wherein Z 9 and 10 Z 1 0 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 conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 15 and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein R 1 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); R 7 is (Ci-C 6 )alkoxy, hydroxy, or NZ 9
    Z
    1 o wherein Z 9 and Zio are hydrogen;
    R
    8 is hydrogen; R 9 is (CI-C 6 )alkylcarbonyl; X, is S; and L is CH2. In certain embodiments, the present invention provides uses for conjugates of Formula 20 (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 hvdrogen or acetyl; R2, R3, R 4 , and R. are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is (Cv-C 6 )alkoxy, hy droxy or NZ 9 Zio wherein Z 9 and Zie are hydrogen; Rs is hydrogen; R 9 is 25 (C Cr)alkylcarbonyl; X 1 is S; and L is C- 2 . In certain embodiments, the present invention provides uses for panoetical comp ositions for preparing, or for the~ manufacture of, med icament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell 30 type I and type II diabetes and Latent Autoimune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrer and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acety; R2, R 3 , R4, and Rs are independently hydrogen, trifiuorometnyl, or WO 2010/106082 PCT/EP2010/053418 2,4-difluorophenyl; R 6 is formula (i); R7 is (Ci-C 6 )alkoxy, hydroxy, or NZ 9 Zio wherein Z 9 and Z1o are hydrogen; Rs is hydrogen; R 9 is (Ci-C 6 )alkylcarbonyl; 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 5 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 formula (i); R 7 is 10 (Cj-C 6 )alkoxy, hydroxy, or NZ 9
    Z
    1 0 wherein Z 9 and Z 1 0 are hydrogen; R 8 is hydrogen; R 9 is
    (CIC
    6 )alkylcarbonyl; X, 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, 15 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); R7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R 9 is acetyl; X 1 is S; and L is CH 2 . In certain embodiments, the present invention provides uses for conjugates of Formula 20 (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, [i-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, is hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; 25 R6 is formula (i); R 7 is amino, tbxy methoxy, or hydox P, is h drogn: R. is acety!; X is S; and L is CH2. in certain embodiments, the present invention provides uses for conjuates of Formula (l) for preparing, or for the manufacture of, a mnedicament for reducing advanced glycated end 30 lipoproteins in a patient, wherein R 1 is hydrogen or acetyl; R2, R, R4, and RK are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); Ki amino, ethoxy, rnethoxy, or hydIroxy; R is hydrogen; R9 is acetyh; Xi is S; and Lis CH 3 . In certain emnbodinents, the prsent ivention provde uses for pharmaceutical cpai WO 2010/106082 PCT/EP2010/053418 dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type 1I diabetes and Latent Autoimmune Diabete s of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable 5 carrier and 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, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R8 is hydrogen; R 9 is acetyl; Xi is S; and L is CH 2 . In certain embodiments, the present invention provides uses for pharmaceutical 10 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 R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 15 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; Rs is hydrogen; R 9 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, 20 cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R, is hydrogen or acetyl; R2, R1, R 4 , and Rj are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyi; and R( is (L) N-acetylcysteine. In certain embodiments, the present invention provides uses for conjugatcs of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin 25 resistance, elevated free fatty acids, elevated triglycerides, P-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type I diabetes and Latent Automnmune Diabetes of< Adulthood, and any form of diabetes mellitus including type I and type II diabetes, in a patient, wherein R 1 is hydrogen or acety; R2, RK, R4, and RK 30 N etlytie In certain embodiments, the present invention provides ue f -or conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid perxidation icuing, btnot lirnited to, oxidation of low- density lipo rot i in ap tie t <, erei R.> is . hydrogen. or at yl;A~ R2 R- R4 an- r WO 2010/106082 PCT/EP2010/053418 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 treating 5 dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 10 R, is hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 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 15 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; andR is (L) N-acetylcysteine. 20 In another aspect, the present invention provides uses for conjugates of Formula (1) 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, 25 15, 16, 17,orl1. In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a miedicament for treating dysiipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 30 and Latent Autoimmune Diabetes of Adulthood, 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, l3, 14, 15, 16, 17, or re. In certain embodirnents, the pesent i ntion provides uses fo cojutesoformula (I frprpaigorfr hemnuacue fameicmntfo edcigadane gyctd n WO 2010/106082 PCT/EP2010/053418 products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Fornula (1) 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 5 compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, i-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 10 conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (1) is selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15i 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 15 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 pharmaceuticals acceptable salt thereof wherein the conjugate of Form-ifula (is selected from Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. 20 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 I (salnacedin). 25 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, fVcell dysfunction, metabolic syndrome, and any form of diabe mellius including type I and type Ii diabetes andl Latent Autoimmnune Diabetes of Adulthood, in a patient, wherein the conjugate of Fornula (I) is Example i (salnacedin). 30 ~In certain embodiments, the present invention provide uses for co.nugate of Formula (1) for preparing, or for the mannufactuare of, a medicamenit for treatng hyprglycemia in a patet, wherein the conjugate of Formula (1) is Examnple a t sancedin).
    WO 2010/106082 PCT/EP2010/053418 In certain embodiments, the present invention provides uses for conjugates of Formula (1) for preparing, or for the manufacture of, a medicament for reducing free free fatty acids in a patient, wherein the conjugate of Formula (1) is Example I (salnacedin). In certain embodiments, the present invention provides uses for conjugates of Formula 5 (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 10 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, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and 15 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 (1), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example I (sainacedin). In certain embodiments, the present invention provides uses for pharmaceutical 20 compositions for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the pharmaceutical composition comprises at least one pharmacy ticaily acceptable carrier and a coniugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example I (salnacedin). In certain embodiments, the present invention provides uses for pharmaceutical 25 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 pharmaceuticals acceptable carrier and a cnjugate o Formula (1), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is Example I (salnacedin). In certain embodiments, the present invention provides uses for pharmaceutical 30cornpositions for preparing, or for the manufacture of, a medicament for reducing triglycerides in a patient, wherein the pharmaceutical compostion 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 i (salnacedin).
    WO 2010/106082 PCT/EP2010/053418 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 5 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 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, 10 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 (1) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin 15 resistance, elevated free fatty acids, elevated triglycerides, f-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 20 (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 (1) is Example 4. In certain embodiments, the present invention provids se fr pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating 25 dyslipidemia, insulin resistance, elevated free fatty acids, elevatd triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and typne 11 diabetes and Latent Autoimmune Diabetes of A dulthood, in a ptient, w herein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein 30t the conjugate of Formula (I) is Example 4. In certain embodiments, the present inventionhre compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated>' end adcts and/or lipid perxidation iclding, hut not lirnited to, oxidation of low-ensiy lioproeinsin a patient, wherein the phannaceutieal comnposition comprises at Y3 WO 2010/106082 PCT/EP2010/053418 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 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, 5 neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or 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 treating dyslipidemia, insulin 10 resistance, elevated free fatty acids, elevated triglycerides, p-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 7. In certain embodiments, the present invention provides uses for conjugates of Formula 15 (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 20 dyslipidemia, insulin resistance, elevated free fatty acids, ele vated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and tyne It diabetes and Latent Autoimmiine Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmacy cutically a tablh carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein 25 the conjugate of Formula (I) is Example 7. In certain embodiments th present invention provides uses for pharmaceutical compositions for preparing,. or for the manufacture of; a medicamnent for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteis in a patient, wherein the pharmaceutical composition comprises at 30 least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (l) is Examlple 7. In another aspect, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a meiaent for treating atherosclerosis, neuropathy, neptiropathy, retinopathy, inflamrmatoryn'dises C~hronic Obstruceive Pulmonary Diease,> WO 2010/106082 PCT/EP2010/053418 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 5 products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (1) 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, p-cell dysfunction, hyperglycemia, 10 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 10. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating 15 dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, p-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 20 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 25 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 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, in certain embodiments, th presen inven action provides uses for conjugates of Formula (I) for prepari, or for the manufacture , a medicamnent for treating dyslipidema, ins reitne -cell dysfuinction, metabolie syndrome,- and any for ofdiaete mrellitus WO 2010/106082 PCT/EP2010/053418 including type I and type 11 diabetes, in a patient, wherein the conjugate of Formula (I) is Example 1. 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 5 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 10 (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 15 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 dyslipidenia, Insulin resistance, p-cell dysfunction, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of 20 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 25 hperglycemia 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 Examnpe13 In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing free fatty 3) 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 certan embodimnts thepresent inve'ntion provide uses frpanmacutical comnpositions ir preparing, or for the mufacr of, a medicament for reducing cc4 WO 2010/106082 PCT/EP2010/053418 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. 5 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 10 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 15 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, -cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes 20 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 (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 25 lipoproteins in a patient, wherein the conjugate of Formula (1) is Example 16. n certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament ibr treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including 30 tyeIadtpe II diabetes and Latent Autoirnmune 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 16. 43 WO 2010/106082 PCT/EP2010/053418 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 5 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, 10 cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R, 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; Z6 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 15 independently (C-C 6 )alkoxy, (C C)alkoxycarbonyl, (C C)alkoxysulfonyl, (CI-C 6 )alkyl,
    (CI-C
    6 )alkylcarbonyl, (CI-C 6 )alkylcarbonyloxy, (C-C 6 )alkylsulfonyl, (C C)alkylthio, carboxy, cyano, formyl, halo(CI -C 6 )alkoxy, halo(CI -C 6 )alkyl, halogen, hydroxy, hydroxvy(Ci-C 6 )a1kyi, mercapto, nitro, phenyl, -NZ 7 Zs, or (NZ7,Z 8 )carbonyl; and Z 7 and Z 8 are independently hydrogen, (CIC 6 )alkyl, or (C C)alkylcarbonyl. 20 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, p-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, is hydrogen or 25 acetyl; R 2 , R 3 , R4, and R, are independently hydroen, halo(CC 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R is -NZ 6 ; Zs is hydrogen; Z, is hydrogen, (C 1 & )alkyi, (C 1 e 6 s~alkylcarbonyi, phenyl, phenyi(CH 2 )-, or pheny i(CH2)2-, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently
    (C&
    6 )alkoxy, (C >C 6 )alkoxycarbonyl, (C jC 6 )alkoxysulfonyl, ( C 6 )alkyi, hydrox'y( CeCs)alyl, mercapto, nitro, phenyl, -NZ 7 Zs, or (NZ7Zs)carbonyL; and 7 andZar independently hydrogen, (CvC 6 )alkyl, or (Ce C)alkylcarbonyl 44 WO 2010/106082 PCT/EP2010/053418 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 , R4, and R 5 are 5 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 Z6; Z 5 is hydrogen; Z 6 is 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 (C 1
    -C
    6 )alkoxy,
    (C-C
    6 )alkoxycarbonyl, (C1C 6 )alkoxysulfonyl, (C-C 6 )alkyl, (CI -C 6 )alkylcarbonyl, 10 (CI-C 6 )alkylcarbonyloxy, (C-C 6 )alkylsulfonyl, (C -C 6 )alkylthio, carboxy, cyano, formyl, halo (CC 6 )alkoxy, halo(CI -C 6 )alkyl, halogen, hydroxy, hydroxy(Ci-C 6 )alkyl, mercapto, nitro, phenyl, -NZ7Zs, or (NZ7Zs)carbonyl; and Z7 and Z 8 are independently hydrogen,
    (C
    1
    -C
    6 )alkyl, or (C-C 6 )alkylcarbonyl. In certain embodiments, the present invention provides uses for pharmaceutical 15 compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-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 20 conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R 2 , R 3 , R 1 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; R6 is -NZsZ 6 ; Z. is hydrogen; Z6 is 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 25 independently (C 1
    -C
    6 )alkoxy, (C 1C)alkoxycarbonyl, (C C U)alkoxysulfony, (C 1
    -C
    6 )alkyl, (CI-C)alkylcarbonyl, (C- 6 C)alkylcarbonyloxy, (C 1
    >
    6 )alkylsulfony1 (C C 6 )alkylthio, carb~oxy, cyano, form, halo(C-Cs~alkoxy, halo(C-Cialkvi, nalogen, hydroxy, hydroxy(C 1
    -C
    6 )alkyl, mercapto, nitro, phenyl, -NZ 7 Zs, or (N/ ~)carbonyi; and Z7 and Zsar compositions for preparing, or for the manufacture of a rnedicametnt for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of lwdensity lipoproteins in a patient, where in the phar maceutical composition comprises at leat ne hamaceutically~, aceptable carr icr and a conjug~ate of Formula (1), or a WO 2010/106082 PCT/EP2010/053418 pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, halo(C 1
    -C
    6 )alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z 6 is hydrogen, (CI-C 6 )alkyl,
    (C
    1
    -C
    6 )alkylcarbonyl, phenyl, phenyl(CH2)-, or phenyl(CH 2
    )
    2 -, wherein the phenyl is 5 optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (CI-C6)alkoxy, (CI-CS)alkoxycarbonyl, (C-C 6 )alkoxysulfonyl, (CI -C 6 )alkyl, (C-C 6 )alkylcarbonyl,
    (C
    1
    -C
    6 )alkylcarbonyloxy, (CC)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_)carbonyl; and Z7 and Z 8 are independently hydrogen, 10 (CI -C6)alkyl, or (C 1
    -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 15 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 Z6; Z 5 is hydrogen; Z 6 is hydrogen, (CeC 6 )alkyl, (C 1
    -C
    6 )alkylcarbonyl. In certain embodiments, the present invention provides uses for conjugates of Formula (l) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty 20 acids, elevated triglycerides, p-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, is hydrogen or acetyl; R2, R 3 , R 4 , and R 5 are independently hydrogen, halo(C 1
    -C
    6 )alkyl, or halogen; R6 is -NZ 5 Z,; Z 5 is hydrogen; Z6 is hydrogen, (C-C 6 )alkyl, (C 1
    -C
    6 )alkylcarbonyl. 25 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 glyated nd products and/or lipid peroxidation inc'luding, but not limited to, ox idation of low-density lipoproteins in a patient, wherein R; is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, halo(C;-C 6 )alkyl, or phenyl wherein the phenyl is opionally In certain embodiments, the preset inton provi des uses for pharmaceutical compositions for preparing, or for the man ufacr of a mdicament for treating dyslipidemia, insuliresistan'ce, eleve fat a ,e tiglyce , -~cel4 WO 2010/106082 PCT/EP2010/053418 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 5 R 1 is hydrogen or acetyl; R 2 , R-, R 4 , and R 5 are independently hydrogen, halo(Cp-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 pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced 10 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; R2, R 3 , R4, and R 5 are independently hydrogen, halo(CI-C 6 )alkyl, or phenyl wherein the phenyl is optionally 15 substituted with 1 or 2 halogens; R 6 is -NZ 5 Z6; Z 5 is hydrogen; Z 6 is hydrogen, (CI-C 6 )alkyl,
    (C
    1
    -C
    6 )alkylcarbonyl. In another aspect, the present invention provides uses for conjugates of Formula (1) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, 20 cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R, is hydrogen or acetyl; R 2 , R3, R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is -NZ 5 Z6; Zs is hydrogen; and Z6 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 25 resistance, elevated fatty a ids, elevated triglycerides, pcl dysfun action, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Aulthood, in a patient, wherein Ri is hlydrogen or acetyl; R2 RP R4 and RI are independently hydrogen, trifluoromethyl, or 2,4difluorophenyl; 30 In certain embodiments, the present invention provides uses for conjugates of Fonmula (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 hydrogpen or acetyl; R2 R3 R4 and Rs are arI WO 2010/106082 PCT/EP2010/053418 independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; and Z6 is hydrogen. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating 5 dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-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 10 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 Z6; Z 5 is hydrogen; and Z6 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 15 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; R2, R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is -NZsZ 6 ; Z 5 is hydrogen; and Z 6 is hydrogen. 20 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; R2, R 3 , R4, and R5 are independently hydrogen, halo(CI-C 6 )alkyl, or 25 phenyl wherein the phenyl is optionally substituted with I or halogen ns; R6 is -NZ5Z6; Z5 is hydrogen; Z is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C-C 6 )alkoxy, (C C 6 )alkoxycarbonyl, (C-C 6 )alkoxysulfonyl,
    (C
    1 Cs)alkyl, (C 1 -Cs)alkylcarbonyl, (C 1
    -C
    6 )alkylcarbonyloxy, (C 1
    C
    6 )alkylsulfonyi,
    (C
    1 K )alkylthio, carboxy, cyano, formyl, halo(C 1
    -C
    6 )alkoxy, halo(C 1
    -C
    6 )alkyl, halogen, 30 hydroxy hydroxy(C 1
    -C
    6 )aikyl, rmercapto, nitro, pheny_ -N7V 5 or (N~yscroy;adZ and Zs are independently hydrogen, (C 1 -Csalkyl, or (C- ,,alkylcarbonyl. In certain embodimrents, the present inventio provides uses for conjugates of Fonmula (I) for preparn g, or for the manufacture of, a rnedicanment tor treating dyslipidemia insli resstnc, leatd ftt aid, leate tigycries p-el dyfnton yegcma WO 2010/106082 PCT/EP2010/053418 metabolic syndrome, and any form of diabetes mellitus including type I and type 1I diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein R, is hydrogen or acetyl; R2, 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 5 phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1
    -C
    6 )alkoxy, (C 1
    -C
    6 )alkoxycarbonyl, (C 1
    -C
    6 )alkoxysulfonyl, (CC)alkyl,
    (C
    1
    -C
    6 )alkylcarbonyl, (C C)alkylcarbonyloxy, (C 1
    -C
    6 )alkylsulfonyl, (C-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
    Z
    8 )carbonyl; and Z 7 and Zs are 10 independently hydrogen, (C-CW)alkyl, or (C 1
    -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 15 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 ; Zs is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently
    (C-C
    6 )alkoxy, (C C 6 )alkoxycarbonyl, (C C 6 )alkoxysulfony, (C 1
    -C
    6 )alkyl
    (C
    1
    -C
    6 )alkylcarbonyl, (C C)alkylcarbonyloxy, (C 1
    -C
    6 )alkylsulfonyl, (C 1
    -C
    6 )alkylthio, 20 carboxy, cyano, formyl, halo(C-C 6 )alkoxy, halo(Cj-C6)alkyl, halogen, nydroxy, hydroxy(CI-C 6 )alkyl, mercapto, nitro, phenyl, -NZ 7
    Z
    8 , or (NZ 7
    Z
    8 )carbonyl; and Z7 and Zs are independently hydrogen, (C 1
    -C
    6 )alkyl, or (C 1 -C6)alkylcarbonyl. In certain embodiments, the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating 25 dyslipidemia, insulin resistance, levated fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form ofdiabetes mellitus including type I andntype Il diabetes and Latent Autoimmune Diabetes of Adulthood, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conugteof Formula (I), orapharmaceutically acceptable salt thereof, whereinR1i 30 hydrogen or acetyl; R2, R, R4, and Rs are independently hydrogen, halo(CvC 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with l or 2~ halogens; R 6 is -- N1Z 6 ; Z5 is hydrogen; Zs is phenyl, wherein the phenyl is optionally_ sbstituted ith ,2, 3, 4, or 5 groups that are independently (C 1 eCjakorxy, (C Q~)alkoxy'carbony ~( s~lkoxysulfonyh, (C es~alyl, C ~)alkylicarbonyl, (C A ~i alkycaboylox, ~(C slkysulfonyil, ...... n49 WO 2010/106082 PCT/EP2010/053418
    (C
    1
    -C
    6 )alkylthio, carboxy, cyano, formyl, halo(CI-C6)alkoxy, halo(C 1
    -C
    6 )alkyl, halogen, hydroxy, hydroxy(C I-C6)alkyl, mercapto, nitro, phenyl, -NZ 7
    Z
    8 , or (NZ 7 ZS)rbonyl; and Z 7 and Z 8 are independently hydrogen, (CIC 6 )alkyl, or (C -C6)alkylcarbonyl. In certain embodiments, the present invention provides uses for pharmaceutical 5 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 10 are independently hydrogen, halo(CI-C 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R6 is -NZ 5
    Z
    6 ; Zs is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (CI-C6)alkoxy, (CI -C 6 )alkoxycarbonyl, (CC)alkoxysulfonyl, (CC)alkyl, (CI -C 6 )alkylcarbonyl, (CI -C 6 )alkylcarbonyloxy, (C -C 6 )alkylsulfonyl, (C -C 6 )alkylthio, 15 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 Zs)carbonyl; and Z 7 and Z 8 are independently hydrogen, (C C)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, 20 nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R, 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 I 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 I or 2 groups that 25 are independently halo(CvC.)alkyl or halogen. In ceai mbodiments, the present invention provides uses for conjugates of Formula (i) for preparing, or for the manufacture of, a medicament for threat dyslipieia i resistance, elevated fatty acids, elevated triglycerides, p3-cell dysfunction, hyperglycemia, metabolic syndrome, and any formn of diabetes mellitus including type I and type II diabetes 30 and Latent Autoimmnune Diabetes of Adulthood, in a patient, wherein RK is hydrogen or acetyl; R2, R 3 , R4, and Rs are independently hydrogen, halo(CvQs)alkyl, or phenyl wherein the pheny is optionally substituted with 1 or 2 halogens; Ra is -NbK; Z is hydrogen; Ze is phenyl, wherein tihe phenyl is optionally substituted wih or 2 gps~ that independently hal(C ~salkl r hloen.
    WO 2010/106082 PCT/EP2010/053418 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 Ri is hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are 5 independently hydrogen, halo(CI-C 6 )alkyl, or phenyl wherein the phenyl is optionally substituted with I or 2 halogens; R 6 is -NZ 5
    Z
    6 ; Zs is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with I or 2 groups that are independently halo(C 1
    -C
    6 )alkyl or halogen. In certain embodiments, the present invention provides uses for pharmaceutical 10 compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent utoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable 15 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, 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; Z6 is phenyl, wherein the phenyl is optionally substituted with I or2 groupsthat are independently halo(C 1
    -C
    6 )alkyl or halogen. 20 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 25 pharmaceutically acceptable salt there wherein Ri is hydrogen or acetyL; R R 3 , R 4 , and R 5 are independently hydrogen, halo(CvCr)alkyl, or phenyl wherein the phenyl is optionally substituted with 1 or 2 halogens; R 6 is -NZsZ 6 ; Zs is hydrogen; Zs is phenyl, wherein the phenyl is optionally substituted with I or 2 groups that are independently halo(Ci C 6 )alkyl or halogen. preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pumonary Disease, cardiovascular diseases, and metabolic dses in mammal or patient, wherein Ra is hyrge ractl RU, R<, R4, an Rsar ineednl y gn trfuoromethy, or ;;i,:' 7 7 WO 2010/106082 PCT/EP2010/053418 2,4-difluorophenyl; R 6 is -NZ5Z6; Z 5 is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with I 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 5 resistance, elevated fatty acids, elevated triglycerides, p-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 -NZsZ 6 ; Zs is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with 1 10 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 15 independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is -NZsZ 6 ; Z 5 is hydrogen; Z6 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 pharmaceutiai compositions for preparing, or for the manufacture of, a medicament for treating 20 dyslipidemia, insulin resistance, elevated fatty acids, elevated triglycerides, p-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I nd tvne 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 25 R 1 is hydrogen or acetyl; R 2 , R 3 , R 4 , and Ri are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R( is --NZsZ; Z is hydrogen; Ze, is phenyi, wherein the phenyl is optionally substituted with I or 2 groups that are indepndently trifluoromethyl or Ci. in certain embodiments, the present invention provides uses for pharmaceutical 30glycated end products and/or lipid peroxidation including, but not lirnited to, oxidation of low-density lipoproteins in a patient, wherein th pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (l), or a pharuiaceutically acceptal sal theeoheei Ri is hydrogen o act; R2, R, R4, an RsV arc independently hydrogen, trifluoromethyl, or 2,4-diflurophenyi; Ra is N/~e Z- 7i WO 2010/106082 PCT/EP2010/053418 hydrogen; Z 6 is phenyl, wherein the phenyl is optionally substituted with I 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 5 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 (1) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate. 10 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, p-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, 15 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 or conjugates of Formula (I) or Formula (IV) for preparing, or for the manufacture of, a medicament for reducing 20 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) or Formula (IV) is N-(3,5-bis(trifluoromethyl)phenyl )-5-chloro-2-hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoy l)-4-chlorophenyl acetate. In certain embodiments, the present invention provides uses for pharmaceutical 25 compositions for preparing, or for the manufa ture of, a medicament for treating dyslipidemia, insulin resistance, eevated fattv acids, eevated tri lycerides, P-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, whri the pharmaceuticals copstio coie aes oe phoarmaceuically acceptable 30 carrier and a conjugate of Formula (i) or Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Forrmula (I) or Formula (IV) is N-(3,5-bis(triflunoromethyl)phenyl)-5-chloro-2-hydroxybenzamideo 23,5-bis(triuo rornethyl)phenylcarbamoyl)-4-chlory ace~tate. '0: WO 2010/106082 PCT/EP2010/053418 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 5 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-hydroxybenzamide or 2-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-4-chlorophenyl acetate. 10 In another aspect, the present invention provides conjugates of Formula (I)
    R
    2 R
    R
    3 0 R4O
    R
    5
    R
    6 (I) or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen, (C 1 C )alkylcarbonyl, or A; 15 R2 R 3 , R4, and R are independently hydrogen, (C 6Calkoxy, (Cel)alkoxycarbonyl, (CI-C)alkoxysulfonyl, (C-C)alkyl, (CI-C 6 )alkylcarbonyl, (CI-C 6 )alkylcarbonyloxy,
    (CI-C
    6 )alkyisulfonyl, (CC6)alkylthio, carboxy, cyano, formyl, halo(C 1 -%)alkoxy, halo(C1-C 6 )alkyl, halogen, hydroxy, hydroxy(C-C)alkyl, mercapto, nitro, phenyl, -NZiZ2, or (NZIZ2)carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that 20 are independently CvC 6 )alkoxy, (C 6 C)alkoxycarbonyl, (CC)alkoxysulfonyl, (C]-C)alkyl, (C -C 6 )alkylcarbonyl, (C -C)alkylcarbonyloxy, (C]-)alkylsulfonyl, (CC)alkylthio, carboxy, cyano formyl, halo(Cj-C6)alkoxy, halo(CIC 6 )a Ikyl, ha logen, hydroxy, hydroxy (jsalkyl, mercapto, nitro, phenyl, NZ 3
    Z
    4 , (NZ 3
    Z
    4 )carbonyl; Zij, Z2, Z3, an Z4 ar ineenety ydroge, (C> jshjalky , or (C~~lylabnl 25 R 6 is hydroxy, -N/7 6 o, IQ-4 WO 2010/106082 PCT/EP2010/053418 X1-L X1-L NIHN r H R9 N 7R N' 2N N IN' S+ N H H I I , N
    R
    8 0 R 8 0 R 9
    R
    8 formula (i) formula (ii) formula (iii) +0 +0 N OH 0 OH, OH ' -0 HOC HO0S 0 OH N O H H 0 H 00 ±10 ' OH o / I 5 *or provided that when R 6 is hydroxy, then R, is A
    Z
    5 and Z 6 are independently hydrogen, (C]-CWalkyi (C I-C 6 )aikylcarbonyl. phenyl, phen d(CFT- or phenyl(CH 2
    )
    2 wherein th phenyl is optionally substituted with 1, 2, 3, 4, or01 op t eidp~dn~ CC)io (C(~ 6 akxy-ro io Iu k (C CjAikxsnni ~j )iyC- 6 aklabn ,( Cjlye lXy, (C15)~ysloy,( 1
    -
    6 aklho croy ynfryhi( 1 &)loy WO 2010/106082 PCT/EP2O10/053418
    (C
    1 -Cc)alkyl carbon 'lo xy, carboxy, cyano, forrnyl, lialo(Ci -C 6 )alkoxy, halo(Cj -C,)alkvl, halogen, hydroxy, or hydrox y(C 1
    -C
    6 )alkyP Rg is hydrogen or (CI-C 6 )alkyl, R,) is hydrogen, (CI-C6)alkyl, or (C 1
    &C
    6 )alkvlcarbonyl; Rio is (CI-C(s)alkoxy.. (Ci.-Wsalkyl, (C 1
    -C
    6 )aikylthio, hydrox, or -NZ 9 Zoc;
    Z
    9 and Zpn are independently hydrogen, (CI<-C6)alkyl, or (CI-C6)alkvlcarbony1; X, and X 2 are independently 0 or S; L is (C -C6)alkylene; A is
    R
    3 R~ 0 QHS r R4HN- A N N H H 10) R 5 a 0. S-S ,0 0 0 = 00 HS NV S H H H 0 or 0 Riz, is hydrogen, (C 1
    -C
    6 )aikylcarbonyl, or B;
    R
    2 ., R 3 a, R4,, and R 5 a are independently hydrogen, (C 1-Cealko. y,
    (C-C
    6 )alkoxyearbonyl, 1.I-C6)alkoxysulfonyl, (C -C6)alkyl, (C-C 6 alkylearbonyl, 15 (C 1 ,-(C,,)alkvlcarbonylo xy, (C 1 -C(,)alky IsulfonyL, (C 1
    -C
    6 )a-Ikylthio, carboxy, cy ano, form'], (CI-C6)alkoxysulfonyl, (C 1
    -C
    6 )alkyi, (C 1
    &
    6 )alkyicarbonyl, (C 1 %6)alkylearbonylo xy, 20 (C 1
    -C
    6 )alkvlsulfo nyl, (C 1 -C~alkylthio, carboxy yano, formvl.I halo (C 1 &,)- kxy (Ciak bi l 25 is WO 2010/106082 PCT/EP2010/053418 Rb Rib R2) 1b R : 0 0 HS~ 0 0 S 0 S R HN N N H H R5b , OS-S 0 0 0/ 0 0 /' 00 HS NAS O O HH H N S N S 0 ,or 0 Rib is hydrogen, (C 1
    &
    6 )alkylcarbonyl, or C; R2b, Rab, R4b, and RSb are independently hydrogen, (CI-C 6 )alkoxy, 5 (C 1
    C
    6 )alkoxycarbonyl, (C-C 6 )aikoxysulfonyl, (C-C 6 )alkyl, (C 1
    C
    6 )alkylcarbonyi, (CI -C 6 )alkylcarbonyloxy, (C -C)alkylsulfonyl, (C -C,)alkylthio, carboxy, cyano, formyl, halo(C1 -C6)alko xy, halo(CI -C 6 )alkyl, halogen, hydroxy, hydroxy(C-C 6 )alkyl, mercapto, nitro, phenyl, -NZlbZ2b, or (NZIbZ2)carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C-C 6 )alkoxy, (C-C 6 )alkoxycarbonyl, 10 (C -C 6 )alkoxysulfonyl, (C -C 6 )alkyl, (CIC 6 )alkylcarbonyl, (C C)alkylcarbonyloxy,
    (CI-C
    6 )alkylsulfonyl, (CI-C 6 )alkylthio, carboxy, cyano, formyl, halo(Ci -C 6 )alkoxy, halo(Ci-C 6 )alkvl, halogen, hydroxy, hydroxy(C 1
    -C
    6 )alkyl, mercapto, nitro, phenyl, -NZm3Z4b, or (NZ3mZ 4 )carbonyl; Zib, Z-b Z3, and Z4b are independently hydrogen, (C 1 -C)alkyl, or 15 (CI-C6)alkylearbonyl; and 0 ~ 0 HS HS 0 f~SN - s H SS O, S-S , 0 SO H10 1 N poie that Horua()de 0o nops H is hyroe or 0ctl 2 4 n 20 Rsar hdrge;an R i () -aeylyseie,(D Naetlestin, r0+ N-ctlyti provided that Formula ( I) doe np 0 s he ecm ass e.1 ~P.L n WO 2010/106082 PCT/EP2010/053418 N-acetyi-S-[(2',4'-difluoro-4-hydroxy[1,1'-biphenyl]-3-vl)carbonyl]-L-cysteine methyl ester; N-acetyl-S-[(2',4'-difluoro-4-hydroxy[1,1'-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[1,1'-biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester; and 5 N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[1,1'-biphenyl]-3-vl)carbonyl]-L-cysteine ethyl ester. In another aspect, the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R2, R 3 , R 4 , and R 5 are independently hydrogen, halo(C 1
    -C
    6 )alkyl, halogen, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups 10 that are independently C -C 6 )alkoxy, (C, rC-()alkoxycarbonyl, (CI-C 6 )alkoxysulfonyl, (C-C)alkyl, (C 1
    C
    6 )alkylcarbonyl, (C I-C)alkylcarbonyloxy, (C C6)alkylsulfonyl,
    (CI-C
    6 )alkylthio, carboxy, cyano, formyl, halo(C1-Cs)alkoxy, halo(Ci-C 6 )alkyl, halogen, hydroxy, hydroxy(C 1
    -C
    6 )alkyl, mercapto, nitro, phenyl, -NZ 3
    Z
    4 , or (N 3
    Z
    4 )carbonyl; R 6 is formula (i); R 7 is (C]-C 6 )alkoxy, (CI-C 6 )alkyl, (CI-C6)alkylthio, hydroxy, or -NZ 9 Zio; Rs is 15 hydrogen or (CvC 6 )alkyl; R 9 is (CIC 6 )alkylcarbonyl; X, is 0 or S; L is (CIC 6 )alkylene; and
    Z
    3 , Z 4 , Z 9 , and Zio are independently hydrogen, (CvC 6 )alkyl, or (CI-C 6 )alkylcarbonyl; provided that Formula (1) does not encompass Ri is hydrogen or acetyl; R2, R3, R4, and Rj are hydrogen; and R6 is ( N-acetylcysteine, (D) N-acetylcysteine, or 1 ) N-acetyleyseine. In another aspect, the present invention provides conjugates of Formula (1) wherein Ri 20 is hydrogen or acetyl; R 2 , R3, R 4 , and R5 are independently hydrogen or phenyl, wherein the phenyl is optionally substituted with I or 2 groups that are independently halo(C I-C 6 )alkoxy, halo(Ci C 6 )alkyl, or halogen; R6 is formula (i); R7 is (CI-C6)alkoxy or hydroxy; RS is hydrogen or (CrC 6 )alkyl; R, is (CI-C6)alkylcarbonyl; X, is O or S; and L is (Cf-C6)alkylene: provided that Formula (1) does not encompass R, is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are 25 hydrogen; and R, is (L) N-acetyleysteine, (D) N-acetylcysteine or ( N-acetylcysteine. In another aspect, the present invention provides conjugates of Formula (1) wherein Ri is hydrogen or acetyl1; R2, R, R4, and R. are independentQl hdrogen orpheny, whceen the phenyl is optionally substtued with I or 2 halogen groups; KR: isfrmula (i); R7 is ethoxy, mrethoxy, or hydroxy; R is hydrogen or nethyl; R9 is acetyl; Xi is 0 or S; and L is CH2; 30 roided that Focrmula (I) does not ernompass Rbi hydrogen or cetyl; R2 R3 R4 and Rs ae hydrog'en; and R 1 is (L) N-acetylcysteine (D) N-acetyleysteine, 0r (i) N acetyeysteine. In another apet the pre sent invetio prove ides co njugates ofFormua (I) weenir WO 2010/106082 PCT/EP2010/053418 In another aspect, the present invention provides conjugates of Formula (1) wherein R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, halo(CI-C)alkyl, or halogen; R6 is formula (i); R 7 is (CI-C6)alkoxy, (CIC 6 )alkyl, (C 1
    &
    6 )alkylthio, hydroxy, or -NZuZio; R 8 is hydrogen or (C-C)alkyl; R 9 is (CIC 6 )alkvlcarbonyl; Xi is 0 or S; L is 5 (C 1
    -C
    6 )alkylene; and Z 9 , and Zio are independently hydrogen, (C]-W)alkyl, or
    (C
    1
    -C
    6 )alkylcarbonyl; provided that Formula (1) does not encompass R, 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 (1) N-acetylcysteine. In another aspect, the present invention provides conjugates of Formula (I) wherein R, 10 is hydrogen or acetyl; R 2 , R 3 , R 4 , and R5 are independently hydrogen or halo(C1-C6)alkyl; R 6 is formula (i); R 7 is (C 1 -C)alkoxy or hydroxy; R8 is hydrogen or (C 1 -C)alkyI; R 9 is (Ci-C 6 )alkylcarbonyl; X 1 is 0 or S; and L is (CI-C 6 )alkylene; provided that Fonrula (I) does not encompass R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are hydrogen; and R 6 is (L) N-acetyleysteine, (D) N-acetyleysteine, or ( ) N-acetylcysteine. 15 In another aspect, the present invention provides conjugates of Formula (I) wherein R 1 is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen or trifluormethyl; R 6 is formula (i); R 7 is ethoxy, methoxy. or hydroxy; Rs is hydrogen or methyl; R 9 is acetyl; XI is 0 or S; and L is CH 2 ; provided that Formula () 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 (±) 20 N-acetylcysteine. In another aspect, the present invention provides conjugates of Formula (I) wherein R 1 is hydrogen or acetyl; one of R 2 , R 3 , R 4 , and R 5 ais trifluormethyl and the rest are hydrogen;
    R
    6 is formula (i); R is hydroxy; Rs is hydrogen; R9 is acetyl; X, is S; and L is CH 2 . 25 In another aspect, the present invention provides conjugates of Formula (1) wherein R, is hydrogen or acetyl; R 2 , R3, R 4 , and R 5 are independently hydrogen, halo(C 1
    &
    6 )alkyl, or halogen; Rs, is -iNLs~a; Zs is hydrogeni; Ze is hydrogen, (C s~aky, (C-"~alklcaronyt, phenyl, phenyl(CH2), or phenyl(CHu~ 2 - wherein the phenyl is optionally substituted with 1, 2,3,4, or 5 groups that are independently (CeiCs)alkoxy, (Ce Q)alkoxycarhonyl, 30 ~(C+O)alkoxysulfonyl, (Ce'fs)alkyl, (C Os)alkylcarbonyl, ( C 6 )alkylearbonyloxy, (C I~akylsutony, (CvCs,)aikylthio, carhoxy, cyano, formyi, halo(Ce&s)alkoxy, halo( ,s akyl, haloge, Ihydro,', hyroxy(~Ce4> alkyl, ercap3to, nitro, plheny -NZ7Z, or (NZ7Zs rny; an Z7 and Z are indepen~dently hydrogen, (C~~lyo (C: -akylarbnyl 30o WO 2010/106082 PCT/EP2010/053418 In another aspect, the present invention provides conjugates of Formula (I) wherein R, is hydrogen or acetyl; R2, R 3 , R4, and R5 are independently hydrogen, halo(C-C 6 )alkyl, or halogen; R6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z 6 is hydrogen, (C 1
    &
    6 )alkyl, (C-C)alkylcarbonyl. In another aspect, the present invention provides conjugates of Formula (I) wherein R, 5 is hydrogen or acetyl; R2, 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 Z6 is hydrogen. In another aspect, the present invention provides conjugates of Formula (1) 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;Z 6 ; Z 5 is hydrogen; Z 6 is phenyl, wherein the phenyl is optionally 10 substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C 6 )alkoxy,
    (C-C
    6 )alkoxycarbonyl, (C -C6)alkoxysulfonyl, (CI -C)alkvl, (C -C6)alkylcarbonyl, (Ce-C 6 )alkylcarbonyloxy, (CrC 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 ZS, or (NZ 7 Zs)carbonyl; and Z 7 and Z 8 are independently hydrogen, 15 (CC 6 )alkyl, or (CI-C 6 )alkylcarbonyl. In another aspect, the present invention provides conjugates of Formula (1) 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 -N56; Zs is hydrogen; Z6 is phcnyl, wherein thephenyl is optionally substituted with I or 2 groups that are independently halo(CI-Cs)alkyl or halogen. 20 In another aspect, the present invention provides conjugates or Formula (I) wherein R1 is hydrogen or acetyl; R 2 , R 3 , R4. and R 5 are independently hydrogen, trifluoromethyl, or Cl;
    R
    6 is -NZ 5
    Z
    6 ; Z 5 is hydrogen; Z6 is phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently trifluoromethyl or Cl. 25 Representative conjugates of Formula (1) include, but are not limited to, the compounds shown below, wherein R 1 is hydrogen or acetyl, 2 R, R 'Q 0 0O 0 HU N H OH - ~ ~ -'-,>-H , . >Un WO 2010/106082 PCT/EP2010/053418 S0 x( 0 o 0 0 0 s s 0 s H H OH O O NH 2 NyNN N N) " N 0-' N N ) H H H H O H O HN O H 0 H H 0 O NH NH 1RR 1 R S0 0 00s ~ ~ O H H OHNH2 N N N N O N OO NH N H H H H H H N O 0 0 0 0 NH NH F3C , -O F 3 C O F 3 C O FC O C O - 0 -- 0 1 - - r- 0 - 0 O Os O s 0 S S o S, H H N OH N ON' N N NH 2 N N N N, H H H H H NH 0 0 0 0 a NH NH RP R1 F F~ F 1 F
    F
    3 C 0O F 3 C ,,-,F 3 CFO F C 0 F C 0 F F H H N OH NN N NH 2 N N N N-, Hy H H H H NHH 5 0 0 0 0 0 NN
    F
    3 ~ OF 3 C 0O FC ,O F 3 C, O F C0 s- 0) S,0 S, 0 -_ 0 H H OH0 - IH 2 YN N, N,, N N N N y H H H H- H F F
    F
    WO 2010/106082 PCT/EP2010/053418 R1 R1 7 F F 0 ~ 0 -. 0 s K-,s, F F 0 HN H H
    NH
    2 Nr N N N S OH N N H H H NH NH 0 0 R, R1, F F O F ~> 0 - 0 -~ 0 F OH F O FO OHO F F F S S N NH2N H H
    H
    0 0 r O O NH NH
    F
    1 ~ FF O 0 0 0 0 O 0 F F F S -S OHOAO F OF H H N NH 2 N N N N H H 0 H 1 F~ 0 -*> OH 00 F 0 -~ F 0 i H H N, NH 2 >N7 NNNl R, Fl 0 a 0 0 H0HN0 HP 0l 0 0 00 6 2 WO 2010/106082 PCT/EP2010/053418
    F
    3 C O0 F 3 C 0 F 3 C 0 O HN 0 HN O HN S OH S O~ S 0 N N ),, N H H H O 0 0 0 0 0 R11
    F
    3 C F 0 Os HN F 0 HN N s NH 2 N S OH H - AH s I O 0 0 0 , 1 1 F O F O F 0 s HN F 0 HN N O S O H HyN y O 0 0 0 F >0 itt F O HN SN
    NH
    2 0 OH OH H 0 0 N H O spp 0 OH OH H OH H OH F3CC OO HS 0 H Nf NH 2 kO HS OHF 0K WO 2010/106082 PCT/EP2010/053418 O 0 H IH i N N H y 0 0 N. N O NH 2 O OH 0 O OH HS OH N 0 Cy HS HS H 0 0 N H H O N2 NO H I IH 0 N H HS S0 N 02 ,-,, N
    OHOH
    0 HH HH H N N H H O N N Y ONSO N O O NH OHH HSH 0 N 0 N H Y HS S N O 0OOH O NH 2 0 HS H 0H0 N N H H _y 0 NN N 0 N 011 HS 'H S, 0 H H H 9 1 9-N 9 0H H OH 0 0 S,,,,N N IHS OH Hi H F 0 sH 000 F F y 0 N t, A WO 2010/106082 PCT/EP2010/053418 0 0 0 H H 0y ) -k Nl 0 N HS S N H S N 0 N 0 0 NH 2 0 0 OH SOHS F F F 0 H 0 H N N H 0H O N 0 N OH S H S HS F F H 0H NN F H u O~ ON H S 0 0 H O F H S HS H F3CF 0 O FCO P F3F 3 Hi NS 0 S ,,' 05 H WO 2010/106082 PCT/EP2010/053418 HSH y O H 0 N 0 O H H S N H N H -Y N S0 HS 0 OHS N & H H N N O H 0 H H N H N N 'N Sa 0 0 O S T F 3 C 0o TF 3 C 0 NHF 2 HS H 0 H S-- N O 0N 02 N _ H 0 H N c N 0 O 0CO ' H HS N S N HS O OH 00 00 H I H N N 99 99 H
    H
    0 ~ 0 ~2 ~ s N HH 0 H0 0 0 fl0 H ,T H S H 0 H H N N0 S 0 002 H H 1< H N FC0 S HSH 0 HN WO 2010/106082 PCT/EP2010/053418 o 0 H H N N 0 H 0 0 H H N H O N N ON OH F N OH F- NI o- & 0 0Y 0 0 F, 3 C 0 H 0 H ' F 3 C 0H NO NO 0 0 0 0 NH 2 0 H H O . N O 0 H O O H H~ O O,-Y H0S- N N N 0 N H 0 N H O H HS F NNHS 0 OH 0 0 00 F F HH N N 0 0 N11 S H " H N N- OHS) o 0 H 0 F N 2 F F //0
    HO
    WO 2010/106082 PCT/EP2010/053418 HO q H O O0O OH HOOO H O O H 0 HO HK , OH H 1/1 O OH N OH H 0 O OH 00 H OH H OO OH 0 H n r) - 0 OH HOH ,,u HO HN 0 0 0 o 0 OH 0 OHo rs 0 WO 2010/106082 PCT/EP2010/053418 O - O" 000 0 06 0 0 0 0 OH 0 0 0 - OOH - 0 HO, OH 0/ " -O 0 00 0 OH H OH OH F 0 OH 5 OF0 OH-'O 5 F OH O 69 WO 2010/106082 PCT/EP2010/053418 OH - 0 O HO F 0 F F OH F, OH F0 HO 0 0 F -0 F F O OH FF F F OHO 0
    F
    WO 2010/106082 PCT/EP2010/053418 0 0 0 S H 0 HO HN O 0 O FOO F F F 0 0 OH OH 0 0 'O OH IN H IH F o"~ "o - F F F 0 OH 0 0 N OH O OH F F F HO HO F O 0 OH 0 s QO O 0 OH F F 5 0 WO 2010/106082 PCT/EP2010/053418 F F F F 0 0 s OH 0 0 0 OH 0 O O H F 0 F F OHO 0 O F F O OH Y 5 O H 0 OH 00 WO 2010/106082 PCT/EP2010/053418 OH 0 F 3 C O/ HO / -CF 3 0 OH OH - 0
    F
    3 C HO
    CF
    3 - - 0 /O- CF 3 0 HO OH - 0
    F
    3 C O 01-1 OH F3C N OH OH 0 - 0 r 3 0 0'/ N OH YHH OH iOlO HO 0 0 0 0 CF 3 7 .3 WO 2010/106082 PCT/EP2010/053418 0 oH 0 0 0 0
    F
    3 O OH HO o "O CF 3 OH - 0
    F
    3 C O o O OH HO HO O OH 0 0
    F
    3 C O O OH HO HO O 0 OH
    F
    3 C O 0 H O u OH 0 O 5 O 0 s~s I
    F
    3 0, 0 HOO 74A WO 2010/106082 PCT/EP2010/053418
    F
    3 C O 0 OH 0
    F
    3 C O O0 o 0 0 0 0 0 0 NH NH NH HS 0 HS 0 HS 0 O O -O - 0 0 0 0 S s S H N H HN N S OH N NS 0 H H H O 0 0 0 0 0 00 0 0 NHH N H HS O HS
    F
    3 C 0
    F
    3 C O H 0 0 0 0 O 0 NH NH HS o HS O F -C
    F
    3 C O HN HN
    SNH
    2 0 O 5 OH 50 09 WO 2010/106082 PCT/EP2010/053418 0 NH NH HS Oy HS O F 00 0F O H FS OH S y -yo" N O O 0 ANH ANH HS 0 F F - 0 0 0 S S F S O F SN O OHO O N H
    H
    0 0 H0 0 O O 0 H NH NH Hs 0 HS 0 - N- K- 0 Io H O F3C 0O SS S H H N N H HfRNH H 0 NH NH 0 NH NH O NH NH O 0N0 S NH O O H H F3C HO S S N N NN N N N ~O NH NH 0OHN NH NH 07 WO 2010/106082 PCT/EP2010/053418 0 SH 0 NH S 0
    F
    3 C 0HO
    F
    3 I ~- o S 0 OH
    F
    3 C 0 H N N N N, H O NYTY H 0 NH NH
    CF
    3
    F
    3 C 0OH F 3 C C OH S 0 OH S O -OH 00 N O N O H H "
    CF
    3
    CF
    3 In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (1), as shown above, and at least one pharmaceutically 5 acceptable carrier. In another aspect, the present invention provides conjugates of Formula (II) 1a R 2 a 0 R 3 a R,0.
    R
    3 0 R 5 , - 0
    R
    5 R6 (II) 10 wherein R, R-, R4, Rs, Ra, R2a R 3 a, R~, and are as defined in Formula (I) of the Summary section, provided that when Re is hydroxy then R 1 a is B, as defined in Formula (I) of the Summary section. R2, R 3 , R 4 , Rs, are independently hydrogen, trifluoromrethyl, or 2,4-ifluorophen yl; Rois as 15 defined in Formula (I) of the Summary section; R;a s hydroge or acetyl; and Rla, Raa, R.a and Rsa,> are indepedently hydrogen, trifluoromethyl or 2,4-dif1luorophenyl.
    WO 2010/106082 PCT/EP2010/053418 In another aspect, the present invention provides conjugates of Formula (II) wherein
    R
    2 , R 3 , R4, R 5 , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is N-acetylcysteine, (L) N-acetylcysteine, or (D) N-acetylcysteine; RIa is hydrogen or acetyl; and one of R2a, R3a, R4a, and R 5 a is C(O)-R6a and the rest are hydrogen; and R6a is as defined 5 in Formula (I). Representative conjugates of Formula (11) include, but are not limited to, the compounds shown below, wherein Ria is hydrogen or acetyl. I Ia1a l l1a O0 o o 0 00 0~ oOss Osss OH N N NH 2 HH H H NN O O O O O NH NH R1a 1a R1a 1a Rla O -,0,,0 o o o K o~ o A> N OH o N oH N N H - 0)~ NH ~ N NINI H N 0N N N Y H H 6 H 0 H 0 H O NH NH Ria R,a Ia RIa RIa ooo ~ o 0 N 'f-O 0 0N 0 0N 0 H H H HH0 0H0 0 0 ~0 Hi H <-.OH <' O <H - -. 4 NN N N N HH HH H H 10 0 0 06 NN 7'X WO 2010/106082 PCT/EP2010/053418 R R m ~ 1 i O1'r:. CF 3 0 , CF 3 0 CF 3 O)a CFA 0 CF,
    F
    3 C O F 3 F3C F 3 C, 0O F 3 C 0O F 3 C 0O K)0 0 0~ 0 0 I I H H OH 0" I- NH 2 -'rN N yNI N" Y N N' o- ' N N H o Hy H H H ~NN O 0 0 NH H la Rla Ria a CF U 0~ CF 3 0~ CF3 0 CF 3 0~ CF; O Vz
    F
    3 C, ,O FC 0 F 3 C 'e-O- F 3 C, 0O F 3 C ~ ~0 00 S SSS S H H N Ny ",0_, SrH O 0H N N 2 N N N HH H H H H H 0 0 0 0 0 NH NH ,l ila F ia la l 01r CF3 O CF 3 0 ~ CF 3 0. CF 3 0. CF 3 O0 0 0 0 Q FC 0 F 3 C , 0 F 3 C 0 F3C 0 F 3 C Tll 0~ 9 Q0 0 - H H N N-l N N Y H H H H H NN O 0 0 0 0 NH H N NH NH 'NH -N O00 -0 0 S H 0, SH 0 SH 0 .. SH 0 SH 0,, 00 Hj 0. 0 0 O 0 H 0 0± 0 ' AH S" S2 '79 WO 2010/106082 PCT/EP2010/053418 1a R1aa 0O 0 >0 >0 0>0 >0 ,::, 0 0 ::, 0 0 -l 0 0 O HN s HN 0 HN SSS0 N S OH N S SO Hy H)- Hy O 0 0 0 0 0 NH NH NH O SH o SH O SH O S O S O N N O N H HH N~ H O 0 0SH 0 0 00 0 O O K-0 0 0 00 0 0 HN 0 HN 0 HN s OH ')N 'S'- Y ND~rS 0 o'" O 0 0 0 u C) 0 NH H NH /SH SH _, ur rr 0 A N-'S 0-' A N S -r-, H Hjr 0 0 >'0 0 > >Y0 0 0 0 - 0 o 0 HNk 0 s H N H H N NH AN S N N N,, H 0 0 H 0 0 NN WO 2010/106082 PCT/EP2010/053418 S S 0 HO NH 0 0 NH 0= O0 OOH O 0 O OH OH OH HO HO 7 00OH 00 OH OO OH OH HO 00 / OH /F 0H Oo 0 NH NH 01 0 SH r o o O N O SH 0 S O OHH H 0 WO 2010/106082 PCT/EP2010/053418 0 0 NH NH NH O SH O O SH o SH N N 0 N s 0 H 0 >H H 0 0 O H 0 0 0 K-0 -ll 0 0 OSOOS NL OH AN o"AN H 0H 0H 0 0 0 0 NH NH NH O SH O0 0 S O SH SH 0 H' 0 o > 0 K-; 0 0 0 0 0 0 HN 0 HN N NH 2 N OH N H H H -0 0 0 0 0 0 0 NH NH 0 0 SH Os - SH 0 0 O 0 n; 0 Q 0 HN 0j HN 0 > 0 00 0 WO 2010/106082 PCT/EP2010/053418 0 NH 00
    OR
    1 SHOW 00 0 0 0 O 0 OH 0 HO O OH H 0 O NH NH , O 0 OH OR,, ORia S0 OH 0 OH / N OH O O H O ORia, C O 0 0 0 0 O0OH O~NH 0 OH, 0 R 0 0 OH0 JH 0R 0 WO 2010/106082 PCT/EP2010/053418 S S OH 0 0 ORa 0 , and 0 0 '- 0 00 ORa 0 In another aspect, the present invention provides pharmaceutical compositions 5 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) R2b R 1 b R3b 0 R b R2a R5b O R3a
    R
    2 Ria
    R
    3 0 R 5 a R- -f
    R
    5 R 6 10 (II1) wherein R 2 , R 3 , R 4 , R 5 , R6, R 2 a, R 3 a, R4a, Rsa, Rib, R2b, R3b, R4b, and Rsb are as defined in Formula (I) of the Summary section, provided that when R 6 is hydroxy then Rib is C, as defined in Formula (1) of the Summary section. In another aspect, the present invention provides conjugates of Formula (III) wherein 15 R2, R!3, R 4 , Rs, are independently hydrogen, trifluoromnethyl, or 2,4-difluorophenyl; R 6 is (L) N-acetyleysteine; R 2 a, Raa, R 4 , and Rsa are independently hydrogen, trifluoromnethyl, or 2 ,4-difluo rophenyl; R23, Rae, R4 1 and Rae, are independently hydrogen, trifluoromethyl, or Representative conjugates of Formula (Ill) include, hot are not limited to, the 20 compounds shown below, whrein R , is hydroen or acetyi. R-4 WO 2010/106082 PCT/EP2010/053418 FRib Rib Rlb 1b O '0 0 0 0 0 0 0 O Y-J 0 y 0 '-I 0 0 ~o c~ 0; ,x 0 x' 0 o" 0 x'O 0 N N OH AN AN N N 2 H)r H H Hy 0 0 0 0 0 o 0 0 0 > 0 >0 0;10 o
    K
    H OH S N N N NN,,j ' N NHo H yyH H 0 NH NH 0 0 0 0 Rlb Rib Rib o 0 0 O0 0 0 6H a fl > A85 WO 2010/106082 PCT/EP2010/053418 ib ' OH 0 C0 ; 0 0 OH and OH In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (III), as shown above, and at least one pharmaceutically 5 acceptable carrier. in another aspect, the present invention provides conjugates of Formula (IV) R1, N CF 3 Y H CI (IV) 10 wherein R 1 is hydrogen, (C 1
    -C
    6 )alkylcarbonyl, O HS HS o 0S NA K H HN0N I N N o~ss H H 6H 0 S-S~ 0 0 o r Representat ive conjugates of Formul~a (IV) fCU hecrpus2hvoeow wherein R{ is hydroen raey WO 2010/106082 PCT/EP2010/053418 yF 3
    F
    3 S '-A 00 0 NH r N CF 3 N CF 3 0 H H CI CI O HS0F3 F 3 C1 SHan H F 3 HN 0 0 N 0 0 - " . 0YF
    NCF
    3 HS H CF 3 HN C 0 C CI SH and
    CF
    3 R1 N bCF 3 (I ' H CI In another aspect, the present invention provides pharmaceutical compositions 5 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) -~ 0 10 (V) wherein R is
    R
    10 0 NHH N rq R - 2 N N N S H H WO 2010/106082 PCT/EP2010/053418 -OH 0 + 0 ~ N OO O OH ~$ O OH OH O -/O 0 0O '', O OH ON SO HO HO OH H O O OH 0H H0 O O- O OU +10 OH O S S 1+0 OH ~ 0 or 5R 7 is (C 1
    -C
    6 )aikoxy, (C pC)alkyi, (C-C 6 )aikylthio hydroxy, -NZ 9
    Z
    0 o, or O-phenyi, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently
    (CI-C
    6 )alkoxy, (C 1 -C6)alkoxycarbonyl, (p-C 6 )alkyl, (CI-C 6 )alkylcarbonyl, (C-C6)alkylcarbonyloxy, carboxy, cyano, formyl, halo(C-C)alkoxy, halo(CI-C 6 )alkyl, halogen, hydroxy, or hydroxy(CI-C 6 )alkyl; 10 R 8 is hydrogen or (C vC 6 )alkyl; R9 is hydrogen, (C 1
    -C
    6 )alkyl, or (CI-C 6 )alkylcarbonyl; Rio is (Cv-C 6 )alkoxy, (C 1
    C
    6 )alkylthio, hydroxy, or-NZ9Zio;
    X
    1 and X 2 are independently 0 or S; L is (C 1
    &
    6 )alkylene; and 15 Z 9 and Zie are independently hydrogen, (CvC 6 )aikyi, or (C vCs)alkyicarbony. compounds shown below.
    WO 2010/106082 PCT/EP2010/053418 HN HN HN s OH S O S O S OH S ON y S 0 -,j 0 0 - 0 0 NH 0N 0 O0 HN HN H H HN S NH 2 S N N Ns 0O O O NH NH S OH S H S O9 S NH 2 S N N N" 0 0 0 0 NH NH HN - HN HN S OH S O SO 0 0 0 0 o~ 0 O 0 HN H H I S H H S> NH 2 S N N N, o 0 0 0 NH NH HN- , HNI, ) WO 2010/106082 PCT/EP2010/053418 HN HN HN S OH S O S O O - 0 0 z' 0 0 HN HN H H S NH 2 S-' N N Ns 0- 0 0 0 NH NH 9 H HN HN S- OH S O S 0 SQ x0 0 X 0 0 O 0 O OI H N H HNN H H S NH 2 S N N N O 0 o 0 0 NH NH HN HN HNH HN S O S O O S S O0 0 0 -~ 0 0 0o O 0 IHN HN' 7H H S NH 2 S K 0 0 <0 0 NH NH 0 0 HN -f-,HN lkHN HN-f S r S~ OH S- s S o 14 0 00 00 HN~ HN H H S, Sy OS->S NH 2 5 0 0 0 - 0 0 0 90 WO 2010/106082 PCT/EP2010/053418 HN HN H S OH S O- SO o o 0 0 s NH S N N O OH H 0- 0j 0 0 NH NH HN - HN HN H S S OH S S o o o 0 o HN HN HN HN S S O- S S NH 2 -- 0 0 0 -~ 0 0 0 - HN - HN H _ S OH S o , S 0 - 0 0 - 0 0 00 0 0 H2 UN - HN -H H S NH 2 N N N j~~ K 0 0 NHNH 0 HN - HN -k HNV" HNJ S_,,rS -,OH S, so 0 0 0 0 0 0 HN HN HN HUN S S OH S S NO 0 C 0 0 0 WO 2010/106082 PCT/EP2010/053418 OH OH 0 OH OH OH ~ 00 ~ OH00 OH OH 0, OH - 0 OH 0 OH OH 7O1 O OH 92 WO 2010/106082 PCT/EP2010/053418 00 ~ 00 0 00 0 0 S0~ 0 0 -~ 0 0 O 0 HO' HO 5 0 0 OH 00 HO~0 5C 0 H WO 2010/106082 PCT/EP2010/053418 N OH N OH H H O H O O O OH H ~ O OH 0 H O HH O OH 5 0 s s O- OH S ,S O OH a " WO 2010/106082 PCT/EP2010/053418 0 0 0 0 0 OU 0 0 0 0o . K0 0 0 and 01 0 0 I 0 0 5 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 preent inventirn prides ojugte f F (VI) NH CI 10 e0 (VI) wherein R 6 is . ~0 H 9 N 'N j -1 H H
    R
    8 RyR X28 3 formula (j rr) f formulai) or Os WO 2010/106082 PCT/EP2010/053418 OIH 0st
    ON<>
    0 OH 0"O OH OH O O O 0 0~ ~ OH 0,1 HO HO O O OH OH O0OH YH O1 O H Ar0 ~~~0 SOH ,or 5 R is (C,-C 6 )alkoxy, (C 1
    -C
    6 )alkyl, (CI-C 6 )alkylthio, hydroxy, -NZ 9 Zio, or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ct-C 6 )alkoxy, (CI-C 6 )alkoxycarbonyl, (CI-C 6 )alkyl, (C-C 6 )alkylearbonyl, (CIC6)alkylcarbonyloxy, carboxy, cyano, fornyl, halo(C -C 6 )alkoxy, halo(C-C 6 )alkyl, halogen. hydroxy, or hvdroxy(C-C,)alkvl 10 Rs is hydrogen or (Ci-C 6 )alkyl;
    R
    9 is hydrogen, (C 1 -C6)alkyl, or (CI-C 6 )alkylcarbonyl; Rio is (C C 6 )alkoxy, (CI-C 6 )alkylthio, hydroxy, or -N ZZlo
    X
    1 and X 2 ar idpcendently O or S; L5 is (C Cialkylene; and 15 Z 9 and Zio are independently hydrogen, (C 1 &s)alkyl, or (C- 6 akvcroj WO 2010/106082 PCT/EP2010/053418 NH HN NH HN NH HN C I S OH CI S ON C cl S0 CI 0 Ql NH HN' NH HN CI C, S,, NH, 2 0,yl N yN yN x 0 0 -- 0 0 NH NH CI Cl CIX NH HN Y HN NH HN Cl S OH0I CI . 0 0 -~ 0 0 - 00 CI Cl NHHN NH HN lCS".. NH 2 CI Syy ~X0 0 - 0 0 NH NH N H H N NH HN NH HN> 0 0 o 0 ~ -0 0 NH HN NH HN H ClS>' NH 2 Cl ' ,S >< N,,N N,_ 0 '~0 0 NH NH NHHN HN ~ N HN HN Isci' CIc 00 5> WO 2010/106082 PCT/EP2010/053418 Y-NH Cl 0 Cl OH ~OH CI OH OH C I H N CI 0 c I NH 0, OH CI I 0 O NH 0 /2 NH CI i CI 0 "o
    OR
    WO 2010/106082 PCT/EP2010/053418 00 NH O OH NO NH OH Cl HO HO OO OH cI 0 H I0 O H NH o O ci Ci NH 0 0 0 CCOI S S NH O OH and CI NH 6 0 copine aoth aspectd the Frsent inveiason eanatleston pharmaceuticalolysiion a c WO 2010/106082 PCT/EP2010/053418 In another aspect, the present invention provides conjugates of Formula (VII) Cl NR6 (VII) wherein R6 is R, 0 R 0 R 8 O R R 5 formula (i) formula (ii) formula (iii) ,or OH 0 , OOH OH OH ~ ~ ",1 OH HOO HO 0 'O O OH OH 0 H 0 O OHO 100 r r C 10 R 7 is (C ~)alkoxy, (Cv~salkyl, (CVC 6 )alkylthio, hydroxy, -NZZior -O-phenyi whe rin the phenyl is optionally substituted wih 1, 2, 3, 4, or groups that are independently (C> 4 alkoxy, C>(C7>sa!koxycrony,(W>.ikl C~~lklabnl WO 2010/106082 PCT/EP2010/053418
    (C
    1
    C
    6 )alkylcarbonyloxy, carboxy, cyano, formyl, halo(Cj C 6 )alkoxy, halo(Ci-C6)alkyl, halogen, hydroxy, or hydroxy(C 1
    C
    6 )alkyl;
    R
    8 is hydrogen or (C -C 6 )alkyl;
    R
    9 is hydrogen, (CI-.C 6 )alkyl, or (C -C 6 )alkylcarbonyl; 5 RIO is (C 1
    -C
    6 )alkoxy, (C 1
    -C
    6 )alkylthio, hydroxy, or-NZ 9
    Z
    10 ; X, and X 2 are independently 0 or S; L is (C,-C 6 )alkylene; and
    Z
    9 and Zi 0 are independently hydrogen, (Cp-C 6 )alkyl, or (C,-C 6 )alkvlcarbonyl. 10 Representative conjugates of Formula (VII) include, but are not limited to, the compounds shown below. C1 CI CI ~ 7> N S OH N S N S 0 HN HN HN 0 0 0 N NH N H S NH 2 N N N HN H H O H N - WO 2010/106082 PCT/EP2010/053418 Cl C CI H HN HN,,,, O 0 0 NH NH2 s N N 0 HN H H H O 0 /CI CCC -c //lc N O S OH S O-- N O HN HN HN, CI C n NNH NH V H HI HN HN H O 0 C C N SS OH N S S 0 Hi / IH HN s HN, H 0 0 0 CIOCO /~ / O - WO 2010/106082 PCT/EP2010/053418 S S 0 N S S NH 2 HN HN HN HN O O 0 O CI CI OH N 0 N0 N O O H OH OH CI CI N O, 0 N OH and cI N O <NN 1 03 WO 2010/106082 PCT/EP2010/053418 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. 5 In another aspect, the present invention provides conjugates of Formula (X) F
    R
    6
    CH
    3 H S 0 (VIII) wherein R 6 is
    R
    10 0 X1-~ X1~~L NNH NH 0
    R
    9 , R R9 X2 N N S N )IrR H H
    R
    8 O R 8 0 R9 R 8 formula formula (ii) formula (iii)or +0"" /-OH 0 OH O 10 OH OH O OO0 0 0 HO HO 0 H OH O~ 04O WO 2010/106082 PCT/EP2010/053418 0 H 0 H 0 +0 OH 0"~ K' 1S 0 0 ,HO , 0 ,or
    R
    7 is (CI-C 6 )alkoxy, (C C6)alkyl, (C -C 6 )alkylthio, hydroxy, -NZ 9 Zio, or -0-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently 5 (C 1
    C
    6 )alkoxy, (CI-C 6 )alkoxycarbonyl, (C-C 6 )alkyl, (CI-C 6 )alkylcarbonyl,
    (CIC
    6 )alkylcarbonyloxy, 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 (C1C 6 )alkyl;
    R
    9 is hydrogen, (C 1
    -C
    6 )alkyl, or (CI-C 6 )alkylcarbonyl; 10 RIO is (CI-C6)alkoxy, (CI-C 6 )alkylthio, hydroxy, or -NZ 9 Zio; X, and X 2 are independently 0 or S; L is (C 1 6 )alkylene; and
    Z
    9 and Zio are independently hydrogen, (CpC 6 )alkyl, or (C-C 6 )alkylcarbonyl. 15 Representative conjugates of Formula (VIII) include, but are not limited to, the compounds shown below. F 0 F F HN HN HN 0 H N H H o 0 _0 0 _ 0 0 S _ / SN2N OH N H HH HN 0-5H WO 2010/106082 PCT/EP2010/053418 O 0 0 F Il F HF HN HN HN S OH S 0 S 0 0 0 0 00 0 CH3 O CH 3 O CH, x H S x H x H SHH H H F 0 F 0 HHN HN H H S NH 2 S N N N n O0 0 NH NH /SCH3~ 0 CH 3 Ox. /CH 3 SH O 0 0 F FF HN HN HN S1 OH OH0S S O I o o o 0 0 0 O \F O 3 0/~ H 01 /0H CH CH CH H H H 0 0 FF HN HN H H S,, NH 2 /, N N N H2 F F S S OH NHS 000 0 0 0H H / H HN HN HN HN s" S_- OH. Sl, Y S NH 0 0 0 r 0 0 0 C 0 // OH CH3
    OH
    WO 2010/106082 PCT/EP2010/053418
    CH
    3 OO OO F F 0 H H 0 H
    CH
    3 O H OH -OF O / CH H H 30 0 H 0 0H FF
    OH
    3 O FF OzOH 00O FF OH CO
    HH
    WO 2010/106082 PCT/EP2010/053418 F 0I s 0 H 0 OF OH 9 ~o , H
    CH
    3 F 0 (v 0 00 / O~H 3 I .O 0 / 0 F and H
    OH
    3 0 5 I~ M) WO 2010/106082 PCT/EP2010/053418 In another aspect, the present invention provides conjugates of Formula (IX) 0 0iiiii:0 R6 (IX) 5 wherein R6 is NH NH O X1-L X1-L N NHNH
    R
    9 ,) Ry R9 X2 N N N N )' H H R8 O R 8 O R9 R formula (i) formula (ii) formula (iii) O O O 0> ''O, OH O" HO HO OO OH O HOH O >1 T -N ~ OH OH OH ,H 0 H +0 OH 0 00 10 or werein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 4salkoxy, (C ei 6 )aikoxycarbonyl, (C %salkyl, (C K>alkylcarbonyl, (C e.yakylearbonyloxy, carboxy, ecyano, formyl, halo(C K>)alkoxy, halo(CvCK>alky, WO 2010/106082 PCT/EP2010/053418 Rs is hydrogen or (C 1
    -C
    6 )alkyl;
    R
    9 is hydrogen, (C 1
    C
    6 )alkyl, or (C 1
    -C
    6 )alkylcarbonyl; Rio is (C 1 -C6)alkoxy., (C 1
    C
    6 )alkylthio, hydroxy, or -NZ 9 Zio; X, and X2 are independently 0 or S; 5 L is (CI-C 6 )alkylene; and
    Z
    9 and Z 10 are independently hydrogen, (CpC 6 )alkyl, or (C 1
    -C
    6 )alkylcarbonyl. Representative conjugates of Formula (IX) include, but are not limited to, the compounds shown below. 0 0 0 HN 0 HN S OH S OS 00 0 0 HN 0 HNk H HNt S N N N S 0 I 0 0 NH NH 0 0 S H NH, 10 0 0 95 O HN 0 HN S OH SO 0 0 0IO 0 0 0 H H C0 NH NH 0 0 0 H< N 0 0 WO 2010/106082 PCT/EP2010/053418 O 0 HN HN S OH S o" - 0 0 X 0 0 S NHN O 0 S N 0 0 NH N 0 HN 01010 0 O 0 HN HN 1N 0 00 QHN HN - OH HoI - 0 0 NH NH 00 2 H 0 0 0 HN WO 2010/106082 PCT/EP2010/053418 O 0 HN HN J -- yS-111 1 OH S--<o o" 0 0 0HN I 0 HN 0 H H 0" 0 0 HNkNHN0 0 S NH2 --- 0 0 O 0 HN FIN S-1 l OH o"> 0 0 HNu, 0 HN 11;, yN yNyN-_ I S0 0 NH NH c v 0 0 HNk s- I'I ,_ NH 2 WO 2010/106082 PCT/EP2010/053418 0 0 S HN H HN HN I S",N OH I-11 I- o"< 0 0 I 00 NH H ~0 0 HN S NH 2 0 HN 00 0 HN HN HNl HN 0 HN HNHN N S S OH S S Os - 0 0 0 - , 00 0 o 0 0 0 OH OH, OH OH I VI WO 2010/106082 PCT/EP2010/053418 0 0 00" o", O OH 0 0 O 0 00 HO 0 ~0 0 HO HO O5OH 11A WO 2010/106082 PCT/EP2010/053418 0 c-5 YOH O00 H 0 H 0 O a-Ok OH - , 0 H~ O N OH HO HO O O O o 0O OH O OH NO OH O OH O OH O OO O OH ay -OiIr OH ~ ~ 0 0 D 0 WO 2010/106082 PCT/EP2010/053418 S S O O OH O0 O K OOO O OH 00 0 0 5 tand 0 0 0-11 In another astp! -t, the re n invention provides phairma ceuticai cojmpositions '0 N
    H
    WO 2010/106082 PCT/EP2010/053418 wherein R 6 is H H N S 0S HS , 0 ,or S S Representative conjugates of Formula (X) include, but are not limited to, the compounds shown below. H H H NNH NNOH 0 N HS 0NHS 0H S 0 5 H H H H H H N 0 N 0 N 0 I 0 0 H 0 H 0 H 0 N 0 and H In another aspect, the present invention provides pharmaceutical compositions 10 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) 15 (XI) wherein -7i WO 2010/106082 PCT/EP2010/053418 R1G 0-r- 0 X1--L X1-L jL N NH NH 0
    R
    9 , ,R, R!3 YX H ~ N N N N H H R9 Ry R X28~
    R
    8 0 R 8 0 R9 R 8 formula (i) formula (ii) formula (iii) - 0 +0 > HoH HO HOH 0 OH -NO OO OH HO O O , S, S O OH OH, OH H 9 H 0" -,O 0 ~ R7 is (C I aloxy, (C I C6)alkyl, (C 1 C6)alkylthio, hydroxy, -NZ9Zi1o, or -O-phenyl, wherein the phenyl1 is optionally substituted with 1, 2, 3 , 4, or 5 groups that are independently (C 1 C6)alkoxy, (C I C6)alk1 oxyca rbonyl, (C I C6)alkyl, (C -C,)alkyl1carbiony1, 10 haogn hyroy orhyrxyC o~lk Rs-C)lk: is hyrgecr C,;~lkl ir t Ra ,or( R-o is (C-C)alkoxy, (C>-C 6 )alkylt, h- 6 )yd o, yr ZZoy;ZZ 0 r--hnl whri thany iX2 toal usiue ih ,23 ,o rusta are i dependentlyOorS 1R 8 is hydroglkene; (Cay Z9ad i are independently hydrogen, (CQN ~alyi , or (C 1
    -C
    6 )alkylcarbonyl.
    WO 2010/106082 PCT/EP2010/053418 Representative conjugates of Formuila (XI) include, but arc not limited to, the compounds shown below. HN HN HN o 0 0 0 0 HNI- HN H H S
    NH
    2 -Y~SN~~~ 0 - 0 > )CJ 0 0 NH NH 90 0 HN HN~f- HNI S HS 0" -- S 0 o0 0 z 0 0 HN I HNk S NH 2 "II - ' S N>yN yN, 5o 0 0> '-0 0 0 NH NH 01 0 0 HN -HNI- HN' S -- OH S O0,- S 0 0 HNJ HN H
    NH
    2 - - ,N N -, ~ -< 0 > A 0 ONHNH O0 0 HNI- HN - HNA S 0OH 0> SN 0 00 HN - H19 WO 2010/106082 PCT/EP2010/053418 0 0 HN HN l HN OS < O H S . O~ S 0 O O HN HN H H S ! NH 2 S N N NN O' 8 0 0 0 NH NH Q HN H -N HN O 'N I 5 N<I OH 5 'N S N<,, o N"'NS~ 0 , N N .- N ' 00O ' 0 0 0=O 0 0 O 9 HN HN H H H H HN S
    NH
    2 'N N 'NO- 0 0O NH NH 0 0 0 HN - HN - HNI~ 'SN S OH ' N' So" 0 O N N X 0 ON'0 0 ON 'N0 0 0 0 00 H H H ~~' 'N SN> N~NH 2 'N SN N N<N 1 N X 0 0N ' 0 0 NH NH O 0 HN 11,HN lkHN HN-k S S OH s S Nr1 4)()10 0 0 '- 0 0 0 O 0 O 0 0 IN HN HN, HN 0 0 0 o 0 0 5 0 00 WO 2010/106082 PCT/EP2010/053418 O 0 0 HN HN HN S OH S O" r S 0 0 0 0 -, 0 ~ 0~ , 0- 0 0 HNH H H S NH 2 S N S0 0 0 NH NH 0 0 00 0 0 HN HN HN-J- HNk S S OH S S O ~~~~ sX0 0 0~ ~- 0 0 0 O 0 0 0 HN HN HN HN S S O S S NH 2 0 N - 0 0 0 0 ~- 0 0 0 O 0 HN H N, HN S OH S O S 0 O 0 0 O O O O 0 0 0 0 n n HN HN H H S NH 2 S N N N, Oi O I>.~r- rJ rIU ' roC L] NL 0 0 0 0 HN HN HN HN S S OH S S 07~ 0 0 0 0K 0 00 - HN HN HN 0~ 0 0
    O
    WO 2010/106082 PCT/EP2010/053418 0 - -OH 0'' >O H 'N~ ~X 0 0 OH OH 0 OH 0 H 0 0 O H O H 0 0H 0'0 OH OH 0 0 0 -K 0 OH 0 0 0 00 0 00 0 <-, 122~ WO 2010/106082 PCT/EP2010/053418 > i- 0 00 -- 0 ~ ~ 0 Iz 0 N- S' OH -0 EH 0-11 0-N / N _,S, OH N - '0 H A H H 0 N 0 N 0 " "/ K,, -OH HO H "o O OH 00 HOV H OW 5 0o 0 OH HO'H 0 0 O 0 9 AUr WO 2010/106082 PCT/EP2010/053418 0 HH '0 N , 0 0 0 OH o" ,o 0 O 0 0 O 0 0 O 0H YO O 0s o O OH 11 00 O2 WO 2010/106082 PCT/EP2010/053418 0 0O 0 0 and 00 0 0 0 1 In another aspect, the present invention provides pharmaceutical compositions 5 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 10 (XII), wherein A is ci 0 NH H 0 125 WO 2010/106082 PCT/EP2010/053418 0 OR 2 R2 OR60 . O>R 2 0
    SOR
    26 0> 1 F F F F HO -~ 5 SS >R 2 6 < 0 0 0 0 0 R 20
    CF
    3 o
    CF
    3
    R
    20 IS (C 1-C 4 )alkoxy, hydroxy, or NZ 2 0Z 2 1, 5 Z 2 o and Z 2 , are independently hydrogen or (C 1 C 4 )alkyl; L is selected from
    R
    2 2 R2 - N~ ~r'~ s~R 23
    R
    21 0 0 R 2 1 -%O 0+ - -O--(CR 2
    R
    4 )-0<
    R
    23
    R
    24
    R
    2 3
    R
    24 n, >< >j n I _ " ' N -'' 0
    R
    23
    R
    24
    R
    23
    R
    24 A- , or CR 23
    R
    24 n n is 2, 3, or 4; 10 Y isO0, S, S-S, NH, NCH 3 ;
    R
    2 is Lydrogen or (C,-C4)alk) i
    R
    2 i ydo n~b H(H~ 41( 12C(EH- CHC 3 C"i LH, 15 orHH.(171 ~ 01 hH(01ci~ )- 2 1 26 WO 2010/106082 PCT/EP2010/053418 B is o 0 0 HN NH HN S OR 20 S, -S NH 2 0 , 0 , 0 0 H +0 OH +0 +0 > -~~-~- O' OH HO OH OH
    -
    0 HO HO N OH 5 OH H OH H 0 or OOH 0 / or 0 0
    R
    25 is (CvC 4 )alkoxy, hydroxy, or NZ 2 2Z 2 3; Z22 and Z23 are independently hydrogen or (CvC 4 )alkyi; arnd 10 R~~, is hydrogen, (CvC 6 )alkyl, or (CvCo)alkylcarbonyl. 127 WO 2010/106082 PCT/EP2010/053418 O R 20 0 R20 HO O 0 Oy s -- o o s o o s" o o NH O NH 0 NH O0 0= O R 20 HN 0 H 2 N 0 R 20 HN NH - 0 NH y 0 NH 0= 0 NH O OH 0 OH / 0 OH s o o 0 o s 0 0 s l > o 0 1 E:: -~ NH NH X 0 NH O= 0 0 NH ~-NH oyOH HN
    H
    2 N OOH -NH o s H KN o H 0 NH oH-( 0 Q N N. I>NH 0-, o ~ 0 HN 00 0 0H NH NH 0NH WO 2010/106082 PCT/EP2010/053418 O R20 0 R 20 / 0 R2O HO, 0 O >0 S 0=e- 0y > y 0 0 NH 0 NH 0 NH -- N >NH O R 2 0 HN 0 H 2 N 0 R 2 0 HN >NH o S H N 0I= 0 0 0 O OH 0 OH / 0 OH HO 0 0 S. >= 0 0 -- ,-s >=o > ys 0 s 0 NH 0 NH 0 NH O 0 0 -N/ >NH O OH HN
    H
    2 N O OH #NH O S O O>S 0 0 0, J0 HO 0 0 ONH NNH NH O 0 0 0 S - 0 NH i 0 H~ 12 WO 2010/106082 PCT/EP2010/053418 0 R2 HO 0 R20 0/ O R20 OS O O= S 0 O0 S 0 O NH O NH 0 NH O NH F F F F F O R2 H 2 N
    OR
    2 0 H NH 0O 2 S ONO S 0 NH F F F O O OH O OH 0 OH HO 0 0 0 S 0 0 S O O S O ~ 0 ,H > ~ 0 NH NH - ~ 0 0 F F F F F F -- N /-NH O OH HN
    H
    2 N O OH >NH >O S O0 HNO NH 0 F FOF NH NH HO 00 r0 0 H- O> 0-Q 0-r s , 0N 0~ NH < 0 NH 0 N F F F F 0~ H-N 0NH H N 0 / 7 y =0 0 0H 0- - N WO 2010/106082 PCT/EP2010/053418 & R 0 HO 20 0/ 0 R 20 0/ > 0 Sr a 0 Soc 0 = 0~ NH 0 NH -~0 NH F F F F F F o , R2 HN 20 H 2 N 0 R 20 >-NH 0 HN 0 0 NHNH FF 1 0 F F HOO 0 OH 0/ 01-OH HO 0 0 ->H 00l NH ,X ~ 0 NH 0 00 F F F F F 0 O OH H N H-N 0r-H ,N >0 OS o HN 0~ y 0 -- 0 NH 0 N F F0 HO00 Q= '1"Q -. >0, 0 01=n c -> H >0 NH U NH -~0 0 0= F F'j F F F NNH 0 c H
    H
    2 N 0>c , N 0 NH 3H WO 2010/106082 PCT/EP2010/053418 C, ,2 O OH Uy H H H ON -OH 0 N _ -OH H 0K O, O O O OOOO 0 0 F F F F F F HO00 0 NO S 0 0 S 0 N 'N H N J NHO N 00S N H H 0 H 0 H 0 N/ =NH HN
    H
    2 N H >NH H N0 N H 0 N H 0 HO O O S 0 0 yS 0 NH 0 N N ,HNH HH 0 = HN 0 = -N >=NH HN,
    H
    2 N NH Q 0 YS, . 0 NH 0 N HO SO O N< : O S NO H
    O=
    WO 2010/106082 PCT/EP2010/053418 HO H/ 0NH 0 S 0 0 Y, Io0 S 0 ' O o s 0o N 0 N H N0 N >0N H 0 = H 0 H 0 N>=NH HN
    H
    2 N 0NH O S O S H 0H O H H NN HH 'N 0 0 0 N N H H 0 H 0 0 00 OH H N 0 0 N NI H H N 0 000 00 HO'
    OHJOH
    WO 2010/106082 PCT/EP2010/053418 H NO O OH HO HO 1 0 OH O O0 H S- S O O 0OH H ,and O O N 0 H O 5 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. 10 The present invention provides compounds of Formula (XIII): Rs 0
    R
    2 (XIII) or a pharmaceutically acceptable salt thereof, wherein
    R
    1 is OR 6 or NR 4
    R
    5 ; R2 is HI or 2,4-difluoropheny 1
    ;
    WO 2010/106082 PCT/EP2010/053418 0 0 S-S S-S ,or S-S R4 and R 5 are independently H, (C C 6 )alkyl, (C 3 Cs)cycloalkyl, or
    (C
    3
    -C
    8 )cycloalkyl(C ICC)alkyl, wherein the (CIC 6 )alkyl, (C 3
    C
    8 )cycloalkyl, and
    (C
    3 Cs)cycloalkyl(CvC 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are 5 independently (CI -C 6 )alkoxy, (CI-C)alkoxy(C C 6 )alkyl, (CIC 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; 10 R 6 is H, (C 1
    C
    6 )alkyl, (C 3
    -C
    8 )cycloalkyl, or (C 3 -Cs)cycloalkyl(CI-C 6 )alkyl, wherein the (Ci-C 6 )alkyl, (C 3
    -C
    8 )cycloalkyl, and (C 3 -Cs)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 6 )alkoxycarbonyl, (CI-C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1
    Z
    2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 15 4, or 5 halogens; and Zi and Z 2 are independently H or (CI-C 6 )alkyl. Representative compounds of Formula (XIII) include, but are not limited to, the compounds shown below: 0 0 0 0Q 0 S- O' H O- O 20 0 O 0 0 Q 9 0 0 135 WO 2010/106082 PCT/EP2010/053418 0 0 0 sOH - 00 s- ~NH 2 N N H 9 0 0 0 0Q H n, H O 0 0 0 0 0 s-s ~ - OH -- s-s -, F F 0 00 0 N NH2 HN> FFF FF F 36 WO 2010/106082 PCT/EP2010/053418 O 0 0 OH O F F F F F F 0 0 ~ NH 2 N F F F Y N N F F F 0 0 0 00 S-S OH O- O FF F F F F NH2NN H F F F FF andF phamaeuicll acepabecarir 0i 9hu L /130 WO 2010/106082 PCT/EP2010/053418 0 0 R30) - O St 0 NH R1 R2 (XIV) or a pharmaceutically acceptable salt thereof, wherein
    R
    1 is OR 6 or NR 4
    R
    5 ; 5 R 2 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 6 )alkyl, (C 3 -Cs)cycloalkyl, or
    (C
    3 -Cs)cycloalkyl(CI-C6)alkyl, wherein the (C-C 6 )alkyl, (C 3 -Cs)cycloalkyl, and
    (C
    3
    -C
    8 )cycloalkyl(C 1
    -C
    6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are 10 independently (CI-C 6 )alkoxy, (C 1
    -C
    6 )alkoxy(C 1
    -C
    6 )alkyl, (C -C 6 )alkoxycarbonyl,
    (C,-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 Rs together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N -methylpiperazine, morpholine, or azepane; 15 R 6 is H, (CI-C 6 )alkyl, (C 3 Cs)cycloalkyl, or (C 3 -Cs)cycloalkyl(Ci-C 6 )alkyl, wherein the (C,-C,)alkvl (C-Cs)cycloalkl, and (C( -C)cycloalkyl(C-C)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C 6 )alkoxy,
    (C
    1
    -C
    6 )alkoxy(CI-C6)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, 20 4, or 5 halogens; and Z, and Z 2 are independently H or (CvC6)alkyl. Representate copounds of Fr Ia IV include, but are not i d o, the compounds shw beI low: 38 WO 2010/106082 PCT/EP2010/053418 0 0 0 0 0 0 HO S 0 0 HO S O 0 HO ""S O 0 IH 0 NH 0NH ONH OH OH ON OH O 0 0 0 0 0 O S O O S O OO iS 00 HH NH NH 0 NH OH H O OH O O 0 0 0 0 0 O 500'i'l 0 50 s 0 0 '500-,so O NH O0 NH O 0 NH o 0 0 0 00 HO S HO S HO S NH OH O NH OH O NH OH F F F Y Y F F F 0 0 0 0 O O0 s 0 NH NH o H F F F F F 0 00 00 O NH0 NH0 N OY H0 0 0 139 WO 2010/106082 PCT/EP2010/053418 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. 5 In another aspect, the present invention provides compounds of Formula (XV) HO'S N H R2 (XV) or a pharmaceutically acceptable salt thereof, wherein R, is OR 3 or NR 4
    R
    5 ; 10 R 2 is H or 2,4-difluorophenyl;
    R
    3 is H, (CI-C 6 )alkyl, (C-C 8 )cycloalkyl, or (C 3
    -C
    8 )cycloalkyl(C,-C 6 )alkyl, wherein the (C,-C 6 )alkyl, (C 3 -Cs)cycloalkyl, and (C 3 -Cs)cycloalkyl(Cj-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C,-C 6 )alkoxy, ( -C)alkoxy(C,-C 6 )alkyl, (C)alkoxycarbonyl, (C -C 6 )alkylthio, halogen, hydroxy, 15 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, (C -C 6 )alkyl, (C 3 -Cs)cycloalkyl, or
    (C
    3 -Cs)cycloalkyl(C,-C 6 )alkyl, wherein the (C,-C 6 )alkyl, (C 3 -Cs)cycloalkyl, and
    (C
    3 -Cs)cycloalkyl(C1-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are 20 independently (C-C 6 )alkoxy, (C-C 6 )alkoxy(C,-C 6 )alkyl, (C,-C 6 )alkoxycarbonyl, (CI- aikylthio, haogen, hydroxy, hydroxycarbonyl, NZiZ, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 4 and R together with the nitrogen atom to which the are attached form azeidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morphoine. or aepane: and 25 Zi and Z 2 are idependenly H or (C 1
    -C
    6 )alkyl. Representative compounds of Formula(X)icdebtarnolmtdtth compounds shown below: WO 2010/106082 PCT/EP2010/053418 O 0 ,O O ,,0 0OH O O HO N HO N O HO N H NH2 H H K-40 O0 0 O/O 0,,O 0 H HO HO N OH H O F F F FF F O ,, 0 O ,,O O ,,O HO N HO O NH F F F F- F and F . in another aspect, the present invention provides pharmaceutical compositions 5 comprised of a compound of Formula (XV), as shown above, and at least one Ini another aspect, the prese nt invention provides a compound of Formula (XVI) H 00 0 Q~,O 0 'No HO N H ~HH (XI 10 oacer accepresent to.
    WO 2010/106082 PCT/EP2010/053418 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. 5 In another aspect, the present invention provides compounds of Formula (XVII) H 0 0 N R1 S O 0 0 NH (XVII) or a pharmaceutically acceptable salt thereof, wherein
    R
    1 is OR 2 or NR 4
    R
    5 ; 10 R 2 is H, (CI -. C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C3-Cs)cycloalkyl(C 1
    -C
    6 )alkyl, wherein the (CI-C 6 )alkyl, (C-Cs)cycloalkyl, and (C 3 -Cs)cycloalkyl(C-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CIC 6 )alkoxy,
    (CI-C
    6 )alkoxy(C-C 6 )alkyl, (C C 6 )alkoxycarbonyl, (CI-C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 15 4, or 5 halogens;
    R
    4 and R 5 are independently H, (CI-C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C3-Cs)cycloaIkyl(Ci-C 6 )alkyi, wherein the (C IC 6 )alkyi, (C3-CR)cycloalkyl, and
    (C
    3 -Cs)cycloalkyl(CI C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C 6 )alkoxy, (C-C)alkoxy( Ce -C 6 )alkyl, (C C 6 )alkoxycarbonvl, 20 (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 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
    Z
    1 and Z 2 are independ ently Hi or (Ci-C 6 )alkyi. 25r compound hwnhlw WO 2010/106082 PCT/EP2010/053418 H H H O N O N O N 0 0 0 0 0 HO S O 0 HO S O HO S O O>NH O NH O NH H H H N N N N 0 ~.0 0 O S 0 S 0 S O NH 0 NH 0 NH H H H N N N 9 9 0 0 0T O S 0 0 S 0 0 S 0 O NH 0 NH 0 NH H H H N N N
    H
    2 N S 0 H 2 N S O 0 H 2 N 0 0> NH 0 N H 0 NH H H H 9 N N N 0 0 ~ 0 N NS O 0 N 0 O S 0 HN HN O HN 0O H H H O 0N N -F" 00N 00 . . 0 N ~S 0 N S 0 N S 0 4 H N HN,-fn HN, -n and I In another aspect, the present invention provides pharmaceutical compositions 5 comprised of a compound of Formula (XVIf). as shown above, and at least one pharmaceutically ac cptable carrie~r. In another aspect, the present invention provides compounds of Formula (XVIII) 100 N 0 ( (XViII) WO 2010/106082 PCT/EP2010/053418 R, is OR 2 or NR4Rs;
    R
    2 is H, (CIC 6 )alkyl, (C 3 Cs)cycloalkyl, or (C 3 Cs)cycloalkyl(CI-C 6 )alkyl, wherein the (C C 6 )alkyl, (C 3 -Cs)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 (CpC 6 )alkoxy, 5 (Ce& 6 )alkoxy(Ci alkylyl, (C C 6 )alkoxycarbonyl, (C 4 C)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZIZ2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens;
    R
    3 is 0 0 0 S-S , S-S ,or S-S 10 R 4 and R5 are independently H, (CI-C6)alkyl, (C 3 -Cs)cycloalkyl, or
    (C
    3 -Cs)cycloalkyl(C C 6 )alkyl, wherein the (C-C 6 )alkyl, (C 3 -Cs)cycloalkyl, and
    (C
    3 -Cs)cycloalkyl(Ci-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1
    -C
    6 )alkoxy, (C 1
    -C
    6 )alkoxy(CI-C 6 )alkyl, (C-C 6 )alkoxycarbonyl,
    (CI-C
    6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZIZ 2 , or phenyl, wherein the phenyl 15 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 Z, and Z 2 are independently H or (C 1 C)alkvl. 20 Representative compounds of Formula (XVIII) include, but are not limited to, the compounds shown below: S S cI OH COH rn' NN N C C C1 144 WO 2010/106082 PCT/EP2010/053418 -S -S S N N NN Cl C C, CI S S S S 0 0 0== 0 c C NH NH C NH2 N N N N C1 C1 C 0= = Ci N Cl N C N C IN N H N H N H N Cl C C C S S s S O oo A o N ' N pN r N NN C andi 5 naote secte rsn ivion poides phracuilomsion s o ( a a oamctclyc b c WO 2010/106082 PCT/EP2010/053418 O ,,0 CI N OH H H N C1 (XIX) or a pharmaceutically acceptable salt thereof 5 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) HN 0 0 S R1 '10 0
    R
    3 10 F F (XX) or a p-amacuticaly acceptable salt thereof, whr-n
    R
    1 is OR 2 , NR 4
    R
    5 , or H N O S
    R
    7 0 15 R 2 is (CIC 6 )alkyl (C Cs)cycloalky , or (C-C)cycloalkyIl(C-C 6 )alkyl, wherein the (Ci&s)alkyl (CrCs)cycloalkyl, and (C'I)cycloalkyl(CjC 6 )alkyl are optionally substituted with , 2, 3, or 4 substituents that are independently ( 2)alkoxy, (CnCsalkox(Ce u~alkyl, (Ce~%alkoxycarbonyl, (C C )alkylthio, halogen, hydroxy, hydroxycarbony!, NZiZ2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3 20 4, 0r 5 halogns; Z7 and Z2 are independentliir~l ly R3 is HI or C(O)Rr; 1 46 WO 2010/106082 PCT/EP2010/053418
    R
    4 and R 5 are independently H, (Ct-C 6 )alkyl, (C 3
    -C
    s )cycloalkyl, or
    (C
    3
    -C
    8 )cycloalkyl(C-C 6 )alkyl, wherein the (CI-C 6 )alkyl, (C 3 Cs)cycloalkyl, and (Cr C 8 )cycloalkyl(C C6)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C 6 )alkoxy, (CC)alkoxy(CI-C 6 )alkyl, (CI-C 6 )alkoxycarbonyl, 5 (CIC6)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; R6 is H, (CI-C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C 3 -Cs)cycloalkyl(C-C 6 )alkyl, wherein 10 the (CI-C 6 )alkyl, (C-Cs)cycloalkyl, and (C 3 -Cs)cycloalkyl(C 1
    -C
    6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C6)alkoxy,
    (CI-C
    6 )alkoxy(C-C 6 )alkyl, (CI-C 6 )alkoxycarbonyl, (CI-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; 15 Z 3 and Z 4 are independently H or (CI-C 6 )alkyl; and R- is OR 2 or NR 4
    R
    5 ; provided that the compound is not N-acetyl-S-[(2',4'-difluoro-4-hydroxy[1,1'-biphenyi]-3-yi)carbony']-L-cysteine methyl ester; N-acetyl-S-[(2',4'-difluoro-4-hydroxy[1,1'-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; 20 N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[ 1, l'-biphenyl]-3-yl)carbony1-L-cysteine methyl ester; and N-acetyl-S-[(2',4'-difluoro-4-a tylox y 1,1'-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester. Representative compounds of Formula (XX) include, but are not limited to, the 25 compounds shown below:
    F
    F b~
    FI
    WO 2010/106082 PCT/EP2010/053418 HN 0O HN O HN; O Sl- ~0 S 0O- 0 IS"", O OO HO 0H H F > F HO~ F FF F HN 0o HN 0 HN 0 O s-~ 0 %S 0,,, 0 S'l" 0, HO, 0 HO ~ 0 HO 0 < F F F FF HN,'~J0 HN" 0 HN 0 yO S 0,: 0 S 0 0 SZ~ 0 ~ F 'N F "' F F F F HN 0 HN 0 HN I 0 O' SJ , NH W ~ 0, S,-NH, O,lS,,,,J-,NH 2 HO F0 HOl 0 HO F F0 F FF HN 0 HN 0 ur 0 S NH2 0"~ S,,e NHq 0,S H O 07 0 0y 0 0 'N,< F 'FN," 5 F F F F 148 WO 2010/106082 PCT/EP2010/053418 HN O/ HN O/ HN 0 O> S NH 0 S NH 0 S NH F F F HN O HN LO HN O O S 0N S N O S N HO 0 F FO HO F F F F HN 0 HN 0 HN 0 O S N O s N S N HO 0 O F HO F F F F HN 0 HN O HN O H O HO H/O 0O 0 0 0 0 0 0 0,, F 0 FY FF 11 HN >HN 0 HN OHN 0 HN OHN 0 0~y s~ O<. O 0 S fH C).S1S1O 0O 0 0 0 HO 0 0 0 0 K 0 0 F FF 0,- c HO 0 0 O0 0 H F F4F WO 2010/106082 PCT/EP2010/053418 HN O HN' 0 HN 'O HN 'O HN O HI O O, s se Os OoSASs",s O S HO O HO0 F 0 0 HO- F0 0 FF F HN O HN 0 HN O HN 0 HN HN O O S S O OS S O 0 S0 S O O O O O F OOFO O F F HN O H9 -O HN O HN O HN -O HN O HO F 0 0 HO F 0 0 HO O F F F F HN OHN 0 HN OHN HN O HN O 0 S S NH20 O S S 0 0 S S 0NH2 O O o O6 0~0K F 0 0 H F 0 0 0OT'il F~ F 0 0 F FF H0HNJ 0 HN O HN 0 HN O 0HN' O S HN OS S 0 HO 0 HO 06 0 O O F 0 0 F F
    KF
    WO 2010/106082 PCT/EP2010/053418 HN O HN, O HN O HN O HN 0 HN O O s S HN' 0 S S HN 0 S S HN HO 6- H H HO F O HO F 0 HO F 0 F F IF HN 0 HN 0 HN 0 HN 0 HN 0 0 S-.. S N O S S N 0 S S N 0 O OO O O FO O F F F HN O HN 0 HN O HN 0 HN 0 HN O OyS S NC 0 S S N ONS S HO 0 HO F HO,> F 0 F F and F In another aspect, the present invention provides pharmaceutical compositions 5 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) H x R1 R2 1 0 (XXI) X is absent, halogen, HSO4, 1HPO, CH 3 CO2 or CFCO 2 ; R1 is OR 3 or NR R23 is Hi or 2,4-difluorophenyl; 15 R3 is H, (C( alkyL, (C 3 . Csycloalkyi, or (C Cs yloalky(Ce~sQakyl, wherein the (C> i~alkyl1, (CJ~~ycloakyl and(C Cs4cycoalkyl(hC ~salkyl are optionally substituted with , 2, 3, or 4 substiuents that are independently (C t4Jakoxy, WO 2010/106082 PCT/EP2010/053418
    (C
    1
    -C
    6 )alkoxy(Ci-C 6 )alkyl, (C 1
    C
    6 )alkoxycarbonyl, (CvC 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1
    Z
    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, (C3-Cs)cycloalkyl, or 5 (C 3 -C)cycloalkyl(CI-C 6 )alkyl, wherein the (CI-C6)alkyl, (C -C 8 )cycloalkyl, and
    (C
    3 Cs)cycloalkyl(CI-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C-C 6 )alkoxy, (CI-C 6 )alkoxy(C 1
    C
    6 )alkyl, (CIC 6 )alkoxycarbonyl,
    (C
    1
    -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 10 atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane; and Z, and Z 2 are independently H or (CI-C 6 )alkyl. Representative compounds of Formula (XXI) include, but are not limited to, the 15 compounds shown below, wherein X is absent, Cl, Br, I, HS0 4 , or CH 3
    CO
    2 : OH O OH O OH O N1 N N + + 0 +0 X OH X X OH O ,j OHO OH O - X
    NH
    2 HI OH O OH O OH O N NO + 0 0+ 0 0+0 0 X OH X H XO F F
    FF
    WO 2010/106082 PCT/EP2010/053418 OHO OH 0 OH O NN N + 0 0 + 0 0 + 0 0 X
    NH
    2 X N H N F F F F F and F In another aspect, the present invention provides pharmaceutical compositions comprised of a compound of Formula (XXI), as shown above, and at least one 5 pharmaceutically acceptable carrier. In another aspect, the present invention provides conjugates of Formula (XXII) C1 N-Ri C R2 O (XXII) wherein R 1 is 00 10 0,S-0, HS rl HS N N HH or 0; R2 s (CeC 4 )alkoxy, hydroxy, or NZ 1 Z2; and Za ad Z 2 are independently hydrogen or (C vC 4 )alkyl; 15Representative conjugates of Formula (XXII) include,btarnolihdtote compounds shown below.
    WO 2010/106082 PCT/EP2010/053418 cI c I i N N " Ci R 2 S-S CI OH S-S Ci 0o, s-s CIHN- HI HNk IH NN 0 0N 0 0 0 0 N SH N~j -SH N SH - 0 0 - 0 CI HN- CI HN- CI HN NNI 0 0 0 - 0 0 C;jN S H N -SH N - SH CIOH C' N--X0H C' OH - 0 /,/ O CI HN- CI HN- - ~CI HN N) 0 0 j0 0 10 0 N SH N ,/SH N SH H/ 0 C 0 HN> HY 0 - - 0 0 0 s s H HN 0 0C I HN4 0 5 C I HN -0 ~ I00I 00 N 0~ I C WO 2010/106082 PCT/EP2010/053418 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 carrier. For each of the compounds of Formulae (I-XXII) set forth herein, the invention provides in 5 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 10 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 15 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. 20 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 1L6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or 25 human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XXII), as shown above, or a phannaceutical composition comprised of a compound of Formulae (MI-XXI) and at last one pharmaceutic'ally 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, 30 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 Formulae (I-XXII), as shown above, or a pharmaceuic'at composition comspriseed of a compound of Formulae (I XXII) and at least one phiarmacutically acceptable earrier.
    WO 2010/106082 PCT/EP2010/053418 For each of the compounds of Formulae (I-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 5 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 10 (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 15 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. 20 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 resortion diseases, sepsis, septic shock, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer's disease, Parkinson's diseases, cystic fibrosis, 25 dysfunctions of the immune system, stroke, multiple sclerosis, migraine, pain, inflammatory eye conditions including uveitis, glaucoia and ojuneii ti, Y nerative bon or joint conditions including osteoarthritis, rheumatoid arthritis, rheumatoid spondlitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed points, chronic inflammatory skin conditions, including allergic lesions, lichen 30 planus, pityriasis rosea, eczema, psoriasis, and dermatitis diseases and disorders of the gastrointestinal tract, inclunding inflammary oeiesConsdsae atropic~ gastritis, gastrits varialoforme, ulcerative colitis, coelac disease, regional ilcitis, peptic ulcertion, prticuarly irritahbce bowel syndrome, re-flux oesophagitis', and damage to the gastrointestinal tract resultin from ifctins for exmpe byHicacuterpori fies exml. _wi WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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. 15 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, 20 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 snondylitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed joints, chronic inflammatory skin conditions, including allergic lesions, lichen 25 planus, pityriasis rosea, eczema, psoriasis, and dermatitis, diseases and disorders of the gastrointestinal tract, including inflammatory oel isae rohns iase, atop gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, peptic ulceration, particularly irritable bowel syndrome, reflux oesophagitis, and damiage to the 30 inflammatory lung disorders such as asthma, bronchitis, particularly chronic obstructive pulmonary disease, farmer 's lang, acute respiratory dist rcss syndrome; bacteraemia, endotoxaemia (septic shock), aphthou ucers, gigivitis, pyresis, particularly pain, including inflammatory pain, neuropathic pai, acute pain or pain ofta central origin; meningitis and pancreatit is, and other conditions associated wanth ifammation, central nervous system WO 2010/106082 PCT/EP2010/053418 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 in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical 5 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 10 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: 15 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 (C 1
    -C
    6 )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "(C 1
    -C
    6 )alkoxycarbonyl" as used herein, means a (Ci-C 6 )alkoxy group, as 20 defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of(CI-C 6 )alkoxycarbonyI include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "(CiC 6 )alkoxysulfonyl" as used herein, means a (CvC 6 )alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, 25 as defined herein. Representati' v xampls of(C 1
    -C
    6 )alkoxysulfonyl include, but are not limited to, methoxysulfony I, ethoxysul fonyI and propoxysulfonyl. The term "(C 1
    C
    6 )alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 3 to 6 carbon atoms. Representative examples of(CvC)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, see-butyl, 30 iso-butyl, tert-butyi, n-pentyl, isopentyl, neopentyl, n-hexyi, 3-methylhexyl, 2,2-d imethy lpentyl, and hexyL. The term "Ce~&~alkylcarbonyl" as used herein, means a (CeC4 aly group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined WO 2010/106082 PCT/EP2010/053418 herein. Representative examples of (CI-C6)alkylcarbonyl include, but are not limited to, acetyl, I-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term "(CI-C 6 )alkylcarbonyloxy" as used herein, means a (CI-C 6 )alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. 5 Representative examples of (CI-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(CH3)-, -C(CH 3 )r-, -CH 2
    CH
    2 -, 10 -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-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. 15 The term "(CI-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 (C I 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. 20 The term "carboxy" as used herein, means a -CO 2 H group. The term "cyano" as used herein, means a -CN group. The term formall" as used herein, means a -C(O) group. The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F. The term "halo(CI -C6)alkoxy" as used herein, means at least one halogen, as defined 25 herein, appended to the parent molecular moiety through a (CI-C 6 )alkoxy group, as defined herein. R epresentative examples ofh aoC 1 Cal ko inc eludm but .are not liit ued t chloromethoxy, 2-fl uoroethoxy, trifluoromethoxy, and pentafluo roethoxy. The term "halo(Cm-C 6 )alkyl" as used nerinm, means at least one halogen, as defined 30 herein. Representative examples of halo(Ci C,)alkyl include, but are not limited to, chloromethyi, 2- fluoroethyl, trifluloromethyIn penafluoroethyl, and 2-chloro-3-fluoropentyl. The term "HI-TB" as used herein means 2-hydroxy-4-(trifluoromethyI)benzoic acid, a metabo lite of triflusal. Conjugiates comprised of H-TB and one or more antioxidants are spcificall con"~tern'plated by the present invention.
    WO 2010/106082 PCT/EP2010/053418 The term "hydroxy" as used herein, means an -OH group. The term "hydroxy(C 1
    -C
    6 )alkyl" as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (CpC6)alkyl group, as defined herein. Representative examples of hydroxy(CIC6)alkyl include, but are not limited 5 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 ac-amino acids, or derivatives thereof such 10 as esters or amides, that can exist as stereoisomers, wherein the asymmetric or chiral center is present at the u-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 112, 1994. Further, compounds of the present invention may contain a stereocenter that is not an a-carbon of an 15 u-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 20 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 ait 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 tal ire 25 product from the auxiliary, (2) direct separation of the mixture of optical enantiomers on hiral chromatographic columns, or (3) formation of a diastereomeric salt followed by sc crtalization of one of the diasteeomeric salts. 'Th present invention also provides pharmaceutical compositions which comprise compounds of the present invention fornmlated together with one or more non-toxic 30) pharmaceutically accept able carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral ieton, orifor rectal WO 2010/106082 PCT/EP2010/053418 The term pharmaceuticallyy 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 pharmaceutical acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and 5 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 10 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 15 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 20 (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 25 pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.7 Eamples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glyceroi, and ~Oesters such as ethyl oleate. Proper tluidity 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 compositionsrrmay ascotain adjuvants such as preservative agents, wetting agentsn emusifying agns and dispersing agents. Prevention of the action of 1 :i1 WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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, polyoxyethylene sorbitol and sorbitan esters, 15 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 targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a 20 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 25 tablets, dragees, capsules, pills, and granules can be prepared with coatin s and shells such as enteric coatines- release controlling coatings and other coatings well know -n 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., 30 tablet ing lubricants and other tableting 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 atnd can also be of such composition that they release the active ingredient(s) only, or preferntiall,in a certain part WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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 15 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 20 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 25 inert pha rmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) fill rs or extenders such as starches, lactose, sucrose, glucose, mannitol and salicylic acid; b) binders such as carboxymethyleelulose,. alginates, gelatin, polyvinylpy'rrohidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) 30 solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammoniumn compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay, and i) lubricants such as tale, calciumo stearate, magnesium stearate, solid polyethylene glyc~ols ,sodiumn lauryl sulfate, and mnixtures. thereof. in the case or capsules, tablets and pills, the dage--form may alocmprise bufferin agns WO 2010/106082 PCT/EP2010/053418 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 5 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. 10 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. 15 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 20 benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, 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 25 agents. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, spray:, 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 30 required. Ophthalmic forrmulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams arid gels may contain, in addition to an active compound ofmths invention, animal and vegetable fats, oils, waxs, paraffins, starch, I tA WO 2010/106082 PCT/EP2010/053418 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, tale, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or 5 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 10 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. 15 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 20 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 25 the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and lik 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 30 effective to achieve the desired therapeutic response for a particular patient, compositions, and mo de of administration. The seleted dosage level will depend upon the activity of the particular compound, the route of adrnsration, thc severity of the condition being treated, and the condition and prior medical history of the patient being treated.
    WO 2010/106082 PCT/EP2010/053418 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 5 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, 10 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 15 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 fornied by the in vivo biotransformation of conjugates of Formula (I). The present invention contemplates conjugates of Formula (I) and 20 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 25 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 30 scope of the appended claims. Preara ion ofCmondsoth0Jvn o an(3 WO 2010/106082 PCT/EP2010/053418 Scheme I
    R
    2 I R2 R 3 0
    R
    3 HS L coupling R,4 0 o + reagents R4J +5O R9,NY'J Ry ----------- R5 S, L
    R
    5 OH 0 0
    R
    9 ' R 7 (1) (2)
    R
    8 0 Formula (1)
    R
    2 R R2 1 R 3 O HO L coupling R 0 0 reagents 4 R4 + RR R5 O L (P OH
    R
    8 0
    R
    9 . Ry (1) (2)N
    R
    8 0 Formula (1) Conjugates of Formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R7, R 8 , R 9 , and L are as defined in the Summary section herein, are prepared as described EP 0 080 229, BE 900328, or 5 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 '-carbonyldiimidazole (CDI), 1,1 '-thiocarbonyldiimidazole, 1,1' 10 carbonylbis(2-methylimidazole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrocloride (EDCI), benzotriazol-1-yl-oxy-tis-pyrrolidino phosphoniumhexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluoronhosphate (PyBrop) 0-(-7-azabenzotriazol-!-yl)-N,.N,N,-teamethyluronium hexafluorophosphate, N-[(dimethylamino)(31H-[1 ,2,3]triazolo [4,5-bpyridin-3 1 yoxy)methylene] N- methylmethanamrinium, benzotriazol-1 yio xytris~dimnethy lamino)phosphonium hexafiluorophosphate (BOP), B is(2-oxo-3 oxazolidiny l)phosphinic chlobride (BOP Cl), I1,3-dicyclohexylcarbodimide (DCC) 1p IHyroxy 7-~.aabenzotrole (HOT),- 1 1-hydroxybenzotriazol 1 e hydrat (HOBT)'~, 3-hydroxy-1,2,3 benzotrazi-(3H)-one (HOOBT), O-(7-azabenzotriazo-1 -yl) NN, N N tetamthluonumhexflorphspat (HT)V-eztiao--lNNN, WO 2010/106082 PCT/EP2010/053418 tetramethyluronium hexafluorophosphate (HBTU), and O-benzotriazol- I -yl-N,N,N',N' tetramethyluronium tetrafluoroborate (TBTU). Scheme 2 R2 i R2 Ri R2 R4 R3O RII HS -
    R
    3 0 chlorinating R 3 O 0 R4 .. O reagent R + R9, N R75 R R 8 0 R
    R
    5 OH RR C0 R9, R7 (1) (3) (2) R 8 0 Formula (1) R2 R1 1R2 R1
    R
    3 R- 0 chlorinating R 3 0 HO ~-~ reagent r4~ R4 O 4 O + N9 7 aO
    R
    5 OH R 5 Cl R 8 0 R9 RN (1) (3) (2) 5 Formula (1) Alternatively, conjugates of Formula (1), wherein R 1 , R 2 , R3, R 4 , R5, R 7 , R 8 , R 9 , and L are as defined in Formula (1) of the Summary section herein, are prepared as described in Scheme 2. Acids of formula (1) arc treated with a chlorinating reagent such as thionyl chloride (or PCI 3 ) in an appropriate solvent to provide acid chlorides of formula (3). 1o 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 vith heating, to provide conjugates of Formula (I).
    WO 2010/106082 PCT/EP2010/053418 Scheme 3 R1a R2a R2
    R
    2 a R1a 0 R3a OH R 3 a 0 coupling 0 R + reagents R2
    R
    4 a 4 R4a 0 R
    R
    5
    R
    6 R 5 a OH 0 Formula (1) (4)
    R
    5 R Formula (Il) Conjugates of Formula (11), wherein R 2 , R 3 , R 4 , R 5 , R 6 , Ri, R2a, R3., R4a, and R5a, are as defined in Formula (I) of the Summary section herein, are prepared as described in Scheme 5 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 10 treated with a conjugate of Formula (I) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (II). Scheme 4 R2b R1b
    R
    1 a R2a R3b 0
    O
    2 R a ROb R4b f a R3b 0 coupling R 5 b 0 Ra R3a
    R
    3 0 R 5 a + reagents 0 4b R2 0 R4a R4 5b OH
    R
    3 O R5, R5 R6 Formula (l!) O4 5fFormula (,i RQe KR, and Rsm are as defined in Formula (I) of the Summary section herein, are prepared as described in Scheme 4. C'oniugates of Formula (II) arc treated with a benzoic acid of formula (5) in the presence of one or more coupling reagents, as disclosed in Schme 1, in an 2apropriate solvent to provide conjugates of Formula (III). Alternatively, a conjugate of WO 2010/106082 PCT/EP2010/053418 Formula (5) 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). 5 Scheme 5 O 0 H O chlorinatng agent ' CI SS 0 OH 0 O o ci base R2 - 0 R2 a ~O CI' u 2
    R
    1 S~ R 1 (A) compounds of Formula (XIII) Compounds of Formula (XIII), wherein R 2 is H or 2,4-difluorophenyl and R, is as 10 defined herein, are prepared as described in Scheme 5. Lipoic acid is treated with a chlorinating agent (such as thionyl chloride or POCII or PC3) to provide the corresponding acid chloride. Phenols of formula (A) are treated with the acid chloride of lipoic acid in the presence of ibase, sulh as trietyi noiariiiii isopropyletyaine, to provide compunds of Formula (XIII).
    WO 2010/106082 PCT/EP2010/053418 Scheme 6 OH 0 R1 I ORN 0 O +I 0 2 R2 NO 2 (A) (B) 0 -NH R, 0 HN O (B) + 0 SH 0 S O
    R
    3 (C) R2 R3 compounds of Formula (XIV) OH O 0 R 0 HN 0 R HN H SO C l O R 3 0 , +- 0 01 2 0 (D) 0 R R3 (A) compounds of Formula (XIV)
    R
    1 0 H
    H
    2 Nsfu-OH -O 4N-- 1n0H (B) + A E R2 0 compounds of Formula (XV) 5 Compounds of Formula (XIV) and (XV), wherein R2 is H or 2,4-difluorophenvl and
    R
    1 and R 3 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 carbonoclioridate to prove ide carbonates of formula (B). Carbonates of formula (B) are 10 treated with derivatives of N-acetyleysteine (compounds of formula (C)) to provide compounds of Formula (XIV). Bioorganic Med. Chm,13 (19) pg 5592 (2005). Alternatively, acyl chlorides of formula (D), prepared using similar methodology as disclosed in Bul. Chem. Soc. 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 15 trea ting taurine with carbonates of formula (B). 1 '7 WO 2010/106082 PCT/EP2010/053418 Scheme 7 OH C1 O O O A+ 0 ~- 0 N
    NO
    2 N NO 2 H H (E) H (E) + H 2 N OH A N O 0 H H compound of Formula (XVI) 0 HN H)' 0 S 0 (E) + NR0 O R 3 0 Nz: (C) compounds of Formula (XVII) 0 HN N OH C S OR 3 O SIOR3 HO (D) H compounds of Formula (XVIl) 5 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). 10 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. Soc. Japan, 37 (2) pgs 242-244, (1964), are treated with acetaminophen to provide compounds of Forrnula (XVII). 15 WO 2010/106082 PCT/EP2010/053418 Scheme 8 0 0 HO chlorinating agent CI SS , Cl O R 1 N + CI base C R 1 CI (F) compounds of Formula (XVIII) O OH H N H or + H 2 N <,O H N 0 0 O c 0 0 H N compound of Formula (XIX) CC 5 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 POCl3, or PCl 3 ) to provide the corresponding acid chloride. Amines of formula (F) are treated with the acid chloride of lipoic acid in thenresence of base, such as triethylamine or diisopropylethylamine, to provide compounds of Formula (XVIII) wherein 10 R, is as defined herein. The compound of Formula (XIX) is prepared by treating 2(2,6-dichlorophenylamino)be nzoic acid with taurine in the presence of coupling reagents. Coupling reagents useful for preparing the compound of Formula (XIX) include bt are not limited to, dimethyl aminopyridine (DMAP), 1 ,3-di-tert-butylcarbodiimnide, 15 1,1'-carbonyldiimiidazole (CDI), 1,1'-thiocarbonyldiiridazoe, 1,1'-carbonylbis(2 methylimnidazole), I -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ubenzotriazoi-i -yl-oxy-tris-pyrrolidino- phosphoniumhexafiuorophosphate (PyBOP), bromo trispyrrolidinlo-phosphoniumn hexafluorophosphate (Pyfirop), O-(-7-azabenzotriao- -yl) N,NN',N',-tetramethyluronium hexafluorophosphate, N [(dimecthyiamuino)(3 20[12,3]triazolo[4,5-bpyridin-3-yboxy)menthylene]- N-menthylmet hanaminiurn, benzotriazol- 15 75 WO 2010/106082 PCT/EP2010/053418 yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Bis(2-oxo-3 oxazolidinyl)phosphinic chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), 1 -Hydroxy 7-azabenzotriazole (HOAT), I -hydroxybenzotriazole hydrate (HOBT), 3-hydroxy-1,2,3 benzotriazin-4(3H)-one (HOOBT), 0-(7-azabenzotriazol-1-yl)-NN,N',N' 5 tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N' tetramethyluronium hexafluorophosphate (HBTU), and O-benzotriazol- I -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. 10 Scheme 9 0 rT O chlorinating 0 reagent R2 R ' OH Cl (G) (H) 0 O 0NHO NH R T (H) + HS S R1 S S R1 0 O (J) 0 compounds of Formula (XX) Compounds of Formula (XX), wherein R 2 is H or 2,4-difluorophenyl and R, 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 PCI 3 ) in an appropriate solvent to provide 15 acid chloride of formula (H). Acid chlorides of formula (H) are treated with compounds of formula (J) and a hase such as triethylamine (or diisopropylethylamine) to provide compounds ofl Formula (XX). Alternatively, the compounds of Formula (XX) are prepared using similar methodology as that described in European patent application no. 88112)028.l (publication no. 20 17Ai WO 2010/106082 PCT/EP2010/053418 Scheme 10 /PG /PG group p chlorinating agent N + OH + OH + CI (K) (L) /PG OH PG O + ~x 0 base +N 0
    R
    2 + Cl R2O (A) R 1 (L) (M) R 1 /PG + + deprotect R2'O 2R 2 O (M) R 1 R1 compounds of Formula (XXI) Compounds of Formula (XXI), wherein R 2 is H or 2,4-difluorophenvl and R, is as defined herein, are prepared as described in Scheme 10. (3-Carboxy-2 5 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 triethyam~ine, diisoroplthyamn,v~ imdze or soiu hyrd to prvd a copon o-f formula (K), wherein PG is a hydroxy protecting group. The compound of formula (K) is 10 treated with a chlorinating agent (such as thionyl chloride or POCl 3 or PC 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 (M1) to provide compounds of Formula (XXI). In 15 particular, the methoxyme thyl, methylthiomethyl, tert-butyldimethylsiiyi, tert butyldiphenylsilyl, or benzyl protecting groups are removed by treating compounds of inrmulna (M with: PhK m E in 'H 2 C1 2 ; , oi 2 in CHCN Bu 4 N> in: THE: Bu4N*F~ in T HF; and BE 3 Et 2 0 NaI in CH 3 CN, respectively. 1,~~
    -'AS
    WO 2010/106082 PCT/EP2010/053418 Scheme 11 0 OH 9 C - 0 0 0 0
    CO
    2 H CI O C13 O O C13 base R4 R4 (N) (0) 0 OH 0 L-N-acetylcysteine S CO 2 H S 2 H (0) NHAc NHAc base R4 R4 (P) Formula (I) Compounds of Formula (1), wherein R 2 is H or 2,4-difluorophenyl, are prepared as described in Scheme 1L A compound of formula (N) is treated with 2,2,2-trichloroethyl 5 chlorocarbonate and a base such as triethylamine in acetone at -3 OC to provide the anhydride of formula (0). Compounds of formula (0) are treated with L-N-acetylcysteine and triethylamine dropwise in acetone at 0 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 (I). 10 Exmple 1 OH N 0 H Os N OH 15 Salnacedin (R2aetamd - ydroxbenzoythio)propanoic acid The title compound is prepared using the procedures described in EP 0 0801 229.
    WO 2010/106082 PCT/EP2010/053418 Example 2 OH -l 0 Oss H 0 (R)-methyl 2-acetamido-3- (2-hydroxybenzoylthio)propanoate The title compound is prepared using similar procedures as described in EP 0 080 229. 5 Example 3 OH ,0 H 0 (R)-ethyl 2-acetamido-3 -(2-hydroxybenzoylthio) propanoate The title compound is prepared using similar procedures as described in EP 0 080 10 22929. Example 4 0 OH (R)-2-acetamido-3-(2-acetoybenz~ythiol praoic acid1 15 The title compound is prepared using similar procedures as described inEP08029 noi q17 WO 2010/106082 PCT/EP2010/053418 Example 5 0 0 Oss H 0 (R)-methy 2-acetamido-3-(2-acetoxybenzoylthio~propanoate The title compound is prepared using similar procedures as described in EP 0 080 229. 5 Example 6 01 0 100 AN H 0 The title compound is prepared using similar procedures as described in EP 0 080 229. E p 15 Example 7 F3COH K- -O Os8 WO 2010/106082 PCT/EP2010/053418
    F
    3 C ' OH 0 O H 0 (R)-methyl 2-acetamido -3-(2-hdroxy-4-(trifluoromethylbenzoylthio)propaoate The title compound is prepared using similar procedures as described in EP 0 080 229. 5 Example 9
    F
    3 C0 OH O OsO H 0 (R)-ethyl 2-acetamido-3 -(2-hydroxy-4-(trifluoromethyl)benzoylthio)propano ate The title compound is prepared using similar procedures as described in EP 0 080 229. 10 Example 10 0 F 1C- -O H 0 iOH N OH (Rh:actaidt3-2-aetoy--(tifuoromethylfbenzoylthio propanoicacid The title compound is prepared using similar procedures as described in EP 0 080 229 WO 2010/106082 PCT/EP2010/053418 Example 11 F3CO IC0 0 3 > N- 0 " Oss H 0 (R)-methyl 2-acetamido -3 -(2-acetoxy-4-(trifluoromethyl)benzoylthio propanoate The title compound is prepared using similar procedures as described in EP 0 080 229. 5 Example 12 0 ,
    F
    3 C O N H 0 (R)-ethyl 2-acetamido-3-(2-acetoxy-4-(trifluoromethyl)benzo vlthio)propanoate The title compound is prepared using similar procedures as described in EP 0 080 229. 10 Example 13 OH - 0 F F N OH H 0 (R)-2-acetamido-3-(2',4'-difl oro-4-hydroxybiphenylcarbonylthio)propanoic acid 15 title compound was also commercially available. However, alternatively the Compound was synthesized as follows. Example 13a To a solution of 2',4'difluoro-4-hydroxy-1, i'-diphenyl-3-carboxylic acid (Diflunisal, 82.5 g, 0.329 mol) dissolved in acetone (450 mL) and cooled to -10 CQ (refrigerant mixture: iceEtH) asaded ts (11 L,0.75 ol)slwl (adto: 5mn-itra WO 2010/106082 PCT/EP2010/053418 temperature: from -8 'C to 9 'C. To the resulting solution was added 2,2.2-trichloroethyl chloroformate (100 mL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below 0*C: from -10 'C to 0 C). The mixture was stirred for 1 h at 0 'C (a white precipitate of triethylamine hydrochloride was gradually formed). At the end of the reaction, 5 the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4x1 80 nL) and the filtrate was evaporated under vacuum at 30 'C. The oily residue was taken with Et 2 0 (150 mL) 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 10 acetyl-L-cysteine (N-Ac-Cys, 53.81 g, 0.329 mol) and Et 3 N (46 nL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 1 5'C: from 0 'C to 15 C). The reaction mixture was stirred at 15 'C for 4 h. The mixture was cooled to -12 'C (internal temperature), and Et 3 N (115 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12 'C (internal temperature), and at the end of the reaction, the mixture 15 was filtered under vacuum and the precipitate was washed with acetone (3x150 mL). The oily precipitate was suspended in CH 2 Cl 2 (400 mL), cooled to 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 CH 2 Cl 2 (2x400 mL). The combined organic layers were washed with a 10% HCI aqueous solution (1x500 mL) and with 20 water (2x600 mL), were dried over anhydrous Na 2
    SO
    4 , filtered and concentrated. The residue was purified by trituration with Et 2 0 (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et 2 O (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 (Rft 0.3 25 CH 2 Cl 2 /MeOH/Ac OH 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: SH-NMR (CD 3 0D, 250 MHz, 6): 8.00 (mn, I H, ArH); 7.66 (dm, J 8.2 Hz, I H, ArH); 7.50 (in, 1H1, ArHI); 7.06 (in, 3H1, ArH); 4.74 (in, 11H, ClH); 3.77 (dd, 1= 4.7 and 13.7 Hz, 1H1, CH); 3.40 (m, 1iH, CH); 1.98 (s, 3H1,1CH3); MS-E1+ mn/i: 396.00 (M+1I); LC-MS: M+1l: 396.00; 30 purity: 96.52% (HPLC mrethod: SunFire C18 3.5 urn 2.1xi00 mmi flow: 0.3 mnL/rnin, gradient: A:B 3 min 10:90 +t from 10:90 to 95:5 in 17 minm 10 min 95:5; A' CH3CN:MeOH l:1; B: NH 4 OAc buffer 5 mMN pH 7). M18 WO 2010/106082 PCT/EP2010/053418 Example 13b Synthesis of (2R)-2-(Acetylamino)-3-{[(2',4'-difluoro-4-hydroxy-1,1'- biphenyl-3 yl)carbonyllthio}propanoic acid L-Lysine Salt OH 0 S C0 2 H NHAc F
    NH
    2
    H
    2 N 5 F OH Starting material (GMC-3b, 18.33 g, 46.37 mmol, Example 13a) was dissolved in acetone (300 mL) and L-Lysine (L-Lys, 6.44 g, 44.05 mmol) dissolved in H 2 0 (60 mL) was added. Acetone (100 mL) was added and the mixture was stirred at room temperature 10 for I 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) 6 7.77 (in, I H, ArH); 7.50 (d, J= 8.5 Hz, I H, ArH); 7.23 (m, 1 H, ArH); 6.90 (i, 3H, ArH); 4.47 (in, I H, CH); 3.73-3.59 (in, 2H, CH); 3.25 (m, 1 H, CH); 2.97 15 (t, J =7.4 Hz, 2H, CH 2 ); 1.94 (s, 3H, CH 3 ); ); 1.84 (in, 2H, CH 2 ); 1.67 (in, 2H, CH 2 ); 1.44 (in, 2H, CH 2 ); MS-EIl m/z: 396.00 (M+I-L-Lys); LC- M S: M+1 1-L-Lys: 396.00; purity: 99.59% (HPLC method: SunFire C18 3.5 um, 2.1x100 mm, flow: 0.3 mL/min, gradient: A-1:B 3 min 1 0:U90 fro 1:k to I9 I 1111 in LU 111111 in 95: 5 13; A: C N: VIUJI 1:1 ID :
    NH
    4 0Ac buffer 5 mM pH 7). 20 Example 14 OH F Fi 1 (R-methyl 2-acetamido (2t14'difluorih ydroxyviphencylcarbonylthio~propanoat The title compound is prepared usin similar procedures as described in BE 900328.
    WO 2010/106082 PCT/EP2010/053418 Example 15 OH 0 F F O 0 , N H 0 (R)-ethyl 2-acetamido-3 -(2',difluoro-4-hydroxybiphenylcarbonylthio)propanoate The title compound is prepared using similar procedures as described in BE 900328. 5 Example 16 0 0 F F O ,, Nl~OH H 0 (R-2-acetamido-3 -(4-acetoxy-2 ',4'-difluorobiphenylcarbonylthio~propanoe acid The title compound is prepared using similar procedures as described in BE 900328. 10 Example 17 0 F F 0 kN 0 H R -methyl 2 tamidoydifl bthio propaaate The title compound is prepared using similar procedures as desrbed in BE 900328. 1 5 WO 2010/106082 PCT/EP2010/053418 Example 18 0 0 F F O 0 H 0 (R)-ethyl 2-acetamido-3 anoate The title compound is prepared using similar procedures as described in BE 900328. 5 0 0 0 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 10 Methyl 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 colun chromatography to obtain the desired compound (160 mg) as a pale yellow solid. 'H-NMR (DMSO) S: 1.29 (i, 2H); 1.55 (in, 4H); 1.80 (in, 4H); 2.23 (in, 2H); 2.58 (in, 3H); 3.80 (s, 3H); 7.18 (m, 2H); 7.44 (in, IH); 7.94 (in, 15 1H). 0 200 Example 20 tert Butyi 2-(5-((R)-1, 2 -dihioa-3-y)pentanoyioxy)benzoate 20 The title compound was prepared in a similar manner as that described in Example 1 9 except using tert-butyl 2-hydroxybenzoate instead of methyl 2-hy droxybenzoate. ~lNMR' WO 2010/106082 PCT/EP2010/053418 (DMSO) 6: 1.29 (m, 2H); 1.40 (s, 9H); 1.55 (m, 4H); 1.80 (in, 4H); 2.23 (in, 2H); 2.58 (in, 3H); 7.18 (in, 2H); 7.44 (in, 1H); 7.94 (m, 1H). 0 A0 0 5 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. 'H-NMR (DMSO) 6: 1.29 (in, 2H); 1.55 (m, 4H); 1.80 (in, 4H); 2.23 (m, 2H); 21.58 (rn, 311); 5.51 (in, 10 2H); 7.18 (in, 7H); 7.44 (in, I H); 7.94 (m, I 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 15 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'C with a 12-h light / 12-h dark cycle 20 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 Values, Spain). Chemicals. The chemicals N-Acetyl-cysteine and Sodium Saiyaeweeprhs from 25 Sigma (Sigma Aldrich, St. Louis, MO, USA) and PBS was purchase from Inviion. l The were purchase from Galchimia, S.L. (Galchimia S.L., A Coruna, Spain). All the Compounds were dissolved in PBS, with lysine salt when indicated, and the pH of the compounds without lyiews adjusted wit NxaOH 6N until pH 7. 30 WO 2010/106082 PCT/EP2010/053418 INS-1E 0-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 -cells. INS I E cells were seeded at a density of 80.000 cells / cm 2 in 96 wells plates 4 days before the 5 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 10 the addition of the stressing medium, apoptosis was measured with Apo-One Homogeneous Caspase 3/7 Assay (Promega) which determine the activity of caspase 3 and 7. Cells were frozen at -80"C for 2 hours, defrost at room temperature and incubated in the presence of 100 pl of caspase reactive for 20 hours. Resulting fluorescence was read at 485/530 (excitation/emission wave lenght). The background apoptosis, in absence of stressing 15 condition, was determined with INS1 E cells cultured in the presence of fasting medium (RPMI 5 mN 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 20 Beta-cell destruction was induced in cd-i mice afteI hors of fasting by a sngle 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 25 this case PBS pH 74. At the end of the treatment, at day 4, animals were killed and the plasma collc ted and kept at -20C until used. Microomal ica easla, In vitro cleavage experiments were performed substantiallas described in Singh et al., 1996, In 30 vitro metabolism of a potent HWl -protease inhibitor (141 W94) using rat, monkey and human liver S9, Rapid Common. Mass Spectrom. 10: 1 01 9- 1026. Briefly, conjugate compounds of the invention were incubated at a final concentration of I microM for 1 hour in the presence of' human or rat liver microsome S9 (obtained from Xenotech). Atthe end of incubation at each of th time points repoted, an equal vol umue 0f an organic maiure (ac§etontileemetanol, '08 WO 2010/106082 PCT/EP2010/053418 50/50, v/v) was added to the incubation mixture followed by centrifugation. 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 I microM. All samples were analyzed by HPLC-MS/MS and the peak areas corresponding to the expected 5 metabolites (generally, antioxidant and anti-inflammatory cleavsasge products) were determined by HPLC-MS/IMS. 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. 10 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 Vall6s, 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. 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 15 from the Tail Vein, using a rapid glucose analyzer (Accu-Chek Aviva; 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 CO 2 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. 20 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 UI/kg (Humulin®). The glycemia levels were determined at the indicated time in blood from the Tail Vein, after the Insulin 25 injection using a rapid glucose analyzer. Intraperitonea Gucoe Tolerante Test. At the fourth week of treatment, a Glucose Tolerance Test was done to the mieate an overnight fasting. The animals received an ip injection of Glucose 0.5 g/kg (Glucosmon 50 30 @) The glvcemia levels were determined in blood at the indicated time from the Tail Vein after r the Glucose injection using a rapid glucose analyzer.
    WO 2010/106082 PCT/EP2010/053418 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 5 immunosorbent assay method (CrystalChem, Downers Grove, IL). Total pancreas insulin content has been determined after extraction of insulin with a mixture Ethanol (70 %) / HCI (0.15 N) from pancreas homogenates. Preparation of pancreas sections and immunohistochemical analyses. 10 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-tm 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). Deparaffinized and dehydrated sections were microwaved in citrate buffer (pH 15 6.0) for antigen retrieval, then were incubated in Tris 100 mM pH 7.4 containing 3% BSA, and 0.010% 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 20 pig IgG (Vector Laboratories), diIuted 1:100 in PBS containing donkey serum l0%, 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 tetrahydrochloride (DAB) (Vector Laboratories). The sections were mounted using Fluoromount G (Electron Microscopy Sciences). Sections were then examined 25 using a Nikon 6E-00 upright microscope, and microscopic pictures were obtained with a digital camera Oly5pus DP 7 using Olympus-SIS Cell F software. This program and Fiji Software were used to measure pancreas sections and isets areas considered to be statistically significant. Statisticaly significant differences are indicated as follow: *, P < 0.05; ** P < 0.01; **,P< 0.001.
    WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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 m6thanol. Under these conditions, the free acid was stable over 3 and 24 hours in the water/m6thanol mixture at neutral pH and room temp6rature, 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 15 comparable stability in the water/m6thanol 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/mathanol. These results are shown in Figure l. 20 li UJ Jy11 Ul g1 S 11 1I Iif RI U Ut .~ U L L ~S U ill VILIV U iiI aL 20 Thecapacty fo conljugaiteso hneto to be cleaved was tested i ir sn a 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 25 both rat and human liver microsomes. Similar experiments were performed in plasma from rat or hum-an for salicylate-NAC or diflunisal-NA2C conjugates ;these results are show'n in Figures 3 and 4, respectively. Cleavage of conjugates of the invention in vivo was assayed by oral administration of 30 salicylate-NAC or diflunisal-NAC conjugates to rats. As shown in Figure 5, both the conjugate and the NAC compoonents wecre quickly cleared from the systernic circulation (within 8 hours), while both salicylate and diflunisal persisted between 8 and 24 hours after dmnitrtin 30N WO 2010/106082 PCT/EP2010/053418 The effects of salicylate-NAC or difiunisal-NAC conjugates on glycemia or insulemia in vivo was assayed using alloxan-treated ed- I mice. The alloxan model is a well-known model of -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 . 5 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. 10 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. 15 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/daxsalicylate-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. 20 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 21U/kg human insulin (Humulin@). Tail vein blood was 25 assay ed for glucose concentration in mice treated with ly sine (1.5 mmol/kg/da), salicylate NAC (1.5 mmol/kg/day, as the lysine salt) or difiunisal-NAC (0.5 mmol/kg day, as the lysine salt). The difiunisal-NA C conjugate showed the greatest sustained insulin sensitivity over the 3-hour time course of thse experiments, as shown in Figure 9. overnight fast. The animals received an ip injection of Glucose 0.5 g/kg (Glucosmo~n 50@ and glycemia levels were determined fro~m tai vein blood. Lysine (1.5 mmnoilkgday), salicylate-NAC (L5 rmmol/kg/day, as the lysin salt) or diflunisal-NAC (0.5 rnmol/kg/day, as 300 WO 2010/106082 PCT/EP2010/053418 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 5 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 10 gain in db/db mice was also assayed after chronic oral administration of lysine (1.5 mmol/kg/day), salicylate-NAC (1.5 inmol/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 15 water, as shown in Figure 13. A comparison of diflunisal and NAC levels in blood after oral administration was perforTid in rats by administration of the diflunisal-NAC conjugate (GMC-252) or the individual components separately (i.e., not chemically conjugated). Conjugate (20 mg/kg) or 20 the equivalent amount of difliunisal and NAC were adminit red and blood ayed 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. 25 Pancreatic beta-cell protection of conjugates of the invention was assayed using alloxan-treated cd-I mice. In these experiments, salicylate-NAC (0.38 mmnol/kg) or an mice and glycemia assayed over a 4-day timecourse. As shown in Figure 17, both the 30 conjugate and the combination reduced glycemia, although only the conjugate showed a sa tistically-significant reduction. Similar results are shown for diflunisal-NAC conjugtate administration (0.38 mmoi/kg). In addition, the conjugate sho wed statistically-significant potection of pancreatic beta-cell function (as assessed by plasma insulin levels) i namce treated with, alloxan. Similar experiments wre perfrmed~ company the efects ofsaicyliate 1ed I WO 2010/106082 PCT/EP2010/053418 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 5 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 10 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 trigleerides 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 15 size were increased without affecting pancreatic weight. The effects of diflunisal-NAC (GMC-252) oral administration on glyxcemia 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 20 lowering of plasma gly emia compared wIth this conventional Type II Diabetes drug. 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 25 islet cell function improved as assayed by ELISA for pancreatic insulin. Several parameters of certain conjugates of the invention were assayecd and the results including salnacedin, in Type 2 diabetic animal models as cornpared to control or to animals treated with salicylate or an antioxidant alone (e.g. salicylic acid alone or N-acetylcystcine aln) The ata described herei further provides that conjugates of Formula (I), sucha saliclateNAC nifusina-NAC poses ston hpoipidemcadat-ibtcefcsa of_ _.nc dm WO 2010/106082 PCT/EP2010/053418 well as antioxidant properties in different animal models of diabetes useful in preventing the development of p-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 5 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. 10 193
    权利要求:
    Claims (27)
    [1] 1. A method for treating metabolic disorders that includes Type I diabetes, Type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection 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) R, R, R3 0 0 RK40 R 5 R 6 (I) or a pharmaceutically acceptable salt thereof, wherein R, is hydrogen, (Ci-C 6 )alkylcarbonyl, or A; R2, R3, R4, and R5 are independently hydrogen, (C IC 6 )alkoxy, (CI-C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C C)alkyl, (C-C6)alkylcarbonyl, (C -C 6 )alkylcarbonyloxy, (CI-C 6 )alkylsulfonyl, (C 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, -NZIZ 2 , or (NfiZ2)Carbony, 7Wherein the phenyl is optionally substituted with 1, 2, 4, or 5 that are independently (CIC 6 )alkoxy, (C-C)alkoxycarbonyl, (C-C)alkoxysulfonyl, (C- 1 C)alKyi, (CIC-)alkylcarbonyi, (CIC)alkyic rbonylox, (C~s)alkyisulfonvi, (CIC 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 C 6 )alkoxy, halo(C 1 C)alkyl, halogen, hydroxy, hydroxy(Cr-C 6 )alkyl, mercapto, nitro., phenyl, -NZ 3 Z 4 , (NZ 3 Z 4 )carbonyl; Zi, Z 2 , Z 3 , and Z 4 are independently hydrogen, (Cp.C 6 )alkyl, or (C-C6)alkylcarbonyl; R6 is hydroxy, -NZ 5 Z6, R, 0 0 X X NH NH 0 9~v -V>7 H9 2 DT NN R 0 R 8 0 R 9 Rf formula (I) formula (ii) formula (i6i) WO 2010/106082 PCT/EP2010/053418 OH HO OH, OH O05 O 0 KO OH O HO HO g0 0 OH O , - OH HH O OH 0 O" O 0 S S 10 OH O 0 ,or provided that when Re - ihydroxy, tLhen RI i A Z, and Z 6 are independently hydrogen, (Ci-C 6 )alkyl, (CI-C 6 )alkylcarbonyl, phenyl, phenyi(CH2)-, 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, (C IC 6 )alkoxycarbonyl, (CC)alkoxysulfonyl, (CI-C)alkyl, (CI-C)alkylearbonyl, (CI-C 6 )alkylcarbonyloxy, (CI-C 6 )alkylsulfonyl, (CI-C 6 )alkylthio, carboxy, cyano, formyl, halo(CI-C )alkoxy, halo(Ci-C 6 )alkyl, halogen, hydroxy, hydroxy(CI-C 6 )alkyl, mercapto, nitro, phenyl, -NZ7Z8, or (NZ7ZS)carbonyl; Z 7 and Zs are independently hydrogen, (CIC 6 )alkyl, or (Ct-C 6 )aikylearbony; R7 is (C1~)alkoxy, (CV je 6)alkyi, (CI-s)alkylthio, hydroxy, -NZrZ o, or--hnl wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C 1 -C 6 )alkoxy, ( C~)alkoxycarbonyl, (C 1 Cr)alkyl, (C 1 C)alkylcarbonylI, (C 1 -Q)alkylcarbonyloxy, carboxry, cy ano, formnyl, halo(C 1 -salkoxy, halo(C 7 Cs)alkyl, halogen, hydroxy, or hydroxy(C V)alkyl; Rs, is hydrogen or ( C)alkyi; RV is hydrogen, (Ce-Q <alkyr (C 7 <. alkyca rbony; R -s( esalkoxy, (C ;~~ly, (C ~jalkylthio, hydroxy, or NrgZ m; WO 2010/106082 PCT/EP2010/053418 Z 9 and Z 1 0 are independently hydrogen, (C 1 -C 6 )alkyl, or (CiC 6 )alklcarbonyl; Xi and X 2 are independently 0 or S; L is (CI-C 6 )alkylene; Ais Rj0 R 2 a 1a0 R3a 0 HS 0 S R 4 N HN N N R 5 .a, - H 0H 0 N0/ 0 N H N HH H 0 ,or 0 RIa is hydrogen, (CI-C 6 )alkylcarbonyl, or B; RIa, R3a, R4a, and R5a are independently hydrogen, (CI-C 6 )alkoxy, (C-.)alkoxycarbonyl, (CI-C 6 )alkoxysulfonyl, (CI -C 6 )alkyl, (C -C 6 )alkylcarbonyl, (CIC 6 )alkylearbonyloxy, (CI-C6)alkylsulfonyl, (C-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, -NZiaZ 2 a, or (NZIaZ 2 a)carbonyl, 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, (-Ce)alkoxysulfonyl, (C 6 C)alkyl, (C -C 6 )alkylcarbonyl, (CI -C 6 )alkylcarbonyloxy, (C-C 6 )alkylsulfonyl, (C 1 -C 6 )alkylthio, carboxy, cyano, formyl, halo(C 1 C 6 )alkoxy, )alkyl, halogenhydroxy, hy C )aky, mcato, ntr, phny, -NZa or (NZ 3 aZ4a)carbonyl; Zia, Z2a, Z 3 ., and Z 4 , are independently hydrogen, (C 1 -C 6 )alkyl, or (C -C 6 )alkylcarbonyl; B is WO 2010/106082 PCT/EP2010/053418 R2b Rb 0 R3b OHS 0 HN N N H H R5b O, S-S 0, 0 , 00 HS S HSN SN) H)- H ) 0 ,or 0 Rib is hydrogen, (Cv-C 6 )alkylearbonyl, or C; R2b, R3b, R4b, and R5b are independently hydrogen, (CI-C6)alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C -C 6 )alkoxysulfonyi, (Cr-C 6 )alkyl, (CI-C 6 )alkylcarbonyl, (C-C 6 )alkylcarbonyloxy, (C-C 6 )alkylsulfonyl, (CI-C 6 )alkylthio, carboxy, cyano, formyl, halo(C1 -C 6 )alkoxy, halo(CI -C 6 )alkyl, halogen, hydroxy, hydroxy(C -C 6 )alkyl, mercapto, nitro, phenyl, -NZIbZ2b, or (NZibZ 2 b)carbonyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently CI-C()alkoxy, (CI-C 6 )alkoxycarbonyl, (C -C 6 )alkoxysulfonyl, (CIC 6 )alkyl, (CI-C 6 )alkylcarbonyl, (C -C 6 )alkylcarbonyloxy, (C-C 6 )alkylsulfonyl, (C-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, -NZ3bZ4., or (NZ3tZ4b)carbonyl; ZIb, Z2b, Z3b, and ZO are independently hydrogen, (CI-C6)alkyl, or (C-C 6 )alkylcarbonyl; and C is 0 0 0 0 HS ONO N 'INN N N os-s , H 0, H 0H 0 -0 0 SS W' HH
    [2] 2. The method according to claim~ c R9i WO 2010/106082 PCT/EP2010/053418 R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl.
    [3] 3. The method according to claim I wh rein R 1 is hydrogen or acetyl; R 2 , R 3 , R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 7 is (Ci-C 6 )alkoxy or hydroxy; Rs is hydrogen; R 9 is (CI-C 6 )alkylcarbonyl; X 1 is S; and L is CH 2 .
    [4] 4. The method according to claim I 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 7 is ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R 9 is acetyl; X, is S; and L is CH 2 .
    [5] 5. The method according to claim 1 wherein R, is hydrogen or acetyl; R 2 , R3, R 4 , and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 is (L) N-acetylcysteine.
    [6] 6.~~~~~~~ TemtoacodntoclaiM1 whriIh ojgt fFrua()i Example 1, 2, 3,4, 5,6, 7,8, 9,10,1I1, 12, 13, 14,15,16, 17, orl18.
    [7] 7. P - vnni
    [8] 8. The method according to claim 1 wherein the conjugate of Formula (I) is Example 4.
    [9] 9. The method according to claim I wherein the conjugate of Formula (I) is Eaple 7. 198 WO 2010/106082 PCT/EP2010/053418
    [10] 10. The method according to claim I wherein the conjugate of Formula (I) is Example 10.
    [11] 11. The method according to claim I wherein the conjugate of Formula (1) is Example 13.
    [12] 12. The method according to claim 1 wherein the conjugate of Formula (I) is Example 16.
    [13] 13. A method of treating metabolic disorders that includes type I diabetes, t ype II diabletes, Latent Autoimmune Diabetes of Adulthood (LADA), hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection 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) and at least one pharmaceutically acceptable carrier.
    [14] 14. The method according to claim 13 wherein the conjugate of Formula (1) is Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.
    [15] 15. The method according to claim 13 wherein the conjugate of Formula (I) is Example 1.
    [16] 16. The method according to claim 13 wherein the conjugate of Formula (I) is Example 4.
    [17] 17. The metho accordinigto claimt 13~ wwum the conjupae of F orm (1 is Example 7.
    [18] 19. The method according to claim 13 wherein the conjugate of Formula (I) is Example 130. 3 The i eta aIodn ocam1 hri h ojgt fFrua()i 0is WO 2010/106082 PCT/EP2010/053418
    [19] 20. The method according to claim 13 wherein the conjugate of Formula (I) is Example 16.
    [20] 21. A compound of Formula (XIII) R 3 0 O R1 R2 (XIII) or a pharmaceutically acceptable salt thereof, wherein R, is OR 6 or NR 4 Rs; R 2 is H or 2,4-difluorophenyl; R 3 is 0 0 0 S-S S-S or S-S R 4 and R, are independently H, (C 1 -C 6 )alkyl, (C -Cg)cycloalkyl, or (C 3 -Cs)cycloalkyl(CI-C 6 )alkyl, wherein the (C-C 6 )alkyl, (C 3 -Cs)cycloalkyl, (- C y ay(C 1 -('I -)alkyl are optionally substituted with123 or 4 substituents that are mdpcendently (CC)alkoxy, (CI-C 6 )alkoxy(CI-C 6 )alkyl, (C-C,)alkoxycarbonyl, (CIC 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZIZ2, 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-methylpiperazin e, morpholine, or az'pane; R s H, CiCs)alkyl, (CrC)cycloalkyl, 0r (Cr )ycloalkyl(CiC 6 )alkyl, wherein the (C 1 &s~alkyl, (C 2 -Cslcycloalkyl, (CmCslcycloalkyl(C Cslalkyl are optionally substituted with 1,2 3,o4sustetstaarinpedtx !(GC akxy -C 6 ~)alkoxy(C-C 6 )alkyl, (-C )alkoxycarbonyl, (( C )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; and Z 1 and Z 2 are independently H or (Ci-C&)alkyl. WO 2010/106082 PCT/EP2010/053418
    [21] 22. A compound of Formula (XIV) 0 0 R 3 1R 0, NH R R2 (XIV) or a pharmaceutically acceptable salt thereof, wherein Ri is OR6 or NR 4 Rs; R 2 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 6 )alkyl, (C 3 C 8 )cycloalkvl, or (C 3 -C)cycloalkyl(C 1 -C 6 )alkyl, wherein the (C -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (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(C-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; 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, (CpC 6 )alkyl, (W-C)cycloalkyl, or (CpCs)cycloalky (CC Olk yl, wherein the (CI-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -Cs)cycloalkyl(CI-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C 6 )alkoxy, (Cp-C 6 )alkoxy(Cj-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; and Z and Z 2 are independently H or (Ci& 6 )alkyl.
    [22] 23. A cmpound of Formula (XV) HO N HR WO 2010/106082 PCT/EP2010/053418 or a pharmaceutically acceptable salt thereof, wherein R 1 is OR 3 or NR4R 5 ; R2 is H or 2,4-difluorophenyl; R 3 is H, (C 1 -C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C 3 -CS)cycloalkyl(C1-C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -CS)Cycloalkyl, (C,-C 8 )cycloalkyl(C-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C 6 )alkoxy, (C-C 6 )alkoxy(CI-C 6 )alkyl, (CIC 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-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(CI-C6)alkyl, wherein the (C-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -Cs)cycloalkyl(C C6)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 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& 6 )aikyl.
    [23] 24. A compound of Formula (XVI) H O ,O HO' N Oa H (XVI) or a pharmaceutically acceptable salt thereof H O N O 0 O> NH (XVI WO 2010/106082 PCT/EP2010/053418 R 1 is OR 2 or NR4R 5 ; R 2 is H, (C 1 -C 6 )alkyl, (C 3 C 8 )cycloalkyl, or (C 3 Cs)cycloalkyl(CvC 6 )alkyl, wherein the (CI-C 6 )alkyl, (Ci-C 8 )cycloalkyl, (C 3 Cs)cycloalkyl(C 1 -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, (CC)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, (C 1 -C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C 3 -CS)cycloalkyl(CI-C 6 )alkvl, wherein the (C-C6)alkyl, (C 3 -Cs)cycloalkyl, (C3-C 8 )cycloalkyl(CI-C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C)alkoxy, (C IC 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; 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.
    [24] 26. A compound of Formula (XVIII) 0 9l P3 R, N C1 (XVIII) or a pharmaceutically acceptable salt thereof, wherein R 1 is OR 2 or NR 4 R; R2 is H, (CvQs)alkyl, (C 3 rCs)cycloalkyl, or (CyCs)cycloalkyl(CvC 6 )alkyl, wherein the (C 2 )alk yl, (Cr Cs)eyeloalky 1, (C 3 &s)cycloalky (C )alkyl are optionally substituted with I, 2, 3, or 4 substituents that are independently (e t)alkoxy, (C <)alkoxy(Cj eC 6 )alkyl, ( C 6 )alkoxycarbonyl, (Ce 0 )alkylthio, halogen, hy droxy, hydroxycarbonyl, NZ 1 Z 2 , or pheniyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 h R3 is WO 2010/106082 PCT/EP2010/053418 0 0 0 S-S , S-S ,or S-S R4 and R 5 are independently H, (C 1 -C 6 )alkyl, (C 3 Cs)cycloalkyl, or (C 3 rCs)cVcloalkyl(CIeC 6 )alkyl, wherein the (C-C 6 )alkyl, (C 3 -CS)cycloalkyl, (C 3 Cs)cycloalkyl(CIC 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C 6 )alkoxy, (CI-C 6 )alkoxy(C 1 C 6 )alkyl, (CI-C 6 )alkoxycarbonyl, (C 1 -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, and Z 2 are independently H or (C 1 -C 6 )alkyl.
    [25] 27. A compound of Formula (XX) HN O 0 S R1 '10 0 R 3 F F (XX) or a pharmaceutically acceptable salt thereof, wherein R, is OR, NR 4 R 5 , or H N 0 S R7 0 R 2 is (CCC-aiky (C-scycloalkyl, or (C3-Cstcolkyl(C 1 CA)alkyl wherein the (CvC 6 )alkyl, (Cr)cycloalky, (C Cs)cycloalkyl(C alkyl are optionally substituted with (Ce~Q~alkoxycarbonyl, ( C )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ2, o phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens Z 4 and Z 2 are independently H1 or (CvCr))alkyi; R3 is H or C(O)Rs; WO 2010/106082 PCT/EP2010/053418 R 4 and R 5 are independently H, (CvC 6 )alkyl, (C 3 rCs)cycloalkyl, or (C 3 -C 8 )cycloalkyl(CI-C 6 )alkyl, wherein the (C IC6)alkyl, (CrC 8 )cycloalkyl, (C 3 -Cs)cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (CI-C)alkoxy, (C1-C)alkoxy(CI -C 6 )alkyl, (CIC 6 )alkoxycarbonyl, (C-C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZiZ2, 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, (C1C)alkyl, (C 3 -Cs)cycloalkyl, or (C3-Cs)cycloalkyl(CI C 6 )alkyl, wherein the (C 1 C 6 )alkyl, (C 3 C 8 )cycloalkyl, (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 -C 6 )alkoxy(C IC 6 )alkyl, (CIC 6 )alkoxycarbonyl, (CI-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-eC 6 )alkyl; and R 7 is OR 2 or NR 4 R 5 ; provided that the compound is not N-acetyl-S-[(2',4'-difluoro-4-hydroxy[,I' iphenyl]-3 yl)carbonyl]-L-cysteine methyl ester; N-acetyl-S-[(2',4'-difluoro-4-hydroxy[1,1'-biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester; N-acetyl-S-[(2',4-difluoro-4-acetyloxy[ i,1 -biphenyl]-3-yl)carbonyl]-L-cysteine methyl ester; and N-acetyl-S-[(2',4'-difluoro-4-acetyloxy[1,1 -biphenyl]-3-yl)carbonyl]-L-cysteine ethyl ester.
    [26] 28. A compound of Formula (XXI) I HO0 + R12 (XXI) X is absent, halogen, HSO4, HPOF 4 , CH 3 CO2, orCIC; R, is OR 3 or NRRs; R2 is HI or 2,4diluorhny1; WO 2010/106082 PCT/EP2010/053418 R 3 is H, (CI-C6)alkyl, (C 3 -Cs)cycloalkyl, or (C 3 -Cs)cycloalkyl(Ci-C 6 )alkyl, wherein the (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -Cs)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 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-C 6 )alkyl, (C 3 -Cs)cycloalkyl, or (C 3 -Cs)cycloalkyl(C 1 -C 6 )alkyl, wherein the (Ci-C 6 )alkyl, (C 3 -Cs)cycloalkyl, (C 3 -Cs)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 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 Zi and Z 2 are independently H or (CI-C 6 )alkyl.
    [27] 29. A compound according to any one of claims 21 to 28 for use in the treatment of metaboic disorders that includes Type I diabetes, Type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient.
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    同族专利:
    公开号 | 公开日
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    AU2010224866B2|2014-03-06|
    AU2010224866C1|2015-01-15|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1583602A|1977-05-26|1981-01-28|Sterwin Ag|N-acetyl-para-aminophenyl-n'-acetyl-amino-thioalkanoic acid ester derivatives|
    IT1134458B|1980-11-26|1986-08-13|Real Sas Di Alberto Reiner|N-ACETYL-CISTEIN DERIVATIVE FOR THERAPEUTIC ACTIVITY, PROCEDURE FOR ITS PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS|
    IT1194117B|1981-11-20|1988-09-14|Isnardi Pietro & C Spa|SALICYL DERIVATIVES OF N-ACETYLCISTEIN|
    IT1190987B|1982-09-07|1988-02-24|Pharma Edmond Srl|ACETYLSALICYLIC ACID THIOESTERS, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    US5656620A|1984-01-28|1997-08-12|Ismail; Roshdy|Method for treating pain|
    IT1206515B|1983-08-09|1989-04-27|Guidotti & C Spa Labor|N-ACETYLCISTEIN EDERIVATES 2 ', 4'S-CARBOXYMETHYLCISTEIN AD-DIFLUORO-4-HYDROXY- ANTI-INFLAMMATORY ACTIVITY, 3-CARBOXYLIS OF MUCOLITICS, PROCEDURE FOR THEIR PREPARATION AND RELATIVE COMPOSITIONS.|
    ES8609231A1|1985-12-03|1986-09-01|Farmhispania|Antiinflammatory N-acetyl-benzoyl-mercapto-alanine prepn.|
    ES8800144A1|1986-05-09|1987-11-01|Lasa Lab|N-acetyl cysteine thioester prepn.|
    EP0254032A3|1986-06-20|1990-09-05|Schering Corporation|Neutral metalloendopeptidase inhibitors in the treatment of hypertension|
    IT1213301B|1986-07-14|1989-12-20|Zambon Spa|COMPOSITIONS FOR THE TREATMENT OF SYNDROMES FROM ISCHEMIA AND REPERFUSION|
    IT1228537B|1987-07-30|1991-06-20|Magis Farmaceutici|EXISTING ACTION CISTEIN DERIVATIVES|
    US5610180A|1988-01-29|1997-03-11|Virginia Commonwealth University|Ionizable congeners of aromatic and aliphatic alcohols as anti-leukemia agents|
    US8178516B2|1992-06-30|2012-05-15|Sylvan Labs, LLC|Compositions and method for treatment of chronic inflammatory diseases|
    DE4327462A1|1993-08-16|1995-02-23|Carl Heinrich Dr Weischer|N-Acetyl-p-aminophenol derivatives for controlling pain|
    RU2054936C1|1994-04-07|1996-02-27|Елизарова Евгения Павловна|Membrane-stabilizing agent for treatment of patient with insulin-dependent and insulin-independent diabetes mellitus|
    DE4444051A1|1994-12-10|1996-06-13|Rhone Poulenc Rorer Gmbh|Pharmaceutical, oral preparation|
    US5871769A|1996-01-18|1999-02-16|Fleming & Company, Pharmaceuticals|Methods and compositions for the prevention and treatment of diabetes mellitus|
    KR20000035992A|1996-09-10|2000-06-26|메디녹스, 인크.|Polydithiocarbamate-containing macromolecules and the use thereof for therapeutic and diagnostic applications|
    US6896899B2|1996-12-31|2005-05-24|Antioxidant Pharmaceuticals Corp.|Pharmaceutical preparations of glutathione and methods of administration thereof|
    CZ96798A3|1997-04-02|1998-10-14|Sankyo Company Limited|Dithiolan derivatives, process of their preparation and their therapeutic effects|
    AUPO612397A0|1997-04-11|1997-05-08|University Of Queensland, The|Novel diflunisal esters and related compounds|
    BR9809819A|1997-05-14|2001-09-18|Atherogenics Inc|Compounds and methods for inhibiting vcam-1 expression|
    US6852878B2|1998-05-14|2005-02-08|Atherogenics, Inc.|Thioketals and thioethers for inhibiting the expression of VCAM-1|
    US20020004515A1|1997-06-18|2002-01-10|Smith Stephen Alistair|Treatment of diabetes with thiazolidinedione and metformin|
    US5972986A|1997-10-14|1999-10-26|G.D. Searle & Co.|Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia|
    WO2004096256A1|2001-01-23|2004-11-11|The United States Of America, As Represented By The Secretary Of The Navy|Methods for preventing and treating loss of balance function due to oxidative stress|
    US7323496B2|1999-11-08|2008-01-29|Theracos, Inc.|Compounds for treatment of inflammation, diabetes and related disorders|
    US6197340B1|1998-05-28|2001-03-06|Medical Research Institute|Controlled release lipoic acid|
    CA2319495A1|1998-06-08|1999-12-16|Advanced Medicine, Inc.|Multibinding inhibitors of microsomal triglyceride transferase protein|
    CA2339218C|1998-07-31|2008-10-28|Mount Sinai Hospital|Methods and compositions for increasing insulin sensitivity|
    US6852760B1|1998-09-17|2005-02-08|Akesis Pharmaceuticals, Inc.|Compositions and methods for treatment for glucose metabolism disorders|
    US6201028B1|1998-12-08|2001-03-13|The Rockefeller University|Methods and compositions for prevention and treatment of atherosclerosis and hyperlipidemia with non-steroidal anti-inflammatory drugs|
    IT1311924B1|1999-04-13|2002-03-20|Nicox Sa|PHARMACEUTICAL COMPOUNDS.|
    US20010051184A1|1999-05-20|2001-12-13|Madalene C.Y. Heng|Method for using soluble curcumin to inhibit phosphorylase kinase in inflammatory diseases|
    JP4618845B2|1999-06-09|2011-01-26|杏林製薬株式会社|Substituted phenylpropionic acid derivatives as human peroxisome proliferator-activated receptor alpha agonists|
    EP1200075A4|1999-06-15|2003-05-02|Nutri Logics Inc|Nutrient formulations for disease reduction, and related treatment and component screening methods|
    US6309663B1|1999-08-17|2001-10-30|Lipocine Inc.|Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents|
    AU7995300A|1999-10-05|2001-05-10|Bethesda Pharmaceuticals, Inc.|Dithiolane derivatives|
    US20020045580A1|1999-11-24|2002-04-18|Sacks Meir S.|Compositions for raising uric acid levels and methods of using same|
    US20020155163A1|1999-12-27|2002-10-24|Samuel D. Benjamin|Integrated multi-vitamin and mineral combination|
    US20080213785A1|2000-04-20|2008-09-04|Andrew Levy|Method of predicting a benefit of antioxidant therapy for prevention or treatment of vasclar disease in hyperglycemic individuals|
    US20080044399A1|2000-04-20|2008-02-21|Andrew Levy|Vitamin E supplementation for reducing cardiovascular events in individuals with DM and the Hp 2-2 genotype|
    US20020037855A1|2000-05-05|2002-03-28|Fritz Stanislaus|Stabilized medicament containing cysteinyl derivatives|
    US6429223B1|2000-06-23|2002-08-06|Medinox, Inc.|Modified forms of pharmacologically active agents and uses therefor|
    US6355666B1|2000-06-23|2002-03-12|Medinox, Inc.|Protected forms of pharmacologically active agents and uses therefor|
    US6365176B1|2000-08-08|2002-04-02|Functional Foods, Inc.|Nutritional supplement for patients with type 2 diabetes mellitus for lipodystrophy|
    IT1319201B1|2000-10-12|2003-09-26|Nicox Sa|DRUGS FOR DIABETES.|
    WO2002036202A2|2000-11-02|2002-05-10|Nutrition 21, Inc.|Methods and compositions for the improvement of insulin sensitivity, reduction of hyperglycemia, and reduction of hypercholesterolemia with chromium complexes and alpha lipoic acid|
    US6589948B1|2000-11-28|2003-07-08|Eukarion, Inc.|Cyclic salen-metal compounds: reactive oxygen species scavengers useful as antioxidants in the treatment and prevention of diseases|
    AT532070T|2000-12-14|2011-11-15|Brigham & Womens Hospital|INFLAMMATORY MARKERS FOR DETECTING AND PREVENTING DIABETES MELLITUS|
    AT279920T|2000-12-28|2004-11-15|Fresenius Kabi Austria Gmbh|STABLE INFUSION SOLUTION OF DICLOFENAC SALTS, THEIR PRODUCTION AND USE|
    JP2002226457A|2001-02-02|2002-08-14|Ajinomoto Co Inc|New cystine derivative and inflammation factor activation inhibitor|
    US6566401B2|2001-03-30|2003-05-20|The Board Of Trustees Of The Leland Stanford Junior University|N-acetylcysteine compositions and methods for the treatment and prevention of drug toxicity|
    RS20100077A|2001-04-30|2010-10-31|Trommsdorff Gmbh. & Co. Kg. Arzneimittel|Pharamceutically active uridine esters|
    US6669955B2|2001-08-28|2003-12-30|Longwood Pharmaceutical Research, Inc.|Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin|
    DK1429734T3|2001-09-21|2008-05-13|Egalet As|Solid dispersions of carvedilol for controlled release|
    FR2835433B1|2002-02-01|2006-02-17|Richard Lab M|USE OF 1- -5-METHHOXY-2-METHYL-1H-INDOLE-3ACETIC 4- PHENYL ESTER FOR THE PRODUCTION OF A MEDICAMENT FOR INHIBITING COX2 EXCLUSIVELY|
    EP1496940A2|2002-03-14|2005-01-19|Bayer Pharmaceuticals Corporation|Methods of treating diabetes using pde 11a inhibitors|
    US7670612B2|2002-04-10|2010-03-02|Innercap Technologies, Inc.|Multi-phase, multi-compartment capsular delivery apparatus and methods for using same|
    US6960683B2|2002-07-12|2005-11-01|Atherogenics, Inc.|Salt forms of poorly soluble probucol esters and ethers|
    US7148211B2|2002-09-18|2006-12-12|Genzyme Corporation|Formulation for lipophilic agents|
    ES2411961T5|2002-11-01|2017-04-27|Rutgers, The State University Of New Jersey|Supply vehicles in geode form|
    CN1233629C|2002-11-22|2005-12-28|贵州省中国科学院天然产物化学重点实验室|Sulfolipid compound with neural nourishing function and synthetic method and application thereof|
    US8093292B2|2002-11-22|2012-01-10|Bionexus, Ltd.|Methods for the treatment of HIV-1 related fat maldistribution, fasting hyperlipidemia and modification of adipocyte physiology|
    US8017651B2|2002-11-22|2011-09-13|Bionexus, Ltd.|Compositions and methods for the treatment of HIV-associated fat maldistribution and hyperlipidemia|
    MXPA02012315A|2002-12-13|2004-06-24|Univ Autonoma Metropolitana|Pharmaceutical compound containing silimarine and carbopol, fabrication process and its use as regenerator of pancreatic tissue and cells of endogenous secretion damaged by diabetes mellitus.|
    US20090036516A1|2003-01-13|2009-02-05|Ctg Pharma S.R.L.|Compounds for treating metabolic syndrome|
    US20050020654A1|2003-03-15|2005-01-27|Pershadsingh Harrihar A.|Novel PPAR agonists, pharmaceutical compositions and uses thereof|
    US7981915B2|2003-04-30|2011-07-19|Beth Israel Deaconess Medical Center|Methods for modulating PPAR biological activity for the treatment of diseases caused by mutations in the CFTR gene|
    AT500404A1|2003-07-17|2005-12-15|Jsw Res Forschungslabor Gmbh|CHEMICAL COMPOUNDS CONTAINED TOCOPHEROL AND AT LEAST ONE MORE PHARMACEUTICAL ACTIVE|
    US8173840B2|2003-07-29|2012-05-08|Signature R&D Holdings, Llc|Compounds with high therapeutic index|
    US20070041925A1|2003-09-22|2007-02-22|Beiersdorf Ag|Skin and hair care preparation containing a combination of protein hydrolyzates|
    US20070254055A1|2003-11-21|2007-11-01|Trustees Of Tufts College|Therapeutic Avenanthramide Compounds|
    US7078064B2|2003-12-03|2006-07-18|George Zabrecky|Compositions and methods useful for treating and preventing chronic liver disease, chronic HCV infection and non-alcoholic steatohepatitis|
    US20050143356A1|2003-12-08|2005-06-30|Vanderbilt University|Selective inhibition of cyclooxygenase 1 in the treatment of diabetic nephropathy|
    JP2007527418A|2003-12-29|2007-09-27|プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ|Composition for treating or preventing obesity and insulin resistance disorders|
    DK1767219T3|2004-03-10|2010-05-10|Shimoda Biotech Pty Ltd|Stable injectable diclofenac compositions|
    CN1956726B|2004-03-23|2011-04-13|生命线营养健康公司|Composition and method for releasing mammal inflammation and oxidation stress|
    WO2005112914A2|2004-04-20|2005-12-01|Atherogenics, Inc.|Phenolic antioxidants for the treatment of disorders including arthritis, asthma and coronary artery disease|
    CA2566861A1|2004-05-17|2005-12-08|Combinatorx, Incorporated|Methods and reagents for the treatment of immunoinflammatory disorders|
    JP4218601B2|2004-06-29|2009-02-04|トヨタ自動車株式会社|Air-fuel ratio sensor deterioration judgment system for compression ignition internal combustion engine|
    MX2007000142A|2004-06-30|2007-03-26|Combinatorx Inc|Methods and reagents for the treatment of metabolic disorders.|
    US8252321B2|2004-09-13|2012-08-28|Chrono Therapeutics, Inc.|Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like|
    US20080038316A1|2004-10-01|2008-02-14|Wong Vernon G|Conveniently implantable sustained release drug compositions|
    AU2005296565A1|2004-10-22|2006-04-27|Kirin Beer Kabushiki Kaisha|Transcriptional factor Nrf2 activator and food having the function of the same imparted thereto|
    US20060099279A1|2004-11-09|2006-05-11|Council Of Scientific & Industrial Research|Novel anti-diabetic herbal formulation|
    CN102240278A|2004-12-08|2011-11-16|矫正诊疗公司|Methods, assays and compositions for treating retinol-related diseases|
    EP1836160A1|2004-12-24|2007-09-26|CTG Pharma S.r.l.|Compounds for treating metabolic syndrome|
    US20060166901A1|2005-01-03|2006-07-27|Yu Ruey J|Compositions comprising O-acetylsalicyl derivatives of aminocarbohydrates and amino acids|
    WO2006079021A2|2005-01-20|2006-07-27|Sirtris Pharmaceuticals, Inc.|Use of sirtuin-activating compounds for treating flushing and drug induced weight gain|
    WO2006076767A1|2005-01-21|2006-07-27|Medvet Science Pty. Ltd.|A method of treating cellular damage|
    US20060172012A1|2005-01-28|2006-08-03|Finley John W|Anti-inflammatory supplement compositions and regimens to reduce cardiovascular disease risks|
    US20080033027A1|2005-03-21|2008-02-07|Vicus Therapeutics Spe 1, Llc|Drug combination pharmaceutical compositions and methods for using them|
    EP2374508A1|2005-03-21|2011-10-12|Vicus Therapeutics SPE 1, LLC|Combination of angiotension receptor blockers and NSAIDs for use in ameliorating cachexia|
    CA2606053A1|2005-04-21|2006-11-02|Glenn Goldstein|N-acetylcysteine amide for the treatment of diseases and conditions associated with oxidative stress|
    US20060270635A1|2005-05-27|2006-11-30|Wallace John L|Derivatives of 4- or 5-aminosalicylic acid|
    US20070149466A1|2005-07-07|2007-06-28|Michael Milburn|Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders|
    US20090325975A1|2005-07-15|2009-12-31|Helmut H Buschmann|Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain|
    ES2431050T3|2005-08-04|2013-11-22|Sirtris Pharmaceuticals, Inc.|Benzothiazoles and thiazolopyridines as modulators of sirtuin|
    US7666898B2|2005-11-03|2010-02-23|Ilypsa, Inc.|Multivalent indole compounds and use thereof as phospholipase-A2 inhibitors|
    DE102005057178A1|2005-11-30|2007-07-19|Basf Ag|Use of zinc salts of lipoic acid for the treatment of lipid metabolism disorders|
    EP1957109A2|2005-12-02|2008-08-20|Sirtris Pharmaceuticals, Inc.|Modulators of cdc2-like kinases and methods of use thereof|
    JP2009518415A|2005-12-05|2009-05-07|バイオマリンファーマシューティカルインコーポレイテッド|Methods and compositions for treatment of disease|
    US20070231273A1|2006-03-31|2007-10-04|Jie Wu|Method for Decreasing Blood Glucose Levels|
    WO2007117048A1|2006-04-10|2007-10-18|Seoul National University Industry Foundation|Inhibitors against g6pd enzyme for treating and preventing oxidative stress and/or inflammatory related diseases and method for screening the same|
    US20080015251A1|2006-04-10|2008-01-17|Yissum Research Development Co., Of The Hebrew University Of Jerusalem|Means and method for treating lipotoxicity and other metabolically related phenomena|
    WO2007127913A2|2006-04-28|2007-11-08|Joslin Diabetes Center, Inc.|Reducing risk of type 2 diabetes |
    EP2038251A4|2006-07-09|2010-04-21|Techfields Biochem Co Ltd|Positively charged water-soluble prodrugs of aspirin|
    ES2616315T3|2006-07-18|2017-06-12|Techfields Biochem Co. Ltd|Water-soluble ibuprofen prodrugs positively charged with a very fast skin penetration rate|
    EP2756843A3|2006-07-25|2014-08-20|Techfields Biochem Co. Ltd|Positively charged water-soluble prodrugs of diclofenac with very fast skin penetration rate|
    CN101500983B|2006-07-26|2015-09-16|于崇曦|There is the positively charged water-soluble diflunisal of rapid skin penetration speed and the prodrug of related compound|
    WO2008027547A2|2006-08-31|2008-03-06|The Brigham And Women's Hospital, Inc.|Antioxidant therapies|
    CA2661649C|2006-09-03|2014-12-30|Techfields Biochem Co. Ltd|Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate|
    WO2008127355A2|2006-10-06|2008-10-23|Celtaxsys, Inc.|Chemorepulsion of cells|
    US7498048B2|2006-11-16|2009-03-03|Jose Angel Olalde Rangel|Renal phyto-nutraceutical composition|
    NO2118279T3|2007-01-16|2018-04-21|||
    US20100120807A1|2007-03-08|2010-05-13|Irm Llc|Compounds and compositions as modulators of gpr119 activity|
    US20090169497A1|2007-12-31|2009-07-02|Horwitz Lawrence D|Treatment and Prevention of Skin Injury Due to Exposure to Ultraviolet Light|
    WO2009089011A2|2008-01-08|2009-07-16|Sirtris Pharmaceuticals, Inc.|Resveratrol formulations|
    US8524772B2|2008-05-09|2013-09-03|Tiara Pharmaceuticals, Inc.|Controlled release of N-acetylcysteine for reduction of systemic and/or vascular inflammation|
    AU2009248057B2|2008-05-13|2013-02-21|Genmedica Therapeutics Sl|Salicylate conjugates useful for treating metabolic disorders|
    JP2012520343A|2009-03-16|2012-09-06|ジェンメディカ・セラピューティックス・ソシエダッド・リミターダ|Combination therapy for the treatment of metabolic disorders|MX2010012649A|2008-05-20|2010-12-21|Neurogesx Inc|Carbonate prodrugs and methods of using the same.|
    BRPI0912326A2|2008-05-20|2015-10-06|Neurogesx Inc|water soluble acetaminophen analogs|
    US8466197B2|2010-12-14|2013-06-18|Genmedica Therapeutics Sl|Thiocarbonates as anti-inflammatory and antioxidant compounds useful for treating metabolic disorders|
    CN103384529B|2010-12-21|2015-08-12|雀巢产品技术援助有限公司|Be suitable for the method and composition controlling animal blood glucose|
    CN103945839B|2011-09-16|2018-02-09|根梅迪卡治疗公司|For treating the drug regimen containing antiinflammatory and antioxidant conjugate of dysbolism|
    WO2013037984A1|2011-09-16|2013-03-21|Genmedica Therapeutics Sl|Anti-inflammatory and antioxidant conjugates useful for treating metabolic disorders|
    EP2758133A4|2011-09-22|2015-05-27|Acorda Therapeutics Inc|Acetaminophen conjugates, compositions and methods of use thereof|
    WO2013168011A1|2012-05-10|2013-11-14|Mahesh Kandula|Compositions and methods for the treatment of chronic pain|
    US9382211B2|2012-07-10|2016-07-05|Xpd Holdings, Llc|Stabilized multi-functional antioxidant compounds and methods of use|
    EP2908849B1|2012-08-31|2019-04-17|Board Of Regents, The University Of Texas System|A method to improve pharmacokinetics of drugs|
    US9029342B2|2012-09-17|2015-05-12|Board Of Regents Of The University Of Texas System|Compositions of matter that reduce pain, shock, and inflammation by blocking linoleic acid metabolites and uses thereof|
    ES2562162T3|2012-10-02|2016-03-02|Reemtsma Cigarettenfabriken Gmbh|Package for tobacco related items and package manufacturing method|
    CN105636583B|2013-09-13|2019-08-20|板井昭子|Aqueous solution preparation and its manufacturing method|
    HUE048345T2|2013-11-08|2020-07-28|Promentis Pharm Inc|Substituted n-acetyl-l-cysteine derivatives and related compounds|
    CN106255677A|2014-02-06|2016-12-21|比奥考金特有限责任公司|Comprise improved composition and the method for resveratrol|
    WO2016040342A1|2014-09-08|2016-03-17|Kansas State University Research Foundation|Early lactation administration of non-steroidal anti-inflammatory drugs to increase whole-lactation milk yield|
    US10206904B2|2015-07-17|2019-02-19|The Board Of Regents Of The University Of Oklahoma|Licofelone derivatives and methods of use|
    KR101601685B1|2015-08-24|2016-03-09|여명바이오켐 주식회사|Taxifolin derivative with high anti-oxidant effect and cosmetic composition therefrom|
    WO2018174839A1|2017-03-18|2018-09-27|Nguyen Mark Quang|Cysteine, n-acetylcysteine and penicillamine prodrugs, pharmaceutical compositions thereof, and methods of use|
    WO2018170765A1|2017-03-22|2018-09-27|深圳市博奥康生物科技有限公司|Rna interference vector of imd16 gene and application thereof|
    KR102048982B1|2017-11-10|2019-11-26|원광대학교 산학협력단|Idebenone derivative compound and cosmetic composition comprising the same|
    法律状态:
    2014-07-03| FGA| Letters patent sealed or granted (standard patent)|
    2014-08-21| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 14 JUL 2014 . |
    2015-01-15| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 14 JUL 2014 |
    2018-10-11| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
    优先权:
    申请号 | 申请日 | 专利标题
    US16064209P| true| 2009-03-16|2009-03-16||
    US61/160,642||2009-03-16||
    US17795809P| true| 2009-05-13|2009-05-13||
    US61/177,958||2009-05-13||
    US22762009P| true| 2009-07-22|2009-07-22||
    US61/227,620||2009-07-22||
    PCT/EP2010/053418|WO2010106082A1|2009-03-16|2010-03-16|Anti-inflammatory and antioxidant conjugates useful for treating metabolic disorders|
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